Dr. Charles K.

N. Chan is a
Professor and
Vice-Chair of
Medicine at the
University of
Toronto. His hospital leadership
roles include posts as the Medical
Director of the Toracic Business
Unit and Endoscopy services at
the University Health Network
(UHN), the Chair of the Medical
Advisory Committee at the
UHN, the Head of Respirology
at the UHN and Mount Sinai
Hospital, and the Interim Head
of Respirology at the Womens
College Hospital in Toronto. Dr.
Chans research focuses on clinical
studies in idiopathic pulmonary
fbrosis as well as pneumonia
and pulmonary complications in
immunosuppresed hosts. Overall,
Dr. Chan has more than 110
original publications and has
contributed to 26 book chapters.
Past newsletters:
Idiopathic Pulmonary Fibrosis:
optimizing the diagnosis and
multi-disciplinary decision-
making by Dr. Gerard Cox, MD,
MB, FRCPCI, FRCPC
IPF: understanding the natural
history and epidemiology of this
fatal disease by Dr. Charlene D.
Fell, MD, MSc, FRCPC, FCCP
Upcoming newsletters:
The next several newsletters will
be based on presentations from
the US "PFF Summit 2013: From
Bench to Bedside".
If you wish to receive the
newsletters by email, wish to
subscribe or unsubscribe, or have
any questions, please contact:
Anna Liachenko, MSc
514-435-7860
anna@z-zinc.com
Idiopathic Pulmonary Fibrosis: how recent
randomized controlled trials inform clinical treatment of
IPFthe therapeutic trials roller coaster ride
By Charles K.N. Chan, MD, FRCPC, FCCP, FACP
Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease, characterized by progressive pulmonary insuffciency.
1

The natural history is variable and unpredictable. The median time of survival is 2 to 5 years following the
diagnosis.
2
Historically, clinical trials for IPF had many limitations, from small size to short duration and
variable patient population. Not surprisingly, the more recent, larger, randomized, double-blind trials have
contradicted some of the recommendations of the 2011 ATS/ERS/JRS/ALAT guidelines. The combination of
prednisone, azathioprine and N-acetylcysteine has now been found associated with increased mortality, side
effects and hospitalizations.
3
Anticoagulation therapy may be benefcial for patients with rapid deterioration,
but it did not show improvement in ACE-IPF trial.
4
Pirfenidone is the only pharmacological treatment that
has been granted regulatory approval for the treatment of IPF in Canada, South Korea, Japan and Europe.
Pirfenidone reduces the risk of death from IPF or disease progression by 26% over a studied period of
72 months.
5
Side effects of pirfenidone are generally mild and reversible, and may be manageable with dose
adjustments. This newsletter will examine the recent clinical trials in IPF and is based on the Section 1
Accredited Group Learning Activity co-developed with the Canadian Thoracic Society and presented at the
Canadian Respiratory Conference in Quebec City in April 2013.
Tis is a newsletter series in the continuing educational program
designed to bring you articles by leading Canadian respirologists.
Symptoms of Idiopathic Pulmonary Fibrosis
IPF is a rare type of interstitial pneumonia with no known cause or cure. It is characterized by a progressive,
non-reversible fbrosis of the lungs and interstitium, with minimal associated infammation.
6
An asymptomatic
period may last from months to years. Te initial symptoms often include exertional dyspnea and dry cough,
later followed by inspiratory bibasilar crackles, fatigue, cyanosis and clubbing of the fngertips.
7
Once
symptoms are present, the disease progression is often very rapid, with the majority of patients dying from
pulmonary insufciency within 2 to 5 years.
2
Early accurate diagnosis is crucial for stabilizing the disease
Te natural history of IPF is variable. Some patients experience mild to moderate symptoms for a number
of years, while others decline very rapidly.
8
Tose who sufer from mild to moderate symptoms and appear
relatively stable may experience sudden acute exacerbations, often leading to hospitalizations and death.
8
Te
median survival time following the diagnosis is very short shorter than with many common malignancies.
9
At
this time, we are not able to predict how IPF will progress in a particular patient. Tus, early accurate diagnosis
and timely therapeutic intervention is crucial for stabilizing disease progression.
IPF should be suspected in any adult over the age of 40 presenting with an unexplained dyspnea and dry
cough. Tese initial symptoms are similar to asthma and chronic obstructive pulmonary disease (COPD), and
it has been suggested that pathogenesis of IPF and COPD may be linked. Diagnosis of IPF is based on well
established criteria: exclusion of known causes of interstitial lung disease and high resolution computerized
tomography showing the pattern of the usual interstitial pneumonia.
10
When test fndings are unclear or
contradicting, multi-disciplinary discussion involving a respirologist, a radiologist and a pathologist (if a lung
biopsy is necessary) is recommended.
1,10,11,12
In the July 2013 newsletter, Dr. Gerard Cox, Professor of Medicine at McMaster University, discussed the
optimal diagnosis of IPF. To receive a complimentary copy, please email anna@z-zinc.com.
Learning objectives:
1. Review the current standard of care for patients with IPF
2. Discuss the lessons learned from recent randomized clinical trials in
the treatment of IPF
3. Examine the selection of clinical end points
4. Become aware of the limitations of the existing treatment guidelines
by the American Thoracic Society and European Respiratory Society
Sponsored by an unrestricted educational grant from InterMune. Based on Section 1 Accredited Group Learning Activity co-developed with the Canadian Thoracic Society.
The Honeycomb Network
THE IPF EXPERT EXCHANGE
Challenges of randomized clinical trials in IPF
Over the years, a number of treatments have been studied for their
benefts in IPF. However, study designs had limitations. Possibly, these
limitations contributed to the lack of evidence in treatment favour.
IPF studies were generally small, evaluating 80 to 200 patients.
Compounded by the heterogeneous natural history of IPF, this limits
the power for statistical analysis. Patients with similar initial condition
at the start of a trial would difer signifcantly in their state of health
after several months. Most studies were stopped at about 6 months,
with only a few continued up to 18 months.
Te median survival of IPF patients following the diagnosis is 2 to
5 years, hence demonstration of a survival beneft as the primary end
point would require a large cohort of patients followed for at least 3 to
5 years. Such studies are expensive and may still fail to show benefts
due to heterogeneity of disease progression and difculties in patient
retention. Terefore, the majority of IPF phase III clinical trials to date
have used surrogate end points such as forced vital capacity (FVC) as
a substitute for the primary end point of survival, often supported by
secondary end points such as the 6 minute walk test (6MWT) and the
quality-of-life questionnaire.
New therapeutic directions
IPF should be managed with a methodical approach and regular
patient evaluations. Both pharmacological and non-pharmacological
strategies are useful. Te treatment goal is to optimize the quality of life
and to delay IPF progression in patients with milder disease.
1,13

Historically, IPF has been treated with anti-infammatory and
immuno-modulatory medications. Some of the recommendations were
based on consensus and common practice rather than robust clinical
data. New randomized clinical trials revealed that these options may not
ofer advantage and may harm IPF patients. At the same time, several
trials showed that IPF decline can be attenuated with anti-fbrotic and
anti-proliferative medication. With the emergence of this signifcant
new clinical data, some recommendations of ATS/ERS/JRS/ALAT
guidelines
1
are expected to be revised.
NAC and triple therapy
For decades, IPF has been managed with a combination of
prednisone and either azathioprine or cyclophosphamide. However,
a 2003 Cochrane review
14
failed to fnd any proven beneft of using
corticosteroids in treating IPF. Following this review, Demedts et
al.
15
found that triple therapy with prednisone, azathioprine and
N-acetylcysteine (NAC) ofered a 4% protection from decline in
FVC over 12 months. NAC may be benefcial because of its ability
to enhance the cellular production of antioxidant glutathione, thereby
combating the oxidative stress implicated in the development of IPF.
Since azathioprine depletes glutathione in the liver, NAC potentially
ofers protection from azathioprine toxicity.
16
To understand the efects of NAC alone versus triple therapy
(prednisone/azathioprine/NAC), IPF clinical research network
(IPFnet) sponsored the current PANTHER-IPF trial.
3
A pre-planned
interim analysis revealed that triple therapy was associated with greater
mortality (11% vs. 1%, p = 0.01), more hospitalizations (29% vs. 8%,
p 0.001) and more serious adverse events (31% vs. 9%, p = 0.001)
than placebo. Tus, the National Heart, Lung and Blood Institute
discontinued the triple therapy arm. Te trial arms with NAC only and
placebo are on-going.
Anticoagulation
IPF patients are at an increased risk of serious thrombotic events. A
2005 Japanese study by Kubo et al.
17
found that anticoagulation increases
survival in IPF patients with advanced disease. Patients were assigned to
receive prednisolone alone or prednisolone plus anticoagulant therapy
(oral warfarin in an outpatient setting and low molecular weight heparin
for rehospitalized patients with severely progressive respiratory failure).
Te study was small (n = 56), unblinded and had methodological
problems with patient selection and diagnostic criteria.
To further investigate potential benefts of anticoagulation, IPFnet
sponsored a double-blind, randomized, placebo-controlled ACE-IPF
4
trial. 145 patients were enrolled. Tose in the warfarin group did not
have any improvement in quality-of-life measures, and there were 14
deaths in that group compared with three in the placebo group. Te
trial was stopped early. Te deaths in the treatment group did not
seem to be related to known risks of warfarin but rather resulted from
worsening of respiratory conditions.
Te Japanese study enrolled patients identifed during hospitalization
while ACE-IPF
4
trial enrolled generally younger and healthier IPF
patients. Hence, anticoagulation may still be benefcial in patients with
advanced IPF, especially those presenting with rapid deterioration.
Autopsies of patients who died from an IPF-related acute exacerbation
show difuse alveolar damage with a substantial amount of fbrins.
Clinical trial data for pirfenidone
Pirfenidone is the only pharmacological treatment approved for the
treatment of IPF in Canada, South Korea, Japan and Europe. Its an
oral anti-infammatory, anti-fbrotic and antioxidant agent that impacts
TNF, TGF and fbroblast migration.
18

Pirfenidone is metabolized in the liver into its active form. Te main
0 12 24 36 48 60 72
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Study 004 placebo
Study 006 placebo
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FIGURE 2. Change in forced vital capacity (FVC) % predicted (% pred) per week
from baseline in the CAPACITY 004 and 006 study comparing pirfenidone
(2403 mg/day) or placebo in patients with idiopathic pulmonary fbrosis (IPF).
CAPACITY: Clinical Studies Assessing Pirfenidone in IPF: Research of Effcacy
and Safety Outcomes. Eur Respir Rev 2013; 22:163168.
FIGURE 1. SP3 trial. Primary end point. Eur Respir J 2010; 35(4):821-829.
5
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Pirfenidone 1200 mg/d
Pirfenidone 1800 mg/d
Placebo
Pirfenidone 1800 mg/d vs placebo: p = 0.042
Pirfenidone 1200 mg/d vs placebo: p = 0.039
Pirfenidone 1800 mg/d vs placebo at Week 52
Absolute difference: 70 mL
Relative difference: 44%
side efects are nausea, photosensitivity, rash, fatigue, cold symptoms,
loss of appetite and a minor rise in gGT.
18
Tese side efects are very
mild and can easily be managed with dose adjustments.
Te clinical efcacy of pirfenidone was shown in three Phase
III, randomized, double-blind, placebo-controlled trials: SP3 and
CAPACITY programme (studies 004 and 006). Te RECAP
(PIPF-012) study is an open-label extension to the CAPACITY studies.
Te collective data provide evidence that pirfenidone reduces decline
in lung function in IPF patients. It is also well tolerated. Adherence
to treatment in the trials was high despite a dosing schedule of 3 times
per day.
SP3
19
trial, published in 2010, was Japanese multicentre,
randomized, double-blind trial of 271 IPF patients who were randomly
assigned to receive pirfenidone 1800 mg/day, pirfenidone 1200 mg/day
or placebo. Treatment with pirfenidone 1800 mg/day signifcantly
reduced mean decline in the primary end point of vital capacity over
52 weeks, compared with placebo (-0.09 L versus -0.16 L, p = 0.042,
See Figure 1).
In two concurrent trials (004 and 006)
20
, 779 IPF patients were
randomly assigned to oral pirfenidone or placebo for at least 72 weeks in
110 centres in Australia, Europe and North America. CAPACITY trials
used pirfenidone 2403 mg/day to adjust for the higher body mass index
of the Caucasian vs. Japanese population. Both trials were randomized,
double-blind and placebo-controlled with almost identical design.
Tey evaluated the efcacy and safety of pirfenidone 2403 mg/day
(801 mg taken 3x day) in patients with mild to moderate IPF, defned
as in Table 1. CAPACITY 006 study trial also included an arm with
pirfenidone 1197 mg/day (399 mg taken 3x day) to evaluate the dose-
response relationship. Te primary end point was a change in percentage
FVC at week 72.
In the 006 study (See Figure 2), pirfenidone 2403 mg/day produced
a highly statistically signifcant reduction in the mean FVC decline
compared with placebo at week 72 (p = 0.001). A pre-specifed repeated
measures analysis of FVC across all study time-points showed a strongly
positive and signifcant beneft of pirfenidone compared to placebo in
reducing the FVC decline
(p < 0.001).
In the 004 study (See
Figure 2), a signifcant
treatment efect of
pirfenidone 2403 mg/day
compared with placebo at
week 72 was not observed.
Patients in the 004 study
placebo arm had an
unusually small decrease in
lung volume at 72 weeks,
compared to placebo arms
of the other IPF trials (See Figure3). A subsequent post-hoc analysis of
the 004 study identifed that the placebo arm included a high number
of patients with obstructive disease, whose lung volume was already
compromised. Tere was an evidence of statistically signifcant treatment
efect of pirfenidone 2403 mg/day on the mean FVC decline from week
12 until week 48. Te dose-response relationship with pirfenidone was
also observed. Te lower 1197 mg/day dose was superior to placebo but
not as efective as pirfenidone 2403 mg/day.
In the pre-specifed pooled analysis of CAPACITY programme
(See Figure 4), pirfenidone 2403 mg/day had a signifcant treatment
efect on the primary end point of FVC at week 72 (p = 0.005), with
a 2.5% absolute diference and 22.8% relative diference between the
treatment groups. Te positive treatment efect of pirfenidone 2403 mg/
day appeared at week 12 and was sustained throughout subsequent time
points. Te observed treatment efect in this study is clinically relevant
since the minimal clinically important diference for absolute change in
FVC is 2 to 6%. Since the natural history of IPF is heterogeneous, it
is possible that some patients respond extremely well to the treatment
while others do not respond. Further research is needed to help predict
a patients responsiveness to IPF treatment.
Te signifcant efect of pirfenidone 2403 mg/day on primary
end point was supported by a highly signifcant treatment efect of
pirfenidone on the secondary end points (See Figure 5) of %FVC,
6MWT and progression-free survival (defned as time to confrmed
10% decline in percentage predicted FVC, 15% decline in percentage
predicted difusing capacity of carbon monoxide or death). In the
pooled analysis, treatment with pirfenidone 2403 mg/day produced a
26% reduction in the risk of death or IPF progression compared with
placebo (HR 0.74 [95% CI, 0.57 to 0.96], p = 0.025).
An overall 30% risk reduction in IPF progression (p < 0.002) over
a period of about 12 months with pirfenidone compared to placebo
was identifed by Cochrane systematic review of non-steroid agents
for IPF in a meta-analysis of pooled data for 1155 patients enrolled in
CAPACITY programme, SP3 and SP2 (phase II trial of pirfenidone
in IPF patients). Te review was completed before the publication of
CAPACITY programme pooled analysis, but reviewers were provided
access to the full data sets. Clinically meaningful benefts such as
progression-free survival and reduced decline in function as measured
by 6MWT were also found after 72 weeks of therapy.
20
Cough in IPF patients
A persistent dry cough is one of the most prominent features of IPF,
afecting 73-86% of patients.
23
Te aetiology of the cough is unknown
but presumably linked to the lung fbrosis. Unfortunately, the cough
FIGURE 3. Rate of decline in % predicted FVC in placebo arms of CAPACITY
Programme and INSPIRE Study. Adapted from Lancet 2011;377:1760-1769 and
Lancet 2009; 374:222-228.
0 12 24 36 48 60 72
0
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INSPIRE Study interferon
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Pirfenidone 2403 mg/day (n=345)
Placebo (n=347)
Absolute diference
Relative diference
p value
0.5%
28.5%
0.003
2.7%
63.6%
<0.0001
3.5%
57.5%
<0.0001
3.3%
41.6%
<0.0001
2.4%
25.1%
0.0003
2.5%
22.8%
0.005
FIGURE 4. Pooled analysis of CAPACITY 1 and 2 trials. Primary end point.
Lancet 2011; 377:17601769.
Table 1. IPF staging
n
FVC 50% predicted
n
DL
CO
35% predicted
n
6MWT distance 150 metres
FVC = forced vital capacity
DL
CO
= diffusing capacity of carbon monoxide
6MWT = 6 minute walk test
Criteria for mild to moderate IPF
is often disabling and resistant to traditional antitussive therapies.
24

An open label phase II trial of thalidomide 100-400 mg daily assessed
eleven IPF patients who sufered from cough most days of the week.
Ten of these patients noted marked to complete resolution of cough
while on the medication.
25
Talidomide is only available through a
controlled distribution program called RevAid. Only physicians
and pharmacists registered with RevAid are able to prescribe and
dispense this medication. All patients prescribed thalidomide must be
registered in this program by their physician.
Best supportive care and non-pharmacological
therapies
Best supportive care is an important treatment strategy in
all patients with IPF. It is defned as a proactive approach to
symptomatic treatment and may include oxygen therapy, pulmonary
rehabilitation, opiates, antirefux therapy, withdrawal of steroids and
other immunosuppressants, early recognition of terminal decline and
liaison with palliative care specialists.
13
Long-term oxygen therapy has been recommended for hypoxemic
patients with IPF on the basis of positive outcomes in surrogate clinical
trials involving patients with COPD.
26,27
Pulmonary rehabilitation,
which has a clearly demonstrated beneft in patients with COPD,
has only a modest improvement in patient specifc outcomes, such as
quality-of-life and dyspnea scores in patients with pulmonary fbrosis
in short term studies.
28,29
Data examining the treatment of pulmonary
hypertension
30-34
in IPF is limited, hence no approach is recommended
at this time.
1
Co-morbidities, such as COPD and gastroesophageal
refux should be treated in IPF patients.
1
Lung transplantation is clearly benefcial and prolongs life in IPF
patients with impaired pulmonary physiology. Unfortunately, only a
small proportion of patients with IPF undergo lung transplantation as
many patients are ineligible for the procedure due to geographic location,
older age, co-morbidities or severely limited functional status.
35
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Favours
placebo
Favours
Pirfenidone 2403 mg/d
Standardized treatment effect
Categorical %FVC
Progression-free survival
6MWT distance
Lowest SpO2 during 6MWT
%DLCO
Dyspnea (UCSD SOBQ)
Time to worsening
-0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0
FIGURE 5. Pooled analysis of CAPACITY programme (004 and 006) Secondary
end points. Lancet 2011; 377:17601769.