ANGGOTA KELOMPOK :

1. REZKI PERMATASARI (2008062078)

2. RATNA HAPSARI (2008062079)
3. DEVI INDRIA WARDANI (2008062096)

Checklist telaah artikel untuk terapi (Critical Appraisal)

Cek Nilai
No Kriteria
Iya Tidak 1 2 3
Permasalahan dinyatakan secara jelas (halaman 350
1  
baris 1)
2 Permasalahan penting (page 350 line 1)  

3 Hipotesis dinyatakan dengan jelas  

4 Asumsi-asumsi dinyatakan dengan jelas  

5 Keterbatsan penelitian disebutkan  

6 Istilah penting didefiniskan 

Rancangan penelitian dinyatakan secara jelas dan
7  
lengkap
Rancangan penelitian sesuai untuk memecahkan
8  
masalah
9 Populasi sampel disebutkan jelas  

10 Cara pengambilan sampel sesuai  

11 Prosedur pengambilan sampel dijelaskan  

Prosedur pengumpulan sampel sesuai dengan
12  
masalah yang akan dipecahkan
Prosedur pengambilan sampel dilaksanakan secara
13  
tepat
Validitas dan reabilitas pengumpulan data
14  
ditetapkan
15 Metode dipilih sesuai dengan analisis  
Hasil disajikan dengan dinyatakan dengan jelas dan
16  
lengkap
17 Kesimpulan dinyatakan dengan jelas  
Penerapan hasil-hasil penelitian dibatasi populasi
18  
dari mana sampel berasal
19 Laporan ditulis dengan jelas, sistematis dan objektif  

TOTAL SCORE= 42 12 30

Interpretasi hasil : Skor total > 38 dapat dinyatakan jurnal yang dinilai memiliki validitas, reabilitas, dan
applicability yang baik.
Albuterol multidose dry powder inhaler and albuterol
hydrofluoroalkane versus placebo in children with
persistent asthma
Paul Y. Qaqundah, M.D.,1 Herminia Taveras, Ph.D., M.P.H.,2 Harald Iverson, Ph.D.,3 and Paul
4
Shore, M.D., M.S.

ABSTRACT
Background: Many children struggle with albuterol hydrofluoroalkane (HFA) inhalers. Albuterol multidose dry powder
inhaler (MDPI) may simplify rescue bronchodilator use in children.
Objective: To demonstrate the comparability of albuterol MDPI and albuterol HFA in children with asthma.
Methods: This phase II, multicenter, double-blind, double-dummy, single-dose, five-period, crossover study randomized
patients (ages 4 –11 years) with persistent asthma and prestudy forced expiratory volume in 1 second (FEV 1) of 60 –90% of
predicted to 1 of 10 treatment sequences that contained albuterol MDPI (90 and 180 mg), albuterol HFA (90 and 180 mg),
and placebo MDPI and placebo HFA. Efficacy was evaluated by measuring the area under the baseline-adjusted percent-
predicted FEV1–time curve over 6 hours (PPFEV1 AUC0 – 6) after dosing. Safety was evaluated by adverse events.
Results: The full analysis set included 61 patients. Albuterol MDPI and albuterol HFA significantly improved PPFEV 1
AUC0 – 6 versus placebo (p # 0.0107). Mean improvement ( standard error [SE]) in PPFEV 1 AUC0 – 6 versus placebo with
albuterol MDPI at 90 and 180 mg was similar (21.2 4.87 [95% confidence interval { I}, 11.60 –30.81], and 22.6 4.87 [95%
CI, 13.00 –32.20], % hour, respectively). Mean improvement ( SE) with albuterol HFA 180 mg was significantly (p 0.0226)
greater versus albuterol HFA 90 mg (23.7 4.85 [95% CI, 14.13–33.23], and 12.5 4.85 [95% CI, 2.93–22.05], % hour,
respectively). All doses of albuterol were well tolerated.
Conclusion: Albuterol MDPI 90 and 180 mg and albuterol HFA 180 mg provided similar and significant FEV 1
improvements versus placebo; albuterol HFA 90 mg was significant versus placebo but seemed less effective based on
absolute improvements in FEV1. ClinicalTrials.gov identifier: NCT01899144
(Allergy Asthma Proc 37:350 –358, 2016; doi: 10.2500/aap.2016.37.3986)

A pproximately 6.8 million children in the United States

currently have asthma, a chronic respira-tory disorder that
causes chest tightness, shortness of
breath, wheezing, and cough as a result of inflamma-tory
1–3
and hyperreactive airway obstruction. Albu-terol, a short-
acting b2 adrenergic agonist, has a bron-
epartment of Pediatrics, Hoag Medical Group, Huntington Beach, Cali-
fornia, 2Clinical Research and Development, Teva Pharmaceuticals, Miami, Florida,
3 4
Statistics epartment, Teva Pharmaceuticals, Miami, Florida, and Clinical Research
and evelopment, Teva Pharmaceuticals, Frazer, Pennsylvania
This study was sponsored by Teva Branded Pharmaceutical Products R&D, Inc.
Medical writing assistance was provided by Lisa Feder, Ph.D., Peloton Advantage,
and was funded by Teva Branded Pharmaceutical Products R&D, Inc. Teva provided
a full review of the article
H. Taveras and H. Iverson are employees of Teva Pharmaceuticals, Miami, Florida.
P. Shore was an employee of Teva Pharmaceuticals, Frazer, Pennsylvania, at the time
of manuscript preparation. P.Y. Qaqundah has no conflicts of interest pertaining to
this article
Presented in poster format at the American Academy of Allergy, Asthma & Immu-
nology annual scientific meeting, Los Angeles, California, March 4 –7, 2016. A subset
of the data was presented in poster format at the American Thoracic Society Interna-
tional Conference, San Francisco, California, May 13–18, 2016
Address correspondence to Paul Y. Qaqundah, M.D., Hoag Medical Group, 19582
Beach Blvd., Suite 350, Huntington Beach, CA 92648 E-mail address:
pqaqundah@aol.com
Published online August 15, 2016
Copyright © 2016, OceanSide Publications, Inc., U.S.A.
chodilatory effect that rapidly reverses acute airflow
obstruction and alleviates the symptoms of an acute asthma
3
attack. The safety and efficacy of long-term inhaled
albuterol use is well documented.
4
Until recently, the only available inhaler device for
delivery of albuterol was the metered-dose inhaler (MDI),
which delivers the drug in aerosolized form. Usage errors
with MDIs are common, especially in children, because
these inhalers require the coordina-tion of actuation with
5,6
inhalation. Good inhaler tech-nique is an important aspect
7
of asthma control. Proper use of an MDI can be difficult
for patients to learn, as demonstrated by two studies, one of
which found that 65% of patients failed to use their MDI
8
correctly even after instruction and another that found that
half of the pediatric patients (55%) enrolled (ages 6 –10
9
years) used MDIs improperly. The inability to coordinate
manual actuation with inhalation may compromise drug
delivery to the airways, which potentially results in
6
suboptimal efficacy.
A novel, inhalation-driven, albuterol multidose dry
powder inhaler (MDPI) that does not require patient
coordination of device actuation with inhalation has been
developed with the goal of reducing administra-

350 September–October 2016, Vol. 37, No. 5

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tion errors associated with conventional MDIs. An al-
buterol MDPI (ProAir RespiClick; Teva Pharmaceuti-cals,
Inc., Frazer, PA), approved in March 2015 by the U.S. Food
and Drug Administration for adolescent and adult patients
with reversible bronchospasm, has been shown to provide
efficacy and safety comparable with those of an available
10,11
albuterol hydrofluoroalkane (HFA) inhaler. Satisfaction
with this device was recently assessed in an open-label
study that included patients $4 years of age with asthma or
chronic ob-structive pulmonary disease: 83% of the patients
re-ported being somewhat to very satisfied with the MDPI
with an integrated dose counter, 92% were sat-isfied with
the ease of holding and handling the in-haler, and 85% were
12
satisfied with the ease of learning to use the inhaler. This
article reports on a study that was designed to demonstrate
the comparability of al-buterol MDPI and albuterol HFA in
children with per-sistent asthma.
METHODS
Study Description
This was a phase II, randomized, double-blind, dou-ble-
dummy, placebo-controlled, single-dose, five-treat-ment,
five-period, ten-sequence, five-way crossover study of
pediatric patients at 14 sites across the United States
(ClinicalTrials.gov identifier: NCT01899144; study number:
ABS-AS-201). The objective of the study was to
demonstrate the comparability of albuterol MDPI and
albuterol HFA for the treatment of persis-tent asthma in
children ages 4 to 11 years.
Ethical Conduct
The study was conducted in accordance with the
International Council for Harmonisation Good Clinical
Practice Consolidation Guideline (E6), and applicable
regulations of the U.S. Code of Federal Regulations Title
21, Parts 50, 54, 56, 312, and 314, and European Union
13
Directive 2001/20/EC. Before study initiation, the study
protocol was submitted to the appropriate independent
ethics committee or institutional review board for review
and approval. The parents or guard-ians of all enrolled
patients provided written, informed consent before any
study-related procedures, and as-sent from the patients
themselves was obtained when applicable.
Inclusion Criteria
Patients who met the following criteria were eligible for
inclusion in the study: boys or premenarchal girls between
the ages of 4 and 11 years (inclusive) as of the screening
visit, in otherwise good health, with a documented diagnosis
of persistent asthma of at least 6 months’ duration and on
stable low-dose inhaled corticosteroid (#200 mg fluticasone
propi-
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onate per day or equivalent), leukotriene modifiers, or
inhaled cromones, or on b2-agonists alone as needed, for a
minimum of 4 weeks before the screening visit and with the
expectation of maintenance for the duration of the study.
Patients were required to have a forced expiratory volume in
1 second (FEV1) value of 60 –90% predicted for age,
height, and sex, and to dem-onstrate at least 15%
reversibility of FEV1 within 30 minutes after inhalation of
180 mg of albuterol. In ad-dition, patients were required to
demonstrate an ac-ceptable inhalation technique with both
the MDPI and the HFA, and be able to self-perform
spirometry and peak expiratory flow (PEF) measurements.
Exclusion Criteria
Patients with a known hypersensitivity to albuterol or any
inactive agent in the inhaler formulations, a history of
respiratory infection or disorder that was not resolved within
4 weeks before the screening visit, an asthma exacerbation
that required oral corticosteroids within 3 months or
hospitalization within 6 months of the screening visit, an
inability to tolerate or unwilling-ness to comply with the
required washout periods, and/or a history of life-
threatening asthma were inel-igible for participation in the
study. Patients who used prohibited concomitant
medications, were treated with systemic corticosteroids
within 6 weeks of the screen-ing visit, participated in a
previous albuterol MDPI trial at any time, or who received
any investigational drug as part of a trial within 30 days of
the screening visit were also ineligible. Study participants
could not have any nonasthmatic acute or chronic
conditions.
Randomization Criteria
The patients were randomized at the first treatment visit
and were permitted to remain in the study if, before dosing
at each treatment visit, they continued to be in good health,
had not experienced any adverse event (AE) that would
prevent further participation, had not used any prohibited
concomitant medications, had not used rescue albuterol for
at least 6 hours before each treatment visit, and were able to
correctly use each inhaler device. Patient’s FEV 1 level had
to remain within 60 –90% of predicted value and 20% of the
study qualifying value measured at the screening visit, and
patients could not have experienced an asthma exacerbation
or upper respiratory tract infection or received any
additional treatment for asthma.
Study Design
The study design is shown in Fig. 1. Eligible patients
were randomized to 1 of 10 treatment sequences based on
Latin squares that contained single doses of albu-terol
MDPI 90 mg, albuterol MDPI 180 mg, albuterol HFA 90
mg, albuterol HFA 180 mg, or placebo MDPI
351
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and placebo HFA (0 mg albuterol). The 90 and 180 mg
doses of albuterol HFA were chosen because they are the
14
approved doses in pediatric patients. The 90 and 180 mg
doses of albuterol MDPI were chosen based on the
approved doses of inhaled albuterol HFA in pedi-atric
patients. The intent of the study was to demon-strate the
comparability of albuterol MDPI and albu-terol HFA
inhalers. All the patients received inhalations from two
separate MDPIs (active or pla-cebo) and two separate HFAs
(active or placebo) to deliver the appropriate doses while
maintaining blinding.
After the initial screening visit, each patient received one
of the five treatments at five treatment visits over the study
duration; each treatment visit was separated by a washout
period of between 2 and 7 days. At each treatment visit, an
initial FEV1 was measured at 30 minutes and again just
before dispensation of the study treatment. Additional FEV1
measurements were taken at 5, 15, 30, 45, 60, 120, 180,
240, 300, and 360 minutes after treatment. Blood pressure
and pulse rate mea-surements were recorded within 5
minutes before each FEV1 measurement for up to 4 hours to
determine treatment effects. Patients received paper diaries
to record morning PEF values between treatment visits,
AEs, and the use of rescue medication. Albuterol HFA
inhalers (ProAir HFA; Teva Respiratory, LLC, Hor-sham,
PA) were provided as rescue medication.
Efficacy
Spirometry was the primary measurement to evalu-ate
study end points. Each center was provided with a standard
spirometer, and site personnel received stan-dardized
training. Predicted FEV1 values were com-puted and
adjusted for age, height, and sex for patients ages 4 to 5
15 16
years and for patients ages 6 to 11 years by using the
American Thoracic Society/European Thoracic Society
17
criteria applicable to pediatric pa-tients. Serial FEV1
measurements (the highest of three acceptable maneuvers)
were obtained at 5, 15, 30, 45, 60, 120, 180, 240, 300, and
360 minutes after the completion of study drug
administration at each treatment visit. The primary efficacy
end point was the baseline-adjusted area under the percent-
predicted FEV1-versus-time curve over 6 hours (PPFEV1
AUC0 – 6 [% hour]) after treatment.
352
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Figure 1. Study design. FEV1 Forced
expiratory volume in 1 second; HFA
hydrofluoroalkane; MDI me-tered-dose
inhaler; MDPI multidose dry powder
inhaler.
The baseline-adjusted area under the FEV1-versus-time
curve over 6 hours (FEV1 AUC0 – 6 [L hour]) after treatment
was the secondary efficacy end point. Addi-tional efficacy
end points included baseline-adjusted maximum FEV 1 and
maximum FEV1 values within 6 hours after treatment; time,
in minutes, to increases of at least 15% and 12% in baseline
PPFEV1 in patients within 30 minutes after treatment;
duration, in hours, of 15% and 12% responses for those
patients who re-sponded within 30 minutes; response rate
based on $15% and $12% increases in baseline PPFEV1
within 30 minutes after treatment; and time, in minutes, to
maximum PPFEV1.
Safety
Safety assessments included tabulation of AEs and
serious AEs (SAEs), including severity and relation-ship to
study drug; SAEs were defined as AEs that resulted in
death, life-threatening events, events that required or
prolonged hospitalization, persistent or significant disability
or incapacity, or congenital abnor-mality or birth defect.
Other safety assessments in-cluded laboratory evaluations,
physical examination findings, and a 12-lead
electrocardiogram result. Vital signs were documented,
which coincided with FEV1 measurement intervals for up to
4 hours after dosing at each treatment visit.
Statistics
The intent-to-treat (ITT) population included all ran-
domized patients based on the treatment initially as-signed,
regardless of the treatment received. All pa-tients in the ITT
population who had a baseline assessment at the screening
visit and received at least one dose of the study medication
with at least one postbaseline assessment were included in
the full anal-ysis set, which was the primary analysis set for
efficacy parameters. The per-protocol population consisted
of all randomized patients who had no major protocol
violations determined before unblinding and served as the
supportive population. The safety population in-cluded all
patients in the ITT population who received at least one
dose of the study medication.
The primary statistical tool was the mixed-effect analysis
of variance with fixed effects of sequence,
September–October 2016, Vol. 37, No. 5
treatment group, and period; and the random effect for the Table 1 Patient demographics and baseline clinical
patient within sequence. An appropriate contrast was
characteristics (ITT population) (N 61)
derived from this model for the following com-parison of
interest with respect to the primary efficacy variable, Sex, no. (%)
PPFEV1 AUC0 – 6 (% hour): the mean differ-ence between Boys 38(62)
each active group and placebo at each dose level, tested in a Girls 23(38)
sequential manner. The sequen-tial order of comparisons Age, mean SD, y 9 1.6
was albuterol MDPI 180 mg with placebo, albuterol MDPI Race, no. (%)
90 mg with placebo, al-buterol HFA 180 mg with placebo, White 28(46)
and albuterol HFA 90 mg with placebo. Each test was two- Black 29(48)
sided and done at the 0.05 level of significance. However, if Other 4(7)
a test was not significant at this level, no further tests were Height, mean SD, cm 138.7 10.2
done. This sequential manner of performing the tests Weight, mean SD, kg 38.2 12.8
2
ensured that the overall alpha level for the entire series was BMI, mean SD, kg/m 19.5 4.35
not 0.05. Duration of asthma, no. (%)
6 mo to 1 y 1(2)
1 to 5 y 22(36)
RESULTS 5 to 10 y 30(49)
10 to 15 y 8(13)
Patients Airway reversibility, mean SD, % 24.1 10.2
Of the 102 patients, ages 4 to 11 years, who were Baseline PPFEV1, mean SD, % 72.9 7.2
screened for inclusion in the study, 33 did not meet ITT Intent-to-treat; SD standard deviation; BMI body mass
inclusion criteria, 3 were lost to follow-up, 1 withdrew
index; PPFEV1 percent-predicted forced expi-ratory
consent, and 4 did not pass the screening for other causes,
volume in 1 second.
which resulted in 61 patients who met the eligibility criteria
and were randomized into the study. All 61 enrolled patients
were assessable for efficacy and safety. The per-protocol 12% and 15% response onset among patients who had such
analysis included 56 pa-tients, and 57 of the 61 enrolled responses were comparable between patients treated with
patients completed the study. A total of four patients (7%) albuterol MDPI and those who received albuterol HFA
withdrew from the study, all for other reasons (erroneously (Table 4).
randomized at treatment visit 1; did not meet FEV 1 criteria; All active treatments resulted in a shorter time to
package insert discretion; did not meet 20% change in FEV 1 maximum PPFEV1 ( 45 to 50 minutes) compared with
from qualifying value at screening at treatment visit 2 after patients who received placebo; no difference was noted
3 attempts). No patients died or discontinued due to AEs. between the 90 and 180 mg doses for either albuterol MDPI
Patient demographics and baseline clinical characteristics or albuterol HFA (Table 4). Based on a $15% increase in
are summarized in Table 1. All patients had asthma that was FEV1 over baseline within 30 minutes after dosing, all
diagnosed at least 6 months be-fore participation in the active groups had significantly higher re-sponse rates than
study, and eight patients had a $10-year history of asthma. placebo (response rate, 17%; p # 0.0119), although the
Most of the patients had no previous experience with a dry response rate with albuterol MDPI (45– 46%) was
powder inhaler, and only one patient had no experience with somewhat greater than the rate for albuterol HFA 90 mg
an MDI. (37%) or albuterol HFA 180 mg (41%) (Table 4). Using a
threshold of $12% increase in FEV1 value from baseline
within 30 minutes of dosing, the response rate was greater
Efficacy than for placebo in all active groups but highest for albuterol
Baseline-adjusted PPFEV1 AUC0 – 6 was significantly MDPI (57–58% for albuterol MDPI; 54% for albuterol HFA
greater in all active treatment groups compared with patients 90 mg; 47% for albuterol HFA 180 mg versus 20% for
who received placebo (p # 0.0107) (Table 2 and Fig. 2). The placebo; p # 0.0007) (Table 4).
patients treated with albuterol MDPI 90 mg and 180 mg had
similar increases in PPFEV1 AUC0 – 6 (Table 2), whereas
patients treated with albu-terol HFA 180 mg had Safety
significantly greater PPFEV1 AUC0 – 6 than those treated There were no deaths or SAEs, and no withdrawals due to
with albuterol HFA 90 mg (p 0.0226) (Table 2). Similar AEs. There were two reported AEs after treat-ment with
patterns were seen in baseline-adjusted FEV 1 AUC0 – 6, albuterol MDPI 180 mg (otitis media and urticaria), and
maximum FEV1 value over 6 hours, and maximum PPFEV 1 there were no AEs associated with al-buterol MDPI 90 mg.
over 6 hours after treatment (Table 3). The mean and Six AEs were reported by five patients after treatment with
median times to albuterol HFA 90 mg,

Allergy and Asthma Proceedings 353

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Table 2 Primary efficacy end point, baseline-adjusted PPFEV1 AUC0 – 6 (% hr) (full analysis set)
Placebo Albuterol MDPI Albuterol MDPI Albuterol HFA Albuterol HFA
(N 61) 90 g (N 61) 180 g (N 61) 90 g (N 61) 180 g (N 61)
n 59 58 59 59 59
Mean SE 25.4 6.25 46.6 6.27 48.0 6.24 37.9 6.25 49.1 6.26
95% CI 12.94–37.81 34.13–59.07 35.56–60.39 25.43–50.30 36.61–61.50
Active–placebo
Mean SE 21.2 4.87 22.6 4.87 12.5 4.85 23.7 4.85
95% CI 11.62–30.81 13.00–32.20 2.93–22.05 14.13–33.23
p Value 0.0001 0.0001 0.0107 0.0001
90 mg–180 mg
Mean SE 1.4 4.88 11.2 4.87
95% CI 11.00 to 8.23 20.80 to 1.59
p Value 0.7772 0.0226
PPFEV1 Percent-predicted forced expiratory volume in 1 second; AUC 0 – 6 area under the curve over 6 hr; MDPI multidose
dry powder inhaler; HFA hydrofluoroalkane; SE standard error; CI confidence interval.

including headache, constipation, diarrhea, and py-rexia.
One patient reported upper abdominal pain after treatment
with albuterol HFA 180 mg, and one case of viral gastritis
was reported in a patient who received placebo. There were
no clinically significant effects on vital signs or other safety
parameter findings.
DISCUSSION
In this phase II, single-dose, five-way crossover study,
children with asthma treated with albuterol MDPI and with
albuterol HFA, each at dosages of 90 and 180 mg,
experienced significant improvements in baseline-adjusted
PPFEV 1 AUC 0 – 6 (the primary effi-cacy end point)
compared with the patients who received placebo. The
magnitude of effect was sim-ilar in patients treated with
albuterol MDPI 90 mg and 180 mg, whereas improvement
from baseline was greater in patients treated with albuterol
HFA
180 mg compared with albuterol HFA 90 mg; PPFEV1
AUC0 – 6 in the albuterol HFA 180 mg group was
similar to that observed in both the albuterol MDPI 90 m g
and 180 mg groups. This pattern was repeated for most of
the secondary end points as well. Time to onset and duration
of effect, whether measured by $ 12% or $ 15% response,
were similarly greater than placebo with all active
treatments. Both albuterol MDPI and albuterol HFA were
generally well toler-ated, with no SAEs or study
withdrawals due to AEs.
In a similar randomized, double-blind, placebo-con-
trolled, single-dose, five-way crossover study, 71 adult
patients were treated with albuterol MDPI 90 mg, al-buterol
MDPI 180 mg, albuterol HFA 90 mg, albuterol HFA 180
11
mg, or placebo. Although similar to the present study in
that patients in all active treatment groups experienced
significant (p 0.0001) improve-ments from baseline in
PPFEV1 AUC0 – 6, the adult study differed from the
pediatric study in that there was no difference between the
response of the adult patients treated with albuterol HFA 90
mg and albu-

Figure 2. Mean percent-predicted FEV1 by treatment

and time point (full analysis set). FEV 1 Forced expi-
ratory volume in 1 second; HFA hydrofluoroalkane;
MDPI multidose dry powder inhaler.

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 AllergyandAsthmaProceedings355 Table 3 Additional efficacy end points (full analysis set)
Placebo Albuterol MDPI 90 Albuterol MDPI 180 Albuterol HFA 90 Albuterol HFA 180
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(N 61) g (N 61) g (N 61) g (N 61) g (N 61)

Baseline-adjusted FEV1 AUC0–6 (L hr):
secondary efficacy end point
No. patients 59 58 59 59 59
Mean SE 0.48 0.14 0.88 0.14 0.93 0.14 0.74 0.14 0.93 0.14
95% CI 0.20–0.76 0.60–1.16 0.65–1.20 0.46–1.02 0.65–1.21
Active–placebo
Mean SE 0.40 0.10 0.45 0.10 0.26 0.10 0.45 0.10
Copyright(c)OceansidePublications,Inc.Allrightsreserved.

95% CI 0.21–0.59 0.26–0.64 0.08–0.45 0.26–0.64

p Value 0.0001 0.0001 0.0062 0.0001
90 mg–180 mg
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Mean SE 0.05 0.10 0.19 0.10

95% CI 0.23 to 0.14 0.38 to 0.00
p Value 0.6342 0.0488
Baseline-adjusted maximum FEV1 over 6 hr, L
No. patients 59 58 59 59 59
Mean SE 0.19 0.02 0.27 0.02 0.28 0.02 0.26 0.02 0.29 0.02
95% CI 0.14–0.24 0.23–0.32 0.24–0.33 0.21–0.31 0.24–0.34
Active–placebo
Mean SE 0.09 0.02 0.10 0.02 0.07 0.02 0.10 0.02
95% CI 0.05–0.12 0.06–0.13 0.04–0.10 0.07–0.14
p Value 0.0001 0.0001 0.0001 0.0001
90 mg–180 mg
Mean SE 0.01 0.02 0.03 0.02
95% CI 0.04 to 0.02 0.06 to 0.00
p Value 0.5421 0.0688
Baseline-adjusted maximum percent-predicted
FEV1 over 6 hr, %
No. patients 59 58 59 59 59
Mean SE 9.83 1.15 14.21 1.16 14.71 1.15 13.21 1.15 14.97 1.15
95% CI 7.53–12.12 11.91–16.51 12.42–17.00 10.91–15.50 12.67–17.26
Active–placebo
Mean SE 4.38 0.85 4.88 0.85 3.38 0.85 5.14 0.85
95% CI 2.70–6.06 3.20–6.57 1.70–5.06 3.47–6.81
p Value 0.0001 0.0001 0.0001 0.0001
90 mg–180 mg
Mean SE 0.50 0.86 1.76 0.85
95% CI 2.19 to 1.18 3.44 to 0.08
p Value 0.5578 0.0407
MDPI Multidose dry powder inhaler; HFA hydrofluoroalkane; FEV1 forced expiratory volume in 1 second; AUC0 – 6 area under the curve over 6 hours; SE
standard error; CI confidence interval.
 356
Table 4 Response rates, time to response, and duration of response of albuterol MDPI versus albuterol HFA (full analysis set)
Placebo Albuterol MDPI Albuterol MDPI 180 Albuterol HFA Albuterol HFA 180
Delivered by

(N 61) 90 g (N 61) g (N 61) 90 g (N 61) g (N 61)

Response rate based on 15% increase in baseline
PPFEV1 within 30 min
Responders, no. (%) 10 (17.0) 26 (44.8) 27 (45.8) 22 (37.3) 24 (40.7)
For

Ingenta

Model estimated rate SE 0.10 0.04 0.43 0.09 0.43 0.09 0.30 0.08 0.37 0.09
95% CI 0.01–0.18 0.24–0.61 0.25–0.62 0.14–0.47 0.19–0.54
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Difference from placebo SE 0.33 0.09 0.34 0.09 0.21 0.08 0.27 0.09
95% CI 0.15–0.51 0.15–0.52 0.05–0.37 0.10–0.45
p Value 0.0006 0.0005 0.0119 0.0027
Response rate based on 12% increase in baseline
PPFEV1 within 30 min
Responders, no. (%) 12 (20.3) 33 (56.9) 34 (57.6) 32 (54.2) 28 (47.5)
Model estimated rate SE 0.14 0.05 0.59 0.09 0.60 0.08 0.55 0.09 0.47 0.09
95% CI 0.04–0.24 0.43–0.76 0.43–0.77 0.37–0.72 0.29–0.64
Difference from placebo SE 0.45 0.09 0.46 0.09 0.41 0.09 0.33 0.09
95% CI 0.27–0.64 0.28–0.64 0.22–0.59 0.14–0.51
p Value 0.0001 0.0001 0.0001 0.0007
Time (min) to 15% response among responders
within 30 min
No. patients — 26 27 22 24
Mean SD — 10.7 4.79 10.4 6.96 9.4 5.41 12.8 7.88
Median — 8.8 8.0 8.4 8.4
Min, max — 4.8, 18.5 4.7, 29.7 4.0, 26.6 4.2, 28.7
Time (min) to 12% response among responders
September–October 2016, Vol. 37, No. 5

within 30 min
No. patients — 33 34 32 28
Mean SD — 11.9 7.20 9.9 6.10 9.1 5.28 9.7 5.70
Median — 8.9 8.1 8.1 8.3
Min, max — 3.1, 29.9 4.7, 29.7 4.0, 29.4 4.1, 27.2
Time (min) to maximum PPFEV1 over 6 hr
No. patients 59 58 59 59 59
Mean 75.9 47.6 45.0 50.1 44.7
p Value vs placebo — 0.0130 0.0054 0.0265 0.0048
p Value 90 mg vs 180 mg — — 0.7667 — 0.5363
Duration (hr) of 15% response among
responders within 30 min
No. patients — 26 27 22 24
Mean SD — 2.8 2.37 3.0 2.29 2.4 2.21 2.8 2.48
 terol HFA 180 mg. In addition, an exploratory analysis
indicated that improvements in mean FEV1 AUC0 – 6 in

Albuterol HFA 180

predicted forced expiratory volume in 1 second; SE standard error; CI

patients treated with albuterol MDPI and albuterol HFA
were not significantly different at both the 90-and 180-mg
g (N 61) dosages.
Similar to the present study, albuterol dry powder inhalers

03. 492.
2,0. 5.9

2,0. 5.9
have been demonstrated to be safe, effec-tive, and easy to
18 –20 18
32.

53.
use for children with persistent asthma. Kemp et al.
28
performed dose-ranging and 12-week efficacy and safety
studies that compared aerosol and powder albuterol with
placebo, and both studies showed similar efficacy and safety
profiles be-tween the two formulations.
Albuterol MDPI 180 Albuterol HFA

Limitations of this study included the single-dose design,

the small patient numbers, and the lack of patient-preference
questionnaires to assess inhaler preferences. The strengths
of this study included the crossover design, the double-
g (N 61) 90 g (N 61)

blind, double-dummy dosing, and the high rate of study

72. 2.35

completion achieved (57 of the 61 enrolled patients

2,0. 5.9

2,0. 5.9

completed the study).

91.

32.
32

CON LUSION
In this study in children ages 4 to 11 years, albuterol
minminimum;maxmaximum.
33. 2.18

MDPI was significantly more effective than placebo across

1,0. 5.9

1,0. 5.9

all study end points and had similar safety and efficacy
92.

83.
34

compared with albuterol HFA. Significant im-provements in

(N 61 )9 0g (N 61 )

—82.

—33

—73.
—2,0.5.9

—1,0.5.9
—23.2.24

h yd ro fl uo ro alkan e;P PFEV

Placebo Alb uterolMDPI

baseline-adjusted PPFEV1 AUC0 – 6 were observed with

percent-

albuterol MDPI 90 mg and 180 mg in pediatric patients

compared with patients who re-ceived placebo. Data from
this clinical trial were re-viewed by the U.S. Food and Drug
1

Administration in their evaluation and, in April 2016,

approval of the expanded indication for treatment of patients
4 years of age and older.

REFERENCES
1. FastStats—Asthma. Updated: May 14, 2015. Centers for Disease
Control and Prevention. Available online at http://www.cdc.
gov/nchs/fastats/asthma.htm; accessed August 13, 2015.
2. Albuterol oral inhalation. Updated: September 1, 2010. MedlinePlus.
Available online at http://www.nlm.nih.gov/
medlineplus/druginfo/meds/a682145.html; accessed Janu-ary 29,
confidence interval; SD standard deviation;

2016.
MDPI Multidose dry powder inhaler; HFA
Duration (hr) of 12% response amongresponderswithin30minNo.patients

3. Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and

Management of Asthma. Bethesda, MD: National Heart, Lung, and
Blood Institute, U.S. Department of Health and Human Services,
2007.
4. Ramsdell JW, Klinger NM, Ekholm BP, and Colice GL. Safety of
long-term treatment with HFA albuterol. Chest 115:945–951, 1999.
5. Burkhart PV, Rayens MK, and Bowman RK. An evaluation of
children’s metered-dose inhaler technique for asthma medica-tions.
Nurs Clin North Am 40:167–182, 2005.
Table 4 Continued

6. Levy ML, Hardwell A, McKnight E, and Holmes J. Asthma patients’

inability to use a pressurised metered-dose inhaler (pMDI) correctly
correlates with poor asthma control as defined by the Global Initiative
for Asthma (GINA) strategy: A retro-spective analysis. Prim Care
Mean SD
Min, max

Min, max

Respir J 22:406 – 411, 2013.

Median

Median

7. Baddar S, Jayakrishnan B, and Al-Rawas OA. Asthma control:

Importance of compliance and inhaler technique assessments. J
Asthma 51:429 – 434, 2014.

Allergy and Asthma Proceedings 357

Delivered by Ingenta to: Ryerson University Library IP: 95.181.217.250 On: Tue, 11 Oct 2016 00:53:23
Copyright (c) Oceanside Publications, Inc. All rights reserved.
For permission to copy go to https://www.oceansidepubl.com/permission.htm
 8. Hardwell A, Barber V, Hargadon T, et al. Technique training does not
improve the ability of most patients to use pressurised me-tered-dose
inhalers (pMDIs). Prim Care Respir J 20:92–96, 2011.
9. Scarfone RJ, Capraro GA, Zorc JJ, and Zhao H. Demonstrated use of
metered-dose inhalers and peak flow meters by children and
adolescents with acute asthma exacerbations. Arch Pediatr Adolesc
Med 156:378 –383, 2002.
10. ProAir RespiClick [package insert]. Horsham, PA: Teva Respi-ratory,
2016.
11. Kerwin EM, Taveras H, Iverson H, et al. Pharmacokinetics, phar-
macodynamics, efficacy, and safety of albuterol (salbuterol) multi-
dose dry-powder inhaler and ProAir® hydrofluoroalkane for the
treatment of persistent asthma: Results of two randomized dou-ble-
blind studies. Clin Drug Investig 36:55– 65, 2016.
12. Given J, Taveras H, and Iverson H. Prospective, open-label eval-
uation of a new albuterol multidose dry powder inhaler with
integrated dose counter. Allergy Asthma Proc 37:199 –206, 2016.
13. Guidance for Industry E6 Good Clinical Practice: Consolidated
Guidance. Rockville, MD: U.S. Department of Health and Hu-man
Services, Food and Drug Administration, 1996.
14. ProAir HFA [package insert]. Horsham, PA: Teva Respiratory, LLC,
2012.
15. Eigen H, Bieler H, Grant D, et al. Spirometric pulmonary func-tion in
healthy preschool children. Am J Respir Crit Care Med 163:619 –
623, 2001.
16. Quanjer PH, Borsboom GJ, Brunekreef B, et al. Spirometric reference
values for white European children and adoles-cents: Polgar revisited.
Pediatr Pulmonol 19:135–142, 1995.
17. Beydon N, Davis SD, Lombardi E, et al. An official American
Thoracic Society/European Respiratory Society statement: Pul-
monary function testing in preschool children. Am J Respir Crit Care
Med 175:1304 –1345, 2007.
18. Kemp JP, Furukawa CT, Bronsky EA, et al. Albuterol treat-ment for
children with asthma: A comparison of inhaled powder and aerosol. J
Allergy Clin Immunol 83:697–702, 1989.
19. Goren A, Noviski N, Avital A, et al. Assessment of the ability of
young children to use a powder inhaler device (Turbuhaler). Pediatr
Pulmonol 18:77– 80, 1994.
20. Hagmolen of ten Have W, van de Berg NJ, Bindels PJ, et al.
Assessment of inhalation technique in children in general prac-
tice: Increased risk of incorrect performance with new device.
J Asthma 45:67–71, 2008. e

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