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In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical

transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK
Clinical Study Register.

The following guiding principles have been applied to the disclosure:


 Information will be excluded in order to protect the privacy of patients and all named
persons associated with the study
 Patient data listings will be completely removed* to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research
proposal. For further information please see the Patient Level Data section of the GSK
Clinical Study Register.
 Aggregate data will be included; with any direct reference to individual patients excluded
*Complete removal of patient data listings may mean that page numbers are no longer consecutively
numbered
CONFIDENTIAL 2011N112864_00
The GlaxoSmithKline group of companies ADC113874

Division: Worldwide Development


Information Type: Clinical Study Report
Control: Active-control-without-placebo

Title: A Randomized, Double-Blind, Parallel Group, Multicenter Study


of the Effects of Fluticasone Propionate/Salmeterol Combination
Product 250/50mcg BID (ADVAIR DISKUS™) in Comparison
to Salmeterol 50mcg BID (SEREVENT DISKUS™) on the Rate
of Exacerbations of Chronic Obstructive Pulmonary Disease
(COPD) Following Hospitalization

Phase: IV

Compound Number: CCI18781+GR33343; GSK586129

Effective Date: 23-OCT-2012

Subject: COPD, Exacerbations, Hospitalization, Quality of Life, Biomarkers.

Author(s):

Indication Studied: COPD

Initiation Date: 30-Apr-2010

Completion Date: 08-May-2012

Early Termination Date: N/A

Date of Report: October 2012

Earlier CSRs N/A

This study was performed in compliance with Good Clinical Practices and
GlaxoSmithKline Standard Operating Procedures for all processes involved, including
the archiving of essential documents.

Copyright 2012 the GlaxoSmithKline group of companies. All rights reserved.


Unauthorised copying or use of this information is prohibited.

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Table of Contents
Page

TITLE PAGE ........................................................................................................... 1


Abbreviations .......................................................................................................... 8
ETHICS AND GOOD CLINICAL PRACTICE .......................................................... 10
1. INTRODUCTION ................................................................................................ 11
1.1. Background .................................................................................................... 11
1.2. Rationale ........................................................................................................ 12
2. STUDY OBJECTIVE(S) ...................................................................................... 15
2.1. Primary ........................................................................................................... 15
2.2. Secondary ...................................................................................................... 15
3. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ................... 16
4. INVESTIGATIONAL PLAN ................................................................................. 16
4.1. Study Design .................................................................................................. 16
4.2. Discussion of Study Design ............................................................................ 21
4.3. Protocol Amendments .................................................................................... 21
4.3.1. Amendment No. 01(07-Jun-2010) ....................................................... 21
4.3.2. Amendment No.: 02 (13-Dec-2010) ..................................................... 22
4.4. Selection of Study Population......................................................................... 22
4.4.1. Inclusion Criteria .................................................................................. 22
4.4.2. Exclusion Criteria ................................................................................. 24
4.4.3. Withdrawal Criteria .............................................................................. 25
4.5. Treatments ..................................................................................................... 26
4.5.1. Investigational Products ....................................................................... 26
4.5.2. Dosage and Administration .................................................................. 27
4.5.3. Dose Rationale .................................................................................... 28
4.5.4. Treatment Assignment ......................................................................... 28
4.5.5. Assignment of Subject Identifier .......................................................... 28
4.5.6. Assignment of Randomization Number ............................................... 29
4.5.7. Blinding ................................................................................................ 29
4.5.8. Product Accountability ......................................................................... 30
4.5.9. Treatment Compliance ........................................................................ 30
4.5.10. Prior and Concomitant Medications and Non-Drug Therapies ........... 30
4.5.11. Treatment after the End of the Study ................................................. 32
4.5.12. Treatment of Investigational Product Overdose ................................. 32
4.6. Study Assessments and Procedures .............................................................. 32
4.6.1. Efficacy Assessment ............................................................................ 32
4.6.2. Safety Assessments ............................................................................ 33
4.7. Data Quality Assurance .................................................................................. 33
4.8. Statistical Analyses ........................................................................................ 35
4.8.1. Sample Size Considerations ................................................................ 35
4.8.2. Analysis populations ............................................................................ 35
4.8.3. Multiple Comparisons and Multiplicity .................................................. 36
4.8.4. Efficacy Analyses................................................................................. 36
4.8.5. Other Efficacy Analyses ....................................................................... 36

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4.8.6. Safety Analyses ................................................................................... 38


4.8.7. Other Safety Measures ........................................................................ 38
4.8.8. Health Outcomes Analyses.................................................................. 38
5. STUDY POPULATION RESULTS ...................................................................... 40
5.1. Disposition of Study Subjects ......................................................................... 40
5.1.1. Screen Failures.................................................................................... 42
5.1.2. Post-Randomization Withdrawals ........................................................ 42
5.2. Protocol Deviations ........................................................................................ 43
5.3. Populations Analyzed ..................................................................................... 44
5.4. Demographics and Baseline Characteristics .................................................. 44
5.4.1. Demographic Characteristics ............................................................... 44
5.4.2. COPD Characteristics, Smoking History and Therapy ......................... 44
5.4.3. Baseline Pulmonary Function .............................................................. 45
5.5. Current Medical Conditions ............................................................................ 46
5.6. Prior and Concomitant Medications ................................................................ 47
5.6.1. Previous COPD Medications ............................................................... 47
5.6.2. COPD Concomitant Medications ......................................................... 48
5.6.3. Non-COPD Concomitant Medications Used by ≥5% of Study
Subjects in either Treatment Group – ITT Population ..................... 51
5.7. Exposure and Treatment Compliance ............................................................ 53
5.7.1. Exposure to Study Drug ....................................................................... 53
5.7.2. Treatment Compliance ........................................................................ 53
6. EFFICACY RESULTS ........................................................................................ 54
6.1. Primary Efficacy Results................................................................................. 54
6.2. Secondary Efficacy Results ............................................................................ 56
6.3. Related Efficacy Endpoints............................................................................. 57
6.3.1. Time to First Exacerbation of COPD Requiring Treatment with Oral
Corticosteroids, Antibiotics, and/or Hospitalization (alone and in
combination) – ITT Population ........................................................ 57
6.3.2. Probability of premature withdrawal of subject from the study – ITT
Population ....................................................................................... 58
6.3.3. Pre-dose AM FEV1 - ITT Population ................................................... 59
6.3.4. Supplemental Use of Albuterol – ITT Population ................................. 61
6.3.5. Change in Biomarkers of Systemic Inflammation – ITT Population ..... 62
6.4. Health Outcomes ............................................................................................ 66
6.4.1. CRQ-SAS Domain scores (Dyspnea, Fatigue, Emotional function,
Mastery) as measured by CRQ-SAS .............................................. 66
6.4.2. Symptoms Assessment Using the EXAcerbations of Chronic
Pulmonary Disease Tool (EXACT).................................................. 70
6.5. Post-hoc Analyses .......................................................................................... 75
6.5.1. Summary of COPD Exacerbations Requiring Oral Corticosteroids,
Antibiotics and/or Hospitalization - Sub-group Analyses ................. 75
6.5.2. Summary of Pre-dose FEV1 – Sub-group Analyses ............................ 78
7. SAFETY RESULTS ............................................................................................ 82
7.1. Adverse Events .............................................................................................. 82
7.1.1. Most Common Adverse Events during Treatment ............................... 82

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7.1.2. Drug-Related Adverse Events Post Randomization ............................ 82


7.1.3. Adverse Events Leading to Withdrawal from the Study ....................... 84
7.2. Serious and Other Significant Adverse Events ............................................... 86
7.2.1. Serious Adverse Events during Treatment .......................................... 86
7.2.2. Serious Adverse Events Post-Treatment ............................................. 89
7.2.3. Deaths ................................................................................................. 90
7.2.4. Pneumonia Adverse Events Post Randomization................................ 91
7.3. Medical Device Incidents, Near-Incidents, Malfunctions and Remedial
Action ..................................................................................................... 91
7.4. Pregnancies ................................................................................................... 91
8. DISCUSSION AND CONCLUSIONS.................................................................. 92
8.1. Discussion ...................................................................................................... 92
8.2. Conclusions .................................................................................................... 94
9. REFERENCES ................................................................................................... 96
10. POST-TEXT TABLES AND FIGURES ............................................................. 103
11. CASE NARRATIVES ........................................................................................ 104
STUDY POPULATION DATA SOURCE TABLES .................................................. 305
Table 5.1 Summary of Analysis Populations (Safety Population) .......................... 305
Table 5.2 Summary of Inclusion/Exclusion Criteria Not Met (Screen Failure
Population) (Screen failure Population) .................................................. 306
Table 5.3 Summary of Enrollment by Investigator (Intent-to-Treat Population) ..... 307
Table 5.4 Summary of End of Study Record (Intent-to-Treat Population) ............. 310
Table 5.5 Summary of Protocol Deviations (Intent-to-Treat Population) ............... 311
Table 5.6 Summary of Inclusion/Exclusion Criteria Deviations (Intent-to-Treat
Population) ............................................................................................. 312
Table 5.7 Summary of Demographic Characteristics (Intent-to-Treat
Population) ............................................................................................. 313
Table 5.8 Summary of Race and Racial Combinations (Intent-to-Treat
Population) ............................................................................................. 314
Table 5.9 Summary of Race and Racial Combination Details (Intent-to-Treat
Population) ............................................................................................. 315
Table 5.10 Summary of Disease Characteristics (Intent-to-Treat Population) ....... 316
Table 5.11 Summary of Baseline Pulmonary Function Tests (Intent-to-Treat
Population) ............................................................................................. 318
Table 5.12 Summary of Current Medical Conditions (Intent-to-Treat Population) . 320
Table 5.13 Summary of Prior COPD Medication Use (Intent-to-Treat
Population) ............................................................................................. 321
Table 5.14 Summary of COPD Concomitant Medications (Intent-to-Treat
Population) ............................................................................................. 331
Table 5.15 Summary of Non-COPD Concomitant Medications (Intent-to-Treat
Population) ............................................................................................. 340
Table 5.16 Summary of Exposure to Study Drug (Intent-to-Treat Population) ...... 372
Table 5.17 Summary of Treatment Compliance (Intent-to-Treat Population) ........ 373
Table 5.18 Listing of Reasons for Study Withdrawal (Intent-to-Treat Population) . 374
Table 5.19 Listing of Subjects for Whom the Treatment Blind Was Broken
(Intent-to-Treat Population)..................................................................... 392

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Table 5.20 Listing of Protocol Deviations (Intent-to-Treat Population) .................. 393


Table 5.21 Listing of Subjects with Inclusion/Exclusion Criteria Deviations
(Intent-to-Treat Population)..................................................................... 397
Table 5.22 Relationship of Medication Class, Dictionary Term and Verbatim
Text (Intent-to-Treat Population) ............................................................. 398
Table 5.23 Listing of Demographic Characteristics (Intent-to-Treat Population) ... 555
Table 5.24 Listing of Race (Intent-to-Treat Population) ......................................... 614
Table 5.25 Listing of Exposure to Double-Blind Study Drug (Intent-to-Treat
Population) ............................................................................................. 638
EFFICACY DATA SOURCE FIGURES .................................................................. 662
Figure 6.1 Time to First COPD Exacerbation Requiring OCS, Antibiotics and/or
Hospitalization (Intent-to-Treat Population) ............................................ 662
Figure 6.2 Mean Pre-dose FEV1 Change from Baseline (L) (Intent-to-Treat
Population) ............................................................................................. 663
Figure 6.3 Mean Supplemental Albuterol Use (puffs/day) (Intent-to-Treat
Population) ............................................................................................. 664
Figure 6.4 Time to Study Withdrawal (Intent-to-Treat Population)......................... 665
EFFICACY DATA SOURCE TABLES .................................................................... 666
Table 6.1 Summary of COPD Exacerbations Requiring Oral Corticosteroids,
Antibiotics and/or Hospitalization (Intent-to-Treat Population) ................ 666
Table 6.2 Analysis of COPD Exacerbations Requiring Hospitalization (Intent-to-
Treat Population) .................................................................................... 668
Table 6.3 Analysis of COPD Exacerbations Requiring Oral Corticosteroids,
Antibiotics and/or Hospitalization (Intent-to-Treat Population) ................ 669
Table 6.4 Summary of Time to First COPD Exacerbation Requiring OCS,
Antibiotics and/or Hospitalization (Intent-to-Treat Population) ................ 670
Table 6.5 Summary of Pre-dose FEV1 (L) (Intent-to-Treat Population) ................ 671
Table 6.6 Summary of Supplemental Albuterol Use (puffs/day) (Intent-to-Treat
Population) ............................................................................................. 673
Table 6.7 Summary of Biomarkers hs-CRP, SP-D and CC-16 (Intent-to-Treat
Population) ............................................................................................. 676
Table 6.8 Analysis of Biomarker hs-CRP (High Sensitivity C Reactive Protein)
(Intent-to-Treat Population)..................................................................... 678
Table 6.9 Analysis of Biomarker SP-D (Surfactant Protein D) (Intent-to-Treat
Population) ............................................................................................. 681
Table 6.10 Analysis of Biomarker CC-16 (Clara Cell Secretory Protein-16)
(Intent-to-Treat Population)..................................................................... 684
Table 6.11 Summary of Time to Withdrawal from the Study (Intent-to-Treat
Population) ............................................................................................. 687
Table 6.12 Listing of COPD Exacerbations Requiring Oral Corticosteroids,
Antibiotics and/or Hospitalization (Intent-to-Treat Population) ................ 688
Table 6.13 Summary of COPD Exacerbations Requiring OCS, Antibiotics
and/or Hosp - FEV1 >=30% & No Prior ICS Use (FEV1>=30%
Predicted and No Prior ICS Population) ................................................. 728

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Table 6.14 Summary of COPD Exacerbations Requiring OCS, Antibiotics


and/or Hosp - FEV1 >=30% and Prior ICS Use (FEV1>=30%
Predicted and Prior ICS Population) ....................................................... 730
Table 6.15 Summary of COPD Exacerbations Requiring OCS, Antibiotics
and/or Hosp - FEV1 >=30% and Concurrent Tio (FEV1>=30%
Predicted and Concurrent Tio Population) .............................................. 732
Table 6.16 Summary of COPD Exacerbations Requiring OCS, Antibiotics
and/or Hosp - FEV1>=30% & No Concurrent Tio (FEV1>=30%
Predicted and No Concurrent Tio Population) ........................................ 734
Table 6.17 Analysis of COPD Exacerbations Requiring OCS, Antibiotics and/or
Hosp - FEV1 >=30% and Prior ICS Use (>=30% Predicted and Prior
ICS Population) ...................................................................................... 736
Table 6.18 Analysis of COPD Exacerbations Requiring OCS, Antibiotics and/or
Hosp - FEV1>=30% and Concurrent Tio (FEV1>=30% Predicted and
Concurrent Tio Population) ..................................................................... 737
Table 6.19 Analysis of COPD Exacerbations Requiring OCS, Antibiotics &/or
Hosp - FEV1 >=30% & No Concurrent Tio (FEV1>=30% Predicted
and No Concurrent Tio Population) ........................................................ 738
Table 6.20 Summary of Pre-dose FEV1 (L) - Baseline Post-bronchodilator
FEV1 >=30% and No Prior ICS Use (FEV1>=30% Predicted and No
Prior ICS Population) .............................................................................. 739
Table 6.21 Summary of Pre-dose FEV1 (L) - Baseline Post-bronchodilator
FEV1 >=30% and Prior ICS Use (>=30% Predicted and Prior ICS
Population) ............................................................................................. 741
Table 6.22 Summary of Pre-dose FEV1 (L) - Baseline Post-bronchodilator
FEV1 >=30% and Concurrent Tiotropium Use (>=30% Predicted and
Concurrent Tio Population) ..................................................................... 743
Table 6.23 Summary of Pre-dose FEV1 (L) - Baseline Post-bronchodilator
FEV1 >=30% and No Concurrent Tio Use (>=30% Predicted and No
Concurrent Tio Population) ..................................................................... 745
HEALTH OUTCOMES DATA SOURCE TABLES .................................................. 747
Table 7.1 Summary of CRQ-SAS (Intent-to-Treat Population) .............................. 747
Table 7.2 Summary of EXACT Total Score (Intent-to-Treat Population) ............... 758
Table 7.3 Summary of EXACT Breathlessness Score (Intent-to-Treat
Population) ............................................................................................. 761
Table 7.4 Summary of EXACT Cough and Sputum Score (Intent-to-Treat
Population) ............................................................................................. 764
Table 7.5 Summary of EXACT Chest Symptoms Score (Intent-to-Treat
Population) ............................................................................................. 767
SAFETY DATA SOURCE TABLES ........................................................................ 770
Table 8.1 Summary of All Adverse Events During Treatment (Intent-to-Treat
Population) ............................................................................................. 770
Table 8.2 Summary of Most Common (>3%) Adverse Events During Treatment
(Intent-to-Treat Population)..................................................................... 783
Table 8.3 Summary of All Adverse Events Post-Treatment (Intent-to-Treat
Population) ............................................................................................. 784

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Table 8.4 Summary of Serious Adverse Events During Treatment (Intent-to-


Treat Population) .................................................................................... 788
Table 8.5 Summary of Serious Adverse Events Post-Treatment (Intent-to-Treat
Population) ............................................................................................. 793
Table 8.6 Summary of Fatal Serious Adverse Events During Treatment (Intent-
to-Treat Population) ................................................................................ 795
Table 8.7 Summary of Drug-Related Adverse Events Post Randomization
(Intent-to-Treat Population)..................................................................... 797
Table 8.8 Summary of Adverse Events Leading to Withdrawal from the Study
(Intent-to-Treat Population)..................................................................... 799
Table 8.9 Summary of Pneumonia Adverse Events Post Randomization
(Intent-to-Treat Population)..................................................................... 802
Table 8.10 Listing of All Adverse Events (Intent-to-Treat Population) ................... 803
Table 8.11 Listing of Subject Numbers for Individual Adverse Events (Intent-to-
Treat Population) .................................................................................... 1121
Table 8.12 Listing of Fatal Serious Adverse Events (Safety Population) (Safety
Population) ............................................................................................. 1156
Table 8.13 Listing of Non-Fatal Serious Adverse Events (Safety Population)
(Safety Population) ................................................................................. 1162
Table 8.14 Listing of Adverse Events Leading to Withdrawal from the Study
(Intent-to-Treat Population)..................................................................... 1233
Table 8.15 Listing of Pneumonia Adverse Events (Intent-to-Treat Population) ..... 1254
Table 8.16 Listing of Pneumonia Chest X-Rays (Intent-to-Treat Population) ........ 1261
Table 8.17 Listing of Pneumonia Chest X-rays - Cultures and Clinical Findings
(Intent-to-Treat Population)..................................................................... 1268
Table 8.18 Listing of Pneumonia Chest X-rays - Treatment and Outcome
(Intent-to-Treat Population)..................................................................... 1272
Table 8.19 Relationship of Adverse Event System Organ Class, Preferred
Term and Verbatim Text (Intent-to-Treat Population) ............................. 1275
Table 8.20 Summary of Vital Signs (Intent-to-Treat Population) ........................... 1303
Table 8.21 Listing of Positive Pregnancy Tests (Intent-to-Treat Population) ......... 1305

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Abbreviations
AE Adverse Event
ALT Alanine transaminase
AM Ante meridiem
ANCOVA Analysis of covariance
AST Aspartate aminotransferase
ATS American Thoracic Society
BID Bis in die (Twice daily)
CC-16 Clara cell secretory protein-16
CHF Congestive heart failure
CI Confidence interval
CIB Clinical investigator brochure
COPD Chronic Obstructive Pulmonary Disease
CRP C-reactive protein
CRQ-SAS Chronic Respiratory Disease Questionnaire - Self-Administered
Standardized format
CYP2C9 Cytochrome P450 2C9
DNA Deoxyribonucleic acid
ECG Electrocardiogram
eCRF Electronic Case Report Form
ER Emergency Room
EXACT EXAcerbations of Chronic pulmonary disease Tool
FDA Food and Drug Administration
FEV1 Forced expiratory volume in 1 second
FSC Fluticasone propionate/salmeterol combination
FVC Forced Vital Capacity
GCP Good Clinical Practice
GCSP Global Clinical Safety and Pharmacovigilance
GOLD Global Initiative for Chronic Obstructive Lung Disease
GSK GlaxoSmithKline
HLA-B Major histocompatibility complex, class I, B
hr Hour
hs-CRP High Sensitivity C-reactive protein
ICF Informed consent form
ICH International Conference on Harmonization
ICS Inhaled corticosteroid
IEC Independent Ethics Committee
IgM Immunoglobulin M
IL-6 Interleukin 6
IL-8 Interleukin 8
IND Investigational New Drug
IRB Institutional Review Board
ITT Intent-to-Treat
IVRS Interactive Voice Response System
LABA Long-acting Beta agonist
mcg Microgram
MedDRA Medical Dictionary for Regulatory Activities

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MDI Metered dose inhaler


mL Milliliter
Mths Months
NDA New Drug Application
NHAINES III Third National Health and Nutrition Examination Survey
PARC Pulmonary and activation-regulated chemokine
PEF Peak expiratory flow
PFT Pulmonary function test
PGx Pharmacogenetics
PK Pharmacokinetics
PM Post meridiem
SAE Serious adverse event
SAL Salmeterol
SE Standard error
SGRQ St. George Respiratory Questionnaire
SNP Single nucleotide polymorphism
SP-D Surfactant Protein D
SPM Study procedure manual
TNF-α Tumor necrosis factor α
UGT-1A1 Uridine Diphosphate Glucuronosyltransferase 1A1
ULN Upper limit of normal
US United States
yrs Years

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the


group of companies GlaxoSmithKline group of companies
ADVAIR™ DISKUS™ SAS
DISKUS™ Spiriva
SEREVENT™ DISKUS™

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ETHICS AND GOOD CLINICAL PRACTICE


The study protocol, amendments, and the informed consent were reviewed and
approved by a national independent review board. Further, the study
was conducted in accordance with the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
Good Clinical Practice (GCP) and applicable country-specific requirements, including
US 21 Code of Federal Regulations (CFR) 312.3(b) for constitution of independent
ethics committees. Ethics committee or institutional review board approvals are
maintained in the Sponsor’s study file.

This study was conducted in accordance with ICH GCP and all applicable subject privacy
requirements, and, the ethical principles that are outlined in the Declaration of Helsinki
2008.

Investigators were trained to conduct the study in accordance with GCPs and the study
protocol as defined in ICH E3, Section 9.6. Written commitments were obtained from
investigators to comply with GCP and to conduct the study in accordance with the
protocol. Study monitoring was performed in accordance with ICH E6, Section 5.18.

Written informed consent was obtained from each study subject prior to the
performance of any study-specific procedures. Investigators were instructed to
provide each study subject as much time as necessary to review the document, to
inquire about details of the trial, and to decide whether or not to participate in the
study.

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1. INTRODUCTION

1.1. Background
Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal
inflammatory response of the lung to noxious particles and gases, and airflow limitation,
primarily a consequence of prolonged exposure to cigarette smoke [Donaldson, 2002].
Current evidence indicates variability in COPD symptoms throughout the day, with many
patients reporting limitations in activity and shortness of breath during the morning
[Partidge, 2009]. COPD is a multicomponent disease [Kardos, 2006] that includes
structural changes, inflammation, airflow limitation, mucociliary dysfunction and
systemic effects. Further, there is accumulating evidence of systemic inflammation in
association with COPD, including systemic oxidative stress and activation of circulating
inflammatory cells [Agusti, 2003].

The American Thoracic Society (ATS) and the European Respiratory Society (ERS)
define an acute exacerbation of COPD as an event in the natural course of the disease
characterized by a change in the patient baseline dyspnea, cough and/or sputum
production beyond day-to-day variability, sufficient to warrant a change in management
[Celli, 2004]. However, there does not seem to be a full agreement on the definition of a
COPD exacerbation [Burge, 2000]. As accepted definition for a moderate to severe
exacerbation of COPD is a worsening of respiratory symptoms requiring the
administration of additional medicines, often systemic corticosteroids or antibiotics,
and/or hospitalizations. Patients with COPD are susceptible to exacerbation,
characterized by an episodic worsening of the condition usually manifested by a varying
level of dyspnea, cough and sputum production [Anthonisen, 1987]. Patients who
experience an acute exacerbation of COPD often have poor prognoses and an increased
risk of mortality that correlate with the frequency of severe exacerbations [Soler-
Cataluna, 2005]. Exacerbations of COPD are associated with reduced lung function,
deterioration of quality of life (QOL), increased unscheduled visits, medical intervention
and hospital admissions, and mortality. Further, repeated exacerbations often lead to a
more rapid rate of decline in lung function [Niewoehner, 2006].

The costs associated with hospitalization for an acute exacerbation of COPD contribute
significantly to the burden of disease [Hilleman, 2000]; reaching up to 70% of the total
cost of COPD medical care in the United States [Niewoehner, 2006]. COPD
exacerbations account for 60% of the direct costs attributed to the disease [Dusser, 2008],
with severe exacerbations that lead to unscheduled hospital visits and admissions
accounting for an estimated $10 billion in the United States in the year 2003 alone
[Niewoehner, 2006]. In 2003, in the US, over 600,000 hospitalizations were attributed to
exacerbation of COPD, requiring an average stay of 5 days at a mean cost exceeding
$16,000 [HCUPnet, available at: http://hcup.ahrq.gov/HCUPnet.asp].

There is convincing evidence that patients hospitalized with COPD are at an increased
risk of subsequent readmission and death [Sin, 2001]. The prevention of exacerbations of
COPD is increasingly receiving due attention and becoming an integral component of
COPD management. The clinical benefits of ICS and LABA treatments in the reduction

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of COPD exacerbation rates are well documented [Ferguson, 2008; Anzueto, 2009], as
evidenced by results of 15 clinical trials, involving 7,388 patients, on LABA therapy and
10 clinical trials that randomized 3,734 patients, comparing ICS to placebo [Wilt, 2005].
Acute exacerbations of COPD inflict a heavy burden on the affected patients in addition
to pharmaco-economic costs. Consequently, further evidence of a beneficial treatment
effect of ICS/LABA on the rate of exacerbation could help alleviate the socioeconomic
burden of the disease.

1.2. Rationale
The purpose of this study is to evaluate the treatment effects of FSC 250/50mcg BID in
comparison to SAL 50 mcg BID, both via DISKUS, on exacerbations of COPD requiring
treatment with oral corticosteroids (OCS), antibiotics, and/or hospitalization (alone and in
combination), over a 29-week treatment period. The primary efficacy measure is the rate
of exacerbation requiring hospitalization.

An exacerbation of COPD is characterized by an acute worsening of respiratory


symptoms associated with a variable degree of physiological deterioration [Seemungal,
2000] and defined by the WHO and US National Heart Lung and Blood Institute Global
Initiative for Chronic Obstructive Lung Disease (GOLD) as “an event in the natural
course of the disease characterized by a change in the patient’s baseline dyspnoea, cough,
and/or sputum, that is beyond normal day-to-day variations, is acute in onset, and may
warrant a change in regular medication in a patient with underlying COPD” [Rabe,
2007]. Acute exacerbations of COPD lead to worsening of health status of patients with
the disease [Nashimura, 2009; Bourbeau, 2007; Andenaes, 2006; Wang, 2005; Doll,
2005], with a potentially sustained effect. Patients who experience exacerbations of
COPD show a steeper rate of decline in health status than their stable counterparts. This
is supported by evidence showing that patients with frequent exacerbations had
statistically significantly worse St George’s Respiratory Questionnaire (SGRQ) [Jones,
1992] and Chronic Respiratory Disease Questionnaire (CRQ) [Nashimura, 2009] scores
than those with less frequent exacerbations.

A recent report by Escarrabill showed that while the majority of patients who experience
an acute exacerbation of COPD recover quickly, mortality rates exceed 10% during
hospitalization and increase to 25-40% during the year after hospital discharge
[Escarrabill, 2009]. Other data show that although 75% of those patients who survive
regain their pre-event pulmonary function within five weeks post-hospitalization, 7% of
patients do not recover even after five months following the acute episode
[Seemungal, 2000]. Approximately, 80% of those patients have a lung function recovery
within 3 months, 9% experience another exacerbation prior to recovery and 3.5% have an
intermediate recovery). Importantly, 63% of patients discharged from hospital after an
acute exacerbation of COPD experience subsequent exacerbations and readmissions
[Hernandez, 2009]. In the report by Hernandez et al., COPD has the highest rate of
unplanned hospitalization, at 97%, with chronic cardiovascular disorders a distant second
at 80% [Hernandez, 2009]. Moreover, after a hospitalization for COPD, patients are
more likely to experience a functional (i.e. activity of daily living) decline [Leff, 2005]
and psychological disorders, including, anxiety and depression [Cole, 2006; Gruffydd-
Jones, 2007], which contribute to readmission.

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There is accumulating evidence of increased local and systemic inflammation associated


with an acute exacerbation of COPD [Rohde, 2008; Papi, 2006; Fujimoto, 2005; Hurst,
2006b]. Various biomarkers have been identified in association with the disease state and
disease progression. The levels of circulating leukocytes, fibrinogen, C-reactive protein
(CRP) and tumor necrosis factor Alpha (TNF-α) are elevated in patients with COPD in
comparison to controls [Gan, 2004]. The level of CRP has been reported to be a
predictor of mortality in COPD [De Torres, 2006; Dahl, 2007; Higashimoto, 2009], while
high plasma fibrinogen levels and elevated neutrophil [Higashimoto, 2009] counts are
associated with a faster % predicted decline in forced expiratory volume in 1 second
(FEV1) [Donaldson, 2004]. Further, there is evidence that patients with frequent COPD
exacerbations have a faster rise in inflammatory biomarkers [Higashimoto, 2009].
However, a direct correlation between local airway and systemic inflammation has not
been clearly demonstrated in some earlier reports [Donaldson, 2004; Vernooy, 2002].
More recent reports lend support to a reverse association between systemic inflammation
and airway obstruction during hospitalization [Rohde, 2008; Hurst, 2006a].

Biomarkers of interests associated with COPD severity are selected for the purposes of
this study, including, surfactant protein D (SP-D), Clara cell secretory protein 16 (CC-16)
and high sensitivity C-reactive protein (CRP).

CRP is an acute phase reactant produced in the liver in response to Il-6 stimulation
[Pepys, 2003] and is well established as a reliable biomarker of systemic inflammation in
COPD [Dahl, 2007; Gan, 2005], with high levels reported in stable patients and correlates
with arterial oxygen tension and 6-mimute walking distance [De Torres, 2006]. Sputum
levels of IL-6 and IL-8 are known to increase during an exacerbation of COPD
[Rohde, 2008]. The latter report shows an increase in IL-6 in association with local
inflammation and severe impairment of lung function in patients with an acute
exacerbation of COPD attributed to respiratory viruses. Similarly, analysis of data from
the Third National Health and Nutrition Examination Survey (NHANES) shows that
more than 52% of patients with moderate to severe COPD had above normal levels of
CRP [Mannino, 2003]. In a recent report on the assessments of 36 biomarkers involving
a population of 90 patients studied before and during an acute exacerbation of COPD,
CRP was highlighted as the most selective indicator differentiating an exacerbation from
day-to-day variations in symptoms [Hurst, 2006a]. However, while some
epidemiological studies [Dahl, 2007; Man, 2006] of patient with mild-to-moderate COPD
have shown that CRP levels were predictors of mortality, this was not found to be the
case in a study of patients with moderate-to-severe COPD [De Torres, 2008]. Decreases
in CRP levels have been reported in response to inhaled corticosteroid (ICS) treatment
[Gan, 2004; Gan, 2005], supporting the utility of this marker in COPD therapy.

Surfactant protein D (SP-D) is an innate immune hydrophilic molecule of the collagen-


containing C-type lectin family or collectins [Kishore, 2006] and produced by epithelial
type II cells of the alveoli and Clara cells [Voorhout, 1992]. SP-D is also synthesized on
other extra-pulmonary mucosal surfaces [Madsen, 2000] and endothelial cells
[Sørensen, 2006], and is in circulation reportedly as a leakage product [Hartl, 2006;
Sorensen, 2007]. Basal levels of serum SP-D vary considerably and are modulated by
various factors, including genetic polymorphisms, gender, age, and smoking status
[Sørensen, 2006]. Serum levels of SP-D increase significantly as a result of interstitial

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lung disease and cystic fibroses [Hartl, 2006; Sorensen, 2007], possibly due to increased
vascular permeability or secretory dysfunction [Hartl, 2006]. Also, SP-D has been
associated with pulmonary injury [Umetani, 2002; Miyata, 2002], pathogen clearance
[Clark, 2003] and apoptosis [Clark, 2002]. Serum SP-D measurements have been used as
a biomarker of COPD [Sin, 2007; Sin, 2008a; Lomas, 2009] and have been shown to
decrease in response to treatment with FSC [Sin, 2008]. Serum SP-D concentrations are
elevated in smokers and are reported to be more valuable as indicators of the efficacy of
treatment intervention in COPD than FEV1 and FVC [Lomas, 2009].

Clara cell secretory protein-16 (CC-16) is a dimeric protein present predominantly in the
bronchioles and the small and large airways [Van Vyve, 1995], but also present in the
nose and urogenital tract [Lakind, 2007]. Serum level of CC-16 are mainly reflective of
the protein production in the lower respiratory tract [Shijubo, 1997], which has led to the
selection of CC-16 as a biomarker in COPD. CC-16 helps in the protection against
oxidative stress and carcinogenesis, and functions as an immunosuppressant. There is
evidence of increased serum concentrations of CC-16 following acute exposure to
various xenobiotics including smoke [Lakind, 2007]. Also, there are reports of low levels
of the protein in smokers [Shijubo, 1997] as well as in COPD patients [Lomas, 2009;
Bernard, 1992; Pilette, 2001]. Treatment with the ICS fluticasone propionate has been
shown to decrease serum levels of CC-16 that were increased in response to ozone
exposure [Alexis, 2008]. The involvement of CC-16 in airway protection against
pathogens and pollutants coupled with the finding that levels of the protein correlate with
the severity of COPD has led to the hypothesis that patients with low serum
concentrations of CC-16 could be at higher risk of COPD exacerbations [Braido, 2007].

ICS have been shown to reduce both the frequency of exacerbations and the rate of
decline in health status in patients with COPD [Burge, 2000; Spencer, 2001;
Spencer, 2004]. There is strong evidence indicating that treatment of COPD with long-
acting β-agonist (LABA) as monotherapy confers significant improvements of
exacerbation rates, pulmonary function, quality of life and rescue medication use, with
minimal untoward outcomes [Rodrigo, 2008]. ICS in combination with LABA are a
valuable treatment for COPD measured by gains in quality of life, improvement in
symptoms, reduction of exacerbations and rate of deterioration in lung function
[Chung, 2009]. The clinical benefits of ICS/LABA combination therapy in patients with
severe exacerbation of COPD with respect to reduction in exacerbation rate, and
improvement of lung function and health status are generally well accepted [Celli, 2004;
Rodrigo, 2008]

Results of a 52-week study [Ferguson, 2008] show that treatment with fluticasone
propionate/salmeterol combination therapy (ADVAIR/SERETIDE) 250/50 mcg BID
(FSC 250/50), both in the DISKUS formulation, confers superior efficacy in reduction of
moderate/severe COPD exacerbations compared with salmeterol 50 mcg (SAL 50) alone,
in subjects with a history of COPD exacerbation. In addition, FSC 250/50 was superior
to SAL 50 in measures of time to first moderate/severe COPD exacerbation and the
annual rate of moderate/severe COPD exacerbations requiring treatment with OCS.
Improvements in pre-dose AM FEV1 were better maintained with FSC 250/50 than with
SAL 50 over the 52-week treatment period. Subject-recorded symptoms of shortness of
breath, night-time awakenings due to COPD, AM peak expiratory flow (PEF),

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supplemental rescue bronchodilator (albuterol) use, and SGRQ health related quality of
life scores, significantly favoured FSC 250/50 over SAL 50. These results were
corroborated by findings from a replicate study in measures of reduction of
moderate/severe COPD exacerbations [Anzueto, 2009]. Specifically, in comparison to
SAL 50 mcg, treatment with FSC 250/50 mcg BID significantly reduced the annual rate
of exacerbations requiring hospitalization by 36% (p=0.043), exacerbations requiring
OCS (OCS) by 34% (p<0.001) and exacerbations hospitalization, OCS and/or antibiotics
by 30.4% (p<0.001). The information derived from this study could contribute
significantly to further the understanding of the clinical and therapeutic effects
attributable to ICS in the FSC 250/50 mcg BID in DISKUS formulation in comparison to
SAL 50 alone therapy, in measures of reduction of exacerbation requiring treatment with
OCS, antibiotics, and/or hospitalization. Of particular interest, the results of this study
may help further elucidate the clinical benefits of FSC 250/50 mcg BID therapy on the
rate of exacerbation requiring hospitalization, in patients previously hospitalized for
exacerbations of COPD.

2. STUDY OBJECTIVE(S)

2.1. Primary
To compare the treatment effects of FSC 250/50 mcg BID vs. salmeterol 50 mcg BID,
both via DISKUS, on the rate of exacerbation requiring hospitalization and clinical
outcomes (fewer relapses) over 29 weeks.

2.2. Secondary
To assess the treatment effects of FSC 250/50 mcg BID vs. salmeterol 50 mcg BID, both
via DISKUS, on the rate of COPD exacerbation requiring treatment with OCS,
antibiotics, and/or hospitalization (alone and in combination).

Other objectives are to compare the treatment with FSC 250/50 mcg BID to SAL50 mcg
BID , both via DISKUS, on the time to first exacerbations requiring treatment with OCS,
antibiotics and/or hospitalization (alone and in combination), pre-dose AM FEV1, the
probability of premature withdrawal of subject from the study, supplemental rescue
medication use, change in select biomarkers of systemic inflammation, domain scores for
dyspnea, fatigue, emotional function and mastery, assessment of COPD symptoms and to
further assess safety of the treatments.

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3. INVESTIGATORS AND STUDY ADMINISTRATIVE


STRUCTURE
All investigators and responsible study site staff attended an investigator training meeting
and/or separate study site initiation visit to review study protocol procedures, study
requirements, and GCP responsibilities. Investigators and staff were given opportunity to
discuss any aspect of the study protocol and GCP requirements. Training records were
reviewed to ensure investigators and staffs were qualified to conduct the study and to
document training in GCP. Any staff lacking in GCP training were either sent to a GCP
training course or provided an electronic GCP training module. Documentation of GCP
training was confirmed prior to staff participation in the study.

Principal investigators signed the investigator page of the protocol to confirm their
commitment to conduct the study in accord with the protocol and GCP. The signed
documents have been archived within individual investigator study files.

Written informed consent was obtained from each subject prior to the performance of any
study-specific procedures. The subject was provided as much time as necessary to
review the document, to inquire about details of the trial, and to decide whether or not to
participate in the study. The informed consent was signed and dated by the study subject
and by the study site person who conducted the informed consent discussion. Study data
were collected through Inform, the electronic case report form database.

In accordance with applicable regulations, GCP and GSK procedures, GSK monitors
contacted the site prior to the start of the study to review with the site staff the protocol,
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK
requirements. When reviewing data collection procedures, the discussion included
identification, agreement and documentation of data items for which the CRF served as
the source document. GSK monitored the study to ensure that: (1) the data are authentic,
accurate, and complete; (2) the safety and rights of subjects were protected; (3) the study
was conducted in accordance with the currently approved protocol and any other study
agreements, GCP and all applicable regulatory requirements.

Laboratory services and sample analyses were performed by Quest Diagnostics, Van
Nuys, CA.

4. INVESTIGATIONAL PLAN

4.1. Study Design


Study conduct details not mandated to be present in the clinical study protocol were
provided in the Study Procedures Manual (SPM) for the study.

This randomized, double-blind, parallel-group, active comparator, multicenter study was


conducted in the United States, Argentina and Norway. FSC 250/50mcg BID and SAL
50mcg BID, via DISKUS, were evaluated over 29 weeks.

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The study population included:

 Patients hospitalized for a duration not exceeding 10 days due to an acute


exacerbation of COPD, and were randomized to study treatment within 14 days post-
discharge.
 Patients with COPD, who were treated with OCS or OCS and antibiotics, and held
for observation in the emergency department (i.e. emergency room, ER) for at least
24 hours due to an acute exacerbation of COPD; then were randomized to study
treatment within 14 days post-discharge.
 Patients who received OCS or OCS and antibiotics for treatment of an exacerbation
of COPD during a physician’s office visit or ER visit of less than 24 hours in the 14
days prior to randomization, and who were hospitalized within the previous six
months due to an acute exacerbation of COPD.
Each study subject was screened to ascertain that he/she met all the study specific
eligibility criteria (i.e. all the inclusion and none of the exclusion criteria, without waivers
or exemptions).

Eligible patients were randomized to receive treatment with either FSC 250/50 mcg BID
or SAL 50 mcg BID, both delivered via the DISKUS device. Following screening (Visit
1), the randomization visit (Visit 2) occurred within 14 days post-discharge from the
hospital or ER or following the physician’s office visit (for an exacerbation of COPD
requiring treatment with OCS, or OCS and antibiotics, and a 6-month history of a
hospitalization for a COPD exacerbation(Visits 1 and 2 could occur on the same day)).
Three additional visits were scheduled: one at three weeks (21 2 days) post-discharge or
physician’s office or ER visit (Visit 3), another three months thereafter (Visit 4) and a
final visit at an additional three-month interval (Visit 5). Telephone calls were be made
to each study subject at approximately 10 days after randomization (Visit 2), six weeks
after Visit 3 and six weeks after Visit 4, and a follow-up call two weeks following the
completion (or discontinuation) of study treatment, for the assessment of AEs,
exacerbations of COPD and COPD medications.

Besides the investigational products, all other ICS, LABA and ICS/LABA combination
therapies were withheld during the study treatment period. Background therapies
(defined as COPD medications that the study patient was taking during the study
concurrently with the investigational product/study drug) with other classes of
medications started prior to the subject’s study entry were permitted. OCS and
antibiotics were allowed for the treatment of COPD exacerbations. Albuterol was
supplied to study subjects for use as needed throughout the study.

Subjects who required treatment with OCS and/or antibiotics for a prolonged period of up
to 28 days after the initial hospital or ER discharge or the physician’s office visit (for an
exacerbation of COPD requiring treatment with orals corticosteroids or OCS and
antibiotics) were withdrawn from the study. An interactive voice response system was
used for the randomization of blinded study drug and for the management of
investigational drug supply. Study drug assignment was stratified by tiotropium (e.g.
Spiriva) background therapy and by previous ICS use.

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A chronological schematic of the experimental study design is presented in Figure 1 and


the Time and Event schedule of presented in Table 1. Each study subject was considered
to have completed the study when he/she completed all study visits and the two-week
follow-up telephone call.

Figure 1 Chronological schematic of Experimental Design

Note: 1. Time from hospital discharge, ER, or physician’s office visit (due to the recent exacerbation) to
Randomization (Visit 2) is  14 days. Visit 1 and Visit 2 can occur during the hospitalization,
ER visit, physician’s office visit and up to 14 days thereafter.

2. Total study subjects’ participation is approximately 29 weeks (unless subject is prematurely


withdrawn from the study).

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Table 1 Time and Events Table

Procedure Screening Treatment period Unscheduled Premature Follow-


Visit1 Discontinuation up
Visit Number V1 V2 V3 V4 V5
Study Day2 -9 to 14 -9 to 14 21 (2) 111 (4) 201 (4) (Any day) (Any day) 215 (2)
(3 Wks) (V3 + 3 Mths) (V4 + 3 Mths)
Written Informed Consent3 X
Subject Demography X
Medical History (including X
vaccinations/immunizations)
Disease History X
Smoking History X
Therapy History and Current COPD therapy X
Inclusion/Exclusion Criteria X
Smoking Status Assessment X X X X X X X
Efficacy Assessments
Assessment of COPD Exacerbation X X X X X X X
Requirement for Additional COPD Intervention: X X X X X X X
oral corticosteroids, antibiotics, and/or
hospitalization
Questionnaires Assessments4 X X X X X1 X
Spirometry5 X X X X X
Assessment of Albuterol Use and Treatment X X X X X
Compliance
Laboratory Assessments
Blood draws for biomarker analyses X X X X X X
Pharmaco-genetics (Pgx) Sampling6 X
Safety Assessments
Urine Pregnancy Tests7 X X X X X
12-Lead ECG X
Physical Exam/Chest X-Ray Review8 X X X X
Vital Signs X X X X X X X
Adverse Events and Serious Adverse Events9 X X X X X X X
Concomitant Medications X X X X X X X
Telephone Call10 X

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Procedure Screening Treatment period Unscheduled Premature Follow-


Visit1 Discontinuation up
Investigational Product
Dispense Study Drug - ADVAIR DISKUS 250/50 or X X X
SAL50
Assess Study Drug Compliance X X X X X
Dispense Albuterol (as needed) X X X
Collect Study DISKUS and Albuterol X X X X
1. If an unscheduled visit occurs within one week (7 days) prior to a scheduled visit, study assessments from the latter will be performed during the former; this includes the CRQ-
SAS. The CRQ-SAS will not be administered during an unscheduled visit if the unscheduled visit does not occur within one week prior to a scheduled visit.
2. Day 1 is the first day post discharge from index hospitalization (for 10 days), ER (for  24 hour stay) or physician’s office visit for an exacerbation of COPD requiring treatment
with OCS, or OCS and antibiotics. The Screening Visit (V1) and the Randomization Visit (V2) can occur on the same day, and up to 14 days after discharge or office visit. Follow-
up telephone call to occur two weeks (2 days) following Visit 5 or premature discontinuation.
3. Subject must give consent and sign the Informed Consent Form prior to performing any procedure
4. Questionnaires: CRQ-SAS must be administered during study visit before any other assessment; the EXACT is taken by the patient every evening one hour before bedtime,
approximately.
5. Visit 1 spirometry (pre-bronchodilator) will be performed if a patient has no record (within the previous year) of one in his/her medical chart. Pre-bronchodilator and Post-
bronchodilator spirometry will be performed at Visit 2; while only pre-bronchodilator spirometry will preformed at Visit 3, Visit 5 and all premature withdrawal visits.
6. Pharmacogenetics sampling may be performed preferably at Visit 2, or any visit thereafter.
7. Applicable to all female subjects, with the exception of post-menopausal and surgically sterile females
8. A chest X-ray or CT scan performed within six months prior to Visit 2; if the subject does not have such a record, a chest X-ray must be obtained.
9. Only SAEs related to study participation need to be collected from Visit 1 (Screening) to Visit 2 (Randomization).
10. A site staff must make a telephone call to their respective study subject, approximately, 10 days after randomization (Visit 2), six weeks after Visit 3 and six weeks after Visit 4, and
a follow-up call two weeks following the completion of study treatment, for the assessment of AEs, exacerbations of COPD and COPD medication.

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4.2. Discussion of Study Design


The study, as designed, was intended to assess the differential clinical benefits conferred
by FSC 250/50 mcg BID in comparison to SAL 50 mcg BID, both delivered via
DISKUS, over 29 weeks, on measures of rate of exacerbation requiring hospitalization, in
patients recently discharged from the hospital, ER or physician’s office visit as a
consequence of an acute exacerbation of COPD. The study was designed with the
objective of adding to the current body of evidence on the clinical utility of FSC 250/50
mcg on the treatment of exacerbation of COPD. Moreover, the study design provided the
opportunity for the assessment of select biomarkers that may influence biological and
clinical responses to treatment with FSC 250/50 mcg BID and SAL 50 mcg BID and/or
that may be associated with COPD progression. It was recognized that the eligibility
requirement of hospitalization as a precursor to subject enrolment and the timing of
subject study entry added a level of complexity to the implementation of the study.

4.3. Protocol Amendments


Two protocol amendments were implemented for ease of study feasibility, extending the
timeframe of patient eligibility for study entry, allowing the use of any approved
formulation of albuterol (ventolin, salbutamol) as rescue medication, and facilitating
completion of questionnaires and patient reported outcomes. Other minor clarifications
were made.

4.3.1. Amendment No. 01(07-Jun-2010)

Details of protocol amendment 01 are as follows:

 A clarification was made to the study visit schedules and visit windows as Visit
3 (2 days), Visit 4 (4 days) and Visit 5 (4 days). Visit 3 was scheduled at 21
(2) days post-discharge from index hospitalization, emergency room visit or
physician’s office visit for an exacerbation of COPD requiring treatment with
oral corticosteroids or oral corticosteroids and antibiotics.
 A clarification was made, updating references to “during the study” to indicate
“during the study treatment period”, in the Table 3 of Prohibited Medications
and Exclusion Periods.
 A clarification was made detailing “previous ICS use” as “within one month
prior to the index hospitalization, emergency room visit or physician’s office
visit for an exacerbation of COPD requiring treatment with oral corticosteroids
or oral corticosteroids and antibiotics”
 A clarification was made, for clarity, to the standards for spirometry.
 The potential participation of other countries in the conduct of the study, besides
the United States, was noted.

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4.3.2. Amendment No.: 02 (13-Dec-2010)

Details of protocol amendment 02 are as follows:

 The timeframe for prospective patients’ eligibility to enter the study, from index
hospitalization discharge, emergency room visit or physician’s office visit (for
an exacerbation of COPD requiring treatment with oral corticosteroids or oral
corticosteroids and antibiotics) to study entry was extended from 10 days to 14
days.
 A clarification was made to the Inclusion/Exclusion criteria, specifying study
subject must be able to read, comprehend, and record information in the
country-specific language presented (e.g. English if presented in English,
Spanish if presented in Spanish, Norwegian if presented in Norwegian, etc.).
 An additional formulation of albuterol (ventolin, salbutamol), salbutamol
inhalation powder or the VENTOLIN DISKUS, was permitted.

4.4. Selection of Study Population


Various assumptions were made with respect to the study population considering the
severity of COPD (i.e. recent experience of an exacerbation of COPD requiring
hospitalization) and the anticipated available concomitant therapies. An attempt was
made to restrict the enrolment of patients on tiotropium background therapy to less than
33% of the total. Study drug was stratified by background tiotropium therapy and by ICS
use within the one month preceding the index hospitalization, emergency room visit or
physician’s office visit for an exacerbation of COPD requiring treatment with OCS, or
OCS and antibiotics. Further, the intent was to limit the number of subjects with
previous ICS use to 50% of the total number of subject enrolled, over the 29-week
duration of the study.

Study subjects were selected based upon the following specified inclusion and exclusion
criteria.

4.4.1. Inclusion Criteria

Subjects eligible for enrolment in this study must have met all of the following criteria:

1. Male or female of 40 years of age at screening.


2. Current or former smokers with a 10 pack-year cigarette smoking history [number
of pack years = (number of cigarettes per day / 20) X number of years smoked (e.g.,
10 pack-years is equal to 20 cigarettes per day for 10 years, or 10 cigarettes per day
for 20 years]. Former smokers are defined as those who have quit smoking for at
least 3 months prior to the screening visit.

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3. Any of the following populations:


 Patients hospitalized for a duration not exceeding 10 days due to an acute
exacerbation of COPD, eligible patients must be randomized within 14 days post-
discharge.
 Patients with COPD who were treated with OCS or OCS and antibiotics, and held for
observation in the emergency department (i.e. emergency room, ER) for at least 24
hours due to an acute exacerbation of COPD; eligible patients must be randomized
within 14 days post-discharge.
 Patients who received OCS or OCS and antibiotics for treatment of an exacerbation
of COPD during a physician’s office visit or ER visit of less than 24 hours in the 14
days prior to randomization, and who have been hospitalized within the previous six
months due to an acute exacerbation of COPD.
4. Clinical diagnosis of COPD (for at least 6 months). The following definition of
COPD from the American Thoracic Society (ATS) will be used: COPD is a disease
state characterized by the presence of airflow obstruction due to chronic bronchitis or
emphysema; the airflow obstruction is generally progressive, may be accompanied
by airway hyper-reactivity, and may be partially reversible [American Thoracic
Society, 1995].
5. Documented evidence (within a year prior to Visit 1) in the medical chart of
spirometry confirming the diagnosis of COPD and/or spirometry performed prior to
randomization (Visit 2) that confirms pre-bronchodilator FEV1/FVC ratio < 0.70 and
pre-bronchodilator FEV1 <70% of predicted.
6. Review and subject’s completion of written informed consent: a subject-signed and
dated written informed consent (form) must be obtained prior to any study
procedure, and the subject must be willing to comply with all the requirements of the
study protocol.
7. Subject must be able to read, comprehend, and record information in the country-
specific language presented (e.g. English if presented in English, Spanish if
presented in Spanish, Norwegian if presented in Norwegian, etc.).
To be eligible for entry into the study, females of childbearing potential must commit to
the consistent and correct use of an acceptable method of birth control starting on the day
of visit 1, throughout the clinical trial, and for a period after the trial to account for
elimination of the drug (minimum of six days), as defined by any one of the following:

 Abstinence (females of childbearing potential who are not sexually active must
commit to complete abstinence from intercourse)
 Oral contraceptive (either combined estrogen/progestin or progestin only)
 Injectable progestogen
 Implants of levonorgestrel or etonogestrel
 Percutaneous contraceptive patches
 Intrauterine device (IUD) or intrauterine system (IUS) with a documented
failure rate of less than 1% per year,

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 Male partner who is sterile (vasectomy with documentation of azoospermia)


prior to the female subject’s entry into the study and is the sole sexual partner
for that female subject, or
 Double-barrier method; condom or occlusive cap (diaphragm or cervical /vault
caps) plus spermacide.

4.4.2. Exclusion Criteria

Subjects meeting any of the following criteria were not to be enrolled in the study:

1. Diagnosis of pneumonia, congestive heart failure (CHF), or other complicating co-


morbid condition while hospitalized within the last 6 months for an exacerbation of
COPD.
2. Historical or current evidence of clinically significant uncontrolled disease including,
but not limited to, those listed below. Significant is defined as any disease that, in
the opinion of the investigator, would put the safety of the subjects at risk through
study participation, or which would affect the safety analysis or other analyses if the
disease/condition exacerbated during the study.
 A previous lung resection surgery (e.g. lobectomy, pneumonectomy, etc) within
the year preceding Visit 1 (Screening)
 Asthma as primary diagnosis
 Lung cancer
 Cystic fibrosis, pulmonary fibrosis, active tuberculosis, or sarcoidosis
 Clinically significant cardiac arrhythmias
 Uncontrolled hypertension
 Unstable angina
 Current malignancy or a previous history of cancer in remission for < 5yrs
(localized basal cell or squamous cell carcinoma of the skin that has been
resected is not excluded)
 Uncontrolled diabetes mellitus
 Uncontrolled hyperthyroidism or hypothyroidism
 Immunologic compromise
 Cushing’s or Addison’s disease
3. An abnormal 12-lead electrocardiogram (ECG) at Visit 1 (Screening) deemed to be
clinically significant by the investigator.
4. A chest X-ray or computed tomography (CT) scan performed in the 6 months
preceding Visit 1 that revealed evidence of clinically significant abnormalities not
believed to be due to the presence of COPD. If the subject does not have a record of
a chest X-ray, one must be obtained and reviewed prior to randomization.
5. Female patients with a positive urine pregnancy test at Visit 1.

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6. Any infirmity, physical disability, or geographic location that would limit


compliance for scheduled visits.
7. Any adverse reaction, immediate or delayed, hypersensitivity to any Beta-agonist,
sympathomimetic drug, or corticosteroid including any components of the study drug
formulations.
8. Limited ability to provide a valid informed consent due to psychiatric disease,
intellectual deficiency, poor motivation, current substance abuse (including illicit
drugs and alcohol), or neurological disorders that might interfere with completion of
study procedures or hearing problems that may impede effective communication.
9. Study site staff (i.e. participating investigator, sub-investigator, study coordinator,
employee of the participating investigator) or family members of site staffs.
The use of medications that were contraindicated for the study drugs was not permitted.

4.4.3. Withdrawal Criteria

Study subjects were permitted to voluntarily discontinue participation in this study at any
time. Further, any investigator, at his/her discretion, could discontinue any subject from
participation in this study at any time. All investigators with discontinued subjects from
their sites were instructed to make every effort to schedule withdrawn study subjects for a
Premature Discontinuation Visit as soon as possible following the discontinuation.
Further, the reasons for each subject’s withdrawal was required to be recorded in the
electronic case report form (eCRF) and to include the following: AE, consent withdrawn,
lost to follow-up, protocol violation, lack of efficacy, COPD exacerbation, and
investigator’s discretion. Specific regards were required to distinguish withdrawals due
to an AE, COPD exacerbation, and protocol violation. The occurrence of a SAE that
resulted in withdrawal was instructed to be recorded as withdrawal due to “adverse
event”.

Per protocol instructions, study subjects who experienced an acute exacerbation of COPD
within three weeks of hospital discharge or of the physician’s office visit for an
exacerbation of COPD requiring treatment with OCS or OCS and antibiotics, were
withdrawn from the study. Moreover, subjects who required treatment with OCS, or
OCS and antibiotics for a prolonged period of up to 28 days after the initial hospital or
ER discharge or the physician’s office visit (for an exacerbation of COPD requiring
treatment with orals corticosteroids or OCS and antibiotics) were required to be
withdrawn from the study. Subjects who were withdrawn from the study were not
replaced.

In instances where subjects withdrawn from the investigational product treatment before
the completion of the treatment period (i.e., before Visit 5, per study design), the date of
the premature withdrawal was recorded and entered in the eCRF.

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Patients who consented to participate in the study by signing the study ICF, who
underwent at least one study procedure and were assigned a subject identifier but not
randomized in the study, were classified as having failed screening. A corresponding
entry was made through the Interactive Voice Recognition System (IVRS) and the
following information on each patient who failed screening was entered in the eCRF:

 Date of the Screening Visit


 Subject Identifier
 Subject’s Demographic information (including race, age, and gender)
 Reason the subject was not randomized
 Any SAE that occurred after the subject’s signature of the ICF
Re-screening of subjects was not allowed without prior authorization of GSK or
designee.

4.5. Treatments

4.5.1. Investigational Products

Fluticasone propionate/salmeterol 250/50 mcg BID in the DISKUS formulation


(ADVAIR DISKUS) is a combination product containing a corticosteroid and a long-
acting beta2-adrenergic agonist and is indicated in the US for the maintenance treatment
of airflow obstruction and reducing exacerbations in patients with COPD.

Salmeterol xinafoate Inhalation Powder (SEREVENT DISKUS) is indicated for the long-
term, twice-daily (morning and evening), administration in the maintenance treatment of
bronchospasm associated with COPD (including emphysema and chronic bronchitis).

Double-blind study medication was manufactured by GlaxoSmithKline (GSK) and


provided by Clinical Trial Supplies of GSK Research and Development. Each DISKUS
contained 60 doses of study medication. Study centers were instructed to store the study
supplied DISKUS inhalers at temperatures between 2 and 25C in a dry place and
protected from direct sunlight. Batch information for blinded study medication is
presented in Table 2.

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Table 2 Clinical Trial Supplied Investigational Medications and Batch


Numbers

Study Treatment Medication Batch Number


ADVAIR/ DISKUS (FSC 250/50mcg)
FLUTICASONE/SALMETEROL, EW, 250/50 MCG, MDPI-W, 60 DOSE R436088
FLUTICASONE/SALMETEROL, EW, 250/50 MCG, MDPI-W, 60 DOSE R492024
FLUTICASONE/SALMETEROL, EW, 250/50 MCG, MDPI-W, 60 DOSE R492024
FLUTICASONE/SALMETEROL, EW, 250/50 MCG, MDPI-W, 60 DOSE R492024
FLUTICASONE/SALMETEROL, EW, 250/50 MCG, MDPI-W, 60 DOSE R539545
FLUTICASONE/SALMETEROL, EW, 250/50 MCG, MDPI-W, 60 DOSE R539545
FLUTICASONE/SALMETEROL, EW, 250/50 MCG, MDPI-W, 60 DOSE R539545
SEREVENT DISKUS (SAL 50mcg)
SALMETEROL, AK, 50 MCG, MDPI-W, 60 DOSE R454012
SALMETEROL, AK, 50 MCG, MDPI-W, 60 DOSE R484872
SALMETEROL, AK, 50 MCG, MDPI-W, 60 DOSE R484872
SALMETEROL, AK, 50 MCG, MDPI-W, 60 DOSE R484872
SALMETEROL, AK, 50 MCG, MDPI-W, 60 DOSE R544710
SALMETEROL, AK, 50 MCG, MDPI-W, 60 DOSE R544710

All study subjects received albuterol as relief medication. GlaxoSmithKline Clinical


Trial Supplies made available a bulk supply of albuterol (MDI, DISKUS or nebules) to
each investigational site.The contents of the label were in accordance with all applicable
regulatory requirements.

4.5.2. Dosage and Administration

Following screening, eligible subjects were randomized (1:1) to one of the following two
double-blind treatment groups for a duration of 29 weeks:

1. FSC 250/50mcg BID


2. Salmeterol 50mcg BID
Each DISKUS contained 60 doses of study medication. Study subjects were instructed to
self-administer medication twice every day (one inhalation in the morning and another
inhalation in the evening), approximately 12 hours apart. Investigators were instructed to
advise each subject to adhere to this dosing regimen throughout the study and required to
instruct each subject on how to properly use the DISKUS inhaler. Investigators were
asked to oversee each study subject self-administer the first dose of blinded study drug in
the clinic at the end of Visit 2.

All study participants received supplemental albuterol (MDI, DISKUS and/or nebules)
for their use on an as-needed basis throughout the study.

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4.5.3. Dose Rationale

This study was intended to compare doses of FSC 250/50mcg BID and SAL 50mcg BID
that are indicated in the US for maintenance treatment of airflow obstruction and
reducing exacerbations in patients with COPD, and of bronchospasm associated with
COPD (including emphysema and chronic bronchitis), respectively.

4.5.4. Treatment Assignment

Study subjects were assigned to one of the two study treatments, either FSC 250/50 mcg
or SAL 50 mcg, in accordance with the randomization schedule. An Interactive Voice
Response System (IVRS) was utilized for this study, provided as a means for central
allocation of study drug. Each investigator was supplied with sufficient clinical supplies
to conduct the trial. Additional supplies were forwarded to sites as needed during the
study.

All study medications were supplied by GSK. The study medication was forwarded to
respective study sites after all the applicable regulatory and ethical approvals were
received, reviewed and approved by GSK.

At Randomization (Visit 2) study subjects were assigned to study treatment in accordance


with a randomization schedule and stratified (1:1) based on background tiotropium
therapy and previous (within one month prior to the index hospitalization, emergency
room visit or physician’s office visit for an exacerbation of COPD requiring treatment
with OCS or OCS and antibiotics) use of ICS, to ensure that comparable numbers of
subjects received either of the two study treatments.

4.5.5. Assignment of Subject Identifier

During the Screening visit (Visit 1), following completion of the informed consent
process for each study subject (the subject confirmed his/her willingness to participate
voluntarily in the study by signing the ICF) and one additional procedure was performed,
a unique subject-specific identifier was assigned to the subject completing the visit.
Subject identifiers were used to identify individual subjects during the course of the
study. Study investigators (and delegate) were required to make a telephone call to the
IVRS to register each study subject at the time of the subject’s screening.

A subject could be screened and randomized to study treatment on the same day; hence,
the Screening visit (V1) and the Randomization visit (Visit 2) could occur on the same
day.

Re-screening of subjects was not allowed without prior authorization of GSK or


designee. Each study subject who was re-screened received the same subject identifier
assigned at his/her earlier screening.

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4.5.6. Assignment of Randomization Number

The site staff responsible for the study (Principal investigator, Sub-investigator or Study
Coordinator) at each study site was required per protocol to make a telephone call
through the IVRS to randomize each subject eligible to participate in the study (following
screening) at their respective study center. During the telephone call, the IVRS
confirmed the subject’s identifier (also used as the subject’s number in Inform) and
provided two additional numbers:

 A treatment pack number that identified the DISKUS inhaler of double-blind


medication that should have been dispensed to the subject from the
Investigator’s inventory
 A randomization number
For all subsequent visits when the study medication was to be dispensed to each subject,
a telephone call was made to IVRS for the next treatment pack number to be assigned
from the Investigator’s inventory.

Although the study medication was stored at each site, the investigator or designee was
required to make a telephone call to the IVRS to obtain study medication assignments.
All calls to IVRS were confirmed with faxes that were sent to the Investigator’s site
(from where the call was made) upon completion of each call. Detailed instructions and
worksheets on the use of the IVRS were forwarded to all sites at study start.

Subjects were assigned to study treatment in accordance with the randomization schedule
and based on background tiotropium treatment and previous ICS use.

4.5.7. Blinding

The investigator or treating physician could unblind a subject’s treatment assignment


only in the case of an emergency, when knowledge of the study treatment was essential
for the appropriate clinical management or welfare of the subject. Whenever possible,
the investigator was required to first discuss options with the GSK Medical Monitor or
appropriate GSK study personnel before unblinding the subject’s treatment assignment.
If this was impractical, the investigator was instructed to notify GSK as soon as possible,
but without revealing the treatment assignment of the unblinded subject, unless that
information was important for the safety of subjects currently in the study. The date and
reason for the unblinding was recorded in the appropriate data collection tool.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff could unblind the
treatment assignment for any subject with an SAE. If the SAE required that an expedited
regulatory report be sent to one or more regulatory agencies, a copy of the report,
identifying the subject’s treatment assignment, could be sent to clinical investigators in
accordance with local regulations and/or GSK policy.

Any study subject for whom the treatment blind was broken was withdrawn
(discontinued) from the study and the primary reason for the discontinuation (the event or
condition which led to the unblinding) was recorded in the electronic CRF (eCRF).

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4.5.8. Product Accountability

In accordance with local regulatory requirements, the investigator, designated site staff,
or head of the medical institution (where applicable) was required to document the
amount of GSK investigational product dispensed and/or administered to study subjects,
the amount returned by study subjects, and the amount received from and returned to
GSK, when applicable. Product accountability records were maintained throughout the
course of the study.

Drug dispensing and accountability logs were maintained for the double-blind
medications and supplemental albuterol, on which the investigator or designee recorded
the number of units dispensed to and returned (MDI, DISKUS and nebules) by each
subject at each clinic visit. Study subjects were required to return all used and unused
study medication and supplemental albuterol MDI and DISKUS, and the investigator or
designee was instructed to reconcile or resolve any discrepancies in the number of study
treatment inhalers dispensed and returned.

4.5.9. Treatment Compliance

During each study visit, from Visit 2 to Visit 5, including unscheduled visits where
medication was returned and a subject was premature discontinued, the number of
remaining doses from each blinded DISKUS inhaler dispensed to the subject completing
the visit was entered in the Compliance section in the eCRF.

4.5.10. Prior and Concomitant Medications and Non-Drug Therapies

4.5.10.1. Permitted Medications and Non-drug Therapies

All medications taken by each subject during the study (concomitant medications) were
recorded in the eCRF.

All background COPD medications, with the exception of ICS and LABA, alone or in
combination, were allowed, including the following:

 Albuterol was provided for use as relief medication for use on an as needed basis
throughout the study but was to be withheld for at least 6 hours prior to all study
visits where pulmonary function testing was performed. If a subject had taken
albuterol within 6 hours prior to pulmonary function testing, the visit was
rescheduled.
 Short courses of OCS were permitted for acute treatment of exacerbation of COPD,
not to exceed 14 days.
 Tiotropium therapy started prior to, and during, the index exacerbation was allowed
during the study. However, tiotropium therapy scheduled to start after randomization
and during the treatment period of the study was not be permitted. Assignment to
blinded study medication was to be stratified based on tiotropium use to ensure equal
numbers of subjects using the drug in each treatment group.

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 Antihistamines, nasal decongestants and/or other intranasal medications for the


treatment of rhinitis were allowed.
 Beta-blockers were allowed provided study subjects were on a stable dose for at least
30 days prior to the screening visit (Visit 1) and this dose was maintained throughout
the study.
 Beta-blocker eye drops were permitted.
 Immunotherapy for the treatment of allergies was allowed.
 Flu shots were allowed.
 Intranasal corticosteroids were allowed
 Intranasal cromolyns or nedocromil were allowed
Use of systemic corticosteroids for non-respiratory related medical treatment was
permitted; however, the investigator were required to notify GSK or designee if this
occurred in order to determine subject eligibility.

Use of systemic antibiotics for non-respiratory related medical treatment was permitted.

Oxygen therapy was permitted during the study.

The following medications were permitted but the investigators were advised to use with
extreme caution as they may potentiate the effects of FSC or SAL on the vascular system:

 monoamine oxidase inhibitors


 tricyclic antidepressants
Participation in a pulmonary rehabilitation program was allowed provided the pulmonary
rehabilitation program was not initiated within 8 weeks of Visit 1. In addition, subjects
who were enrolled in a pulmonary rehabilitation program at study start should have
maintained participation in the program for the duration of the study.

Also, herbal therapies were allowed and were to be recorded in the eCRF.

4.5.10.2. Prohibited Medications and Non-drug Therapies

Treatment of study subjects with concomitant inhaled corticosteroids and long-acting


Beta2-agonists (other than study drug) was not permitted during the study treatment
period. A list of medications prohibited during the study with details of the times the
medication was required to be withheld is provided in Table 3.

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Table 3 Prohibited Medications and Exclusion Periods

Medication Exclusion Period


Inhaled Corticosteroids Use not permitted during the study treatment period
(e.g. fluticasone propionate)
Systemic Corticosteroids (Oral or IV) Permitted at study entry, permitted for use of short
courses for treatment of COPD exacerbations, not to
exceed 14 days
Long-acting beta2-agonists Use not permitted during the study treatment period
(e.g., salmeterol or formoterol)
ICS/LABA combination product Use not permitted during the study treatment period
(e.g., Advair)
Tiotropium Use not to be started during study treatment period
(permitted if started prior to randomization)
Strong Inhibitors of the cytochrome Use not permitted during the study treatment period
p450 Cyp 3A4 (e.g., ritonavir and
ketoconazole)
Other Investigational Medication(s) Use not permitted within 30 days prior to Visit 1 and
Use not permitted during the study

4.5.11. Treatment after the End of the Study

All participating investigators were instructed to advise all study subjects, prior to
completion of the study, to consult their healthcare providers to ensure appropriate
treatment is not interrupted upon completion of the study.

4.5.12. Treatment of Investigational Product Overdose

An overdose is defined as a dose greater than the total doses described in Section 4.5.2
(Dosage and Administration), which results in clinical signs and symptoms, and
potentially adverse reactions. Investigators were advised that in the event of an overdose
of study medication, they should use clinical judgment in treating the overdose and
contact the study medical monitor. Further, the investigators were advised to refer to the
relevant document(s) for detailed information regarding warnings, precautions,
contraindications, AEs, and other significant data pertaining to the study drug(s) being
used in this study. Such documents may include, but not be limited to, the approved
product labeling for FSC, SAL and albuterol.

4.6. Study Assessments and Procedures

4.6.1. Efficacy Assessment

The study endpoints are summarized as follows:

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Primary

 The rate of COPD exacerbations requiring hospitalization that occur more than
21 days post-discharge or physician’s office visit for an exacerbation of COPD
requiring treatment with OCS or OCS and antibiotics.
Secondary

 The rate of COPD exacerbations requiring treatment with OCS, antibiotics,


and/or hospitalization (alone and in combination).
Related Efficacy Endpoints

 Time to first exacerbation requiring treatment with OCS, antibiotics, and/or


hospitalization (alone and in combination).
 Probability of premature withdrawal of subject from the study.
 Pre-dose AM FEV1.
 Supplemental use of albuterol.
 Change in biomarkers of systemic inflammation, including, SP-D, CC-16 and
hs-CRP.
Health Outcomes

 Domain scores (dyspnea, fatigue, emotional function, mastery and health status)
as measured by CRQ-SAS.
 Symptoms (congestion, cough, phlegm, mucus, chest discomfort, shortness of
breath and sleep disturbance) assessed by EXACT.

4.6.2. Safety Assessments

 Type and incidence of adverse events.

4.7. Data Quality Assurance


In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors
contacted the clinical centers prior to the start of the study to review with the site staff the
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and
GSK requirements. When reviewing data collection procedures, the discussion included
identification, agreement and documentation of data items for which the eCRF served as
the source document.

GSK staffs monitored the study to ensure that the:

 Data are authentic, accurate, and complete.


 Safety and rights of subjects were being protected.
 Study was conducted in accordance with the currently approved protocol and any
other study agreements, GCP, and all applicable regulatory requirements.

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The investigator and the head of the medical institution (where applicable) agreed to
allow the monitor direct access to all relevant documents.

To ensure compliance with GCP and all applicable regulatory requirements, GSK
informed all investigators of the possibility of a quality assurance audit of the site
records, and the regulatory agencies may conduct a regulatory inspection at any time
during or after completion of the study. In the event of an audit or inspection, the
investigator (and institution) agreed to grant the auditor(s) and inspector(s) direct access
to all relevant documents and to allocate their time and the time of their staff to discuss
any findings/relevant issues.

GSK staff informed all investigators of the time period for retaining the site records in
order to comply with all applicable regulatory requirements. The minimum retention
time and the strictest standard applicable were agreed upon, as dictated by local
laws/regulations, GSK standard operating procedures, and/or institutional requirements.

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4.8. Statistical Analyses

4.8.1. Sample Size Considerations

The sample size for this study was calculated to demonstrate superiority of FSC250/50
over SAL50 in the primary efficacy measure, rate of exacerbations requiring
hospitalization. Estimates of exacerbation rates for the SAL50 and FSC250/50 treatment
groups of 0.25 and 0.14 for a 6-month treatment period, respectively, were based on the
population of subjects with a previous hospitalization due to COPD in the year prior to
screening from 2 previous year-long GSK COPD studies [Ferguson, 2008; Anzueto,
2009]. Using the rate estimates of 0.25 and 0.14, for SAL50 and FSC 250/50
respectively, and negative binomial regression with a dispersion factor of 0.2, it was
estimated that 360 subjects per treatment group would provide 90% power to detect a
44% reduction in the rate of exacerbations requiring hospitalization in the FSC250/50
treatment group compared with the SAL50 treatment group at the 0.05 significance level.
4.8.2. Analysis populations

Three populations were defined for this study: Safety Population, Screen Failure
Population and Intent-to-Treat (ITT) Population.

4.8.2.1. Safety Population

The Safety population included all subjects screened in the study (i.e., assigned a subject
number and performed at least one study procedure). This population included screen
failures and randomized subjects. This population was used for listings of serious
adverse events and for a summary of the analysis populations.

4.8.2.2. Screen Failure Population

The Screen Failure population included all subjects screened for inclusion in the study
but were withdrawn from the study prior to randomization to blinded study drug.
Reasons for screen failure and inclusion/exclusion criteria not met were summarized for
this population.

4.8.2.3. Intent-to-Treat Population

The ITT population included all subjects who were randomized to study drug. For all
subjects in the ITT population, it was assumed that at least one dose of blinded study
drug was taken since the first dose was to be administered at the site following
randomization. Treatment group assignment was based only on randomization
(regardless of any inadvertent errors in dispensing of study drug that may occur during
the study). The ITT population was the primary analysis population for summaries and
analyses of demographic/background, efficacy, health outcomes and safety data.

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4.8.3. Multiple Comparisons and Multiplicity

Multiplicity considerations were made for analyses of efficacy measures.

A single primary efficacy measure was defined for this study with all other efficacy
measures defined as secondary or related. A primary analysis of each efficacy measure
was also specified with comparisons at any other time points to be interpreted as
supportive. Similarly, there is only one treatment comparison of interest in this study.
The inferential significance level for all statistical tests is 0.05. All statistical tests tested
two-sided hypotheses of no difference between treatment groups.

For interpretation of results and to control overall Type I error rate, step-down principles
for testing of efficacy measures were implemented. The primary efficacy measure served
as gatekeeper for analysis of the single secondary efficacy measure. The secondary
efficacy measure served as gatekeeper for the set of related, other efficacy measures
(nested below the secondary measure).

Should the statistical test for the primary efficacy measure fail to reject the null
hypothesis of no treatment difference at the significance level of 0.05, then all subsequent
analyses of the secondary efficacy measure and related other efficacy measures would be
interpreted as descriptive only. Should the statistical test fail to reject the null hypothesis
of no treatment difference at the significance level of 0.05 for the secondary efficacy
measure, then all subsequent analyses of related efficacy measures (nested under the
secondary efficacy measure) would be interpreted as descriptive only. No further
multiplicity adjustment was planned for the related efficacy endpoints.

4.8.4. Efficacy Analyses

4.8.4.1. Primary Efficacy Analysis

The primary efficacy measure was COPD exacerbations requiring hospitalization. The
primary analysis compared the rate of COPD exacerbations requiring hospitalization
between treatment groups using a negative binomial regression model with terms for
treatment group, pooled investigator, randomization stratum and baseline severity
(baseline FEV1 percent predicted), with log (time of treatment) as an offset variable.

4.8.4.2. Secondary Efficacy Analysis

The secondary efficacy measure was the rate of exacerbations requiring treatment with
OCS, antibiotics and/or hospitalization. The secondary efficacy measure was analyzed in
the same manner as the primary efficacy measure, rate of exacerbations requiring
hospitalization.

4.8.5. Other Efficacy Analyses

Other efficacy measures were biomarkers including SP-D, CC-16 and hs-CRP; time to
first COPD exacerbation requiring treatment with OCS, antibiotics and/or hospitalization;
pre-dose FEV1; supplemental albuterol use; and the probability of study withdrawal.

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Biomarkers SP-D, CC-16 and hs-CRP: The primary analysis of each biomarker was
mean change from baseline compared between treatment groups at Endpoint. As SP-D,
CC-16 and hs-CRP were non-normally distributed, the biomarker values were log-
transformed prior to analysis. Endpoint was defined as the last measurement during the
29-week treatment period and baseline was defined as the biomarker measure from
Randomization (Visit 2). Log-transformed SP-D, CC-16, hs-CRP values and change
from baseline values were summarized with descriptive statistics by treatment group and
an analysis of covariance (ANCOVA) model including terms for treatment group, pooled
investigator, randomization stratum and baseline was used to test statistical differences
between treatment groups at Endpoint and each visit (Visits 3, 4 and 5, Weeks 3, 16 and
29, respectively).

Time to first COPD exacerbation requiring treatment with OCS, antibiotics and/or
hospitalization: Time to first COPD exacerbation requiring treatment with OCS,
antibiotics and/or hospitalization were summarized by treatment group using Kaplan-
Meier estimates. A Cox proportional hazards regression model was used to compare time
to first exacerbation between treatment groups. The hazard ratio for the treatment
comparison was derived from a Cox proportional hazards model with terms for baseline
disease severity (baseline FEV1 percent predicted), pooled investigator, randomization
stratum and treatment group in the model.

Pre-dose FEV1: The primary analysis of pre-dose FEV1 was mean change from baseline
compared between treatment groups at Endpoint. Endpoint was defined as the last
scheduled measurement of pre-dose FEV1 during the 29-week treatment period and
baseline was defined as the pre-dose FEV1 measure from Randomization (Visit 2). FEV1
measures and change from baseline values were summarized with descriptive statistics by
treatment group and an ANCOVA model including terms for treatment group, pooled
investigator, randomization stratum and baseline was used to test statistical differences
between treatment groups at Endpoint and each visit (Visits 3 and 5, Weeks 3 and 29,
respectively).

Supplemental albuterol use: The primary analysis of supplemental albuterol use


compared mean values between treatment groups at Endpoint. Mean supplemental
albuterol use was summarized with descriptive statistics by treatment group at Endpoint,
for the overall 29-week treatment period, and for each of the Weeks 1-4, Weeks 5-8,
Weeks 9-12, Weeks 13-16, Weeks 17-20, Weeks 21-24 and Weeks 25-29 time periods.
An ANCOVA model, including terms for treatment group, pooled investigator,
randomization stratum and baseline severity (baseline FEV1 percent predicted), was used
to test statistical differences in treatment group means at Endpoint, for the overall 29-
week treatment period, and each 4-week (or 5-week) time period.

Probability of study withdrawal: The probability of study withdrawal was summarized


with Kaplan-Meier estimates and compared between treatment groups using a Cox
proportional hazards regression model with terms for baseline severity (baseline FEV1
percent predicted), pooled investigator, randomization stratum and treatment group in the
model.

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4.8.6. Safety Analyses

4.8.6.1. Adverse Events

Adverse events were coded using the Medical Dictionary for Regulatory Activities
(MedDRA) and were reported using the primary System Organ Class (SOC) and
preferred term.

Adverse event summaries reported the number (%) of subjects experiencing any adverse
event, the number (%) of subjects with an adverse event by SOC, and the number (%) of
subjects with an adverse event by preferred term within each SOC.

Separate summaries of adverse events occurring during the study were reported by
treatment group for the ITT population. Summaries were generated for adverse events
occurring during treatment (during the double-blind treatment period) and post-treatment
(post treatment stop date and/or during the 2-week follow-up period).

4.8.7. Other Safety Measures

Other safety measures included vital sign measurements of blood pressure and heart rate
collected at Randomization (Visit 2), Weeks 3, 16 and 29 (Visits 3-5, respectively) and
Early Withdrawal. Vital sign measurements were summarized with descriptive statistics
by treatment group and visit.

4.8.8. Health Outcomes Analyses

4.8.8.1. Humanistic Measures

CRQ-SAS: The CRQ-SAS was administered at Randomization (Visit 2) and at all


subsequent visits including the Early Withdrawal visit. Baseline was determined from
the Randomization (Visit 2) questionnaire and Endpoint was determined from the last
questionnaire collected during the treatment period or at the Early Withdrawal visit. The
primary analysis was mean change from baseline scores compared between treatment
groups at Endpoint. CRQ-SAS domain scores and change from baseline values were
summarized with descriptive statistics at Endpoint and each visit for which the CRQ-SAS
was administered. An ANCOVA model, including terms for treatment group, pooled
investigator, randomization stratum and baseline, was used to test statistical differences
in treatment group mean changes from baseline at Endpoint and each visit.

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EXACT: The EXACT Total score and 3 respiratory symptom domain scores
(Breathlessness, Cough and Sputum, and Chest Symptoms) were each scored on a 0–100
scale with higher scores indicating a more severe COPD state. The primary analysis
compared mean total and domain scores between treatment groups at Endpoint. Mean
total and domain scores were summarized with descriptive statistics by treatment group at
Endpoint, for the overall 29-week treatment period, and for each of the Weeks 1-4, 5-8,
9-12, 13-16, 17-20, 21-24 and 25-29 time periods. An ANCOVA model, including terms
for treatment group, pooled investigator, randomization stratum and baseline severity
(baseline FEV1 percent predicted), was used to test statistical differences in treatment
group means at Endpoint, for the overall 29-week treatment period, and each 4- (or 5-)
week time period.

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5. STUDY POPULATION RESULTS

5.1. Disposition of Study Subjects


A total of 734 patients, each with a clinical diagnosis of COPD, were screened in
Argentina, Norway and the United States, of whom 639 patients met the clinical study
protocol- defined eligibility criteria for randomization to either of the two study drugs.
There were 314 patients randomized to receive FSC 250/50 and 325 patients to SAL 50.
A total of 81 study centers participated in the study, including 23 in Argentina (240
subjects, 38%), four in Norway (13 subjects, 2%) and 54 in the United States (386
subjects, 60%), with enrolment per center ranging from a minimum of 1 (<1%) to a
maximum of 34 (5%) subjects. There were 23 centers with at least 10 subjects enrolled.
A consort diagram of the summary of the disposition of study subjects, including
screening failures, number of patients withdrawn and number randomized to study
treatment, is presented in Figure 2.

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Figure 2 Summary Diagram of the Disposition of Study Subjects

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5.1.1. Screen Failures

The screen failure population is comprised of all subjects screened for study eligibility
but not randomized to study treatment. Adverse Events and reasons for study withdrawal
were summarized for this population. Ninety five (13%) patients within the Safety
Population failed screening, 79 (83%) of whom did not meet the study protocol-defined
inclusion/exclusion criteria. The other screen failures, involved 6 (6%) patients who
withdrew consent, 6 (6%) withdrawn at the Investigators’ discretions, 2 (2%) protocol
deviations and 2 (2%) patients lost to follow-up. A summary of the screen failures
related to inclusion/exclusion criteria is provided in Table 4.

Table 4 Summary of Inclusion/Exclusion Criteria Not Met (Screen Failure


Population)

Criterion Not Met Patients Not Randomized


(N=95)
Any Inclusion/Exclusion Criterion Deviations 79 (83%)
Inclusion Criteria
Male or non-pregnant female >=40 years of age 2 (2%)
Smoking History 3 (3%)
Exacerbation History 7 (7%)
Clinical Diagnosis of COPD 4 (4%)
Documented FEV1 % predicted <70% & FEV1/FVC<=0.7 52 (55%)
Informed Consent 4 (4%)
Language Comprehension 2 (2%)
Exclusion Criteria
Diagnosis of Complicating Co-morbid Condition 10 (11%)
Clinically significant uncontrolled disease 7 (7%)
Clinically significant abnormal 12-lead ECG 1 (1%)
Clinically significant abnormal chest x-ray or CT 1 (1%)
Limiting factor for scheduled visit compliance 4 (4%)
Limited ability to provide valid informed consent 1 (1%)
Data source: Table 5.2.

5.1.2. Post-Randomization Withdrawals

A total of 412 (64%) subjects completed the study, from the 639 patients (Intent-to-Treat
population) randomized to study treatments, with 227 (36%) withdrawn prematurely
from the study. Post-randomization, 106 (34%) and 121 (37%) subjects receiving
treatment with FSC250/50 and SAL 50, respectively, were withdrawn from the study. A
summary of the reasons for subjects’ premature withdrawal from the study, as determined
by the investigators, classed by treatment group, is presented in Table 5, a listing is
provided in Table 5.18.

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Table 5 Summary of Reasons of Subjects’ Premature Withdrawals –Intent –


to-Treat Population

Reasons of Subjects’ Premature FSC250/50 SAL50 Total


Withdrawals –Intent –to-Treat Population (N=314) (N=325) (N=639)
Completion Status
Completed 208 (66%) 204 (63%) 412 (64%)
Withdrawn 106 (34%) 121 (37%) 227 (36%)
Primary/sub-reason for withdrawal
Adverse event 28 (9%) 28 (9%) 56 (9%)
Lack of efficacy 16 (5%) 25 (8%) 41 (6%)
Adverse event 0 3 (<1%) 3 (<1%)
Protocol deviation 14 (4%) 12 (4%) 26 (4%)
Adverse event 0 1 (<1%) 1 (<1%)
Lost to follow-up 10 (3%) 7 (2%) 17 (3%)
Investigator discretion 13 (4%) 17 (5%) 30 (5%)
Adverse event 0 1 (<1%) 1 (<1%)
Withdrew consent 25 (8%) 32 (10%) 57 (9%)
Adverse event 1 (<1%) 0 1 (<1%)
Note: Subjects may have only one primary reason for withdrawal. A sub-reason of Adverse event is reported for
subjects reporting an adverse event leading to withdrawal with the primary reason for withdrawal.
Data Source: Table 5.4.

5.2. Protocol Deviations


There were 44 (7%) subjects within the Intent-to-Treat population with protocol
deviations recorded, including 18 (6%) and 26 (8%) in study subjects randomized to FSC
250/50 and SAL 50, respectively. These deviations were related to study eligibility
criteria and the use of prohibited medication. The summary of the protocol deviation is
presented in Table 4, and a listing of protocol deviations is provided in Table 5.20.

Table 6 Summary of Protocol Deviations

Protocol Deviations FSC 250/50 SAL 50 Total


(N=314) (N=325) (N=639)
Any Protocol Deviation 18 (6%) 26 (8%) 44 (7%)
Inclusion Criteria Violation 7 (2%) 3 (<1%) 10 (2%)
Male or non-pregnant female >=40 years of age 1 (<1%) 0 1 (<1%)
Exacerbation history 2 (<1%) 2 (<1%) 4 (<1%)
Documented FEV1 % predicted <70% & FEV1/FVC<=0.7 4 (1%) 1 (<1%) 5 (<1%)
Exclusion Criteria Violation 3 (<1%) 4 (1%) 7 (1%)
Diagnosis of complicating co-morbid condition 2 (<1%) 1 (<1%) 3 (<1%)
Clinically significant uncontrolled disease 1 (<1%) 1 (<1%) 2 (<1%)
Limited ability to provide valid informed consent 0 2 (<1%) 2 (<1%)
Use of Prohibited Medication 8 (3%) 20 (6%) 28 (4%)
Note: Subjects may have had more than one protocol deviation.
Data Source: Table 5.5; Table 5.6.

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5.3. Populations Analyzed


The ITT population, comprising of 639 subjects, was used for all outcome analyses,
including, demographic/baseline, efficacy, safety, and health outcomes assessments.
There were 314 and 325 subjects, randomized to the FSC 250/50 and SAL50 treatment
groups, respectively. The efficacy and health outcomes data were generated from a total
of 639 subjects. The safety analyses data pertaining to AEs from the ITT population
reported by the investigators were categorized by the randomization, the double-blind
treatment, and the post-treatment periods. Other AEs analyzed and reported pertained to
the screen failure population, the subjects not randomized to double-blind study drug and
not included in the ITT population.

5.4. Demographics and Baseline Characteristics

5.4.1. Demographic Characteristics

The demographic characteristics of the ITT population are provided in Table 5.7., Table
5.8., and Table 5.9.; a compilation summary is presented in Table 7. The study treatment
groups were comparable demographically. The majority of the study subjects were of
White race (91%), and a proportionate representation of females (46%).

Table 7 Demographic Characteristics

Demographic Characteristics FSC 250/50 Sal 50 Total


(N=314) (N=325) (N=639)
Mean 63.1 62.7 62.9
Age Median 63.0 62.0 63.0
(Range) (40- 84) (40-84) (40-84)
Sex Female: n (%) 140 (45%) 151 (46%) 291 (46%)
African American/African Heritage 26 (8%) 22 (7%) 48 (8%)
American Indian or Alaska Native 1 (<1%) 2 (<1%) 3 (<1%)
- Central/South Asian Heritage 0 0 0
Asian - Japanese/East Asian Heritage 0 1 (<1%) 1 (<1%)
Race - South East Asian Heritage 0 0 0
Native Hawaiian or Other Pacific Islander 1 (<1%) 0 1 (<1%)
White 284 (90%) 300 (92%) 584 (91%)
African American/African Heritage & American 1 (<1%) 0 1 (<1%)
Indian or Alaskan Native
American Indian or Alaskan Native & White 1 (<1%) 0 1 (<1%)
Data source Table 5.7, Table 5.8, Table 5.9.

5.4.2. COPD Characteristics, Smoking History and Therapy

Baseline patient data pertaining to COPD characteristics and cigarette smoking history
are presented in Table 8. Also presented are data relating to stratification to double-blind
study treatment based on background tiotropium therapy and previous use of ICS. These
baseline data are comparable between the two treatments, FSC 250/50 and SAL 50.

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Table 8 Summary of COPD Characteristics

FSC 250/50 Sal 50 Total


(N=314) (N=325) (N=639)
Duration of COPD (Yrs) Mean (SD) 7.0 (5.66) 6.6 (5.22) 6.8 (5.44)
Chronic Bronchitis 114 (36%) 129 (40%) 243 (38%)
COPD Type (n, %) Emphysema 121 (39%) 119 (37%) 240 (38%)
Both 79 (25%) 77 (24%) 156 (24%)
Exacerbations Requiring 0 1 (<1%) 2 (<1%) 3 (<1%)
Hospitalization in the last 1 229 (73%) 238 (73%) 467 (73%)
12 Months (n; %) 2 84 (27%) 85 (26%) 169 (26%)
Exacerbations Requiring 0 107 (34%) 109 (34%) 216 (34%)
OCS/Antibiotics in the last 1 83 (26%) 92 (28%) 175 (27%)
12 Months (n; %) 2 72 (23%) 69 (21%) 141 (22%)
2 52 (17%) 55 (17%) 107 (17%)
Smoking History (n, %) Current Smoker 136 (43%) 155 (48%) 291 (46%)
Former Smoker 178 (57%) 170 (52%) 348 (54%)
Number of Pack-years Mean (SD) 52.0 (29.96) 56.3 (33.42) 54.2 (31.81)
Body Mass Index Mean (SD) 28.0 (6.85) 28.3 (6.95) 28.2 (6.90)
Concurrent Tiotropium Use and
103 (33%) 103 (32%) 206 (32%)
Previous Use of ICS
Concurrent Tiotropium Use and
18 (6%) 22 (7%) 40 (6%)
COPD Therapy No Previous Use of ICS
Randomization Stratum (n. No Concurrent Tiotropium Use
%) 139 (44%) 144 (44%) 283 (44%)
and Previous Use of ICS
No Concurrent Tiotropium Use
54 (17%) 56 (17%) 110 (17%)
and No Previous Use of ICS
Data Source: Table 5.10.

5.4.3. Baseline Pulmonary Function

In the ITT population, data pertaining to pulmonary function tests recorded at baseline
are summarized in Table 9, and provided in Table 5.11. The mean baseline pre-
bronchodilator FEV1 values expressed as a percentage of predicted normal were 38.5 and
41.2% of predicted, for the FSC 250/50 and SAL 50 groups, respectively. The values
reflect a population of COPD patients with moderate to severe airway obstruction.
Comparatively, the two treatment groups had high proportions of subjects who were non-
reversible, 74% and 76%, respectively for the FSC 250/50 and SAL 50 treatment groups.

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Table 9 Summary of Baseline Pulmonary Function Tests

Baseline Pulmonary Function Test FSC 250/50 Sal 50 Total


(N=314) (N=325) (N=639)
n 313 325 638
FEV1 (L)
Mean (SD) 1.08 (0.476) 1.14 (0.467) 1.11 (0.472)
n 313 325 638
FEV1 % of Predicted
Mean (SD) 38.5 (14.82) 41.2 (16.85) 39.9 (15.93)
n 312 324 636
Post-BD FEV1 (L)
Mean (SD) 1.22 (0.522) 1.25 (0.493) 1.24 (0.508)
n 312 324 636
Post-BD FEV1 % of Predicted
Mean (SD) 43.2 (16.06) 44.8 (16.25) 44.0 (16.16)
n 312 324 636
Post-BD FVC (L)
Mean (SD) 2.44 (0.826) 2.49 (0.753) 2.47 (0.790)
n 312 324 636
Post-BD FEV1/FVC
Mean (SD) 0.49 (0.127) 0.50 (0.124) 0.50 (0.126)
n 312 324 636
FEV1 % Reversibility
Mean (SD) 15.1 (23.79) 12.1 (16.69) 13.6 (20.52)
n 312 324 636
Reversibility Non-reversible 232 (74%) 245 (76%) 477 (75%)
Reversible 80 (26%) 79 (24%) 159 (25%)
Data Source: Table 5.11.
Reversibility testing was performed following subjects self-administration of 4 puffs (360mcg) of albuterol.

5.5. Current Medical Conditions


A high proportion of study subjects in both treatment groups (94% in the FCS 250/50
group and 92% of the SAL 50 group) of the ITT population had COPD co-morbidities.
More than half (61%) of the subjects had diagnoses of cardiovascular disorders. A
summary of these medical conditions reported by the investigators is presented in
Table 10, and a list is provided in Table 5.12.

Table 10 Summary of Medical Conditions

FSC 250/50 SAL 50 TOTAL


Medical condition classification (N=314) (N=325) (N=639)
n (%) n (%) n (%)
Any condition 295 (94%) 298 (92%) 593 (93%)
Cardiovascular disorders 190 (61%) 198 (61%) 388 (61%)
Musculoskeletal and connective tissue disorders 151 (48%) 152 (47%) 303 (47%)
Gastrointestinal disorders 140 (45%) 151 (46%) 291 (46%)
Respiratory, thoracic and mediastinal disorders 129 (41%) 148 (46%) 277 (43%)
Psychiatric disorders 125 (40%) 126 (39%) 251 (39%)
Cardiac disorders 113 (36%) 117 (36%) 230 (36%)
Endocrine disorders 81 (26%) 100 (31%) 181 (28%)
Eye disorders 78 (25%) 87 (27%) 165 (26%)
Nervous system disorders 74 (24%) 74 (23%) 148 (23%)
Metabolism and nutrition disorders 69 (22%) 66 (20%) 135 (21%)
Investigations 73 (23%) 59 (18%) 132 (21%)
Vascular disorders 54 (17%) 65 (20%) 119 (19%)

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FSC 250/50 SAL 50 TOTAL


Medical condition classification (N=314) (N=325) (N=639)
n (%) n (%) n (%)
Renal and urinary disorders 61 (19%) 54 (17%) 115 (18%)
General disorders and administration site conditions 54 (17%) 60 (18%) 114 (18%)
Reproductive system and breast disorders 64 (20%) 49 (15%) 113 (18%)
Blood and lymphatic system disorders 39 (12%) 49 (15%) 88 (14%)
Skin and subcutaneous tissue disorders 41 (13%) 40 (12%) 81 (13%)
Ear and labyrinth disorders 34 (11%) 23 (7%) 57 (9%)
Neoplasms benign, malignant and unspecified 21 (7%) 19 (6%) 40 (6%)
(including cysts and polyps)
Hepatobiliary disorders 19 (6%) 17 (5%) 36 (6%)
Immune system disorders 16 (5%) 20 (6%) 36 (6%)
Infections and infestations 13 (4%) 21 (6%) 34 (5%)
Congenital, familial and genetic disorders 3 (<1%) 2 (<1%) 5 (<1%)
Injury, poisoning and procedural complications 2 (<1%) 2 (<1%) 4 (<1%)
Data source: Table 5.12.

5.6. Prior and Concomitant Medications

5.6.1. Previous COPD Medications

Nearly all (>99%) the subjects in the ITT population had previous use of COPD
medications. The list of all medications for the treatment of COPD, used prior to study
entry, tabulated by organ system class is provided in Table 5.13. A summary of the
COPD medications used by 10% of the study subjects in either treatment group, prior to
study entry is presented in Table 11.

Table 11 Summary of Previous COPD Medications Used by 10% of Study


Subjects in either Treatment Group – ITT Population

FSC 250/50 SAL 50


Medication Ingredient (N=314) (N=325)
n (%) n (%)
Any medication 310 (99%) 324 (>99%)
RESPIRATORY SYSTEM
Any medication 305 (97%) 322 (>99%)
SALBUTAMOL 216 (69%) 232 (71%)
SALMETEROL XINAFOATE+FLUTICASONE PROPIONATE 128 (41%) 140 (43%)
TIOTROPIUM BROMIDE 101 (32%) 111 (34%)
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE 90 (29%) 107 (33%)
OXYGEN 92 (29%) 86 (26%)
IPRATROPIUM BROMIDE 82 (26%) 73 (22%)
BUDESONIDE+FORMOTEROL FUMARATE 62 (20%) 43 (13%)
SALBUTAMOL SULFATE 36 (11%) 32 (10%)
GUAIFENESIN 24 (8%) 36 (11%)
BUDESONIDE 21 (7%) 31 (10%)

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FSC 250/50 SAL 50


Medication Ingredient (N=314) (N=325)
n (%) n (%)
SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND
INSULINS
Any medication 276 (88%) 287 (88%)
PREDNISONE 184 (59%) 195 (60%)
METHYLPREDNISOLONE SODIUM SUCCINATE 81 (26%) 82 (25%)
METHYLPREDNISOLONE 32 (10%) 38 (12%)
MEPREDNISONE 32 (10%) 33 (10%)
HYDROCORTISONE 31 (10%) 26 (8%)
BUDESONIDE 21 (7%) 31 (10%)
ANTIINFECTIVES FOR SYSTEMIC USE
Any medication 250 (80%) 257 (79%)
INFLUENZA VACCINE 72 (23%) 76 (23%)
LEVOFLOXACIN 69 (22%) 78 (24%)
MOXIFLOXACIN 43 (14%) 49 (15%)
AZITHROMYCIN 41 (13%) 49 (15%)
PNEUMOCOCCAL VACCINE 46 (15%) 36 (11%)
CEFTRIAXONE 35 (11%) 43 (13%)
ALIMENTARY TRACT AND METABOLISM
Any medication 240 (76%) 249 (77%)
PREDNISONE 184 (59%) 195 (60%)
HYDROCORTISONE 31 (10%) 26 (8%)
BUDESONIDE 21 (7%) 31 (10%)
DERMATOLOGICALS
Any medication 194 (62%) 202 (62%)
METHYLPREDNISOLONE SODIUM SUCCINATE 81 (26%) 82 (25%)
METHYLPREDNISOLONE 32 (10%) 38 (12%)
HYDROCORTISONE 31 (10%) 26 (8%)
BUDESONIDE 21 (7%) 31 (10%)
SENSORY ORGANS
Any medication 187 (60%) 187 (58%)
METHYLPREDNISOLONE SODIUM SUCCINATE 81 (26%) 82 (25%)
METHYLPREDNISOLONE 32 (10%) 38 (12%)
HYDROCORTISONE 31 (10%) 26 (8%)
VARIOUS
Any medication 103 (33%) 101 (31%)
OXYGEN 92 (29%) 86 (26%)
CARDIOVASCULAR SYSTEM
Any medication 73 (23%) 66 (20%)
HYDROCORTISONE 31 (10%) 26 (8%)
Data source: Table 5.13.

5.6.2. COPD Concomitant Medications

In the ITT population, 45% (n=141) and 52% (n=169) of the study subjects in the FSC
250/50 and SAL 50 groups, respectively used at least one medication for COPD
concomitantly. A summary of the COPD concomitant medications used by 2% of the

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study subjects in either treatment group is presented in Table 12. A complete list of all
the COPD concomitant medications used during the study is provided in Table 5.14.

Table 12 Summary of COPD Concomitant Medications Used by 2% of Study


Subjects in either Treatment Group – ITT Population

FSC250/50 SAL 50
Medication Ingredient (N=314) (N=325)
n (%) n (%)
Any medication 141 (45%) 169 (52%)
SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND
INSULINS
Any medication 112 (36%) 140 (43%)
PREDNISONE 82 (26%) 87 (27%)
METHYLPREDNISOLONE SODIUM SUCCINATE 33 (11%) 27 (8%)
METHYLPREDNISOLONE 16 (5%) 30 (9%)
MEPREDNISONE 10 (3%) 18 (6%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)
ANTIINFECTIVES FOR SYSTEMIC USE
Any medication 105 (33%) 126 (39%)
LEVOFLOXACIN 25 (8%) 40 (12%)
AZITHROMYCIN 29 (9%) 34 (10%)
MOXIFLOXACIN 22 (7%) 28 (9%)
DOXYCYCLINE 13 (4%) 17 (5%)
CEFTRIAXONE 11 (4%) 14 (4%)
AMOXICILLIN 5 (2%) 12 (4%)
AMOXICILLIN+CLAVULANIC ACID 9 (3%) 5 (2%)
CIPROFLOXACIN HYDROCHLORIDE 7 (2%) 7 (2%)
AMOXICILLIN TRIHYDRATE+CLAVULANATE POTASSIUM 5 (2%) 7 (2%)
AMPICILLIN+SULBACTAM 4 (1%) 8 (2%)
CLARITHROMYCIN 6 (2%) 3 (<1%)
INFLUENZA VACCINE 1 (<1%) 7 (2%)
SULFAMETHOXAZOLE+TRIMETHOPRIM 3 (<1%) 5 (2%)
CIPROFLOXACIN 5 (2%) 2 (<1%)
PIPERACILLIN SODIUM+TAZOBACTAM SODIUM 5 (2%) 2 (<1%)
ALIMENTARY TRACT AND METABOLISM
Any medication 99 (32%) 120 (37%)
PREDNISONE 82 (26%) 87 (27%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)

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FSC250/50 SAL 50
Medication Ingredient (N=314) (N=325)
n (%) n (%)
RESPIRATORY SYSTEM
Any medication 86 (27%) 119 (37%)
SALBUTAMOL 35 (11%) 50 (15%)
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE 23 (7%) 17 (5%)
IPRATROPIUM BROMIDE 14 (4%) 21 (6%)
OXYGEN 15 (5%) 18 (6%)
SALMETEROL XINAFOATE+FLUTICASONE PROPIONATE 10 (3%) 13 (4%)
IPRATROPIUM 8 (3%) 9 (3%)
DEXAMETHASONE 5 (2%) 11 (3%)
GUAIFENESIN 8 (3%) 8 (2%)
LEVOSALBUTAMOL HYDROCHLORIDE 5 (2%) 7 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
ACETYLCYSTEINE 6 (2%) 4 (1%)
THEOPHYLLINE 5 (2%) 4 (1%)
TIOTROPIUM BROMIDE 5 (2%) 4 (1%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)
SENSORY ORGANS
Any medication 68 (22%) 82 (25%)
METHYLPREDNISOLONE SODIUM SUCCINATE 33 (11%) 27 (8%)
METHYLPREDNISOLONE 16 (5%) 30 (9%)
DEXAMETHASONE 5 (2%) 11 (3%)
CIPROFLOXACIN HYDROCHLORIDE 7 (2%) 7 (2%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
ACETYLCYSTEINE 6 (2%) 4 (1%)
CIPROFLOXACIN 5 (2%) 2 (<1%)
DERMATOLOGICALS
Any medication 63 (20%) 86 (26%)
METHYLPREDNISOLONE SODIUM SUCCINATE 33 (11%) 27 (8%)
METHYLPREDNISOLONE 16 (5%) 30 (9%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)
CARDIOVASCULAR SYSTEM
Any medication 19 (6%) 36 (11%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
BETAMETHASONE 1 (<1%) 6 (2%)
VARIOUS
Any medication 20 (6%) 21 (6%)
OXYGEN 15 (5%) 18 (6%)
ACETYLCYSTEINE 6 (2%) 4 (1%)
Data source: Table 5.14.

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5.6.3. Non-COPD Concomitant Medications Used by 5% of Study


Subjects in either Treatment Group – ITT Population

The majority of the study subjects were taking non-COPD medications concomitantly.
These included 88% (n=276) and 90% (n=292) of all patients randomized to FSC 250/50
and SAL 50, respectively. A summary of these medications used by 5% of study
subjects in either treatment group within the ITT Population is presented in Table 13, and
a complete list is provided in Table 5.15.

Table 13 Summary of Non-COPD Concomitant Medications Used by 5% of


Study Subjects in either Treatment Group – ITT Population

FSC250/50 SAL 50
Medication Ingredient (N=314) (N=325)
n (%) n (%)
Any medication 276 (88%) 292 (90%)
CARDIOVASCULAR SYSTEM
Any medication 217 (69%) 229 (70%)
SIMVASTATIN 43 (14%) 58 (18%)
FUROSEMIDE 41 (13%) 58 (18%)
LISINOPRIL 46 (15%) 52 (16%)
ENALAPRIL 28 (9%) 42 (13%)
HYDROCHLOROTHIAZIDE 28 (9%) 23 (7%)
GLYCERYL TRINITRATE 14 (4%) 19 (6%)
AMLODIPINE 14 (4%) 17 (5%)
AMLODIPINE BESILATE 16 (5%) 13 (4%)
DILTIAZEM 14 (4%) 15 (5%)
METOPROLOL 17 (5%) 12 (4%)
ATORVASTATIN CALCIUM 11 (4%) 15 (5%)
CARVEDILOL 9 (3%) 16 (5%)
ALIMENTARY TRACT AND METABOLISM
Any medication 209 (67%) 225 (69%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
OMEPRAZOLE 51 (16%) 53 (16%)
VITAMINS NOS 30 (10%) 25 (8%)
METFORMIN 27 (9%) 27 (8%)
PANTOPRAZOLE 17 (5%) 22 (7%)
POTASSIUM CHLORIDE 17 (5%) 19 (6%)
VITAMIN D NOS 20 (6%) 12 (4%)
RANITIDINE 14 (4%) 17 (5%)
RANITIDINE HYDROCHLORIDE 13 (4%) 17 (5%)
DOCUSATE SODIUM 15 (5%) 14 (4%)
ESOMEPRAZOLE MAGNESIUM 17 (5%) 11 (3%)
SODIUM CHLORIDE 15 (5%) 10 (3%)

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FSC250/50 SAL 50
Medication Ingredient (N=314) (N=325)
n (%) n (%)
NERVOUS SYSTEM
Any medication 204 (65%) 229 (70%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
PARACETAMOL 41 (13%) 50 (15%)
ALPRAZOLAM 38 (12%) 35 (11%)
PARACETAMOL+HYDROCODONE BITARTRATE 37 (12%) 35 (11%)
IBUPROFEN 30 (10%) 34 (10%)
LORAZEPAM 27 (9%) 24 (7%)
CLONAZEPAM 22 (7%) 22 (7%)
NICOTINE 16 (5%) 26 (8%)
GABAPENTIN 17 (5%) 16 (5%)
PARACETAMOL+OXYCODONE HYDROCHLORIDE 12 (4%) 16 (5%)
MUSCULO-SKELETAL SYSTEM
Any medication 142 (45%) 164 (50%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
IBUPROFEN 30 (10%) 34 (10%)
DICLOFENAC 8 (3%) 15 (5%)
BLOOD AND BLOOD FORMING ORGANS
Any medication 143 (46%) 152 (47%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
POTASSIUM CHLORIDE 17 (5%) 19 (6%)
ENOXAPARIN SODIUM 14 (4%) 15 (5%)
CLOPIDOGREL BISULFATE 9 (3%) 19 (6%)
SODIUM CHLORIDE 15 (5%) 10 (3%)
RESPIRATORY SYSTEM
Any medication 107 (34%) 106 (33%)
LORATADINE 15 (5%) 16 (5%)
SODIUM CHLORIDE 15 (5%) 10 (3%)
DERMATOLOGICALS
Any medication 93 (30%) 90 (28%)
GLYCERYL TRINITRATE 14 (4%) 19 (6%)
GENITO URINARY SYSTEM AND SEX HORMONES
Any medication 99 (32%) 81 (25%)
IBUPROFEN 30 (10%) 34 (10%)
SENSORY ORGANS
Any medication 84 (27%) 78 (24%)
SODIUM CHLORIDE 15 (5%) 10 (3%)
DICLOFENAC 8 (3%) 15 (5%)
ANTIINFECTIVES FOR SYSTEMIC USE
Any medication 71 (23%) 73 (22%)
INFLUENZA VACCINE 14 (4%) 16 (5%)
SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND
INSULINS
Any medication 48 (15%) 54 (17%)
LEVOTHYROXINE SODIUM 16 (5%) 22 (7%)
Data Source: Table 5.15.

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5.7. Exposure and Treatment Compliance

5.7.1. Exposure to Study Drug

The exposure to study drug was comparable within the two treatment group. The mean
exposure values are 152.2 days and 145.4 days for the FSC 250/50 and SAL 50 treatment
groups, respectively. A summary of the data pertaining to study subjects’ exposure to
study medication is presented in Table 14; and provided in Table 5.16.

Table 14 Summary of Exposure to Study Drug

Exposure to study drug (days) - Double-blind DISKUS FSC 250/50 SAL 50


(N=314) (N=325)
n 302 317
Mean 152.2 145.4
SD 70.16 73.29
Median 190.0 189.0
Data source: Table 5.16.

5.7.2. Treatment Compliance

Treatment compliance data pertaining to study subjects’ use of the blinded study
medication in the DISKUS devices formulation are similar across the two treatment
groups. Data on treatment compliance are presented in Table 15, and provided in Table
5.17. Compliance was similar with mean values of 91.9% and 92.4% for the FSC 250/50
and SAL 50 treatment groups, respectively.

Table 15 Summary of Treatment Compliance

Double-blind DISKUS compliance (%) FSC 250/50 SAL 50


(N=314) (N=325)
n 263 286
Mean 91.9 92.4
SD 16.21 21.30
Median 95.7 95.5
Data Source: Table 5.17.

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6. EFFICACY RESULTS

6.1. Primary Efficacy Results


The primary endpoint was the rate of exacerbation requiring hospitalization that occurs
more than 21 days post-discharge or physician’s office visit for an exacerbation of COPD
requiring treatment with OCS or OCS and antibiotics.

Fifty exacerbations were reported from 43 (14%) study subjects from the FSC 250/50
treatment group and 51 exacerbations from 39 (12%) subjects in the SAL 50 group,
resulting in mean annual rates of exacerbations of 0.44 and 0.48, respectively. The
primary causes of the highest number of exacerbations requiring OCS, antibiotics and/or
hospitalization for FSC 250/50 and SAL 50 were unknown etiology (35 and 45,
respectively), upper respiratory tract infection (24 and 26, respectively), lower respiratory
tract infection (18 and 22, respectively), tobacco smoke (13 in each group), cold air/cold
weather (13 and 14, respectively), and upper respiratory tract infection other than
common cold (10 and 14, respectively).

The data on exacerbation requiring hospitalization are summarized in Table 16.

Table 16 Summary of COPD Exacerbations Requiring Hospitalization – ITT


Population

Summary of COPD Exacerbations Requiring Hospitalization – ITT FSC 250/50 SAL 50


Population (N=314) (N=325)
Number of Subjects with an Exacerbation Yes 43 (14%) 39 (12%)
Requiring Hospitalization No 271 (86%) 286 (88%)
0 271 (86%) 286 (88%)
Number of Subjects by Number of Exacerbations 1 36 (11%) 31 (10%)
Requiring Hospitalization 2 7 (2%) 5 (2%)
3 0 2 (<1%)
4 0 1 (<1%)
Number of exacerbations requiring hospitalization Yes 50 (32%) 51 (28%)
No 106 (68%) 131 (72%)
Data source: Table 6.1

The statistical analyses of the data on the COPD exacerbations requiring hospitalization
showed a mean annual exacerbation rate of 0.44 and 0.48, for the FSC 250/50 (N=314)
and SAL 50 (N=325) treatment groups, respectively. This was equivalent to a treatment
comparison ratio of 0.917 (p-value=0.710). A summary of the data on the FSC 250/50
and SAL 50 treatment comparison is presented in Table 17 and provided in Table 6.2.

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Table 17 Analysis of COPD Exacerbations Requiring Hospitalization

Analysis of COPD Exacerbations Requiring Hospitalization – ITT FSC250/50 SAL 50


Population (N=314) (N=325)
n 314 325
Mean annual exacerbation rate 0.44 0.48
Ratio 0.917
Treatment Comparison (FSC 95% CI (0.581, 1.447)
250/50 vs. SAL 50)
p-value 0.710
Data source: Table 6.2.
Exacerbation rates are annualized rate estimates

A complete tabulation of the exacerbation data is presented in Table 18, and also
provided in Table 6.1.

Table 18 Summary of COPD Exacerbations Requiring Hospitalization – ITT


Population

Summary of COPD Exacerbations Requiring Hospitalization – ITT FSC 250/50 SAL 50


Population (N=314) (N=325)
Number of Subjects with an 102 (32%) 115 (35%)
Exacerbation Requiring OCS,
Antibitocs and/or Hospitalization
Number of Exacerbations 156 182
Requiring OCS, Antibitocs and/or
Hospitalization
0 212 (68%) 210 (65%)
1 58 (18%) 75 (23%)
Number of Subjects by Number 2 35 (11%) 22 (7%)
of Exacerbations 3 8 (3%) 12 (4%)
4 1 (<1%) 4 (1%)
5 0 1 (<1%)
6 0 1 (<1%)
Number of Subjects with an
Yes 43 (14%) 39 (12%)
Exacerbation Requiring
Hospitalization No 271 (86%) 286 (88%)
0 271 (86%) 286 (88%)
Number of Subjects by Number 1 36 (11%) 31 (10%)
of Exacerbations 2 7 (2%) 5 (2%)
Requiring Hospitalization 3 0 2 (<1%)
4 0 1 (<1%)
Number of exacerbations Yes 50 (32%) 51 (28%)
requiring hospitalization No 106 (68%) 131 (72%)

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Summary of COPD Exacerbations Requiring Hospitalization – ITT FSC 250/50 SAL 50


Population (N=314) (N=325)
Cold air/Cold weather 13 (8%) 14 (8%)
Other NSAIDS 0 0
Withholding or reducing COPD meds. 3 (2%) 1 (<1%)
Unknown etiology 35 (22%) 45 (25%)
Lack of efficacy 1 (<1%) 5 (3%)
Lower respiratory infection 18 (12%) 22 (12%)
Common cold 4 (3%) 5 (3%)
Number of exacerbations by Upper respiratory infection other 10 (6%) 14 (8%)
primary cause than common cold
Tobacco smoke 13 (8%) 13 (7%)
Upper respiratory infection 24 (15%) 26 (14%)
Air pollution 4 (3%) 8 (4%)
Allergy 1 (<1%) 4 (2%)
Exercise 2 (1%) 0
Stress/Emotions 5 (3%) 5 (3%)
Beta-blockers 0 0
Aspirin 0 0
Other 23 (15%) 20 (11%)
Data source: Table 6.1

6.2. Secondary Efficacy Results


The secondary endpoint is the rate of COPD exacerbations requiring treatment with OCS,
antibiotics, and/or hospitalization (alone and in combination). There were 156 and 182
exacerbation of COPD reported in the FSC 250/50 and SAL 50 treatment groups,
respectively. The mean annual rates of COPD exacerbations requiring OCS, antibiotics
and/or hospitalization were 1.49 and 1.81 for the FSC 250/50 (N=314) and SAL 50
(N=325) treatment groups, respectively (P-value = 0.136). The exacerbations of COPD
as categorized in the FSC 250/50 and SAL 50 treatment groups included, respectively, 50
(32%) and 51 (28%) exacerbations requiring hospitalization, 140 (90%) and 167 (92%)
exacerbations treated with OCS, and 121 (78%) and 144 (79%) exacerbations treated
with antibiotics. A summary of the data on the COPD exacerbations requiring OCS,
antibiotics and/or hospitalization is presented in Table 19, and provided in Table 6.1.

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Table 19 Summary of COPD Exacerbations Requiring Oral Corticosteroids,


Antibiotics and/or Hospitalization – ITT Population

Summary of COPD Exacerbations Requiring Oral Corticosteroids, FSC 250/50 SAL 50


Antibiotics and/or Hospitalization – ITT Population (N=314) (N=325)
Number of Subjects with an Exacerbation 102 (32%) 115 (35%)
Number of Exacerbations 156 182
Number of exacerbations requiring hospitalization
Yes 50 (32%) 51 (28%)
No 106 (68%) 131 (72%)
Number of exacerbations treated with OCS
Yes 140 (90%) 167 (92%)
No 16 (10%) 15 (8%)
Number of exacerbations treated with antibiotics
Yes 121 (78%) 144 (79%)
No 35 (22%) 38 (21%)
Data Source: Table 6.1.

A summary of the statistical analysis of comparative data on the COPD exacerbations


requiring OCS, antibiotics and/or hospitalization is presented in Table 20, and provided
in Table 6.3.

Table 20 Analysis of COPD Exacerbations Requiring Oral Corticosteroids,


Antibiotics and/or Hospitalization – ITT Population

Analysis of COPD Exacerbations Requiring Oral Corticosteroids, FSC250/50 SAL


Antibiotics and/or Hospitalization – ITT Population (N=314) (N=325)
Mean annual exacerbation rate 1.49 1.81
Ratio 0.823
Treatment Comparison (FSC250/SAL50) 95% CI (0.637, 1.063)
p-value 0.136
Data Source: Table 6.3.
Exacerbation rates are annualized rate estimates

6.3. Related Efficacy Endpoints

6.3.1. Time to First Exacerbation of COPD Requiring Treatment with


Oral Corticosteroids, Antibiotics, and/or Hospitalization (alone
and in combination) – ITT Population

The time to onset of first exacerbation of COPD requiring treatment with OCS,
antibiotics, and/or hospitalization (alone and in combination) was predetermined as a
related endpoint of interest. A Kaplan-Meier graphical representation of the results is
presented in Figure 3. A summary of the data summarized with Kaplan-Meier estimates
is provided in Table 6.4. The data analyses indicate a treatment comparison (FSC 250/50
vs. SAL 50) hazard ratio of 0.830 (p-value = 0.174).

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Figure 3 Time to First COPD Exacerbation requiring OCS, Antibiotics and or


Hospitalization – ITT Population

6.3.2. Probability of premature withdrawal of subject from the study –


ITT Population

The data on the probability of subject withdrawal from the study, presented in Kaplan-
Meier graphical format is shown in Figure 4, and provided in Table 6.11. The treatment
comparison hazard ratio is 0.865 (p-value = 0.279).

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Figure 4 Time to Withdrawal from the Study

6.3.3. Pre-dose AM FEV1 - ITT Population

The summary of the pre-dose FEV1 data over the 29-week duration of the study is
presented in Table 21, and in graphical format in Figure 5; also, the data summary is
provided in Table 6.5. In treatment comparison, the pre-dose AM FEV1 LS mean
difference at Endpoint was 0.10 L (SE = 0.028). The mean FEV1 change from baseline
recorded at Endpoint was 0.14 L for the FSC 250/50 treatment group and 0.04 for the
SAL 50 treated group (95% CI: 0.04,0.16; p-value<0.001).

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Table 21 Summary of Pre-dose AM FEV1 – ITT Population

FSC 250/50 SAL 50 LS Mean Diff 95% CI


Pre-dose AM FEV1 (N=314) (N=325) Std Error p-value
n 313 325
Baseline FEV1 Mean 1.08 1.14
SE 0.027 0.026
n 281 271
FEV1 Mean 1.22 1.18
Endpoint SE 0.034 0.031 0.10 (0.04,0.16)
n 280 271 0.028 <0.001
FEV1 Change
from baseline Mean 0.14 0.04
SE 0.021 0.019
n 281 270
FEV1 Mean 1.19 1.17
Week 3 SE 0.032 0.032 0.08 (0.03,0.14)
n 280 270 0.028 0.004
FEV1 Change
from baseline Mean 0.11 0.02
SE 0.019 0.021
n 208 203
FEV1 Mean 1.23 1.19
Week 29 SE 0.041 0.034 0.12 (0.06,0.19)
n 207 203 0.033 <0.001
FEV1 Change
from baseline Mean 0.16 0.03
SE 0.026 0.021
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Diffs are calculated as FSC250/50 – SAL 50.
Data Source: Table 6.5.

Figure 5 Summary of Pre-Dose FEV1 (L) – ITT Population

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6.3.4. Supplemental Use of Albuterol – ITT Population

The data summary on the study subjects’ use of supplemental albuterol as rescue
medication are presented in graphical format in Figure 6, and provided in Table 6.6. The
mean daily use of albuterol from Week 1 to Week 29 was 5.8 puffs per day for the FSC
250/50 treatment group versus 6.1 puffs per day for the SAL 50 group (p-value = 0.522).
The equivalent measures on endpoint were 6.0 and 5.9 for FSC 250/50 and SAL 50,
respectively (p-value = 0.871). The data on daily albuterol use were collected using a
hand-held electronic device with transmission capability and were part of the patient
reported outcomes (PRO). These data had a variable subject completion rate throughout
the study as shown in Table 22, also provided in Table 6.6.

Table 22 Summary of Supplemental Albuterol Use (puffs/day)

Daily Albuterol Use FSC250/50 SAL 50 LS Mean Diff 95% CI


(N=314) (N=325) Std Error p-value
n 296 304 -0.2 (-1.0,0.5)
Weeks 1-29 Mean 5.8 6.1 0.38 0.522
SE 0.31 0.30
n 294 301 -0.0 (-0.9,0.9)
Weeks 1-4 Mean 6.3 6.3 0.44 0.999
SE 0.37 0.31
n 252 246 -0.2 (-1.1,0.7)
Weeks 5-8 Mean 5.9 5.9 0.45 0.666
SE 0.36 0.36
n 234 234 -0.2 (-1.1,0.6)
Weeks 9-12 Mean 5.7 5.6 0.44 0.575
SE 0.36 0.34
n 223 229 -0.0 (-0.9,0.9)
Weeks 13-16 Mean 5.6 5.2 0.46 0.989
SE 0.39 0.34
n 219 210 0.2 (-0.7,1.1)
Weeks 17-20 Mean 5.4 4.9 0.47 0.668
SE 0.39 0.34
n 215 199 0.2 (-0.7,1.0)
Weeks 21-24 Mean 5.3 4.8 0.44 0.736
SE 0.35 0.36
n 210 186 0.5 (-0.4,1.5)
Weeks 25-29 Mean 5.5 4.6 0.49 0.269
SE 0.42 0.33
n 294 302 0.1 (-0.8,0.9)
Endpoint Mean 6.0 5.9 0.42 0.871
SE 0.36 0.31
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline severity (baseline FEV1 percent predicted).
LS Mean Diffs are calculated as FSC250/50 - SAL50.
Albuterol use is summarized as puffs/day with nebule use converted to puffs as 1 nebule=2 puffs.
Data Source: Table 6.6.

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Figure 6 Summary of Supplemental Use of Albuterol – ITT Population

6.3.5. Change in Biomarkers of Systemic Inflammation – ITT Population

6.3.5.1. High Sensitivity C - reactive protein

The summary of the comparative data pertaining to high sensitivity CRP is provided in
Table 6.7. The summary of the data analysis of the hs-CRP is presented in Table 23, and
a complete summary is provided in Table 6.8.

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Table 23 Summary Analysis of High Sensitivity C Reactive Protein

Summary Analysis of High Sensitivity FSC250/50 SAL 50 LS Mean Diff 95% CI


C-Reactive Protein (N=314) (N=325) Std Error p-value
n 303 311
Baseline log hs-CRP Mean 1.41 1.37
SE 0.078 0.083
n 302 299
log hs-CRP Mean 1.42 1.46
Endpoint SE 0.072 0.074 -0.04 (-0.23,0.16)
Change from n 292 290 0.099 0.702
baseline Mean 0.04 0.09
SE 0.090 0.096
n 276 263
log hs-CRP Mean 1.51 1.63
Week 3 SE 0.076 0.080 -0.13 (-0.34,0.07)
Change from n 267 257 0.105 0.201
baseline Mean 0.15 0.25
SE 0.092 0.102
n 222 223
log hs-CRP Mean 1.36 1.41
Week 16 SE 0.083 0.083 -0.10 (-0.32,0.12)
Change from n 215 216 0.113 0.369
baseline Mean -0.07 0.11
SE 0.105 0.105
n 200 204
log hs-CRP Mean 1.32 1.43
Week 29 SE 0.084 0.087 -0.14 (-0.37,0.09)
Change from n 194 198 0.115 0.230
baseline Mean -0.14 0.10
SE 0.106 0.113
n 54 66
log hs-CRP Mean 1.61 1.43
Early Withdrawal SE 0.186 0.162 0.25 (-0.25,0.75)
Change from n 52 65 0.253 0.324
baseline Mean 0.22 0.10
SE 0.246 0.235
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 – SAL 50.
Data Source: Table 6.8.

6.3.5.2. Surfactant Protein D

The data on surfactant protein D pertaining to the treatment comparison between FSC
250/50 and SAL 50 are provided in Table 6.7. The analysis of the data is provided in
Table 6.9 and a summary is presented in Table 24.

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Table 24 Summary Analysis of Surfactant Protein D

Summary Analysis of Surfactant Protein D FSC250/50 SAL 50 LS Mean 95% CI


(N=314) (N=325) Diff p-value
Std Error
n 293 309
Baseline log SP-D Mean 4.60 4.64
SE 0.044 0.050
n 298 300
log SP-D Mean 4.93 5.00
Endpoint SE 0.040 0.042 -0.04 (-0.13,0.05)
Change from n 281 288 0.047 0.385
baseline Mean 0.34 0.37
SE 0.039 0.041
n 269 267
log SP-D Mean 4.71 4.80
Week 3 SE 0.045 0.048 -0.08 (-0.16,0.01)
Change n 257 257 0.041 0.070
from Mean 0.10 0.17
baseline SE 0.030 0.035
n 224 221
log SP-D Mean 4.85 5.02
Week 16 SE 0.047 0.048 -0.14 (-0.25,-0.04)
Change from n 211 212 0.054 0.008
baseline Mean 0.23 0.35
SE 0.048 0.046
n 205 204
log SP-D Mean 5.04 5.10
Week 29 SE 0.044 0.048 -0.03 (-0.13,0.08)
Change from n 191 195 0.054 0.634
baseline Mean 0.40 0.40
SE 0.048 0.052
n 54 68
log SP-D Mean 4.64 4.76
Early Withdrawal SE 0.105 0.094 -0.10 (-0.33,0.12)
Change from n 52 67 0.114 0.375
baseline Mean 0.22 0.32
SE 0.082 0.081
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 – SAL 50.
Data source: Table 6.9.

6.3.5.3. Clara Cell Secretory Protein 16

The comparative data pertaining to change in the biomarker Clara Cell 16 between FSC
250/50 and SAL 50 are provided in Table 6.7. The analysis of the data is provided in
Table 6.10 and a summary is presented in Table 25.

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Table 25 Analysis of Biomarker CC-16 (Clara Cell Secretory Protein-16)

Summary of Analysis of CC - 16 FSC250/50 SAL 50 LS Mean Diff 95% CI


(N=314) (N=325) Std Error p-value

n 310 320
Baseline log CC-16 Mean 1.66 1.66
SE 0.039 0.038
n 299 302
Endpoint log CC-16 Mean 1.59 1.58 0.00 (-0.07,0.08)
SE 0.042 0.043 0.040 0.907
Change n 296 300
from Mean -0.08 -0.08
baseline SE 0.030 0.029
n 273 266
log CC-16 Mean 1.69 1.65
Week 3 SE 0.040 0.042 0.04 (-0.01,0.09)
Change n 270 265 0.027 0.131
from Mean 0.04 -0.00
baseline SE 0.020 0.020
n 223 223
log CC-16 Mean 1.51 1.52
Week 16 SE 0.047 0.050 -0.01 (-0.10,0.07)
Change n 220 221 0.043 0.738
from Mean -0.15 -0.14
baseline SE 0.033 0.031
n 206 204
log CC-16 Mean 1.50 1.55
Week 29 SE 0.050 0.053 -0.02 (-0.12,0.08)
Change n 203 202 0.051 0.711
from Mean -0.13 -0.11
baseline SE 0.037 0.039
n 54 70
log CC-16 Mean 1.83 1.70
Early SE 0.096 0.078 0.05 (-0.11,0.21)
Withdrawal Change n 54 70 0.081 0.537
from Mean 0.01 -0.01
baseline SE 0.066 0.052
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 – SAL 50.
Data source: Table 6.10.

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6.4. Health Outcomes

6.4.1. CRQ-SAS Domain scores (Dyspnea, Fatigue, Emotional function,


Mastery) as measured by CRQ-SAS

6.4.1.1. Mastery Domain

The health outcomes’ results evaluating the Mastery component of the CRQ-SAS are
summarized in Table 26. The data from the study subjects’ scores are provided in Table
7.1.

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Table 26 Summary of CRG-SAS Mastery Domain – ITT Population

Mastery Domain Score FSC250/50 SAL 50 LS Mean Diff 95% CI


(N=314) (N=325) Std Error p-value
n 312 321
Baseline Domain score Mean 3.71 3.83
SE 0.079 0.081
n 286 291
Domain score Mean 4.65 4.66
Endpoint SE 0.090 0.089 0.04 (-0.18,0.26)
Change from n 286 291 0.113 0.718
baseline Mean 0.99 0.85
SE 0.094 0.093
n 255 252
Domain score Mean 4.51 4.59
Week 3 SE 0.091 0.093 -0.01 (-0.23,0.20)
Change from n 255 252 0.111 0.895
baseline Mean 0.86 0.82
SE 0.087 0.090
n 213 205
Domain score Mean 4.67 4.74
Week 16 SE 0.100 0.106 -0.01 (-0.27,0.24)
Change from n 213 205 0.130 0.931
baseline Mean 0.95 0.96
SE 0.105 0.111
n 197 190
Domain score Mean 4.84 5.02
Week 29 SE 0.104 0.103 -0.07 (-0.33,0.19)
Change from n 197 190 0.134 0.601
baseline Mean 1.17 1.19
SE 0.114 0.114
n 51 58
Domain score Mean 4.11 3.84
Early SE 0.238 0.191 0.30 (-0.26,0.87)
Withdrawal Change from n 51 58 0.285 0.291
baseline Mean 0.47 -0.05
SE 0.226 0.189
Data Source: Table 7.1.
Note: LS Mean Difference, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 - SAL.

6.4.1.2. Fatigue Domain

Data from the health outcomes that assessed the Fatigue component of the CRQ-SAS are
summarized in Table 27. The data from the study subjects’ scores are provided in Table
7.1.

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Table 27 Summary of CRQ-SAS Fatigue Domain – ITT Population

Fatigue Domain FSC250/50 SAL 50 LS Mean Diff 95% CI


(N=314) (N=325) Std Error p-value
n 312 321
Baseline Domain score Mean 3.23 3.21
SE 0.072 0.074
n 286 291
Domain score Mean 4.10 4.00
Endpoint SE 0.087 0.081 0.09 (-0.11,0.29)
n 286 291 0.100 0.371
Chg from baseline Mean 0.90 0.80
SE 0.088 0.076
n 255 252
Week 3 Domain score Mean 3.92 3.78
SE 0.081 0.082 0.12 (-0.07,0.30)
n 255 252 0.096 0.226
Chg from baseline Mean 0.73 0.64
SE 0.074 0.078
n 213 205
Domain score Mean 4.19 4.02
Week 16 SE 0.089 0.101 0.18 (-0.05,0.41)
n 213 205 0.117 0.131
Chg from baseline Mean 0.95 0.84
SE 0.094 0.097
n 197 190
Domain score Mean 4.26 4.27
Week 29 SE 0.102 0.098 0.07 (-0.17,0.30)
n 197 190 0.120 0.573
Chg from baseline Mean 1.05 1.03
SE 0.107 0.091
n 51 58
Early Domain score Mean 3.63 3.44
Withdrawal SE 0.234 0.171 0.10 (-0.42,0.63)
n 51 58 0.265 0.702
Chg from baseline Mean 0.36 0.20
SE 0.215 0.166
Data Source: Table 7.1.
Note: LS Mean Difference, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 - SAL.

6.4.1.3. Emotional Function Domain

Data from the Emotional Function domain score of the CRQ-SAS were analyzed and are
summarized in Table 28. The data from the study subjects’ scores are also provided in
Table 7.1.

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Table 28 Summary of CRQ-SAS Emotional Function Domain – ITT Population

FSC250/50 SAL LS Mean 95% CI


Emotional Function Domain (N=314) (N=325) Diff Std p-value
Error
n 312 321
Baseline Domain score Mean 3.73 3.81
SE 0.071 0.074
n 286 291
Domain score Mean 4.59 4.54
Endpoint SE 0.080 0.079 0.08 (-0.11,0.27)
Chg from n 286 291 0.096 0.430
baseline Mean 0.89 0.77
SE 0.083 0.078
n 255 252
Domain score Mean 4.47 4.39
Week 3 SE 0.082 0.085 0.09 (-0.09,0.27)
Chg from n 255 252 0.092 0.329
baseline Mean 0.79 0.69
SE 0.071 0.072
n 213 205
Domain score Mean 4.60 4.53
Week 16 SE 0.086 0.096 0.08 (-0.13,0.30)
Chg from n 213 205 0.110 0.457
baseline Mean 0.89 0.85
SE 0.090 0.090
n 197 190
Domain score Mean 4.75 4.78
Week 29 SE 0.093 0.094 0.06 (-0.16,0.29)
Chg from n 197 190 0.114 0.589
baseline Mean 1.07 1.02
SE 0.100 0.093
Domain score n 51 58
Mean 4.11 4.10
Early SE 0.212 0.173 0.10 (-0.42,0.61)
Withdrawal Chg from n 51 58 0.259 0.707
baseline Mean 0.28 0.08
SE 0.202 0.182
Data Source: Table 7.1.
Note: LS Mean Difference, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 - SAL.

6.4.1.1. Dyspnea Domain

Data from the Dyspnea domain scores of the CRQ-SAS were analyzed and are presented
in Table 29. The data summary from the study subjects’ scores is also provided in Table
7.1.

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Table 29 Summary of CRQ-SAS Dyspnea Domain – ITT Population

Dyspnea Domain FSC250/50 SAL 50 LS Mean 95% CI


(N=314) (N=325) Diff Std Error p-value
n 312 321
Baseline Domain score Mean 3.71 3.59
SE 0.082 0.082
n 285 291
Endpoint Domain score Mean 4.41 4.32
SE 0.090 0.092 0.04 (-0.18,0.25)
Chg from n 285 291 0.111 0.752
baseline Mean 0.73 0.74
SE 0.095 0.088
n 255 252
Domain score Mean 4.37 4.22
Week 3 SE 0.085 0.092 0.09 (-0.11,0.29)
Chg from n 255 252 0.101 0.374
baseline Mean 0.70 0.67
SE 0.080 0.084
n 212 205
Domain score Mean 4.63 4.45
Week 16 SE 0.092 0.112 0.21 (-0.04,0.47)
Chg from n 212 205 0.130 0.104
baseline Mean 0.96 0.78
SE 0.111 0.112
n 197 190
Domain score Mean 4.53 4.65
Week 29 SE 0.102 0.111 -0.05 (-0.31,0.21)
Chg from n 197 190 0.133 0.697
baseline Mean 0.89 0.92
SE 0.113 0.109
n 51 58
Domain score Mean 3.85 3.45
Early SE 0.260 0.201 0.02 (-0.58,0.63)
Withdrawal Chg from n 51 58 0.305 0.935
baseline Mean 0.12 0.13
SE 0.241 0.200
Data Source: Table 7.1.
Note: LS Mean Difference, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 - SAL.

6.4.2. Symptoms Assessment Using the EXAcerbations of Chronic


Pulmonary Disease Tool (EXACT).

Symptoms characteristic of COPD, including, congestion, cough, phlegm, mucus, chest


discomfort, shortness of breath and sleep disturbance, were evaluated within the ITT
population through the study using the EXACT. These symptoms were evaluated
progressively throughout the study at four-week intervals and tabulated in categories,
including, Breathlessness Score, Cough and Sputum Score, Chest Symptoms Score.
Further, the EXACT total score data were also tabulated.

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6.4.2.1. EXACT Total Score

Data collected from the EXACT total score were analyzed comparatively per treatment
group, FSC 250/50 vs. SAL 50. The results of the analysis are summarized and presented
in Table 30, and provided in Table 7.2.

Table 30 Summary of EXACT Total Score – ITT Population

EXACT Total Score FSC250/50 SAL 50 LS Mean 95% CI


(N=314) (N=325) Diff Std p-value
Error
n 296 304 -0.9 (-2.8,1.0)
Weeks 1-29 Mean 36.0 36.9 0.97 0.356
SE 0.76 0.75
n 294 301 -1.5 (-3.3,0.4)
Weeks 1-4 Mean 36.9 38.2 0.93 0.115
SE 0.70 0.72
n 252 246 -0.8 (-3.0,1.3)
Weeks 5-8 Mean 35.5 35.8 1.10 0.445
SE 0.82 0.82
n 234 234 -1.0 (-3.3,1.4)
Weeks 9-12 Mean 35.3 35.6 1.20 0.418
SE 0.90 0.86
n 223 229 0.2 (-2.3,2.7)
Weeks 13-16 Mean 35.2 34.0 1.26 0.879
SE 0.94 0.93
n 219 210 0.2 (-2.4,2.9)
Weeks 17-20 Mean 34.5 33.3 1.34 0.859
SE 0.98 1.03
n 215 199 1.0 (-1.7,3.7)
Weeks 21-24 Mean 34.4 32.5 1.38 0.471
SE 1.04 1.07
n 210 186 1.6 (-1.2,4.5)
Weeks 25-29 Mean 34.5 31.7 1.46 0.264
SE 1.06 1.12
n 294 302 -0.6 (-2.8,1.7)
Endpoint Mean 35.9 36.4 1.17 0.632
SE 0.91 0.89
Data Source: Table 7.2.
Note: LS Mean Difference, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value. LS Mean Differences are calculated as FSC250/50 - SAL.
The EXACT score is on a 0-100 scale with higher scores indicating a more severe state.

6.4.2.2. EXACT Breathlessness Score

Data summary on the treatment comparison, FSC 250/50 vs. SAL 50, corresponding to
the EXACT Breathlessness component of the EXACT were summarized and are
presented in Table 31, and are also provided in Table 7.3.

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Table 31 Summary of EXACT Breathlessness Score

Breathlessness score FSC250/50 SAL 50 LS Mean Diff 95% CI


(N=314) (N=325) Std Error p-value

n 296 304
Weeks 1-29 Mean 38.2 39.9 -1.9 (-4.6,0.7)
SE 1.04 1.07 1.34 0.149
n 294 301
Weeks 1-4 Mean 38.2 40.5 -2.5 (-5.1,0.1)
SE 0.98 1.08 1.32 0.055
n 252 246
Weeks 5-8 Mean 37.4 38.1 -1.6 (-4.6,1.4)
SE 1.16 1.21 1.54 0.300
n 234 234
Weeks 9-12 Mean 37.7 38.0 -1.5 (-4.7,1.8)
SE 1.22 1.27 1.65 0.375
n 223 229
Weeks 13-16 Mean 38.1 36.8 -0.3 (-3.6,3.1)
SE 1.29 1.31 1.71 0.876
n 219 210
Weeks 17-20 Mean 36.8 36.6 -1.3 (-4.8,2.3)
SE 1.33 1.44 1.82 0.493
n 215 199
Weeks 21-24 Mean 36.7 36.0 -0.9 (-4.6,2.8)
SE 1.40 1.50 1.88 0.639
n 210 186
Weeks 25-29 Mean 37.2 35.0 0.3 (-3.5,4.1)
SE 1.36 1.55 1.92 0.874
n 294 302
Endpoint Mean 38.7 40.3 -1.8 (-4.9,1.2)
SE 1.20 1.25 1.56 0.238
Data Source: Table 7.3.
LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country, randomization
stratum and baseline severity (baseline FEV1 percent predicted). LS Mean Diffs are calculated as FSC250/50 – SAL
50.
The EXACT score is on a 0-100 scale with higher scores indicating a more severe state.

6.4.2.3. EXACT Cough and Sputum Score

The results of the EXACT Cough and Sputum score were analyzed for treatment
comparison differences and are presented in Table 32. These data are also provided in
Table 7.4.

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Table 32 Summary of EXACT Cough and Sputum Score

EXACT Cough and sputum score FSC250/50 SAL 50 LS Mean Diff 95% CI
(N=314) (N=325) Std Error p-value
n 296 304
Weeks 1-29 Mean 27.2 27.7 -0.6 (-3.0,1.8)
SE 0.90 0.88 1.23 0.643
n 294 301
Weeks 1-4 Mean 29.3 30.8 -1.7 (-4.3,0.9)
SE 0.93 0.95 1.32 0.203
n 252 246
Weeks 5-8 Mean 26.7 27.5 -1.2 (-4.0,1.6)
SE 0.98 1.04 1.42 0.393
n 234 234
Weeks 9-12 Mean 25.6 26.5 -1.2 (-4.2,1.8)
SE 1.10 1.07 1.54 0.426
n 223 229
Weeks 13-16 Mean 24.8 24.4 -0.1 (-3.1,2.9)
SE 1.09 1.08 1.53 0.956
n 219 210
Weeks 17-20 Mean 24.7 22.4 1.8 (-1.4,4.9)
SE 1.12 1.18 1.60 0.264
n 215 199
Weeks 21-24 Mean 24.6 21.6 2.6 (-0.5,5.8)
SE 1.18 1.16 1.61 0.101
n 210 186
Weeks 25-29 Mean 24.6 20.9 3.0 (-0.4,6.3)
SE 1.23 1.22 1.71 0.083
n 294 302
Endpoint Mean 26.0 26.9 -1.0 (-3.9,1.9)
SE 1.09 1.08 1.47 0.497
Data Source: Table 7.4.
LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline severity (baseline FEV1 percent predicted). LS Mean Diffs are calculated as
FSC250/50 – SAL 50.
The EXACT score is on a 0-100 scale with higher scores indicating a more severe state.

6.4.2.4. EXACT Chest Symptoms Score

The results of the EXACT Chest Symptoms Scores were analyzed comparatively, FSC
250/50 vs. SAL 50, and are presented in Table 33. The summary analysis is also provided
in Table 7.5.

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Table 33 Summary of EXACT Chest Symptoms Score

EXACT Chest symptoms score FSC250/50 SAL 50 LS Mean Diff 95% CI


(N=314) (N=325) Std Error p-value

n 296 304
Weeks 1-29 Mean 26.6 27.0 -0.5 (-3.2,2.3)
SE 1.01 1.07 1.40 0.746
n 294 301
Weeks 1-4 Mean 27.6 28.8 -1.3 (-4.0,1.4)
SE 0.97 1.05 1.37 0.329
n 252 246
Weeks 5-8 Mean 26.3 25.8 -0.1 (-3.2,3.0)
SE 1.11 1.20 1.59 0.960
n 234 234
Weeks 9-12 Mean 25.9 25.5 -0.2 (-3.6,3.2)
SE 1.22 1.29 1.75 0.908
n 223 229
Weeks 13-16 Mean 25.3 23.4 0.9 (-2.7,4.4)
SE 1.30 1.31 1.80 0.625
n 219 210
Weeks 17-20 Mean 25.1 22.5 1.4 (-2.2,5.1)
SE 1.33 1.40 1.85 0.435
n 215 199
Weeks 21-24 Mean 25.3 21.5 2.9 (-0.9,6.7)
SE 1.39 1.40 1.91 0.129
n 210 186
Weeks 25-29 Mean 25.5 19.9 4.5 (0.6,8.4)
SE 1.40 1.45 1.98 0.024
n 294 302
Endpoint Mean 27.1 26.2 0.7 (-2.6,4.0)
SE 1.22 1.27 1.67 0.670
Data Source: Table 7.5.
LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country, randomization
stratum and baseline severity (baseline FEV1 percent predicted). LS Mean Diffs are calculated as FSC250/50 – SAL 50.
The EXACT score is on a 0-100 scale with higher scores indicating a more severe state.

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6.5. Post-hoc Analyses

6.5.1. Summary of COPD Exacerbations Requiring Oral


Corticosteroids, Antibiotics and/or Hospitalization - Sub-group
Analyses

Additional data analyses were performed post-hoc to compare exacerbations of COPD


requiring OCS, antibiotics and hospitalizations by subject sub-groups, on the basis of:

 Baseline Post-bronchodilator FEV1 % Predicted 30% and No Prior ICS Use


 Baseline Post-bronchodilator FEV1 % Predicted 30% and Prior ICS Use
 Baseline Post-bronchodilator FEV1 % Predicted 30% and Concurrent
Tiotropium Use
 Baseline Post-bronchodilator FEV1 % Predicted 30% and No Concurrent
Tiotropium Use.
A summary of these data is presented in Table 34, and provided in Table 6.13,
Table 6.14, Table 6.15 and Table 6.16.

Table 34 Summary of COPD Exacerbations Requiring Oral Corticosteroids,


Antibiotics and/or Hospitalization

Baseline Post-bronchodilator FEV1 % Predicted 30% and No Prior ICS Use


FSC250/50 SAL 50
(N=60) (N=66)
Number of Subjects with an Exacerbation 21 (35%) 24 (36%)
Number of Exacerbations 38 34
0 39 (65%) 42 (64%)
1 8 (13%) 17 (26%)
Number of Subjects by Number of Exacerbations 2 10 (17%) 5 (8%)
3 2 (3%) 1 (2%)
4 1 (2%) 1 (2%)
Number of Subjects with an Exacerbation Yes 8 (13%) 10 (15%)
Requiring Hospitalization No 52 (87%) 56 (85%)
0 52 (87%) 56 (85%)
Number of Subjects by Number of Exacerbations 1 6 (10%) 9 (14%)
Requiring Hospitalization 2 2 (3%) 0
3 0 1 (2%)
Yes 10 (26%) 12 (35%)
Number of exacerbations requiring hospitalization
No 28 (74%) 22 (65%)
Yes 37 (97%) 31 (91%)
Number of exacerbations treated with OCS
No 1 (3%) 3 (9%)
Yes 29 (76%) 29 (85%)
Number of exacerbations treated with ABX
No 9 (24%) 5 (15%)
Baseline Post-bronchodilator FEV1 % Predicted 30% and Prior ICS Use
FSC250/50 SAL 50
(N=180) (N=193)
Number of Subjects with an Exacerbation 49 (27%) 66 (34%)

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Number of Exacerbations 74 106


0 131 (73%) 127 (66%)
1 28 (16%) 43 (22%)
Number of Subjects by Number of Exacerbations 2 17 (9%) 11 (6%)
3 4 (2%) 8 (4%)
4 0 3 (2%)
5 0 1 (<1%)
Number of Subjects with an Exacerbation Yes 21 (12%) 19 (10%)
Requiring Hospitalization No 159 (88%) 174 (90%)
0 159 (88%) 174 (90%)
Number of Subjects by Number of Exacerbations 1 18 (10%) 15 (8%)
Requiring Hospitalization 2 3 (2%) 2 (1%)
3 0 1 (<1%)
4 0 1 (<1%)
Yes 24 (32%) 26 (25%)
Number of exacerbations requiring hospitalization
No 50 (68%) 80 (75%)
Yes 64 (86%) 95 (90%)
Number of exacerbations treated with OCS
No 10 (14%) 11 (10%)
Yes 56 (76%) 78 (74%)
Number of exacerbations treated with ABX
No 18 (24%) 28 (26%)
Baseline Post-bronchodilator FEV1 % Predicted 30% and Concurrent Tiotropium Use
FSC250/50 SAL 50
(N=88) (N=95)
Number of Subjects with an Exacerbation 28 (32%) 32 (34%)
Number of Exacerbations 40 56
0 60 (68%) 63 (66%)
1 17 (19%) 19 (20%)
2 10 (11%) 5 (5%)
3 1 (1%) 5 (5%)
Number of Subjects by Number of Exacerbations 4 0 3 (3%)
Number of Subjects with an Exacerbation Yes 15 (17%) 9 (9%)
Requiring Hospitalization No 73 (83%) 86 (91%)
0 73 (83%) 86 (91%)
Number of Subjects by Number of Exacerbations 1 14 (16%) 6 (6%)
Requiring Hospitalization 2 1 (1%) 1 (1%)
3 0 1 (1%)
4 0 1 (1%)
Yes 16 (40%) 15 (27%)
Number of exacerbations requiring hospitalization
No 24 (60%) 41 (73%)
Yes 37 (93%) 51 (91%)
Number of exacerbations treated with OCS
No 3 (8%) 5 (9%)
Yes 31 (78%) 49 (88%)
Number of exacerbations treated with ABX
No 9 (23%) 7 (13%)
Baseline Post-bronchodilator FEV1 % Predicted 30% and No Concurrent Tiotropium Use
FSC250/50 SAL 50
(N=152) (N=164)
Number of Subjects with an Exacerbation 42 (28%) 58 (35%)
Number of Exacerbations 72 84

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0 110 (72%) 106 (65%)


1 19 (13%) 41 (25%)
Number of Subjects by Number of Exacerbations 2 17 (11%) 11 (7%)
3 5 (3%) 4 (2%)
4 1 (<1%) 1 (<1%)
5 0 1 (<1%)
Number of Subjects with an Exacerbation Yes 14 (9%) 20 (12%)
Requiring Hospitalization No 138 (91%) 144 (88%)
0 138 (91%) 144 (88%)
Number of Subjects by Number of Exacerbations 1 10 (7%) 18 (11%)
Requiring Hospitalization 2 4 (3%) 1 (<1%)
3 0 1 (<1%)
Yes 18 (25%) 23 (27%)
Number of exacerbations requiring hospitalization
No 54 (75%) 61 (73%)
Yes 64 (89%) 75 (89%)
Number of exacerbations treated with OCS
No 8 (11%) 9 (11%)
Yes 54 (75%) 58 (69%)
Number of exacerbations treated with ABX
No 18 (25%) 26 (31%)
Data Source: Table 6.13, Table 6.14, Table 6.15, Table 6.16.

The data analyses of exacerbations of COPD requiring OCS, antibiotics and


hospitalization of the sub-groups, including subjects with 1) baseline post-bronchodilator
FEV1 % predicted 30% and prior ICS use, 2) baseline post-bronchodilator FEV1 %
predicted 30% and concurrent tiotropium use and 3) baseline post-bronchodilator FEV1
% predicted 30% and no concurrent tiotropium use, are presented in Table 35, and also
provided in Table 6.17, Table 6.18 and Table 6.19. Limited data were available on the
sub-group of subjects with baseline post-bronchodilator FEV1 % predicted 30% and no
prior ICS and could not be analyzed appropriately.

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Table 35 Analysis of COPD Exacerbations Requiring Oral Corticosteroids,


Antibiotics and/or Hospitalization by Subgroup

Overall FSC250/50 SAL 50


(N=314) (N=325)
Baseline Post-bronchodilator FEV1 % Predicted 30% and Prior ICS Use
n 180 193
Mean exacerbation rate 1.54 2.28
Ratio 0.677
Treatment Comparison 95% CI (0.472, 0.972)
p-value 0.035
Baseline Post-bronchodilator FEV1 % Predicted 30% and Concurrent Tiotropium Use
n 88 95
Mean exacerbation rate 1.00 1.48
Ratio 0.673
Treatment Comparison 95% CI (0.410, 1.105)
p-value 0.122
Baseline Post-bronchodilator FEV1 % Predicted 30% and No Concurrent Tiotropium Use
n 152 164
Mean exacerbation rate 1.88 2.22
Ratio 0.847
Treatment Comparison 95% CI (0.577, 1.243)
p-value 0.395
Note: Annualized rate estimates, ratio, CI and p-value are from a negative binomial regression model with terms for
treatment, country, randomization stratum, baseline severity and time on treatment.
Data Source: Table 6.17, Table 6.18, Table 6.19.

6.5.2. Summary of Pre-dose FEV1 – Sub-group Analyses

Lung function data analyses were performed by study subject subgroups based on the
following characteristics:

 Baseline Post-bronchodilator FEV1 % Predicted 30% and No Prior ICS Use


 Baseline Post-bronchodilator FEV1 % Predicted 30% and Prior ICS Use
 Baseline Post-bronchodilator FEV1 % Predicted 30% and Concurrent
Tiotropium Use
 Baseline Post-bronchodilator FEV1 % Predicted 30% and No Concurrent
Tiotropium Use
A summary of the data and the analyses of treatment comparisons are presented in
Table 36 and provided in Table 6.20, Table 6.21, Table 6.22 and Table 6.23.

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Table 36 Summary of Pre-dose FEV1 by Sub-group

Baseline Post-bronchodilator FEV1 % Predicted 30% and No Prior ICS Use


FSC 250/50 SAL 50 LS Mean Diff 95% CI
(N=60) (N=66) Std Error p-value
n 60 66
Baseline FEV1 Mean 1.28 1.26
SE 0.057 0.054
n 57 59
FEV1 Mean 1.52 1.39
Endpoint SE 0.083 0.072 0.13 (-0.04,0.29)
Change from n 57 59 0.083 0.123
baseline Mean 0.25 0.13
SE 0.064 0.051
n 57 59
FEV1 Mean 1.51 1.33
Week 3 SE 0.078 0.068 0.17 (0.02,0.32)
Change from n 57 59 0.076 0.025
baseline Mean 0.24 0.06
SE 0.060 0.045
n 43 49
FEV1 Mean 1.48 1.38
Week 29 SE 0.104 0.071 0.17 (-0.01,0.35)
Change from n 43 49 0.091 0.063
baseline Mean 0.26 0.11
SE 0.080 0.047
Baseline Post-bronchodilator FEV1 % Predicted 30% and Prior ICS Use
FSC250/50 SAL 50 LS Mean Diff 95% CI
(N=180) (N=193) Std Error p-value
n 180 193
Baseline FEV1 Mean 1.20 1.26
SE 0.033 0.031
n 162 159
FEV1 Mean 1.30 1.28
Endpoint SE 0.039 0.036 0.10 (0.03,0.17)
n 162 159 0.036 0.006
Change from
baseline Mean 0.12 0.01
SE 0.027 0.025

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n 162 158
FEV1 Mean 1.26 1.27
Week 3 SE 0.036 0.036 0.07 (0.00,0.13)
n 162 158 0.033 0.044
Change from
baseline Mean 0.08 -0.00
SE 0.024 0.025
n 120 120
FEV1 Mean 1.32 1.26
Week 29 SE 0.047 0.041 0.13 (0.05,0.21)
n 120 120 0.041 0.002
Change from
baseline Mean 0.14 0.01
SE 0.032 0.028
Baseline Post-bronchodilator FEV1 % Predicted 30% and Concurrent Tiotropium Use
FSC250/50 SAL 50 LS Mean 95% CI
(N=88) (N=95) Diff p-value
Std Error
n 88 95
Baseline FEV1 Mean 1.17 1.19
SE 0.044 0.041
n 79 71
FEV1 Mean 1.24 1.21
Endpoint Change from SE 0.055 0.052 0.02 (-0.09,0.12)
baseline n 79 71 0.053 0.758
Mean 0.07 0.06
SE 0.037 0.041
n 79 71
FEV1 Mean 1.20 1.16
Week 3 SE 0.053 0.051 0.03 (-0.07,0.13)
n 79 71 0.050 0.600
Change from
baseline Mean 0.03 0.02
SE 0.037 0.038
n 58 52
FEV1 Mean 1.25 1.17
Week 29 SE 0.064 0.048 0.07 (-0.04,0.18)
n 58 52 0.055 0.237
Change from
Mean 0.09 0.05
baseline
SE 0.042 0.038

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Baseline Post-bronchodilator FEV1 % Predicted 30% and No Concurrent Tiotropium Use


FSC250/50 SAL 50 LS Mean Diff 95% CI
(N=152) (N=164) Std Error p-value
n 152 164
Baseline FEV1 Mean 1.25 1.31
SE 0.037 0.034
n 140 147
FEV1 Mean 1.43 1.36
Endpoint SE 0.047 0.042 0.16 (0.07,0.25)
n 140 147 0.044 <0.001
Change from
baseline Mean 0.21 0.03
SE 0.035 0.027
n 140 146
FEV1 Mean 1.39 1.34
Week 3 SE 0.043 0.040 0.14 (0.06,0.22)
n 140 146 0.040 <0.001
Change from
Mean 0.17 0.01
baseline
SE 0.031 0.027
n 105 117
FEV1 Mean 1.42 1.35
Week 29 SE 0.059 0.046 0.18 (0.08,0.28)
n 105 117 0.052 <0.001
Change from
baseline Mean 0.21 0.03
SE 0.043 0.031
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment, country,
randomization stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50 - Salmeterol.
Data Source: Table 6.20, Table 6.21, Table 6.22, Table 6.23.

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7. SAFETY RESULTS

7.1. Adverse Events


The list of all adverse event experiences (AEs) reported during the study were
summarized for the screen failure population (i.e., all subjects screened for inclusion in
the study but were discontinued from the study prior to randomization to either of the
blinded study drug) and the ITT population. Adverse events experienced by any study
subject in the ITT population that occurred during treatment and post-treatment were
collected and summarized. A total of 185 (59%) and 205 (63%) subjects reported
adverse events during the treatment period in the FSC 250/50 and SAL 50 treatment
groups, respectively. The lists of all AEs reported during treatment and post-treatment,
categorized by organ system, are provided in Table 8.1 and Table 8.3, respectively.

7.1.1. Most Common Adverse Events during Treatment

The most common AEs, reported within the ITT population by at least 3% of study
subjects in any treatment group, during the treatment period included: COPD, headache,
upper respiratory tract infection, back pain diarrhea, peripheral edema and nausea. A
summary of these AEs is presented in Table 37, and also provided in Table 8.2.

Table 37 Summary of Most Common (>3%) Adverse Events during Treatment

Adverse Event FSC 250/50 SAL 50


(N=314) (N=325)
Any event 185 (59%) 205 (63%)
Chronic obstructive pulmonary disease 47 (15%) 51 (16%)
Headache 19 (6%) 19 (6%)
Upper respiratory tract infection 15 (5%) 20 (6%)
Back pain 10 (3%) 13 (4%)
Diarrhea 11 (4%) 10 (3%)
Edema peripheral 6 (2%) 14 (4%)
Nausea 5 (2%) 13 (4%)
Data Source: Table 8.2.

7.1.2. Drug-Related Adverse Events Post Randomization

Post-randomization, 19 (6%) and 22 (7%) of study subjects experienced AEs that were
adjudicated by the study investigators and attributed to the FC 250/50 and SAL 50
treatments, respectively. A summary of these drug-related AEs is presented by system
organ class in Table 38, and provided in Table 8.7.

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Table 38 Summary of Drug-Related Adverse Events Post Randomization

Summary of Drug-Related Adverse Events Post Randomization FSC 250/50 SAL 50


by System Organ Class Preferred Term (N=314) (N=325)
Any event 19 (6%) 22 (7%)
Respiratory, thoracic and mediastinal disorders
Any event 7 (2%) 10 (3%)
Dysphonia 6 (2%) 4 (1%)
Chronic obstructive pulmonary disease 1 (<1%) 2 (<1%)
Cough 0 3 (<1%)
Oropharyngeal pain 0 2 (<1%)
Nasal congestion 0 1 (<1%)
Throat irritation 1 (<1%) 0
Infections and infestations
Any event 4 (1%) 7 (2%)
Oral candidiasis 3 (<1%) 4 (1%)
Candidiasis 0 2 (<1%)
Oropharyngeal candidiasis 1 (<1%) 0
Upper respiratory tract infection 0 1 (<1%)
Psychiatric disorders
Any event 2 (<1%) 3 (<1%)
Anxiety 1 (<1%) 2 (<1%)
Depression 0 1 (<1%)
Sleep disorder 1 (<1%) 0
Gastrointestinal disorders
Any event 2 (<1%) 2 (<1%)
Dry mouth 0 2 (<1%)
Diarrhoea 1 (<1%) 0
Oral pain 1 (<1%) 0
Cardiac disorders
Any event 1 (<1%) 2 (<1%)
Tachycardia 0 2 (<1%)
Palpitations 1 (<1%) 0
General disorders and administration site conditions
Any event 1 (<1%) 1 (<1%)
Chest discomfort 1 (<1%) 1 (<1%)
Localised oedema 1 (<1%) 0
Oedema peripheral 1 (<1%) 0
Musculoskeletal and connective tissue disorders
Any event 1 (<1%) 1 (<1%)
Muscle spasms 1 (<1%) 1 (<1%)
Skin and subcutaneous tissue disorders
Any event 1 (<1%) 1 (<1%)
Angioedema 0 1 (<1%)
Skin discolouration 1 (<1%) 0
Eye disorders
Any event 0 1 (<1%)
Conjunctival haemorrhage 0 1 (<1%)
Nervous system disorders
Any event 1 (<1%) 0

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Summary of Drug-Related Adverse Events Post Randomization FSC 250/50 SAL 50


by System Organ Class Preferred Term (N=314) (N=325)
Headache 1 (<1%) 0
Renal and urinary disorders
Any event 1 (<1%) 0
Urinary retention 1 (<1%) 0
Data Source: Table 8.7.

7.1.3. Adverse Events Leading to Withdrawal from the Study

During the study, 29 (9%) and 33 (10%) of the study subjects assigned to FSC 250/50
and SAL 50 treatment, respectively, experienced AEs that led to their withdrawal from
the study. A list of these AEs leading to withdrawal from the study, summarized by
system organ class, is presented Table 39, and provided in Table 8.8.

Table 39 Summary of Adverse Events Leading to Withdrawal from the Study

Adverse Events Leading to Withdrawal from the Study by System FSC 250/50 SAL 50
Organ Class Preferred Term (N=314) (N=325)

Any event 29 (9%) 33 (10%)


Respiratory, thoracic and mediastinal disorders
Any event 14 (4%) 20 (6%)
Chronic obstructive pulmonary disease 13 (4%) 18 (6%)
Respiratory failure 3 (<1%) 0
Dysphonia 1 (<1%) 0
Dyspnoea 0 1 (<1%)
Nasal congestion 0 1 (<1%)
Oropharyngeal pain 0 1 (<1%)
Infections and infestations
Any event 7 (2%) 7 (2%)
Pneumonia 2 (<1%) 4 (1%)
Oral candidiasis 2 (<1%) 0
Bronchitis 0 1 (<1%)
Encephalitis herpes 1 (<1%) 0
Pneumonia streptococcal 1 (<1%) 0
Respiratory tract infection 0 1 (<1%)
Sepsis 0 1 (<1%)
Urinary tract infection 1 (<1%) 0
Cardiac disorders
Any event 3 (<1%) 3 (<1%)
Atrial fibrillation 0 1 (<1%)
Cardiac arrest 1 (<1%) 0
Cardiac failure congestive 1 (<1%) 0
Cardio-respiratory arrest 0 1 (<1%)
Myocardial infarction 0 1 (<1%)
Palpitations 1 (<1%) 0

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Adverse Events Leading to Withdrawal from the Study by System FSC 250/50 SAL 50
Organ Class Preferred Term (N=314) (N=325)

Gastrointestinal disorders
Any event 2 (<1%) 1 (<1%)
Constipation 0 1 (<1%)
Dry mouth 0 1 (<1%)
Gastrointestinal haemorrhage 1 (<1%) 0
Oral pain 1 (<1%) 0
Nervous system disorders
Any event 3 (<1%) 0
Cerebrovascular accident 1 (<1%) 0
Convulsion 1 (<1%) 0
Hypoxic-ischaemic encephalopathy 1 (<1%) 0
Ischaemic stroke 1 (<1%) 0
Myoclonus 1 (<1%) 0
General disorders and administration site conditions
Any event 1 (<1%) 1 (<1%)
Chest discomfort 0 1 (<1%)
Sudden death 1 (<1%) 0
Metabolism and nutrition disorders
Any event 2 (<1%) 0
Hyperglycaemia 1 (<1%) 0
Metabolic acidosis 1 (<1%) 0
Neoplasms benign, malignant and unspecified (including cysts
and polyps)
Any event 0 2 (<1%)
Colon cancer 0 1 (<1%)
Peritoneal carcinoma metastatic 0 1 (<1%)
Psychiatric disorders
Any event 1 (<1%) 1 (<1%)
Anxiety 1 (<1%) 1 (<1%)
Vascular disorders
Any event 2 (<1%) 0
Hypotension 1 (<1%) 0
Hypovolaemic shock 1 (<1%) 0
Injury, poisoning and procedural complications
Any event 1 (<1%) 0
Hip fracture 1 (<1%) 0
Renal and urinary disorders
Any event 1 (<1%) 0
Renal failure 1 (<1%) 0
Skin and subcutaneous tissue disorders
Any event 0 1 (<1%)
Angioedema 0 1 (<1%)
Data Source: Table 8.8

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7.2. Serious and Other Significant Adverse Events

7.2.1. Serious Adverse Events during Treatment

A total of 75 (24%) and 82 (25%) study subjects in the FSC 250/50 and SAL 50
treatment groups, respectively, experienced serious adverse events during study
treatment. A list of all the serious adverse events that were reported during treatment,
summarized by organ system class, is presented in Table 40. These are also provided in
Table 8.4.

Table 40 Summary of Serious Adverse Events during Treatment

Serious Adverse Event FSC 250/50 SAL 50


(N=314) (N=325)
Any event 75 (24%) 82 (25%)
Respiratory, Thoracic and Mediastinal Disorders
Any event 48 (15%) 57 (18%)
Chronic obstructive pulmonary disease 47 (15%) 51 (16%)
Acute respiratory failure 3 (<1%) 5 (2%)
Respiratory failure 4 (1%) 1 (<1%)
Dyspnoea 1 (<1%) 2 (<1%)
Atelectasis 0 1 (<1%)
Bronchospasm 0 1 (<1%)
Hypoxia 0 1 (<1%)
Pleural effusion 0 1 (<1%)
Pulmonary embolism 0 1 (<1%)
Infections and Infestations
Any event 20 (6%) 13 (4%)
Pneumonia 7 (2%) 5 (2%)
Bronchitis 3 (<1%) 3 (<1%)
Cellulitis 2 (<1%) 1 (<1%)
Lobar pneumonia 2 (<1%) 1 (<1%)
Urinary tract infection 3 (<1%) 0
Sepsis 1 (<1%) 1 (<1%)
Cystitis 1 (<1%) 0
Encephalitis herpes 1 (<1%) 0
Escherichia sepsis 1 (<1%) 0
Infective exacerbation of chronic obstructive airways disease 0 1 (<1%)
Lymphangitis 1 (<1%) 0
Pneumonia streptococcal 1 (<1%) 0
Respiratory tract infection 0 1 (<1%)
Sinusitis 1 (<1%) 0
Upper respiratory tract infection 0 1 (<1%)
Urosepsis 1 (<1%) 0

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Serious Adverse Event FSC 250/50 SAL 50


(N=314) (N=325)
Cardiac Disorders
Any event 4 (1%) 10 (3%)
Angina pectoris 2 (<1%) 1 (<1%)
Cardiac failure congestive 1 (<1%) 2 (<1%)
Acute myocardial infarction 1 (<1%) 1 (<1%)
Atrial fibrillation 1 (<1%) 1 (<1%)
Acute coronary syndrome 0 1 (<1%)
Angina unstable 0 1 (<1%)
Cardio-respiratory arrest 0 1 (<1%)
Coronary artery disease 1 (<1%) 0
Myocardial infarction 0 1 (<1%)
Sinus tachycardia 0 1 (<1%)
Supraventricular tachycardia 0 1 (<1%)
Tachycardia 0 1 (<1%)
Ventricular extrasystoles 0 1 (<1%)
Nervous System Disorders
Any event 4 (1%) 5 (2%)
Transient ischaemic attack 0 2 (<1%)
Carotid artery stenosis 1 (<1%) 0
Convulsion 1 (<1%) 0
Hypoaesthesia 0 1 (<1%)
Hypoxic-ischaemic encephalopathy 1 (<1%) 0
Ischaemic stroke 1 (<1%) 0
Myoclonus 1 (<1%) 0
Presyncope 1 (<1%) 0
Syncope 0 1 (<1%)
Tension headache 0 1 (<1%)
Gastrointestinal Disorders
Any event 3 (<1%) 4 (1%)
Abdominal hernia 0 1 (<1%)
Duodenal ulcer 1 (<1%) 0
Gastrointestinal haemorrhage 0 1 (<1%)
Inguinal hernia, obstructive 0 1 (<1%)
Irritable bowel syndrome 0 1 (<1%)
Melaena 1 (<1%) 0
Nausea 1 (<1%) 0
Upper gastrointestinal haemorrhage 1 (<1%) 0
Vomiting 1 (<1%) 0
General Disorders and Administration Site Conditions
Any event 4 (1%) 3 (<1%)
Chest pain 1 (<1%) 3 (<1%)
Non-cardiac chest pain 1 (<1%) 0
Oedema peripheral 1 (<1%) 0
Sudden death 1 (<1%) 0

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Serious Adverse Event FSC 250/50 SAL 50


(N=314) (N=325)
Metabolism and Nutrition Disorders
Any event 4 (1%) 3 (<1%)
Dehydration 2 (<1%) 1 (<1%)
Gout 0 1 (<1%)
Hyperglycaemia 0 1 (<1%)
Hypoglycaemia 0 1 (<1%)
Hyponatraemia 1 (<1%) 0
Metabolic acidosis 1 (<1%) 0
Vascular Disorders
Any event 6 (2%) 1 (<1%)
Hypotension 2 (<1%) 1 (<1%)
Arterial thrombosis limb 1 (<1%) 0
Hypertension 1 (<1%) 0
Labile hypertension 1 (<1%) 0
Orthostatic hypotension 1 (<1%) 0
Injury, Poisoning and Procedural Complications
Any event 4 (1%) 1 (<1%)
Femur fracture 0 1 (<1%)
Hip fracture 1 (<1%) 0
Limb traumatic amputation 1 (<1%) 0
Pneumothorax traumatic 1 (<1%) 0
Rib fracture 1 (<1%) 0
Neoplasms benign, malignant and unspecified (including cysts
and polyps)
Any event 2 (<1%) 3 (<1%)
Adenoma benign 1 (<1%) 0
Bone neoplasm malignant 1 (<1%) 0
Colon cancer 0 1 (<1%)
Non-small cell lung cancer 0 1 (<1%)
Peritoneal carcinoma metastatic 0 1 (<1%)
Renal and Urinary Disorders
Any event 4 (1%) 1 (<1%)
Renal failure acute 2 (<1%) 0
Calculus ureteric 1 (<1%) 0
Renal failure 1 (<1%) 0
Urinary retention 0 1 (<1%)
Psychiatric Disorders
Any event 2 (<1%) 1 (<1%)
Mental status changes 2 (<1%) 0
Confusional state 0 1 (<1%)
Blood and Lymphatic System Disorders
Any event 0 2 (<1%)
Iron deficiency anaemia 0 1 (<1%)
Leukocytosis 0 1 (<1%)
Musculoskeletal and Connective Tissue Disorders
Any event 1 (<1%) 1 (<1%)
Costochondritis 0 1 (<1%)
Rhabdomyolysis 1 (<1%) 0

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Serious Adverse Event FSC 250/50 SAL 50


(N=314) (N=325)
Ear and Labyrinth Disorders
Any event 0 1 (<1%)
Vertigo 0 1 (<1%)
Hepatobiliary Disorders
Any event 1 (<1%) 0
Cholangitis 1 (<1%) 0
Cholelithiasis 1 (<1%) 0
Data Source: Table 8.4.

7.2.2. Serious Adverse Events Post-Treatment

During the post-treatment period, 16 (5%) patients who participated in the study FSC
250/50 treatment group and 8 (2%) from the SAL 50 treatment group experienced SAEs.
A list of the SAEs reported during the post-treatment period is presented in Table 41 and
also provided in Table 8.5.

Table 41 Summary of Serious Adverse Events Post-Treatment

Serious Adverse Event by System Organ Class Preferred Term FSC250/50 SAL
(N=314) (N=325)
Any event 16 (5%) 8 (2%)
Respiratory, thoracic and mediastinal disorders
Any event 6 (2%) 6 (2%)
Chronic obstructive pulmonary disease 4 (1%) 5 (2%)
Hypoxia 1 (<1%) 0
Pulmonary bulla 0 1 (<1%)
Pulmonary embolism 1 (<1%) 0
Respiratory failure 1 (<1%) 0
Infections and infestations
Any event 5 (2%) 3 (<1%)
Pneumonia 3 (<1%) 1 (<1%)
Bronchitis 1 (<1%) 1 (<1%)
Cellulitis 0 1 (<1%)
Urinary tract infection 1 (<1%) 0
Nervous system disorders
Any event 3 (<1%) 0
Carotid artery stenosis 1 (<1%) 0
Cerebrovascular accident 1 (<1%) 0
Syncope 1 (<1%) 0
Cardiac disorders
Any event 2 (<1%) 0
Atrial fibrillation 1 (<1%) 0
Cardiac arrest 1 (<1%) 0
Gastrointestinal disorders
Any event 1 (<1%) 0
Gastrointestinal haemorrhage 1 (<1%) 0

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Serious Adverse Event by System Organ Class Preferred Term FSC250/50 SAL
(N=314) (N=325)
General disorders and administration site conditions
Any event 1 (<1%) 0
Death 1 (<1%) 0
Vascular disorders
Any event 1 (<1%) 0
Hypovolaemic shock 1 (<1%) 0
Data Source: Table 8.5.

7.2.3. Deaths

During the study treatment period, 7 fatalities occurred in the ITT population, consequent
to serious adverse event experiences. These included 4 (1%) reported within the FSC
250/50 group and 3 (1%) from the SAL 50 treated group. A summary of these fatal
serious adverse events is presented in Table 42, and also provided in Table 8.6.

Table 42 Summary of Fatal Serious Adverse Events during Treatment

Fatal Serious Adverse Events during Treatment by System Organ FSC250/50 SAL 50
Class Preferred Term (N=314) (N=325)
Any event 4 (1%) 3 (<1%)
Cardiac disorders
Any event 0 2 (<1%)
Cardio-respiratory arrest 0 1 (<1%)
Myocardial infarction 0 1 (<1%)
Infections and infestations
Any event 1 (<1%) 1 (<1%)
Bronchitis 1 (<1%) 0
Sepsis 0 1 (<1%)
Respiratory, thoracic and mediastinal disorders
Any event 2 (<1%) 0
Chronic obstructive pulmonary disease 2 (<1%) 0
Respiratory failure 1 (<1%) 0
General disorders and administration site conditions
Any event 1 (<1%) 0
Sudden death 1 (<1%) 0
Metabolism and nutrition disorders
Any event 1 (<1%) 0
Metabolic acidosis 1 (<1%) 0
Nervous system disorders
Any event 1 (<1%) 0
Convulsion 1 (<1%) 0
Hypoxic-ischaemic encephalopathy 1 (<1%) 0
Myoclonus 1 (<1%) 0
Renal and urinary disorders
Any event 1 (<1%) 0
Renal failure 1 (<1%) 0

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Fatal Serious Adverse Events during Treatment by System Organ FSC250/50 SAL 50
Class Preferred Term (N=314) (N=325)
Vascular disorders
Any event 1 (<1%) 0
Hypotension 1 (<1%) 0
Data Source: Table 8.6.

7.2.4. Pneumonia Adverse Events Post Randomization

Per clinical study protocol, all suspected cases of pneumonia that occurred during the
study were required to be closely reviewed with the assistance of a chest X-ray. All
confirmed diagnoses of pneumonia were recorded as AEs and are presented in Table 43
and also provided in Table 8.9.

Table 43 Summary of Pneumonia Adverse Events Post Randomization

Pneumonia Adverse Events Post Randomization FSC 250/50 SAL 50


(N=314) (N=325)
Any event 13 (4%) 10 (3%)
Pneumonia 10 (3%) 9 (3%)
Lobar pneumonia 2 (<1%) 1 (<1%)
Pneumonia streptococcal 1 (<1%) 0
Data Source: Table 8.9.

7.3. Medical Device Incidents, Near-Incidents, Malfunctions and


Remedial Action
No incidents, near incidents or malfunctions were reported with the use of the medical
device(s) manufactured or marketed, by GSK or by a third party for GSK, for this study.

7.4. Pregnancies
There were no pregnancies reported to have occurred during the study.

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8. DISCUSSION AND CONCLUSIONS

8.1. Discussion
The primary endpoint of this study, the rate of COPD exacerbations requiring
hospitalization, was not achieved. The lack of exacerbation reduction was noted despite
the positive spirometric data verifying the effect of the FSC 250/50. The findings are in
contrast to the two prior trials documenting the ability of FSC 250/50 to reduce the rate of
exacerbations when treatment is started in stable COPD patients within a year of an
exacerbation [Anzueto, 2009; Ferguson, 2008].

The lack of study drug effect seen in this study may be related to differences in the
current design compared to the previous studies. The current study was designed to test
an early intervention strategy, treatment within two weeks of a hospitalization or
exacerbation. Subjects, therefore, may have been in a more convalescent state than in the
previous studies. As such, the study drug therapy was initiated within 14 days following
discharge from the index exacerbation. In the previous studies, treatment was started in
stable patients within one year following the index exacerbation. The study eligibility
criteria of the study had variables that introduced a differential response to therapy. For
example, the baseline values for inflammatory biomarkers in our study were elevated,
suggesting a high degree of systemic inflammation throughout the study. Additionally,
the majority of the study subjects had been treated with systemic steroids immediately
prior to study entry.

We identified three clinical variables that were associated with a larger effect size of FSC
250/50. These were: (1) a baseline post-bronchodilator FEV1 of 30% of predicted, (2)
the prior use of ICS and (3) exacerbations requiring OCS, antibiotics and/or
hospitalization, instead of only those requiring hospitalization, as the endpoint. The prior
use of ICS may identify key variables associated with corticosteroid responsiveness in
COPD identified through clinical practice. The subgroup of subjects with a baseline
post-bronchodilator FEV1 of 30% of predicted was also more steroid-responsive.
Furthermore, FSC 250/50 was relatively more efficacious at reducing the rate of
exacerbation requiring OCS, antibiotics and/or hospitalization (mean annual exacerbation
rate, FSC 250/50: 1.49, SAL 50: 1.81; Ratio: 0.823; 95% CI: 0.637, 1.063; p-value =
0.136), compared to those requiring hospitalization (mean annual exacerbation rate, FSC
250/50: 0.44, SAL 50: 0.48; Ratio: 0.917; 95% CI: 0.581, 1.447; p-value = 0.710).

When the subgroup of subjects with both the prior use of ICS and a baseline post-
bronchodilator FEV1 of 30% of predicted was analyzed post-hoc, a significant effect of
FSC 250/50 in reducing the rate of COPD exacerbations requiring OCS, antibiotics
and/or hospitalization was noted (mean annual exacerbation rate, FSC 250/50: 1.54, SAL
50: 2.28; Ratio: 0.677; 95% CI: 0.472, 0.972; p-value = 0.035). Thus, FSC 250/50 might
have shown statistically significant reduction of the rate of COPD exacerbations if the
cohort had been defined with the additional criteria of prior ICS use and higher baseline
post-bronchodilator FEV1, and if the exacerbation endpoint had been extended to include
those requiring OCS and antibiotics, not just hospitalization.

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An increase in pre-dose FEV1 of 0.10±0.03 L (LSM difference±SE, FSC 250/50 vs. SAL
50; 95% CI: 0.04, 0.16; p-value <0.001) was noted at endpoint (Table 21, Figure 5) in
response to FSC 250/50 when compared to SAL 50. This is a relatively large
bronchodilator response to FP add-on when compared to the effect of FP seen in similar
studies [Anzueto, 2009; Ferguson, 2008]. It may be that the decentralized spirometry
testing that was used in this study is less accurate than that used in previous studies, or
the large effect of FSC 250/50 on FEV1 could be related to the possibility of a relatively
high level of systemic inflammation in our cohort.

In post hoc analysis, the group of subjects with both a baseline post-bronchodilator FEV1
of 30% of predicted and prior ICS use showed a significant bronchodilator response to
added FP (increase of 0.13±0.04, p = 0.002, FSC 250/50 vs. SAL 50). An effect of
similar magnitude was seen in the group with a baseline post-bronchodilator FEV1 of
30% of predicted and without prior ICS use, but this was not significant, perhaps
because of greater variability in a smaller group. Thus, prior use of ICS was not
associated with a superior bronchodilator response to ICS add-on in all sub-groups.

In this study, subjects who were on tiotropium therapy at time of enrolment were allowed
to stay on tiotropium for the duration of the study (as background therapy). This
inclusion criterion was incorporated into the study design to enhance enrollment of
patients. Approximately, 38% of subjects were on tiotropium resulting in two additional
treatment-defined subgroups: “SAL 50 + tiotropium” and “FSC 250/50 + tiotropium”. In
post hoc analysis, the two sub-groups on tiotropium with baseline post-bronchodilator
FEV1 % predicted ≥ 30% were slightly more responsive to treatment intervention than
the other two subgroups not on tiotropium therapy (mean annual exacerbation rate, FSC
250/50 + tiotropium: 1.00, SAL 50 + tiotropium: 1.48; Ratio: 0.673; 95% CI: 0.410,
1.105; p-value = 0.122, compared to FSC 250/50: 1.88, SAL 50: 2.22; Ratio: 0.847; 95%
CI: 0.577, 1.243; p-value = 0.395). These results suggest that the exacerbation-reducing
benefit of FP add-on in this post-exacerbation cohort is the same or greater when added
to two bronchodilators (resulting in “triple therapy”) as it is when tiotropium is added to
SAL 50 alone.

Several other efficacy endpoints did not reach statistical significance. These included (1)
the time to first exacerbation requiring OCS, antibiotics &/or hospitalization, (2) the
probability of premature withdrawal of subject from the study and (3) supplemental
albuterol use. These endpoints may have failed to demonstrate efficacy for the same
reasons as discussed above for the primary efficacy endpoint.

The change in the biomarkers of systemic inflammation, including SP-D, CC-16 and hs-
CRP, were not statistically significant in treatment comparisons, except for the mean log
SP-D week-16 change from baseline (p = 0.008). The measures of these biomarkers
remained elevated throughout the study period, potentially indicative of sustained
systemic inflammation, which is known to be a component of COPD [Barnes, 2010].
The elevated level of inflammatory biomarkers at baseline was possibly reflective of the
subjects’ enrollment immediately following an exacerbation.

The safety data are consistent with the currently known safety profile of the two
treatment interventions.

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The study of relatively early intervention immediately after a severe clinical exacerbation
of COPD has several intrinsic difficulties. First, the recruitment of COPD patients with
recent exacerbations and associated hospitalization requires the selection of clinical
centers with the ability to achieve subject enrolment following hospital discharge.
Second, the burden of the recent acute illness may have discouraged or biased study
participation. Third, the seasonality of exacerbations of COPD (more common during the
colder months [Jenkins, 2012] could have affected recruitment. Seasonality might also
have influenced the results by introducing cohort bias if exacerbations parameters, such
as etiology and severity, vary by season. Thus, a 12-month assessment period of the
endpoint might have improved the likelihood of reaching the pre-specified objectives of
the study.

Further, there was a low frequency of COPD exacerbations observed in this study during
the 29 weeks. Only a minority of study subjects (approximately, 32% and 35% of the
subject randomized to FSC 250/50 and SAL 50, respectively) experienced an
exacerbation of COPD requiring OCS, antibiotics and/or hospitalization. This finding,
possibly, biased the cohort, because difference in COPD severity such as the frequency of
prior exacerbations, might have contributed to the observed results [Suissa, 2012]. The
design of future studies may want to focus on subjects with more than one exacerbation
of COPD as an inclusion criterion. These results also suggest that certain baseline FEV1
may be more predictive of response.

8.2. Conclusions
The conclusions of this study of FSC250/50 in comparison to SAL 50, administered
within 14 days of discharge after exacerbation of COPD, are as follows:
 There was no statistical difference between the FSC 250/50 and the SAL 50
treatment groups (per primary and secondary endpoints assessments). The study
did not reach the designed objectives, possibly due to the lack of steroid
responsiveness in subgroups such as those with baseline post-bronchodilator
FEV1 of <30% of predicted and those without prior ICS use.
 The spirometric data confirmed the superior efficacy of FSC 250/50 over SAL
50 in measures of lung function within this study.
 The data on the selected biomarkers, hs-CRP, CC-16 and SP-D, remained
abnormally high throughout the study, possibly indicative of systemic
inflammation beyond the effect of the study treatment.
 Other clinical variables that may have introduced subtle bias of the cohort
include (1) the willingness to participate among the screened cohort, (2) the
seasonality of exacerbations of COPD in a 6-month study and (3) the low
frequency of exacerbators, who constituted only a minority of subjects over the
duration of the study.
 Overall, the safety data were consistent with the known safety profile of the
study drugs.

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 Post hoc analyses suggest that the observed treatment effect size could be
optimized using a cohort with post-bronchodilator FEV1 of ≥30% of predicted
and prior ICS use, who experienced COPD exacerbations requiring OCS,
antibiotics and/or hospitalization.

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10. POST-TEXT TABLES AND FIGURES


Not Applicable

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103
This section contained patient narratives which are textual descriptions of medical history,
treatment and outcome for individual patients who experienced a clinically important adverse
event including serious adverse events during the trial. They have been excluded to protect
patient privacy. This data may be made available subject to an approved research proposal and
a determination of the ability to provide information from the specific narratives whilst protecting
the patient’s privacy. For further information please see the Patient Level Data section of
the GSK Clinical Study Register.
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Population: Safety
Table 5.1
Summary of Analysis Populations

Total
(N=734)
-----------------------------------------------------------------------------------------------------------
Safety population 734

Screen failure population 95 (13%)

Reason Did not meet inclusion/exclusion criteria 79 (83%)


Protocol deviation 2 (2%)
Lost to follow-up 2 (2%)
Investigator discretion 6 (6%)
Withdrew consent 6 (6%)
Intent-to-Treat population 639 (87%)

Note: Percentages for screen failure reasons are based on the Screen failure population.

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Population: Screen failure
Table 5.2
Summary of Inclusion/Exclusion Criteria Not Met (Screen Failure Population)

Not Randomized
Criterion (N=95)
-------------------------------------------------------------------------------------------------------
Any criteria deviations 79 (83%)

Inclusion criteria
Male or non-pregnant female >=40 years of age 2 (2%)
Smoking history 3 (3%)
Exacerbation history 7 (7%)
Clinical diagnosis of COPD 4 (4%)
Documented FEV1 % predicted <70% & FEV1/FVC<=0.7 52 (55%)
Informed consent 4 (4%)
Language comprehension 2 (2%)
Exclusion criteria
Diagnosis of complicating comorbid condition 10 (11%)
Clinically significant uncontrolled disease 7 (7%)
Clinically significant abnormal 12-lead ECG 1 (1%)
Clinically significant abnormal chest x-ray or CT 1 (1%)
Limiting factor for scheduled visit compliance 4 (4%)
Limited ability to provide valid informed consent 1 (1%)

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Population: Intent-to-Treat
Table 5.3
Summary of Enrollment by Investigator

Country/ FSC250/50 Salmeterol Total


Investigator (Centre ID) (N=314) (N=325) (N=639)
--------------------------------------------------------------------------------------------------
Argentina
120 (38%) 120 (37%) 240 (38%)
0 1 (<1%) 1 (<1%)
1 (<1%) 0 1 (<1%)
6 (2%) 8 (2%) 14 (2%)
0 3 (<1%) 3 (<1%)
14 (4%) 15 (5%) 29 (5%)
4 (1%) 3 (<1%) 7 (1%)
4 (1%) 4 (1%) 8 (1%)
4 (1%) 3 (<1%) 7 (1%)
2 (<1%) 3 (<1%) 5 (<1%)
2 (<1%) 4 (1%) 6 (<1%)
2 (<1%) 2 (<1%) 4 (<1%)
3 (<1%) 5 (2%) 8 (1%)
12 (4%) 12 (4%) 24 (4%)
10 (3%) 10 (3%) 20 (3%)
8 (3%) 7 (2%) 15 (2%)
7 (2%) 5 (2%) 12 (2%)
2 (<1%) 1 (<1%) 3 (<1%)
11 (4%) 12 (4%) 23 (4%)
10 (3%) 7 (2%) 17 (3%)
2 (<1%) 0 2 (<1%)
6 (2%) 8 (2%) 14 (2%)
3 (<1%) 2 (<1%) 5 (<1%)
7 (2%) 5 (2%) 12 (2%)

Norway
4 (1%) 9 (3%) 13 (2%)
0 1 (<1%) 1 (<1%)
2 (<1%) 5 (2%) 7 (1%)
0 2 (<1%) 2 (<1%)
2 (<1%) 1 (<1%) 3 (<1%)

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Population: Intent-to-Treat
Table 5.3
Summary of Enrollment by Investigator

Country/ FSC250/50 Salmeterol Total


Investigator (Centre ID) (N=314) (N=325) (N=639)
--------------------------------------------------------------------------------------------------
United States
All investigators 190 (61%) 196 (60%) 386 (60%)
3 (<1%) 4 (1%) 7 (1%)
2 (<1%) 3 (<1%) 5 (<1%)
1 (<1%) 2 (<1%) 3 (<1%)
5 (2%) 3 (<1%) 8 (1%)
2 (<1%) 1 (<1%) 3 (<1%)
2 (<1%) 2 (<1%) 4 (<1%)
12 (4%) 9 (3%) 21 (3%)
0 3 (<1%) 3 (<1%)
17 (5%) 17 (5%) 34 (5%)
0 1 (<1%) 1 (<1%)
3 (<1%) 3 (<1%) 6 (<1%)
3 (<1%) 3 (<1%) 6 (<1%)
3 (<1%) 1 (<1%) 4 (<1%)
5 (2%) 5 (2%) 10 (2%)
0 2 (<1%) 2 (<1%)
9 (3%) 8 (2%) 17 (3%)
3 (<1%) 3 (<1%) 6 (<1%)
1 (<1%) 1 (<1%) 2 (<1%)
1 (<1%) 1 (<1%) 2 (<1%)
2 (<1%) 2 (<1%) 4 (<1%)
4 (1%) 5 (2%) 9 (1%)
6 (2%) 5 (2%) 11 (2%)
3 (<1%) 3 (<1%) 6 (<1%)
1 (<1%) 1 (<1%) 2 (<1%)
1 (<1%) 2 (<1%) 3 (<1%)
3 (<1%) 4 (1%) 7 (1%)
3 (<1%) 4 (1%) 7 (1%)
2 (<1%) 3 (<1%) 5 (<1%)
2 (<1%) 2 (<1%) 4 (<1%)
0 1 (<1%) 1 (<1%)
4 (1%) 3 (<1%) 7 (1%)

308
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Population: Intent-to-Treat
Table 5.3
Summary of Enrollment by Investigator

Country/ FSC250/50 Salmeterol Total


Investigator (Centre ID) (N=314) (N=325) (N=639)
-- -----------------------------------------------------------------------
2 (<1%) 1 (<1%) 3 (<1%)
5 (2%) 5 (2%) 10 (2%)
10 (3%) 9 (3%) 19 (3%)
3 (<1%) 3 (<1%) 6 (<1%)
2 (<1%) 4 (1%) 6 (<1%)
6 (2%) 8 (2%) 14 (2%)
1 (<1%) 0 1 (<1%)
1 (<1%) 1 (<1%) 2 (<1%)
6 (2%) 3 (<1%) 9 (1%)
5 (2%) 5 (2%) 10 (2%)
0 1 (<1%) 1 (<1%)
7 (2%) 9 (3%) 16 (3%)
4 (1%) 5 (2%) 9 (1%)
6 (2%) 5 (2%) 11 (2%)
3 (<1%) 3 (<1%) 6 (<1%)
0 2 (<1%) 2 (<1%)
2 (<1%) 2 (<1%) 4 (<1%)
1 (<1%) 1 (<1%) 2 (<1%)
4 (1%) 4 (1%) 8 (1%)
2 (<1%) 4 (1%) 6 (<1%)
5 (2%) 6 (2%) 11 (2%)
4 (1%) 3 (<1%) 7 (1%)
8 (3%) 5 (2%) 13 (2%)

309
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Population: Intent-to-Treat
Table 5.4
Summary of End of Study Record

FSC250/50 Salmeterol Total


(N=314) (N=325) (N=639)
------------------------------------------------------------------------------------------------------------
Completion Status
Completed 208 (66%) 204 (63%) 412 (64%)
Withdrawn 106 (34%) 121 (37%) 227 (36%)

Primary/subreason for withdrawal


Adverse event 28 (9%) 28 (9%) 56 (9%)
Lack of efficacy 16 (5%) 25 (8%) 41 (6%)
Adverse event 0 3 (<1%) 3 (<1%)
Protocol deviation 14 (4%) 12 (4%) 26 (4%)
Adverse event 0 1 (<1%) 1 (<1%)
Lost to follow-up 10 (3%) 7 (2%) 17 (3%)
Investigator discretion 13 (4%) 17 (5%) 30 (5%)
Adverse event 0 1 (<1%) 1 (<1%)
Withdrew consent 25 (8%) 32 (10%) 57 (9%)
Adverse event 1 (<1%) 0 1 (<1%)

Note: Subjects may have only one primary reason for withdrawal. A subreason of Adverse event is reported
for withdrawal.

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Population: Intent-to-Treat
Table 5.5
Summary of Protocol Deviations

FSC250/50 Salmeterol Total


Protocol deviation (N=314) (N=325) (N=639)
-----------------------------------------------------------------------------------------------------------
Any protocol deviation 18 (6%) 26 (8%) 44 (7%)

Inclusion criteria violation 7 (2%) 3 (<1%) 10 (2%)


Exclusion criteria violation 3 (<1%) 4 (1%) 7 (1%)
Use of prohibited medication 8 (3%) 20 (6%) 28 (4%)

311
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Population: Intent-to-Treat
Table 5.6
Summary of Inclusion/Exclusion Criteria Deviations

FSC250/50 Salmeterol Total


Criterion (N=314) (N=325) (N=639)
------------------------------------------------------------------------------------------------------
Any criteria deviations 10 (3%) 7 (2%) 17 (3%)

Inclusion criteria
Male or non-pregnant female >=40 years of age 1 (<1%) 0 1 (<1%)
Exacerbation history 2 (<1%) 2 (<1%) 4 (<1%)
Documented FEV1 % predicted <70% & FEV1/FVC<=0.7 4 (1%) 1 (<1%) 5 (<1%)
Exclusion criteria
Diagnosis of complicating comorbid condition 2 (<1%) 1 (<1%) 3 (<1%)
Clinically significant uncontrolled disease 1 (<1%) 1 (<1%) 2 (<1%)
Limited ability to provide valid informed consent 0 2 (<1%) 2 (<1%)

312
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Population: Intent-to-Treat
Table 5.7
Summary of Demographic Characteristics

FSC250/50 Salmeterol Total


(N=314) (N=325) (N=639)
-----------------------------------------------------------------------------------------------------------
Age (y) n 314 325 639
Mean 63.1 62.7 62.9
SD 9.15 9.30 9.22
Median 63.0 62.0 63.0
Min. 40 40 40
Max. 84 84 84
Age group (y) n 314 325 639
18-64 178 (57%) 192 (59%) 370 (58%)
65-74 98 (31%) 95 (29%) 193 (30%)
>=75 38 (12%) 38 (12%) 76 (12%)

Sex n 314 325 639


Female 140 (45%) 151 (46%) 291 (46%)
Male 174 (55%) 174 (54%) 348 (54%)

Ethnicity n 314 325 639


Hispanic/Latino 116 (37%) 120 (37%) 236 (37%)
Not Hispanic/Latino 198 (63%) 205 (63%) 403 (63%)

313
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Population: Intent-to-Treat
Table 5.8
Summary of Race and Racial Combinations

FSC250/50 Salmeterol Total


Race (N=314) (N=325) (N=639)
---------------------------------------------------------------------------------------------------------
n 314 325 639
African American/African Heritage 26 (8%) 22 (7%) 48 (8%)
American Indian or Alaska Native 1 (<1%) 2 (<1%) 3 (<1%)
Asian 0 1 (<1%) 1 (<1%)
Central/South Asian Heritage 0 0 0
Japanese/East Asian Heritage/ 0 1 (<1%) 1 (<1%)
South East Asian Heritage
Native Hawaiian or other Pacific Islander 1 (<1%) 0 1 (<1%)
White 284 (90%) 300 (92%) 584 (91%)
African American/African Heritage & American Indian or Alaska 1 (<1%) 0 1 (<1%)
Native
American Indian or Alaska Native & White 1 (<1%) 0 1 (<1%)

314
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Population: Intent-to-Treat
Table 5.9
Summary of Race and Racial Combination Details

FSC250/50 Salmeterol Total


Race (N=314) (N=325) (N=639)
-----------------------------------------------------------------------------------------
n 314 325 639
African American/African Heritage 26 (8%) 22 (7%) 48 (8%)
American Indian or Alaska Native 1 (<1%) 2 (<1%) 3 (<1%)
Asian - Central/South Asian Heritage 0 0 0
Asian - East Asian Heritage 0 0 0
Asian - Japanese Heritage 0 1 (<1%) 1 (<1%)
Asian - South East Asian Heritage 0 0 0
Asian - Mixed Race 0 0 0
Native Hawaiian or other Pacific Islander 1 (<1%) 0 1 (<1%)
White - Arabic/North African Heritage 1 (<1%) 1 (<1%) 2 (<1%)
White - White/Caucasian/European Heritage 283 (90%) 298 (92%) 581 (91%)
White - Mixed Race 0 1 (<1%) 1 (<1%)
Mixed Race 2 (<1%) 0 2 (<1%)

315
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Population: Intent-to-Treat
Table 5.10
Summary of Disease Characteristics

FSC250/50 Salmeterol Total


(N=314) (N=325) (N=639)
----------------------------------------------------------------------------------------------------
Duration of COPD (yrs)
n 314 325 639
Mean 7.0 6.6 6.8
SD 5.66 5.22 5.44
Median 6.0 5.0 5.4
Min. 0.5 0.3 0.3
Max. 34.0 30.0 34.0
COPD type
n 314 325 639
Chronic bronchitis 114 (36%) 129 (40%) 243 (38%)
Emphysema 121 (39%) 119 (37%) 240 (38%)
Both 79 (25%) 77 (24%) 156 (24%)

Exacs in last 12 mos req hospitalization


n 314 325 639
0 1 (<1%) 2 (<1%) 3 (<1%)
1 229 (73%) 238 (73%) 467 (73%)
>=2 84 (27%) 85 (26%) 169 (26%)

Exacs in last 12 mos req OCS/antibiotic


n 314 325 639
0 107 (34%) 109 (34%) 216 (34%)
1 83 (26%) 92 (28%) 175 (27%)
2 72 (23%) 69 (21%) 141 (22%)
>=3 52 (17%) 55 (17%) 107 (17%)
History of smoking use
n 314 325 639
Current smoker 136 (43%) 155 (48%) 291 (46%)
Former smoker 178 (57%) 170 (52%) 348 (54%)

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Population: Intent-to-Treat
Table 5.10
Summary of Disease Characteristics

FSC250/50 Salmeterol Total


(N=314) (N=325) (N=639)
----------------------------------------------------------------------------------------------------
Number of pack years
n 314 325 639
Mean 52.0 56.3 54.2
SD 29.96 33.42 31.81
Median 45.0 49.0 46.0
Min. 10 10 10
Max. 162 258 258
Body Mass Index
n 313 323 636
Mean 28.0 28.3 28.2
SD 6.85 6.95 6.90
Median 27.1 27.5 27.3
Min. 15 14 14
Max. 56 60 60

COPD therapy randomization stratum


n 314 325 639
Concurrent tiotropium use and prior ICS use 103 (33%) 103 (32%) 206 (32%)
Concurrent tiotropium use and no prior ICS use 18 (6%) 22 (7%) 40 (6%)
No concurrent tiotropium use and prior ICS use 139 (44%) 144 (44%) 283 (44%)
No concurrent tiotropium use and no prior ICS use 54 (17%) 56 (17%) 110 (17%)

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Table 5.11
Summary of Baseline Pulmonary Function Tests

FSC250/50 Salmeterol Total


(N=314) (N=325) (N=639)
-----------------------------------------------------------------------------------------------------------
FEV1 (L) n 313 325 638
Mean 1.08 1.14 1.11
SD 0.476 0.467 0.472
Median 1.03 1.10 1.06
Min. 0.16 0.32 0.16
Max. 2.69 2.83 2.83
FEV1 % predicted n 313 325 638
Mean 38.5 41.2 39.9
SD 14.82 16.85 15.93
Median 36.7 40.1 38.3
Min. 6 9 6
Max. 77 145 145

Post-bronchodilator FEV1 (L) n 312 324 636


Mean 1.22 1.25 1.24
SD 0.522 0.493 0.508
Median 1.16 1.20 1.17
Min. 0.18 0.35 0.18
Max. 2.87 2.89 2.89

Post-bronchodilator FEV1 % predicted n 312 324 636


Mean 43.2 44.8 44.0
SD 16.06 16.25 16.16
Median 42.0 44.8 43.0
Min. 13 11 11
Max. 86 95 95
Post-bronchodilator FVC (L) n 312 324 636
Mean 2.44 2.49 2.47
SD 0.826 0.753 0.790
Median 2.35 2.45 2.40
Min. 0.30 0.91 0.30

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Table 5.11
Summary of Baseline Pulmonary Function Tests

FSC250/50 Salmeterol Total


(N=314) (N=325) (N=639)
-----------------------------------------------------------------------------------------------------------
Post-bronchodilator FVC (L) Max. 5.00 4.65 5.00

Post-bronchodilator FEV1/FVC n 312 324 636


Mean 0.49 0.50 0.50
SD 0.127 0.124 0.126
Median 0.49 0.50 0.49
Min. 0.11 0.26 0.11
Max. 0.99 0.87 0.99

FEV1 % reversibility n 312 324 636


Mean 15.1 12.1 13.6
SD 23.79 16.69 20.52
Median 10.4 9.9 10.1
Min. -16 -54 -54
Max. 282 113 282

Reversibility n 312 324 636


Nonreversible 232 (74%) 245 (76%) 477 (75%)
Reversible 80 (26%) 79 (24%) 159 (25%)

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Table 5.12
Summary of Current Medical Conditions

FSC250/50 Salmeterol Total


Medical condition classification (N=314) (N=325) (N=639)
-----------------------------------------------------------------------------------------------------------
Any condition 295 (94%) 298 (92%) 593 (93%)

Cardiovascular disorders 190 (61%) 198 (61%) 388 (61%)


Musculoskeletal and connective tissue disorders 151 (48%) 152 (47%) 303 (47%)
Gastrointestinal disorders 140 (45%) 151 (46%) 291 (46%)
Respiratory, thoracic and mediastinal disorders 129 (41%) 148 (46%) 277 (43%)
Psychiatric disorders 125 (40%) 126 (39%) 251 (39%)
Cardiac disorders 113 (36%) 117 (36%) 230 (36%)
Endocrine disorders 81 (26%) 100 (31%) 181 (28%)
Eye disorders 78 (25%) 87 (27%) 165 (26%)
Nervous system disorders 74 (24%) 74 (23%) 148 (23%)
Metabolism and nutrition disorders 69 (22%) 66 (20%) 135 (21%)
Investigations 73 (23%) 59 (18%) 132 (21%)
Vascular disorders 54 (17%) 65 (20%) 119 (19%)
Renal and urinary disorders 61 (19%) 54 (17%) 115 (18%)
General disorders and administration site conditions 54 (17%) 60 (18%) 114 (18%)
Reproductive system and breast disorders 64 (20%) 49 (15%) 113 (18%)
Blood and lymphatic system disorders 39 (12%) 49 (15%) 88 (14%)
Skin and subcutaneous tissue disorders 41 (13%) 40 (12%) 81 (13%)
Ear and labyrinth disorders 34 (11%) 23 (7%) 57 (9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 21 (7%) 19 (6%) 40 (6%)
Hepatobiliary disorders 19 (6%) 17 (5%) 36 (6%)
Immune system disorders 16 (5%) 20 (6%) 36 (6%)
Infections and infestations 13 (4%) 21 (6%) 34 (5%)
Congenital, familial and genetic disorders 3 (<1%) 2 (<1%) 5 (<1%)
Injury, poisoning and procedural complications 2 (<1%) 2 (<1%) 4 (<1%)

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Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
Any medication 310 (99%) 324 (>99%)

RESPIRATORY SYSTEM
Any medication 305 (97%) 322 (>99%)
SALBUTAMOL 216 (69%) 232 (71%)
SALMETEROL XINAFOATE+FLUTICASONE PROPIONATE 128 (41%) 140 (43%)
TIOTROPIUM BROMIDE 101 (32%) 111 (34%)
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE 90 (29%) 107 (33%)
OXYGEN 92 (29%) 86 (26%)
IPRATROPIUM BROMIDE 82 (26%) 73 (22%)
BUDESONIDE+FORMOTEROL FUMARATE 62 (20%) 43 (13%)
SALBUTAMOL SULFATE 36 (11%) 32 (10%)
GUAIFENESIN 24 (8%) 36 (11%)
BUDESONIDE 21 (7%) 31 (10%)
FORMOTEROL FUMARATE 25 (8%) 23 (7%)
DEXAMETHASONE 26 (8%) 21 (6%)
THEOPHYLLINE 18 (6%) 23 (7%)
TIOTROPIUM 19 (6%) 21 (6%)
MOMETASONE FUROATE 18 (6%) 18 (6%)
ACETYLCYSTEINE 16 (5%) 16 (5%)
IPRATROPIUM 15 (5%) 17 (5%)
MONTELUKAST SODIUM 17 (5%) 6 (2%)
LEVOSALBUTAMOL HYDROCHLORIDE 11 (4%) 11 (3%)
PROAIR (NOS) 7 (2%) 14 (4%)
SALBUTAMOL+IPRATROPIUM 5 (2%) 12 (4%)
FLUTICASONE PROPIONATE 6 (2%) 10 (3%)
BENZONATATE 8 (3%) 6 (2%)
ANTIBIOTICS NOS 6 (2%) 7 (2%)
FORMOTEROL 4 (1%) 9 (3%)
SALMETEROL+FLUTICASONE 4 (1%) 7 (2%)
MOMETASONE 4 (1%) 6 (2%)
PREDNISOLONE 5 (2%) 5 (2%)

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Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
BUDESONIDE+FORMOTEROL 6 (2%) 3 (<1%)
BRONCHODILATOR (NOS) 3 (<1%) 4 (1%)
TUSSIONEX (NOS) 3 (<1%) 4 (1%)
SALBUTAMOL+IPRATROPIUM BROMIDE 4 (1%) 2 (<1%)
SALMETEROL 2 (<1%) 4 (1%)
ARFORMOTEROL TARTRATE 4 (1%) 1 (<1%)
BETAMETHASONE 3 (<1%) 1 (<1%)
GUAIFENESIN+DEXTROMETHORPHAN HYDROBROMIDE 2 (<1%) 2 (<1%)
MOMETASONE+FORMOTEROL 2 (<1%) 2 (<1%)
ROBITUSSIN (NOS) 3 (<1%) 1 (<1%)
AMINOPHYLLINE 1 (<1%) 2 (<1%)
CODEINE+GUAIFENESIN 1 (<1%) 2 (<1%)
FLUTICASONE 1 (<1%) 2 (<1%)
HYCODAN (NOS) 1 (<1%) 2 (<1%)
INDACATEROL MALEATE 2 (<1%) 1 (<1%)
LEVALBUTEROL TARTRATE 2 (<1%) 1 (<1%)
SALMETEROL XINAFOATE 2 (<1%) 1 (<1%)
ANTIFLU (NOS) 2 (<1%) 0
BECLOMETASONE DIPROPIONATE 0 2 (<1%)
CODEINE PHOSPHATE+GUAIFENESIN+PHENIRAMINE MALEATE 1 (<1%) 1 (<1%)
DIPHENHYDRAMINE 2 (<1%) 0
FENOTEROL HYDROBROMIDE+IPRATROPIUM BROMIDE 2 (<1%) 0
FLUNISOLIDE 0 2 (<1%)
SALBUTAMOL SULFATE+IPRATROPIUM 1 (<1%) 1 (<1%)
TRIAMCINOLONE ACETONIDE 0 2 (<1%)
ANTI-ASTHMATICS 0 1 (<1%)
AZELASTINE HYDROCHLORIDE 0 1 (<1%)
BISOLVON (NOS) 0 1 (<1%)
CODEINE PHOSPHATE+GUAIFENESIN 0 1 (<1%)
CODEINE+PROMETHAZINE 1 (<1%) 0
COUGH COLD PREPARATIONS NOS 0 1 (<1%)
DEXTROMETHORPHAN HYDROBROMIDE 1 (<1%) 0

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Population: Intent-to-Treat
Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
FENOTEROL+IPRATROPIUM BROMIDE 1 (<1%) 0
FLUTICASONE FUROATE 0 1 (<1%)
HYDROCODONE 0 1 (<1%)
HYDROCODONE BITARTRATE+HOMATROPINE METHYLBROMIDE 1 (<1%) 0
INHALED ALPHA AND BETA ADRENORECEPTOR AGONISTS (NOS) 0 1 (<1%)
LEVOSALBUTAMOL 1 (<1%) 0
LORATADINE 0 1 (<1%)
MOMETASONE FUROATE+FORMOTEROL FUMARATE 0 1 (<1%)
MONTELUKAST 1 (<1%) 0
PARACETAMOL+HYDROCODONE 1 (<1%) 0
PIRBUTEROL ACETATE 1 (<1%) 0
PROMETHAZINE 1 (<1%) 0
ROBITUSSIN AC (NOS) 1 (<1%) 0
SALBUTAMOL+BECLOMETASONE 0 1 (<1%)
SALMETEROL+FLUTICASONE PROPIONATE 0 1 (<1%)
SODIUM CHLORIDE 0 1 (<1%)
TERBUTALINE SULFATE 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)
XYLOMETAZOLINE HYDROCHLORIDE+IPRATROPIUM BROMIDE 0 1 (<1%)
ZAFIRLUKAST 1 (<1%) 0

SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS


Any medication 276 (88%) 287 (88%)
PREDNISONE 184 (59%) 195 (60%)
METHYLPREDNISOLONE SODIUM SUCCINATE 81 (26%) 82 (25%)
METHYLPREDNISOLONE 32 (10%) 38 (12%)
MEPREDNISONE 32 (10%) 33 (10%)
HYDROCORTISONE 31 (10%) 26 (8%)
BUDESONIDE 21 (7%) 31 (10%)
DEXAMETHASONE 26 (8%) 21 (6%)
HYDROCORTISONE ACETATE 15 (5%) 13 (4%)
PREDNISOLONE 5 (2%) 5 (2%)

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Population: Intent-to-Treat
Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
BETAMETHASONE 3 (<1%) 1 (<1%)
CORTICOSTEROID NOS 2 (<1%) 1 (<1%)
TRIAMCINOLONE ACETONIDE 0 2 (<1%)
HYDROCORTISONE SODIUM SUCCINATE 0 1 (<1%)
METHYLPREDNISOLONE HEMISUCCINATE 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)
ANTIINFECTIVES FOR SYSTEMIC USE
Any medication 250 (80%) 257 (79%)
INFLUENZA VACCINE 72 (23%) 76 (23%)
LEVOFLOXACIN 69 (22%) 78 (24%)
MOXIFLOXACIN 43 (14%) 49 (15%)
AZITHROMYCIN 41 (13%) 49 (15%)
PNEUMOCOCCAL VACCINE 46 (15%) 36 (11%)
CEFTRIAXONE 35 (11%) 43 (13%)
DOXYCYCLINE 24 (8%) 25 (8%)
CLARITHROMYCIN 22 (7%) 13 (4%)
AMPICILLIN+SULBACTAM 16 (5%) 12 (4%)
AMOXICILLIN+CLAVULANIC ACID 10 (3%) 15 (5%)
AMOXICILLIN TRIHYDRATE+CLAVULANATE POTASSIUM 14 (4%) 6 (2%)
AMOXICILLIN 7 (2%) 9 (3%)
CEFUROXIME AXETIL 7 (2%) 7 (2%)
CIPROFLOXACIN HYDROCHLORIDE 7 (2%) 7 (2%)
ANTIBIOTICS NOS 6 (2%) 7 (2%)
CIPROFLOXACIN 8 (3%) 5 (2%)
OPTAMOX (NOS) 3 (<1%) 6 (2%)
AMOXICILLIN+CLAVULANATE 6 (2%) 2 (<1%)
VANCOMYCIN 4 (1%) 4 (1%)
CEFEPIME 3 (<1%) 3 (<1%)
H1N1 INFLUENZA VACCINE 4 (1%) 2 (<1%)
INFLUENZA VIRUS VACCINE INACTIVATED 5 (2%) 1 (<1%)
PIPERACILLIN SODIUM+TAZOBACTAM SODIUM 4 (1%) 2 (<1%)

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Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
SULFAMETHOXAZOLE+TRIMETHOPRIM 5 (2%) 1 (<1%)
CEFALEXIN 2 (<1%) 3 (<1%)
CLAVULANIC ACID 2 (<1%) 2 (<1%)
MOXIFLOXACIN HYDROCHLORIDE 3 (<1%) 1 (<1%)
AMPICILLIN 1 (<1%) 2 (<1%)
SULBACTAM 2 (<1%) 1 (<1%)
TRIVALENT INFLUENZA VACCINE 2 (<1%) 1 (<1%)
AMOXICILLIN+SULBACTAM 0 2 (<1%)
BENZYLPENICILLIN 1 (<1%) 1 (<1%)
CEFDINIR 0 2 (<1%)
CEFEPIME HYDROCHLORIDE 1 (<1%) 1 (<1%)
CEFPODOXIME 2 (<1%) 0
CEFUROXIME 1 (<1%) 1 (<1%)
DOXYCYCLINE HYCLATE 0 2 (<1%)
ERYTHROMYCIN 1 (<1%) 1 (<1%)
GEMIFLOXACIN MESILATE 1 (<1%) 1 (<1%)
GENTAMICIN 1 (<1%) 1 (<1%)
AMOXICILLIN TRIHYDRATE 0 1 (<1%)
AZTREONAM 1 (<1%) 0
BIAXIN (NOS) 1 (<1%) 0
CEFOTAXIME SODIUM 0 1 (<1%)
CLINDAMYCIN 0 1 (<1%)
DORIPENEM 1 (<1%) 0
DOXYCYCLINE HYDROCHLORIDE 1 (<1%) 0
FLUCONAZOLE 0 1 (<1%)
GENTAMICIN SULFATE 0 1 (<1%)
IMIPENEM+CILASTATIN SODIUM 0 1 (<1%)
OSELTAMIVIR 0 1 (<1%)
PIPERACILLIN 1 (<1%) 0
QUINOLONES (NOS) 1 (<1%) 0

ALIMENTARY TRACT AND METABOLISM

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Population: Intent-to-Treat
Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
Any medication 240 (76%) 249 (77%)
PREDNISONE 184 (59%) 195 (60%)
HYDROCORTISONE 31 (10%) 26 (8%)
BUDESONIDE 21 (7%) 31 (10%)
DEXAMETHASONE 26 (8%) 21 (6%)
HYDROCORTISONE ACETATE 15 (5%) 13 (4%)
STEROIDS NOS 7 (2%) 8 (2%)
ANTIBIOTICS NOS 6 (2%) 7 (2%)
PREDNISOLONE 5 (2%) 5 (2%)
VANCOMYCIN 4 (1%) 4 (1%)
RANITIDINE 4 (1%) 3 (<1%)
BETAMETHASONE 3 (<1%) 1 (<1%)
BECLOMETASONE DIPROPIONATE 0 2 (<1%)
DOXYCYCLINE HYCLATE 0 2 (<1%)
TRIAMCINOLONE ACETONIDE 0 2 (<1%)
ACETYLSALICYLIC ACID 1 (<1%) 0
HYDROCORTISONE SODIUM SUCCINATE 0 1 (<1%)
MAGNESIUM 1 (<1%) 0
MAGNESIUM SULFATE 1 (<1%) 0
OMEPRAZOLE 1 (<1%) 0
PROMETHAZINE 1 (<1%) 0
SODIUM CHLORIDE 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)

DERMATOLOGICALS
Any medication 194 (62%) 202 (62%)
METHYLPREDNISOLONE SODIUM SUCCINATE 81 (26%) 82 (25%)
METHYLPREDNISOLONE 32 (10%) 38 (12%)
HYDROCORTISONE 31 (10%) 26 (8%)
BUDESONIDE 21 (7%) 31 (10%)
DEXAMETHASONE 26 (8%) 21 (6%)
MOMETASONE FUROATE 18 (6%) 18 (6%)

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Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
HYDROCORTISONE ACETATE 15 (5%) 13 (4%)
FLUTICASONE PROPIONATE 6 (2%) 10 (3%)
ANTIBIOTICS NOS 6 (2%) 7 (2%)
MOMETASONE 4 (1%) 6 (2%)
PREDNISOLONE 5 (2%) 5 (2%)
BETAMETHASONE 3 (<1%) 1 (<1%)
FLUTICASONE 1 (<1%) 2 (<1%)
BECLOMETASONE DIPROPIONATE 0 2 (<1%)
DIPHENHYDRAMINE 2 (<1%) 0
ERYTHROMYCIN 1 (<1%) 1 (<1%)
GENTAMICIN 1 (<1%) 1 (<1%)
TRIAMCINOLONE ACETONIDE 0 2 (<1%)
CLINDAMYCIN 0 1 (<1%)
FLUCONAZOLE 0 1 (<1%)
GENTAMICIN SULFATE 0 1 (<1%)
HYDROCORTISONE SODIUM SUCCINATE 0 1 (<1%)
MAGNESIUM SULFATE 1 (<1%) 0
METHYLPREDNISOLONE HEMISUCCINATE 0 1 (<1%)
PHENOL+LEVOMENTHOL 0 1 (<1%)
PROMETHAZINE 1 (<1%) 0
TRIAMCINOLONE 0 1 (<1%)
SENSORY ORGANS
Any medication 187 (60%) 187 (58%)
METHYLPREDNISOLONE SODIUM SUCCINATE 81 (26%) 82 (25%)
METHYLPREDNISOLONE 32 (10%) 38 (12%)
HYDROCORTISONE 31 (10%) 26 (8%)
DEXAMETHASONE 26 (8%) 21 (6%)
ACETYLCYSTEINE 16 (5%) 16 (5%)
HYDROCORTISONE ACETATE 15 (5%) 13 (4%)
CIPROFLOXACIN HYDROCHLORIDE 7 (2%) 7 (2%)
ANTIBIOTICS NOS 6 (2%) 7 (2%)

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Population: Intent-to-Treat
Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CIPROFLOXACIN 8 (3%) 5 (2%)
PREDNISOLONE 5 (2%) 5 (2%)
HEPARIN SODIUM 2 (<1%) 4 (1%)
AMPICILLIN 1 (<1%) 2 (<1%)
CORTICOSTEROID NOS 2 (<1%) 1 (<1%)
HEPARIN CALCIUM 1 (<1%) 2 (<1%)
BENZYLPENICILLIN 1 (<1%) 1 (<1%)
ERYTHROMYCIN 1 (<1%) 1 (<1%)
GENTAMICIN 1 (<1%) 1 (<1%)
TRIAMCINOLONE ACETONIDE 0 2 (<1%)
AZELASTINE HYDROCHLORIDE 0 1 (<1%)
GENTAMICIN SULFATE 0 1 (<1%)
HEPARIN (NOS) 0 1 (<1%)
HYDROCORTISONE SODIUM SUCCINATE 0 1 (<1%)
SODIUM CHLORIDE 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)

VARIOUS
Any medication 103 (33%) 101 (31%)
OXYGEN 92 (29%) 86 (26%)
ACETYLCYSTEINE 16 (5%) 16 (5%)
INDACATEROL MALEATE 2 (<1%) 1 (<1%)
INDACATEROL 2 (<1%) 0
MEDICATION UNKNOWN 0 2 (<1%)
COMPRESSED AIR 0 1 (<1%)
GLUCOSE 1 (<1%) 0
MAGNESIUM SULFATE 1 (<1%) 0
CARDIOVASCULAR SYSTEM
Any medication 73 (23%) 66 (20%)
HYDROCORTISONE 31 (10%) 26 (8%)
DEXAMETHASONE 26 (8%) 21 (6%)

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Population: Intent-to-Treat
Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
HYDROCORTISONE ACETATE 15 (5%) 13 (4%)
PREDNISOLONE 5 (2%) 5 (2%)
HEPARIN SODIUM 2 (<1%) 4 (1%)
BETAMETHASONE 3 (<1%) 1 (<1%)
HEPARIN CALCIUM 1 (<1%) 2 (<1%)
ALDACTONE (NOS) 0 1 (<1%)
ATENOLOL 0 1 (<1%)
FUROSEMIDE 0 1 (<1%)
HEPARIN (NOS) 0 1 (<1%)
HYDROCORTISONE SODIUM SUCCINATE 0 1 (<1%)
BLOOD AND BLOOD FORMING ORGANS
Any medication 6 (2%) 9 (3%)
HEPARIN SODIUM 2 (<1%) 4 (1%)
HEPARIN CALCIUM 1 (<1%) 2 (<1%)
ACETYLSALICYLIC ACID 1 (<1%) 0
ENOXAPARIN SODIUM 0 1 (<1%)
GLUCOSE 1 (<1%) 0
HEPARIN (NOS) 0 1 (<1%)
MAGNESIUM SULFATE 1 (<1%) 0
SODIUM CHLORIDE 0 1 (<1%)
GENITO URINARY SYSTEM AND SEX HORMONES
Any medication 6 (2%) 9 (3%)
ANTIBIOTICS NOS 6 (2%) 7 (2%)
CLINDAMYCIN 0 1 (<1%)
SILDENAFIL 0 1 (<1%)
NERVOUS SYSTEM
Any medication 5 (2%) 5 (2%)
METAMIZOLE SODIUM 1 (<1%) 1 (<1%)
ACETYLSALICYLIC ACID 1 (<1%) 0

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Table 5.13
Summary of Prior COPD Medication Use

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
HYDROCODONE 0 1 (<1%)
LORAZEPAM 0 1 (<1%)
MORPHINE 0 1 (<1%)
NICOTINE 1 (<1%) 0
PARACETAMOL+CAFFEINE+BUTALBITAL 1 (<1%) 0
PARACETAMOL+HYDROCODONE 1 (<1%) 0
PARACETAMOL+HYDROCODONE BITARTRATE 1 (<1%) 0
PHENOL+LEVOMENTHOL 0 1 (<1%)
PROMETHAZINE 1 (<1%) 0
MUSCULO-SKELETAL SYSTEM
Any medication 1 (<1%) 0
ACETYLSALICYLIC ACID 1 (<1%) 0

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
Any medication 141 (45%) 169 (52%)

SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS


Any medication 112 (36%) 140 (43%)
PREDNISONE 82 (26%) 87 (27%)
METHYLPREDNISOLONE SODIUM SUCCINATE 33 (11%) 27 (8%)
METHYLPREDNISOLONE 16 (5%) 30 (9%)
MEPREDNISONE 10 (3%) 18 (6%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)
METHYLPREDNISOLONE ACETATE 3 (<1%) 3 (<1%)
HYDROCORTISONE ACETATE 1 (<1%) 2 (<1%)
TRIAMCINOLONE ACETONIDE 1 (<1%) 2 (<1%)
CORTICOSTEROID NOS 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)
ANTIINFECTIVES FOR SYSTEMIC USE
Any medication 105 (33%) 126 (39%)
LEVOFLOXACIN 25 (8%) 40 (12%)
AZITHROMYCIN 29 (9%) 34 (10%)
MOXIFLOXACIN 22 (7%) 28 (9%)
DOXYCYCLINE 13 (4%) 17 (5%)
CEFTRIAXONE 11 (4%) 14 (4%)
AMOXICILLIN 5 (2%) 12 (4%)
AMOXICILLIN+CLAVULANIC ACID 9 (3%) 5 (2%)
CIPROFLOXACIN HYDROCHLORIDE 7 (2%) 7 (2%)
AMOXICILLIN TRIHYDRATE+CLAVULANATE POTASSIUM 5 (2%) 7 (2%)
AMPICILLIN+SULBACTAM 4 (1%) 8 (2%)
CLARITHROMYCIN 6 (2%) 3 (<1%)

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
INFLUENZA VACCINE 1 (<1%) 7 (2%)
SULFAMETHOXAZOLE+TRIMETHOPRIM 3 (<1%) 5 (2%)
CIPROFLOXACIN 5 (2%) 2 (<1%)
PIPERACILLIN SODIUM+TAZOBACTAM SODIUM 5 (2%) 2 (<1%)
AMOXICILLIN+CLAVULANATE 3 (<1%) 2 (<1%)
DOXYCYCLINE HYCLATE 2 (<1%) 3 (<1%)
OPTAMOX (NOS) 2 (<1%) 3 (<1%)
VANCOMYCIN 3 (<1%) 2 (<1%)
AMOXICILLIN TRIHYDRATE 0 3 (<1%)
CEFEPIME 1 (<1%) 2 (<1%)
ERYTHROMYCIN 2 (<1%) 1 (<1%)
ANTIBIOTICS NOS 2 (<1%) 0
CEFALEXIN 2 (<1%) 0
CEFEPIME HYDROCHLORIDE 1 (<1%) 1 (<1%)
CEFUROXIME AXETIL 2 (<1%) 0
CLAVULANIC ACID 0 2 (<1%)
INFLUENZA VIRUS VACCINE INACTIVATED 1 (<1%) 1 (<1%)
PNEUMOCOCCAL VACCINE 0 2 (<1%)
AMIKACIN 1 (<1%) 0
AMIKACIN SULPHATE 1 (<1%) 0
BENZYLPENICILLIN 0 1 (<1%)
BIAXIN (NOS) 1 (<1%) 0
CEFADROXIL 1 (<1%) 0
CEFDINIR 0 1 (<1%)
CEFOTAXIME SODIUM 1 (<1%) 0
CEFTRIAXONE SODIUM 0 1 (<1%)
CLINDAMYCIN 1 (<1%) 0
DORIPENEM 0 1 (<1%)
DOXYCYCLINE MONOHYDRATE 0 1 (<1%)
LINEZOLID 1 (<1%) 0
MOXIFLOXACIN HYDROCHLORIDE 1 (<1%) 0
SULBACTAM 0 1 (<1%)

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
SULFAMETHOXAZOLE 1 (<1%) 0
TRIMETHOPRIM 1 (<1%) 0
UNASYNA NOS 1 (<1%) 0
UNIFLOX (NOS) 0 1 (<1%)

ALIMENTARY TRACT AND METABOLISM


Any medication 99 (32%) 120 (37%)
PREDNISONE 82 (26%) 87 (27%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)
DOXYCYCLINE HYCLATE 2 (<1%) 3 (<1%)
SODIUM CHLORIDE 2 (<1%) 3 (<1%)
VANCOMYCIN 3 (<1%) 2 (<1%)
HYDROCORTISONE ACETATE 1 (<1%) 2 (<1%)
STEROIDS NOS 1 (<1%) 2 (<1%)
TRIAMCINOLONE ACETONIDE 1 (<1%) 2 (<1%)
ANTIBIOTICS NOS 2 (<1%) 0
MAGNESIUM SULFATE 2 (<1%) 0
OMEPRAZOLE 1 (<1%) 1 (<1%)
BECLOMETASONE 0 1 (<1%)
CYPROHEPTADINE 1 (<1%) 0
EPINEPHRINE 1 (<1%) 0
LACTULOSE 0 1 (<1%)
MAGNESIUM 0 1 (<1%)
NYSTATIN 1 (<1%) 0
ONDANSETRON 1 (<1%) 0
PANTOPRAZOLE 1 (<1%) 0
PROMETHAZINE 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
RESPIRATORY SYSTEM
Any medication 86 (27%) 119 (37%)
SALBUTAMOL 35 (11%) 50 (15%)
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE 23 (7%) 17 (5%)
IPRATROPIUM BROMIDE 14 (4%) 21 (6%)
OXYGEN 15 (5%) 18 (6%)
SALMETEROL XINAFOATE+FLUTICASONE PROPIONATE 10 (3%) 13 (4%)
IPRATROPIUM 8 (3%) 9 (3%)
DEXAMETHASONE 5 (2%) 11 (3%)
GUAIFENESIN 8 (3%) 8 (2%)
LEVOSALBUTAMOL HYDROCHLORIDE 5 (2%) 7 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
ACETYLCYSTEINE 6 (2%) 4 (1%)
THEOPHYLLINE 5 (2%) 4 (1%)
TIOTROPIUM BROMIDE 5 (2%) 4 (1%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)
FORMOTEROL FUMARATE 3 (<1%) 4 (1%)
SALBUTAMOL SULFATE 3 (<1%) 4 (1%)
SALBUTAMOL+IPRATROPIUM 3 (<1%) 4 (1%)
BUDESONIDE+FORMOTEROL FUMARATE 3 (<1%) 3 (<1%)
BRONCHODILATOR (NOS) 2 (<1%) 3 (<1%)
GUAIFENESIN+DEXTROMETHORPHAN HYDROBROMIDE 2 (<1%) 3 (<1%)
SODIUM CHLORIDE 2 (<1%) 3 (<1%)
BENZONATATE 1 (<1%) 3 (<1%)
ROBITUSSIN (NOS) 1 (<1%) 3 (<1%)
LORATADINE 1 (<1%) 2 (<1%)
ROBITUSSIN AC (NOS) 0 3 (<1%)
TRIAMCINOLONE ACETONIDE 1 (<1%) 2 (<1%)
ANTIBIOTICS NOS 2 (<1%) 0
ARFORMOTEROL TARTRATE 1 (<1%) 1 (<1%)

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CODEINE PHOSPHATE+GUAIFENESIN+PHENIRAMINE MALEATE 1 (<1%) 1 (<1%)
CODEINE+GUAIFENESIN 1 (<1%) 1 (<1%)
DEXTROMETHORPHAN 0 2 (<1%)
FORMOTEROL 1 (<1%) 1 (<1%)
MOMETASONE 0 2 (<1%)
MOMETASONE FUROATE 2 (<1%) 0
MOMETASONE FUROATE+FORMOTEROL FUMARATE 1 (<1%) 1 (<1%)
MONTELUKAST SODIUM 2 (<1%) 0
PROAIR (NOS) 1 (<1%) 1 (<1%)
TIOTROPIUM 1 (<1%) 1 (<1%)
ACETYLSALICYLIC ACID+CHLORPHENAMINE MALEATE+PHENYLPROPANOLAMINE 1 (<1%) 0
BITARTRATE
AMINOPHYLLINE 0 1 (<1%)
BECLOMETASONE 0 1 (<1%)
CICLESONIDE 0 1 (<1%)
CODEINE PHOSPHATE 0 1 (<1%)
CODEINE PHOSPHATE+CHLORPHENAMINE MALEATE+IODINATED GLYCEROL 1 (<1%) 0
CYPROHEPTADINE 1 (<1%) 0
DESLORATADINE 0 1 (<1%)
DEXTROMETHORPHAN HYDROBROMIDE+CHLORPHENAMINE MALEATE+PHENYLEPHRINE 0 1 (<1%)
HYDROCHLORIDE
DORNASE ALFA 1 (<1%) 0
EPINEPHRINE 1 (<1%) 0
FLUTICASONE 1 (<1%) 0
GUAIFENESIN+DEXTROMETHORPHAN 0 1 (<1%)
HYCODAN (NOS) 0 1 (<1%)
HYDROCODONE BITARTRATE+HOMATROPINE METHYLBROMIDE 1 (<1%) 0
OXYMETAZOLINE HYDROCHLORIDE 0 1 (<1%)
PARACETAMOL+CHLORPHENAMINE MALEATE+PSEUDOEPHEDRINE HYDROCHLORIDE 1 (<1%) 0
PARACETAMOL+DEXTROMETHORPHAN HYDROBROMIDE+PSEUDOEPHEDRINE 1 (<1%) 0
HYDROCHLORIDE+DOXYLAMINE SUCCINATE
PARACETAMOL+HYDROCODONE 0 1 (<1%)

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
PHENOL 0 1 (<1%)
PROMETHAZINE 0 1 (<1%)
SALBUTAMOL+IPRATROPIUM BROMIDE 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)
TUSSIONEX (NOS) 0 1 (<1%)

SENSORY ORGANS
Any medication 68 (22%) 82 (25%)
METHYLPREDNISOLONE SODIUM SUCCINATE 33 (11%) 27 (8%)
METHYLPREDNISOLONE 16 (5%) 30 (9%)
DEXAMETHASONE 5 (2%) 11 (3%)
CIPROFLOXACIN HYDROCHLORIDE 7 (2%) 7 (2%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
ACETYLCYSTEINE 6 (2%) 4 (1%)
CIPROFLOXACIN 5 (2%) 2 (<1%)
SODIUM CHLORIDE 2 (<1%) 3 (<1%)
ERYTHROMYCIN 2 (<1%) 1 (<1%)
HYDROCORTISONE ACETATE 1 (<1%) 2 (<1%)
TRIAMCINOLONE ACETONIDE 1 (<1%) 2 (<1%)
ANTIBIOTICS NOS 2 (<1%) 0
AMIKACIN 1 (<1%) 0
AMIKACIN SULPHATE 1 (<1%) 0
BENZYLPENICILLIN 0 1 (<1%)
CORTICOSTEROID NOS 0 1 (<1%)
EPINEPHRINE 1 (<1%) 0
KETOROLAC TROMETAMOL 0 1 (<1%)
OXYMETAZOLINE HYDROCHLORIDE 0 1 (<1%)
POTASSIUM CHLORIDE+SODIUM CHLORIDE 1 (<1%) 0
TRIAMCINOLONE 0 1 (<1%)

DERMATOLOGICALS

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
Any medication 63 (20%) 86 (26%)
METHYLPREDNISOLONE SODIUM SUCCINATE 33 (11%) 27 (8%)
METHYLPREDNISOLONE 16 (5%) 30 (9%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)
BUDESONIDE 5 (2%) 3 (<1%)
BETAMETHASONE 1 (<1%) 6 (2%)
METHYLPREDNISOLONE ACETATE 3 (<1%) 3 (<1%)
ERYTHROMYCIN 2 (<1%) 1 (<1%)
HYDROCORTISONE ACETATE 1 (<1%) 2 (<1%)
TRIAMCINOLONE ACETONIDE 1 (<1%) 2 (<1%)
ANTIBIOTICS NOS 2 (<1%) 0
MAGNESIUM SULFATE 2 (<1%) 0
MOMETASONE 0 2 (<1%)
MOMETASONE FUROATE 2 (<1%) 0
AMIKACIN 1 (<1%) 0
AMIKACIN SULPHATE 1 (<1%) 0
BECLOMETASONE 0 1 (<1%)
BETAMETHASONE SODIUM PHOSPHATE+BETAMETHASONE ACETATE 0 1 (<1%)
CLINDAMYCIN 1 (<1%) 0
FLUTICASONE 1 (<1%) 0
NYSTATIN 1 (<1%) 0
PHENOL 0 1 (<1%)
PROMETHAZINE 0 1 (<1%)
TRIAMCINOLONE 0 1 (<1%)
CARDIOVASCULAR SYSTEM
Any medication 19 (6%) 36 (11%)
DEXAMETHASONE 5 (2%) 11 (3%)
HYDROCORTISONE 6 (2%) 8 (2%)
PREDNISOLONE 4 (1%) 7 (2%)

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
BETAMETHASONE 1 (<1%) 6 (2%)
FUROSEMIDE 1 (<1%) 2 (<1%)
HYDROCORTISONE ACETATE 1 (<1%) 2 (<1%)
BUMETANIDE 0 1 (<1%)
EPINEPHRINE 1 (<1%) 0
METHYLDOPA+HYDROCHLOROTHIAZIDE 0 1 (<1%)
NIMODIPINE 0 1 (<1%)
PHENOL 0 1 (<1%)

VARIOUS
Any medication 20 (6%) 21 (6%)
OXYGEN 15 (5%) 18 (6%)
ACETYLCYSTEINE 6 (2%) 4 (1%)
MAGNESIUM SULFATE 2 (<1%) 0
MEDICATION UNKNOWN 2 (<1%) 0
COMPRESSED AIR 1 (<1%) 0

NERVOUS SYSTEM
Any medication 6 (2%) 11 (3%)
PARACETAMOL 1 (<1%) 2 (<1%)
FENTANYL 1 (<1%) 1 (<1%)
MIDAZOLAM 1 (<1%) 1 (<1%)
PARACETAMOL+HYDROCODONE BITARTRATE 1 (<1%) 1 (<1%)
ACETYLSALICYLIC ACID+CHLORPHENAMINE MALEATE+PHENYLPROPANOLAMINE 1 (<1%) 0
BITARTRATE
BUPROPION HYDROCHLORIDE 0 1 (<1%)
CODEINE PHOSPHATE 0 1 (<1%)
DROPERIDOL 1 (<1%) 0
KETOROLAC TROMETAMOL 0 1 (<1%)
METAMIZOLE SODIUM 0 1 (<1%)
MORPHINE SULFATE 1 (<1%) 0
PARACETAMOL+HYDROCODONE 0 1 (<1%)

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Table 5.14
Summary of COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
PHENOL 0 1 (<1%)
PROMETHAZINE 0 1 (<1%)

BLOOD AND BLOOD FORMING ORGANS


Any medication 5 (2%) 5 (2%)
SODIUM CHLORIDE 2 (<1%) 3 (<1%)
ENOXAPARIN 0 2 (<1%)
MAGNESIUM SULFATE 2 (<1%) 0
EPINEPHRINE 1 (<1%) 0
POTASSIUM CHLORIDE+SODIUM CHLORIDE 1 (<1%) 0
GENITO URINARY SYSTEM AND SEX HORMONES
Any medication 5 (2%) 0
ANTIBIOTICS NOS 2 (<1%) 0
CLINDAMYCIN 1 (<1%) 0
NYSTATIN 1 (<1%) 0
TAMSULOSIN 1 (<1%) 0
MUSCULO-SKELETAL SYSTEM
Any medication 0 1 (<1%)
KETOROLAC TROMETAMOL 0 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
Any medication 276 (88%) 292 (90%)

CARDIOVASCULAR SYSTEM
Any medication 217 (69%) 229 (70%)
SIMVASTATIN 43 (14%) 58 (18%)
FUROSEMIDE 41 (13%) 58 (18%)
LISINOPRIL 46 (15%) 52 (16%)
ENALAPRIL 28 (9%) 42 (13%)
HYDROCHLOROTHIAZIDE 28 (9%) 23 (7%)
GLYCERYL TRINITRATE 14 (4%) 19 (6%)
AMLODIPINE 14 (4%) 17 (5%)
AMLODIPINE BESILATE 16 (5%) 13 (4%)
DILTIAZEM 14 (4%) 15 (5%)
METOPROLOL 17 (5%) 12 (4%)
ATORVASTATIN CALCIUM 11 (4%) 15 (5%)
CARVEDILOL 9 (3%) 16 (5%)
LOSARTAN 13 (4%) 9 (3%)
ATENOLOL 11 (4%) 10 (3%)
FISH OIL 10 (3%) 11 (3%)
DIGOXIN 7 (2%) 13 (4%)
ATORVASTATIN 9 (3%) 10 (3%)
HYDROCHLOROTHIAZIDE+LISINOPRIL 9 (3%) 10 (3%)
HEPARIN (NOS) 12 (4%) 6 (2%)
METOPROLOL TARTRATE 10 (3%) 7 (2%)
PRAVASTATIN 10 (3%) 6 (2%)
VALSARTAN 4 (1%) 10 (3%)
ROSUVASTATIN CALCIUM 3 (<1%) 10 (3%)
AMIODARONE 7 (2%) 5 (2%)
DILTIAZEM HYDROCHLORIDE 7 (2%) 5 (2%)
LIDOCAINE 5 (2%) 7 (2%)
PRAVASTATIN SODIUM 5 (2%) 7 (2%)
TRIAMTERENE+HYDROCHLOROTHIAZIDE 8 (3%) 3 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
LOVASTATIN 6 (2%) 3 (<1%)
METOPROLOL SUCCINATE 5 (2%) 4 (1%)
ROSUVASTATIN 8 (3%) 1 (<1%)
SPIRONOLACTONE 2 (<1%) 7 (2%)
TERAZOSIN 4 (1%) 5 (2%)
CLONIDINE 4 (1%) 4 (1%)
FENOFIBRATE 4 (1%) 4 (1%)
GEMFIBROZIL 2 (<1%) 6 (2%)
LOSARTAN POTASSIUM 6 (2%) 2 (<1%)
VERAPAMIL 5 (2%) 3 (<1%)
NICOTINIC ACID 2 (<1%) 5 (2%)
DEXAMETHASONE 3 (<1%) 3 (<1%)
DOXAZOSIN MESILATE 4 (1%) 2 (<1%)
HYDROCORTISONE 3 (<1%) 3 (<1%)
ISOSORBIDE MONONITRATE 2 (<1%) 4 (1%)
NIFEDIPINE 2 (<1%) 4 (1%)
BENAZEPRIL HYDROCHLORIDE+AMLODIPINE BESILATE 3 (<1%) 2 (<1%)
EZETIMIBE 4 (1%) 1 (<1%)
HYDROCHLOROTHIAZIDE+LOSARTAN POTASSIUM 2 (<1%) 3 (<1%)
OMEGA-3 MARINE TRIGLYCERIDES 4 (1%) 1 (<1%)
RAMIPRIL 3 (<1%) 2 (<1%)
TERAZOSIN HYDROCHLORIDE 2 (<1%) 3 (<1%)
AMLODIPINE BESILATE+VALSARTAN 1 (<1%) 3 (<1%)
BISOPROLOL 2 (<1%) 2 (<1%)
BISOPROLOL FUMARATE 0 4 (1%)
DOXAZOSIN 2 (<1%) 2 (<1%)
LIDOCAINE HYDROCHLORIDE 4 (1%) 0
TORASEMIDE 2 (<1%) 2 (<1%)
VERAPAMIL HYDROCHLORIDE 2 (<1%) 2 (<1%)
AMIODARONE HYDROCHLORIDE 0 3 (<1%)
BENAZEPRIL 0 3 (<1%)
DRONEDARONE 2 (<1%) 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
FELODIPINE 2 (<1%) 1 (<1%)
HEPARIN CALCIUM 1 (<1%) 2 (<1%)
HYDRALAZINE 1 (<1%) 2 (<1%)
HYDROCHLOROTHIAZIDE+VALSARTAN 2 (<1%) 1 (<1%)
INDOMETACIN 1 (<1%) 2 (<1%)
SIMVASTATIN+EZETIMIBE 1 (<1%) 2 (<1%)
BUMETANIDE 0 2 (<1%)
CANDESARTAN CILEXETIL 1 (<1%) 1 (<1%)
CLONIDINE HYDROCHLORIDE 2 (<1%) 0
COLESTYRAMINE 1 (<1%) 1 (<1%)
COLMIBE (NOS) 0 2 (<1%)
FENOFIBRIC ACID 1 (<1%) 1 (<1%)
HEPARIN SODIUM 2 (<1%) 0
HYDROCHLOROTHIAZIDE+BISOPROLOL 1 (<1%) 1 (<1%)
IRBESARTAN 2 (<1%) 0
ISOSORBIDE 1 (<1%) 1 (<1%)
LABETALOL 1 (<1%) 1 (<1%)
METOLAZONE 0 2 (<1%)
NEBIVOLOL HYDROCHLORIDE 2 (<1%) 0
OLMESARTAN 0 2 (<1%)
OMEGA-3-ACID ETHYL ESTERS 0 2 (<1%)
PENTOSAN POLYSULFATE SODIUM 0 2 (<1%)
PREDNISOLONE 1 (<1%) 1 (<1%)
SOTALOL 2 (<1%) 0
TADALAFIL 2 (<1%) 0
TELMISARTAN 0 2 (<1%)
TRIAMTERENE 2 (<1%) 0
UBIDECARENONE 1 (<1%) 1 (<1%)
VALSARTAN+ALISKIREN FUMARATE 0 2 (<1%)
ACETAZOLAMIDE 0 1 (<1%)
ALDACTONE (NOS) 1 (<1%) 0
ALISKIREN FUMARATE 0 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
ALPROSTADIL 1 (<1%) 0
AMLODIPINE BESILATE+ATORVASTATIN CALCIUM 0 1 (<1%)
BAMETHAN SULFATE 0 1 (<1%)
BENAZEPRIL HYDROCHLORIDE 1 (<1%) 0
BETAMETHASONE 1 (<1%) 0
BETAMETHASONE VALERATE 0 1 (<1%)
BETAXOLOL 1 (<1%) 0
CANDESARTAN 1 (<1%) 0
COLESEVELAM HYDROCHLORIDE 0 1 (<1%)
DIGITOXIN 1 (<1%) 0
DIUREX (NOS) 0 1 (<1%)
EPINEPHRINE 0 1 (<1%)
FLECAINIDE 1 (<1%) 0
FLECAINIDE ACETATE 0 1 (<1%)
FLUOCINONIDE 1 (<1%) 0
FLUVASTATIN 0 1 (<1%)
HYDROCHLOROTHIAZIDE+AMILORIDE HYDROCHLORIDE 1 (<1%) 0
HYDROCHLOROTHIAZIDE+AMLODIPINE BESILATE+ALISKIREN FUMARATE 0 1 (<1%)
HYDROCHLOROTHIAZIDE+ENALAPRIL 1 (<1%) 0
HYDROCHLOROTHIAZIDE+FOSINOPRIL 1 (<1%) 0
HYDROCHLOROTHIAZIDE+IRBESARTAN 1 (<1%) 0
HYDROCHLOROTHIAZIDE+TELMISARTAN 0 1 (<1%)
INDAPAMIDE+PERINDOPRIL 1 (<1%) 0
ISOSORBIDE DINITRATE 0 1 (<1%)
LERCANIDIPINE 1 (<1%) 0
MAGNESIUM CHLORIDE 0 1 (<1%)
METHYLDOPA 1 (<1%) 0
METHYLDOPA+HYDROCHLOROTHIAZIDE 0 1 (<1%)
NADOLOL 1 (<1%) 0
NIMODIPINE 0 1 (<1%)
NITRENDIPINE 0 1 (<1%)
OMEGA-3 TRIGLYCERIDES 1 (<1%) 0

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
PENTOXIFYLLINE 1 (<1%) 0
PHENYLEPHRINE HYDROCHLORIDE 1 (<1%) 0
PROPAFENONE 1 (<1%) 0
PROPAFENONE HYDROCHLORIDE 1 (<1%) 0
PROPRANOLOL 1 (<1%) 0
SILODOSIN 0 1 (<1%)
TENSOPRIL (NOS) 0 1 (<1%)
TIMOLOL 0 1 (<1%)

ALIMENTARY TRACT AND METABOLISM


Any medication 209 (67%) 225 (69%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
OMEPRAZOLE 51 (16%) 53 (16%)
VITAMINS NOS 30 (10%) 25 (8%)
METFORMIN 27 (9%) 27 (8%)
PANTOPRAZOLE 17 (5%) 22 (7%)
POTASSIUM CHLORIDE 17 (5%) 19 (6%)
VITAMIN D NOS 20 (6%) 12 (4%)
RANITIDINE 14 (4%) 17 (5%)
RANITIDINE HYDROCHLORIDE 13 (4%) 17 (5%)
DOCUSATE SODIUM 15 (5%) 14 (4%)
ESOMEPRAZOLE MAGNESIUM 17 (5%) 11 (3%)
SODIUM CHLORIDE 15 (5%) 10 (3%)
GLIPIZIDE 10 (3%) 14 (4%)
ONDANSETRON 9 (3%) 14 (4%)
NYSTATIN 9 (3%) 13 (4%)
INSULIN ASPART 8 (3%) 13 (4%)
METFORMIN HYDROCHLORIDE 9 (3%) 12 (4%)
ERGOCALCIFEROL+CALCIUM 7 (2%) 11 (3%)
PROMETHAZINE 4 (1%) 14 (4%)
INSULIN GLARGINE 5 (2%) 12 (4%)
MACROGOL 5 (2%) 11 (3%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CALCIUM 8 (3%) 7 (2%)
CALCIUM CARBONATE 2 (<1%) 13 (4%)
GLIBENCLAMIDE 6 (2%) 8 (2%)
PREDNISONE 8 (3%) 6 (2%)
MINERALS NOS+VITAMINS NOS 6 (2%) 7 (2%)
POTASSIUM NOS 10 (3%) 3 (<1%)
ASCORBIC ACID 8 (3%) 4 (1%)
FAMOTIDINE 8 (3%) 4 (1%)
INSULIN NOS 5 (2%) 7 (2%)
TRIAMCINOLONE ACETONIDE 8 (3%) 3 (<1%)
GLIMEPIRIDE 3 (<1%) 6 (2%)
INSULIN LISPRO 4 (1%) 4 (1%)
LANSOPRAZOLE 5 (2%) 3 (<1%)
MAALOX (NOS) 6 (2%) 2 (<1%)
METOCLOPRAMIDE 3 (<1%) 5 (2%)
METRONIDAZOLE 6 (2%) 2 (<1%)
COLECALCIFEROL 2 (<1%) 5 (2%)
INSULIN DETEMIR 3 (<1%) 4 (1%)
LOPERAMIDE HYDROCHLORIDE 5 (2%) 2 (<1%)
SENNA 3 (<1%) 4 (1%)
VANCOMYCIN 3 (<1%) 4 (1%)
CLOTRIMAZOLE 4 (1%) 2 (<1%)
DEXAMETHASONE 3 (<1%) 3 (<1%)
HYDROCORTISONE 3 (<1%) 3 (<1%)
MAGIC MOUTHWASH (NOS) 4 (1%) 2 (<1%)
DOCUSATE 3 (<1%) 2 (<1%)
DULCOLAX (NOS) 2 (<1%) 3 (<1%)
INSULIN HUMAN INJECTION, ISOPHANE 0 5 (2%)
MECLOZINE 1 (<1%) 4 (1%)
TRIAMCINOLONE 3 (<1%) 2 (<1%)
BISMUTH SUBSALICYLATE 2 (<1%) 2 (<1%)
CHLORHEXIDINE GLUCONATE 2 (<1%) 2 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
DEXLANSOPRAZOLE 2 (<1%) 2 (<1%)
DICYCLOVERINE HYDROCHLORIDE 3 (<1%) 1 (<1%)
LACTULOSE 1 (<1%) 3 (<1%)
MAGNESIUM OXIDE 2 (<1%) 2 (<1%)
MAGNESIUM SULFATE 4 (1%) 0
PANTOPRAZOLE SODIUM 3 (<1%) 1 (<1%)
RABEPRAZOLE SODIUM 2 (<1%) 2 (<1%)
SUCRALFATE 3 (<1%) 1 (<1%)
TOCOPHEROL 4 (1%) 0
TRIMEBUTINE 0 4 (1%)
ALUMINIUM HYDROXIDE GEL, DRIED+MAGNESIUM HYDROXIDE+DIMETICONE, 2 (<1%) 1 (<1%)
ACTIVATED
CALCITRIOL 1 (<1%) 2 (<1%)
FLEET ENEMA (NOS) 0 3 (<1%)
INSULIN HUMAN 0 3 (<1%)
INSULIN HUMAN+INSULIN ISOPHANE, HUMAN BIOSYNTHETIC 1 (<1%) 2 (<1%)
MAGNESIUM CITRATE 0 3 (<1%)
MAGNESIUM HYDROXIDE 2 (<1%) 1 (<1%)
METOCLOPRAMIDE HYDROCHLORIDE 1 (<1%) 2 (<1%)
OXYBUTYNIN 3 (<1%) 0
PIOGLITAZONE HYDROCHLORIDE 0 3 (<1%)
POTASSIUM GLUCONATE 1 (<1%) 2 (<1%)
SENNOSIDES 2 (<1%) 1 (<1%)
ACETYLSALICYLIC ACID+SODIUM BICARBONATE+CITRIC ACID 1 (<1%) 1 (<1%)
CALCIUM CARBONATE+COLECALCIFEROL 0 2 (<1%)
CHLORPROPAMIDE 2 (<1%) 0
COD-LIVER OIL 1 (<1%) 1 (<1%)
CYPROHEPTADINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
DOXYCYCLINE HYCLATE 0 2 (<1%)
ERGOCALCIFEROL 0 2 (<1%)
ERGOCALCIFEROL+CALCIUM CARBONATE 1 (<1%) 1 (<1%)
GLUCOSE+FRUCTOSE+PHOSPHORIC ACID 1 (<1%) 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
HYOSCYAMINE 1 (<1%) 1 (<1%)
LACTOBACILLUS ACIDOPHILUS 2 (<1%) 0
LACTOBACILLUS NOS 1 (<1%) 1 (<1%)
LAXATIVES, NOS 0 2 (<1%)
MAGNESIUM 1 (<1%) 1 (<1%)
MOSAPRIDE 1 (<1%) 1 (<1%)
PANCRELIPASE 0 2 (<1%)
PARGEVERINE HYDROCHLORIDE 2 (<1%) 0
POLYCARBOPHIL CALCIUM 1 (<1%) 1 (<1%)
PREDNISOLONE 1 (<1%) 1 (<1%)
PROCHLORPERAZINE 2 (<1%) 0
SITAGLIPTIN 1 (<1%) 1 (<1%)
THIAMINE 2 (<1%) 0
THIAMINE HYDROCHLORIDE 2 (<1%) 0
VITAMIN B SUBSTANCES NOS 1 (<1%) 1 (<1%)
ZINC 1 (<1%) 1 (<1%)
ACARBOSE 0 1 (<1%)
ALUMINIUM HYDROXIDE+MAGNESIUM HYDROXIDE+DIMETICONE, ACTIVATED 0 1 (<1%)
ANTIBIOTICS NOS 0 1 (<1%)
ATROPINE SULFATE+DIPHENOXYLATE HYDROCHLORIDE 1 (<1%) 0
ATROPINE SULFATE+HYOSCINE HYDROBROMIDE+PHENOBARBITAL+HYOSCYAMINE 1 (<1%) 0
SULFATE
BECLOMETASONE DIPROPIONATE 1 (<1%) 0
BETAMETHASONE 1 (<1%) 0
BETAMETHASONE VALERATE 0 1 (<1%)
BIFIDOBACTERIUM INFANTIS 1 (<1%) 0
BISACODYL 1 (<1%) 0
CALCIUM ACETATE 0 1 (<1%)
CALCIUM ASCORBATE 1 (<1%) 0
CALCIUM CARBONATE+VITAMIN D SUBSTANCES 1 (<1%) 0
CALCIUM CITRATE 1 (<1%) 0
CALCIUM+VITAMIN D NOS 0 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CHLORDIAZEPOXIDE HYDROCHLORIDE+CLIDINIUM BROMIDE 1 (<1%) 0
CHLORHEXIDINE 1 (<1%) 0
CHROMIUM PICOLINATE 1 (<1%) 0
CIMETIDINE 0 1 (<1%)
CINNARIZINE 0 1 (<1%)
COLECALCIFEROL+CALCIUM CITRATE 0 1 (<1%)
CYPROHEPTADINE 1 (<1%) 0
CYPROHEPTADINE HYDROCHLORIDE+VITAMINS NOS 0 1 (<1%)
DICYCLOVERINE 1 (<1%) 0
DIMETICONE, ACTIVATED 1 (<1%) 0
DIPHENHYDRAMINE HYDROCHLORIDE+HYDROCORTISONE+NYSTATIN 0 1 (<1%)
DOCUSATE CALCIUM 1 (<1%) 0
EPINEPHRINE 0 1 (<1%)
ERGOCALCIFEROL+CALCIUM CITRATE 1 (<1%) 0
ESCULOSIDE 0 1 (<1%)
ESOMEPRAZOLE 1 (<1%) 0
EX-LAX NOS 0 1 (<1%)
HYOSCINE 0 1 (<1%)
HYOSCINE BUTYLBROMIDE 1 (<1%) 0
HYOSCYAMINE SULFATE 0 1 (<1%)
INSULIN ASPART+INSULIN ASPART PROTAMINE 1 (<1%) 0
INSULIN GLULISINE 0 1 (<1%)
IRON+ALLIUM SATIVUM+CALCIUM 0 1 (<1%)
LACTOBACILLUS ACIDOPHILUS+LACTOBACILLUS BULGARICUS 1 (<1%) 0
LEVOCARNITINE 1 (<1%) 0
LOPERAMIDE 0 1 (<1%)
MAGNESIUM CHLORIDE 0 1 (<1%)
MAGNESIUM CITRATE+CALCIUM CITRATE 0 1 (<1%)
MAGNESIUM OXIDE+ALUMINIUM GLYCINATE 0 1 (<1%)
MESALAZINE 0 1 (<1%)
METFORMIN HYDROCHLORIDE+GLIBENCLAMIDE 1 (<1%) 0
METFORMIN HYDROCHLORIDE+ROSIGLITAZONE 0 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
METFORMIN+GLIBENCLAMIDE 1 (<1%) 0
MIGLITOL 1 (<1%) 0
MINERALS NOS+CAROTENOIDS+VITAMINS NOS 0 1 (<1%)
MINERALS NOS+PHYTOSTEROL (NOS)+VITAMINS NOS 0 1 (<1%)
MINERALS NOS+VITAMINS NOS+HERBALS NOS 0 1 (<1%)
MIRACLE MOUTHWASH (NOS) 1 (<1%) 0
MISOPROSTOL 0 1 (<1%)
ONDANSETRON HYDROCHLORIDE 0 1 (<1%)
PHENTERMINE 1 (<1%) 0
PIOGLITAZONE 0 1 (<1%)
PLANTAGO OVATA 0 1 (<1%)
POTASSIUM CITRATE 1 (<1%) 0
PYRIDOXINE 0 1 (<1%)
PYRIDOXINE HYDROCHLORIDE 1 (<1%) 0
RABEPRAZOLE 1 (<1%) 0
REPAGLINIDE 0 1 (<1%)
SAXAGLIPTIN HYDROCHLORIDE 0 1 (<1%)
SODIUM BICARBONATE 0 1 (<1%)
SODIUM FLUORIDE 0 1 (<1%)
SODIUM PHOSPHATE DIBASIC+POTASSIUM PHOSPHATE DIBASIC+SODIUM 1 (<1%) 0
PHOSPHATE MONOBASIC+POTASSIUM PHOSPHATE
VITAMIN B NOS 0 1 (<1%)
ZINC GLUCONATE 1 (<1%) 0

NERVOUS SYSTEM
Any medication 204 (65%) 229 (70%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
PARACETAMOL 41 (13%) 50 (15%)
ALPRAZOLAM 38 (12%) 35 (11%)
PARACETAMOL+HYDROCODONE BITARTRATE 37 (12%) 35 (11%)
IBUPROFEN 30 (10%) 34 (10%)
LORAZEPAM 27 (9%) 24 (7%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CLONAZEPAM 22 (7%) 22 (7%)
NICOTINE 16 (5%) 26 (8%)
GABAPENTIN 17 (5%) 16 (5%)
PARACETAMOL+OXYCODONE HYDROCHLORIDE 12 (4%) 16 (5%)
TRAZODONE 14 (4%) 14 (4%)
DIAZEPAM 11 (4%) 12 (4%)
ZOLPIDEM TARTRATE 7 (2%) 14 (4%)
CITALOPRAM 9 (3%) 11 (3%)
PROMETHAZINE 4 (1%) 14 (4%)
CYCLOBENZAPRINE HYDROCHLORIDE 7 (2%) 10 (3%)
MORPHINE 6 (2%) 11 (3%)
ESCITALOPRAM OXALATE 9 (3%) 7 (2%)
CITALOPRAM HYDROBROMIDE 7 (2%) 7 (2%)
PAROXETINE HYDROCHLORIDE 7 (2%) 7 (2%)
VARENICLINE TARTRATE 3 (<1%) 11 (3%)
KETOROLAC TROMETAMOL 7 (2%) 6 (2%)
OXYCODONE 5 (2%) 8 (2%)
ZOLPIDEM 4 (1%) 9 (3%)
BUPROPION HYDROCHLORIDE 8 (3%) 4 (1%)
FLUOXETINE HYDROCHLORIDE 7 (2%) 5 (2%)
HYDROCODONE 2 (<1%) 10 (3%)
LIDOCAINE 5 (2%) 7 (2%)
PARACETAMOL+HYDROCODONE 5 (2%) 7 (2%)
TEMAZEPAM 7 (2%) 5 (2%)
TRAMADOL 9 (3%) 3 (<1%)
AMITRIPTYLINE 5 (2%) 5 (2%)
BUPROPION 3 (<1%) 7 (2%)
DEXTROPROPOXYPHENE NAPSILATE+PARACETAMOL 4 (1%) 6 (2%)
FENTANYL 6 (2%) 4 (1%)
SERTRALINE HYDROCHLORIDE 4 (1%) 6 (2%)
CYCLOBENZAPRINE 2 (<1%) 7 (2%)
DULOXETINE 3 (<1%) 6 (2%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
QUETIAPINE FUMARATE 3 (<1%) 6 (2%)
TRAMADOL HYDROCHLORIDE 3 (<1%) 6 (2%)
CLONIDINE 4 (1%) 4 (1%)
FLUOXETINE 5 (2%) 3 (<1%)
HYDROMORPHONE HYDROCHLORIDE 4 (1%) 4 (1%)
MIDAZOLAM 5 (2%) 3 (<1%)
MORPHINE SULFATE 4 (1%) 4 (1%)
CARBAMAZEPINE 5 (2%) 2 (<1%)
HYDROXYZINE 4 (1%) 3 (<1%)
BUSPIRONE HYDROCHLORIDE 4 (1%) 2 (<1%)
OXYCODONE HYDROCHLORIDE 0 6 (2%)
PAROXETINE 2 (<1%) 4 (1%)
PREGABALIN 3 (<1%) 3 (<1%)
SERTRALINE 2 (<1%) 4 (1%)
NICOTINE POLACRILEX 3 (<1%) 2 (<1%)
RISPERIDONE 1 (<1%) 4 (1%)
VENLAFAXINE 5 (2%) 0
VENLAFAXINE HYDROCHLORIDE 3 (<1%) 2 (<1%)
ACETYLSALICYLIC ACID+PARACETAMOL+CAFFEINE 2 (<1%) 2 (<1%)
EXCEDRIN (NOS) 3 (<1%) 1 (<1%)
LIDOCAINE HYDROCHLORIDE 4 (1%) 0
MIRTAZAPINE 2 (<1%) 2 (<1%)
PROPOFOL 1 (<1%) 3 (<1%)
ROPINIROLE HYDROCHLORIDE 2 (<1%) 2 (<1%)
TOPIRAMATE 3 (<1%) 1 (<1%)
ZOPICLONE 3 (<1%) 1 (<1%)
ACETYLSALICYLIC ACID+CAFFEINE+SALICYLAMIDE 2 (<1%) 1 (<1%)
AMITRIPTYLINE HYDROCHLORIDE 2 (<1%) 1 (<1%)
ARIPIPRAZOLE 2 (<1%) 1 (<1%)
BUPIVACAINE HYDROCHLORIDE 1 (<1%) 2 (<1%)
BUSPIRONE 2 (<1%) 1 (<1%)
CAPSAICIN 0 3 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CHLORPROMAZINE 1 (<1%) 2 (<1%)
CLONIXIN LYSINE 0 3 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE+PARACETAMOL 2 (<1%) 1 (<1%)
LAMOTRIGINE 2 (<1%) 1 (<1%)
METHADONE 1 (<1%) 2 (<1%)
PARACETAMOL+CAFFEINE+BUTALBITAL 2 (<1%) 1 (<1%)
PETHIDINE HYDROCHLORIDE 1 (<1%) 2 (<1%)
PRAMIPEXOLE DIHYDROCHLORIDE 2 (<1%) 1 (<1%)
ACETYLSALICYLIC ACID+SODIUM BICARBONATE+CITRIC ACID 1 (<1%) 1 (<1%)
ANAESTHETICS, GENERAL 0 2 (<1%)
BUPIVACAINE 2 (<1%) 0
CHLORASEPTIC (NOS) 2 (<1%) 0
CLONIDINE HYDROCHLORIDE 2 (<1%) 0
CODEINE PHOSPHATE+PARACETAMOL 1 (<1%) 1 (<1%)
DEXTROPROPOXYPHENE NAPSILATE 1 (<1%) 1 (<1%)
DONEPEZIL 1 (<1%) 1 (<1%)
ESZOPICLONE 0 2 (<1%)
FIORINAL NOS 1 (<1%) 1 (<1%)
HYDROMORPHONE 1 (<1%) 1 (<1%)
LEVODOPA+CARBIDOPA 1 (<1%) 1 (<1%)
METAMIZOLE SODIUM 0 2 (<1%)
NALBUPHINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
NALOXONE HYDROCHLORIDE+BUPRENORPHINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
OLANZAPINE 2 (<1%) 0
ORPHENADRINE CITRATE 1 (<1%) 1 (<1%)
OXAZEPAM 0 2 (<1%)
OXCARBAZEPINE 2 (<1%) 0
PARACETAMOL+CHLORPHENAMINE MALEATE+PHENYLEPHRINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
PROCHLORPERAZINE 2 (<1%) 0
TRAZODONE HYDROCHLORIDE 1 (<1%) 1 (<1%)
VALPROIC ACID 1 (<1%) 1 (<1%)
ACAMPROSATE CALCIUM 1 (<1%) 0

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
ACTRON (NOS) 1 (<1%) 0
ANALGESIC, NOS 0 1 (<1%)
BIPERIDEN 1 (<1%) 0
BROMFENAC SODIUM 1 (<1%) 0
BUPRENORPHINE HYDROCHLORIDE 0 1 (<1%)
CAFFEINE 1 (<1%) 0
CHLORDIAZEPOXIDE 0 1 (<1%)
CINNARIZINE 0 1 (<1%)
CODEINE PHOSPHATE+PARACETAMOL+CAFFEINE 1 (<1%) 0
DESVENLAFAXINE SUCCINATE 0 1 (<1%)
DEXTROPROPOXYPHENE 0 1 (<1%)
DICLOFENAC POTASSIUM 0 1 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE+IBUPROFEN 0 1 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE+LIDOCAINE HYDROCHLORIDE+ALUMINIUM 0 1 (<1%)
HYDROXIDE+MAGNESIUM HYDROXIDE+DIMETI
DIPHENHYDRAMINE+PARACETAMOL 1 (<1%) 0
DIPOTASSIUM CLORAZEPATE 1 (<1%) 0
DOXEPIN 0 1 (<1%)
EPINEPHRINE+LIDOCAINE HYDROCHLORIDE 0 1 (<1%)
ERGOTAMINE TARTRATE+METAMIZOLE SODIUM+METOCLOPRAMIDE 1 (<1%) 0
HYDROCHLORIDE+CAFFEINE
ESTAZOLAM 0 1 (<1%)
FENTANYL CITRATE 1 (<1%) 0
FLUVOXAMINE MALEATE 0 1 (<1%)
HYDROCODONE+IBUPROFEN 1 (<1%) 0
HYDROXYZINE EMBONATE 0 1 (<1%)
HYDROXYZINE HYDROCHLORIDE 0 1 (<1%)
HYOSCINE 0 1 (<1%)
KETAMINE 0 1 (<1%)
LEVETIRACETAM 1 (<1%) 0
LEVOMEPROMAZINE 1 (<1%) 0
MEMANTINE 0 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
MEMANTINE HYDROCHLORIDE 1 (<1%) 0
METHYLPHENIDATE HYDROCHLORIDE 1 (<1%) 0
MILNACIPRAN HYDROCHLORIDE 0 1 (<1%)
NITRAZEPAM 0 1 (<1%)
NORTRIPTYLINE 1 (<1%) 0
PALIPERIDONE 1 (<1%) 0
PARACETAMOL+CAFFEINE 0 1 (<1%)
PARACETAMOL+OXYCODONE 1 (<1%) 0
PARACETAMOL+TRAMADOL 0 1 (<1%)
PHENYTOIN 0 1 (<1%)
PHENYTOIN SODIUM 1 (<1%) 0
PRIMIDONE 0 1 (<1%)
RIZATRIPTAN BENZOATE 1 (<1%) 0
ROPIVACAINE 1 (<1%) 0
SALICYLAMIDE 1 (<1%) 0
SALSALATE 0 1 (<1%)
SPINAL ANESTHESIA 1 (<1%) 0
SUMATRIPTAN 1 (<1%) 0
TAPENTADOL 1 (<1%) 0
TYLENOL #3 (NOS) 0 1 (<1%)
UNISOM NOS 1 (<1%) 0
MUSCULO-SKELETAL SYSTEM
Any medication 142 (45%) 164 (50%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
IBUPROFEN 30 (10%) 34 (10%)
DICLOFENAC 8 (3%) 15 (5%)
MELOXICAM 13 (4%) 7 (2%)
CYCLOBENZAPRINE HYDROCHLORIDE 7 (2%) 10 (3%)
ALLOPURINOL 5 (2%) 9 (3%)
NAPROXEN SODIUM 8 (3%) 6 (2%)
KETOROLAC TROMETAMOL 7 (2%) 6 (2%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
ALENDRONATE SODIUM 3 (<1%) 7 (2%)
NAPROXEN 5 (2%) 5 (2%)
CYCLOBENZAPRINE 2 (<1%) 7 (2%)
ALENDRONIC ACID 2 (<1%) 5 (2%)
CARISOPRODOL 3 (<1%) 3 (<1%)
CELECOXIB 2 (<1%) 3 (<1%)
COLCHICINE 1 (<1%) 3 (<1%)
DICLOFENAC SODIUM 4 (1%) 0
CAPSAICIN 0 3 (<1%)
INDOMETACIN 1 (<1%) 2 (<1%)
KETOROLAC 3 (<1%) 0
METHOCARBAMOL 1 (<1%) 2 (<1%)
NABUMETONE 2 (<1%) 1 (<1%)
TIZANIDINE HYDROCHLORIDE 2 (<1%) 1 (<1%)
BACLOFEN 1 (<1%) 1 (<1%)
ETODOLAC 2 (<1%) 0
GLUCOSAMINE 1 (<1%) 1 (<1%)
GLUCOSAMINE SULFATE 1 (<1%) 1 (<1%)
HYDROXYCHLOROQUINE SULFATE 1 (<1%) 1 (<1%)
ORPHENADRINE CITRATE 1 (<1%) 1 (<1%)
PIROXICAM 0 2 (<1%)
RISEDRONATE SODIUM 1 (<1%) 1 (<1%)
SODIUM IBANDRONATE 1 (<1%) 1 (<1%)
TIZANIDINE 1 (<1%) 1 (<1%)
BETAMETHASONE+HYDROXOCOBALAMIN+DICLOFENAC POTASSIUM 1 (<1%) 0
BROMFENAC SODIUM 1 (<1%) 0
CHONDROITIN+GLUCOSAMINE HYDROCHLORIDE 1 (<1%) 0
DICLOFENAC DIETHYLAMINE 0 1 (<1%)
DICLOFENAC POTASSIUM 0 1 (<1%)
ETORICOXIB 1 (<1%) 0
GLUCOSAMINE SULFATE POTASSIUM CHLORIDE+MELOXICAM 0 1 (<1%)
HYDROXYCHLOROQUINE 1 (<1%) 0

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
IBANDRONIC ACID 0 1 (<1%)
METAXALONE 0 1 (<1%)
MUSTARD OIL 0 1 (<1%)
PSEUDOEPHEDRINE+NAPROXEN 1 (<1%) 0
QUININE 0 1 (<1%)
SALSALATE 0 1 (<1%)
ZOLEDRONIC ACID 1 (<1%) 0
BLOOD AND BLOOD FORMING ORGANS
Any medication 143 (46%) 152 (47%)
ACETYLSALICYLIC ACID 90 (29%) 97 (30%)
POTASSIUM CHLORIDE 17 (5%) 19 (6%)
ENOXAPARIN SODIUM 14 (4%) 15 (5%)
CLOPIDOGREL BISULFATE 9 (3%) 19 (6%)
SODIUM CHLORIDE 15 (5%) 10 (3%)
CYANOCOBALAMIN 12 (4%) 8 (2%)
HEPARIN (NOS) 12 (4%) 6 (2%)
WARFARIN SODIUM 8 (3%) 9 (3%)
FOLIC ACID 7 (2%) 6 (2%)
POTASSIUM NOS 10 (3%) 3 (<1%)
ACENOCOUMAROL 5 (2%) 7 (2%)
WARFARIN 7 (2%) 5 (2%)
ENOXAPARIN 6 (2%) 3 (<1%)
FERROUS SULPHATE 2 (<1%) 5 (2%)
CILOSTAZOL 3 (<1%) 3 (<1%)
ACETYLSALICYLIC ACID+DIPYRIDAMOLE 0 4 (1%)
CHLORHEXIDINE GLUCONATE 2 (<1%) 2 (<1%)
CLOPIDOGREL 2 (<1%) 2 (<1%)
IRON 3 (<1%) 1 (<1%)
MAGNESIUM SULFATE 4 (1%) 0
PHYTOMENADIONE 2 (<1%) 2 (<1%)
DALTEPARIN SODIUM 1 (<1%) 2 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
HEPARIN CALCIUM 1 (<1%) 2 (<1%)
MAGNESIUM CITRATE 0 3 (<1%)
HEPARIN SODIUM 2 (<1%) 0
PENTOSAN POLYSULFATE SODIUM 0 2 (<1%)
PRASUGREL 0 2 (<1%)
RED BLOOD CELLS, CONCENTRATED 1 (<1%) 1 (<1%)
SODIUM CHLORIDE+GLUCOSE 1 (<1%) 1 (<1%)
BIVALIRUDIN 1 (<1%) 0
BLOOD TRANSFUSION, AUXILIARY PRODUCTS 1 (<1%) 0
CETYLPYRIDINIUM 1 (<1%) 0
CHLORHEXIDINE 1 (<1%) 0
DIPYRIDAMOLE 1 (<1%) 0
EPINEPHRINE 0 1 (<1%)
FERROUS FUMARATE+POLYSACCHARIDE-IRON COMPLEX 0 1 (<1%)
FERROUS GLUCONATE 0 1 (<1%)
FONDAPARINUX 1 (<1%) 0
GLUCOSE 0 1 (<1%)
GLUCOSE INJECTION 0 1 (<1%)
HYDROXOCOBALAMIN 0 1 (<1%)
INTRAVENOUS FLUID (NOS) 1 (<1%) 0
PLASMA 0 1 (<1%)
PLATELETS, HUMAN BLOOD+PLASMA 1 (<1%) 0
POTASSIUM CHLORIDE+SODIUM CHLORIDE+CALCIUM CHLORIDE+DL-LACTIC ACID 0 1 (<1%)
SODIUM SALT
SODIUM BICARBONATE 0 1 (<1%)
UREA 0 1 (<1%)
RESPIRATORY SYSTEM
Any medication 107 (34%) 106 (33%)
LORATADINE 15 (5%) 16 (5%)
SODIUM CHLORIDE 15 (5%) 10 (3%)
FLUTICASONE PROPIONATE 14 (4%) 10 (3%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
GUAIFENESIN 14 (4%) 9 (3%)
MONTELUKAST SODIUM 10 (3%) 12 (4%)
CETIRIZINE HYDROCHLORIDE 6 (2%) 12 (4%)
PROMETHAZINE 4 (1%) 14 (4%)
BENADRYL (NOS) 9 (3%) 7 (2%)
HYDROCODONE 2 (<1%) 10 (3%)
LIDOCAINE 5 (2%) 7 (2%)
PARACETAMOL+HYDROCODONE 5 (2%) 7 (2%)
MOMETASONE FUROATE 4 (1%) 7 (2%)
TRIAMCINOLONE ACETONIDE 8 (3%) 3 (<1%)
OXYGEN 6 (2%) 4 (1%)
FEXOFENADINE HYDROCHLORIDE 3 (<1%) 4 (1%)
FLUNISOLIDE 2 (<1%) 5 (2%)
ROBITUSSIN (NOS) 4 (1%) 3 (<1%)
DEXAMETHASONE 3 (<1%) 3 (<1%)
DIPHENHYDRAMINE 2 (<1%) 3 (<1%)
MECLOZINE 1 (<1%) 4 (1%)
TRIAMCINOLONE 3 (<1%) 2 (<1%)
CETIRIZINE 3 (<1%) 1 (<1%)
CHLORHEXIDINE GLUCONATE 2 (<1%) 2 (<1%)
CICLESONIDE 2 (<1%) 2 (<1%)
DESLORATADINE 2 (<1%) 2 (<1%)
LIDOCAINE HYDROCHLORIDE 4 (1%) 0
MUPIROCIN 3 (<1%) 1 (<1%)
SUDAFED (NOS) 2 (<1%) 2 (<1%)
ACETYLCYSTEINE 0 3 (<1%)
BENZONATATE 1 (<1%) 2 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE+PARACETAMOL 2 (<1%) 1 (<1%)
FLUTICASONE 1 (<1%) 2 (<1%)
FLUTICASONE FUROATE 1 (<1%) 2 (<1%)
GUAIFENESIN+DEXTROMETHORPHAN HYDROBROMIDE 3 (<1%) 0
HYCODAN (NOS) 2 (<1%) 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
IPRATROPIUM BROMIDE 2 (<1%) 1 (<1%)
OXYMETAZOLINE HYDROCHLORIDE 1 (<1%) 2 (<1%)
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE 3 (<1%) 0
TUSSIONEX (NOS) 1 (<1%) 2 (<1%)
AZELASTINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
BENZOCAINE+LEVOMENTHOL 2 (<1%) 0
CHLORPHENAMINE MALEATE 0 2 (<1%)
CYPROHEPTADINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
FEXOFENADINE 0 2 (<1%)
IPRATROPIUM 2 (<1%) 0
MONTELUKAST 1 (<1%) 1 (<1%)
PARACETAMOL+CHLORPHENAMINE MALEATE+PHENYLEPHRINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
PARACETAMOL+CHLORPHENAMINE MALEATE+PSEUDOEPHEDRINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
PARACETAMOL+DEXTROMETHORPHAN HYDROBROMIDE+PSEUDOEPHEDRINE 1 (<1%) 1 (<1%)
HYDROCHLORIDE+DOXYLAMINE SUCCINATE
PREDNISOLONE 1 (<1%) 1 (<1%)
PSEUDOEPHEDRINE 1 (<1%) 1 (<1%)
ZAFIRLUKAST 0 2 (<1%)
AMBROXOL HYDROCHLORIDE+BUTETAMATE CITRATE 1 (<1%) 0
ANTIBIOTICS NOS 0 1 (<1%)
BACITRACIN 0 1 (<1%)
BECLOMETASONE DIPROPIONATE 1 (<1%) 0
BETAMETHASONE 1 (<1%) 0
BETAMETHASONE VALERATE 0 1 (<1%)
BROMHEXINE HYDROCHLORIDE 0 1 (<1%)
CAMPHOR+LEVOMENTHOL 0 1 (<1%)
CETYLPYRIDINIUM 1 (<1%) 0
CHERATUSSIN AC (NOS) 0 1 (<1%)
CHLORHEXIDINE 1 (<1%) 0
CODEINE+GUAIFENESIN 0 1 (<1%)
CYPROHEPTADINE 1 (<1%) 0

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
DEXTROMETHORPHAN HYDROBROMIDE 1 (<1%) 0
DIABETIC TUSSIN (NOS) 1 (<1%) 0
EPINEPHRINE 0 1 (<1%)
GUAIFENESIN+DEXTROMETHORPHAN HYDROBROMIDE+PSEUDOEPHEDRINE 0 1 (<1%)
HYDROCHLORIDE
GUAIFENESIN+PHENYLEPHRINE HYDROCHLORIDE 1 (<1%) 0
GUAIFENESIN+PSEUDOEPHEDRINE HYDROCHLORIDE 0 1 (<1%)
KETOTIFEN 0 1 (<1%)
LEVOCETIRIZINE HYDROCHLORIDE 0 1 (<1%)
MOMETASONE 0 1 (<1%)
PHENYLEPHRINE HYDROCHLORIDE 1 (<1%) 0
POVIDONE-IODINE 0 1 (<1%)
PSEUDOEPHEDRINE+NAPROXEN 1 (<1%) 0
SALBUTAMOL 0 1 (<1%)
SALBUTAMOL+IPRATROPIUM 1 (<1%) 0
TYLENOL COLD AND SINUS (NOS) 1 (<1%) 0
TYLENOL COLD NOS 0 1 (<1%)
TYLENOL SINUS (NOS) 1 (<1%) 0
DERMATOLOGICALS
Any medication 93 (30%) 90 (28%)
GLYCERYL TRINITRATE 14 (4%) 19 (6%)
FLUTICASONE PROPIONATE 14 (4%) 10 (3%)
NYSTATIN 9 (3%) 13 (4%)
PROMETHAZINE 4 (1%) 14 (4%)
BENADRYL (NOS) 9 (3%) 7 (2%)
FLUCONAZOLE 4 (1%) 8 (2%)
LIDOCAINE 5 (2%) 7 (2%)
MOMETASONE FUROATE 4 (1%) 7 (2%)
TRIAMCINOLONE ACETONIDE 8 (3%) 3 (<1%)
FINASTERIDE 4 (1%) 4 (1%)
METRONIDAZOLE 6 (2%) 2 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CLOTRIMAZOLE 4 (1%) 2 (<1%)
DEXAMETHASONE 3 (<1%) 3 (<1%)
HYDROCORTISONE 3 (<1%) 3 (<1%)
METHYLPREDNISOLONE 1 (<1%) 5 (2%)
METHYLPREDNISOLONE SODIUM SUCCINATE 2 (<1%) 4 (1%)
ACYCLOVIR 2 (<1%) 3 (<1%)
AMMONIUM LACTATE 3 (<1%) 2 (<1%)
DIPHENHYDRAMINE 2 (<1%) 3 (<1%)
TRIAMCINOLONE 3 (<1%) 2 (<1%)
CHLORHEXIDINE GLUCONATE 2 (<1%) 2 (<1%)
CLINDAMYCIN 3 (<1%) 1 (<1%)
LIDOCAINE HYDROCHLORIDE 4 (1%) 0
MAGNESIUM SULFATE 4 (1%) 0
METHYLPREDNISOLONE ACETATE 2 (<1%) 2 (<1%)
MUPIROCIN 3 (<1%) 1 (<1%)
TOCOPHEROL 4 (1%) 0
CALCITRIOL 1 (<1%) 2 (<1%)
CORTISONE 1 (<1%) 2 (<1%)
FLUTICASONE 1 (<1%) 2 (<1%)
COD-LIVER OIL 1 (<1%) 1 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
PREDNISOLONE 1 (<1%) 1 (<1%)
AMIKACIN 1 (<1%) 0
ANTIBIOTICS NOS 0 1 (<1%)
BACITRACIN 0 1 (<1%)
BECLOMETASONE DIPROPIONATE 1 (<1%) 0
BETAMETHASONE 1 (<1%) 0
BETAMETHASONE VALERATE 0 1 (<1%)
BETAMETHASONE+CLOTRIMAZOLE 1 (<1%) 0
CAMPHOR+LEVOMENTHOL 0 1 (<1%)
CETYLPYRIDINIUM 1 (<1%) 0
CHLORHEXIDINE 1 (<1%) 0

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CLINDAMYCIN HYDROCHLORIDE 0 1 (<1%)
CLOBETASOL PROPIONATE 0 1 (<1%)
COAL TAR 0 1 (<1%)
DESONIDE 1 (<1%) 0
DIFLUPREDNATE 1 (<1%) 0
ECONAZOLE 1 (<1%) 0
ERYTHROMYCIN 1 (<1%) 0
ETHINYLOESTRADIOL+CYPROTERONE ACETATE 0 1 (<1%)
FLUOCINONIDE 1 (<1%) 0
GENTAMICIN 1 (<1%) 0
GENTAMICIN SULFATE 1 (<1%) 0
ISOSORBIDE DINITRATE 0 1 (<1%)
MOMETASONE 0 1 (<1%)
NEOMYCIN SULFATE+POLYMYXIN B SULFATE+BACITRACIN ZINC 1 (<1%) 0
PETROLATUM 0 1 (<1%)
POLYETHYLENE 0 1 (<1%)
POVIDONE-IODINE 0 1 (<1%)
SALICYLIC ACID 1 (<1%) 0
SULFADIAZINE SILVER 0 1 (<1%)
TERBINAFINE HYDROCHLORIDE 0 1 (<1%)
UREA 0 1 (<1%)
UREA HYDROGEN PEROXIDE 1 (<1%) 0
GENITO URINARY SYSTEM AND SEX HORMONES
Any medication 99 (32%) 81 (25%)
IBUPROFEN 30 (10%) 34 (10%)
NYSTATIN 9 (3%) 13 (4%)
NAPROXEN SODIUM 8 (3%) 6 (2%)
NAPROXEN 5 (2%) 5 (2%)
TAMSULOSIN 8 (3%) 2 (<1%)
TERAZOSIN 4 (1%) 5 (2%)
FINASTERIDE 4 (1%) 4 (1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
METRONIDAZOLE 6 (2%) 2 (<1%)
TAMSULOSIN HYDROCHLORIDE 4 (1%) 3 (<1%)
CLOTRIMAZOLE 4 (1%) 2 (<1%)
DOXAZOSIN MESILATE 4 (1%) 2 (<1%)
ESTRADIOL 3 (<1%) 2 (<1%)
TERAZOSIN HYDROCHLORIDE 2 (<1%) 3 (<1%)
CLINDAMYCIN 3 (<1%) 1 (<1%)
DOXAZOSIN 2 (<1%) 2 (<1%)
DUTASTERIDE 1 (<1%) 3 (<1%)
ESTROGENS CONJUGATED 1 (<1%) 3 (<1%)
VARDENAFIL HYDROCHLORIDE 2 (<1%) 2 (<1%)
MAGNESIUM HYDROXIDE 2 (<1%) 1 (<1%)
OXYBUTYNIN 3 (<1%) 0
TIBOLONE 2 (<1%) 1 (<1%)
TOLTERODINE TARTRATE 0 3 (<1%)
DARIFENACIN HYDROBROMIDE 1 (<1%) 1 (<1%)
MEGESTROL ACETATE 1 (<1%) 1 (<1%)
RALOXIFENE HYDROCHLORIDE 1 (<1%) 1 (<1%)
SOLIFENACIN SUCCINATE 1 (<1%) 1 (<1%)
TADALAFIL 2 (<1%) 0
ALPROSTADIL 1 (<1%) 0
ANTIBIOTICS NOS 0 1 (<1%)
BACITRACIN 0 1 (<1%)
CIMICIFUGA RACEMOSA 0 1 (<1%)
CLINDAMYCIN HYDROCHLORIDE 0 1 (<1%)
ECONAZOLE 1 (<1%) 0
ESTRADIOL CIPIONATE 0 1 (<1%)
ESTROGEN NOS 1 (<1%) 0
ESTROGENS CONJUGATED+MEDROXYPROGESTERONE ACETATE 1 (<1%) 0
ESTROPIPATE 1 (<1%) 0
ETHINYLOESTRADIOL+CYPROTERONE ACETATE 0 1 (<1%)
ETHINYLOESTRADIOL+NORETHISTERONE ACETATE 1 (<1%) 0

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
FURADONINE 1 (<1%) 0
MEDROXYPROGESTERONE 1 (<1%) 0
MEDROXYPROGESTERONE ACETATE 1 (<1%) 0
MISOPROSTOL 0 1 (<1%)
NORETHISTERONE 0 1 (<1%)
OXYBUTYNIN HYDROCHLORIDE 0 1 (<1%)
PHENAZOPYRIDINE 1 (<1%) 0
POVIDONE-IODINE 0 1 (<1%)
SILDENAFIL CITRATE 0 1 (<1%)
SILODOSIN 0 1 (<1%)
TOLTERODINE 0 1 (<1%)
VARDENAFIL 1 (<1%) 0

SENSORY ORGANS
Any medication 84 (27%) 78 (24%)
SODIUM CHLORIDE 15 (5%) 10 (3%)
DICLOFENAC 8 (3%) 15 (5%)
HEPARIN (NOS) 12 (4%) 6 (2%)
MACROGOL 5 (2%) 11 (3%)
KETOROLAC TROMETAMOL 7 (2%) 6 (2%)
LIDOCAINE 5 (2%) 7 (2%)
TRIAMCINOLONE ACETONIDE 8 (3%) 3 (<1%)
CIPROFLOXACIN HYDROCHLORIDE 5 (2%) 4 (1%)
CLONIDINE 4 (1%) 4 (1%)
DEXAMETHASONE 3 (<1%) 3 (<1%)
HYDROCORTISONE 3 (<1%) 3 (<1%)
METHYLPREDNISOLONE 1 (<1%) 5 (2%)
METHYLPREDNISOLONE SODIUM SUCCINATE 2 (<1%) 4 (1%)
ACYCLOVIR 2 (<1%) 3 (<1%)
TRIAMCINOLONE 3 (<1%) 2 (<1%)
BRIMONIDINE TARTRATE 2 (<1%) 2 (<1%)
CHLORHEXIDINE GLUCONATE 2 (<1%) 2 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
CIPROFLOXACIN 4 (1%) 0
DICLOFENAC SODIUM 4 (1%) 0
LATANOPROST 2 (<1%) 2 (<1%)
LIDOCAINE HYDROCHLORIDE 4 (1%) 0
TRAVOPROST 1 (<1%) 3 (<1%)
ACETYLCYSTEINE 0 3 (<1%)
ARTIFICIAL TEARS NOS 2 (<1%) 1 (<1%)
CORTISONE 1 (<1%) 2 (<1%)
HEPARIN CALCIUM 1 (<1%) 2 (<1%)
INDOMETACIN 1 (<1%) 2 (<1%)
KETOROLAC 3 (<1%) 0
OXYMETAZOLINE HYDROCHLORIDE 1 (<1%) 2 (<1%)
AZELASTINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
BIMATOPROST 1 (<1%) 1 (<1%)
CLONIDINE HYDROCHLORIDE 2 (<1%) 0
HEPARIN SODIUM 2 (<1%) 0
ISOSORBIDE 1 (<1%) 1 (<1%)
PIROXICAM 0 2 (<1%)
PREDNISOLONE 1 (<1%) 1 (<1%)
TIMOLOL MALEATE+BRIMONIDINE TARTRATE 0 2 (<1%)
ACETAZOLAMIDE 0 1 (<1%)
AMIKACIN 1 (<1%) 0
AMPICILLIN 1 (<1%) 0
ANTIBIOTICS NOS 0 1 (<1%)
BACITRACIN 0 1 (<1%)
BETAXOLOL 1 (<1%) 0
BRINZOLAMIDE 1 (<1%) 0
BROMFENAC SODIUM 1 (<1%) 0
CHLORHEXIDINE 1 (<1%) 0
DESONIDE 1 (<1%) 0
DEXAMETHASONE+TOBRAMYCIN 0 1 (<1%)
DICLOFENAC DIETHYLAMINE 0 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
EPINEPHRINE 0 1 (<1%)
ERYTHROMYCIN 1 (<1%) 0
GENTAMICIN 1 (<1%) 0
GENTAMICIN SULFATE 1 (<1%) 0
HYDROCORTISONE+NEOMYCIN+POLYMYXIN B 0 1 (<1%)
HYOSCINE 0 1 (<1%)
INTERFERON BETA 1 (<1%) 0
KETOTIFEN 0 1 (<1%)
LOTEPREDNOL ETABONATE 0 1 (<1%)
NEOMYCIN SULFATE+POLYMYXIN B SULFATE+BACITRACIN ZINC 1 (<1%) 0
OFLOXACIN 1 (<1%) 0
PHENYLEPHRINE HYDROCHLORIDE 1 (<1%) 0
POLYMYXIN B SULFATE+TRIMETHOPRIM 0 1 (<1%)
PROXYMETACAINE HYDROCHLORIDE 0 1 (<1%)
SALICYLIC ACID 1 (<1%) 0
SODIUM CHLORIDE+HYPROMELLOSE 1 (<1%) 0
TEARS NATURALE (NOS) 1 (<1%) 0
TIMOLOL 0 1 (<1%)
UREA HYDROGEN PEROXIDE 1 (<1%) 0

ANTIINFECTIVES FOR SYSTEMIC USE


Any medication 71 (23%) 73 (22%)
INFLUENZA VACCINE 14 (4%) 16 (5%)
AMOXICILLIN 7 (2%) 11 (3%)
LEVOFLOXACIN 8 (3%) 7 (2%)
AZITHROMYCIN 4 (1%) 10 (3%)
FLUCONAZOLE 4 (1%) 8 (2%)
CEFALEXIN 6 (2%) 4 (1%)
SULFAMETHOXAZOLE+TRIMETHOPRIM 3 (<1%) 7 (2%)
CIPROFLOXACIN HYDROCHLORIDE 5 (2%) 4 (1%)
CEFTRIAXONE 5 (2%) 3 (<1%)
METRONIDAZOLE 6 (2%) 2 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
PIPERACILLIN SODIUM+TAZOBACTAM SODIUM 6 (2%) 2 (<1%)
MOXIFLOXACIN 5 (2%) 2 (<1%)
PNEUMOCOCCAL VACCINE 3 (<1%) 4 (1%)
VANCOMYCIN 3 (<1%) 4 (1%)
ACYCLOVIR 2 (<1%) 3 (<1%)
DOXYCYCLINE 2 (<1%) 3 (<1%)
AMOXICILLIN TRIHYDRATE+CLAVULANATE POTASSIUM 3 (<1%) 1 (<1%)
CIPROFLOXACIN 4 (1%) 0
CLINDAMYCIN 3 (<1%) 1 (<1%)
MUPIROCIN 3 (<1%) 1 (<1%)
CEFAZOLIN SODIUM 0 3 (<1%)
CLARITHROMYCIN 1 (<1%) 2 (<1%)
INFLUENZA VIRUS VACCINE INACTIVATED 1 (<1%) 2 (<1%)
MOXIFLOXACIN HYDROCHLORIDE 2 (<1%) 1 (<1%)
BIAXIN (NOS) 0 2 (<1%)
DOXYCYCLINE HYCLATE 0 2 (<1%)
GATIFLOXACIN 1 (<1%) 1 (<1%)
TETANUS TOXOID+DIPHTHERIA TOXOID 0 2 (<1%)
VALACICLOVIR HYDROCHLORIDE 1 (<1%) 1 (<1%)
AMIKACIN 1 (<1%) 0
AMOXICILLIN+CLAVULANATE 0 1 (<1%)
AMOXICILLIN+CLAVULANATE POTASSIUM 1 (<1%) 0
AMOXICILLIN+CLAVULANIC ACID 0 1 (<1%)
AMPICILLIN 1 (<1%) 0
ANTIBIOTICS NOS 0 1 (<1%)
BENZATHINE BENZYLPENICILLIN 1 (<1%) 0
CEFTRIAXONE SODIUM 1 (<1%) 0
CEFUROXIME 1 (<1%) 0
CLAVULANIC ACID 0 1 (<1%)
CLINDAMYCIN HYDROCHLORIDE 0 1 (<1%)
DAPTOMYCIN 0 1 (<1%)
EFAVIRENZ+EMTRICITABINE+TENOFOVIR DISOPROXIL FUMARATE 1 (<1%) 0

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Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
ERYTHROMYCIN 1 (<1%) 0
FURADONINE 1 (<1%) 0
GENTAMICIN 1 (<1%) 0
GENTAMICIN SULFATE 1 (<1%) 0
ISONIAZID 1 (<1%) 0
LAMIVUDINE+ABACAVIR 0 1 (<1%)
LINEZOLID 1 (<1%) 0
OFLOXACIN 1 (<1%) 0
OSELTAMIVIR 1 (<1%) 0
OSELTAMIVIR PHOSPHATE 0 1 (<1%)
PIPERACILLIN+TAZOBACTAM 1 (<1%) 0
RITONAVIR+LOPINAVIR 0 1 (<1%)
SULFADIAZINE SILVER 0 1 (<1%)
TENOFOVIR DISOPROXIL FUMARATE 0 1 (<1%)
TRIMETHOPRIM 1 (<1%) 0
VALACICLOVIR 0 1 (<1%)
VARICELLA ZOSTER VIRUS VACCINE, LIVE, OKA STRAIN 0 1 (<1%)
VORICONAZOLE 0 1 (<1%)
SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS
Any medication 48 (15%) 54 (17%)
LEVOTHYROXINE SODIUM 16 (5%) 22 (7%)
LEVOTHYROXINE 8 (3%) 7 (2%)
PREDNISONE 8 (3%) 6 (2%)
TRIAMCINOLONE ACETONIDE 8 (3%) 3 (<1%)
DEXAMETHASONE 3 (<1%) 3 (<1%)
HYDROCORTISONE 3 (<1%) 3 (<1%)
METHYLPREDNISOLONE 1 (<1%) 5 (2%)
METHYLPREDNISOLONE SODIUM SUCCINATE 2 (<1%) 4 (1%)
TRIAMCINOLONE 3 (<1%) 2 (<1%)
METHYLPREDNISOLONE ACETATE 2 (<1%) 2 (<1%)
CORTISONE 1 (<1%) 2 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
GLUCAGON 1 (<1%) 1 (<1%)
PREDNISOLONE 1 (<1%) 1 (<1%)
BETAMETHASONE 1 (<1%) 0
BETAMETHASONE VALERATE 0 1 (<1%)
MELATONIN 1 (<1%) 0
THIAMAZOLE 0 1 (<1%)
VARIOUS
Any medication 27 (9%) 23 (7%)
OXYGEN 6 (2%) 4 (1%)
MAGNESIUM SULFATE 4 (1%) 0
ACETYLCYSTEINE 0 3 (<1%)
COMPRESSED AIR 2 (<1%) 1 (<1%)
MEDICATION UNKNOWN 2 (<1%) 1 (<1%)
ALLIUM SATIVUM 1 (<1%) 1 (<1%)
AMBIGUOUS MEDICATION 0 2 (<1%)
BIMATOPROST 1 (<1%) 1 (<1%)
NALOXONE HYDROCHLORIDE+BUPRENORPHINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
NUTRITIONAL SUPPLEMENT NOS 1 (<1%) 1 (<1%)
STARCH 2 (<1%) 0
ALOE BARBADENSIS+SORBITOL+LEVOMENTHOL+CAPSAICIN+GLUCOSAMINE 1 (<1%) 0
HYDROCHLORIDE+DIMETHYL SULFONE+FATTY ACI
ASCORBIC ACID+ANANAS COMOSUS+HESPERIDIN+AESCULUS 1 (<1%) 0
HIPPOCASTANUM+RUSCUS ACULEATUS+MELILOTUS OFFICINALI
BLOOD TRANSFUSION, AUXILIARY PRODUCTS 1 (<1%) 0
CONTRAST MEDIA NOS 0 1 (<1%)
EUTERPE OLERACEA 0 1 (<1%)
GINSENG 1 (<1%) 0
GLUCOSE 0 1 (<1%)
HEDERA HELIX 1 (<1%) 0
HYDROXOCOBALAMIN 0 1 (<1%)
IOHEXOL 0 1 (<1%)

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Population: Intent-to-Treat
Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
IOPAMIDOL 1 (<1%) 0
IOVERSOL 0 1 (<1%)
IRON+ALLIUM SATIVUM+CALCIUM 0 1 (<1%)
LECITHIN+WHEY PROTEIN 1 (<1%) 0
MINERALS NOS+VITAMINS NOS+HERBALS NOS 0 1 (<1%)
NALTREXONE 0 1 (<1%)
PLANTAGO OVATA 0 1 (<1%)
POLYETHYLENE 0 1 (<1%)
PYGEUM AFRICANUM+PUMPKIN OIL+MINERALS NOS+SERENOA REPENS 1 (<1%) 0
EXTRACT+LYCOPENE+URTICA DIOICA EXTRACT+VITA
QUININE+CITRIC ACID+WATER+CORN SYRUP 1 (<1%) 0
RHODIOLA NOS 0 1 (<1%)

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS


Any medication 13 (4%) 10 (3%)
ESTRADIOL 3 (<1%) 2 (<1%)
METHOTREXATE 4 (1%) 1 (<1%)
ESTROGENS CONJUGATED 1 (<1%) 3 (<1%)
LEUPRORELIN ACETATE 1 (<1%) 1 (<1%)
MEGESTROL ACETATE 1 (<1%) 1 (<1%)
RALOXIFENE HYDROCHLORIDE 1 (<1%) 1 (<1%)
ANASTROZOLE 0 1 (<1%)
DENOSUMAB 1 (<1%) 0
ESTRADIOL CIPIONATE 0 1 (<1%)
IMMUNOTHERAPY{NOS} 1 (<1%) 0
INTERFERON BETA 1 (<1%) 0
MEDROXYPROGESTERONE 1 (<1%) 0
MEDROXYPROGESTERONE ACETATE 1 (<1%) 0

ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS


Any medication 8 (3%) 4 (1%)
METRONIDAZOLE 6 (2%) 2 (<1%)

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Table 5.15
Summary of Non-COPD Concomitant Medications

ATC Level 1 FSC250/50 Salmeterol


Ingredient (N=314) (N=325)
----------------------------------------------------------------------------------------------------
HYDROXYCHLOROQUINE SULFATE 1 (<1%) 1 (<1%)
HYDROXYCHLOROQUINE 1 (<1%) 0
QUININE 0 1 (<1%)

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Table 5.16
Summary of Exposure to Study Drug

FSC250/50 Salmeterol
(N=314) (N=325)
-------------------------------------------------------------------------------------------------------
Double-blind DISKUS
Exposure to study drug (days) n 302 317
Mean 152.2 145.4
SD 70.16 73.29
Median 190.0 189.0
Min. 1 1
Max. 222 245

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Table 5.17
Summary of Treatment Compliance

FSC250/50 Salmeterol
(N=314) (N=325)
--------------------------------------------------------------------------------------------------
DISKUS compliance (%) n 263 286
Mean 91.9 92.4
SD 16.21 21.30
Median 95.7 95.5
Min. 29 14
Max. 173 262

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Population: Intent-to-Treat
Table 5.18
Listing of Reasons for Study Withdrawal

Date of
Sub- Study Study Primary Reason for
Treatment Centre ject Withdrawal Day Study Withdrawal Subreason Comment
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the Sponsor Clinical Study Register.

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Table 5.19
Listing of Subjects for Whom the Treatment Blind Was Broken

Date
Blind Study
Treatment Centre Subj. Broken Day Reason
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the Sponsor Clinical Study Register.

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Population: Intent-to-Treat
Table 5.20
Listing of Protocol Deviations

Treatment Centre Subj. Protocol Deviation


This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the Sponsor Clinical Study Register.

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Population: Intent-to-Treat
Table 5.21
Listing of Subjects with Inclusion/Exclusion Criteria Deviations

Treatment Centre Subj. Type Criterion


This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the Sponsor Clinical Study Register.

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM ACARBOSE ascarbosa
ACETYLSALICYLIC ACID AAS
ASA
ASA (Aspirin)
ASPIRIN
ASPRIN
A[sprin
Acetyl salicylic acid
Adult Aspirin
Albyl-E
Aspirin
Aspirin (Bayer)
Aspirin - bayer
Aspirine
Aspirineta
Asprin
Aspyrin
Baby Aspirin
Bayer ASA
ENTERIC COATED ASPIRIN
Ecotrin
aas
acetilsalicilic acid
acetylsalicylic acid
albyl E
asa
aspirin
aspirina
aspirine
asprin
cardioaspirin
ecotrin
enteric coated aspirin

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM ACETYLSALICYLIC ACID+SODIUM Alka-Seltzer
BICARBONATE+CITRIC ACID
Alka-sultzer
ALUMINIUM HYDROXIDE GEL, DRIED+MAGNESIUM Mylanta
HYDROXIDE+DIMETICONE, ACTIVATED
mylanta
ALUMINIUM HYDROXIDE+MAGNESIUM Mag-al Plus
HYDROXIDE+DIMETICONE, ACTIVATED
ANTIBIOTICS NOS Antibiotics
Empiric Antibiotic Therapy
IV Antibiotics
IV antibiotics
Unknown iv antibiotics
antibiotic
antibiotics
antibotics
intravenous antibotics ( name
unknown)
iv antibiotics
unknown antibiotics
unknown antibotic
unknown iv antibiotics
ASCORBIC ACID Vitamin C
vitamin c
ATROPINE SULFATE ATROPINE SULFATE
ATROPINE SULFATE+DIPHENOXYLATE lomotil
HYDROCHLORIDE
ATROPINE SULFATE+HYOSCINE Donnatal Elixir
HYDROBROMIDE+PHENOBARBITAL+HYOSCYAMINE
SULFATE
BECLOMETASONE beclometasone
BECLOMETASONE DIPROPIONATE Q-VAR 80
QVAR
beconase aq

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM BECLOMETASONE DIPROPIONATE qvar
BETAMETHASONE BETAMETASONE
BETHAMETASONE
Betametasone
CORTEROID RETARD
CORTIPYREN
Corteroid Retard
betametasona
betametasone
betamethasone
corteriod retard
corteroid retard
BETAMETHASONE VALERATE BETAMETHASONE OINTMENT
BIFIDOBACTERIUM INFANTIS Align
BISACODYL Bisacodyl
BISMUTH Bismute
BISMUTH SUBSALICYLATE PEPTO BISMOL
Pepto-Bismol
pepto bismol
BUDESONIDE BUDESONIDA
BUDESONIDE
Budenoside
Budesonid
Budesonide
Budesonide 200 mg
Budesonide neb
Neumotex 200
Neumotex Bronquial Forte
PULMICORT
PULMICORT RESPULES
Pulmicort
Pulmicort Nebs
Pulmicort nebs
budeson

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM BUDESONIDE budesonid
budesonide
neumotex
pulmicort
CALCITRIOL Calcitriol
calcitriol
calcitroil
CALCIUM CALCIUM
Calcium
calcium
CALCIUM ACETATE CALCIUM ACETATE
CALCIUM ASCORBATE ester C
CALCIUM CARBONATE CALCIUM CARBONATE
Calcium Carbonate
Caltrate
Fortical vitamin
Oscal
Tums
Tums Antacid
calcium carbonate
tums
CALCIUM CARBONATE+COLECALCIFEROL Calcigran Forte (calcium and
vitamin D)
calsigran forte
CALCIUM CARBONATE+VITAMIN D SUBSTANCES Caltrate Vitamin D
CALCIUM CITRATE Calcium citrate
CALCIUM GLUCONATE Gluconato of Calcium
Gluconato of calcium
CALCIUM+VITAMIN D NOS oscal D
CHLORDIAZEPOXIDE HYDROCHLORIDE+CLIDINIUM Librax 5/2.5
BROMIDE
CHLORHEXIDINE Chlorhexidine Soap
CHLORHEXIDINE GLUCONATE Chlorhexidine Gluconate
Peridex

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM CHLORHEXIDINE GLUCONATE chlorhexidine gluconate
chlorohexadine mouth wash
CHLORPROPAMIDE Chlorpropamide
Chlorpropamide
CHROMIUM PICOLINATE chromium picolinate
CIMETIDINE Tagamet
CINNARIZINE cinnarizine
CLOTRIMAZOLE Clotrimazole 1%
Mycelex Troches
Mycolex Troche
Mycolex Trouche
clotrimazole 10 mg torche
mycelex troches
COD-LIVER OIL Cod Liver Oil
Cod liver oil
COLECALCIFEROL CHOLECALCIFEROL
VITAMIN D3
Vitamin D3
cholecalciferal
vitamin D3
COLECALCIFEROL+CALCIUM CITRATE citracal maximum
CYPROHEPTADINE Cyproheptadine
CYPROHEPTADINE HYDROCHLORIDE Periactin
CYPROHEPTADINE HYDROCHLORIDE+VITAMINS NOS SUDEVIL VITA
DEXAMETHASONE Dexametasone
DEXAMETASONA
DEXAMETASONE
Decadron
Decodron
Desamethasone
Dexametasona
Dexametasone
Dexametazone
Dexamethasone

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM DEXAMETHASONE decadron
dexametason
dexametasona
dexametasone
dexamethasone
dexametosana
DEXLANSOPRAZOLE Dexilant
Kapidex
dexilant
kapidex
DICYCLOVERINE dicyclomine
DICYCLOVERINE HYDROCHLORIDE Bentyl
bentyl
DIMETICONE, ACTIVATED Gas X
DIPHENHYDRAMINE Duke's Magic Mouthwash
HYDROCHLORIDE+HYDROCORTISONE+NYSTATIN
DOCUSATE Docusate
docosate
docusate
DOCUSATE CALCIUM docusate ca
DOCUSATE SODIUM COLACE
Colace
DOCUSATE NA
DOCUSATE SODIUM
DOCUSATE SODIUM STOOL SOFTNER
Docusate Sodium
Docusate sodium
Phillip's Stool Softener
RAD Col Rite Stool Softner
colace
docusate na
docusate sodium
DOCUSATE SODIUM+SENNOSIDES Sennosides-Docusate
DOMPERIDONE domperidona

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM DOMPERIDONE domperidone
DOXYCYCLINE HYCLATE Docycycline Hyclate
Doxycycline Hyc
Doxycycline Hyclate
Doxycycline hyclate
doxycycline hycalate
doxycycline hyclate
DULCOLAX (NOS) DULCOLAX
Dulcolax
dulcolax
EPINEPHRINE Adrenaline
Epipen
Primatene Mist
adrenalina
epinephrine
ERGOCALCIFEROL Ergocalciferal
Ergocalciferol
ERGOCALCIFEROL+CALCIUM CALCIUM WITH VITAMIN D
Calcium +D
Calcium 600 + D
Calcium D
Calcium w vitamin D
Calcium with Vitamin D
Calcium/Vitamin D
calcium and vitamin D
calcium vitamin D
calcium with vitamin D
calcium/vitamin D
calcium/vitamin d
calicum + vitamin d
caltrate D
ERGOCALCIFEROL+CALCIUM CARBONATE Vitamin D + Calcium Carbonate
calcium carbonate D tab
ERGOCALCIFEROL+CALCIUM CITRATE Citrus Calcium with D

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM ESCULOSIDE esculina
ESOMEPRAZOLE Esomeprazole
ESOMEPRAZOLE MAGNESIUM NEXIUM
Nexium
nexium
EX-LAX NOS ex-lax
FAMOTIDINE Famotidine
Pepcid
Pepcid AC
Pepsid
famotidine
pepcid
FLEET ENEMA (NOS) Fleet Enema
Fleet enema
fleet enema
GLIBENCLAMIDE EUGLUCON
GLIDANIL
GLYBURIDE
Glibenclamide
Glyberide
Glyburide
glibenclamide
glyburide
GLIMEPIRIDE Amaryl
Glimepiride
amaryl
glimepirida
glibe
nclamida
glimepiride
GLIPIZIDE GLIPIZIDE
Glipizide
Glipizide ER
Glipizide xl

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM GLIPIZIDE Glucotrol
Gucotrol
glipizide
glipizide XL
glucotrol
GLUCOSE+FRUCTOSE+PHOSPHORIC ACID CVS Nausea Relief
CVS anti nausea liquid
medication
CVS brand Nausea Relief
medicine
HYDROCORTISONE HIDROCORTISONE
HYDROCORTISONE
HYDROCORTISONE CREAM
Hidrocortisona Klonal
Hidrocortisone
Hidrocotisone
Hydrocortisone
Hydrocortisone cream 2.5%
Hydrocortosone
hidrocortisone
hidrocortizone
hidrocotisone
hydrcortizone
hydricortison
hydrocortisone
hydrocortisone 100 mg
hydrocortisone 500 mg
hydrocortisone cream 2.5%
hydrocortizone
HYDROCORTISONE ACETATE HIDROCORTISONA
Hidrocortisona
hidrocortisona
hidrocortisona 100mg
HYDROCORTISONE SODIUM SUCCINATE Solu-Cortef

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM HYOSCINE HIOSINE
HYOSCINE BUTYLBROMIDE Buscapina
HYOSCYAMINE hyoscyamine
HYOSCYAMINE SULFATE Levsin
INSULIN ASPART ASPARTIC INSULINE
Insulin Aspart
Insulin aspart
Insulin aspart sliding scale
Novo Log Flex Pen
Novolog
Novolog Aspart insulin
Novolog Flex Pen
Novolog Flexpen
Novolog sliding scale insulin
novolog
INSULIN ASPART+INSULIN ASPART PROTAMINE NovoLog 70/30
INSULIN DETEMIR Levemir
Levemir Flexpen
levemir
INSULIN GLARGINE Lantus
Lantus 100/ml
Lantus Insulin
lantus
INSULIN GLULISINE Apidra
INSULIN HUMAN Novolin R
human insulin
novelin R Insulin
novolin R
INSULIN HUMAN INJECTION, ISOPHANE INSULIN NPH HUMAN 100UNIT/ML
NOVOLIN N
Insulin NPH Human
Novolin N
humulin n
insulin novolin

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM INSULIN HUMAN INJECTION, ISOPHANE novolin
INSULIN HUMAN+INSULIN ISOPHANE, HUMAN Humulin
BIOSYNTHETIC
humulin
INSULIN LISPRO HUMALOG SLIDING SCALE
Humalog
Humalog 100/ml
humalog
humalog injection
INSULIN NOS INSULINA
Insulin
Insulin 70/30
Insulin regular
Insulin sliding scale
Insuline
NOVILIN INSULIN
REGULAR INSULIN
Regular Insulin
insulin
insulin (unspecified)
regular insulin
IRON+ALLIUM SATIVUM+CALCIUM Garlique
LACTOBACILLUS ACIDOPHILUS Acidophilus
acidophilus
LACTOBACILLUS ACIDOPHILUS+LACTOBACILLUS Floranex
BULGARICUS
LACTOBACILLUS NOS LACTOBACILLUS
lactobacillus chew tab
LACTULOSE Lactulose
lactulose
LANSOPRAZOLE Lanzopral
Lanzoprazol
Prevacid
prevacid

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM LAXATIVES, NOS Vegetable Laxative
laxative tea
LEVOCARNITINE L-Carnitine
LOPERAMIDE Loperamide
LOPERAMIDE HYDROCHLORIDE Imodium
imodium
MAALOX (NOS) MAALOX
Maalox
maalox
MACROGOL MIRALAX
MiraLax
Miralax
Polyethylene Glycol
miralax
mirolax
polyethylene glycol
MAGIC MOUTHWASH (NOS) Magic Mouth Wash
Magic Mouth Wash Swish and
Swollow
Magic Mouthwash
magic mouth wash
MAGNESIUM Holomagnesium
Magnesium
magnesium
MAGNESIUM CHLORIDE magnesium chloride
MAGNESIUM CITRATE Citrate
citroma
magnesium citrate
MAGNESIUM CITRATE+CALCIUM CITRATE Mag. Citrate
MAGNESIUM HYDROXIDE Magnesium hydroxide
Milk of Magnesia
magnesium hydroxide
milk of magnesia
MAGNESIUM OXIDE Magnesium Oxide

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM MAGNESIUM OXIDE magnesium oxide
MAGNESIUM OXIDE+ALUMINIUM GLYCINATE novalox
MAGNESIUM SULFATE Magnesium Sulfate
Magnesium sulfate
magnesium sulfate
MECLOZINE Meclizine
meclizine
MESALAZINE Asacol
METFORMIN METFORMIN
METFORMIN XR
METFORMINA
Metformin
Metformin XR
Metformina
Metformine
metformin
metformina
metformine
METFORMIN HYDROCHLORIDE GLUCOPHAGE
Glucophage
METFORMIN HCL
Metformin HCL
Metformin HCL ER
glucophage
metformin hcl
METFORMIN HYDROCHLORIDE+GLIBENCLAMIDE glucovance
METFORMIN HYDROCHLORIDE+ROSIGLITAZONE AVANDEMENT
METFORMIN+GLIBENCLAMIDE Glyb/Met formin
METOCLOPRAMIDE Afipram
Metoclopramide
Reliveran
metoclopram
metoclopramida
metoclopramide

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM METOCLOPRAMIDE reliveran
METOCLOPRAMIDE HYDROCHLORIDE Reglan
reglan
METRONIDAZOLE Flagyl
MetroGel
flagyl
metronidazol
metronidazole
MICONAZOLE NITRATE Monistat
MIGLITOL glyset
MINERALS NOS+CAROTENOIDS+VITAMINS NOS Persevision with lutein
MINERALS NOS+PHYTOSTEROL (NOS)+VITAMINS NOS Centrum Cardio
MINERALS NOS+VITAMINS NOS Centrum Silver
Centrum multivitamin
Ocuvite
One A Day
Tandum Plus
multivitamin/mineral
prenatal vitamins
solaray spectro vite ultra
womens health senior
multivitamin/multimineral
MINERALS NOS+VITAMINS NOS+HERBALS NOS hair and nail vitamin
MIRACLE MOUTHWASH (NOS) MIRACLE MOUTHWASH
MISOPROSTOL Misoprostol
MOSAPRIDE MASAPRIDE
Mosapride
NYSTATIN Mycostatin
Mycostatin mix
NISTATINE
Nystantin
Nystantin Syrup
Nystatin
Nystatin Cream

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM NYSTATIN Nystatin Swish/Swallow
mycostatin
nistatine
nystatin
nystatin swish and swallow
OMEPRAZOLE GASTEC
OMEPRAZOL
OMEPRAZOLE
Omeperazole
Omeprazol
Omeprazole
Omeprazole CR
Omeprazole Dr
Omeprazole EC
Omeprozole
PRILOSEC
PROCELAC
Prilosec
Prilosec OTC
Prilosec(Omeprazole)
Ulcozol
losec
omeprazol
omeprazole
omeprezole
omperazole
prilosec
prilosec otc
ulcozol
ONDANSETRON Ondansefron
Ondansetron
Zofran
ondansetron
zofran

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM ONDANSETRON HYDROCHLORIDE Ondansetron HCL
OXYBUTYNIN oxybutnin
oxybutynin
oxytrol patch
PANCRELIPASE Creon
zenpen
PANTOPRAZOLE PANTOP
PROTONIX
Pantoprazole
Pantoprozole
Protonix
pantoprazol
pantoprazole
patoprazol
protonix
PANTOPRAZOLE SODIUM Somac
pantoprazole NA
somac
PARGEVERINE HYDROCHLORIDE SERTAL
Sertal
PHENTERMINE Phentermine
PHOSPHORIC ACID, SODIUM SALT sodium phosphate
PIOGLITAZONE pioglitazone
PIOGLITAZONE HYDROCHLORIDE Actos
PLANTAGO OVATA Reguloid
POLYCARBOPHIL CALCIUM Fiber Con
Fibercon
POTASSIUM CHLORIDE Chlorocon
K Dur
K-Dur
K-dur
KCL
KCl
KDur

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM POTASSIUM CHLORIDE KLOR-CON
Klor-Con
Klor-Con-M
Klor-Cor
Klor-con 10
Micro K
POTASSIUM CHLORIDE
Potassium CL
Potassium Chloride
Potassium chloride
control K (potasium chloride)
klor-con
potassium Chloride
potassium chloride
potassiumn chloride
POTASSIUM CITRATE potassium citrate
POTASSIUM GLUCONATE Potassium gluconate
potassium gluconate
POTASSIUM NOS Potasium
Potassium
potassium
POTASSIUM PHOSPHATE DIBASIC potassium phosphate
PREDNISOLONE Prednisolon
Prednisolone
prednisolon
prednisolone
prednisolone opthalmic drops
PREDNISONE Deltisone
DELTISONE
DELTISONE B 40
Deltisona
Deltisone
METILPRES 20
Metilpres

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM PREDNISONE PREDNISONE
PREDNISONE TAPER
PREDNISONE TAPER PACK
Predinsone
Predisone
Predisone 20 mg
Predisone 20mg
Predisone Taper
Prednisione Taper
Prednisona 20 mg
Prednisone
Prednisone Taper
Prednisone (Taper)
Prednisone 10 mg dose Pack
Prednisone 10mg taper
Prednisone 125mg
Prednisone 20 mg
Prednisone 20mg
Prednisone 60mg
Prednisone 60mg taper
Prednisone Taper
Prednisone Taper 40 mg x 4 days
30 mg x2 days; 20 mg x3 days 10
mg x3 days
Prednisone Taper pac
Prednisone dose Pack
Prednisone dose pak
Prednisone taper
Prednisone taper by 10 mg every
2 days
Prenisone
Sterapred
Sterapred DS
Sterapred Dose Pk 12 day

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM PREDNISONE Sterapred dosepak
deltasone
deltisona
deltisone
deltisone 20
metilpres
predisone
prednisine dose Pak
prednisona
prednisone
prednisone (12 day taper)
prednisone (9day taper)
prednisone 20 mg
prednisone 30 mg
prednisone 5mg
prednisone burst
prednisone prn
prednisone taper
prednisone taper (20 mg to
zero, decrease by 5mg every 3
days)
prednisone taper (for copd
exacerbation)
prednisone taper 60 mg x2
days;40 mgx2 days;20 mg x2
days; 10 mgx 1 day
prednisone taper pac
prednisone taper pack
prednisone taper pak
prrednisone
sterapred
PROCHLORPERAZINE Compazine
PROMETHAZINE PHENERGAN
PROMETHAZINE

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM PROMETHAZINE Phenergan
Phenergan Injection
Promethazine
phenergan
promethazine
promethazone
PYRIDOXINE pyridoxine
PYRIDOXINE HYDROCHLORIDE B6 VITAMIN
RABEPRAZOLE RABEPRAZOL
RABEPRAZOLE SODIUM Aciphex
RABEPRAZOLE NA
aciphex
RANITIDINE RANITIDINE
Ranitidina
Ranitidine
TAURAL
ranitidina
ranitidine
taural
RANITIDINE HYDROCHLORIDE RANITIDINE HCL
Ranitidine HCL
Rantidine
Zantac
Zantac OTC
ranitidine hcl
rantidine
zantac
REPAGLINIDE repaglinide
SAXAGLIPTIN HYDROCHLORIDE onglyza
SENNA Senna Plus
SennaGen
Senokot
senokot
SENNOSIDES Sennosides

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM SITAGLIPTIN Januvia
januvia
SODIUM BICARBONATE Sodium bicarbonate
SODIUM CHLORIDE saline
IV BOLUS SALINE nacl
NaCL
NaCl
NaCl 0.45%
NaCl 0.9%
Nasal Saline
Nasal Saline Rinse
Normal Saline
Normal saline
SODIUM CHLORIDE
SODIUM CHLORIDE 0.65% NASAL
SOLUTION
Saline
Saline Nasal Sp
Saline Spray
Sodium Chloride
Sodium chloride
deep sea nasal spray (sodium
chloride)
normal saline
normal saline bolus
normal saline boulus taper
ocean nasal spray
saline
saline nasal spray
sodiu chloride 0.9%
sodium Chloride
sodium chloride
sodium chloride 0.9%
sodium choloride

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM SODIUM FLUORIDE sodium floride
SODIUM PHOSPHATE DIBASIC+POTASSIUM neutra phos (250 K+ 160 Na+)
PHOSPHATE DIBASIC+SODIUM PHOSPHATE
MONOBASIC+POTASSIUM PHOSPHATE
STEROIDS NOS IV Steroids
IV steroids
Intravenous Steroids
Steriods
Steroids
UNKNOWN IV STEROIDS
Unk inhaled steroid
Unknown IV Steroid
Unspecified IV Steriod
high dose IV steroids
high dose steroids
intravenous steroids ( name
unknown )
iv steroids
steroids
unknown iv steroids
unknown steroids
SUCRALFATE Carafate
Carafate Suspension
carafate
sucralfate
THIAMINE Thiamine
thiamine
THIAMINE HYDROCHLORIDE Vitamin B1
thiamine hcl
TOCOPHEROL Vitamin E
vitamin e
TRIAMCINOLONE Triacinolone
Triamcinolone
Triamcinolone 0.1%

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM TRIAMCINOLONE Triamincinolo
triamcinolone
TRIAMCINOLONE ACETONIDE Kenalog
Nasacort
Nasacort AQ
Triamcinolone Acetonide
Triamcinolone acetonide 0.1%
Triamcinolone/Acetonide
aristocort
kenalog
TRIMEBUTINE DEBRIDAT
MIOPROPAN
trimebutine
VANCOMYCIN VANCOMICIN
VANCOMYCIN
Vancomycin
Vancomycin`
vancomicyn
vancomycin
VITAMIN B NOS vitamin b
VITAMIN B SUBSTANCES NOS Super B Complex
super b-complex
VITAMIN D NOS VITAMIN D
VITAMIN-D
Vitamin D
vitamin D
vitamin d
VITAMINS NOS Centrium silver vitamins
MULTIVITAMINS
MUTI-VITAMIN
Multi Vitamin
Multi Vitamins
Multi vitamin
Multi vitamins

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM VITAMINS NOS Multi-Vitamin
Multi-vitamin
Multiple Vitamin
Multivitamin
Multivitamins
Multvitamin
Theragran
VITAMIN
mulitivitamin
multi vitamin
multi-vitamin
multivitamin
multivitamins
multvitamin
ZINC Zinc Cold lozenge
zinc
ZINC GLUCONATE zicam cold remedy

ANTIINFECTIVES FOR SYSTEMIC USE ACYCLOVIR Acyclovir


Zovirax
Zovirax Ointment
acyclovir
AMIKACIN AMIKACINE
Amikacin
AMIKACIN SULPHATE Amikacina
AMOXICILLIN AMOCICILLIN
AMOXICILINA
AMOXICILLIN
AMOXICILLYN
AMOXICYLIN
Amoxacillin
Amoxicilina
Amoxiciline
Amoxicillan

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE AMOXICILLIN Amoxicillin
Amoxicilline
Amoxidal
Amoxil
Amoxilin
Amoxyllin
Trifamox 500
amoxicilin
amoxicilina
amoxiciline
amoxicillian
amoxicillin
amoxidal
amoxil
amoxixilin
trifamox plus
AMOXICILLIN TRIHYDRATE Amoxillin
TRIFAMOX DUO
trifamox duo
AMOXICILLIN TRIHYDRATE+CLAVULANATE AUGMENTIN
POTASSIUM
Augmentin
Augmentine
OPTAMOX DUO
Optamox Duo
Optamox Duo 1
Optamox Duo 1g
augmentin
clavulin
clavulox
optamox duo
AMOXICILLIN+CLAVULANATE Amoxicillin + Clavulanate
Amoxicillin Clavulanate
Amoxicillin clavulanate

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE AMOXICILLIN+CLAVULANATE amixicillin/clavulanic
amoxicilin / clavulanic
amoxicilin-clavulanate
amoxicilin-clavulanic
amoxicilin/clavulanic
amoxiciline clavulanico
amoxiciline-clabulanic 1g
amoxicillin clavulanate
amoxicillin/clavulanate
amoxicillin/clavulanic
AMOXICILLIN+CLAVULANATE POTASSIUM Amoxicillin/Clavulanate
Potassium
AMOXICILLIN+CLAVULANIC ACID AMIXICILLYN /CLAVULANIC ACID
AMOCICILLYN/CLAVULANIC ACID
AMOCICILLYN/CLAVULONIC ACID
AMOXICILIN/CLAVULANIC
AMOXICILINE-CLAVULANIC
AMOXICILLIN/CLAVULANIC ACID
AMOXICILLYN/CLAVULANIC ACID
Amocicilina + Acido Clavulanico
Amoxacillin Clavulanic
Amoxacillin clavulanic
Amoxacillin/clavulanic acid
Amoxi Clav 875/125
Amoxicilin-clavulanic
Amoxiciline -Clavulanic Acid
Amoxiciline-Clavulanic
Amoxiciline-clavulanic
Amoxicillin / Clavulanic Acid
Amoxicillin clavulanic
Amoxicillin+clavulanic acid
amoclav
amoclav duo
amoxicilin-clavulanic acid

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE AMOXICILLIN+CLAVULANIC ACID amoxicilina-clavulanico
amoxiciline + clavulanic Ac.
amoxiciline-clavulanic
amoxiciline/clavulanic acid
amoxicillin - clavulanic acid
amoxicillin and clavulanic acid
amoxicillin clavulanic acid
amoxicillin+ clavulanic acid
amoxicillin/ clavulanic acid
amoxicillin/clavulanic acid
amoxicillin/clavulanic acid
(augmentin)
amoxicillin/clavulanic acid
875/125
amoxicillin7clavulanic acid
amoxicilline/clavulanic acid
amoxicillyn + clavulanic acid
AMOXICILLIN+SULBACTAM Amoxicillin sulbactam
amoxiciline sulbactam
amoxicillin/ sulbactam 875/125
mg
trifamox ibl duo
AMPICILLIN ampicilin
ampiciline
ampicillin
AMPICILLIN+SULBACTAM AMICICILLYN/SULBACTAN
AMPICILIN+SULBACTAM
AMPICILIN-SULBACTAM
AMPICILIN/SULBACTAM
Ampi Bis Plus
Ampicilina / Sulbactam
Ampicilina-sulbactam
Ampicilina/sulbactan
Ampiciline-Sulbactam

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE AMPICILLIN+SULBACTAM Ampiciline-sulbactam
Ampiciline/Sulbactan
Ampicillin Sulbactan
Ampicillin sulbactam
Ampicillin sulbactan
Ampicillin/sulbactam
Ampicilline Sulbactan
ampi/sulbactam
ampicilin-sulbactan
ampicilin/sulbactam
ampicilina / sulbactam
ampicilina-sulbactam
ampicilina/sulbactam
ampiciline-sulbactam
ampicillin plus sulbactam
ampicillin sulbactam
ampicillin+sulbactam
ampicillin/sulbactam
ampicillin/sulbactam 1.5 g
ANTIBIOTICS NOS Antibiotics
Empiric Antibiotic Therapy
IV Antibiotics
IV antibiotics
Unknown iv antibiotics
antibiotic
antibiotics
antibotics
intravenous antibotics ( name
unknown)
iv antibiotics
unknown antibiotics
unknown antibotic
unknown iv antibiotics
AZITHROMYCIN AZITHROMYCIN

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE AZITHROMYCIN AZITROMICIN
Azithiromycin
Azithromyacin
Azithromyacin 250mg
Azithromycin
Azithromycin (IV)
Azithromycin 500mg
Azithromycin Injection
Azitromax
Azitromicin
Azitromicine
Azythromycin
Intravenous Azithromycin
Z Pack
Z Pack taper
Z Pak
Z pack
Z-Pack
Z-pack
Z-pak
ZITHROMAX
ZITHROMAX TAPER
Zithramax
Zithromax
Zithromax (Z-Pak)
Zithromax 250 mg
Zithromax 500mg
Zithromax pac
Zithromycin
Zitrhomax
Zitrhromax
Zitrhromx
Zpac
Zpack

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE AZITHROMYCIN Zpak
azithromax
azithromycin
azithromycin (for copd
exacerbation)
azithromycin intravenous
azithromycin oral
azitromicin
azitromicina
azitromicyn
azytromicin
z pack
z-pack
z-pak
zithromax
zithromax 500 mg
zithromycin IV
zpak
AZTREONAM Azactam
BENZATHINE BENZYLPENICILLIN benzathine penicillin
BENZYLPENICILLIN Penicillin
penicillin
BIAXIN (NOS) BIAXIN
Biaxin
biaxin
CEFADROXIL cefadroxilo
CEFALEXIN Cephalexin
Keflex
cefalexin
cefalexina
cephalexin
keflex
CEFAZOLIN SODIUM Ancef
CEFDINIR Cefdimir

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE CEFDINIR Omnicef
CEFEPIME Cefepime
cefepime
CEFEPIME HYDROCHLORIDE Maxipime
CEFOTAXIME SODIUM CEFOTAXIME SODIUM
Cefotaxim
CEFPODOXIME cefpodoxime
CEFTRIAXONE CEFTRIAXONA
CEFTRIAXONE
CEFTRIAZONE
Ceftriaxone
Ceftriazone
Intravenous Rocephin
ROCEPHIN
Rocephin
Rocephin 1 Gm IM
Rochepin
ceftriaxona
ceftriaxone
ceftriazone
certriaxone
rocephin
CEFTRIAXONE SODIUM ceftriaxone sodium
rocephine
CEFUROXIME Cefuroxine
Cefuroxmine
cefuroxime
CEFUROXIME AXETIL CEFTIN
Ceftin
ceftin
CIPROFLOXACIN Ciprofloxacin
Ciprofloxacin
Ciprofloxacine
Ciproflozacin

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE CIPROFLOXACIN Ciproxin
ciprofloxacin
ciprofloxacin 400mg
ciprofloxacin 500 mg
ciprofloxacine
ciprofloxocin
ciproxin
CIPROFLOXACIN HYDROCHLORIDE CIPRO
Cipro
Cipro 500 MG BID
Ciprofloxacin HCL
cipro
ciproflaxacin hcl
CLARITHROMYCIN CLARITRIMICINE
CLARITROMICIN
CLARITROMICINE
CLARITROMICYN
Clarimax 500
Clarithromycin
Clarithromycin 500 mg
Claritomicina 500
Claritromicina
Claritromicina 500
Claritromicine
Klacid
clarimax
clarithromycin
clarithromycin 500 mg
claritromicina
claritromicina 500mg
claritromicina iset
claritromicine 500mg
claritromicyn
CLAVULANIC ACID Clavulanic acid

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE CLAVULANIC ACID clavulanic acid
CLINDAMYCIN CLINDAMICINE
Clindamyacin
Clindamycin
cleocin
clindamycin
CLINDAMYCIN HYDROCHLORIDE Clindamycin HCL
DAPTOMYCIN DAPTOMYCIN
DORIPENEM Doribax
DOXYCYCLINE DOXYCYCLINE
Doxicycline
Doxyclycline
Doxycxline
Doxycycline
Doxycyline
Doxylin
VIBRAMYCIN
Vibramycin
doxycyclin
doxycycline
doxycyline
doxylin
vibramycin
DOXYCYCLINE HYCLATE Docycycline Hyclate
Doxycycline Hyc
Doxycycline Hyclate
Doxycycline hyclate
doxycycline hycalate
doxycycline hyclate
DOXYCYCLINE HYDROCHLORIDE doxycycline hcl
DOXYCYCLINE MONOHYDRATE doxcycline monohydrate
EFAVIRENZ+EMTRICITABINE+TENOFOVIR Atripla
DISOPROXIL FUMARATE
ERYTHROMYCIN ERYTHROMYCIN

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE ERYTHROMYCIN Ery-max
Erythromycin
erythromycin
FLUCONAZOLE Diflucan
Fluconazole
diflucan
fluconazole
FURADONINE Nitrofurantoine
nitrofurantoina
GATIFLOXACIN Zymaxid
zymar
GEMIFLOXACIN MESILATE factive
GENTAMICIN Gentamicin
gentamicin
gentamycin
GENTAMICIN SULFATE Garamycin
gentamycin sulfate
H1N1 INFLUENZA VACCINE H1N1 Flu Vaccine
H1N1 Vaccine
H1N1 vaccine
HINI Flu vaccine
IMIPENEM imipenem
IMIPENEM+CILASTATIN SODIUM primaxin
INFLUENZA VACCINE 2010-2011 INFLUENZA VACCINE
FLU VACCINATION
FLU VACCINE
Flu Vaccination
Flu Vaccine
Flu shot
Flu vaccine
INFLUENZA VACCINE
Influenza Flu vaccine
Influenza Immunization
Influenza Vaccination

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE INFLUENZA VACCINE Influenza Vaccine
Influenza Vaccine 0.5mg IM
Influenza Vaccine 2010
Influenza injection
Influenza vaccination
Influenza vaccine
Vacuna Istivac
anti flu vaccine
antiinfluenza vaccine
flu shot
flu vaccine
influenza immunization
influenza vaccina
influenza vaccination
influenza vaccine
influenza-vac
infuenza vaccine
INFLUENZA VIRUS VACCINE INACTIVATED Fluarix
Fluzone Vaccine
Influenza vac
Istivac
fluvirin
influvac
ISONIAZID isoniazide
LAMIVUDINE+ABACAVIR Epizcom
LEVOFLOXACIN IV Levaquin
LEVAQUIN
LEVOFLAXINE
LEVOFLOXACIN
LEVOFLOXACINA
LEVOFLOXACINA 750
LEVOFLOXACINE
Levaquin
Levaquin (po)

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE LEVOFLOXACIN Levnquin
Levoflaxacin
Levofloxacin
Levofloxacina
Levofloxacine
Levofloxacine 500 mg
Levofloxacine 750 mg
Lexobron
Misile
bactocilina
lEVAQUIN
levaquin
levoflaxacin
levoflaxin
levofloxacin
levofloxacin 500 mg
levofloxacina
levofloxacina 500
levofloxacine
levofloxacine 750 mg
levofloxiacin
levoquin
lovafloxacin
LINEZOLID Linezolid
lINEZOLID
METRONIDAZOLE Flagyl
MetroGel
flagyl
metronidazol
metronidazole
MICONAZOLE NITRATE Monistat
MOXIFLOXACIN AVELOX
Avelox
Avelox (IV)

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE MOXIFLOXACIN Avelox (po)
Avelox 400
Avelox IV
Avelox po
IV Avelox
Moxifloxacin
Moxifloxacin 400mg IVPB
Moxifloxacin 400mg po
avelox
avelox 400mg
avelox iv
moxifloxacin
moxifloxacine
moxifloxican
MOXIFLOXACIN HYDROCHLORIDE Avalox
Moxifloxacin HCL
Moxifloxacin hcl
Vigamox
moxifloxacin HCL
MUPIROCIN Bactroban
Bactroban Nasal
Mupirocin 2 %
bactroban ointment
OFLOXACIN Oxfloxacin otic
OPTAMOX (NOS) Optamox
optamox
OSELTAMIVIR oseltamivir
OSELTAMIVIR PHOSPHATE Tamiflu
PIPERACILLIN PIPERACILLIN
PIPERACILLIN SODIUM+TAZOBACTAM SODIUM Tazonam
Zosyn
zosyn
PIPERACILLIN+TAZOBACTAM PIPERACILLIN PLUS TAZOBACTAM
piperacilina tazobactam

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE PNEUMOCOCCAL VACCINE PNEUMOCOCCAL VACCINE
Pnemonia Vaccine
Pneumo 23
Pneumoccal Vaccine
Pneumococcal Vaccine
Pneumococcal Vaccine
(Pneumovax)
Pneumococcal vaccine
Pneumococcocal Vaccine
Pneumonia Vaccination
Pneumonia Vaccine
Pneumonia vaccine
Pneumonvax 23
Pneumovax
Pneumovax 23
Pneumovax Injection
Pneumovax Vaccine
Pneumovax injection
Pneumovax vaccine
Vacuna Pneumo 23
anti pneumococcal vaccine
p-pneumovax
pmeumonia vaccine
pneumo-vac
pneumococal vaccine
pneumococcal vaccination
pneumococcal vaccine
pneumonia shot
pneumonia vaccine
pneumovax
QUINOLONES (NOS) quinolone
RITONAVIR+LOPINAVIR Kaletra
SULBACTAM SULBACTAN
sulbactam

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTIINFECTIVES FOR SYSTEMIC USE SULFADIAZINE SILVER Silvadene Cream
SULFAMETHOXAZOLE sulfametoxazol
SULFAMETHOXAZOLE+TRIMETHOPRIM BACTRIM
Bactrim
Bactrim DS
Bactrim DS
(sulfamethoxazole/trimethoprim)
Bactrium
bactrim
bactrim DS
bactrim ds
TENOFOVIR DISOPROXIL FUMARATE TENOFOVIR DISOPROXIL FUMARATE
TETANUS TOXOID+DIPHTHERIA TOXOID Tetanus/Diptheria toxoid
Tetnus/Diphtheria/toxoid
TRIMETHOPRIM trimethoprim
trimetroprima
TRIVALENT INFLUENZA VACCINE Flu trivalent vaccine
TRIVALENT FLU VACCINE
UNASYNA NOS unasyna
UNIFLOX (NOS) uniflox
VALACICLOVIR Valacyclovir
VALACICLOVIR HYDROCHLORIDE Valacyclovir HCL
Valtrex
VANCOMYCIN VANCOMICIN
VANCOMYCIN
Vancomycin
Vancomycin`
vancomicyn
vancomycin
VARICELLA ZOSTER VIRUS VACCINE, LIVE, OKA Zostavax
STRAIN
VORICONAZOLE V-Fend

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
ANTINEOPLASTIC AND ANASTROZOLE Arimidex
IMMUNOMODULATING AGENTS
DENOSUMAB XGEVA
ESTRADIOL Estradiol
estradiol
vagifem
ESTRADIOL CIPIONATE Depo-Estradiol
ESTROGENS CONJUGATED Premarin
premarine
IMMUNOTHERAPY{NOS} Immuontherapy Injections
INTERFERON BETA Avonex
LEUPRORELIN ACETATE Eligard
Lupon
MEDROXYPROGESTERONE Mediprogesterone
MEDROXYPROGESTERONE ACETATE Depo-Provera
MEGESTROL megestrol
MEGESTROL ACETATE Megace
METHOTREXATE Methorexate
Methotrexate
methotrexate
RALOXIFENE HYDROCHLORIDE EVISTA
Evestia
ANTIPARASITIC PRODUCTS, HYDROXYCHLOROQUINE hydroxychloroquine
INSECTICIDES AND REPELLENTS
HYDROXYCHLOROQUINE SULFATE Plaquenil
plaquenil
METRONIDAZOLE Flagyl
MetroGel
flagyl
metronidazol
metronidazole
QUININE Quinine

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS ACENOCOUMAROL ACECUMAROL
ACENOCUMAROL
Acenocumarol
acenocoumarol
acenocumarol
sintron
ACETYLSALICYLIC ACID AAS
ASA
ASA (Aspirin)
ASPIRIN
ASPRIN
A[sprin
Acetyl salicylic acid
Adult Aspirin
Albyl-E
Aspirin
Aspirin (Bayer)
Aspirin - bayer
Aspirine
Aspirineta
Asprin
Aspyrin
Baby Aspirin
Bayer ASA
ENTERIC COATED ASPIRIN
Ecotrin
aas
acetilsalicilic acid
acetylsalicylic acid
albyl E
asa
aspirin
aspirina
aspirine

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS ACETYLSALICYLIC ACID asprin
cardioaspirin
ecotrin
enteric coated aspirin
ACETYLSALICYLIC ACID+DIPYRIDAMOLE Aggrenox
Aggrenox 25/200
Asasantin
aggrenox
BIVALIRUDIN Angiomax
BLOOD TRANSFUSION, AUXILIARY PRODUCTS blood products
CETYLPYRIDINIUM cetylpridinum menthol throat
lozenge
CHLORHEXIDINE Chlorhexidine Soap
CHLORHEXIDINE GLUCONATE Chlorhexidine Gluconate
Peridex
chlorhexidine gluconate
chlorohexadine mouth wash
CILOSTAZOL CILOSTAZOL
Pletal
cilostazol
CLOPIDOGREL Clopidogrel
clopidogrel
CLOPIDOGREL BISULFATE CLOPIDOGREL BISULFATE
Clopidogrel Bisulfate
PLAVIX
Plavix
plavix
CYANOCOBALAMIN B-12
CYANOCOBALAMIN
Cyanocobalamin
VITAMIN B 12
VITAMIN B12
Vitamin B 12
Vitamin B-12

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS CYANOCOBALAMIN Vitamin B12
Vitamin B12 Injection
cyanocobalamin
cyanocobalamine
vitamin B12
vitamin b12
DALTEPARIN Dalteparin
DALTEPARIN SODIUM Fragmin
DIPYRIDAMOLE Dipyridamole
ENOXAPARIN Clexane
ENOXAPARIN
Enoxaparin
Enoxaparine
clexane (enoxaparine)
enoxaparin
ENOXAPARIN SODIUM ENOXAPARIN SODIUM
LOVENEX
LOVENOX
LOVONOX
Lovennox
Lovenox
Lovenox 40 mg
klexane
lovenox
EPINEPHRINE Adrenaline
Epipen
Primatene Mist
adrenalina
epinephrine
EPTIFIBATIDE integrilin
FERROUS FUMARATE+POLYSACCHARIDE-IRON Tandem
COMPLEX
FERROUS GLUCONATE ferrous gluconate
FERROUS SULPHATE Duroferon depo

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS FERROUS SULPHATE FERROUS SULFATE
Ferrous Sulfate
Ferrous sulfate
FOLIC ACID FOLIC ACID
Folic Acid
Folic acid
Folvite
folic acid
FOLIC Poly-Iron 150 Forte
ACID+CYANOCOBALAMIN+POLYSACCHARIDE-IRON
COMPLEX
FONDAPARINUX Fondaparinux
GLUCOSE Dextrose 5%
dextrose (d50)
glucose liquid
GLUCOSE INJECTION D 50 W
GLUCOSE+WATER dextrose 50% / water 50ml
HEPARIN (NOS) HEPARIN
HEPARIN SLIDING SCALE
HEPARIN TAPER
Heparin
Heparin Injection
heparin
herparin
HEPARIN (NOS)+SODIUM CHLORIDE heparin/ 0.9% NS
HEPARIN CALCIUM CALCIPARINE
Calciparine
calcic heparine
calciparine
HEPARIN SODIUM HEPARINE
Heparin sodium
Heparina
Heparine
heparin sodium

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS HEPARIN SODIUM heparina
heparine
HYDROXOCOBALAMIN hydroxocobalamin
INTRAVENOUS FLUID (NOS) Hydration
IRON IRON
Iron
iron
IRON DEXTRAN iron dextran
MAGNESIUM CITRATE Citrate
citroma
magnesium citrate
MAGNESIUM SULFATE Magnesium Sulfate
Magnesium sulfate
magnesium sulfate
PENTOSAN POLYSULFATE SODIUM Elmiron
elmiron
PHYTOMENADIONE K Vitamin
Phytonadione
VITAMIN K
Vitamin K
vitamin K
PLASMA Fresh frozen plasma
fresh frozen plasma
PLATELETS, HUMAN BLOOD+PLASMA 5 times concetration platelet
rich plasma
POTASSIUM CHLORIDE Chlorocon
K Dur
K-Dur
K-dur
KCL
KCl
KDur
KLOR-CON
Klor-Con

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Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS POTASSIUM CHLORIDE Klor-Con-M
Klor-Cor
Klor-con 10
Micro K
POTASSIUM CHLORIDE
Potassium CL
Potassium Chloride
Potassium chloride
control K (potasium chloride)
klor-con
potassium Chloride
potassium chloride
potassiumn chloride
POTASSIUM CHLORIDE+SODIUM CHLORIDE Normal Saline with 10KCL
POTASSIUM CHLORIDE+SODIUM CHLORIDE+CALCIUM Lactated Ringers
CHLORIDE+DL-LACTIC ACID SODIUM SALT
POTASSIUM NOS Potasium
Potassium
potassium
PRASUGREL Effient
RED BLOOD CELLS, CONCENTRATED BLOOD PACKED RED CELLS
packed red blood cells
packed red cells
SODIUM BICARBONATE Sodium bicarbonate
SODIUM CHLORIDE saline
IV BOLUS SALINE nacl
NaCL
NaCl
NaCl 0.45%
NaCl 0.9%
Nasal Saline
Nasal Saline Rinse
Normal Saline
Normal saline

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS SODIUM CHLORIDE SODIUM CHLORIDE
SODIUM CHLORIDE 0.65% NASAL
SOLUTION
Saline
Saline Nasal Sp
Saline Spray
Sodium Chloride
Sodium chloride
deep sea nasal spray (sodium
chloride)
normal saline
normal saline bolus
normal saline boulus taper
ocean nasal spray
saline
saline nasal spray
sodiu chloride 0.9%
sodium Chloride
sodium chloride
sodium chloride 0.9%
sodium choloride
SODIUM CHLORIDE+GLUCOSE D5 1/2 NS
dextrose 5%- 1/2 ns
UREA urea cream 20%
WARFARIN WARFARIN
Warfarin
warfarin
WARFARIN SODIUM COUMADIN
Coumaden
Coumadin
Coumadine
Jantoven
Warfarin Sodium
coumadin

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
BLOOD AND BLOOD FORMING ORGANS WARFARIN SODIUM warfarin na
CARDIOVASCULAR SYSTEM ACETAZOLAMIDE acetazolamide
ALDACTONE (NOS) Aldactone
aldactone
ALISKIREN FUMARATE Tekturna
ALPROSTADIL Alprostadil
AMIODARONE AMIODARONE
Amiodarona
Amiodarone
amiodarona
amiodarone
amodiarona
AMIODARONE HYDROCHLORIDE amiodarone HCL
atlansil
cordarone
AMLODIPINE AMLODIPINE
Amlodipin
Amlodipina
Amlodipine
Amlodopine
amlodipina
amlodipine
amlodopine
amoldipine
AMLODIPINE BESILATE AMLODIPINE BESYLATE
Amlodipine Besylate
Ilduc
NORVASC
Norvasc
Pelmec
TERLOC
norvasc
AMLODIPINE BESILATE+ATORVASTATIN CALCIUM caduet

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM AMLODIPINE BESILATE+VALSARTAN ExForge
Exforge
amlodipina - valsartan
ATENOLOL ATENOLOL
Atenelol
Atenolol
Preventil
atenolol
ATORVASTATIN ATORVASTATIN
ATORVASTATINA
Atorvastatin
atorvastatin
atorvastatina
atorvastatine
ATORVASTATIN CALCIUM LIPITOR
Lipitor
ampliar
lipitor
BAMETHAN SULFATE bametano sulfato
BENAZEPRIL Benazepril
benazepril
BENAZEPRIL HYDROCHLORIDE Benazepril HCL
BENAZEPRIL HYDROCHLORIDE+AMLODIPINE Lotrel
BESILATE
BENZOCAINE benzocaine
BETAMETHASONE BETAMETASONE
BETHAMETASONE
Betametasone
CORTEROID RETARD
CORTIPYREN
Corteroid Retard
betametasona
betametasone
betamethasone

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM BETAMETHASONE corteriod retard
corteroid retard
BETAMETHASONE VALERATE BETAMETHASONE OINTMENT
BETAXOLOL BETOPIC-S 0.25%
BISOPROLOL Bisoprolol
bisoprolol
BISOPROLOL FUMARATE Emconcor
Zebeta
concor
corbis
BUMETANIDE Bumetanide
Bumex
CANDESARTAN candesartan
CANDESARTAN CILEXETIL Atacand
dacten
CARVEDILOL CARVEDILOL
COREG
Cardevilol
Carvedilol
Carveilol
Coreg
carvedilol
coreg
coritensil
crvedilol
CLONIDINE Clonidine
clonidine
CLONIDINE HYDROCHLORIDE CLONIDINE HCL
clonidine HCL
COLESEVELAM HYDROCHLORIDE Welchol
COLESTYRAMINE Cholestyramine
COLMIBE (NOS) Colmibe
colmibe
DEXAMETHASONE Dexametasone

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM DEXAMETHASONE DEXAMETASONA
DEXAMETASONE
Decadron
Decodron
Desamethasone
Dexametasona
Dexametasone
Dexametazone
Dexamethasone
decadron
dexametason
dexametasona
dexametasone
dexamethasone
dexametosana
DIGITOXIN digitoxin
DIGOXIN DIGOXIN
Digitek
Digoxin
Lanicor
Lanoxin
digoxin
digoxine
DILTIAZEM DILTIAZEN
Dilitiazen
Diltiazem
Diltiazem ER
Diltiazem/ER
diltiazem
diltiazen
DILTIAZEM HYDROCHLORIDE CARDIZEM CD
Cardizem
Dilacor XR
Diltiazem HCL

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM DILTIAZEM HYDROCHLORIDE Taztia XT
Tilazem
cardizem
cardizem cd
cartia
cartia xt
DIUREX (NOS) Diurex
DOBUTAMINE DOBUTAMINE
DOPAMINE HYDROCHLORIDE dopamina
DOXAZOSIN Doxazosin
doxazosin
DOXAZOSIN MESILATE Doxazosin Mesylate
cardura
doxazosin mesylate
DRONEDARONE Multaq
dronedarone
multaq
ENALAPRIL ENALAPRIL
Enalapril
Glioten
LOTRIAL
Lotrial
Lotrial 10
enalapril
lotrial
EPINEPHRINE Adrenaline
Epipen
Primatene Mist
adrenalina
epinephrine
EZETIMIBE Ezetimibe
Zetia
zetia
FELODIPINE Felodipine ER

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM FELODIPINE PLENDIL
felodipine
FENOFIBRATE Fenofibrate Micronized
TRIGLIDE
Tri Cor
Trichor
Tricor
fenofibrate
FENOFIBRIC ACID Trilipix
FISH OIL FISH OIL
Fish Oil
Fish oil
fish oil
FLECAINIDE flecainide
FLECAINIDE ACETATE tambocor
FLUOCINONIDE Lidex 0.05%
FLUVASTATIN Fluvastatin
FUROSEMIDE FUROSEMIDE
Furosemida
Furosemide
LASIX
Lasix
furosemid
furosemida
furosemide
lasix
nurivan
GEMFIBROZIL Gemfibrozil
gemfibrozil
lopid
GLYCERYL TRINITRATE NITROGLICERINE
NITROGLYCERIN
NITROSTAT
NTG

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM GLYCERYL TRINITRATE Niroglycerin
Nitro Paste
NitroQuick
Nitroglicerine
Nitroglycerin
Nitroglycerin Sublingual
Nitroglycerine
Nitroglyercin
Nitrogylcerin
Nitrolinqual
Nitrostat
nitroglycerin
nitrolglycerin
nitropaste
nitrostat
GUANFACINE HYDROCHLORIDE tenex
HEPARIN (NOS) HEPARIN
HEPARIN SLIDING SCALE
HEPARIN TAPER
Heparin
Heparin Injection
heparin
herparin
HEPARIN CALCIUM CALCIPARINE
Calciparine
calcic heparine
calciparine
HEPARIN SODIUM HEPARINE
Heparin sodium
Heparina
Heparine
heparin sodium
heparina
heparine

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM HYDRALAZINE HYDRALAZINE
Hydralazine
HYDROCHLOROTHIAZIDE HCTZ
HCTZ/hydrodiuril
HYDROCHLOROTHIAZIDE
HYDROCHOLOROTHARIDE
Hidrochlothiazide
Hidroclorotiazida
Hydrochloriothiazide
Hydrochlorothiazide
Hydrochlorthiazide
Maxide
hctz
hidroclorotiazida
hydrochlorithiazide
hydrochlorothiazide
hydrochlorotiazide
hydrocholothazide
hydroclorotiazida
HYDROCHLOROTHIAZIDE+AMILORIDE HYDROCHLORIDE normorix mite
HYDROCHLOROTHIAZIDE+AMLODIPINE Amturnide
BESILATE+ALISKIREN FUMARATE
HYDROCHLOROTHIAZIDE+BISOPROLOL Bisoprolol HCTZ
Bisoprolol hydrochlorothiazide
HYDROCHLOROTHIAZIDE+ENALAPRIL enalapril - hidroclorotiazida
HYDROCHLOROTHIAZIDE+FOSINOPRIL fosinopril/hctz
HYDROCHLOROTHIAZIDE+IRBESARTAN Avalide
HYDROCHLOROTHIAZIDE+LISINOPRIL Lisinipril/Hydrochlorothiazide
Lisinopril HCTZ
Lisinopril-HCTZ
Lisinopril/HCT
Lisinopril/HCTZ
Pinzide
Prinzide

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM HYDROCHLOROTHIAZIDE+LISINOPRIL Zestoretic
hctz/lisinopril
lisimiprol/HCTZ
lisinopril/HCTZ
lisinopril/hydrochlorothiazide
zestoretic
HYDROCHLOROTHIAZIDE+LOSARTAN POTASSIUM HYZAAR
Hyzaar
LOSACOR D
PAXON D
HYDROCHLOROTHIAZIDE+TELMISARTAN Micardis HCT 40-15.5
HYDROCHLOROTHIAZIDE+VALSARTAN DIOVAN D (VALSARTAN/HCTZ)
Diovan HCT
Diovan/HCT
HYDROCORTISONE HIDROCORTISONE
HYDROCORTISONE
HYDROCORTISONE CREAM
Hidrocortisona Klonal
Hidrocortisone
Hidrocotisone
Hydrocortisone
Hydrocortisone cream 2.5%
Hydrocortosone
hidrocortisone
hidrocortizone
hidrocotisone
hydrcortizone
hydricortison
hydrocortisone
hydrocortisone 100 mg
hydrocortisone 500 mg
hydrocortisone cream 2.5%
hydrocortizone
HYDROCORTISONE ACETATE HIDROCORTISONA

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM HYDROCORTISONE ACETATE Hidrocortisona
hidrocortisona
hidrocortisona 100mg
HYDROCORTISONE SODIUM SUCCINATE Solu-Cortef
INDAPAMIDE+PERINDOPRIL Preterax
INDOMETACIN Indocin
Indomethacin
IRBESARTAN Avapro
irbesartan
ISOSORBIDE Isosorbide
isosorbide
ISOSORBIDE DINITRATE ISORDIL
ISOSORBIDE MONONITRATE IMDUR
ISOSORBIDE MONONITRATE
Imdur
imdur
isosorbide monotitrate
LABETALOL Labetalol
LERCANIDIPINE LECARDIPINA
LIDOCAINE Lidocaine
Lidocaine 1%
Lidoderm Patch
Xylocaine
Xylocaine 1%
lidocaine
lidocaine 1%
lidocaine ointment
lidocaine patch
LIDOCAINE HYDROCHLORIDE LIDOCAINE HCL
Lidocaine Viscous
Lidocaine Viscous 2.0%
Xylocaine 2%
lidocaine HCL 1%
LISINOPRIL LISINIPRIL

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Population: Intent-to-Treat
Table 5.22
Relationship of Medication Class, Dictionary Term and Verbatim Text

ATC Level 1 Ingredient(s) Verbatim Text


------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR SYSTEM LISINOPRIL LISINOPRIL
Lisinapril
Lisinipril
Lisinopril
Lisinoprol
PRINIVIL
Prinivil
Zestril
lisinipril
lisiniprol
lisinopril
zestril
LOSARTAN LOSARTAN
Losartan
Losartán
losartan
LOSARTAN POTASSIUM Cozaar
LOSARTAN POTASSIUM
Losacor
Losartan Potassium
cozaar
losartan potassium
LOVASTATIN LOVASTATIN
Lovastatin
MEVACOR
lovastatin
MAGNESIUM CHLORIDE magnesium chloride
METHYLDOPA Aldomet
METHYLDOPA+HYDROCHLOROTHIAZIDE Hydromet
hydromet
METOLAZONE Zaroxolyn
metolazone
METOPROLOL Metoprolol
Metropolol

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