Recently Completed Trials in IPF:
What have we learned?
Where do we go from here?
Charlene D Fell
University of Calgary
Disclosures
Scientific Advisory Board
–
–
Actelion
InterMune
Speaker’s Fees
–
GSK, AstraZeneca, Boehringer Ingelheim
Objectives
List recent clinical trials in IPF and their outcomes
Discuss the challenges in selecting clinically meaningful
endpoints for clinical trials in IPF
Discuss how the natural history of IPF and IPF
phenotypes contribute to challenges faced in
designing clinical trials for this disease
Recent Phase 3 Trials in IPF
Intervention
N
Pirfenidone (CAPACITY)
PIPF-004
PIPF-006
435
344
Change in FVC%
Change in FVC%
Positive
Negative
N-acetylcysteine
IFIGENIA
182
Change in VC and DLCO
Positive
IFN-1b
GIPF-001
INSPIRE
330
826
Progression-free survival
Survival time from randomization
Negative
Negative
Imatinib
119
Time to disease progression or death
Negative
Bosentan
BUILD 1
BUILD 3
158
616
Change in 6MWD
Death or disease progression
Negative
Negative
Sildenafil
STEP-IPF
180
Change in 6MWD
Negative
Ambrisentan
ARTEMIS-IPF
ARTEMIS-PH
600
225
Death or disease progression
Change in 6MWD
Negative
Negative
(NAC+predinsone+AZA)
Primary Outcome
Status
Recent Phase 3 Trials in IPF
Intervention
N
Pirfenidone (CAPACITY)
PIPF-004
PIPF-006
435
344
Change in FVC%
Change in FVC%
Positive
Negative
N-acetylcysteine
IFIGENIA
182
Change in VC and DLCO
Positive
IFN-1b
GIPF-001
INSPIRE
330
826
Progression-free survival
Survival time from randomization
Negative
Negative
Imatinib
119
Time to disease progression or death
Negative
Bosentan
BUILD 1
BUILD 3
158
616
Change in 6MWD
Death or disease progression
Negative
Negative
Sildenafil
STEP-IPF
180
Change in 6MWD
Negative
Ambrisentan
ARTEMIS-IPF
ARTEMIS-PH
600
225
Death or disease progression
Change in 6MWD
Negative
Negative
(NAC+predinsone+AZA)
Primary Outcome
Status
Challenges in selecting endpoints for IPF trials
Optimal endpoint characteristics
–
–
–
–
–
–
Clinically meaningful
Reproducible
Responsive
Safe
Simple
Cheap
CAPACITY Trials
Phase III, RDBPC trial
– PIPF-004: pirfenidone 1197mg/day vs.
2403mg/day vs. placebo
– PIPF-006: pirfenidone 2403mg/day vs. placebo
“Early IPF”
1º Endpoint: % change in FVC at w 72
CE-14
PIPF-004
Mean change from
baseline in %FVC
0
-5
-10
Pirfenidone 2403 mg/d
-15
0
Pirfenidone 1197 mg/d
Placebo
12
Pirfenidone 2403 mg/d vs Placebo
Absolute difference, %
1.4
Relative difference, %
53.5
p-value
0.061
24
36
Weeks
48
60
72
2.5
4.6
4.8
4.1
4.4
65.2
63.7
52.3
38.3
35.3
0.014 < 0.001 < 0.001 < 0.001 0.001
Slide courtesy of InterMune
CE-23
PIPF-006
Mean change from
baseline in %FVC
0
-5
-10
Pirfenidone 2403 mg/d
Placebo
-15
0
12
24
36
48
60
72
1.9
27.3
0.005
0.6
7.6
0.172
0.6
6.5
0.501
Weeks
Absolute difference, %
Relative difference, %
p-value
-0.4
-31.5
0.021
2.8
62.1
< 0.001
2.4
48.2
0.011
Slide courtesy of InterMune
PIPF-004 and PIPF-006
Mean change from
baseline in %FVC
0
-5
-10
-15
0
12
24
36
48
60
72
Weeks
 In PIPF-006, patients in the placebo arm
had more stable disease
Data courtesy of InterMune
CAPACITY: Analysis
Did we choose the right endpoint?
– FVC of 10% an accepted surrogate marker for mortality in IPF
Was the trial long enough?
− 72 weeks
Was n large enough?
−
> 750 patients
BUILD-3
Phase III RDBPC trial
Bosentan 125 mg BID vs. placebo (2:1)
“Early IPF”
– Biopsy proven UIP
– <5% honeycombing on HRCT
Composite 1º endpoint:
– Time to death, disease progression, or hospitalization
King, TE. AJRCCM. 181:A6838. 2010
BUILD-3 Primary Outcome
Bosentan
(n=407)
Placebo
(n=209)
Death
11
6
Hospitalization
19
6
FVC 10%
DLCO 15%
128
82
158 (38%)
94 (45%)
Combined
HR 0.85 (0.66 - 1.1), p=0.21
King, TE. AJRCCM. 181:A6838. 2010
BUILD-3 Analysis
Did we choose the right outcome?
− Time to death, disease progression, or hospitalization
Was the trial long enough?
− 4 week intervention
− 1 year follow up
Was n large enough?
− Needed 202 events to detect a 35% RRR in 1º endpoint
STEP-IPF
Phase III, RDBPC trial
Sildenafil 20 mg TID vs. placebo (1:1)
“Late IPF”
– DLCO <35% predicted
1º outcome: proportion of patients with an increase in 6MWD of
20% or more
Zisman, D et al. NEJM. 363:620. 2010
STEP-IPF
1º Outcome
Improvement of 20% or
more in 6MWD
– Sildenafil: 9 of 89
– Placebo: 6 of 91
– p=0.39
Zisman, D et al. NEJM. 363:620. 2010
STEP-IPF: Analysis
Did we choose the right outcome?
–
–
–
–
20% increase in 6MWD at 12 w
Baseline 6MWD = 265m; 20% = 51m
After 12 w pulmonary rehab: 53m
MCID in 6MWD is estimated to be 24-40m
Was the trial long enough?
– 12 weeks of blinded therapy
Was n large enough?
– 180 patients
Zisman, D et al. NEJM. 363:620. 2010
Salhi B. et al. CHEST. 137:273-9. 2010
ARTEMIS
•
•
•
•
ARTEMIS-IPF
ARTEMIS-PH
Phase III, RDBPC trial
Ambrisentan 10 mg OD vs. placebo
IPF
1 Outcome: Time to death or
disease progression
•
•
•
•
Phase III, RDBPC trial
Ambrisentan 10 mg OD vs. placebo
IPF + PAH
1 Outcome: change in 6MWD
Early termination: failed to meet endpoints at interim analysis
www.ClinicalTrials.gov
Selecting trial outcomes for IPF:
Survival
FVC
6MWD
• Clinically
meaningful



• Reproducible



• Responsive
?
?
?
• Safe



• Simple



• Cheap



3 Important Lessons from Recent Clinical Trials
Most patients have stable disease
Stable disease is punctuated by periods of acute deterioration
There are probably multiple phenotypes of IPF
0.2
0.4
0.6
IFN (INSPIRE)
0.0
Survival
0.8
1.0
Survival in IPF may be better than we think it is…
0
2
4
6
8
Years
Flaherty et al. AJRCCM. 2003
King et al. Lancet. 2004
Change in physiologic and dyspnea indices
In patients in the placebo arm of GIPF-001
Who survived during follow up.
Change in FVC and dyspnea in 36
patients in the placebo arm of GIPF001 who died during follow up.
FVC
Dyspnea
Martinez, FJ et al. Ann Int Med. 2005
GIPF-001 Trial: IFN-gamma in IPF
The majority of patients with IPF have a stable
course.
Patients with mild/moderate disease can have acute
exacerbations of IPF.
– More frequent evaluation of patients
– Early referral for lung transplantation
Martinez, FJ et al. Ann Int Med. 2005
Raghu, G. et al. AJRCCM 183.788-824. 2011
Pulmonary hypertension and IPF
Lettieri C J et al. Chest 2006;129:746-752
Gender differences in PH in IPF patients
Subanalysis of the STEP-IPF Trial
Characteristic
Men
N=86
Women
N=19
p
Age
67.8
67.6
0.92
FVC%
56.8
55.6
0.73
DLCO%
25.7
26.0
0.60
Mean RVSP
45.2
32.5
0.002
Prevalence of PH (PASP≥40)
34%
0%
<0.0001
RA Hypertrophy
13%
0%
0.0004
RV Systolic Dysfunction
20%
10%
0.03
LV Systolic Dysfunction
5%
10%
0.91
Han, MK et al. AJRCCM. 181:A1112. 2010
Emphysema and IPF
Mejía M et al. Chest 2009;136:10-15
Challenges in selecting endpoints for IPF trials
Optimal endpoint characteristics
–
–
–
–
–
–

Clinically meaningful
Reproducible
Responsive
Safe
Simple
Cheap
Applicable across all phenotypes
Some challenges in clinical research in IPF
Patients with IPF are more stable than once thought
There are likely multiple phenotypes of IPF
–
–
–
–
Males vs. Females
IPF and PAH
IPF and emphysema
….others?
Acute exacerbations must be accounted for in trial outcomes
Summary
Pirfenidone is promising but lacks regulatory approval in Canada
The role of ET antagonists in IPF is unclear
– Clinical trials have been negative
Most patients have stable disease
– Stable disease is punctuated by acute exacerbations
There are probably multiple IPF phenotypes
Intervention
N-acetylcysteine
PANTHER
N
Primary Outcome
Status
390
Change in FVC
Recruiting
Anticoagulation (warfarin)
ACE-IPF
256
Time to death, hospitalization, or
FVC by 10%
Recruiting
Macitetan
MUSIC
156
Change in FVC
Recruiting
BIPF 1120
485
Annual rate of decline of FVC (ml/52 wk)
CC-930
36
Safety of CC-930
Recruiting
48
Safety of FG-3019
Recruiting
(NAC vs. NAC+predinsone+AZA vs. P)
(phase 2)
FG-3019
(phase 2a open label)
Not yet recruiting
What can we learn from these trials?
www.ClinicalTrials.gov
Thank You
What is Idiopathic Pulmonary Fibrosis?
Chronic, progressive fibrotic pulmonary disease
No known cause
No effective therapies currently available outside Japan
Mean survival after diagnosis is 3 years
May 2005
Nov 2005
Apr 2006
Slides courtesy of Dr. M Kelly
Thannickal VJ et al. Annu Rev Med. 2004.
Refer for lung transplantation
Management
of IPF
Enroll in a clinical trial
Weak evidence against the use of:
–
–
–
–
Combined NAC/AZA/prednisone
NAC monotherapy
Anticoagulation
Pirfenidone
Pulmonary rehabilitation
Supportive care/palliation
Raghu, G. et al. AJRCCM 183.788-824. 2011
• Retrospective analysis of patients in the placebo arm
of GIPF-001
• 36 patients in the placebo arm died
• 31 had deaths related to IPF
Primary Cause
of Death
Acute Deaths
(n=15)
Subacute Deaths
(n=16)
Progression of
IPF
6
14
Pneumonia
4
0
ARDS
2
0
Cor Pulmonale
1
0
Other
0
1
Unknown
2
1
Martinez, FJ et al. Ann Int Med. 2005
INSPIRE Trial: IFN-gamma in IPF
Baseline
6MWD
HR
95% CI
p
<250
2.7
1.5,4.8
0.001
250-349
1.5
0.9, 2.6
0.106
<-50
4.3
2.6, 7.1
<0.001
-50 to -26
3.6
2.0, 6.7
<0.001
>350
Change in
6MWD
>-25
Du Bois et al. AJRCCM. 2010:A1103
A classification of IPF based on simple lung function criteria
Egan JJ et al. Thorax 60:270-273. 2005
“I like to say that we can describe the conduct of a
trial three ways: it can be trustworthy, fast, or cheap.
Generally speaking, a trial can have only two of
these characteristics. If a trial is fast and cheap, it is
unlikely to be trustworthy.”
Zivin, JA. Scientific American 282(4):69-75. 2000
Some challenges in clinical research in IPF
Heterogeneity in outcomes
Uncertain surrogate markers of mortality
– FVC 10% or 5%?
The problem of missing data (LOCF not appropriate in this disease)
Inadequate # of expert clinical sites
Agents are expected to stabilize disease, not reverse it.
–
–
Treatment effects will be small.
Therefore need longer/larger trials to see an effect.
Patients are referred late in their course - ineligible for “early IPF” trials
FVC
Time