Clinical trial NCT02951429
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Hoffmann-La Roche
Start date: 2016-12-31; Completion date: 2020-08-22
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase IIb, randomized, placebo-controlled, multicenter, international study will evaluate the efficacy, safety, and tolerability of sildenafil or placebo added to pirfenidone (Esbriet) treatment in participants with advanced IPF and intermediate or high probability of Group 3 pulmonary hypertension (PH) who are on a stable dose of pirfenidone with demonstrated tolerability. Participants will be randomized to receive 1 year of treatment with either oral sildenafil or matching placebo while continuing to take pirfenidone.

Detailed description:

Arms: arm 1: Participants will receive pirfenidone along with placebo matched to sildenafil, orally, three times a day (TID) for 52 weeks. arm 2: Participants will receive pirfenidone along with sildenafil, orally, TID for 52 weeks.
Interventions: intervention 1: Pirfenidone intervention 2: Placebo intervention 3: Sildenafil
Intervention descriptions: intervention 1: Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses. intervention 2: Placebo matched with sildenafil. intervention 3: Sildenafil will be given as 20 mg, TID.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A PHASE IIb, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF SILDENAFIL 
ADDED TO PIRFENIDONE IN PATIENTS WITH ADVANCED 
IDIOPATHIC PULMONARY FIBROSIS AND RISK OF GROUP 3 
PULMONARY HYPERTENSION  
NCT Number: 
 NCT02951429 
Document Date: 
Protocol Version 2: 01-Dec-17 
 
 
 
 


PROTOCOL AMENDMENT APPROVAL 
[This space is reserved for the electronic signature] 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
Protocol MA29957, Version 2 
PROTOCOL 
TITLE: 
A PHASE IIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF SILDENAFIL ADDED TO 
PIRFENIDONE IN PATIENTS WITH ADVANCED 
IDIOPATHIC PULMONARY FIBROSIS AND RISK OF 
GROUP 3 PULMONARY HYPERTENSION  
PROTOCOL NUMBER: MA29957 
 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-005131-40 
IND NUMBER: 
67284 
TEST PRODUCTS: 
Pirfenidone (RO0220912) and sildenafil (RO0280296) 
MEDICAL MONITOR: 
 MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1 (19-July-2016) 
DATE AMENDED: 
Version 2:  See electronic date stamp below 
 
01-Dec-2017 13:33:46
Title
Approver's Name
Company Signatory
Date and Time (UTC)
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
2/Protocol MA29957, Version 2 
PROTOCOL AMENDMENT, VERSION 2.0: 
RATIONALE 
Protocol MA29957 has been amended to reflect the feedback received after the start of 
the study from the Steering Committee, sites or ethic committees.  The changes to the 
protocol along with a brief rationale for each change are summarized below: 
• 
Title, Sections 1.2, 1.3, 2, 3.1, 3.3.2, 3.3.5, 4.1, 4.1.1, and 6.4.1, Figure 2, and 
Figure 3 were updated to clarify the terminology related to characterization of the 
eligible patient population.  The term “intermediate or high probability” of Group 3 
pulmonary hypertension reflects the 2015 European Society of Cardiology (ESC)/ 
European Respiratory Society (ERS) guideline and it is related to 
echocardiography assessments.  As in this study, the patients are eligible based 
on right heart catheterization (RHC) or ECHO data, the terminology “risk of 
Group 3 pulmonary hypertension” is considered more appropriate.  Hence 
throughout the protocol, when describing the eligible population “intermediate or 
high probability” of Group 3 pulmonary hypertension was changed to “risk” of 
Group 3 pulmonary hypertension. 
• 
Section 1.3 was updated to include collection from randomized patients of the 
most recent high-resolution computed tomography (HRCT) scans performed 
prior to entering the study.  Following availability of data from the RISE-IIP study 
(Nathan et al 2016, ERS) which showed an increased incidence of death both 
from the main study and the open-label extension period, the intention is to 
collect HRCT from randomized patients to support, if considered necessary, an 
in-depth analysis of any case of death in the current study.  Moreover in view of 
the fact that results from RHC which allows to characterize the severity of 
pulmonary vascular disease will be available only in small proportion of 
patients (majority of the patients so far being eligible are based on ECHO data), 
having the possibility to potentially evaluate baseline HRCT for signs of 
pulmonary vascular disease might be considered relevant for the study.  
• 
Section 3.1 was updated to include clarification to the text that the washout 
period can be part of the Run-in period, if the Run-in period is applicable.  In the 
protocol version 1, this text was provided only as a footnote to Figure 1.  This has 
been added now also to the text.  
• 
Section 3.1 was updated to include also region Asia-Pacific, as potentially, 
additional countries might join the study. 
• 
Sections 3.1, 3.2, and Figure 1 have been clarified in the protocol that the study 
ends when all patients complete the overall 12 months safety follow-up period, i.e. 
4 weeks follow-up after end of treatment at week 52 plus additional 11 months 
safety follow-up after the Follow up visit at week 56.  Thus, depending on the 
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wording in the protocol, in some instances the follow-up period had to be updated 
from “12” to “11” months. 
• 
Section 4.1.2 additional exclusion criteria based on Sildenafil Safety Reference 
Information # 7 (severe hypotension [BP <90/50 mmHg]) was removed based on 
Sildenafil Safety Reference Information as this is already covered by the main 
exclusion criteria 4, i.e. “Hypotension (blood pressure [BP] <100 mmHg systolic 
or <50 mmHg diastolic), autonomic dysfunction, or conditions in which 
vasodilation may cause an unsafe drop in blood pressure”. 
• 
Section 4.1.2 additional exclusion criteria based on Sildenafil Safety Reference 
Information #10 (use of an alpha blocker) was removed based on Sildenafil 
Safety Reference Information.  Alpha blockers are not contraindicated as per the 
sildenafil label.  Moreover, benign prostatic hyperplasia is a condition quite 
common in the study population's age group.  Nevertheless, the protocol 
highlights repeatedly that these patients should be treated with caution.  Section 
4.3.2.3.2 highlights the fact that patients should be treated with caution if they are 
receiving alpha-blockers or other antihypertensive medication.  Section 5.1.2.7 
states that "Caution is advised when sildenafil is administered to patients taking 
an alpha-blocker as the co-administration may lead to symptomatic hypotension 
in susceptible individuals.  To minimize the potential for developing postural 
hypotension, patients should be hemodynamically stable on alpha-blocker 
therapy prior to initiating sildenafil treatment.  Physicians should advise patients 
what to do in the event of postural hypotensive symptoms.” 
• 
Sections 4.1.2 and 4.4.2 were updated to reflect the correct terminology related 
to “Guanylate cyclase stimulators” from “Guanylate cyclase inhibitors”  
• 
Section 4.5.5 has been clarified that in few countries with local requirements (e.g. 
Egypt, UAE) local laboratory assessments will be performed. 
• 
Section 4.5.16 has been clarified that Sildenafil/placebo could be stopped 
temporarily or permanently, according to the judgment of the Investigator, in case 
of patients with systolic blood pressure (SBP) <100 mmHg or diastolic blood 
pressure (DBP) <50 mmHg  
• 
Section 6 and Section 6.4.1. were updated to clarify the “safety population” 
definition in line with the independent Data Monitoring Committee (iDMC) charter.  
The “per protocol” population definition has been deleted as sensitivity analysis 
of the primary endpoint will be conducted based on the intent-to-treat (ITT) 
population and will include more parameters, not only the per protocol population.  
Details will be added in statistical analysis plan. 
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4/Protocol MA29957, Version 2 
• 
Section 10 reference list was updated to reflect the requirement to refer to 
current version of the IB. 
• 
Appendix 1 (Schedule of Assessment) has been updated to reflect changes in 
the protocol.  In addition, footnotes related to FVC, DLCO and ECHO 
assessments have been updated based on the feedback received from the 
countries regarding the difficult aspect of scheduling two appointments very close 
to each other for the same assessment.  The note has been added to reflect that 
in case ECHO/spirometry at screening collect all information required at Visit 1 
and the patient is eligible and randomized in ≤14 days, the screening 
ECHO/spirometry can be used as baseline assessment. 
The above changes have also been made to the Synopsis and study Informed Consent 
Form, as applicable.  
Additional minor changes have been made to improve clarity and consistency 
throughout the document.  Substantive new information appears in italics.  This 
amendment represents cumulative changes to the original protocol. 
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5/Protocol MA29957, Version 2 
PROTOCOL AMENDMENT, VERSION 2.0: 
SUMMARY OF CHANGES 
PROTOCOL TITLE:  
A PHASE IIb, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO 
CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF SILDENAFIL ADDED TO PIRFENIDONE IN PATIENTS WITH 
ADVANCED IDIOPATHIC PULMONARY FIBROSIS AND INTERMEDIATE OR HIGH 
PROBABILITY RISK OF GROUP 3 PULMONARY HYPERTENSION 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2:  BACKGROUND ON TEST PRODUCTS 
The test products in this Phase IIb trial will be pirfenidone (Esbriet®) and sildenafil 
(generic formulation).  Patients will have advanced IPF and intermediate or high 
probability risk of Group 3 PH, which is considered to be secondary to IPF, and be on a 
stable dose of pirfenidone with demonstrated tolerability. 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
In study MA29957, patients with advanced IPF and intermediate or high probability risk 
of Group 3 PH will be included.  To address potential concerns regarding the RISE-IIP 
premature termination, but most importantly to minimize any potential risk in the study 
patient population in MA29957, a safety plan has been put in place for this study.  The 
safety plan includes: appropriate eligibility criteria, dose modification and/or 
discontinuation guidelines for each identified and potential risk (see Section 5.1), 
collecting from randomized patients the most recent HRCTs performed prior to entering the 
study, monitoring of patients at risk as well as the regular monitoring of patient data by 
an iDMC.  Moreover, the long-standing experience available with sildenafil should also 
be considered. 
SECTION 2:  OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety and tolerability of sildenafil compared to 
placebo added to pirfenidone treatment in patients with advanced IPF and intermediate 
or high probability risk of Group 3 PH.   
SECTION 3.1:  DESCRIPTION OF THE STUDY 
This is a Phase IIb, randomized, placebo-controlled, multicenter, international study of 
the efficacy, safety, and tolerability of combination treatment with sildenafil and 
pirfenidone in patients with advanced IPF and intermediate or high probability risk of 
Group 3 PH, who have been on pirfenidone in a dose range of 1602 to 2403 mg/day with 
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demonstrated tolerability.  For the purposes of this study patients with advanced IPF and 
intermediate or high probability risk of Group 3 PH have to present with: 
• 
advanced IPF as defined by a measurable DLCO ≤40% of predicted value at 
Screening;  
AND 
• 
intermediate or high probability risk of Group 3 PH as defined by 
o mean pulmonary artery pressure (mPAP) ≥20 mmHg together with 
pulmonary artery wedge pressure (PAWP) ≤15 mmHg on a previous right 
heart catheterization (RHC) of acceptable quality 
 
 
OR 
o In the absence of a previous RHC, patients with ECHO showing 
intermediate or high probability of Group 3 PH at screening, as defined by 
the 2015 European Society of Cardiology/European Respiratory Society 
(ESC/ERS) (Peak tricuspid regurgitation velocity [TRV] ≥2.9 m/s), will be 
considered eligible for the study, assuming that they meet all other 
eligibility criteria (Galie et al. 2015) 
In summary, the study consists of 5 phases: 
• 
Run-in period of 12 weeks (if needed) 
• 
Screening period 
o +/- 28-day washout period (if needed); this can be part of the Run-in period if 
the Run-in period is applicable 
o Screening period (up to 28 days). Patients will be evaluated for eligibility 
based on the inclusion and exclusion criteria 
 
• 
Double-blind treatment period (52 weeks) 
• 
Follow-up period (4 weeks)  
• 
In addition, the sponsor will offer the possibility to the patients to receive 
pirfenidone within the study protocol after the Follow-up visit at week 56 visit for 
up to 121 months safety follow-up.  During this time, the patients should be 
evaluated by the treating physician approximately every three months. 
 
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Approximately 176 patients will be enrolled at approximately 75 study centers in Canada, 
Europe (EU) and Eastern Europe, Middle East, and Africa (EEMEA), and potentially 
Asia-Pacific.  No replacements will be made. 
In addition, the sponsor will offer the possibility to the patients to receive pirfenidone 
within the study protocol after the Follow-up visit at week 56 for up to 11 months safety 
follow-up.  During this time, the patients should be evaluated by the treating physician 
approximately every three months. 
SECTION 3.2:  END OF STUDY AND LENGTH OF STUDY 
The study ends when all patients complete the overall 12 months safety follow-up 
described below, i.e., 4 weeks follow-up after end of treatment at week 52 plus additional 
11 months safety follow-up after the Follow-up visit at week 56. 
In addition, the sponsor will offer the possibility to the patients to receive pirfenidone 
within the study protocol after the Follow-up visit at week 56 visit for up to 121 months 
safety follow-up.  During this time, the patients should be evaluated by the treating 
physician approximately every three months.  
SECTION 3.3.2:  RATIONALE FOR PATIENT POPULATION 
In this study, patients with advanced IPF and intermediate or high probability risk of 
Group 3 PH, will be studied.  Overall, there is no robust information regarding the 
efficacy, tolerability and safety of the combination of sildenafil and pirfenidone in patients 
with IPF and there are currently no approved therapies for PH secondary to lung disease 
(Group 3 PH), including PH secondary to IPF.   
SECTION 3.3.5:  RATIONALE FOR BIOMARKER ASSESSMENTS 
Certain biomarkers may be differentially expressed in patients with advanced IPF and 
intermediate or high probability risk of Group 3 PH on pirfenidone treatment (e.g., 
possibly cytokines, chemokines and other cellular and molecular markers of lung injury 
and fibrosis).   
SECTION 4.1:  PATIENTS 
Approximately 176 patients with advanced IPF and intermediate or high probability risk 
of Group 3 PH, who have been on pirfenidone in a dose range of 1602 to 2403 mg/day 
with demonstrated tolerability will be enrolled in this study. 
Key inclusion criteria for the study are presented in Figure 2 and the eligibility criterion 
for intermediate or high probability risk of Group 3 PH (Decision Tree) is further detailed 
in Figure 3. 
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8/Protocol MA29957, Version 2 
SECTION 4.1.1:  INCLUSION CRITERIA 
6. For the purposes of this study patients have to present with:  
• 
advanced IPF is defined as a measurable DLCO ≤40% of predicted value 
at Screening;  
 
AND 
• 
intermediate or high probability risk of Group 3 PH, as defined by: 
o mPAP ≥20 mmHg together with PAWP ≤15 mmHg on a previous RHC of 
acceptable quality. 
      OR 
o In the absence of a previous RHC, patients with ECHO showing 
intermediate or high probability of Group 3 PH at screening, as defined by 
the 2015 ESC/ERS (peak TRV) ≥2.9 m/s), will be considered eligible for 
the study, assuming that they meet all other eligibility criteria (Galie et al 
2015). 
 
SECTION 4.1.2:  EXCLUSION CRITERIA 
17. 
Use of any of the following therapies within 28 days prior to Screening: 
o Use of any medications specifically prescribed for the treatment of PH 
(other than study drug) after the Washout Period and throughout the study, 
including but not limited to endothelin receptor antagonists, prostaglandins, 
guanylate cyclase inhibitors stimulators such as such as riociguat (see 
Section 4.5 of the Sildenafil SPC [Section 1.2.2]) and other 
phosphodiesterase inhibitors 
 
Additional Exclusion Criteria Based on Sildenafil Reference Safety Information 
6. 
Recent history of stroke or myocardial infarction, 
7. 
Severe hypotension (BP <90/50 mmHg)  
8.7. Known hereditary degenerative retinal disorders such as retinitis pigmentosa  
9.8. Patients with anatomical deformation of the penis (such as angulation, cavernosal 
fibrosis or Peyronie's disease), or in patients who have conditions which may predispose 
them to priapism (such as sickle cell anemia, multiple myeloma or leukemia) 
10. Use of an alpha blocker 
11.9. 
Patients with bleeding disorders or active peptic ulceration. 
12.10. 
Patients with rare hereditary problems of galactose intolerance, the Lapp 
lactase deficiency or glucose-galactose malabsorption 
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9/Protocol MA29957, Version 2 
SECTION 4.4.2:  PROHIBITED THERAPY 
• 
Use of any medications specifically prescribed for the treatment of pulmonary 
hypertension (other than study drug) after the Washout Period and throughout 
the study, including but not limited to endothelin receptor antagonists, 
prostaglandins, guanylate cyclase inhibitors stimulators such as such as riociguat 
and other phosphodiesterase inhibitors 
SECTION 4.5.5:  LABORATORY, BIOMARKER, AND OTHER BIOLOGICAL 
SAMPLES 
Blood and urine samples for hematology, biochemistry, biomarkers, urinalysis and 
pregnancy testing will be collected as per the Schedule of Assessments (see Appendix 1) 
and will be analyzed at a central laboratory (exception local laboratory for countries with 
local requirements): 
SECTION 4.5.16:  PATIENT STUDY TREATMENT DISCONTINUATION 
Patients must discontinue study treatment (sildenafil and/or pirfenidone) if they 
experience any of the following (see also Sections 5.1.1 and 5.1.2):  
• 
Inability to tolerate study treatment after efforts have been made to gain 
tolerability  
• 
An elevation in liver test results of the magnitude described below  
• 
Use of a prohibited investigational therapy or concomitant medication  
• 
Sildenafil/placebo will be stopped in any patient with systolic blood pressure 
(SBP) <100 mmHg or diastolic blood pressure (DBP) <50 mmHg; in patients with 
acute coronary syndromes, atrioventricular AV block, life-threatening arrhythmias, 
left ventricular dysfunction (ejection fraction <25%), or clinically significant visual 
changes 
• 
Pregnancy 
• 
Signs or symptoms of angioedema 
• 
Any other treatment-emergent adverse event or toxicity that is unacceptable in 
the opinion of the patient or Investigator  
Sildenafil/placebo will be stopped (temporarily or permanently) in any patient with systolic blood 
pressure (SBP) <100 mmHg or diastolic blood pressure (DBP) <50 mmHg. 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The per protocol (PP) population is defined as all randomized patients who complete the 
52 week treatment period without major protocol violations. 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
10/Protocol MA29957, Version 2 
 
The safety population is defined as all patients randomized, taking at least one dose of 
randomized Sildenafil/Placebo treatment. all treated patients (at least one drug intake of 
pirfenidone or sildenafil).  Patients in the safety population will be assigned to treatment 
groups according to the treatment they received. 
SECTION 6.4.1:  PRIMARY EFFICACY ENDPOINT 
The primary efficacy objective for this study is to evaluate the efficacy of adding sildenafil 
compared with placebo to pirfenidone treatment in patients with advanced IPF and 
intermediate or high probability risk of Group 3 PH. 
The primary analysis will be based on the ITT population, defined as all randomized 
patients.  Patients who discontinue treatment prematurely will be analyzed based on the 
available data.  No imputation method will be applied.  Patients who undergo lung 
transplantation during the study will be withdrawn from the study at the time of 
hospitalization for transplantation.  In addition, sensitivity analysis of the primary endpoint 
will be performed.  The details of those analyses will be provided in the Statistical Analysis Plan. 
As a sensitivity analysis, the analysis will be repeated based on the PP population, 
defined as all randomized patients who will complete the 52 week treatment regimen 
without major protocol violations.  
SECTION 10:  REFERENCES 
F. Hoffmann La Roche Ltd. Investigator’s Brochure RO220912 Esbriet (pirfenidone) 
Eleventh version, July 2016 current version and associated addendums. 
FIGURE 1:  Study Schema  
Footnote Text: ** After the completion of the treatment period (Visit 10) and 4 weeks 
safety follow-up, the possibility will be offered to the patients to receive pirfenidone within 
the study protocol up to 121 months safety follow-up. 
FIGURE 2:  Key Inclusion Criteria for the Study 
Figure has been revised to reflect the change in terminology. 
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11/Protocol MA29957, Version 2 
 
 
FIGURE 3:  Eligibility Criterion for Intermediate and High Risk of Group 3 
PH (Decision Tree) 
Title of the figure has been updated to reflect the change in terminology 
Appendix 1: Schedule of Assessments 
The schedule of assessments has been revised to reflect the changes to the protocol. 
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12/Protocol MA29957, Version 2 
Appendix 1  
Schedule of Assessments 
Day 
Week 
Washouta 
Screeningb 
Double blind treatment phase 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up (FU) 
Additional 
safety FUi 
up to 121 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Informed 
Consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
and Baseline 
Conditions 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain and 
Review 
Historical 
PFTs, HRCT*, 
Surgical Lung 
Biopsy, and 
RHC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Excl-
usion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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13/Protocol MA29957, Version 2 
Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up 
Additional 
safety FU i, 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Approx. 
every 
3 months 
Spirometry 
post broncho-
dilator (FVC, 
FEV1, FEV1/ 
FVC) d 
 
X 
X d1 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
DLCO e 
 
X 
X e1 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
6MWT and 
SpO2 (resting, 
nadir, and end 
of test) f 
 
X 
Xf 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Borg scale 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
WHO 
Functional 
Class 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NT-proBNP, 
CRP, 
aldosterone 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Urinalysis 
 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Urine 
Pregnancy 
Test g 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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14/Protocol MA29957, Version 2 
Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up  
Additional 
safety FU i, 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Serum 
Pregnancy 
Test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
ECHO 
 
X h 
X h1 
 
 
 
 
X 
 
 
 
X 
X 
 
 
SGRQ 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
UCSD SOBQ 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Serum and 
plasma for 
optional 
biomarker 
assessment 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
PAXgene for 
optional 
biomarker 
assessment 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
optional DNA 
biomarker 
assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
15/Protocol MA29957, Version 2 
Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up 
Additional 
safety FU i,  
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Review Dosing 
Adherence 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review Patient 
Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense/ 
Collect Patient 
Diary 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Dispense 
Wallet Card 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pirfenidone 
treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X j 
Dispense 
Sildenafil/ 
Placebo and 
Explain Dosing 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect Unused 
Sildenafil/ 
Placebo and 
Empty Bottles 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
6MWT  6-minute walk test; DLCO  pulmonary diffusion capacity; ECG  electrocardiogram; ECHO  echocardiography; NT-proBNP  N-terminal 
pro-brain natriuretic peptide; RHC  right-heart catheterization; SGRQ  Saint George's Respiratory Questionnaire; UCSD SOBQ = University of 
California San Diego Shortness of Breath questionnaire; SpO2  oxyhemoglobin saturation. 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
16/Protocol MA29957, Version 2 
______________________________________________________________________________________________ 
* Collect from randomized patients the most recent HRCTs performed prior to entering the study  
a Patients taking prohibited medications at the time of consent must, after consent, discontinue the prohibited medications 28 days prior to the 
start of Screening (Day -57 to -29).  If a prohibited medication must be tapered, tapering will be followed by discontinuation, and the 
discontinuation should last at least 28 days (washout period) before the start of screening.  Patients that do not require Washout proceed directly 
to Screening.  In addition, a run-in period will be provided for countries where patients will not be able to take pirfenidone for 12 weeks due to 
reimbursement issues.  After signing the ICF, the 12-week run-in pirfenidone supply will be provided by the Sponsor.   
b The Screening Period of up to 28 days may comprise one or more visits for the convenience of the patient. 
c  Written informed consent will be obtained prior to any study procedures, either prior to Washout or if not applicable, prior to Screening. 
d  Spirometry will be performed only post-bronchodilator.  Reference equations for spirometric indices will be provided in the Procedure Manual. 
d1 Should Spirometry at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening Spirometry 
can be used as baseline 
e  The reported DLCO will be corrected for the current hemoglobin level, using reference equations. 
e1 Should DLCO at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening DLCO can be 
used as baseline 
f The 6MWT will be performed once at each visit highlighted.  At Baseline, it will be performed twice and the better of the two 6MWD values will be 
reported.  Please refer to the 6MWT Procedure Manual. 
g If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
h  ECHO assessment at screening is not required for eligible patients based on RHC criteria.  
h1 Should the ECHO at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening ECHO can be 
used as baseline  
i The sponsor will offer the possibility to the patients to receive pirfenidone within the study protocol up to a 11 months safety follow-up.  During 
this interval, the patients should be evaluated approximately every three months. 
j During the additional safety FU, data related to the pirfenidone administration will not be collected on the CRF.    
 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
17/Protocol MA29957, Version 2 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 23 
PROTOCOL SYNOPSIS .................................................................................... 24 
1. 
BACKGROUND .......................................................................................... 33 
1.1 
Background on idiopathic pulmonary fibrosis (IPF) 
And Advanced IPF with pulmonary hypertension .................. 33 
1.2 
Background on Test Products ............................................... 33 
1.2.1 
Pirfenidone ............................................................................ 34 
1.2.2 
Sildenafil ................................................................................ 36 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 36 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 38 
3. 
STUDY DESIGN ......................................................................................... 41 
3.1 
Description of the Study......................................................... 41 
3.2 
End of Study and Length of Study ......................................... 44 
3.3 
Rationale for Study Design .................................................... 45 
3.3.1 
Rationale for Pirfenidone and Sildenafil Doses 
and Schedule ........................................................................................... 45 
3.3.2 
Rationale for Patient Population ............................................ 45 
3.3.3 
Rationale for Control Group and Double-Blind 
Design 
 .............................................................................................. 45 
3.3.4 
Rationale for Primary Endpoint Selection .............................. 46 
3.3.5 
Rationale for Biomarker Assessments ................................... 46 
3.3.6 
Rationale for Choice of Stratification Factors ......................... 46 
3.3.7 
Rationale for Interim Analyses ............................................... 46 
4. 
MATERIALS AND METHODS .................................................................... 47 
4.1 
Patients .................................................................................. 47 
4.1.1 
Inclusion Criteria .................................................................... 48 
4.1.2 
Exclusion Criteria ................................................................... 49 
4.2 
Method of Treatment Assignment and Blinding ..................... 53 
4.3 
Study Treatment .................................................................... 53 
4.3.1 
Formulation, Packaging, and Handling .................................. 54 
4.3.1.1 Pirfenidone ........................................................................... 54 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
18/Protocol MA29957, Version 2 
4.3.1.2 Sildenafil ............................................................................... 54 
4.3.1.3 Placebo ................................................................................ 54 
4.3.2 
Dosage, Administration, and Compliance .............................. 54 
4.3.2.1 Pirfenidone ........................................................................... 54 
4.3.2.2 Sildenafil or Placebo ............................................................. 55 
4.3.2.3 Precautionary Measures during Treatment with 
Pirfenidone and/or Sildenafil ............................................................... 55 
4.3.2.3.1 Pirfenidone ................................................................... 55 
4.3.2.3.2 Sildenafil ...................................................................... 55 
4.3.2.4 Missed Doses ....................................................................... 57 
4.3.2.5 Dose Modification or Discontinuation ................................... 57 
4.3.2.6 Restarting Study Treatment ................................................. 57 
4.3.3 
Investigational Medicinal Product Accountability ................... 58 
4.3.4 
Continued access of Pirfenidone ........................................... 58 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 59 
4.4.1 
Permitted Therapy ................................................................. 59 
4.4.2 
Prohibited Therapy ................................................................ 59 
4.4.3 
Prohibited Food ..................................................................... 60 
4.4.4 
Additional Restrictions ........................................................... 60 
4.5 
Study Assessments ............................................................... 60 
4.5.1 
Informed Consent Forms and Screening Log ........................ 61 
4.5.2 
Medical History and Demographic Data ................................ 61 
4.5.3 
Physical Examinations ........................................................... 61 
4.5.4 
Vital Signs .............................................................................. 61 
4.5.5 
Laboratory, Biomarker, and Other Biological 
Samples 
 .............................................................................................. 62 
4.5.6 
WHO Functional Class .......................................................... 63 
4.5.7 
GAP Score and Index for IPF ................................................ 63 
4.5.8 
12-lead Electrocardiograms ................................................... 63 
4.5.9 
6-Minute Walk Test and Oxyhemoglobin 
Saturation  .............................................................................................. 63 
4.5.10 
Transthoracic Doppler ECHO ................................................ 64 
4.5.11 
Spirometry (Post bronchodilator) ........................................... 64 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
19/Protocol MA29957, Version 2 
4.5.12 
Diffusing Capacity for Carbon Monoxide ............................... 64 
4.5.13 
Health Status and Health-Related Quality of Life .................. 64 
4.5.14 
UCSD SOBQ ......................................................................... 64 
4.5.15 
Patient Study Discontinuation ................................................ 65 
4.5.16 
Patient Study Treatment Discontinuation............................... 65 
4.5.17 
Study and Site Discontinuation .............................................. 66 
5. 
ASSESSMENT OF SAFETY ....................................................................... 66 
5.1 
Safety Plan ............................................................................ 66 
5.1.1 
Risks Associated with Pirfenidone ......................................... 67 
5.1.1.1 Impaired Hepatic Function ................................................... 67 
5.1.1.2 Photosensitivity Reaction and Rash ..................................... 67 
5.1.1.3 Gastrointestinal Effects ........................................................ 67 
5.1.1.4 Angioedema ......................................................................... 68 
5.1.1.5 Dizziness .............................................................................. 68 
5.1.1.6 Fatigue ................................................................................. 68 
5.1.1.7 Weight Loss ......................................................................... 68 
5.1.2 
Risks Associated with Sildenafil ............................................ 68 
5.1.2.1 Vasodilatory Action ............................................................... 68 
5.1.2.2 Cardiovascular Risk Factors ................................................ 69 
5.1.2.3 Visual Events ....................................................................... 69 
5.1.2.4 Vitamin K Antagonists .......................................................... 69 
5.1.2.5 Veno and Vaso-occlusive Disease ....................................... 69 
5.1.2.6 Priapism ............................................................................... 69 
5.1.2.7 Alpha Blockers ..................................................................... 70 
5.1.2.8 Bleeding Disorders ............................................................... 70 
5.1.2.9 Galactose intolerance ........................................................... 70 
5.1.2.10 Use of Sildenafil with Bosentan .......................................... 70 
5.1.2.11 Concomitant Use with Other PDE5 Inhibitors ..................... 70 
5.1.3 
Management of Patients Who Experience 
Specific Adverse Events .......................................................................... 70 
5.2 
Safety Parameters and Definitions ........................................ 70 
5.2.1 
Adverse Events ..................................................................... 71 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
20/Protocol MA29957, Version 2 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ........................................................................................ 71 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................................... 72 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 72 
5.3.1 
Adverse Event Reporting Period ........................................... 73 
5.3.2 
Eliciting Adverse Event Information ....................................... 73 
5.3.3 
Assessment of Severity of Adverse Events ........................... 73 
5.3.4 
Assessment of Causality of Adverse Events ......................... 74 
5.3.5 
Procedures for Recording Adverse Events ............................ 75 
5.3.5.1 Diagnosis versus Signs and Symptoms ............................... 75 
5.3.5.2 Adverse Events That Are Secondary to Other 
Events 75 
5.3.5.3 Persistent or Recurrent Adverse Events .............................. 75 
5.3.5.4 Abnormal Laboratory Values ................................................ 76 
5.3.5.5 Abnormal Vital Sign Values .................................................. 77 
5.3.5.6 Abnormal Liver Function Tests ............................................. 77 
5.3.5.7 Deaths .................................................................................. 77 
5.3.5.8 Preexisting Medical Conditions ............................................ 78 
5.3.5.9 Lack of Efficacy or Worsening of Advanced IPF 
and PH  ............................................................................................. 78 
5.3.5.10 Hospitalization or Prolonged Hospitalization ...................... 78 
5.3.5.11 Adverse Events Associated with an Overdose 
or Error in Drug Administration ........................................................... 79 
5.3.5.12 Patient-Reported Outcome Data ........................................ 79 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 79 
5.4.1 
Emergency Medical Contacts ................................................ 80 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ....................................... 80 
5.4.2.1 Events That Occur prior to Study Drug Initiation .................. 80 
5.4.2.2 Events That Occur after Study Drug Initiation ...................... 80 
5.4.3 
Reporting Requirements for Pregnancies .............................. 81 
5.4.3.1 Pregnancies in Female Patients ........................................... 81 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
21/Protocol MA29957, Version 2 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients  ............................................................................................. 81 
5.4.3.3 Abortions .............................................................................. 82 
5.4.3.4 Congenital Anomalies/Birth Defects ..................................... 82 
5.5 
Follow-Up of Patients after Adverse Events .......................... 82 
5.5.1 
Investigator Follow-Up ........................................................... 82 
5.5.2 
Sponsor Follow-Up ................................................................ 82 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 82 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 83 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 83 
6.1 
Determination of Sample Size ............................................... 83 
6.2 
Summaries of Conduct of Study ............................................ 84 
6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 84 
6.4 
Efficacy Analyses .................................................................. 84 
6.4.1 
Primary Efficacy Endpoint ...................................................... 84 
6.4.2 
Secondary Efficacy Endpoints ............................................... 85 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 86 
6.5 
Safety Analyses ..................................................................... 86 
6.6 
Interim Analysis ..................................................................... 87 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 87 
7.1 
Data Quality Assurance ......................................................... 87 
7.2 
Electronic Case Report Forms ............................................... 88 
7.3 
Source Data Documentation .................................................. 88 
7.4 
Use of Computerized Systems .............................................. 88 
7.5 
Retention of Records ............................................................. 89 
8. 
ETHICAL CONSIDERATIONS .................................................................... 89 
8.1 
Compliance with Laws and Regulations ................................ 89 
8.2 
Informed Consent .................................................................. 89 
8.3 
Institutional Review Board or Ethics Committee .................... 90 
8.4 
Confidentiality ........................................................................ 91 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
22/Protocol MA29957, Version 2 
8.5 
Financial Disclosure .............................................................. 91 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 91 
9.1 
Study Documentation ............................................................ 91 
9.2 
Protocol Deviations ................................................................ 91 
9.3 
Site Inspections ..................................................................... 91 
9.4 
Administrative Structure......................................................... 92 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 92 
9.6 
Protocol Amendments ........................................................... 93 
10. REFERENCES ........................................................................................... 94 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 40 
Table 2 
Schedule for Pirfenidone Re-titration After an Interruption of 
More Than 14 Consecutive Days ................................................ 57 
Table 3 
Management of Dosing in Patients with Elevated 
Aminotransferase Test Results ................................................... 67 
Table 4 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 74 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 43 
Figure 2 
Key Inclusion Criteria for the Study ............................................. 47 
Figure 3 
Eligibility Criterion for Risk of Group 3 PH (Decision Tree) .......... 48 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Assessments .......................................................... 97 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
23/Protocol MA29957, Version 2 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE IIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF SILDENAFIL ADDED TO 
PIRFENIDONE IN PATIENTS WITH ADVANCED 
IDIOPATHIC PULMONARY FIBROSIS AND RISK 
OF GROUP 3 PULMONARY HYPERTENSION 
PROTOCOL NUMBER: MA29957 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-005131-40 
IND NUMBER: 
67284 
TEST PRODUCTS: 
Pirfenidone (RO0220912) and sildenafil (RO0280296) 
MEDICAL MONITOR: 
 MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol. 
Principal Investigator’s Name (print) 
Principal Investigator’s Signature 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor. 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
24/Protocol MA29957, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IIb, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF SILDENAFIL 
ADDED TO PIRFENIDONE IN PATIENTS WITH ADVANCED 
IDIOPATHIC PULMONARY FIBROSIS AND RISK OF GROUP 3 
PULMONARY HYPERTENSION 
PROTOCOL NUMBER: 
MA29957 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-005131-40 
IND NUMBER: 
67284 
TEST PRODUCT: 
Pirfenidone (RO0220912) and sildenafil (RO0280296) 
PHASE: 
Phase IIb 
INDICATION: 
Idiopathic pulmonary fibrosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and tolerability of sildenafil or placebo added to 
pirfenidone treatment (study treatments) in patients with advanced idiopathic pulmonary fibrosis 
(IPF) and risk of Group 3 pulmonary hypertension (PH) who are on a stable dose of pirfenidone 
with demonstrated tolerability.  Specific objectives and corresponding endpoints for the study 
are outlined below. 
Efficacy Objectives 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of adding sildenafil 
compared with placebo to pirfenidone treatment in patients with advanced IPF and risk of Group 
3 PH.  The primary efficacy endpoint will be evaluated based on a comparison of the proportion 
of patients showing disease progression over 52 weeks of treatment period, as evidenced by 
reaching the following combined endpoint: 
•
Relevant decline in 6-minute walk distance (6MWD) of at least 15% from baseline (as defined
below*), respiratory-related non-elective hospitalization, or all-cause mortality
* Relevant decline in 6MWD from baseline is defined as:
 
Any decline >25% from baseline or 
 
A decline between 15-25% from baseline, if accompanied by at least one of the 
following: 
o
worsening of oxyhemoglobin (SpO2) desaturation during the 6-minute
walk test (6MWT) compared to baseline
o
worsening of the maximum Borg scale during the 6MWT compared to
baseline
o
Increased O2 requirements during the 6MWT compared to baseline
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
25/Protocol MA29957, Version 2 
Secondary Efficacy Objectives (Full details are given in Protocol Section 6.4.2) 
The secondary efficacy objective for this study is to evaluate the efficacy of adding sildenafil 
compared with placebo to pirfenidone treatment on the basis of the following endpoints: 
•
Progression-free survival (PFS), defined as the time to decline in 6MWD of ≥15% compared
with baseline as defined above, respiratory-related non-elective hospitalization, or death
from any cause
•
Proportion of patients with decline in 6MWD of ≥15% from baseline as defined above
•
Time to respiratory-related non-elective hospitalization
•
Time to death from any cause
•
Lung transplantation
•
Time to all-cause non-elective hospitalization
•
Time to respiratory-related death
•
Change from baseline in transthoracic echocardiography (ECHO) parameters
•
Change from baseline in pulmonary function tests (PFTs)
•
Change from baseline in oxyhemoglobin saturation (SpO2) at rest and during the 6-minute
walk test (6MWT)
•
World Health Organization (WHO) Functional Class
•
Dyspnea (assessed by the University of California San Diego Shortness of Breath
Questionnaire – UCSD SOBQ)
•
Health-related quality of life (HRQoL) (assessed by the Saint George’s Respiratory
Questionnaire [SGRQ])
•
N-terminal pro-brain natriuretic peptide (NT-proBNP) level
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of adding sildenafil compared with 
placebo to pirfenidone treatment on the basis of the following endpoints: 
•
Nature, frequency, severity, relationship and timing of treatment-emergent adverse events
•
Changes in vital signs
•
Findings on physical examination
•
Clinical laboratory test results
•
12-lead electrocardiograms (ECGs)
•
Study discontinuation or study drug discontinuation
Study Design 
Description of Study 
This is a Phase IIb, randomized, placebo-controlled, multicenter, international study of the 
efficacy, safety, and tolerability of combination treatment with sildenafil and pirfenidone in 
patients with advanced IPF and risk of Group 3 PH who are on pirfenidone in a dose range of 
1602 to 2403 mg/day with demonstrated tolerability.  For the purposes of this study, patients 
have to present with: 
•
advanced IPF as defined by a measurable pulmonary diffusing capacity (carbon monoxide
diffusing capacity [DLCO]) ≤40% of predicted value at Screening;
AND 
•
risk of Group 3 PH as defined by
o
mean pulmonary artery pressure (mPAP) ≥20 mmHg together with pulmonary artery
wedge pressure (PAWP) ≤15 mmHg on a previous right heart catheterization (RHC) of
acceptable quality
OR
o
in the absence of a previous RHC, patients with ECHO showing intermediate or high
probability of Group 3 PH at screening, as defined by the 2015 European Society of
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
26/Protocol MA29957, Version 2 
Cardiology/European Respiratory Society (ESC/ERS) (Peak tricuspid regurgitation 
velocity [TRV] ≥ 2.9 m/s), will be considered eligible for the study, assuming that they 
meet all other eligibility criteria (Galie et al. 2015) 
Number of Patients 
Approximately 176 patients will be enrolled at approximately 75 study centers in Canada, 
Europe (EU) and Eastern Europe, Middle East, and Africa (EEMEA), and potentially Asia-Pacific. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Ability to comply with the study protocol in the opinion of the Investigator 
• 
Age 40-80 years (inclusive) at Screening 
• 
Diagnosis of IPF for at least 3 months prior to screening  
• 
Confirmation of IPF diagnosis by the Investigator, in accordance with the 2011 international 
consensus guidelines (Raghu et al. 2011), at Screening 
• 
Advanced IPF as defined by a measurable DLCO ≤40% of predicted value at Screening 
and risk of Group 3 PH (as previously defined in Study Design)  
• 
Prior to the start of Screening, receiving pirfenidone for at least 12 weeks, and on a dose in 
the range of 1602 to 2403 mg/day for at least 4 weeks prior to the first Screening Visit.  
During this 4-week period, patients must not have experienced either a new or ongoing 
adverse event of the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) (version 4.03) Grade 2 or higher and considered by the Investigator to 
be related to pirfenidone, or an interruption of pirfenidone treatment of >7 days for any 
reason.  It is expected that the dose of pirfenidone will be in the range of 1602 to 
2403 mg/day throughout the study (in countries where patients will not be able to take 
pirfenidone for 12 weeks due to reimbursement issues, this 12-week run-in supply will be 
provided by the Sponsor). 
• 
WHO Functional Class II or III (Rubin 2004) at Screening 
• 
6MWD of 100 to 450 meters at Screening 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a non-hormonal contraceptive method with a failure rate of 
<1% per year during the Treatment Period and for at least 58 days after the last dose of 
study treatment. 
o 
A woman is considered to be of childbearing potential if she is post-menarcheal, has not 
reached a post-menopausal state (≥12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
o 
Examples of non-hormonal contraceptive methods with a failure rate of <1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
o 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
• 
For men who are not surgically sterile:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating sperm, as defined below: 
o 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
<1% per year during the Treatment Period and for at least 118 days after the last dose 
of study treatment.  Men must refrain from donating sperm during this same period. 
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o 
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for at least 118 days after the last dose of study drug or study 
treatment to avoid exposing the embryo 
Main Exclusion Criteria (Full details are given in Protocol Section 4.1.2) 
Patients who meet any of the following Exclusion Criteria or additional Exclusion Criteria listed 
in the study Protocol will be excluded from study entry: 
• 
History of any of the following types of PH:  Group 1 (pulmonary arterial hypertension 
[PAH]); Group 1 (pulmonary veno-occlusive disease and/or pulmonary capillary 
hemangiomatosis); Group 2 (left-heart disease); Group 3 (due to conditions other than 
interstitial lung disease, including chronic obstructive pulmonary disease [COPD], sleep-
disordered breathing, alveolar hypoventilation, high altitude, or developmental 
abnormalities); Group 4 (chronic thromboembolic pulmonary hypertension); Group 5 (other 
disorders) (Simonneau et al. 2013) 
• 
History of clinically significant cardiac disease in the opinion of the Investigator, including, 
but not limited to:  left ventricular ejection fraction <40%, congestive heart failure Class IV 
New York Heart Association (NYHA), left ventricular outflow obstruction (aortic stenosis, 
idiopathic hypertrophic subaortic stenosis), symptomatic coronary artery disease, 
congestive heart failure requiring hospitalization, second- or third-degree atrioventricular 
block, uncontrolled or clinically significant arrhythmias; uncontrolled systemic hypertension 
• 
History of coexistent and clinically significant (in the opinion of the Investigator) COPD 
(including chronic bronchitis, emphysema), bronchiectasis, asthma, inadequately treated 
sleep-disordered breathing, or any clinically significant pulmonary diseases or disorders 
other than IPF or PH secondary to IPF 
• 
Hypotension (blood pressure [BP] <100 mmHg systolic or <50 mmHg diastolic), autonomic 
dysfunction, or conditions in which vasodilation may cause an unsafe drop in BP 
• 
History of use of drugs and toxins known to cause PAH, including aminorex, fenfluramine, 
dexenfluramine, and amphetamines. (For a full list see Galie et al, 2015) 
• 
Initiating any new cardiac or pulmonary rehabilitation program within 28 days prior to 
Screening and throughout the study 
• 
Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio <0.70 post 
bronchodilator at Screening 
• 
Any impairment other than dyspnea that limits the patient’s ability to walk for at least 6 
minutes or perform other study procedures 
• 
SpO2 saturation measured by pulse oximetry at rest <92% with ≥6 L of supplemental 
oxygen, at the first Screening Visit 
• 
Significant clinical worsening of IPF between the first Screening Visit and Day 1, in the 
opinion of the Investigator 
• 
Any serious medical condition, clinically significant abnormality on ECG at Screening or 
laboratory tests (hematology, serum chemistry, and urinalysis) that, in the opinion of the 
Investigator, may pose an additional risk in administering study treatment to the patient 
• 
Clinical evidence of any active infection which according to the judgment of the Investigator 
may interfere with study conduct, measurement of pulmonary function, or impact the course 
of IPF 
• 
Certain laboratory abnormalities or findings at Screening, including: 
o 
Total bilirubin above the upper limit of normal (ULN) 
o 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × ULN 
o 
Alkaline phosphatase >2.0 × ULN 
o 
Creatinine clearance <30 mL/min, calculated using the Cockcroft-Gault formula 
• 
Pregnant or lactating, or intending to become pregnant during the study 
• 
Extent of emphysema greater than the extent of fibrotic changes (honeycombing and 
reticular changes) on any previous HRCT scan, in the opinion of the Investigator 
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• 
Poorly controlled systemic hypertension (>180 mmHg systolic or >100 mmHg diastolic) 
• 
Use of any of the following therapies within 28 days prior to Screening: 
o 
Investigational therapy, defined as any drug that has not been approved for marketing 
for any indication in the country of the participating site 
o 
Any cytotoxic, immunosuppressive, cytokine modulating, or receptor antagonist agent 
including but not limited to azathioprine, bosentan, ambricentan, macitentan, 
cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene 
antagonists, methotrexate, mycophenolate mofetil, tacrolimus, montelukast, 
tetrathiomolybdate, corticosteroids (>15 mg/day prednisolone or equivalent more than 
28 days), TNF-α inhibitors, imatinib mesylate, and interferon gamma-1b 
o 
Any medications that are specifically used for the treatment of IPF (other than the study 
drug) including those listed above.  N-acetylcysteine (NAC) is acceptable, provided that 
the dose has been stable for 28 days prior to Screening and remains unchanged 
throughout the study 
o 
Use of any medications specifically prescribed for the treatment of PH (other than study 
drug) after the Washout Period and throughout the study, including but not limited to 
endothelin receptor antagonists, prostaglandins, guanylate cyclase stimulators such as 
riociguat (see Section 4.5 of the Sildenafil SPC [Section 1.2.2]) and other 
phosphodiesterase inhibitors 
• 
Vasoactive medications including calcium channel blockers, diuretics, and vasodilators may 
not be added within 28 days prior to screening, and the dose of these medications must be 
held constant as much as possible within 7 days of Screening and throughout the study 
End of Study 
The end of the clinical trial is defined as the date when the last patient completes the last visit 
(LPLV) or the date at which the last data point which is required for the statistical analysis is 
received, whichever is the later date.  LPLV for the primary analysis is expected to occur 
approximately 56 weeks after the last randomized patient begins the Treatment Period. 
The study ends when all patients complete the overall 12 months safety follow up described 
below, i.e., 4 weeks follow-up after end of treatment at week 52 plus additional 11 months safety follow-
up after the Follow-up visit at week 56.  
Length of Study 
For each patient the total length of the study is expected to be up to a maximum of 
approximately 64 weeks, including the Washout Period of 4 weeks, the Screening Period of up 
to 4 weeks, the Treatment Period of 52 weeks, and the Follow-up Period of 4 weeks.   
In addition, the sponsor will offer the possibility to the patients to receive pirfenidone within the 
study protocol after the Follow-up visit at week 56 for up to 11 months safety follow-up. During 
this time, the patients should be evaluated by the treating physician approximately every three 
months. 
Investigational Medicinal Products 
Test Products (Investigational Drugs) 
The test products for this study are pirfenidone and sildenafil. 
Pirfenidone (5-methyl-1-phenyl-2-1(H)-pyridone) will be administered orally three times per day 
(TID) with meals, in a range of 1602 to 2403 mg/day.  Each pirfenidone capsule contains 
267 mg of pirfenidone.  Pirfenidone (Esbriet®) will be supplied by the Sponsor as white, hard 
gelatin capsules printed with “267 mg” in brown ink. 
Sildenafil 20 mg will be administered orally TID, about 4 to 6 h apart.  Sildenafil will be supplied 
by the Sponsor as white, round, biconvex film-coated, tablets.  Sildenafil tablets will by 
encapsulated by a compounding pharmacy to be identical in appearance and size to matching 
placebo.   
Comparator 
Placebo will be administered orally TID, about 4 to 6 h apart.  Placebo will be supplied by the 
Sponsor as a capsule with the same appearance and size as the encapsulated sildenafil. 
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Statistical Methods 
Primary Analysis 
The primary efficacy objective for this study is to evaluate the efficacy of adding sildenafil 
compared with placebo to pirfenidone treatment on disease progression.  The primary endpoint 
will be evaluated based on a comparison of the proportion of patients showing disease 
progression over 52 weeks of treatment period, as evidenced by reaching the following 
combined endpoint:  
• 
Relevant decline in 6MWD of at least 15% from baseline (as defined below*), respiratory-
related non-elective hospitalization, or all-cause mortality 
* Relevant decline in 6MWD from baseline is further specified as: 
 
Any decline >25% from baseline or 
 
A decline between 15-25% from baseline, if accompanied by at least one of the 
following: 
o worsening of SpO2 desaturation during the 6MWT compared to baseline 
o worsening of the maximum Borg scale during the 6MWT compared to 
baseline  
o increased O2 requirements during the 6MWT compared to baseline. 
The primary analysis will be based on the Intent-to-treat (ITT) population, defined as all 
randomized patients.  Patients who discontinue treatment prematurely will be analyzed based 
on the available data.  No imputation method will be applied.  Patients who undergo lung 
transplantation during the study will be withdrawn from the study at the time of hospitalization 
for transplantation.  In addition, sensitivity analysis of the primary endpoint will be performed.  The 
details of those sensitivity analyses will be provided in the Statistical Analysis Plan. The primary 
analysis of the primary endpoint will compare disease progression rates in each treatment arm 
using a Chi-square test with a one-sided significance level α = 0.05. 
Determination of Sample Size  
There are no reference data available on the use of pirfenidone in this patient population with a 
measurable DLCO ≤40% of predicated value and mPAP ≥20 mmHg on RHC.  A total sample 
size of approximately 176 patients is planned, and patients will be randomized 1:1 to the two 
treatment groups.  The statistical hypothesis for the treatment comparison is based on the 
proportion of patients who experienced a ≥15% decline from baseline in 6MWD, were 
hospitalized for cardiac- or respiratory non-elective reasons, or who died, according to a pooled 
analysis of the effects observed in the pirfenidone groups of three large Phase III trials 
(CAPACITY 1, CAPACITY 2, and ASCEND). 
The planned sample size is based on the primary endpoint, proportion of patients with disease 
progression, and assumes 80% power and a one-sided significance level of 5%.  Given the 
disease progression rate of 72% by 52 weeks in the three large registration trials for pirfenidone, 
and assuming an additive effect of sildenafil on pirfenidone, a disease progression rate of 54% 
in the combination treatment group is assumed and an absolute difference of 18% (respectively 
a relative reduction of 25%) in disease progression rates is considered a clinically meaningful 
treatment benefit. 
Interim Analyses 
There are no planned interim efficacy analyses for this study.  Safety interim analyses will be 
performed regularly by an independent Data Monitoring Committee (iDMC).  Efficacy data will 
only be provided if requested by the iDMC.  Further details on the function and logistics (e.g. 
frequency of the meetings) of the iDMC will be provided in the iDMC Charter. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ALAT 
Latin American Thoracic Society 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC0-∞ 
area under the concentration-time curve from time zero 
to infinity 
AV 
atrioventricular 
BID 
twice daily 
BP 
blood pressure 
BUN 
blood urea nitrogen 
cGMP 
cyclic guanosine monophosphate 
CI 
confidence interval 
Cmax 
maximum concentration 
COPD 
chronic obstructive pulmonary disease 
CRP 
C-reactive protein 
CYP 
cytochrome 
DBP 
diastolic blood pressure 
DLCO 
carbon monoxide diffusing capacity/ pulmonary 
diffusing capacity 
DNA 
deoxyribonucleic acid 
EC 
ethics committee 
ECG 
electrocardiogram 
ECHO 
echocardiography 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EEMEA 
Eastern Europe, Middle East, and Africa 
ERS 
European Respiratory Society 
ESC 
European Society of Cardiology 
EU 
European Union 
ERK1/2 
extracellular regulated kinases 1 and 2 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GAP 
gender, age and physiology 
GCP 
Good Clinical Practice  
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GGT 
gamma-glutamyl-transferase 
GWAS 
genome-wide association study 
HR 
hazard ratio 
HRCT 
high-resolution computed tomography 
HRQoL 
health related quality of life 
5-HT 
serotonin 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IL 
Interleukin  
IMP 
investigational medicinal product 
IND 
Investigational New Drug  
IPF 
idiopathic pulmonary fibrosis 
IRB 
independent review board 
ITT 
intent-to-treat  
IxRS 
interactive voice or web-based response system 
JRS 
Japanese Respiratory Society 
LDH 
lactate dehydrogenase 
LPLV 
last patient last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPAP 
mean pulmonary artery pressure 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
NAC 
N-acetylcysteine 
NAION 
nonarteritic ischemic optic neuropathy 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary artery pressure 
PAWP 
pulmonary artery wedge pressure 
PDE5 
phosphodiesterase-5 
PDGF 
platelet-derived growth factor 
PFS 
progression-free survival 
PFTs 
pulmonary function tests 
PH 
pulmonary hypertension 
PK 
pharmacokinetics 
PRO 
patient reported outcome 
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PP 
per-protocol 
QD 
Daily 
QTc 
corrected QT interval 
QTcF 
corrected QT interval using Fridericia’s formula  
RBC 
red blood cells 
RHC 
right heart catheterization 
RNA 
ribonucleic acid 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SGRQ 
Saint George’s Respiratory Questionnaire 
SOP 
standard operating procedure 
SPC 
Summary of Product Characteristics 
SPF 
sun protection factor 
SpO2 
oxyhemoglobin saturation 
TGF-β 
transforming growth factor-beta  
TID 
three times daily 
TRV 
tricuspid regurgitation velocity 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
UV-A 
ultraviolet A 
UV-B 
ultraviolet B 
WBC 
white blood cells 
WHO 
World Health Organization 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON IDIOPATHIC PULMONARY FIBROSIS (IPF) 
AND ADVANCED IPF WITH PULMONARY HYPERTENSION 
Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology 
characterized by fibrosis of the lung interstitium, decrease in lung volume and 
progressive pulmonary insufficiency typically leading to death (Lynch and Toews 1998).  
Idiopathic pulmonary fibrosis is a rare disease; recent prevalence estimates range from 
14.0 to 63.0 per 100,000 in the United States (US) and from 1.25 to 23.4 per 100,000 in 
European Union (EU) (Raghu et al. 2006; Fernández Pérez et al. 2010; Nalysnyk et al. 
2012).  IPF is most prevalent in middle-aged and elderly patients, and most studies have 
found a higher frequency in men than in women (Nalysnyk et al. 2012). 
Although the pathogenesis of IPF remains incompletely understood, the current view is 
that a series of microinjuries to the alveolar epithelium results in release of profibrotic 
mediators, causing fibroblast and myofibroblast proliferation, organization into 
fibroblastic foci, and excessive collagen deposition and accumulation (du Bois, 2010). 
The initial clinical presentation of IPF is typically that of slowly progressive dyspnea and 
non-productive cough.  Lung auscultation reveals fine end inspiratory crackles, initially at 
the base of the lung and ultimately diffusely (American Thoracic Society/European 
Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association 
[ATS/ERS/JRS/ALAT 2011]).  In advanced disease, pulmonary hypertension (PH), 
which may lead to right heart failure often develops.  Pulmonary function tests 
demonstrate a restrictive pattern, with a decrease in lung volumes and diffusing capacity 
for carbon monoxide (DLCO), and oxygen desaturation on exertion.  Chest radiographs 
show diffuse interstitial opacities with volume loss, and high-resolution computed 
tomography (HRCT) scans show a characteristic pattern of peripheral (subpleural), 
bibasilar, reticular infiltrates, associated with architectural distortion, honeycomb 
changes and traction bronchiectasis (ATS/ERS/JRS/ALAT 2011).  A diminished quality 
of life in patients with IPF is well established, with impaired energy level and decreased 
level of independence in concert with respiratory symptoms (Swigris et al. 2005; 
Tomioka et al. 2007). 
To date, two approved IPF therapies are available: Esbriet® (pirfenidone) and Ofev® 
(nintedanib); both therapies have shown to significantly slow the progression of lung 
function decline in IPF, although the disease remains incurable.  There are no approved 
therapies available for PH secondary to IPF. 
1.2 
BACKGROUND ON TEST PRODUCTS 
The test products in this Phase IIb trial will be pirfenidone (Esbriet®) and sildenafil 
(generic formulation).  Patients will have advanced IPF and risk of Group 3 PH, which is 
considered to be secondary to IPF, and be on a stable dose of pirfenidone with 
demonstrated tolerability. 
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1.2.1 
Pirfenidone 
Pirfenidone is an orally active, small molecule (molecular weight, 185.2 g/mol) antifibrotic 
agent, with anti-inflammatory properties.  It has been approved for the treatment of IPF 
in the US, and is indicated in adults for the treatment of mild to moderate IPF in the EU 
and Canada.  The recommended daily maintenance dose in patients with IPF is 
2403 mg/day, administered as three 267 mg capsules (801 mg), three times daily (TID) 
with food, at the same times each day (Esbriet® EU Summary of Product Characteristics 
[SPC] and US label, 2014). 
The broad antifibrotic activity of pirfenidone across organ systems has been 
demonstrated in more than 40 animal studies in models of fibrosis, including fibrosis of 
the liver, heart and kidney as well as several models of lung fibrosis (Schaefer et al. 
2011).  In bleomycin-induced pulmonary fibrosis models, pirfenidone reduced visible 
lung pathology, lung tissue hydroxyproline content, edema (wet-to-dry lung weight), and 
histologic score (Oku et al. 2008; PCLN-PIRF-009).  Additionally, pirfenidone 
administration significantly suppressed bleomycin-induced increases in interleukin 
(IL)-1β, IL-6, monocyte chemoattractant protein-1, and IL-12p40 in these models. 
In cell-based systems, pirfenidone suppressed the proliferation of fibroblasts; attenuated 
the production of profibrotic cytokines, including platelet-derived growth factor (PDGF) 
and transforming growth factor-beta (TGF-β) from human macrophage cell lines; 
promoted release of collagenase from fibroblasts; and reduced the accumulation of 
extracellular matrix components, particularly collagen (Hirano et al. 2006; 
PCLN-PIRF-010). 
Taken together, nonclinical studies conducted in vitro, as well as data derived from 
animal models of fibrosis, provide evidence that pirfenidone reduces levels of profibrotic 
growth factors and cytokines, lessens collagen deposition and reduces interstitial fibrosis; 
all physiological elements thought to be dysregulated in IPF. 
Refer to the current version of the pirfenidone Investigator's Brochure for further details 
on nonclinical studies. (Esbriet [pirfenidone]). 
Pirfenidone pharmacokinetics (PK) have been characterized in humans.  After oral 
administration of a single dose of 801 mg (i.e., 1 of the 3 doses taken daily to reach the 
approved 2403 mg/day) in healthy, fed adults, pirfenidone is absorbed relatively slowly, 
with a mean peak plasma concentration of 7.87 μg/mL approximately 3 to 4 h after 
ingestion.  The area under the concentration-time curve from time zero to infinity (AUC0-∞) 
and the maximum concentration (Cmax) of pirfenidone when administered after a meal 
was significantly lower (using Food and Drug Administration [FDA] bioequivalence 
criteria) than when pirfenidone was given while fasting.  A population PK analysis 
indicated that pirfenidone PK in IPF patients are similar to those in healthy subjects. 
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Clinical studies have shown pirfenidone is primarily metabolized by cytochrome (CYP) 
1A2 with contribution from multiple other CYPs.  The most clinically significant factors 
that can influence pirfenidone PK are moderate to severe hepatic impairment (moderate 
liver cirrhosis [Child-Pugh Class B]) and co-administration of moderate to strong 
CYP1A2 inhibitors or inducers (including smoking), detailed at the following website: 
http://www.medicine.iupui.edu/clinpharm/ddis/main-table/ 
Three randomized, double-blind, placebo-controlled Phase 3 studies evaluating 
pirfenidone in patients with IPF have been conducted: Studies PIPF-004 and PIPF-006, 
(CAPACITY) completed in 2008 (Noble et al. 2011) and Study PIPF-016 (ASCEND) 
completed in 2014 (King et al. 2014).  Studies PIPF-004 and PIPF-006 evaluated the 
efficacy and safety of treatment with pirfenidone for a minimum of 72 weeks; the 
PIPF-016 evaluated treatment with pirfenidone for 52 weeks.  A total of 1247 patients 
were included in the pooled Phase 3 analysis (Studies PIPF-004/006/016), of these 
623 were randomized to treatment with pirfenidone (2403 mg/day) and 624 were 
randomized to treatment with placebo (Noble et al. 2015). 
In the pooled Phase 3 analysis (Studies PIPF-004/006/016), there was a clear effect of 
treatment with pirfenidone in reducing the decline in percent predicted forced vital 
capacity (FVC) compared with placebo (the primary endpoint) (p <0.0001, rank analysis 
of covariance [ANCOVA]).  There was a relative reduction of 43.8% in the proportion of 
patients with a decline in percent predicted FVC ≥10% or death from Baseline at 
Month 12 in the pirfenidone group compared with the placebo group, as well as a 59.3% 
relative increase in the proportion with no decline in percent predicted FVC. 
In the pooled Phase 3 analysis, key secondary endpoints showed a beneficial effect of 
pirfenidone on exercise tolerance, represented by a statistically significantly lower 
decline from baseline to Month 12 in the 6MWT in the pirfenidone group compared with 
the placebo group (p = 0.0004).  There was also a 38% relative reduction in the risk of 
disease progression or death at Month 12 in pirfenidone-treated patients compared with 
placebo-treated patients (hazard ratio [HR] 0.62; 95% confidence interval [CI], 
0.51 − 0.75; p <0.0001).  In the mortality analysis, a 48% relative reduction in the risk of 
death from any cause favoring pirfenidone was seen (HR 0.52; 95% CI, 0.31 − 0.87; 
p = 0.0107, log-rank test).  A smaller proportion of pirfenidone-treated patients died 
compared with placebo-treated patients (3.5% vs. 6.7%, respectively). 
Safety outcomes were assessed in the three Phase 3 studies (Studies 
PIPF-004/006/016) and two ongoing open-label studies (002 and 012 [RECAP]), during 
the period from the first dose until 28 days after the last dose of study drug.  A total of 
1299 patients were included in the analysis.  These findings represent a comprehensive 
analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF 
treated with pirfenidone.  During this long-term, prospective follow-up of up to 9.9 years, 
pirfenidone was safe and generally well tolerated.  Gastrointestinal and skin-related 
events were among the most common adverse events (AEs) and were generally 
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mild-to-moderate in severity and responsive to dose modification.  Elevations of 
aminotransferases typically occurred within the first 6 months of treatment and were 
generally transient, reversible with dose modification or discontinuation and without 
clinical sequelae (Lancaster et al. 2016). 
Refer to the current version of the pirfenidone Investigator's Brochure (Esbriet 
[pirfenidone]) for further details on clinical studies. 
1.2.2 
Sildenafil 
Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor.  It has been approved as a 20 mg 
tablet (sildenafil citrate) for the treatment of pulmonary arterial hypertension in most 
countries worldwide, since 2005.  The recommended daily maintenance dose is 20 mg 
TID, taken with or without food. 
The inhibition of PDE5 by sildenafil enhances the vasodilatory effects of nitric oxide in 
PH by preventing the degradation of cyclic guanosine monophosphate (cGMP), which 
promotes relaxation of vascular smooth muscle and increases blood flow.  In animal 
models and human trials, sildenafil has been found to produce a relatively selective 
reduction in pulmonary artery pressure (PAP) without adverse systemic hemodynamic 
effects (Ghofrani et al. 2002).  Inhibition of PDE5 by sildenafil may also enhance the 
platelet antiaggregatory activity of nitric oxide and inhibit thrombus formation. 
Most side effects of sildenafil are mild to moderate and mainly related to vasodilation 
(headache, flushing, epistaxis) (Galie et al. 2015). 
Refer to the SPC for sildenafil for further information at the following websites:  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2582414d-0ef3-403e-84e8-
1d6c812e7eb1 
 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/0006
38/human med 001033.jsp&mid=WC0b01ac058001d124 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The diagnosis of IPF carries a bleak prognosis, with progressive disability due to 
respiratory insufficiency (Hallstrand et al. 2005).  Pulmonary hypertension is a major 
contributor to morbidity and mortality in patients with advanced IPF with an adverse 
impact on survival (Nadrous et al. 2005, Lettieri et al. 2006.).  This study is designed to 
assess the treatment of patients with advanced IPF who have evidence suggesting PH, 
that is most likely caused by IPF. 
While drugs used to treat PH have either not been effective for treatment of IPF 
(bosentan, ambrisentan, macicentan) or are unlikely to be able to address the 
parenchymal changes in the fibrotic process, anti-fibrotic drugs are unlikely to have any 
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notable effect on the perfusion aspects of interstitial lung diseases (ILDs).  Therefore, 
combination treatment appears as a promising approach to the major clinical problem of 
combined IPF and PH (Wuyts et al. 2014). 
In this study, pirfenidone (Esbriet®) administration will be combined with sildenafil.  As 
sildenafil induces vasodilatation preferentially in well-ventilated lung areas, such 
vasodilatation could improve ventilation-perfusion matching and thus gas exchange in 
patients with IPF (Ghofrani et al. 2002).  The combination of pirfenidone and sildenafil 
represents a promising approach to treat patients with advanced IPF and secondary PH. 
The expected benefits of the sildenafil/pirfenidone combination relate to the anticipated 
improvements in both pulmonary hemodynamics and pulmonary function.  A reduction in 
pulmonary vascular resistance by sildenafil would be expected to improve mean 
pulmonary artery pressure (mPAP), reducing strain on the right ventricle and improving 
cardiac output, assuming that left ventricular function and systemic vascular resistance 
are not adversely affected.  Secondary benefits, such as reduced risk of right heart 
failure, cardiac arrhythmias, cardiac-related hospitalizations, and cardiac-related death 
might also ensue.  Improvement in ventilation/perfusion matching by sildenafil would be 
expected to improve gas transfer in the lung.  An increase in oxyhemoglobin saturation, 
along with an improvement in cardiac output, would be expected to have a beneficial 
effect on functional exercise capacity.  These possible benefits of sildenafil, together with 
the known benefits of pirfenidone in slowing the rate of decline in lung function, might 
have a benefit on reducing respiratory decompensation and related hospitalizations.  
Milara at al. (2016) analyzed the role of sildenafil on vasoconstriction and remodeling of 
pulmonary arteries from patients with IPF and PH.  Ex vivo pulmonary arteries from 
18 donors without lung disease, nine IPF, eight PH+IPF and four PH patients were 
isolated to measure vasodilator and anti-contractile effects of sildenafil in an isometric 
organ bath.  Ventilation/perfusion was explored in an animal model of bleomycin lung 
fibrosis.  Sildenafil relaxed serotonin (5-HT) pre-contracted pulmonary arteries in healthy 
donors and IPF patients and, to a lesser extent, in patients with PH plus IPF, and PH.  
Sildenafil inhibited 5-HT dose-response contraction curve mainly in patients with PH and 
IPF, and PH, but not in healthy donors.  Sildenafil did not impair the ventilation/perfusion 
mismatching induced by bleomycin.  Pulmonary arteries from patients with PH plus IPF 
showed a marked expression of phosphodiesterse-5 and extracellular matrix 
components.  Sildenafil inhibited pulmonary artery endothelial and smooth muscle cell to 
mesenchymal transition by inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) 
and SMAD3 phosphorylation.  These results suggest an absence of direct relaxant effect 
and a prominent anti-contractile and anti-remodeling role of sildenafil in PH plus IPF 
pulmonary arteries that could explain the beneficial effects of sildenafil in IPF patients 
with PH phenotype.  A novelty and strength of this analysis relates to the direct study of 
sildenafil on contractile properties of pulmonary arteries obtained from patients with IPF 
with or without PH, and on markers of proliferation and mesenchymal cell transition.  The 
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originality of the study is further strengthened by the finding of increased PDE5 
expression in pulmonary arteries from patients with IPF with and without PH.  It appears, 
that sildenafil has pleiotropic properties beyond its traditional vasodilatory effects that 
may render it especially attractive as an add-on treatment for IPF (Hassoun and Nathan 
2016). 
Previous clinical trials of sildenafil in IPF patients with PH have generally shown 
inconclusive results (Ghofrani et al. 2002, Collard et al. 2007, Jackson et al. 2010, 
IPFnet, 2010 [STEP-IPF]).  This experience may be a consequence of several factors, 
including small sample size, short observation periods, imprecise definition of study 
populations, or selection of the primary endpoint.  In the STEP-IPF randomized 
controlled trial, the effects of sildenafil were studied in a population of 180 patients with 
advanced IPF, defined as DLCO <35% of the predicted value.  Although this study failed 
to meet its primary endpoint of ≥20% improvement in 6MWD, a number of secondary 
endpoints achieved statistical significance, including DLCO, dyspnea, oxygen saturation, 
and quality of life.  Furthermore, in a subset of this population (119 patients) with 
echocardiograms available for post-hoc review, patients with right ventricular systolic 
dysfunction treated with sildenafil experienced a 99-meter lesser decline in 6MWD and 
improved quality of life compared with those who received placebo. (Han et al. 2013). 
Recently, a study assessing the efficacy and safety of riociguat in patients with 
symptomatic PH associated with idiopathic interstitial pneumonias (IIP) (RISE-IIP) has 
been prematurely terminated (clinicaltrials.gov: NCT02138825) after the independent 
Data Monitoring Committee (iDMC) observed that patients receiving riociguat were at a 
possible increased risk for death and other serious adverse events (SAEs) compared 
with those receiving placebo. 
In study MA29957, patients with advanced IPF and risk of Group 3 PH will be included.  
To address potential concerns regarding the RISE-IIP premature termination, but most 
importantly to minimize any potential risk in the study patient population in MA29957, a 
safety plan has been put in place for this study.  The safety plan includes: appropriate 
eligibility criteria, dose modification and/or discontinuation guidelines for each identified 
and potential risk (see Section 5.1), collecting from randomized patients the most recent 
HRCTs performed prior to entering the study, monitoring of patients at risk as well as the 
regular monitoring of patient data by an iDMC.  Moreover, the long-standing experience 
available with sildenafil should also be considered. 
The Sponsor believes that the benefit-risk comparison for patients participating in this 
study of pirfenidone with sildenafil is positive. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety and tolerability of sildenafil compared to 
placebo added to pirfenidone treatment in patients with advanced IPF and risk of 
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Group 3 PH.  The primary efficacy endpoint will be evaluated based on a comparison of 
the proportion of patients showing disease progression over 52 weeks of treatment 
period, as evidenced by reaching the following combined endpoint: 
• 
Relevant decline in 6MWD of at least 15% from baseline (as defined below*), 
respiratory-related non-elective hospitalization, or all-cause mortality 
* Relevant decline in 6MWD from baseline is defined as: 
 
Any decline >25% from baseline or 
 
A decline between 15-25% from baseline, if accompanied by at least one of 
the following: 
o worsening of SpO2 desaturation during the 6MWT compared to 
baseline 
o worsening of the maximum Borg scale during the 6MWT compared to 
baseline  
o increased O2 requirements during the 6MWT compared to baseline. 
Specific objectives and corresponding endpoints for the study are outlined in Table 1.  
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase IIb, randomized, placebo-controlled, multicenter, international study of 
the efficacy, safety, and tolerability of combination treatment with sildenafil and 
pirfenidone in patients with advanced IPF and risk of Group 3 PH, who have been on 
pirfenidone in a dose range of 1602 to 2403 mg/day with demonstrated tolerability.  For 
the purposes of this study patients with advanced IPF and risk of Group 3 PH have to 
present with: 
• 
advanced IPF as defined by a measurable DLCO ≤40% of predicted value at 
Screening;  
AND 
• 
risk of Group 3 PH as defined by  
o mean pulmonary artery pressure (mPAP) ≥20 mmHg together with 
pulmonary artery wedge pressure (PAWP) ≤15 mmHg on a previous right 
heart catheterization (RHC) of acceptable quality 
 
 
OR 
o In the absence of a previous RHC, patients with ECHO showing 
intermediate or high probability of Group 3 PH at screening, as defined by 
the 2015 European Society of Cardiology/European Respiratory Society 
(ESC/ERS) (Peak tricuspid regurgitation velocity [TRV] ≥2.9 m/s), will be 
considered eligible for the study, assuming that they meet all other 
eligibility criteria (Galie et al. 2015) 
After discussing the risks and benefits of the study with the Investigator and providing 
written informed consent, patients will be provided pirfenidone for the study by the 
Sponsor and will be instructed on proper use.  Patients will be instructed to stop taking 
their commercial pirfenidone and start taking the study-provided pirfenidone. 
Patients will also be required to discontinue all prohibited medications and undergo a 
28-day Washout Period.  After completing the Washout Period, patients will enter 
Screening, which lasts up to 28 days; during Screening, patients will be evaluated for 
eligibility based on the inclusion and exclusion criteria.  Patients not taking a prohibited 
medication will forgo the Washout Period and directly enter Screening. 
A run-in period will be provided for countries where patients will not be able to take 
pirfenidone for 12 weeks due to reimbursement issues.  After signing the informed 
consent form, the 12-week run-in pirfenidone supply will be provided by the Sponsor.  
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After completing the Washout Period, patients will enter Screening.  Patients not taking a 
prohibited medication will forgo the Washout Period and directly enter Screening. 
In summary, the study consists of 5 phases: 
• 
Run-in period of 12 weeks (if needed) 
• 
Screening period 
o +/- 28-day washout period (if needed); this can be part of the Run-in period if 
the Run-in period is applicable  
o Screening period (up to 28 days).  Patients will be evaluated for eligibility 
based on the inclusion and exclusion criteria 
• 
Double-blind treatment period (52 weeks) 
• 
Follow-up period (4 weeks)  
• 
In addition, the sponsor will offer the possibility to the patients to receive 
pirfenidone within the study protocol after the Follow-up visit at week 56 for up to 
11 months safety follow-up.  During this time, the patients should be evaluated by 
the treating physician approximately every three months. 
At the start of Screening, patients will have been on oral pirfenidone taken TID for at 
least 12 weeks, and the dose will have been in the range of 1602 to 2403 mg/day, for at 
least 4 weeks prior to the first Screening Visit.  It is expected that the dose will remain 
within the range of 1602 to 2403 mg/day throughout the study and in accordance with 
the product label.  In addition, in the 4 weeks prior to the first Screening Visit, patients 
must not have experienced either a new or ongoing adverse event of National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, 
which is Grade 2 or higher and considered, by the Investigator to be related to 
pirfenidone, or have had an interruption of pirfenidone treatment of >7 days for any 
reason. 
During Screening, patients may return for the Baseline visit (Day 1) as soon as eligibility 
has been confirmed.  
Patients who meet all eligibility criteria and who provide written, informed consent will be 
randomized 1:1 to receive 1 year (52 weeks) of treatment with either oral sildenafil 
(20 mg) or matching placebo TID while continuing to take pirfenidone.  Treatment with 
sildenafil should be initiated and monitored by a physician experienced in the treatment 
of PAH. 
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Approximately 176 patients will be enrolled at approximately 75 study centers in 
Canada, Europe (EU) and Eastern Europe, Middle East, and Africa (EEMEA), and 
potentially Asia-Pacific.  No replacements will be made. 
Patients who experience a primary endpoint (a decline in 6MWD as defined per protocol 
or an event of respiratory-related non-elective hospitalization) will continue treatment 
and be encouraged to complete the study.   
The randomization will be stratified by previous RHC availability for inclusion (yes/no) 
and by degree of pulmonary function measured by forced expiratory volume in 1 second 
(FEV1)/FVC ratio below/above 0.8. 
Patients will have a total of up to approximately 12 to 13 clinic visits, including one or 
more visits during the Washout and Screening Periods, up to 10 Treatment Period visits, 
and one Follow-up visit (see Figure 1). 
 
Figure 1 Study Schema 
 
 
 
ICF = Informed Consent Form 
 
* Patients will be required to discontinue all prohibited medications and undergo a 28-day Washout Period 
prior to entering the study.  Patients not taking a prohibited medication will directly enter Screening.  A prior 
run-in period will be provided for countries where patients will not be able to take pirfenidone for 12 weeks 
due to reimbursement issues.  The run-in period can include the Washout period (if applicable). 
** After the completion of the treatment period (Visit 10) and 4 weeks safety follow-up, the possibility will be 
offered to the patients to receive pirfenidone within the study protocol up to 11 months safety follow-up. 
 
In addition, the sponsor will offer the possibility to the patients to receive pirfenidone 
within the study protocol after the Follow-up visit at week 56 for up to 11 months safety 
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follow-up.  During this time, the patients should be evaluated by the treating physician 
approximately every three months.  
A patient diary will be used to record adverse events, daily dosing adherence for both 
pirfenidone and sildenafil/placebo, and concomitant medication use from the Screening 
visit until the Follow-up visit.  Also, patients will receive a wallet card that provides 
important information relevant to study participation. 
During the study, assessments will be performed according to the Schedule of 
Assessments (Appendix 1). 
An iDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised.  The iDMC may recommend 
that the Sponsor stop the study for safety concerns. 
A detailed description of the procedures, data flow and the meeting schedule of the 
iDMC will be maintained in a separate iDMC Charter, by the Sponsor and the iDMC. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the clinical trial is defined as the date when the last patient completes the last 
visit (LPLV) or the date at which the last data point which is required for the statistical 
analysis is received, whichever is the later date.  LPLV for the primary analysis is 
expected to occur approximately 56 weeks after the last randomized patient begins the 
Treatment Period. 
The study ends when all patients complete the overall 12 months safety follow-up 
described below, i.e. 4 weeks follow-up after end of treatment at week 52 plus additional 
11 months safety follow-up after the Follow-up visit at week 56. 
The first patient is expected to enroll in the fourth quarter of 2016, and enrollment is 
anticipated to continue for approximately 15 months.  The last patient is expected to 
complete the clinical trial approximately in the first quarter of 2019.  
For each patient, the total length of the study is expected to be up to a maximum of 
approximately 64 weeks, including the Washout Period of 4 weeks, the Screening Period 
of up to 4 weeks, the Treatment Period of 52 weeks, and the Follow-up Period of 
4 weeks.  Patients who enter the 12-week run-in period will be included for a total length 
of 76 weeks. 
In addition, the sponsor will offer the possibility to the patients to receive pirfenidone 
within the study protocol after the Follow-up visit at week 56 for up to 11 months safety 
follow-up.  During this time, the patients should be evaluated by the treating physician 
approximately every three months.  
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Pirfenidone and Sildenafil Doses and Schedule 
In this study, sildenafil or placebo (as a comparator) will be added to ongoing treatment 
of a stable dose of pirfenidone.  The doses will be in accordance with the prescribing 
information for both treatments: pirfenidone at the approved dose for IPF of 801 mg TID 
(or the stable dose they have entered into the study), taken at the same times each day 
with food, and sildenafil at the approved dose for pulmonary arterial hypertension (PAH) 
of 20 mg TID, with or without food.  
Patients must have been on pirfenidone treatment for at least 12 weeks before the 
Screening visit and the dose must have been in the range of 1602 to 2403 mg/day with 
demonstrated tolerability for at least 4 weeks prior to the Screening Visit and throughout 
the study period. 
The combination treatment will continue for 12 months in this study.  Compared to a 
6-month observation period (used in study STEP-IPF), 12 months will likely provide a 
greater number of primary events for the primary analysis, thus increasing the power of 
the study and the clinical validity, and also provide long-term safety data on the 
concomitant use of pirfenidone and sildenafil in this patient population. 
All participants will be managed according to the best judgment of their treating 
physicians as informed by current local clinical practice guidelines and the best clinical 
evidence for patients with IPF and PH.  
3.3.2 
Rationale for Patient Population 
In this study, patients with advanced IPF and risk of Group 3 PH, will be studied.  Overall, 
there is no robust information regarding the efficacy, tolerability and safety of the 
combination of sildenafil and pirfenidone in patients with IPF and there are currently no 
approved therapies for PH secondary to lung disease (Group 3 PH), including PH 
secondary to IPF.   
Clinical trials in IPF, including pirfenidone trials, have generally excluded patients with 
advanced disease and/or PH.  Patients with PH secondary to advanced IPF therefore 
represent a group with high unmet medical need. 
The expected benefits of the pirfenidone/sildenafil combination relate to the anticipated 
improvements in pulmonary hemodynamics in this patient population while the 
progression of fibrosis and decline in lung function are attenuated by pirfenidone. 
3.3.3 
Rationale for Control Group and Double-Blind Design  
A double-blind, randomized trial design was identified to be the most appropriate design 
to allow for an unbiased evaluation of sildenafil taken with pirfenidone as a treatment for 
the study patient population.  The analysis is focused on estimating the size of the 
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difference in the predefined outcomes between sildenafil co-administered with 
pirfenidone compared to placebo and pirfenidone.  Patients are randomly allocated to 
treatment, and patients and Investigator (and other site personnel) remain unaware of 
which treatment is given. 
3.3.4 
Rationale for Primary Endpoint Selection 
The primary endpoint in this double-blind, placebo controlled study will be a composite of 
exercise capacity (using the 6MWT), respiratory-related (non-elective) hospitalizations 
and all-cause mortality.  This has been expanded from the primary endpoint of only 
using the 6MWT in most previous studies.   
3.3.5 
Rationale for Biomarker Assessments 
Genomic, transcriptomic and proteomic profiling of markers associated with the 
molecular pathways and cellular processes of lung injury and fibrosis will be measured. 
Certain biomarkers may be differentially expressed in patients with advanced IPF and 
risk of Group 3 PH on pirfenidone treatment (e.g., possibly cytokines, chemokines and 
other cellular and molecular markers of lung injury and fibrosis).  The blood biomarker 
samples that are being obtained for this study may help identify those serum and plasma 
proteins or blood ribonucleic acid (RNA) biomarkers related to disease progression.  See 
Schedule of Assessments (Appendix 1) for summary of serum, plasma and blood RNA 
biomarker study assessments. 
Genetic polymorphisms have been demonstrated to alter the development and clinical 
course of a number of different diseases.  The purpose of assessing genetic 
polymorphisms in this study is to understand their potential role in the pathogenesis and 
associated clinical outcomes.  The assessment of genetic polymorphisms will only be 
conducted at institutions in which such research is in accordance with institutional 
regulations.   
Patient participation for these assessments is voluntary and declining participation will in 
no way influence eligibility for this study.  See Schedule of Assessments (Appendix 1) for 
summary of serum, plasma and blood deoxyribonucleic acid (DNA) biomarker study 
assessments. 
3.3.6 
Rationale for Choice of Stratification Factors 
The randomization will be stratified by availability of a previous RHC (yes/no) and by 
FEV1/FVC ratio below/above 0.8, to ensure an equal distribution of patients with some 
degree of pulmonary obstruction in both treatment groups.  Stratified randomization is 
included as the treatment outcome may be affected by these factors. 
3.3.7 
Rationale for Interim Analyses 
An iDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised.  The iDMC may recommend 
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that the Sponsor stop the study for safety concerns.  A detailed description of the 
procedures, data flow and the meeting schedule of the iDMC will be maintained in a 
separate iDMC Charter, by the Sponsor and the iDMC.  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 176 patients with advanced IPF and risk of Group 3 PH, who have been 
on pirfenidone in a dose range of 1602 to 2403 mg/day with demonstrated tolerability will 
be enrolled in this study. 
Key inclusion criteria for the study are presented in Figure 2 and the eligibility criterion 
for risk of Group 3 PH (Decision Tree) is further detailed in Figure 3. 
Figure 2 Key Inclusion Criteria for the Study 
 
• 
For the purposes of this study patients have to present with: 
 
 
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Figure 3 Eligibility Criterion for Risk of Group 3 PH (Decision Tree) 
 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Ability to comply with the study protocol in the opinion of the Investigator 
3. Age 40 to 80 years (inclusive) at Screening 
4. Diagnosis of IPF for at least 3 months prior to Screening 
5. Confirmation of IPF diagnosis by the Investigator, in accordance with the 2011 
international consensus guidelines (Raghu et al. 2011), at Screening 
6. For the purposes of this study patients have to present with:  
• 
advanced IPF is defined as a measurable DLCO ≤40% of predicted value 
at Screening;  
 
AND 
• 
risk of Group 3 PH as defined by: 
o mPAP ≥20 mmHg together with PAWP ≤15 mmHg on a previous RHC of 
acceptable quality. 
      OR 
o In the absence of a previous RHC, patients with ECHO showing 
intermediate or high probability of Group 3 PH at screening, as defined by 
the 2015 ESC/ERS (peak TRV) ≥2.9 m/s), will be considered eligible for 
the study, assuming that they meet all other eligibility criteria (Galie et al 
2015). 
 
7. Prior to the start of Screening, receiving pirfenidone for at least 12 weeks, at a 
dose in the range of 1602 to 2403 mg/day for at least 4 weeks prior to the first 
Screening Visit.  During this 4-week period, patients must not have experienced 
either a new or ongoing adverse event of NCI CTCAE (version 4.03) Grade 2 or 
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higher and considered by the Investigator to be related to pirfenidone, or an 
interruption of pirfenidone treatment of >7 days for any reason.  It is expected 
that the dose of pirfenidone will be in the range of 1602 to 2403 mg/day 
throughout the study (in countries where patients will not be able to take 
pirfenidone for 12 weeks due to reimbursement issues, this 12-week run-in 
supply will be provided by the Sponsor) 
8. WHO Functional Class II or III (Rubin 2004) at Screening 
9. 6MWD of 100 to 450 meters at Screening 
10. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a non-hormonal contraceptive method with a 
failure rate of <1% per year during the Treatment Period and for at least 58 days 
after the last dose of study treatment 
o A woman is considered to be of childbearing potential if she is 
post-menarcheal, has not reached a post-menopausal state 
(≥12 continuous months of amenorrhea with no identified cause other than 
menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). 
o Examples of non-hormonal contraceptive methods with a failure rate of 
<1% per year include bilateral tubal ligation, male sterilization, hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices. 
o The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
11. For men who are not surgically sterile: agreement to remain abstinent (refrain 
from heterosexual intercourse) or use contraceptive measures, and agreement to 
refrain from donating sperm, as defined below: 
o With female partners of childbearing potential, men must remain abstinent 
or use a condom plus an additional contraceptive method that together 
result in a failure rate of <1% per year during the Treatment Period and for 
at least 118 days after the last dose of study treatment.  Men must refrain 
from donating sperm during this same period. 
o With pregnant female partners, men must remain abstinent or use a 
condom during the treatment period and for at least 118 days after the last 
dose of study drug or study treatment to avoid exposing the embryo 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
History of any of the following types of PH:  Group 1 (PAH); Group 1 
(pulmonary veno-occlusive disease and/or pulmonary capillary 
hemangiomatosis); Group 2 (left-heart disease); Group 3 (due to conditions 
other than interstitial lung disease, including chronic obstructive pulmonary 
disease [COPD], sleep-disordered breathing, alveolar hypoventilation, high 
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altitude, or developmental abnormalities); Group 4 (chronic thromboembolic 
pulmonary hypertension); Group 5 (other disorders) (Simonneau et al. 2013) 
2. 
History of clinically significant cardiac disease in the opinion of the Investigator, 
including, but not limited to:  left ventricular ejection fraction <40%, congestive 
heart failure Class IV New York Heart Association (NYHA), left ventricular 
outflow obstruction (aortic stenosis, idiopathic hypertrophic subaortic stenosis), 
symptomatic coronary artery disease, congestive heart failure requiring 
hospitalization, second- or third-degree atrioventricular block, uncontrolled or 
clinically significant arrhythmias; uncontrolled systemic hypertension 
3. 
History of coexistent and clinically significant (in the opinion of the Investigator) 
COPD (including chronic bronchitis, emphysema), bronchiectasis, asthma, 
inadequately treated sleep-disordered breathing, or any clinically significant 
pulmonary diseases or disorders other than IPF or PH secondary to IPF 
4. 
Hypotension (blood pressure [BP] <100 mmHg systolic or <50 mmHg diastolic), 
autonomic dysfunction, or conditions in which vasodilation may cause an 
unsafe drop in blood pressure 
5. 
History of use of drugs and toxins known to cause PAH, including aminorex, 
fenfluramine, dexenfluramine, and amphetamines. (For a full list see Galie et al, 
2015) 
6. 
Initiating any new cardiac or pulmonary rehabilitation program within 28 days 
prior to Screening and throughout the study 
7. 
FEV1/FVC ratio <0.70 post bronchodilator at Screening  
8. 
Any impairment other than dyspnea that limits the patient’s ability to walk for at 
least 6 minutes or perform other study procedures 
9. 
SpO2 saturation measured by pulse oximetry at rest <92% with ≥6 L of 
supplemental oxygen, at the first Screening Visit 
10. Significant clinical worsening of IPF between the first Screening Visit and Day 1, 
in the opinion of the Investigator 
11. Any serious medical condition, clinically significant abnormality on ECG at 
Screening or laboratory tests (hematology, serum chemistry, and urinalysis) 
that, in the opinion of the Investigator, may pose an additional risk in 
administering study treatment to the patient 
12. Clinical evidence of any active infection which according to the judgment of the 
Investigator may interfere with study conduct, measurement of pulmonary 
function, or impact the course of IPF 
13. Certain laboratory abnormalities or findings at Screening, including: 
o Total bilirubin above the upper limit of normal (ULN) 
o Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >1.5 × ULN 
o Alkaline phosphatase >2.0 × ULN 
o Creatinine clearance <30 mL/min, calculated using the Cockcroft-Gault 
formula 
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14. Pregnant or lactating, or intending to become pregnant during the study 
15. Extent of emphysema greater than the extent of fibrotic changes 
(honeycombing and reticular changes) on any previous HRCT scan, in the 
opinion of the Investigator 
16. Poorly controlled systemic hypertension (>180 mmHg systolic or >100 mmHg 
diastolic) 
17. Use of any of the following therapies within 28 days prior to Screening: 
o Investigational therapy, defined as any drug that has not been approved for 
marketing for any indication in the country of the participating site 
o Any cytotoxic, immunosuppressive, cytokine modulating, or receptor 
antagonist agent including but not limited to azathioprine, bosentan, 
ambricentan, macitentan, cyclophosphamide, cyclosporine, etanercept, 
iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate 
mofetil, tacrolimus, montelukast, tetrathiomolybdate, corticosteroids 
(>15mg/day prednisolone or equivalent more than 28 days) TNF-α 
inhibitors, imatinib mesylate, and interferon gamma-1b 
o Any medications that are specifically used for the treatment of IPF (other 
than the study drug) including those listed above.  N-acetylcysteine (NAC) 
is acceptable, provided that the dose has been stable for 28 days prior to 
Screening and remains unchanged throughout the study 
o Use of any medications specifically prescribed for the treatment of PH 
(other than study drug) after the Washout Period and throughout the study, 
including but not limited to endothelin receptor antagonists, prostaglandins, 
guanylate cyclase stimulators such as riociguat (see Section 4.5 of the 
Sildenafil SPC [Section 1.2.2]) and other phosphodiesterase inhibitors 
18. Vasoactive medications including calcium channel blockers, diuretics, and 
vasodilators may not be added within 28 days prior to screening, and the dose 
of these medications must be held constant as much as possible within 7 days 
of Screening and throughout the study 
19. History of cancer likely to result in significant disability or to require medical or 
surgical intervention within the next 2 years.  This does not include minor 
surgical procedures for localized skin cancer such as basal cell carcinoma. 
20. Smoked tobacco within 3 months prior to Screening or is unwilling to avoid 
tobacco products (cigarettes, pipe, cigars) throughout the study 
21. Illicit drug or significant alcohol abuse within 12 months prior to Screening, in 
the Investigator’s judgment 
22. Concomitant treatment with strong or moderate cytochrome P450 (CYP)1A2 
inhibitors or moderate CYP1A2 inducers within 4 weeks or 5 drug-elimination 
half-lives, whichever is longer, prior to initiation of study treatment and 
throughout the study 
o Strong CYP1A2 inhibitors: fluvoxamine, enoxacin 
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o Moderate CYP1A2 inhibitors: ciprofloxacin (if dosed at >500 mg twice daily 
[BID]), mexiletene, thiabendazole, oral contraceptives, phenylpropanolamine, 
zileuton 
o Moderate CYP1A2 inducers: montelukast, phenytoin, smoking 
o Inhibitors of P-glycoprotein (e.g., ketoconazole, erythromycin) or CYP3A4 
(e.g., ketoconazole, itraconazole, ritonavir, erythromycin), or their inducers 
(e.g., rifampicin, carbamazepine, phenytoin, St John’s wort).  
23. Hepatic impairment, acute or chronic hepatitis or known liver cirrhosis 
24. Severe renal impairment including end-stage renal disease requiring dialysis 
25. Poorly controlled diabetes mellitus requiring insulin therapy 
26. Known HIV infection 
27. ECG with a heart-rate–corrected QT interval (corrected using Fridericia’s 
formula [QTcF]) ≥500 ms at Screening, or a family or personal history of long 
QT syndrome. 
 
Additional Exclusion Criteria Based on Pirfenidone Reference Safety Information  
1. Any contraindication to pirfenidone, including known hypersensitivity to the active 
substance or any excipient  
2. Pirfenidone should not be used in patients with a history of angioedema due to 
pirfenidone 
3. Concomitant use of fluvoxamine 
Additional Exclusion Criteria Based on Sildenafil Reference Safety Information 
1. Any contraindication to sildenafil, including known hypersensitivity to the active 
substance or any excipient;   
2. Co-administration with nitric oxide donors (such as amyl nitrite) or organic 
nitrates (nitroglycerin) in any form (potentiates the hypotensive effects) 
3. The co-administration of PDE5 inhibitors, including Viagra, with guanylate 
cyclase stimulators, such as riociguat, is contraindicated as it may potentially 
lead to symptomatic hypotension 
4. Combination with the most potent of the CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, ritonavir) 
5. A loss of vision in one eye because of non-arteritic anterior ischaemic optic 
neuropathy (NAION), regardless of whether this episode was in connection or not 
with previous PDE5 inhibitor exposure. 
6. Recent history of stroke or myocardial infarction 
7. Known hereditary degenerative retinal disorders such as retinitis pigmentosa  
8. Patients with anatomical deformation of the penis (such as angulation, 
cavernosal fibrosis or Peyronie's disease), or in patients who have conditions 
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which may predispose them to priapism (such as sickle cell anemia, multiple 
myeloma or leukemia) 
9. Patients with bleeding disorders or active peptic ulceration. 
10. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Patients will be randomized 1:1 to receive either pirfenidone plus sildenafil or pirfenidone 
plus placebo.  The randomization process will be conducted using a validated interactive 
voice or web-based response system (IxRS).  To guard against systematic selection 
bias and ensure comparability of treatment groups, the randomization will be stratified by 
availability of a previous RHC (yes/no) and by FEV1/FVC ratio below/above 0.8 to 
ensure an equal distribution of patients with some degree of pulmonary obstruction in 
both treatment groups.  
To maintain the double-blind nature of the study, the sildenafil and placebo treatments 
will be identical in appearance (see Section 4.3.1.2). 
The investigational site personnel and the patients will be blinded to treatment 
assignment from randomization onwards.  The iDMC and any personnel performing 
interim analysis (as applicable) will be unblinded to treatment throughout the study. 
If unblinding is necessary for patient management (e.g., in the case of a SAE for which 
patient management might be affected by knowledge of treatment assignment), the 
Investigator will be able to break the treatment code by contacting the IxRS.  Treatment 
codes should not be broken except in emergency situations.  If the Investigator wishes to 
know the identity of the study drug for any other reason, he or she should contact the 
Medical Monitor directly.  The Investigator should document and provide an explanation 
for any premature unblinding (e.g., accidental unblinding, unblinding due to a SAE).  
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the Investigator or Sponsor to be 
related to study drug. 
Unblinding should not necessarily result in the withdrawal of a patient from the study.  
Every effort should be made to retain unblinded patients in the study. 
4.3 
STUDY TREATMENT 
The test products for this study (study treatments) are pirfenidone, blinded comparator 
sildenafil and a matching placebo to blinded comparator sildenafil. 
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4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Pirfenidone 
Pirfenidone (Esbriet®), chemical name 5-methyl-1-phenyl-2-1(H)-pyridone, will be 
supplied by the Sponsor as white, hard gelatin capsules printed with “267 mg” in brown 
ink.  Each pirfenidone capsule contains 267 mg of pirfenidone and the following inactive 
ingredients: 
• 
Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, 
magnesium stearate 
• 
Capsule shell: gelatin, titanium dioxide, brown printing ink (includes shellac, iron 
oxide black, iron oxide red, iron oxide yellow, propylene glycol, ammonium 
hydroxide) 
For information on the handling and storage of pirfenidone, see the current version of the 
pirfenidone Investigator's Brochure (Esbriet [pirfenidone]). 
4.3.1.2 
Sildenafil 
Sildenafil will be supplied by the Sponsor as hard gelatin capsule (bovine only) 
containing a white, round, biconvex film-coated, commercial tablet Sildenafil 20mg from 
US market and microcrystalline cellulose as backfill.  Each tablet contains sildenafil 
citrate United States Pharmacopeia (USP), equivalent to 20 mg sildenafil, and the 
following excipients: 
• 
croscarmellose sodium; calcium phosphate, dibasic, anhydrous; magnesium stearate; 
cellulose, microcrystalline; polyethylene glycol 3350; polyethylene glycol 4000; 
polyvinyl alcohol; talc; titanium dioxide 
For information of the sildenafil tablet, see the sildenafil SPC at the following website:  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2582414d-0ef3-403e-84e8-
1d6c812e7eb1 
 
4.3.1.3 
Placebo 
Placebo will be supplied by the Sponsor as a capsule with the same appearance and 
size as the encapsulated sildenafil containing microcrystalline cellulose. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Pirfenidone 
At the start of Screening, patients will have been taking pirfenidone, by oral 
administration, three times per day (TID) with meals for at least 12 weeks, and the dose 
must have been in the range of 1602 to 2403 mg/day for at least 4 weeks (prior to the 
first Screening Visit).  Doses will be taken at the same time each day.  It is expected that 
the dose will remain within the range of 1602 to 2403 mg/day throughout the study. 
A patient diary will be used to record daily dosing adherence for pirfenidone. 
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Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.1. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.2.2 
Sildenafil or Placebo 
Patients who meet all eligibility criteria and provide written informed consent will be 
randomized 1:1 to receive 1 year (52 weeks) of treatment with either oral sildenafil 
20 mg or matching placebo TID, while continuing to take pirfenidone.   
Daily dosing adherence for sildenafil or placebo will be recorded in the patient diary. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.2. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the adverse event eCRF. 
4.3.2.3 
Precautionary Measures during Treatment with Pirfenidone 
and/or Sildenafil 
4.3.2.3.1 
Pirfenidone 
Exposure to sunlight (including indirect light, sunlamps, and tanning beds) should be 
avoided or minimized during pirfenidone treatment due to the possibility of 
photosensitivity reactions or rash.  Patients should be instructed to use sunscreens that 
have a sun protection factor (SPF) ≥50 as well as protection against ultraviolet A (UV-A) 
and ultraviolet B (UV-B) radiation, and also to wear clothing that protects against sun 
exposure and avoid concomitant medications known to cause photosensitivity reactions, 
if possible. 
All doses of pirfenidone are to be taken with food to reduce the likelihood of 
gastrointestinal symptoms. 
Dose titration when pirfenidone is restarted after a treatment interruption is intended to 
enhance tolerability. 
4.3.2.3.2 
Sildenafil 
Sildenafil may cause decreases in blood pressure due to vasodilator effects.  Patients 
should be treated with caution if they have: resting hypotension (blood pressure [BP] 
<90/50 mmHg), hypertension (BP >170/110 mmHg), fluid depletion, severe left 
ventricular outflow obstruction, or autonomic dysfunction, and also patients receiving 
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alpha blockers or other antihypertensive medication.  Sildenafil is not recommended for 
use in patients with pulmonary veno-occlusive disease.   
In post-marketing experience with sildenafil for male erectile dysfunction, serious 
cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac 
death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, 
hypertension and hypotension have been reported in temporal association with the use 
of sildenafil.  Most, but not all, of these patients had pre-existing cardiovascular risk 
factors.  Sildenafil should be used with caution in patients with cardiovascular disease, in 
patients receiving concurrent bosentan and in patients with bleeding disorders or with 
active peptic ulcer disease; as safety and efficacy have not been established. 
Sildenafil should be used with caution in patients with anatomical deformation of the 
penis (angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have 
conditions which may predispose them to priapism (sickle cell anemia, multiple myeloma, 
leukemia).  In the event of an erection that persists longer than 4 h, the patient should 
seek immediate medical assistance.  If priapism is not treated immediately, penile tissue 
damage and permanent loss of potency could result. 
Rare cases of NAION have been reported; risk may be increased with history of vision 
loss.  In the event of any sudden visual defect, the treatment should be stopped 
immediately and alternative treatment should be considered. 
Sildenafil may cause dose-related impairment of color discrimination and should be used 
with caution in patients with retinitis pigmentosa. 
Cases of sudden decrease in hearing and hearing loss with the use of PDE5 inhibitors 
such as sildenafil have been reported. 
Orthostatic hypotension has occurred rarely in patients receiving sildenafil (<2%). 
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory 
effect of sodium nitroprusside in vitro.  There is no safety information on the 
administration of sildenafil to patients with bleeding disorders or active peptic ulceration.  
Therefore, sildenafil should be administered to these patients only after careful 
benefit-risk assessment. 
In PAH patients, there may be a potential for increased risk of bleeding when sildenafil is 
initiated inpatients already using a Vitamin K antagonist, particularly in patients with PAH 
secondary to connective tissue disease. 
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4.3.2.4 
Missed Doses  
If a patient misses a scheduled dose of pirfenidone and/or sildenafil, the dose should be 
skipped.  Regular dosing will resume with the next scheduled dose.  The patient should 
not take any extra doses to make up for missed doses. 
4.3.2.5 
Dose Modification or Discontinuation  
The Investigator will be responsible for monitoring patients as frequently as clinically 
indicated for treatment-emergent adverse events or other toxicities, and for doing so in a 
manner consistent with the instructions in the labels for pirfenidone, sildenafil, and any 
other medications used to treat a study patient.  The Investigator may contact the 
Medical Monitor or designee to discuss dose modification or discontinuation of study 
treatment.  All treatment-emergent adverse events and toxicities will be followed 
according to procedures in this protocol.  If a patient experiences a clinically significant 
treatment-emergent adverse event or toxicity, treatment of symptoms and/or temporary 
dose reduction, interruption, or discontinuation of study treatment should be considered.  
All changes in dosing will be recorded by the patient in the patient diary and by the study 
center in the electronic eCRF. 
If a patient is hospitalized for any reason, the Investigator should consider continuing the 
study treatment if appropriate.  If the patient is hospitalized at an institution that is not 
affiliated with the study center, the Investigator is encouraged to discuss study 
participation with the treating physician at the earliest possible time.  All records 
pertaining to the hospitalization should be obtained by the study center.  The Investigator 
will be responsible for determining the reason for hospitalization (admission to the 
hospital) (respiratory, cardiac, other), distinguishing elective from non-elective 
hospitalization, and determining the cause of death (respiratory, cardiac, other).  The 
sections below identify events that require interruption/discontinuation of study treatment, 
and provide guidance for modifying doses, restarting treatment after an interruption. 
4.3.2.6 
Restarting Study Treatment 
After a treatment interruption, study treatment can be restarted, at the discretion of the 
Investigator.  The schedule for pirfenidone re-titration according to the label, is described 
in Table 2. 
Table 2 
Schedule for Pirfenidone Re-titration After an Interruption of 
More Than 14 Consecutive Days 
Day (relative to restart of pirfenidone treatment) 
Pirfenidone dosage (as tolerated) 
Days 1 to 7 
1 capsule TID, with food 
Days 8 to 14 
2 capsules TID, with food 
Day 15 onwards 
3 capsules TID, with food 
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TID = three times daily 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (pirfenidone, sildenafil and placebo) will be 
provided by the Sponsor.  The study site will acknowledge receipt of IMPs, using the 
IxRS, to confirm the shipment condition and content.  Any damaged shipments will be 
replaced. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) or will be returned to the Sponsor with the 
appropriate documentation.  The site’s method of IMP destruction must be agreed to by 
the Sponsor.  The site must obtain written authorization from the Sponsor before any 
IMP is destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Continued access of Pirfenidone 
The sponsor will offer the possibility to the patient to receive pirfenidone within the study 
protocol for 12 months safety FU after completing visit 10.  
Following this period, the Sponsor will offer post-trial access to pirfenidone free of 
charge to eligible patients in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for advanced IPF and PH or suspected PH 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for advanced IPF and PH or suspected PH 
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• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy continued access to investigational medicines.pdf 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 28 days prior to initiation of study drug to the study completion/ 
discontinuation visit.  A patient diary will be used to record concomitant medications.  All 
such medications should be reported to the Investigator and recorded on the 
Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
All medical therapies necessary to treat the patient’s comorbidities and which are not 
listed below in Section 4.4.2 are permitted in this study. 
Patients of childbearing potential, who use oral contraceptives, hormone-replacement 
therapy, or other maintenance therapy should continue their use. 
Sildenafil and PDE5 inhibitors that are used only intermittently for erectile dysfunction 
are permitted in the 28 days before the start of Screening but not after Screening and 
the remainder of the study.  PDE5 inhibitors other than sildenafil used intermittently for 
erectile dysfunction are not allowed throughout the study. 
Small steroid doses (e.g., 15 mg prednisolone or equivalent) are acceptable during the 
study.  N-acetylcysteine is also acceptable during the study. 
Corticosteroids may be used at the discretion of the investigator, without dose restriction, 
for a period of up to 28 days in patients experiencing an episode of acute IPF 
exacerbation.  The study drug should be continued during this time, if possible. 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study treatment: 
• 
Any cytotoxic, immunosuppressive, cytokine-modulating, or receptor-antagonist 
agent, including but not limited to azathioprine, bosentan, ambrisentan, 
cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene 
antagonists, methotrexate, high dose of corticosteroids (>15mg/day prednisolone or 
equivalent for more than 28 days), mycophenolate mofetil, tacrolimus, montelukast, 
tetrathiomolybdate, TNF-α inhibitors, imatinib mesylate, Interferon gamma-1b and 
tyrosine kinase inhibitors 
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• 
Strong CYP1A2 inhibitors (e.g., fluvoxamine, enoxacin), inhibitors of P-glycoprotein 
(e.g., ketoconazole, erythromycin) or CYP3A4 (e.g., ketoconazole, erythromycin), or 
their inducers (e.g., rifampicin, carbamazepine, phenytoin, phenytoin, St John’s wort) 
• 
Medications that are specifically being used for the treatment of IPF, including but 
not limited to angiotensin converting enzyme inhibitors, colchicine, heparin, warfarin, 
and HMG-CoA reductase inhibitors.  These drugs may be used if given for a 
non-IPF indication if there is no clinically acceptable alternative therapy for the same 
indication 
• 
Use of any medications specifically prescribed for the treatment of pulmonary 
hypertension (other than study drug) after the Washout Period and throughout the 
study, including but not limited to endothelin receptor antagonists, prostaglandins, 
guanylate cyclase stimulators such as riociguat and other phosphodiesterase 
inhibitors 
• 
Any investigational therapy in a clinical study  
• 
Because moderate inhibitors of CYP1A2 (e.g., ciprofloxacin) increase systemic 
exposure of pirfenidone (Esbriet® US label 2014), if ciprofloxacin is administered it 
should be limited to 250 or 500 mg daily (QD), and the patient should be monitored 
close 
• 
Nitric oxide donors (such as amyl nitrite) or nitrates in any form due to the 
hypotensive effects of nitrates 
The above lists of medications are not necessarily comprehensive.  Thus, the 
Investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication is metabolized by or strongly inhibits or induces CYP1A2 or CYP3A4.  In 
addition, the Investigator should contact the Medical Monitor if questions arise regarding 
medications not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
4.4.3 
Prohibited Food 
The consumption of grapefruit juice will be prohibited during the study. 
4.4.4 
Additional Restrictions 
The use of any tobacco product will be prohibited during the study. 
4.5 
STUDY ASSESSMENTS 
The Procedure Manual and Laboratory Manual, referenced below is for specific study 
assessments, are documents that are separate from the protocol.  These manuals will 
include full details of how to perform the procedure or assessment and will be available 
at each site. 
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Please see Appendix 1 for the Schedule of Assessments to be performed during the 
study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
Separate informed consent needs to be given to allow for biomarker analyses. 
All Screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The Investigator will maintain a Screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
Screening failure, as applicable. 
Screening assessments must take place within 28 days prior to baseline, this may 
comprise 1 or more visits for the convenience of the patient. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, reproductive status, smoking 
history, use of alcohol, and drugs of abuse.  In addition, all medications (e.g., 
prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 28 days before the Screening period 
will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity (as allowed by 
local regulations). 
4.5.3 
Physical Examinations 
Physical examinations will be conducted as per the schedule of assessment (see 
Appendix 1).  The directed physical examination should be based on signs and 
symptoms of the patient.  Physicians should pay particular attention to the signs and 
symptoms that are characteristic of IPF and PH.  Additional physical examinations may 
be performed only if clinically indicated.  Physical examinations will include weight (kg); 
in addition, at Baseline, the examination will include height (cm) and body mass index 
(BMI) will be calculated.  If clinically significant abnormalities are observed in a physical 
examination the Investigator will decide if they are new adverse events. 
Physical examination is the responsibility of the principal Investigator or medically 
qualified designee. 
4.5.4 
Vital Signs 
Vital signs will include measurements of: 
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• 
Respiratory rate 
• 
Heart rate 
• 
Systolic and diastolic blood pressure while the patient is in a seated position, after at 
least 5 minutes rest and 
• 
Temperature. 
Vital signs should be measured at Screening and at each subsequent visit (as shown in 
Appendix 1).   
4.5.5 
Laboratory, Biomarker, and Other Biological Samples 
Blood and urine samples for hematology, biochemistry, biomarkers, urinalysis and 
pregnancy testing will be collected as per the Schedule of Assessments (see Appendix 1) 
and will be analyzed at a central laboratory (exception local laboratory for countries with 
local requirements): 
• 
Hematology (hemoglobin, hematocrit, red blood cells [RBC], platelet count, white 
blood cells [WBC] with differential [including neutrophils, lymphocytes, monocytes, 
eosinophils and basophils]) 
• 
Serum chemistry (glucose, blood urea nitrogen [BUN], creatinine, sodium, 
potassium, bicarbonate, total protein, albumin, total bilirubin, direct bilirubin, alkaline 
phosphatase, lactate dehydrogenase [LDH], AST, ALT, gamma-glutamyl-
transferase [GGT]), C-reactive protein [CRP] and NT-proBNP, aldosterone) 
• 
Optional: Serum and plasma collected at Screening and baseline visits for protein 
IPF biomarker measurements  
• 
Optional: Blood PAXgene collected at Screening and baseline visits for 
transcriptomic IPF biomarker measurements 
• 
Optional: Blood for DNA collected at baseline visit for genetic IPF biomarker 
measurements, which may include a genome-wide association study (GWAS)  
• 
Urinalysis (dipstick including pH, specific gravity, glucose, protein, ketones, blood, 
bilirubin and microscopic examination including sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria) 
• 
Pregnancy test: All women of childbearing potential will have serum and urine 
pregnancy tests as per the Schedule of Assessments (see Appendix 1).  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
For sampling procedures, storage conditions, and shipment instructions, see the 
Laboratory Manual for this study. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples. 
Biomarker samples will be destroyed 5 years after the end of the study.  
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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.6 
WHO Functional Class 
World Health Organization Functional Class for PH must be documented at Screening 
(and be in the range 2 to 3) and re-assessed during the study, as outlined in the 
Schedule of Assessments (see Appendix 1). 
The WHO Functional Class will be performed according to standard guidelines. 
4.5.7 
GAP Score and Index for IPF 
The gender, age and physiology (GAP) score and index for IPF will be automatically 
calculated based on the information recorded in the eCRF (age, gender, FVC and 
DLCO).  
4.5.8 
12-lead Electrocardiograms 
Single 12-lead ECG recordings will be obtained at specified timepoints, as outlined in the 
Schedule of Assessments (see Appendix 1). 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible. 
Patients must have been in a supine or semi-supine position for at least 5 minutes prior 
to the recording being taken.  All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws) and should not 
be obtained within 3 hours after any meal.  Circumstances that may induce changes in 
heart rate, including environmental distractions (e.g., television, radio, conversation) 
should be avoided during the pre-ECG resting period and during ECG recording. 
Paper copies of ECG tracings will be kept as part of the patient's permanent study file at 
the site.  The ECG printout must be (1) reviewed by a medically qualified member of the 
study team at the site, (2) annotated to indicate any clinical finding and (3) dated and 
signed by this person and filed in the patient notes. ECG parameters will be entered into 
the eCRF. 
If any ECG abnormality is associated with an adverse event, it must be recorded as 
described in Section 5.2.1. 
4.5.9 
6-Minute Walk Test and Oxyhemoglobin Saturation 
The 6MWT measures the distance that a patient can quickly walk on a flat, hard surface 
in a period of 6 minutes.  Oxyhemoglobin saturation (SpO2) at rest and during the 6MWT 
will be assessed at specified timepoints, as outlined in the Schedule of Assessments 
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(see Appendix 1).  The 6MWT will be performed according to standard procedures (ATS 
Statement, 2002) described in the Procedure Manual. 
The 6MWT will be performed once for the visits highlighted in the Schedule of 
Assessments (Appendix 1).  At Day 1, 6MWT will be performed twice and the better of 
the two 6MWT values will be reported as the baseline value.  It is important to remember 
that for each 6MWT, information on oxyhemoglobin desaturation, Borg scale and O2 
requirements have to be collected. 
4.5.10 
Transthoracic Doppler ECHO 
Transthoracic Doppler ECHO will be assessed at specified timepoints, as outlined in the 
Schedule of Assessments (see Appendix 1). 
The ECHO procedure will be performed according to standard guidelines (Galiè et al. 
2015).  
4.5.11 
Spirometry (Post bronchodilator) 
Spirometry assessments of FVC, FEV1, and FEV1/FVC ratio will be assessed at 
specified timepoints, as outlined in the Schedule of Assessments (see Appendix 1). 
Spirometry will be performed only post bronchodilator, approximately 30 minutes after 
the last puff of short-acting bronchodilator as described in the Procedure Manual.  
Reference equations for spirometric indices will also be provided in the Procedure 
Manual. 
4.5.12 
Diffusing Capacity for Carbon Monoxide 
DLCO will be assessed at specified timepoints, as outlined in the Schedule of 
Assessments (see Appendix 1). 
The reported DLCO will be corrected for the current hemoglobin level, using reference 
equations.  
4.5.13 
Health Status and Health-Related Quality of Life 
HRQoL will be assessed by SGRQ at selected clinical visits as outlined in the Schedule 
of Assessments (see Appendix 1). 
4.5.14 
UCSD SOBQ  
The UCSD SOBQ is a symptom-specific, 24-item, patient-self-administered 
questionnaire that assesses shortness of breath while doing a variety of activities of daily 
living.  It will be assessed at selected clinical visits as outlined in the Schedule of 
Assessments (see Appendix 1). 
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4.5.15 
Patient Study Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the Investigator has the right to withdraw a patient from study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Lung transplantation 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
Every attempt should be made to keep patients on study treatment throughout the 
duration of the trial. 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
The Investigator should show due diligence and explore all possible options to reach a 
patient who fails to attend a visit.  The site must document all attempts to contact the 
patient in the medical records / source documents.  
4.5.16 
Patient Study Treatment Discontinuation 
Patients must discontinue study treatment (sildenafil and/or pirfenidone) if they 
experience any of the following (see also Sections 5.1.1 and 5.1.2): 
• 
Inability to tolerate study treatment after efforts have been made to gain tolerability 
• 
An elevation in liver test results of the magnitude described below  
• 
Use of a prohibited investigational therapy or concomitant medication 
• 
Sildenafil/placebo will be stopped in patients with acute coronary syndromes, 
atrioventricular AV block, life-threatening arrhythmias, left ventricular dysfunction 
(ejection fraction <25%), or clinically significant visual changes 
• 
Pregnancy 
• 
Signs or symptoms of angioedema 
• 
Any other treatment-emergent adverse event or toxicity that is unacceptable in the 
opinion of the patient or Investigator  
Sildenafil/placebo will be stopped (temporarily or permanently) in any patient with systolic blood 
pressure (SBP) <100 mmHg or diastolic blood pressure (DBP) <50 mmHg. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
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4.5.17 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Pirfenidone and sildenafil are both approved treatments and all safety information is 
contained in their respective EU SPCs and US prescribing information.  For this study, 
the Reference Safety Information (RSI) for pirfenidone is the Investigator Brochure (I.B.).  
For this study, the Reference Safety Information (RSI) for sildenafil is the US Prescribing 
Information.  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2582414d-0ef3-403e-84e8-
1d6c812e7eb1 
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.  Safety-related interim analyses will be performed, 
including hospitalizations and all-cause mortality, and the data assessed by the iDMC 
(see Section 3.1).  All procedures are detailed in the Schedule of Assessments 
(Appendix 1). 
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5.1.1 
Risks Associated with Pirfenidone 
5.1.1.1 
Impaired Hepatic Function 
Elevations in ALT and AST >3 × ULN have been reported in patients receiving therapy 
with pirfenidone.  These have rarely been associated with concomitant elevations in 
bilirubin.  Liver function tests (ALT, AST and bilirubin) will be conducted at Screening 
and Day 1 prior to the initiation of study treatment and subsequently at each clinic visit 
during the study.  In the event of significant elevation of liver aminotransferases, the 
dose of pirfenidone should be adjusted or treatment discontinued according to the 
guidelines listed in Table 3. 
Table 3 
Management of Dosing in Patients with Elevated 
Aminotransferase Test Results 
Management or Elevation in 
ALT or AST 
Recommendation 
> 3 to < 5 × ULN without 
hyperbilirubinemia 
Discontinue confounding medications 
Monitor the patient closely, including repeat liver chemistry 
tests. 
Maintain the daily dose at full dose, if clinically appropriate, or 
reduce or interrupt the dose (e.g., until liver chemistry test 
results are within normal limits) with subsequent re-titration to 
full dose as tolerated. 
> 3 to < 5 × ULN with symptoms 
or hyperbilirubinemia 
Discontinue pirfenidone and the patient should not be 
rechallenged 
> 5 × ULN 
Discontinue pirfenidone and the patients should not be 
rechallenged. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal 
5.1.1.2 
Photosensitivity Reaction and Rash 
Exposure to direct sunlight (including sunlamps) should be avoided or minimized during 
treatment with pirfenidone.  Patients should be instructed to use an effective sunblock 
daily, to wear clothing that protects against sun exposure and to avoid other medicinal 
products known to cause photosensitivity.  Patients should be instructed to report 
symptoms of photosensitivity reaction or rash to their Investigator.  Dose adjustments or 
temporary treatment discontinuation may be necessary for photosensitivity reaction or 
rash. 
5.1.1.3 
Gastrointestinal Effects 
In clinical trials, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, 
gastroesophageal reflux disease, and abdominal pain were more frequently reported by 
patients in the pirfenidone treatment groups than in those taking placebo (see Esbriet 
[pirfenidone], current version of the Investigator’s Brochure).  Dose reduction or 
interruption for gastrointestinal events was required in 18.5% of patients in the 
2403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of 
patients in the pirfenidone 2403 mg/day group discontinued treatment due to a 
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gastrointestinal event, as compared to 1.0% in the placebo group.  The most common 
(>2%) gastrointestinal events that led to dose reduction or interruption were nausea, 
diarrhea, vomiting, and dyspepsia.  Dose modifications may be necessary in some 
cases of gastrointestinal adverse reactions.  Taking pirfenidone with food is 
recommended. 
The incidence of gastrointestinal events was higher early in the course of treatment (with 
highest incidence occurring during the initial 3 months) and usually decreased over time. 
5.1.1.4 
Angioedema 
Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue 
which may be associated with difficulty breathing or wheezing have been received in 
association with use of pirfenidone in the post-marketing setting.  Therefore, patients 
who develop signs or symptoms of angioedema following administration of pirfenidone 
should immediately discontinue treatment and should be managed according to 
standard of care.  Pirfenidone should not be used in patients with a history of 
angioedema due to pirfenidone. 
5.1.1.5 
Dizziness 
Dizziness has been reported in patients taking pirfenidone.  Therefore, patients should 
know how they react to this medicinal product before they engage in activities requiring 
mental alertness or coordination.  If dizziness does not improve or if it worsens in 
severity, dose adjustment or even discontinuation of pirfenidone may be warranted. 
5.1.1.6 
Fatigue 
Fatigue has been reported in patients taking pirfenidone.  Therefore, patients should 
know how they react to this medicinal product before they engage in activities requiring 
physical or mental activity. 
5.1.1.7 
Weight Loss 
Weight loss has been reported in patients treated with pirfenidone.  Physicians should 
monitor patients' weight, and when appropriate encourage increased caloric intake if 
weight loss is considered to be of clinical significance. 
5.1.2 
Risks Associated with Sildenafil 
The main risks associated with sildenafil are given below.  A complete list of risks 
associated with sildenafil is provided in the label:  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2582414d-0ef3-403e-84e8-
1d6c812e7eb1 
 
5.1.2.1 
Vasodilatory Action 
When prescribing sildenafil, physicians should carefully consider whether patients with 
certain underlying conditions could be adversely affected by sildenafil’s mild to moderate 
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vasodilatory effects, for example patients with hypotension, patients with fluid depletion, 
severe left ventricular outflow obstruction or autonomic dysfunction. 
5.1.2.2 
Cardiovascular Risk Factors 
In post-marketing experience with sildenafil for male erectile dysfunction, serious 
cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac 
death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, 
hypertension and hypotension have been reported in temporal association with the use 
of sildenafil.  Most, but not all, of these patients had pre-existing cardiovascular risk 
factors. 
5.1.2.3 
Visual Events 
Cases of visual defects have been reported spontaneously in connection with the intake 
of sildenafil and other PDE5 inhibitors.  Cases of non-arteritic anterior ischaemic optic 
neuropathy, a rare condition, have been reported spontaneously and in an observational 
study in connection with the intake of sildenafil and other PDE5 inhibitors.  In the event 
of any sudden visual defect, the treatment should be stopped immediately and 
alternative treatment should be considered. 
5.1.2.4 
Vitamin K Antagonists 
In PAH patients, there may be a potential for increased risk of bleeding when sildenafil is 
initiated in patients already using a Vitamin K antagonist, particularly in patients with 
PAH secondary to connective tissue disease. 
5.1.2.5 
Veno and Vaso-occlusive Disease 
No data are available with sildenafil in patients with PH associated with pulmonary veno-
occlusive disease. However, cases of life threatening pulmonary oedema have been 
reported with vasodilators (mainly prostacyclin) when used in those patients.  
Consequently, should signs of pulmonary edema occur when sildenafil is administered in 
patients with PH, the possibility of associated veno-occlusive disease should be 
considered. 
Sildenafil should not be used in patients with PH secondary to sickle cell anemia.  In a 
clinical study events of vaso-occlusive crises requiring hospitalization were reported 
more commonly by patients receiving sildenafil than those receiving placebo leading to 
the premature termination of this study. 
5.1.2.6 
Priapism 
Sildenafil should be used with caution in patients with anatomical deformation of the 
penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who 
have conditions which may predispose them to priapism (such as sickle cell anemia, 
multiple myeloma or leukemia). 
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Prolonged erections and priapism have been reported with sildenafil in post-marketing 
experience.  In the event of an erection that persists longer than 4 h, the patient should 
seek immediate medical assistance.  If priapism is not treated immediately, penile tissue 
damage and permanent loss of potency could result. 
5.1.2.7 
Alpha Blockers 
Caution is advised when sildenafil is administered to patients taking an alpha-blocker as 
the co-administration may lead to symptomatic hypotension in susceptible individuals.  In 
order to minimize the potential for developing postural hypotension, patients should be 
hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. 
Physicians should advise patients what to do in the event of postural hypotensive 
symptoms. 
5.1.2.8 
Bleeding Disorders 
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory 
effect of sodium nitroprusside in vitro.  There is no safety information on the 
administration of sildenafil to patients with bleeding disorders or active peptic ulceration.  
Therefore, sildenafil should be administered to these patients only after careful 
benefit-risk assessment. 
5.1.2.9 
Galactose intolerance 
Lactose monohydrate is present in the tablet film coat. Patients with rare hereditary 
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption should not take this medicine. 
5.1.2.10 
Use of Sildenafil with Bosentan 
The efficacy of sildenafil in patients already on bosentan therapy has not been 
conclusively demonstrated. 
5.1.2.11 
Concomitant Use with Other PDE5 Inhibitors 
The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor 
products, including Viagra, has not been studied in PAH patients and such concomitant 
use is not recommended. 
5.1.3 
Management of Patients Who Experience Specific Adverse 
Events 
Guidelines for management of specific adverse events are outlined in the labels for 
pirfenidone and sildenafil.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of review of the patient diary for adverse events, dosing 
adherence and concomitant medications, monitoring and recording adverse events, 
including serious adverse events and adverse events of special interest, performing 
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protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice (GCP), an adverse event is 
any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., Screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the Investigator, places the 
patient at immediate risk of death).  This does not include any adverse event that 
had it occurred in a more severe form or was allowed to continue might have 
caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
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• 
Is a significant medical event in the Investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according NCI CTCAE 
version 4.03; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 h after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the Investigator to the 
Sponsor immediately (i.e., no more than 24 h after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
– 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 to Section 5.6.  
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained all adverse events should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events) until 28 days 
after the last dose of study drug.  Instructions for reporting adverse events that occur 
after the adverse event reporting period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (version 4.03) will be used 
for assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
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Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (version 4.03), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
 d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases (or decreases) in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 h after learning 
that the event became serious; see Section 5.4.2 for reporting instructions).  The 
Adverse Event eCRF should be updated by changing the event from "non-serious" to 
"serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the Investigator’s judgment  
It is the Investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
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5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the Investigator’s judgment  
It is the Investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an 
elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, Investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
• 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 h after learning of the 
event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of advanced IPF and PH or suspected PH. 
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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 h after the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 h after the patient was last seen alive and 
stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
If the death is attributed to progression of advanced IPF and PH, "advanced IPF” or 
“advanced PH” or “suspected IPF progression” or “suspected PH progression" should be 
recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the Screening Visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Advanced IPF and PH 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
advanced IPF and PH should be recorded as an adverse event if judged by the 
Investigator to have unexpectedly worsened in severity or frequency or changed in 
nature at any time during the study.  When recording an unanticipated worsening of 
advanced IPF and worsening of PH on the Adverse Event eCRF, it is important to 
convey the concept that the condition has changed by including applicable descriptors 
(e.g., " worsening of IPF” or “exacerbation of IPF” and “worsening of PH"). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
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The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
– 
The patient has not experienced an adverse event 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 h after learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from patient reported outcome (PRO) data by 
the Sponsor, and safety analyses will not be performed using PRO data.  However, if 
any PRO responses suggestive of a possible adverse event are identified during site 
review of the PRO data, the Investigator will determine whether the criteria for an 
adverse event have been met and, if so, will report the event on the Adverse Event 
eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 h after the Investigator learns of the event.  The following is a list of 
events that the Investigator must report to the Sponsor within 24 h after learning of the 
event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
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The Investigator must report new significant follow-up information for the events above 
to the Sponsor immediately (i.e., no more than 24 h after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and independent review board/ethics committee 
(IRB/EC). 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the Investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 h per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all Investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained all adverse events should be reported.  The 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
Investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 h after learning of the event), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
Investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 h after 
learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management from the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to Investigators should be completed 
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and submitted to the Sponsor or its designee immediately (i.e., no more than 24 h after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to Investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 12 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 h after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to Investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The Investigator should discontinue study drugs 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
Investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
118 days (17 weeks) after the last dose of study drug.  A Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 h after learning of the pregnancy), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
Investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  The 
pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy.  After the authorization has 
been signed, the Investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
An Investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
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5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 h after learning of the event; 
see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug, or the female partner of a male patient exposed to study drug, should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF and reported to the 
Sponsor immediately (i.e., no more than 24 h after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The Investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the Investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the Investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the Investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
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emailing the Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to Investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to Investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document{s}: 
• 
Pirfenidone Investigator's Brochure 
• 
US Prescribing information (USPI) for Sildenafil 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The intent-to-treat (ITT) population is defined as all randomized patients.  Patients in the 
ITT population will be assigned to treatment groups as randomized. 
The safety population is defined as all patients randomized, taking at least one dose of 
randomized Sildenafil/Placebo treatment.  Patients in the safety population will be assigned 
to treatment groups according to the treatment they received. 
The primary analysis of the study will be conducted when all patients completed the 
52 weeks treatment phase and the mandatory 4 weeks Follow-up visit.  
6.1 
DETERMINATION OF SAMPLE SIZE 
There are no reference data available on the use of pirfenidone in this patient population 
with a measurable DLCO ≤40% of predicated value and mPAP ≥20 mmHg on RHC.  A 
total sample size of approximately 176 patients is planned, and patients will be 
randomized 1:1 to the two treatment groups.  The statistical hypothesis for the treatment 
comparison is based on the proportion of patients who experienced a ≥15% decline from 
baseline in 6MWD, were hospitalized for cardiac- or respiratory non-elective reasons, or 
who died, according to a pooled analysis of the effects observed in the pirfenidone 
groups of three large Phase III trials (CAPACITY 1, CAPACITY 2, and ASCEND). 
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The planned sample size is based on the primary endpoint, proportion of patients with 
disease progression and assumes 80% power and a one-sided significance level of 5%.  
Given the disease progression rate of 72% by 52 weeks in the three large registration 
trials for pirfenidone, and assuming an additive effect of sildenafil on pirfenidone, a 
disease progression rate of 54% in the combination treatment group is assumed and an 
absolute difference of 18% (respectively a relative reduction of 25%) in disease 
progression rates is considered a clinically meaningful treatment benefit. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Patient enrollment, duration of follow up, discontinuation from the study, and reasons for 
discontinuation will be summarized by treatment arm for all randomized patients.  In 
addition, major protocol violations will be summarized by treatment arm. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographics and baseline characteristics, such as age, sex, and race, will be 
summarized by treatment arms using means or medians for continuous variables and 
proportions for categorical variables.  Medical history will be tabulated by treatment arms.  
Summary of concomitant medications will be displayed by treatment arms in frequency 
tables. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include all randomized patients, with 
patients grouped according to their assigned treatment. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy objective for this study is to evaluate the efficacy of adding sildenafil 
compared with placebo to pirfenidone treatment in patients with advanced IPF and risk 
of Group 3 PH.  
The primary efficacy endpoint will be evaluated based on a comparison of the proportion 
of patients showing disease progression over 52 weeks of treatment period, as 
evidenced by reaching the following combined endpoint: 
• 
Relative decline in 6MWD of at least 15% from baseline (as defined below*), 
respiratory-related non-elective hospitalization, or all-cause mortality 
* Relevant decline in 6MWD from baseline is defined as: 
 
Any decline >25% from baseline or 
 
A decline between 15-25% from baseline, if accompanied by at least one of 
the following: 
o worsening of SpO2 desaturation during the 6MWT compared to 
baseline 
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o worsening of the maximum Borg scale during the 6MWT compared to 
baseline  
o increased O2 requirements during the 6MWT compared to baseline. 
 
The primary analysis will be based on the ITT population, defined as all randomized 
patients.  Patients who discontinue treatment prematurely will be analyzed based on the 
available data.  No imputation method will be applied.  Patients who undergo lung 
transplantation during the study will be withdrawn from the study at the time of 
hospitalization for transplantation.  In addition, sensitivity analysis of the primary endpoint 
will be performed.  The details of those analyses will be provided in the Statistical Analysis Plan.  
The primary analysis of the primary endpoint will compare disease progression rates in 
each treatment arm using a Chi-square test with a one-sided significance level α = 0.05. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy objective for this study is to evaluate the efficacy of adding 
sildenafil compared with placebo to pirfenidone treatment on the basis of the following 
endpoints: 
• 
Progression-free survival, defined as time to decline in 6MWD of ≥15% compared 
with baseline (as defined above), respiratory-related non-elective hospitalization, or 
death from any cause will be analyzed using Kaplan-Meier techniques and the two 
treatment arms will be compared with a log-rank test.  In addition, hazard ratios and 
corresponding 95% CI will be calculated by applying Cox-proportional hazard 
models. 
• 
The proportion of patients with decline in 6MWD of ≥15% from baseline (as defined 
above), will be compared using a Chi-square test with a one-sided significance level 
α=0.05.  The change in 6MWD from baseline to 12 months will be analyzed using a 
rank ANCOVA model with the 6MWD recorded at 12 months as the outcome 
variable and standardized rank baseline 6MWD as a covariate. 
• 
Respiratory-related non-elective hospitalization, all-cause mortality, all-cause non-
elective hospitalization and respiratory-related mortality will be analyzed using 
Kaplan-Meier techniques and the two treatment arms will be compared with a 
log-rank test.  In addition, hazard ratios and corresponding 95% CI will be calculated 
by applying Cox-proportional hazard models. 
• 
Changes from Baseline to End of Treatment for the following ECHO parameters: 
o Peak tricuspid regurgitation velocity (m/s) 
o PAPs 
Pulmonary function tests (PFTs), i.e., FVC, FEV1, FEV1/FVC, and DLCO will be 
analyzed in terms of absolute mean changes from baseline to week 52 of treatment in 
actual and % of predicted values.  In addition, 5% and 10% categorical changes from 
baseline will be summarized descriptively.  The change from baseline for all 
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aforementioned parameters will be compared between the treatment arms using a rank 
ANCOVA with change from baseline as outcome variable and standardized rank 
baseline value as covariate. 
• 
Oxyhemoglobin saturation (SpO2) at rest and during the 6MWD will be summarized 
descriptively over time. 
• 
Borg scale measurement of perceived exertion will be summarized descriptively 
over time. 
• 
Lung transplantation will be analyzed descriptively. 
• 
WHO Functional Class will be summarized descriptively over time. 
• 
Dyspnea as assessed by the UCSD SOBQ will be summarized descriptively over 
time.  The change from baseline will be compared between the treatment arms 
using a rank ANCOVA with change from baseline as outcome variable and 
standardized rank baseline value as covariate. 
• 
HRQoL assessed by SGRQ will be summarized descriptively over time.  The 
change from baseline will be compared between the treatment arms using a rank 
ANCOVA with change from baseline as outcome variable and standardized rank 
baseline value as covariate. 
• 
Changes from baseline in in NT-proBNP levels will be summarized descriptively 
over time. 
For all secondary endpoints p-values will be reported in a descriptive fashion.  No 
multiplicity adjustments for statistical testing will be done. 
6.4.3 
Exploratory Efficacy Endpoints 
The following subgroups will be included in this study for primary and selected 
secondary and efficacy endpoints: stratification factors (patients with RHC available at 
baseline and post bronchodilator FEV1/FVC ratio below/above 0.8), younger versus 
elderly, gender, etc. 
Details of subgroup analyses will be given in the Statistical Analysis Plan (SAP). 
All biomarker analyses will be of exploratory nature and be descriptive only. 
6.5 
SAFETY ANALYSES 
The safety objective for this study is to evaluate the safety of adding sildenafil compared 
with placebo to pirfenidone treatment on the basis of the following analyses.  The safety 
analyses will include all randomized patients who received at least one dose of study 
drug, with patients grouped according to treatment received. 
Safety will be assessed by adverse events, adverse events of Grade ≥3, serious 
adverse events, related adverse events, death, adverse events leading to study drug 
discontinuation or interruption, exposure to study medication, premature withdrawal from 
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the study (including reasons [especially withdrawal of consent]) and from the study 
medication, laboratory parameters, ECG and vital signs and summarized by treatment 
arms.  Adverse events and cause of death will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The incidence of adverse events and serious adverse 
events will be summarized by primary system organ class and preferred term.  
Laboratory parameters, vital signs and ECG parameters will be presented descriptively 
over time and change from baseline will be reported.  Findings on physical examinations 
will be summarized descriptively.  The number and percentage of withdrawals from 
study medication or discontinuation from study together with the reasons will be 
summarized descriptively.  The time from randomization until discontinuation will be 
displayed graphically using Kaplan-Meier techniques. 
No formal statistical testing will be performed for safety parameters. 
Data collected in the safety follow-up (i.e., adverse event and deaths) will be analyzed 
descriptively. 
6.6 
INTERIM ANALYSIS 
There are no planned interim efficacy analyses for this study. 
Safety interim analyses will be performed regularly by an iDMC. Efficacy data will only 
be provided if requested by the iDMC.  
Further details on the function and logistics (e.g. frequency of meetings) of the iDMC will 
be provided in the iDMC Charter. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via electronic data capture 
(EDC) through use of eCRFs.  Sites will be responsible for data entry into the EDC 
system.  In the event of discrepant data, the Sponsor will request data clarification from 
the sites, which the sites will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff. 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee. 
At the end of the study, the Investigator will receive patient data for his or her site(s) in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the European Union or European Economic 
Area will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final IRB/EC 
approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The Investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
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consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
Investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
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8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the Investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The Investigator should document and explain any protocol deviations.  The Investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The Investigator will 
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permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
The study will be overseen by a study management team of the Sponsor consisting of a 
clinical study manager, experienced medical staff (International Medical Director), 
statistician, and data management and quality assurance personnel. 
Study monitoring, including data collection (source verification), site initiation and visits 
and adverse event processing (Medical Monitor) will be conducted by the Sponsor.  The 
management of the database will also be performed by the Sponsor. 
The study will be conducted under the leadership of an Executive Steering Committee.  
The Executive Steering Committee is composed of experts in IPF and PH and 
non-voting members representing Roche.  The Executive Committee, together with the 
Sponsor, developed the study protocol and has overall responsibility for the study 
conduct and publication.  
A separate Steering Committee Charter describing roles and responsibilities of the 
members of this committee will be maintained by the Sponsor. 
The safety of the study will be monitored by the iDMC consisting of clinicians and 
statisticians experienced in conduct and safety review of controlled clinical studies. The 
iDMC will perform interim analyses for safety and, if needed review further safety data 
and give recommendation to the Sponsor.  The study will be conducted using IxRS and 
a central laboratory provider. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following website: 
www.roche.com/roche global policy on sharing of clinical study information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
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Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
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country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
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10. 
REFERENCES 
American Thoracic Society (ATS)/European Respiratory Society 2002. American 
Thoracic Society/European Respiratory Society international multidisciplinary consensus 
classification of the idiopathic interstitial pneumonias. Am J Resp Crit Care Med 2002 
American Thoracic Society/European Respiratory Society/Japanese Respiratory Society 
/Latin American Thoracic Association. An Official ATS/ERS/JRS/ALAT Statement: 
Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and 
Management. Am J Respir Crit Care Med 2011;183:788–824. 
du Bois RM. Strategies for treating idiopathic pulmonary fibrosis. Nat Rev Drug Discov 
2010;9:129–140. 
Collard HR, Anstrom KJ, Schwarz MI, et al. Sildenafil improves walk distance in 
idiopathic pulmonary fibrosis. Chest 2007;131(3):897-9. 
Esbriet® EU SPC. 2014. 
Esbriet® (United States label). 2014. Brisbane, CA: InterMune, Inc.  
Fernández Pérez ER, Daniels CE, Schroeder DR, St Sauver J, Hartman TE, 
Bartholmai BJ, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary 
fibrosis. A population based study. Chest 2010;137:129–137. 
F. Hoffmann-La Roche Ltd. Investigator’s Brochure RO220912 Esbriet (pirfenidone) 
current version and associated addendums. 
 
Galie N, Humbert M, Vachieryc J-L, et al. ESC/ERS Guidelines for the diagnosis and 
treatment of pulmonary hypertension. Eur Heart J 2015;ehv317 67-119. 
Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil foe treatment of lung fibrosis and 
pulmonary hypertension: a randomised controlled trial. Lancet 2002;360(9337):895-900. 
Hallstrand TS, Boitano LJ, Johnson WC, et al. The timed walk test as a measure of 
severity and survival in idiopathic pulmonary fibrosis. Eur Respir J 2005;25:96–103. 
Han MK, Bach DS, Hagan PG, et al. Sildenafil preserves exercise capacity in patients 
with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013; 
143(6):1699–1708. 
Hassoun PM, Nathan SD. Sildenafil for pulmonary hypertension complicating idiopathic 
pulmonary fibrosis: a rationale grounded in basic science. Eur Respir J. 2016 
47(6):1615-1617. 
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Hirano A, Kanehiro A, Ono K, et al. 2006. Pirfenidone modulates airway responsiveness, 
inflammation, and remodeling after repeated challenge. Am J Respir Cell Mol Biol 
35(3):366–377.  
IPFibrosis Clinical Research Network. A controlled trial of sildenafil in advanced 
idiopathic pulmonary fibrosis. N Engl J Med 2010; 363:620-628. 
Jackson RM, Glassberg MK, Ramos CF, et al. Sildenafil therapy and exercise tolerance 
in idiopathic pulmonary fibrosis. Lung 2010;188(2):115-23. 
King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in 
patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083-2092. 
Lancaster L, Albera C, Bradford WZ, et al. Safety of pirfenidone in patients with 
idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials. 
BMJ Open Resp Res 2016;3:e000105 doi:10.1136/bmjresp-2015-000105. 
Lettieri CJ, Nathan SD, Barnett SD, et al. Prevalence and outcomes of pulmonary 
arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006;126:746-752. 
Lynch JP III, Toews GB. Idiopathic pulmonary fibrosis. Fishman's Pulmonary Diseases 
and Disorders. A.P. Fishman. New York, McGraw-Hill. 1998;1:1069–1084. 
Milara J, Escrivá J, Ortiz JL, et al. Vascular effects of sildenafil in patients with 
pulmonary fibrosis and pulmonary hypertension: an ex vivo/in vitro study. Eur Respir J 
2016; 47: 1737–1749. 
Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with 
idiopathic pulmonary fibrosis. Chest 2005;128(4):2393-9. 
Nalysnyk L, Cid-Ruzafa J, Rotella P, et al. Incidence and prevalence of idiopathic 
pulmonary fibrosis: review of the literature. Eur Respir Rev 2012;21:355–361. 
Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic 
pulmonary fibrosis (CAPACITY): two randomised trials: Lancet 2011; 377:1760-1769. 
Noble PW, Albera C, Bradford WZ, et al. Pirfenidone for idiopathic pulmonary fibrosis: 
analysis of pooled data from three multinational phase 3 trials. Eur Respir J. 2016 
Jan;47(1):243-53. 
Oku H, Shimizu T, Kawabata T, et al. Antifibrotic action of pirfenidone and prednisolone: 
different effects on pulmonary cytokines and growth factors in bleomycin-induced murine 
pulmonary fibrosis. Eur J Pharmacol 2008;590:400–408. 
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PCLN-PIRF-009. 2008. Dietary intake of pirfenidone ameliorates bleomycin induced lung 
fibrosis in hamsters. NCR104 Rev 01. InterMune, Inc.  
PCLN-PIRF-010. 2004. Investigations on the mechanism(s) of action of pirfenidone. Ono 
RS1083-T40. InterMune, Inc. 
Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810–816. 
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: 
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. 
Am J Respir Crit Care Med 2011;183:788–824. 
Rubin LJ. Diagnosis and Management of Pulmonary Arterial Hypertension: ACCP 
Evidence-Based Clinical Practice Guidelines CHEST 2004;126:7S–10S). 
Schaefer CJ, Ruhrmund DW, Pan L, et al. Antifibrotic activities of pirfenidone in animal 
models. Eur Respir Rev 2011;20:85–97.  
Simonneau, MD, Gatzoulis MA, Adatia I, et al. Updated Clinical Classification of 
Pulmonary Hypertension. Journal of the American College of Cardiology 2013;Vol 62, 
No. 25, Suppl D  
Swigris JJ, Kuschner WG, Jacobs SS, et al. Health-related quality of life in patients with 
idiopathic pulmonary fibrosis: a systematic review. Thorax 2005;60(7):588–594. 
Tomioka J, Imanaka K, Hashimoto K, et al. Health-related quality of life in patients with 
idiopathic pulmonary fibrosis: Cross-sectional and longitudinal study. Internal Medicine: 
The Japanese Society of Internal Medicine 2007;46(18):1533–1542. 
Wuyts W, Antoniou KM, Borensztain K, et al. Combination therapy: the future of 
management for idiopathic pulmonary fibrosis? Lancet Resp Med 2014: 2(11): 933–42. 
 
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97 
Appendix 1  
Schedule of Assessments 
Day 
Week 
Washouta 
Screeningb 
Double blind treatment phase 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up (FU) 
Additional 
safety FUi 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Informed 
Consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
and Baseline 
Conditions 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain and 
Review 
Historical 
PFTs, HRCT*, 
Surgical Lung 
Biopsy, and 
RHC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Excl-
usion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1 
Schedule of Assessments (cont.) 
Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
98/Protocol MA29957, Version 2 
Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up 
Additional 
safety FU i, 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Approx. 
every 3 
months 
Spirometry 
post broncho-
dilator (FVC, 
FEV1, FEV1/ 
FVC) d 
 
X 
X d1 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
DLCO e 
 
X 
X e1 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
6MWT and 
SpO2 (resting, 
nadir, and end 
of test) f 
 
X 
Xf 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Borg scale 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
WHO 
Functional 
Class 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NT-proBNP, 
CRP, 
aldosterone 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Urinalysis 
 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Urine 
Pregnancy 
Test g 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Appendix 1 
Schedule of Assessments (cont.) 
Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
99/Protocol MA29957, Version 2 
Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up  
Additional 
safety FU i, 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Serum 
Pregnancy 
Test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
ECHO 
 
X h 
X h1 
 
 
 
 
X 
 
 
 
X 
X 
 
 
SGRQ 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
UCSD SOBQ 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Serum and 
plasma for 
optional 
biomarker 
assessment 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
PAXgene for 
optional 
biomarker 
assessment 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
optional DNA 
biomarker 
assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1 
Schedule of Assessments (cont.) 
Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
100/Protocol MA29957, Version 2 
Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up 
Additional 
safety FU i,  
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Review Dosing 
Adherence 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review Patient 
Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense/ 
Collect Patient 
Diary 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Dispense 
Wallet Card 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pirfenidone 
treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X j 
Dispense 
Sildenafil/ 
Placebo and 
Explain Dosing 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect Unused 
Sildenafil/ 
Placebo and 
Empty Bottles 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
6MWT  6-minute walk test; DLCO   pulmonary diffusion capacity; ECG  electrocardiogram; ECHO  echocardiography; NT-proBNP  N-terminal 
pro-brain natriuretic peptide; RHC  right-heart catheterization; SGRQ  Saint George's Respiratory Questionnaire; UCSD SOBQ = University of 
California San Diego Shortness of Breath questionnaire; SpO2  oxyhemoglobin saturation. 
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1 
Schedule of Assessments (cont.) 
Pirfenidone and sildenafil—F. Hoffmann-La Roche Ltd 
101/Protocol MA29957, Version 2 
______________________________________________________________________________________________ 
* Collect from randomized patients the most recent HRCTs performed prior to entering the study  
a Patients taking prohibited medications at the time of consent must, after consent, discontinue the prohibited medications 28 days prior to the 
start of Screening (Day -57 to -29). If a prohibited medication must be tapered, tapering will be followed by discontinuation, and the 
discontinuation should last at least 28 days (washout period) before the start of screening.  Patients that do not require Washout proceed directly 
to Screening.  In addition, a run-in period will be provided for countries where patients will not be able to take pirfenidone for 12 weeks due to 
reimbursement issues.  After signing the ICF, the 12-week run-in pirfenidone supply will be provided by the Sponsor.   
b The Screening Period of up to 28 days may comprise one or more visits for the convenience of the patient. 
c Written informed consent will be obtained prior to any study procedures, either prior to Washout or if not applicable, prior to Screening. 
d Spirometry will be performed only post-bronchodilator.  Reference equations for spirometric indices will be provided in the Procedure Manual. 
d1 Should Spirometry at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening Spirometry 
can be used as baseline 
e The reported DLCO will be corrected for the current hemoglobin level, using reference equations. 
e1 Should DLCO at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening DLCO can be 
used as baseline 
f The 6MWT will be performed once at each visit highlighted.  At Baseline, it will be performed twice and the better of the two 6MWD values will be 
reported.  Please refer to the 6MWT Procedure Manual. 
g If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
h ECHO assessment at screening is not required for eligible patients based on RHC criteria.  
h1 Should the ECHO at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening ECHO can be 
used as baseline 
i The sponsor will offer the possibility to the patients to receive pirfenidone within the study protocol up to a 11 months safety follow up.  During 
this interval the patients should be evaluated approximately every three months. 
j During the additional safety FU, data related to the pirfenidone administration will not be collected on the CRF.    
"Use of this document is governed by the terms of use on the first page of this document."

SAP_001.pdf: 
 
 
CONFIDENTIAL 
 
This is a F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE IIb, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY, SAFETY, AND TOLERABILITY OF 
SILDENAFIL ADDED TO PIRFENIDONE IN PATIENTS WITH 
ADVANCED IDIOPATHIC PULMONARY FIBROSIS AND 
RISK OF GROUP 3 PULMONARY HYPERTENSION 
PROTOCOL NUMBER: 
MA29957 
STUDY DRUG: 
Pirfenidone (Esbriet®) and Sildenafil (RO0280296) 
VERSION NUMBER: 
Version 1.0 Final, 21-August-2019 
IND NUMBER: 
67284 
EUDRACT NUMBER: 
2015-005131-40 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
Sara Prada (Clinipace) 
Frank Gilberg (F. Hoffmann-La Roche Ltd)  
DATE FINAL: 
21 August 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Statistical Analysis Plan MA29957, Version 1.0, Final, 21-August-2019   
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STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
Not applicable, as this is the first version of the Statistical Analysis Plan. 


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Statistical Analysis Plan MA29957, Version 1.0, Final, 21-August-2019   
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TABLE OF CONTENTS 
SIGNATURE PAGE ......................................................................................................... 2 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ........................................ 3 
1. 
BACKGROUND ..................................................................................................... 10 
2. 
STUDY DESIGN ................................................................................................... 11 
2.1 
Protocol Synopsis........................................................................... 12 
2.2 
Outcome Measures ........................................................................ 12 
2.2.1 
Primary Efficacy Outcome Measures.............................................. 12 
2.2.2 
Secondary Efficacy Outcome Measures ......................................... 12 
2.2.3 
Patient-Reported Outcome Measures ............................................ 13 
2.2.4 
Safety Outcome Measures ............................................................. 13 
2.3 
Determination of Sample Size ........................................................ 14 
2.4 
Analysis Timing .............................................................................. 14 
3. 
STUDY CONDUCT ............................................................................................... 14 
3.1 
Randomisation, blinding and unblinding procedures ....................... 15 
3.2 
Independent Review Facility ........................................................... 15 
3.3 
Data Monitoring .............................................................................. 15 
4. 
STATISTICAL METHODS ..................................................................................... 15 
4.1 
Analysis Populations ...................................................................... 16 
4.1.1 
All patients enrolled ........................................................................ 16 
4.1.2 
Intent-to-treat Population ................................................................ 16 
4.1.3 
Per Protocol Population .................................................................. 16 
4.1.4 
Safety Population ........................................................................... 16 
4.1.5 
Safety Follow-up Population ........................................................... 16 
4.2 
Trial Periods, Observation and analysis times ................................ 17 
4.2.1 
Study Days ..................................................................................... 17 
4.2.2 
Baseline and Screening Observations ............................................ 17 
4.2.3 
On-treatment Assessments for Efficacy Analyses 
(Double-blind Treatment Period) ........................................................................ 18 
4.2.4 
On-treatment Assessments for Safety Analyses 
(Double-blind Treatment Period) ........................................................................ 18 


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4.2.5 
Assessments during 11-months Safety Follow-up 
Period 
 ....................................................................................................... 18 
4.2.6 
Cut-off points .................................................................................. 18 
4.3 
Analysis of Treatment Group Comparability ................................... 18 
4.4 
Analysis of Study Conduct .............................................................. 19 
4.4.1 
Patient Disposition .......................................................................... 19 
4.4.2 
Major Protocol Deviations ............................................................... 20 
4.4.3 
Demographic and Baseline Characteristics .................................... 21 
4.4.4 
Previous and Concomitant Medication ........................................... 25 
4.5 
Efficacy Analysis ............................................................................ 25 
4.5.1 
Primary Efficacy Endpoints ............................................................. 25 
4.5.2 
Secondary Efficacy Endpoints ........................................................ 27 
4.5.3 
Exploratory Efficacy Endpoints ....................................................... 31 
4.5.4 
Analyses of Patient-Reported Outcomes ........................................ 31 
4.5.5 
Sensitivity Analyses ........................................................................ 32 
4.5.6 
Subgroup Analyses ........................................................................ 33 
4.6 
Pharmacokinetic and Pharmacodynamic Analyses ........................ 34 
4.7 
Safety Analyses ............................................................................. 34 
4.7.1 
Exposure to Study Medication ........................................................ 35 
4.7.1.1 Treatment duration ........................................................................ 35 
4.7.1.2 Doses and Dose modifications or interruptions .............................. 36 
4.7.2 
Discontinuations from double-blind treatment period ...................... 36 
4.7.3 
Discontinuations from the study ...................................................... 36 
4.7.4 
Adverse Events .............................................................................. 37 
4.7.4.1 Adverse events prior to the double-blind treatment 
period 
 ...................................................................................................... 37 
4.7.4.2 Adverse events during double-blind treatment period .................... 37 
4.7.4.3 Adverse events after the double-blind treatment 
period 
 ...................................................................................................... 40 
4.7.5 
Deaths ............................................................................................ 40 
4.7.6 
Pregnancies ................................................................................... 40 
4.7.7 
Laboratory Data ............................................................................. 40 
4.7.8 
Vital Signs ...................................................................................... 42 
4.7.9 
ECG ............................................................................................... 42 


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4.8 
Safety follow-up analyses ............................................................... 43 
4.9 
Missing Data .................................................................................. 43 
4.10 
Visit Windows ................................................................................. 45 
4.11 
Interim Analyses ............................................................................. 48 
4.12 
Biomarker Analyses (optional) ........................................................ 48 
5. 
REFERENCES ...................................................................................................... 50 
 
 
LIST OF TABLES 
Table 1 Definition of Baseline and Screening Observations ........................................... 17 
Table 2 Visit Windows for 6MWT, laboratory data, vital signs, WHO functional 
class (Assessments made at every planned visit) ................................ 45 
Table 3 Visit Windows for ECG, ECHO and weight data ............................................... 46 
Table 4 Visit Windows for Borg scale, DLCo, spriometry tests and GAP score .............. 47 
Table 5 Visit Windows for NT-ProBNP, CRP, aldosterone and urinalysis ...................... 47 
Table 6 Visit Windows for SGRQ and UCSD SOBQ ...................................................... 48 
Table 7 GAP Index and Staging System ........................................................................ 60 
 
LIST OF APPENDICES 
APPENDIX 1 SCHEDULE OF ASSESSMENTS ............................................................ 52 
APPENDIX 2 ENDPOINT DECISION PROCESS .......................................................... 57 
APPENDIX 3 MEDDRA BROWSER BASKET: ESBRIET – POTENTIAL 
HY’S LAW AEGT ................................................................................................... 58 
APPENDIX 4 CALCULATION OF GAP INDEX CATEGORIES ..................................... 60 
APPENDIX 5 UCSD-SOBQ ........................................................................................... 61 
APPENDIX 6 ST. GEORGE’S RESPIRATORY QUESTIONNAIRE 
(SGRQ) 
 ....................................................................................................... 65 
APPENDIX 7 SCORING ALGORITHM: SGRQ ............................................................. 71 
APPENDIX 8 ACUTE EXACERBATIONS ..................................................................... 78 
 


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LIST OF ABBREVIATIONS 
Abbreviation  
Definition  
AE 
Adverse event  
ALAT  
Latin American Thoracic Society  
ALT  
Aalanine aminotransferase  
ANCOVA  
Analysis of covariance  
AST  
Aspartate aminotransferase  
ATS  
American Thoracic Society  
AUC0-∞  
Area under the concentration-time curve from time zero to 
infinity  
AV  
Atrioventricular  
BCE  
Biostatistical Computing Environment  
BID  
Twice daily  
BMI  
Body Mass Index 
BP  
Blood pressure  
BUN  
Blood urea nitrogen  
cGMP  
Cyclic guanosine monophosphate  
CI  
Confidence interval  
Cmax  
Maximum concentration  
COPD  
cChronic obstructive pulmonary disease  
CRP  
C-reactive protein  
CSP 
Clinical study protocol 
CYP  
Cytochrome  
DBP  
Diastolic blood pressure  
DLco 
Carbon monoxide diffusing capacity/ pulmonary diffusing 
capacity  
DNA  
Deoxyribonucleic acid  
EC  
Ethics committee  
ECG  
Electrocardiogram  
ECHO  
Echocardiography  
eCRF  
Electronic Case Report Form  
EDC  
Electronic data capture  
EEMEA  
Eastern Europe, Middle East, and Africa  
ERS  
European Respiratory Society  
ESC  
European Society of Cardiology  
EU  
European Union  
ERK1/2  
Extracellular regulated kinases 1 and 2  
FDA  
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second  
FVC  
Forced vital capacity  
GAP  
Gender, age and physiology  
GCP  
Good Clinical Practice  
GGT  
Gamma-glutamyl-transferase  
GI 
Gastrointestinal  
GNE  
Genentech drug dictionary  
GWAS  
Genome-wide association study  
HLT 
High level term  
HR  
Hazard ratio  
HRCT  
High-resolution computed tomography  


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HRQoL  
Health related quality of life  
5-HT  
Serotonin  
ICF 
Inform Consent Form  
ICH  
International Conference on Harmonisation  
iDMC  
Independent Data Monitoring Committee  
IL  
Interleukin  
ILD  
Interstitial lung diseases 
IMP  
Investigational medicinal product  
IND  
Investigational New Drug  
IPF  
Idiopathic pulmonary fibrosis  
IRB  
Independent review board  
ITT  
Intent-to-treat  
IxRS  
Interactive voice or web-based response system  
JRS  
Japanese Respiratory Society  
KM  
Kaplan-Meier 
LDH  
Lactate dehydrogenase  
LPLV  
Last patient last visit  
LVEF  
Left ventricular ejection fraction 
MedDRA  
Medical Dictionary for Regulatory Activities  
mPAP  
Mean pulmonary artery pressure  
6MWD  
6-minute walk distance  
6MWT  
6-minute walk test  
NAC  
N-acetylcysteine  
NAION  
Nonarteritic ischemic optic neuropathy  
NCI CTCAE  
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
NT-proBNP  
N-terminal pro-brain natriuretic peptide  
NYHA  
New York Heart Association  
O2 
Oxygen  
PAH  
Pulmonary arterial hypertension  
PAP  
Pulmonary artery pressure  
PAWP  
Pulmonary artery wedge pressure  
PDE5  
Phosphodiesterase-5  
PDGF  
Platelet-derived growth factor  
PDMS  
Protocol Deviation Management System  
PFS 
Progression-free survival  
PFTs  
Pulmonary function tests  
PH  
Pulmonary hypertension  
PK  
Pharmacokinetics  
PRO  
Patient reported outcome  
PP  
Per-protocol  
PT  
Preferred Term 
QD  
Daily  
QTc  
Corrected QT interval  
QTcF  
Corrected QT interval using Fridericia’s formula  
RBC  
Red blood cells  
RHC  
Right heart catheterization  
RNA  
Ribonucleic acid  
SAE 
Serious adverse event  
SAP  
Statistical Analysis Plan  
SBP  
Systolic blood pressure  


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9 
 
SGRQ  
Saint George’s Respiratory Questionnaire  
SMQ 
Standardized MedDRA queries 
SOC  
System Organ Class  
SOP  
Standard operating procedure  
SPC  
Summary of Product Characteristics  
SPF  
Sun protection factor  
SpO2  
Oxyhemoglobin saturation  
TAPSE  
Tricuspid annular plane systolic excursion 
TEAE  
Treatment-emergent adverse event  
TGF-β  
Transforming growth factor-beta  
TID  
Three times daily  
TRV  
Tricuspid regurgitation velocity  
UCSD SOGQ 
University of California San Diego Shortness of Breath 
Questionnaire 
ULN  
Upper limit of normal  
US  
United States  
USP  
United States Pharmacopeia  
UV-A  
Ultraviolet A  
UV-B  
Ultraviolet B  
WBC  
White blood cells  
WHO  
World Health Organization  
 
 
 


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1. 
BACKGROUND 
As described in the Clinical Study Protocol (CSP, Section 1.3), the diagnosis of 
idiopathic pulmonary fibrosis (IPF) carries a bleak prognosis, with progressive disability 
due to respiratory insufficiency (Hallstrand et al. 2005). Pulmonary hypertension (PH) is 
a major contributor to morbidity and mortality in patients with advanced IPF with an 
adverse impact on survival (Nadrous et al. 2005, Lettieri et al. 2006.). This study is 
designed to assess the treatment of patients with advanced IPF who have evidence 
suggesting PH, which is most likely caused by IPF.  
While drugs used to treat PH have either not been effective for treatment of IPF 
(bosentan, ambrisentan, macicentan) or are unlikely to be able to address the 
parenchymal changes in the fibrotic process, anti-fibrotic drugs are unlikely to have any 
notable effect on the perfusion aspects of interstitial lung diseases (ILDs). Therefore, 
combination treatment appears as a promising approach to the major clinical problem of 
combined IPF and PH (Wuyts et al. 2014).  
In this study, pirfenidone (Esbriet®) administration will be combined with sildenafil 
(generic formulation). As sildenafil induces vasodilatation preferentially in well-ventilated 
lung areas, such vasodilatation could improve ventilation-perfusion matching and thus 
gas exchange in patients with IPF (Ghofrani et al. 2002). The combination of pirfenidone 
and sildenafil represents a promising approach to treat patients with advanced IPF and 
secondary PH.  
The expected benefits of the sildenafil/pirfenidone combination relate to the anticipated 
improvements in both pulmonary hemodynamics and pulmonary function. A reduction in 
pulmonary vascular resistance by sildenafil would be expected to improve mean 
pulmonary artery pressure (mPAP), reducing strain on the right ventricle and improving 
cardiac output, assuming that left ventricular function and systemic vascular resistance 
are not adversely affected. Secondary benefits, such as reduced risk of right heart 
failure, cardiac arrhythmias, cardiac-related hospitalizations, and cardiac-related death 
might also ensue. Improvement in ventilation/perfusion matching by sildenafil would be 
expected to improve gas transfer in the lung. An increase in oxyhemoglobin saturation, 
along with an improvement in cardiac output, would be expected to have a beneficial 
effect on functional exercise capacity. These possible benefits of sildenafil, together with 
the known benefits of pirfenidone in slowing the rate of decline in lung function, might 
have a benefit on reducing respiratory decompensation and related hospitalizations.  
The Sponsor is expecting that the benefit-risk comparison for patients participating in 
this study of pirfenidone with sildenafil is positive. 


Pirfenidone and Sildenafil/Placebo — F. Hoffmann-La Roche Ltd 
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11 
 
2. 
STUDY DESIGN 
This is a Phase IIb, randomized, placebo-controlled, multicenter, international study of 
the efficacy, safety, and tolerability of combination treatment with sildenafil and 
pirfenidone in patients with advanced IPF and risk of Group 3 PH, who have been on 
pirfenidone treatment in a dose range of 1602 to 2403 mg/day for at least 12 weeks with 
demonstrated tolerability. 
Approximately 176 patients will be enrolled at approximately 75 clinical centers in 
Canada, Europe (EU) and Eastern Europe, Middle East, Africa (EEMEA), and potentially 
Asia-Pacific. Patients who are withdrawn from the study will not be replaced.  
On providing written informed consent, patients will be instructed to stop taking their 
commercial pirfenidone and start taking the study-provided pirfenidone. 
Patients will also be required to discontinue all prohibited medications and undergo a 28-
day Washout Period. After completing the Washout Period, patients will enter a 
Screening Period, which lasts up to 28 days; during Screening, patients will be evaluated 
for eligibility based on the inclusion and exclusion criteria. Patients that are not taking a 
prohibited medication will forgo the Washout Period and enter Screening directly.  
A run-in period will be provided for countries where patients will not be able to take 
pirfenidone for 12 weeks due to reimbursement issues. After signing the informed 
consent form, the 12 week run-in pirfenidone supply will be provided by the Sponsor.  
In summary, the study consists of 5 phases:  
• 
Run-in period of 12 weeks (if needed)  
• 
Screening period  
o +/- 28-day washout period (if needed); this can be part of the run-in period 
if the run-in period is applicable. 
o Screening period (up to 28 days). Patients will be evaluated for eligibility 
based on the inclusion and exclusion criteria  
• 
Double-blind treatment period (52 weeks)  
• 
Follow-up period (4 weeks)  
• 
Additionally, there will be the possibility for patients to receive pirfenidone within 
the study protocol after the Follow-up visit at week 56, for up to 11-months safety 
follow-up. During this time the patients should be evaluated by the treating 
physician approximately every three months.  
 


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2.1 
PROTOCOL SYNOPSIS 
Please refer to the Protocol Version 2, 01 December 2017 (and its Appendices). 
2.2 
OUTCOME MEASURES 
The primary objective for this study is to investigate the efficacy, safety and tolerability of 
sildenafil compared with placebo when added to pirfenidone in patients with advanced 
IPF and risk of Group 3 PH.  
2.2.1 
Primary Efficacy Outcome Measures 
The primary objective of the study is to evaluate the efficacy of adding sildenafil 
compared with placebo, to pirfenidone treatment. 
The primary efficacy endpoint will be evaluated based on a comparison of the proportion 
of patients showing disease progression over 52 weeks of treatment period, as 
evidenced by reaching the following combined endpoint:  
Relevant decline in 6-minute walk distance (m) (6MWD) of at least 15% from baseline 
(as defined below*), respiratory-related non-elective hospitalization, or all-cause 
mortality  
* Relevant decline in 6MWD from baseline is defined as:  
• 
Any decline >25% from baseline or  
• 
A decline between 15-25% from baseline, if accompanied by at least one of the 
following: 
o worsening of SpO2 desaturation (%) at the end of the 6-minute walk test 
(6MWT) compared to baseline  
o worsening of the maximum Borg scale at the end of the 6MWT compared 
to baseline  
o increased O2 (L) requirements at the end of the 6MWT compared to 
baseline.  
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy objective for this study is to evaluate the efficacy of adding 
sildenafil compared with placebo to pirfenidone treatment. 
The secondary efficacy endpoints are the followings: 
• 
Progression-free survival (PFS), defined as time to decline in 6MWD of ≥15% 
compared with baseline as defined in Section 2.2.1, respiratory-related non-
elective hospitalization, or death from any cause 
• 
Proportion of patients with decline in 6MWD of ≥15% from baseline as defined in 
Section 2.2.1 


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• 
Time to respiratory-related non-elective hospitalization 
• 
Time to death from any cause 
• 
Lung transplantation 
• 
Time to all-cause non-elective hospitalization 
• 
Time to respiratory-related death 
• 
Change from baseline in transthoracic echocardiography (ECHO) parameters 
• 
Change from baseline in pulmonary function tests (PFTs) 
• 
Change from baseline in SpO2 at rest and during the 6MWT (end of test and 
lowest SpO2)  
• 
World Health Organization (WHO) Functional Class 
• 
Dyspnea (assessed by the University of California San Diego Shortness of 
Breath Questionnaire [UCSD SOGQ]) 
• 
Health-related quality of life (HRQoL) (assessed by the Saint George’s 
Respiratory Questionnaire [SGRQ]) 
• 
Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) 
level  
 
2.2.3 
Patient-Reported Outcome Measures 
Patient-reported outcomes (PROs) will be used to assess health-related quality of life 
(HRQoL) and Dyspnea. The two questionnaires used are: 
• 
HRQoL assessed by the SGRQ 
• 
Dyspnea assessed by the UCSD SOBQ 
2.2.4 
Safety Outcome Measures 
The safety objective for this study is to evaluate the safety of adding sildenafil compared 
with placebo to pirfenidone treatment on the basis of the following endpoints:  
• 
Nature, frequency, severity, relationship and timing of treatment-emergent 
adverse events (TEAEs) 
• 
Changes in vital signs 
• 
Clinical laboratory test results 
• 
12-lead electrocardiograms (ECGs) 
• 
Exposure to study drug 


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• 
Study discontinuation or study drug discontinuation 
2.3 DETERMINATION OF SAMPLE SIZE 
There are no reference data available on the use of pirfenidone in this patient population 
with a measurable DLco ≤ 40% of predicated value and mPAP ≥ 20 mmHg on right heart 
catheterization (RHC). A total sample size of approximately 176 patients is planned, and 
patients will be randomized 1:1 to the two treatment groups. The statistical hypothesis 
for the treatment comparison is based on the proportion of patients who experienced a 
≥15% decline from baseline in 6MWD, were hospitalized for cardiac- or respiratory non-
elective reasons, or who died, according to a pooled analysis of the effects observed in 
the pirfenidone groups of three large Phase III trials (CAPACITY 1, CAPACITY 2, and 
ASCEND).  
The planned sample size is based on the primary endpoint, proportion of patients with 
disease progression, and assumes 80% power and a one-sided significance level of 5%. 
Given the disease progression rate of 72% by 52 weeks in the three large registration 
trials for pirfenidone, and assuming an additive effect of sildenafil on pirfenidone, a 
disease progression rate of 54% in the combination treatment group is assumed and an 
absolute difference of 18% (respectively a relative reduction of 25%) in disease 
progression rates is considered a clinically meaningful treatment benefit.  
Patients who are withdrawn from the study will not be replaced. 
2.4 
ANALYSIS TIMING 
Independent data monitoring committees will meet approximately every three months to 
review the accumulating safety data. Additional ad hoc meetings or data reviews can be 
requested at any time by the iDMC or the Sponsor, if warranted. 
The primary analysis of the primary endpoint will be performed when all data points are 
collected on the database up to the last patients last visit (LPLV) that is planned to occur 
at week 56 after randomization of the last patient into the study. Therefore, the primary 
analysis of the study will be conducted when all patients completed the 52 weeks 
treatment phase and the mandatory 4 weeks follow-up visit.  
An analysis of the safety follow-up data will be performed approximately one year after 
the primary analysis for this study has been conducted. 
3. 
STUDY CONDUCT 
The study design is described in Section 2. After the double-blind treatment period (52 
weeks or early discontinuation + 4 weeks follow-up) the sponsor will offer the possibility 
to the patients to receive pirfenidone within the study protocol or up to 11-months safety 
follow-up.  


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 Following, there will be two parts for the analysis: 
• 
Analysis of efficacy and safety data recorded during the double-blind treatment 
period 
• 
Summary of safety data recorded during the 11-month follow-up period when 
patients receive pirfenidone alone. 
3.1 
RANDOMISATION, BLINDING AND UNBLINDING PROCEDURES 
Patients will be randomized 1:1 to receive either pirfenidone plus sildenafil or pirfenidone 
plus placebo. The randomization process will be conducted using a validated interactive 
voice or web-based response system (IxRS). To guard against systematic selection bias 
and ensure comparability of treatment groups, the randomization will be stratified by 
availability of a previous RHC (yes/no) and by FEV1/FVC ratio below/above 0.8 to 
ensure an equal distribution of patients with some degree of pulmonary obstruction in 
both treatment groups.  
To maintain the double-blind nature of the study, the sildenafil and placebo treatments 
will be identical in appearance (see Protocol Section 4.3.1.2).  
The investigational site personnel and the patients will be blinded to treatment 
assignment from randomization onwards. The iDMC and any personnel performing 
interim analysis (as applicable) will be unblinded to treatment throughout the study. 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 
3.3 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will review safety data and advise 
on study conduct approximately every three months. Efficacy data will only be provided if 
requested by the iDMC. For details please see Section 4.11. 
4. 
STATISTICAL METHODS 
Generally, presentations will be provided for each treatment group. 
Categorical data will be summarized using frequencies and percentages (including a 
category for missing, if appropriate). Percentages will be based on the number of 
patients in each treatment group for the analysis population, if not otherwise specified. 
Continuous endpoints will be summarized using descriptive statistics (mean, standard 
deviation, minimum, 25th and 75th quartiles, median, and maximum).  
If not otherwise specified, changes will denote absolute changes and will generally be 
changes from baseline to the corresponding time point. 


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Where data will be summarized over time, the following time points will be presented, as 
applicable: baseline, weeks 1, 3, 6, 12, 19, 26, 32, 39, 45, 52, follow-up visit and early 
discontinuation visit. 
Safety data recorded in the 11-month follow-up period will be presented in a separate 
summary as described in Section 4.8.  
Where applicable other analysis methods will be specified below. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
All patients enrolled 
All patients enrolled are all patients that signed the Inform Consent Form (ICF). 
4.1.2 
Intent-to-treat Population 
The intent-to-treat (ITT) population is defined as all randomized patients. Patients in the 
ITT population will be assigned to treatment groups as randomized (planned treatment). 
The ITT population is the primary analysis population for all efficacy analyses. The time 
period for all efficacy analyses is defined from date of randomization until the 
randomized treatment completion date or the date of early discontinuation, collected on 
the early discontinuation eCRF page for patients not completing the planned 52 weeks 
of treatment. 
4.1.3 
Per Protocol Population 
Not applicable. 
4.1.4 
Safety Population 
The safety population will include all randomized patients who have received at least 
one nonzero or positive dose of randomized study drug (sildenafil/placebo). Patients in 
the safety population will be assigned to treatment groups according to the treatment 
they received (actual treatment). 
All safety analyses for the double-blind period will be performed from the first day of 
randomized sildenafil/placebo treatment until treatment completion/discontinuation date 
plus 28 days.  
4.1.5 
Safety Follow-up Population 
The safety follow-up population will be defined as all patients who have received at least 
one positive dose of pirfenidone after the end of double-blind treatment period without 
being completed or discontinued from the study. 
Safety analyses for the 11-month follow-up period will be performed during the safety 
follow-up period, which starts 29 days after end of double-blind period until end of study. 


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4.2 
TRIAL PERIODS, OBSERVATION AND ANALYSIS TIMES 
Where durations are to be calculated (e.g. treatment duration), these will be derived 
based on the interval in days (end date – start date + 1) and converted to months and 
years if needed, using 30.4375 and 365.25, respectively, as denominator if not otherwise 
specified.  
4.2.1 
Study Days 
Study days will be defined as the number of days since randomization, and is calculated 
as: 
• 
Study day = Assessment date – randomization date + 1, for assessments on or 
after the randomization date. 
• 
Study day = Assessment date – randomization date, for assessments before the 
randomization date. 
The day of randomization will be study day 1.  
4.2.2 
Baseline and Screening Observations 
Table 1 
Definition of Baseline and Screening Observations 
 
Definition 
Baseline data 
Baseline is defined as the last valid assessment up to the date of the 
first intake of randomized study drug (sildenafil/placebo). 
 
This may not be the same as the Day 1 (Week 1) visit as per eCRF. 
In case that Day 1 (Week 1) visit data is missing and the randomized 
treatment is given, data from the screening period will be used as 
baseline. In addition, if randomized treatment is not given then 
baseline will be defined as the last valid assessment collected either. 
 
Generally, it is assumed that measurements referring to the Day 1 
(Week 1) visit have been performed before randomized study drug 
(sildenafil/placebo) was given. 
 
Adverse events occurring on the date of first randomized 
sildenafil/placebo treatment will not be considered baseline, but 
treatment-emergent. 
Screening data Screening measurements are all the measurements performed 
before the randomization date. 
 


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4.2.3 
On-treatment Assessments for Efficacy Analyses (Double-blind 
Treatment Period) 
On-treatment assessments will be the assessments performed on or after the 
randomization date until the double-blind treatment completion or discontinuation date. 
4.2.4 
On-treatment Assessments for Safety Analyses (Double-blind 
Treatment Period) 
On-treatment assessments will be the assessments performed on or after the date of 
first dose of randomized sildenafil/placebo treatment until the double-blind treatment 
completion or discontinuation date plus 28 days.  
4.2.5 
Assessments during 11-months Safety Follow-up Period 
Details of adverse events recorded during the 11-month safety follow-up period will be 
presented. This period starts 29 days after the date of completion of double-blind 
treatment period for patients who completed the double-blind period and received a 
positive dose of Pirfenidone after end of double-blind period, without being completed or 
discontinued the study. The safety follow-up period ends with the study 
completion/discontinuation visit, with a maximum of 11 months. Safety follow-up 
analyses will be presented separately from double-blind treatment phase ones. 
4.2.6 
Cut-off points 
The clinical cut-off for primary analysis at the end of the double-blind treatment period is 
defined as the date when the last patient completes the last visit of the double-blind 
treatment period (LPLV) or the date at which the last data point which is required for the 
statistical analysis (primary analysis) is received, whichever is the later date. LPLV for 
the primary analysis is expected to occur approximately 56 weeks after the last 
randomized patient begins the double-blind treatment period.  
There will be a second cut-off for the end of the study when all patients have completed 
the 11-months safety follow-up which is expected to occur approximately 52 weeks after 
the LPLV for the primary analysis.  
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
To ensure the comparability of the treatment groups, the randomization will be stratified 
by the availability of a previous RHC (yes/no) and by FEV1/FVC ratio (<0.8, ≥0.8) to 
ensure an equal distribution of patients with pulmonary hypertension assessed based on 
RHC (‘gold standard’) or echo and an equal distribution of patients with some degree of 
pulmonary obstruction in both treatment groups respectively. 
These stratification factors will be included in the analysis of the primary endpoint as a 
sensitivity analysis. Please refer to the corresponding Section 4.4.5 for further details. 


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The number and percentage of patients that fall into each of the four groups based on 
the two stratification factors will be presented by treatment group, including the 
frequencies of patients for each category as per eCRF.  
The differences between the stratification factors provided by IxRS and the data 
collected in the eCRF will be listed. Outputs for concordance between the stratification 
factors by eCRF and by IxRS will also be presented.  
4.4 
ANALYSIS OF STUDY CONDUCT 
All analyses described in this section will be performed on the ITT population, presenting 
data by treatment group: pirfenidone/sildenafil and pirfenidone/placebo. 
4.4.1 
Patient Disposition 
An overview on patient disposition, showing number and percentages of patients 
(enrolled), participating in run-in, failed run-in, screened, failed screening, randomized, 
treated, completed or early discontinued the double-blind treatment period, patients 
entering the 11-month safety follow-up period and their current status (ongoing, 
completion, discontinued) in that period will be provided. For patients who have early 
discontinued the double-blind treatment period or the study, frequencies of reasons for 
early discontinuation will be provided.  
The following definitions will be used: 
• 
Patients enrolled: All patients who have signed informed consent, 
• 
Participating in run-in: All patients that participated in the 12-week prior run-in 
period. These are the patients that signed the inform consent, received at least 
one dose of pirfenidone in the corresponding drug-log and had a screening date 
later with about 3 months compared to the ICF signature. 
• 
Run-in failures: All patients that participated in the prior run-in period but were not 
eligible for the study. These are the patients that participated in the run-in period 
but answered “No” to question in the eCRF Subject Eligibility page: “Did Patient 
meet all eligibility criteria?” and they did not fill screening visit. 
• 
Patients screened: All patients who have a screening visit, 
• 
Patients screened having run-in period: All patients who have a screening visit 
and participated in the run-in period. 
• 
Patients screened without run-in period: All patients who have a screening visit 
and did not participate in the run-in period. 
• 
Screening failures: All the patients screened who have filled “Did Patient meet all 
eligibility criteria?”  = “No” 
• 
Patients randomized: All patients who have been randomized to receive either 
sildenafil or placebo, i.e. have a randomization date. 


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• 
Patients randomized and not treated, if any: all randomized patients who have 
not received at least one dose of the randomized treatment. 
 
• 
Patients randomized and treated: all randomized patients who have received at 
least one dose of the randomized treatment. 
 
• 
Completion of double-blind treatment period: eCRF question “Did the patient 
complete course of double-blind treatment?” is ticked “Yes” (eCRF form “Double-
blind treatment Completion/Early Discontinuation”), 
• 
Early discontinuation (non-completion) of double-blind treatment period: eCRF 
question “Did the patient complete course of double-blind treatment?” is ticked 
“No” (eCRF form “Double-blind treatment Completion/Early Discontinuation”), 
• 
Early discontinuation from the study: patients who answered “Yes” to the 
question “Did the Patient early discontinued from the study?” on the Study 
Completion/Early Discontinuation eCRF form and they gave a primary reason of 
discontinuation. 
o Early discontinuation from study within 28 days after double-blind 
treatment end, for patients who didn’t enter the safety follow-up period. 
o Early discontinuation from study entering the 11-month safety follow-up 
period. 
• 
Patients who completed the study: patients who answered “Yes” to the question 
“Did the Patient complete the study?” on the Study Completion/Early 
Discontinuation eCRF form. 
• 
Patients ongoing, if any: patients who didn’t fill the Study Completion/Early 
Discontinuation eCRF form.  
An overview on patient’s enrolment by country and center will be provided. In addition, a 
frequency table of enrollment by country and center will be also presented. 
In addition, a consort diagram with all the categories above will be presented. 
A listing including disposition information and the screening/run-in failure reasons will be 
also created. 
4.4.2 
Major Protocol Deviations 
Major protocol deviations and eligibility violations will be summarized by frequency 
tables and all patients with protocol deviations will be listed. Protocol deviations will be 
collected in PDMS, reviewed by the medical monitors, and will be provided in a SAS 
dataset via Valicert. All deviations provided in that dataset will be considered as major 
protocol deviations.  


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4.4.3 
Demographic and Baseline Characteristics 
Baseline and disease characteristics such as demographics, medical history, tobacco 
and substance use history will be summarized by descriptive statistics or frequency 
tables. 
Demographics 
The following demographic characteristics will be summarized by treatment group:  
• 
Age (years): as entered in the eCRF at the screening visit. 
• 
Age categories: 18 – 64 years, 65 - 84 years, ≥85 years. 
• 
Gender (male/female). 
• 
Race: White, American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, Unknown. In case that 
more than one race will be ticked, a concatenated variable, containing all races 
will be presented (e.g. Asian/White). 
• 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown. 
• 
Weight (kg) at baseline. 
• 
Height (cm) at baseline. 
• 
BMI (kg/m2) at baseline.  
• 
NT-proBNP (pg/mL) at baseline. 
Demographic data will be also listed.  
Data on female reproductive status will be presented descriptively; methods of 
contraception will only be listed within the demographic listing. 
Tobacco Use History and Substance Use 
The history of tobacco use will be summarized with the following characteristics:  
• 
Tobacco use history (never, current, previous). 
• 
Nicotine exposure (pack-years), smokers only. 
Numbers and percentages of patients will be provided for tobacco use history. Nicotine 
exposure will be summarized descriptively. 
Numbers and percentages of patients for following characteristics by treatment group 
will be presented to specify substance use:  
• 
Current substance use (yes/no). 


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• 
Substance use (cannabinoids, amphetamines, opiates, benzodiazepines, 
barbiturates, cocaine, nicotine, other). 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), version 21.1 or above and will be summarized presenting numbers and 
frequencies by primary System Organ Class (SOC) and Preferred Term (PT) by 
treatment group. If patients have more than one disease within a SOC or PT they will be 
counted only once for the respective SOC or PT.  
A listing with past and ongoing medical history data will be also presented. 
WHO Functional Class and GAP Score and Index at Baseline 
The number and percentage of patients with baseline WHO functional class and GAP 
assessments recorded; and the number of patients that fall into each category will be 
summarized by randomized treatment group. 
RHC and ECHO Tests at Screening and Baseline 
RHC is used to identify patients with risk of Group 3 PH. In absence of a previous RHC, 
a peak tricuspid regurgitation velocity (TRV) ≥ 2.9 m/s from ECHO assessment will be 
used for identification of patients with risk of Group 3 PH. 
• 
Right heart catheterization (RHC) (Screening):  
o Is RHC available? (yes/no) 
o Mean pulmonary artery pressure (mPAP) (mmHg),  
o Pulmonary artery wedge pressure (PAWP) (mmHg).  
• 
Transthoracic echocardiography (ECHO) parameters (Screening):  
o Was ECHO performed during Screening? (yes/no),  
o Peak tricuspid regurgitation velocity ≥ 2.9 m/s (yes/no)  
The number and percentage of patients with previous RHC available at Screening will be 
summarized. The mPAP and PAWP will be summarized using descriptive statistics by 
randomized treatment group. The numbers and percentages of patients with ECHO 
performed during Screening and the numbers and percentages of patients with Peak 
tricuspid regurgitation velocity (TRV) > 2.9 m/s will be presented.  
• 
Transthoracic echocardiography (ECHO) parameters (Baseline):  
o Peak tricuspid regurgitation velocity (TRV) (m/s),  
o PAPs (mmHg),   


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The number and percentage of patients with ECHO performed at baseline will be 
presented and the baseline TRV (m/s), PAPs (mmHg), Tricuspid annular plane systolic 
excursion (TAPSE) (cm), Right ventricle basal diameter (cm), Inferior vena cava 
diameter (cm) and Left ventricular ejection fraction (LVEF) (%) values will be 
summarized using descriptive statistics by randomized treatment group. 
 
Time from IPF Diagnosis 
The time in years since the original IPF diagnosis will be calculated as:  
((Date of randomization – Date of IPF diagnosis) + 1) / 365.25, 
and will be summarized descriptively by randomized treatment group. The number and 
percentage of patients with a history of emphysema and historical high-resolution 
computed tomography will also be presented. Descriptive statistics of the time from most 
recent historical high-resolution computed tomography (years) will be presented. As 
above, the date of randomization will be used as reference date for calculation of 
duration. 
Historical Pulmonary Function Test (PFT) 
The number and percentage of patients who performed pulmonary function test (FVC, 
DLco, FEV1, and FEV1/FVC ratio) in the past will be provided. The most recent 
assessment before the screening visit will be collected.  
• 
Carbon monoxide diffusing capacity (DLco) (mmol/min/kPa and % predicted) 
• 
DLco/Va (KCO) (mL/min/mmHg/L and %) 
• 
Forced vital capacity (FVC) (L and % predicted)   
• 
Forced expiratory volume in 1 second (FEV1) (L and % predicted) 
• 
FEV1 (L) / FVC (L) ratio (1) 
These historical pulmonary function test parameters will be summarized using 
descriptive statistics by treatment group. Both, absolute and percent predicted values 
will be presented. A listing of historical pulmonary function test will be also presented. 
Pulmonary Function Test (PFT) at Baseline 
The values recorded for the baseline assessments of the pulmonary function tests 
• 
Carbon monoxide diffusing capacity (DLco) (mmol/min/kPa and % predicted) 
• 
DLco/Va (KCO) (mL/min/mmHg/L and %) 
• 
Forced vital capacity (FVC) (L and % predicted)   
• 
Forced expiratory volume in 1 second (FEV1) (L and % predicted) 


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• 
FEV1 (L) / FVC (L) ratio (1) 
will be summarized using descriptive statistics by treatment group.  
Historical surgery or procedure assessments 
A listing of historical surgeries or procedure assessments will be presented. 
6 Minute Walking Test (6MWT) at Baseline 
The 6MWD measures the distance a patient is able to walk quickly on a flat, hard 
surface in a period of 6 minutes. The 6MWT will be performed according to standard 
procedures (ATS Statement, 2002) described in the Procedure Manual. 
At Day 1, 6MWT will be performed twice and the better of the two 6MWT values will be 
reported as the baseline value. For each 6MWT, information on SpO2, Borg scale and 
O2 requirements will be collected. 
The number and percentage of patients that  
• 
Performed the 6-minute walking test (yes/no),  
• 
Rested for at least 10 minutes (yes/no),  
• 
Stopped the test before 6 minutes (yes/no),  
• 
Required Oxygen (O2) (yes/no) 
at the baseline visit will be summarized by randomized treatment group.   
The values of the parameters recorded for the 6-minute walking distance test  
• 
Vital signs (Heart rate (beats/min), systolic blood pressure (mmHg), diastolic 
pressure (mmHg)) (before the test, at the end of the test) 
• 
Distance walked (m),  
• 
Oxyhemoglobin saturation (SPO2) (before the test (at rest), at the end of the test 
and lowest SPO2 during the test),  
• 
Borg scale result (at the end of the test), 
• 
Oxygen (O2) requirements (L) (at the end of the test) 
will be summarized descriptively by treatment group.  
Stratification Factors  


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The number and percentage of patients that fall into each of the four groups based on 
the two stratification factors:  
• 
previous RHC available (yes, no),  
• 
FEV1/FVC ratio (<0.8, ≥0.8)  
will be presented by treatment group. The stratification factors will be listed. In addition, 
a table of concordance between stratifications and a frequency table presenting the 
factors as per IxRS and as per eCRF will be created. 
Previous Pirfenidone Treatment 
The number and percentage of patients that started with previous pirfenidone treatment 
during a run-in period and patients that were pretreated with commercial pirfenidone 
prior to entering the study will be presented. The duration of previous pirfenidone 
treatment (weeks) before screening during run-in, as commercial pirfenidone and both 
will be summarized descriptively, and it is defined as: ((screening date – first previous 
pirfenidone treatment taken) + 1) / 7. 
4.4.4 
Previous and Concomitant Medication 
Previous and concomitant medications are non-study medications. The previous and 
concomitant medication will be coded using the WHOdrug dictionary.  
Therapies will be classified as previous or concomitant as follows: 
Previous: If the medication end date is prior to randomization date, 
Concomitant: If medication is taken anytime between the randomization date and 28 
days after the double-blind treatment completion/discontinuation.  
All medications will be listed. 
The imputation rules for the missing medication dates are described under Section 4.9. 
4.5 EFFICACY ANALYSIS 
The primary and secondary efficacy analyses will be based on data recorded by patients 
in the ITT population with patients grouped according to planned randomized treatment. 
4.5.1 
Primary Efficacy Endpoints 
The primary efficacy objective for this study is to evaluate the efficacy of adding sildenafil 
compared with placebo to pirfenidone treatment in patients with advanced IPF and risk 
of group 3 PH.  


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The primary efficacy endpoint will be evaluated based on a comparison of the proportion 
of patients showing disease progression over 52 weeks of treatment period, as 
evidenced by reaching the following combined endpoint:  
Relevant decline in 6MWD of at least 15% during the double-blind treatment period 
(≥15% from baseline (as defined below*), respiratory-related non-elective hospitalization, 
or all-cause mortality, during the double-blind treatment period). 
*Relevant decline in 6MWD from baseline is defined as:  
• 
Any relative decline >25% from baseline or  
• 
A relative decline between 15-25% from baseline, if accompanied by at least one 
of the following: 
o worsening of SpO2 desaturation at the end of the 6MWT compared to 
baseline: a worsening of SpO2 desaturation at the end of the 6MWT 
compared to baseline will be defined as any decrease in SpO2 (%) during 
double-blind treatment period. 
o worsening (increase) of the maximum Borg scale at the end of the 6MWT 
compared to baseline during double-blind treatment period. 
o increased O2 requirements at the end of the 6MWT compared to 
baseline: an increase in O2 requirements will be defined as any increase 
of at least 1 liter during the double-blind treatment period. 
A flow chart demonstrating how the different criteria will be used to identify the combined 
endpoint can be found in Appendix 2. 
As patients will not have to discontinue the treatment once they have experienced the 
combined endpoint, it may happen that a patient will experience the combined endpoint 
more than once, but only the first occurrence will be taken into account for the analysis 
of the primary endpoint.  
Patients who discontinue treatment prematurely will be analyzed based on the available 
data at the time of discontinuation or data from the last available visit. No imputation 
method will be applied. Patients who undergo lung transplantation during the study will 
be withdrawn from the study at the time of hospitalization for transplantation.   
A Chi-square test with a one-sided significance level α = 0.05 will be used to compare 
disease progression rates between the two randomized treatment arms. The risk 
difference of disease progression rates (Sildenafil vs. Placebo) together with the 
corresponding Clopper-Pearson 95% confidence interval will be presented. 


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Sensitivity analyses will be performed as described in Section 4.5.5 below. 
4.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy objective for this study is to evaluate the efficacy of adding 
sildenafil compared with placebo to pirfenidone treatment on the basis of the following 
endpoints:  
• 
Progression-free survival (PFS) defined as the time to first occurrence of the 
combined primary efficacy endpoint (decline in 6MWD of ≥15% compared with 
baseline, respiratory-related non-elective hospitalization, or death from any 
cause) as per Section 4.5.1 will be analyzed using Kaplan-Meier (KM) 
techniques.  
o KM plots of time to first occurrence of the combined primary efficacy 
endpoint will be provided by treatment group.  
o Frequencies and percentages of patients with events and patients 
censored will be provided. Descriptive statistics of KM estimates of PFS 
will be presented, together with KM estimates and 95% confidence 
intervals for 1, 3, 6, 12, 19, 26, 32, 39, 45 and 52 weeks survival event 
free rates. 
o The PFS of two randomized treatment groups will be compared with a 
log-rank test.  
o Hazard ratios and corresponding 95% CI will be calculated by applying an 
unstratified Cox-proportional hazard models. 
Patients that do not experience the combined endpoint as defined above during 
the double-blind treatment period will be censored at the time of double-blind 
treatment completion/discontinuation. 
The single components of the combined primary efficacy endpoint (as defined in 
Section 4.5.1) will be further analyzed as follows: 
• 
The relevant decline in 6MWD will be assessed as  
o Proportion of patients with at least one decline in 6MWD of ≥15% from 
baseline (as defined in Section 4.5.1). Number and percentage of patients 
with a relevant decline will be presented by treatment arm and a Chi-
square test with a one-sided significance level α=0.05 will be applied to 
compare the two treatment groups.  


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o Descriptive statistics for 6MWD will be provided for each visit, together 
with the changes from baseline to each visit.  
▪ 
The number and percentage of patients that performed the 6MWT, 
rested for at least 10 minutes, stopped the test before 6 minutes 
and required O2 will be summarized by randomized treatment 
group and by visit.   
▪ 
The values and change from baseline of the parameters recorded 
(distance walked (m), oxygen requirements (L), Borg scale result, 
and values recorded pre-, during and post-test for SPO2 (%), heart 
rate (beats/min), systolic blood pressure (mmHg) and diastolic 
pressure (mmHg)) will be summarized descriptively by treatment 
group and by visit. Additionally, a shift table will be presented 
summarizing categorically the distance walked (<300m, ≥300m) by 
treatment group and visit. 
o The change in 6MWD (m) from baseline to 12 months will be analyzed 
using a rank ANCOVA model with the change from baseline as the 
outcome variable and standardized rank baseline 6MWD as a covariate. 
Patients who discontinue treatment prematurely will be analyzed based 
on the available data at the time of discontinuation or their last available 
visit. No imputation method will be applied. 
• 
All-cause and respiratory related non-elective hospitalization: a frequency table 
will be provided displaying number of patients with at least one non-elective 
hospitalization and the number of non-elective hospitalizations. The duration of 
the hospitalization (weeks) will be also presented descriptively. A frequency table 
presenting the number of patients with acute exacerbations (triggered or 
idiopathic) and the number of acute exacerbations will be also presented. Acute 
exacerbations will be defined as presented by Collard et al, 2016. Please refer to 
Appendix 8 for further specifications. 
• 
The time from randomization to first occurrence (or admission) of each of the 
following events will be analyzed using Kaplan-Meier techniques: 
o Respiratory-related non-elective hospitalization, all-cause non-elective 
hospitalization, all-cause mortality, respiratory-related death and acute 
exacerbation. For acute exacerbations, the admission date of the related 
hospitalization will be used as occurrence date. 
o KM plots of time to first occurrence of the different events will be provided 
by treatment arm.  


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o Frequencies and percentages of patients with events and patients 
censored will be provided. Descriptive statistics of KM estimates of the 
time to first occurrence will be presented, together with KM estimates and 
95% confidence intervals for 1, 3, 6, 12, 19, 26, 32, 39, 45 and 52 weeks 
survival event free rates. 
o Log-rank tests based on the time to the first event (e.g. first 
hospitalization respiratory-related non-elective hospitalization) will be 
used to compare the two treatment arms. 
o Hazard ratios and corresponding 95% CI will be calculated by applying 
Cox-proportional hazard models in which the four groups from the two 
randomization stratification factors are included in the model. 
Patients that do not experience the parameter of interest by the time of 
completion/ discontinuation from the double-blind treatment period will be 
censored. The end date of the double-blind treatment period will be used as 
censoring date, if none of the specific censoring rules, as presented below, will 
apply. 
The following specific censoring rules will be applied: 
▪ 
Respiratory-related non-elective hospitalization (collected in the 
respiratory-related hospitalizations eCRF page): If the patient is 
hospitalized as a result of a respiratory-related condition before 
the end of the double-blind treatment period, the time from 
randomization to the first event will be calculated. Patients that do 
not experience the event will be censored at the date of double-
blind treatment period completion/discontinuation. This will also 
apply for patients that are hospitalized for any other reason. 
▪ 
All-cause mortality: If the patient dies for any reason before the 
end of the double-blind treatment period, the time from 
randomization to the death will be calculated. Patients that are 
alive at their completion/discontinuation of the double-blind 
treatment period will be censored at that time point. 
▪ 
All-cause non-elective hospitalization (taken from AE eCRF page): 
If the patient is hospitalized for any reason before the end of the 
double-blind treatment period, the time from randomization to the 
first event will be calculated. Patients that do not experience the 
event will be censored at the date of completion/discontinuation of 
the double-blind treatment period. 


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▪ 
Respiratory-related mortality: if the dies as a result of a respiratory 
related condition before the end of the double-blind treatment 
period, the time from randomization to the death will be calculated.  
Patients that are alive at their completion/discontinuation of the 
double-blind treatment period will be censored at that time point. 
Patients that die as a result of other causes during the double-
blind treatment period will be censored at their date of death. 
• 
Absolute values and change from baseline to end of treatment for the following 
ECHO parameters will be summarized by visit and treatment group: 
o Peak tricuspid regurgitation velocity (m/s)  
o PAPs (mmHg) 
o TAPSE (tricuspid annular plane systolic excursion) (cm) 
o Right ventricle basal diameter (cm) 
o Inferior vena cava diameter (cm) 
o LVEF (Left Ventricular Ejection Fraction) Result (%) 
• 
Pulmonary function tests (PFTs), i.e. FVC (L and % predicted), FEV1(L and % 
predicted), FEV1 (L) /FVC (L) ratio (1), and carbon monoxide diffusing capacity 
(DLco) (mmol/min/kPA and % predicted) and DLco/Va (KCO) (mL/min/mmHg/L 
and % predicted) will be summarized by treatment group and analyzed in terms 
of  
o absolute values recorded and absolute changes from baseline by visit in 
actual and % of predicted values will be summarized descriptively for all 
parameters described above,  
o 5% and 10% categorical changes of FVC (%) from baseline will be 
summarized including the following categories: decline ≥10%, death or 
lung transplantation; decline of <10% but ≥5%; decline of <5% but ≥0%; 
improvement of >0% but <5%; and improvement of ≥5%. A Cochran-
Mantel-Haenszel test will be applied to the categorical change comparing 
sildenafil and placebo.  
o The change from baseline to week 52 of FVC (%) will be compared 
between the treatment arms using a rank ANCOVA with change from 
baseline as outcome variable and standardized rank baseline value as 
covariate.  


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o A summary table presenting the linear slope analysis using a mixed 
model for the FVC (L) decline from baseline to week 52 will be also 
presented.  
• 
The number and percentage of patients that have lung transplantation will be 
presented by treatment group. Information on the number of patients with lung 
transplantation will be taken from the study discontinuation eCRF page.  
• 
The number and percentages of patients in each of the four categories of WHO 
Functional Class will be presented over time by treatment group. 
• 
GAP stages and index scores taken from the eCRF will be summarized 
categorically and descriptively over time by treatment group. Please refer to 
Appendix 4 for further details. 
• 
Absolute values and changes from baseline in NT-proBNP levels will be 
summarized descriptively over time by treatment group.  
For all secondary endpoints p-values will be reported in a descriptive fashion. No 
multiplicity adjustments for statistical testing will be done.  
4.5.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints are discussed in the subgroup sensitivity analysis and 
biomarker sections.  
4.5.4 
Analyses of Patient-Reported Outcomes 
The St. George’s Respiratory Questionnaire (SGRQ) is an index designed to measure 
and quantify the health status in patients with chronic airflow limitations. The SGRQ is a 
50-item questionnaire, addressing the frequency of respiratory symptoms (items 1 – 8), 
the patient’s current state (sections 9 – 16). From the 50 items a total score, as well as 
three component scores (Symptoms, Activities, Impacts) will be derived. The total score 
ranges from 0, presenting the best possible health status to 100, presenting the worst 
possible health status. 
For details on calculation of SGRQ scores please see Appendix 6  and Appendix 7. 
The change in SGRQ total score will be of primary interest when assessing health-
related quality of life (HRQoL). 
HRQoL assessed by SGRQ total score and by SGRQ component scores for symptoms, 
activity, impacts and total score will be analyzed as follows: 
• 
The absolute score values and changes from baseline for each SGRQ score will 
be presented descriptively over time by treatment group. 


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• 
For the total score only, changes from baseline to week 52 or early 
discontinuation visit will be compared between the treatment arms using a rank 
ANCOVA with change from baseline as outcome variable and standardized rank 
baseline value as covariate.  
• 
Line graphs for the total score will be presented. 
The University of California, San Diego-Shortness of Breath Questionnaire (UCSD-
SOBQ) is a symptom-specific, 24-item, patient-self-administered questionnaire that 
assesses shortness of breath while doing a variety of activities of daily living. Each of the 
24 items will be rated on a 6-point scale. The scores will be summarized to a total score, 
ranging from 0 – 120, from best to worse health status. 
Additional details on the UCSD SOBQ can be found in Appendix 5.  
The total score of the UCSD SOBQ will be summarized as follows: 
• 
The absolute total score and changes from baseline will be presented 
descriptively over time by treatment group. 
• 
Changes from baseline to week 52 or early discontinuation visit will be compared 
between the treatment arms using a rank ANCOVA with change from baseline as 
outcome variable and standardized rank baseline value as covariate.  
• 
Line graphs for the total score will be presented. 
4.5.5 
Sensitivity Analyses 
A sensitivity analysis of the proportion of patients with a decline of at least 15% in the 
6MWD in the ITT population will compare disease progression rates in each treatment 
arm using a logistic regression model.  
In addition, the Cochrane-Mantel-Haenszel test described above will be presented 
stratified by the stratifications factors (the availability of RHC and FEV1/FVC ratio) with a 
one-sided significance level α = 0.05, as per eCRF and IxRS separately. 
Moreover, the primary endpoint analysis will be repeated during the following time period 
in order to assess the impact of events shortly after end of treatment: from 
randomization to 28 days after completion/discontinuation of the randomized treatment. 
Additional analysis of the change in 6MWD from baseline to 52 weeks will follow the 
approach taken in the Step-IPF publication (2010) using a linear mixed model with slope 
measurements for fixed effects estimated from baseline to Week 52 to compare the two 
treatment groups. Only patients with at least three measurements will be included in the 
analysis. The model will also include additional baseline covariates of age, sex, race, 


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height at baseline and Dlco (%) at baseline. The estimated treatment effect and 95% 
confidence intervals will be provided. The same model will be developed for the change 
in FVC (L) from baseline to 52 weeks. 
Further sensitivity analyses will follow the approach taken with the Step-IPF publication 
(2013)  in which a multivariable linear regression estimated the change in 6MWD as a 
function of treatment group, cardiac parameters from ECHO (Peak tricuspid regurgitation 
velocity, PAPs, TAPSE [tricuspid annular plane systolic excursion], Right ventricle basal 
diameter, Inferior vena cava diameter and LVE [Left Ventricular Ejection Fraction]), and 
interactions between treatment group and the cardiac parameters.  
The time to multiple events (e.g. hospitalization before death) will be analyzed using the 
Anderson-Gill counting process approach to Cox models, where outcome (event 
[hospitalization, decline of at least 15% in 6MWD, death], no event) at the end of each 
interval is analyzed. This approach means that all events experienced by the patients 
can be included in the analysis and not just specific events or the time to first event.  
Covariates can also be added to the model, they can either be baseline values or the 
value recorded at the start of the interval. The two randomization stratification factors will 
also be included in the model.  
The frequency and percentage of patients with and without corridor card ID change 
among the study will be presented by treatment arm, presenting frequencies for 0, 1, 2, 
etc number of changes in the corridor card ID. 
In order to measure the change from baseline in NT-proBNP during the double-blind 
treatment period among the different treatment arms,  a mixed model with repeated 
measures per planned visit will be developed including the treatment and the baseline 
NT-proBNP value as covariates. 
4.5.6 
Subgroup Analyses 
Subgroup analyses will be conducted for primary and selected secondary endpoints, as: 
decline in 6MWD of ≥ 15% from baseline, FVC categorical decline, PFS of the combined 
efficacy endpoint, hospitalizations and ECHO parameters summary. When possible, a 
forest plot presenting the results of all subgroups will be developed. 
The following subgroups will be defined: 
• 
RHC as collected in the eCRF: Yes, No, 
• 
FEV1/FVC ratio as collected in the eCRF: <0.8, ≥0.80, 
• 
Gender: Male , Female, 


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• 
Age (years): <65, ≥65, 
• 
PAPs (mmHg) from ECHO assessment at randomization: <40 mmHg , ≥40 
mmHg, 
• 
Percent predicted FVC at baseline: <50%, ≥50%, 
• 
Percent predicted DLco at baseline: ≤25% ,>25%, 
• 
GAP index at baseline: GAP I, GAP II, GAP III, 
• 
Body weight: <60 kg, ≥60 kg, 
• 
BMI: <25 kg/m*2, ≥25 kg/m*2 to ≤30 kg/m*2 and >30 kg/m*2, 
• 
With/without corridor card ID change, 
• 
6MWD at baseline: <300 m, ≥300 m, 
• 
History of Emphysema from Pulmonary Function Test History: Yes, No, 
• 
Patients that died/not died, 
• 
NT-proBNP normal/abnormal: <1 x ULN, ≥1 x ULN. 
The number of patients in each subgroup will be tabulated.  
4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
No pharmacokinetic or pharmacodynamic analyses are planned for this study. 
4.7 
SAFETY ANALYSES 
The safety objective for this study is to evaluate the safety of adding sildenafil compared 
with placebo to pirfenidone treatment on the basis of the following analyses.  
The safety population will be used to present the safety analyses which will include all 
randomized patients who received at least one dose of randomized study drug (sildenafil 
or placebo), with patients grouped according to treatment received.  
No formal statistical testing will be performed for safety parameters.  
Data collected during the 11-month safety follow-up (i.e. adverse event and deaths) will 
be analyzed separately. 


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4.7.1 
Exposure to Study Medication 
Patients participating in this study are to be on a stable dose of pirfenidone for 28 days 
prior to Screening. At the Screening visit patients will be instructed to stop taking their 
commercial pirfenidone and start taking the study-provided pirfenidone. Patients that will 
not be able to take pirfenidone for 12 weeks prior to Screening due to reimbursement 
issues will be supplied with study pirfenidone during a 12-week run-in period. 
Therefore, patients participating in the 12-week run-in period will enter all information on 
pirfenidone intake prior to screening into the drug log. A summary table with the duration 
of the previous pirfenidone treatment during run-in period will be presented as stated in 
section 4.4.3 . Patients not requiring run-in will enter information on pirfenidone intake 
into the drug log from the screening visit onwards. Information on previous commercial 
pirfenidone will be reported as concomitant medication. 
Previous pirfenidone intake during run-in period will be listed together with randomized 
treatment period drug log information. 
It is expected that pirfenidone will be administered during the whole double-blind 
treatment period, with exception of days of treatment interrupted. Randomized treatment 
(sildenafil/placebo) will be added to pirfenidone at or after randomization.  
The main focus will be on the double-blind treatment period. Sildenafil/placebo treatment 
will be considered from the date of first randomized sildenafil/placebo treatment up to the 
date of last positive dose of randomized sildenafil/placebo treatment. Pirfenidone 
treatment will be considered from the date of first randomized sildenafil/placebo 
treatment up to date double-blind treatment was completed, or date of early treatment 
discontinuation. This information will be selected from the eCRF page “Double blind 
treatment completion/Early discontinuation”.   
Summaries of dosing, treatment duration, dose interruptions or reductions during the 
double-blind treatment period will be provided for each treatment separately. 
4.7.1.1 Treatment duration 
The overall treatment duration (weeks) during the double-blind treatment period, 
including and excluding dose interruptions, will be summarized descriptively. The overall 
treatment duration including dose interruptions (weeks) will be defined as follows: 
Pirfenidone: 
• 
Overall pirfenidone treatment duration including dose interruptions (weeks) = 
[(Date of double-blind treatment completion (completers) or date of early 
treatment discontinuation (for patients who early discontinued treatment) as per 
eCRF – date of first intake of randomized pirfenidone treatment during double-
blind treatment period + 1)] / 7. 


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Sildenafil/placebo: 
• 
Overall sildenafil/placebo treatment duration including dose interruptions (weeks) 
= [(Date of last positive dose of randomized (sildenafil/placebo) treatment – date 
of first intake of randomized (sildenafil/placebo) treatment) + 1)] / 7. 
The overall treatment duration excluding dose interruptions will be derived from the 
treatment administration panels using the time windows described above, considering 
only days on treatment, i.e. positive dose. 
Details on treatment administration and interruptions will be listed. 
4.7.1.2 Doses and Dose modifications or interruptions 
The total dose (g), the last daily dose administered (mg) and the average daily dose 
(mg/d) for each of the study treatments will be presented descriptively. The average 
daily dose will be calculated by summing up the number of capsules taken, divided by 
the overall treatment duration including dose interruptions as defined above.  
Numbers and proportions of patients with at least one dose modification, or drug 
interruption, will be presented for each treatment separately. Numbers and proportions 
of patients with 1, 2, 3 or more dose modifications, or treatment interruptions, will be 
given. 
The total number of dose modifications, or treatment interruptions, will be presented 
together with numbers and frequencies of reasons for dose modification, or treatment 
interruption. 
Dose modifications or treatment interruptions will be presented as given in the drug logs.  
4.7.2 
Discontinuations from double-blind treatment period 
Kaplan-Meier (KM) plots for time to double-blind treatment discontinuation due to any 
cause will be provided for all randomized patients and by randomized treatment, from 
the randomization date to the date subject completed or early discontinued from double-
blind treatment period due to any cause, as per eCRF. If the patient completed the 
treatment without treatment discontinuation, then it will be censored to the date of 
treatment completion.  
4.7.3 
Discontinuations from the study 
KM plots for time to study discontinuation will be provided for all randomized patients 
and by randomized treatment, from the randomization date to the date subject 
discontinued from the study, as per eCRF. If the patient completed the study, the patient 
will be censored to the date of study completion.  


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4.7.4 
Adverse Events 
Verbatim descriptions of adverse events (AEs) will be mapped to a preferred term (PT) 
and system organ class (SOC) using the Medical Dictionary for Regulatory Agencies 
(MedDRA®). MedDRA version 21.1 or above, and related SMQ lists will be used for 
coding. 
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03. For AEs of varying severity, the 
most severe grade as documented on the eCRF will be used in the summaries. 
4.7.4.1 Adverse events prior to the double-blind treatment period 
Adverse events that are reported after informed consent but before the first intake of 
randomized treatment will be considered as non-treatment-emergent AEs. These might 
include AEs that occur during the screening period, or during the pirfenidone run-in 
period, if applicable.  
The numbers and percentages of patients with any AEs and any AEs related to 
pirfenidone will be summarized by randomized/not randomized patients, SOC and PT 
based on the number of patients enrolled. Related AEs are AEs that were considered to 
be related to Pirfenidone during the run-in period only. If the relationship of the adverse 
event is missing, it will be considered as related to Pirfenidone. 
4.7.4.2 Adverse events during double-blind treatment period 
The analysis of AEs within the framework of the primary study analysis will focus on 
treatment-emergent AEs (TEAE) based on the safety population.  
For safety analyses on the double-blind treatment period treatment-emergent adverse 
events will be defined as: 
• 
AEs that started or worsened on or after first intake of randomized treatment 
(sildenafil/placebo) until completion/discontinuation of double-blind treatment 
period + 28 days. 
An overview of patient safety profile will present the number and proportion of patients in 
each treatment group experiencing  
• 
Any and any related treatment-emergent adverse events (TEAEs)   
• 
Any and any related serious treatment-emergent adverse events (serious 
TEAEs)   
• 
Any and any related severe treatment-emergent adverse events (TEAEs ≥ Grade 
3) 


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• 
Any and any related TEAEs of special interest (AESI) as recorded in the eCRF 
and defined as an elevated ALT or AST in combination with either an elevated 
bilirubin or clinical jaundice, as defined by Hy’s law; and suspected transmission 
of an infectious agent by the study drug. 
• 
Any and any related gastrointestinal (GI) disorders (MedDRA SOC: GI Disorders)  
• 
Any hepatic side effects (MedDRA AEGT: Esbriet - Potential Hy’s Law AEGT’ 
see Appendix 3)  
• 
Any and any related clinically significant vascular event, defined as any TEAE 
included in at least one of the following AE groups:  
o Any and any related ischemic heart disease (MedDRA SMQ: Ischemic 
heart disease) 
o Any and any related cerebrovascular event (MedDRA SMQ: Central 
nervous system vascular disorders)   
o Any and any related bleeding event (MedDRA SMQ: Haemorrhages) 
o Any and any related thromboembolic event or pulmonary oedema (SMQ 
Embolic and thrombotic events and MedDRA Preferred term PT: 
pulmonary oedema) 
o Any and any related hypotension event (MedDRA high level term (HLT): 
Vascular hypotensive disorders) 
• 
Any and any related photosensitivity or rash (MedDRA Preferred terms Nodular 
rash, Photodermatosis, Photosensitivity reaction, Pruritus, Pruritus generalised, 
Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-
papular, Rash papular, Rash pruritic, Solar dermatitis, Solar urticaria, Sunburn, 
Erythema, Dry skin) 
• 
Any and any related visual effects (MedDRA Preferred term (PT): Optic 
ischaemic neuropathy) 
• 
Any and any related priapism (MedDRA Preferred terms (PT): erection 
increased, priapism, painful erection) 
• 
Any and any related TEAEs leading to death 
• 
Any and any related TEAEs leading to treatment discontinuation 
• 
Any grade 3-4 laboratory liver test results 


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o Any grade 3-4 AST (SGOT) results 
o Any grade 3-4 ALT (SGPT) results 
o Any grade 3-4 Alkaline phosphatase results 
o Any grade 3-4 Total bilirubin results  
Related TEAEs summarized in the safety profile will be considered to be either related to 
pirfenidone or related to sildenafil/placebo, or to both treatments. 
If relationship to study drug is missing, the event will be considered to be related to both 
pirfenidone and sildenafil/placebo.  
The incidence of TEAEs, related TEAEs, serious TEAEs, related serious TEAEs, severe 
TEAEs and related severe TEAEs will be summarized by treatment group, by system 
organ class (SOC) and preferred term (PT). Frequencies and percentages of patients 
experiencing (at least) one event in the respective category will be presented by 
decreasing frequencies of pirfenidone/sildenafil gorup. If patients have more than one 
AE within a SOC or PT they will be counted only once for the respective SOC or PT. 
Additionally the total numbers of TEAEs will be provided for each SOC and overall. 
Summary tables associated with TEAEs that are considered to be related to study drug 
will be presented as follows: TEAEs related to pirfenidone or sildenafil/placebo, TEAEs 
related to pirfenidone and sildenafil/placebo, TEAEs related to pirfenidone, TEAEs 
related to sildenafil/placebo. 
Similar summary presentations will be provided for the incidence of TEAEs leading to 
hospitalization, TEAEs leading to treatment discontinuation (from pirfenidone, 
silfenafil/placebo or both), and TEAEs leading to death. 
Non serious Treatment-emergent Adverse Events with >5% frequency will be also 
presented by SOC and PT. In addition, serious Treatment-emergent Adverse Events, 
fatal serious TEAEs and serious TEAEs related to pirfenidone or sildenafil/placebo will 
be presented in the same table by SOC and PT. 
A summary table presenting the numbers and frequency of patients with TEAEs by most 
extreme CTCAE Grade (Grade 1, Grade 2, Grade 3, Grade 4 and Grade 5) will be 
provided for each SOC and PT by treatment group. In case the most extreme intensity is 
missing, it will be replaced by the initial intensity. If both most extreme and initial intensity 
are missing, the AE will be included in the Grade ≥3 category and a category for 
“missing” will be added.  
Further, Kaplan-Meier curves for time to onset of first adverse event of the most relevant 
TEAEs will be provided by treatment group. These will include the following PTs or 


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groups of AEs: Hypotension, Weight decreased, Fatigue, visual effects, or priapism. One 
Kaplan-Meier curve per PT and treatment group will be created. 
4.7.4.3 Adverse events after the double-blind treatment period 
Post-treatment AEs will be defined as AEs that are reported more than 28 days after the 
end date of double-blind treatment period. If a patient has a post-treatment AE but do 
not enter the safety follow-up period, then those AEs will be listed. If a patient has a 
post-treatment AE during safety follow-up period, please refer to section 4.8 for further 
details on the analysis of these AEs. 
All adverse event data will be listed by patient number and study day of onset including a 
flag variable for identifying the period of the event.  
4.7.5 
Deaths 
Numbers and frequencies of all cause deaths, as well as of respiratory-related deaths 
and deaths due to other cause will be presented by treatment group.  
Numbers and frequencies of deaths occurring within 28 days after end date of double-
blind treatment period, and within/after the first 168 days will be presented in the same 
way.  
All information associated with deaths collected on eCRF panel on study discontinuation 
will be listed. A flag variable will be included in the listing specifying the study period 
when the death occurred. 
Deaths during safety follow-up period will be summarized separately. 
4.7.6 
Pregnancies 
Pregnancy test results will be listed together with demographics, presenting the date and 
study day of pregnancy test and test result. 
4.7.7 
Laboratory Data 
The majority of laboratory parameters will be assessed by a central laboratory although 
local laboratories will be used to assess parameters in some countries. Unplanned local 
laboratory data might be available for patients that have central laboratory support but 
will not be used for the analyses. In addition, local laboratory parameters not collected at 
central laboratory will not be presented in the analyses. All values provided by local 
laboratories will be standardized and converted to SI units by DM. The reference ranges 
from the local laboratories will be applied, if available. Otherwise, global standard ranges 
will be used.  
The results of urine pregnancy tests will be determined locally and will be recorded in the 
eCRF. 


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All parameters will be graded according to NCI CTCAE (CTEP 2010), version 4.03, if 
applicable. Laboratory parameters that cannot be graded according to the corresponding 
NCI CTCAE version 4.03 will be assessed with respect to normal range (low, normal, 
high). 
For laboratory parameters and specific age ranges, the upper limit of normal provided by 
the central laboratory might be higher than the criterion for Grade 1 in NCI CTCAE. In 
such cases, the definitions provided in the NCI CTCAE, corresponding version 4.03 will 
be followed. This means that a shift of a laboratory value above the ULN that 
corresponds to a grade 2 abnormality or higher will be reported as such. Grade 1 
abnormalities will not be reported for such situations. 
Laboratory values that are reported to be below the limit of quantification (e.g. ‘<2’) will 
be considered as to be ‘LOW’ for presentation in shift tables, if the value (e.g. ‘2’) equals 
the lower limit of normal. The value as such (e.g. ‘2’) will be used for descriptive 
statistics. 
The following laboratory parameters will be collected: 
• 
Hematology: complete blood count with platelet count and automated differential, 
i.e. hemoglobin, hematocrit, red blood cells [RBC], platelet count, white blood 
cells [WBC] with differential [including neutrophils, lymphocytes, monocytes, 
eosinophils and basophils  
• 
Serum chemistry:  glucose, blood urea nitrogen [BUN], creatinine, sodium, 
potassium, bicarbonate, total protein, albumin, total bilirubin, direct and total 
bilirubin, alkaline phosphatase, aldosterone, lactate dehydrogenase [LDH], AST, 
ALT, gamma-glutamyl-transferase [GGT]), C-reactive protein [CRP] and NT-
proBNP, aldosterone  
• 
Serum pregnancy test, urine dipstick for pregnancy testing (local). 
For creatinine and pregnancy test result no grading as per NCI CTCAE, version 4.03 is 
possible. 
Clinical laboratory values will be presented separately for CTCAE-gradable and non-
CTCAE gradable parameters by laboratory panel (hematology, serum chemistry).  
For laboratory analyses, visits will be assigned to visit windows as described in Section 
4.10. This will also be valid for possible unscheduled visits. In case that multiple 
evaluable assessments occur within the same visit, the value nearest to the midpoint will 
be used for analyses. Unscheduled local laboratory values that were collected for 
patients with central laboratory support will not be considered for selection, and will 
therefore not be presented in shift tables or summary statistics. 


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The following summaries will be prepared: 
For each laboratory parameter, descriptive statistics of laboratory values at each 
scheduled visit (derived as described above), and absolute changes from baseline to 
post-baseline will be presented by treatment group. 
Shift tables presenting categorical changes in CTCAE grade from baseline to worst 
grade recorded during the double blind period for safety analyses, in the indicated 
direction, will be provided for CTCAE-gradable parameters by treatment group. If no 
CTCAE grade is available for a specific laboratory variable, shift tables will present worst 
changes with respect to normal range category (low, normal, high). 
For CTCAE-gradable parameters, numbers and percentages of patients with laboratory 
values of grade 3 and 4 will be presented over time by treatment group. 
Liver abnormalities (total bilirubin, alkaline phosphatase, ALT (SGPT), AST (SGOT)) of 
grade 3 and 4 will be presented showing numbers and percentages of patients for each 
parameter separately, as well as in combination with at least one of the parameters 
elevated post-baseline by treatment group. Line graphs of liver parameters and NT-
proBNP will be provided. 
Laboratory data for the parameters BNP, CPR and liver toxicities will be listed with 
values for both SI units and original, if available, being presented. 
4.7.8 
Vital Signs 
Vital signs (heart rate, systolic and diastolic blood pressure), respiratory rate, body 
weight and body temperature assessments will be assigned to visit windows as per 
Section 4.10. Descriptive statistics will be used to summarize vital signs data at baseline 
and at each scheduled post-baseline visit, and for the absolute change from baseline to 
each scheduled post-baseline visit by treatment group. Line graphs for systolic and 
diastolic blood pressure will be provided. The body mass index (BMI) will only be 
provided at baseline and presented with the demographic data. 
4.7.9 
ECG 
ECG assessments will be assigned to visit windows as per Section 4.10.  
QTcF values will be assigned to the following intervals: < 500 ms, 500–550 ms, and > 
550 ms.  Numbers and proportions of patients with their maximum QTcF interval 
category will be summarized by treatment group at Screening, Baseline (Week 1), Week 
26 and Week 52 or early discontinuation. Absolute changes from the Baseline to each 
post-baseline visit in QTcF values will be categorized to ≤ 30 ms, 31–60 ms, and > 60 
ms. Numbers and proportions of patients in each category will be presented by 
treatment group for each post-baseline visit.  


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Descriptive statistics for heart rate and QTcF and changes from baseline for each visit 
will be presented by treatment group. 
4.8 
SAFETY FOLLOW-UP ANALYSES 
Data collected during the safety- follow-up period will be analyzed based on the safety 
follow-up population.  
Treatment-emergent adverse events during the 11-month safety follow-up period for 
pirfenidone treatment will be defined as: 
• 
AEs that started or worsened on or after the date of safety follow-up period start 
until the end of the study. 
The overview safety table presented for the double-blind treatment period will be 
repeated for safety follow-up period.  
Summary tables for the incidence of AEs, related AEs, serious AEs, related serious AEs, 
severe AEs and severe related AEs will be summarized by system organ class (SOC) 
and preferred term (PT). Frequencies and percentages of patients experiencing (at 
least) one event in the respective category will be presented by decreasing frequencies. 
If patients have more than one AE within a SOC or PT they will be counted only once for 
the respective SOC or PT. Additionally, the total numbers of AEs will be provided for 
each SOC and overall.  
All AEs collected during safety follow-up period will be listed together with the ones at 
double-blind treatment period. 
Deaths during the safety follow-up period will be tabulated as described in section 4.7.5 
and listed together with deaths during the double-blind treatment period.  
Data will be presented by planned randomized treatment labeled as ‘Randomized 
pirfenidone + sildenafil’ and ‘Randomized pirfenidone + placebo’. 
 
4.9 
MISSING DATA 
In general, missing data will not be imputed. Exceptions will be made for the data related 
to adverse events and concomitant medications as described below. 
For adverse events, missing start dates will only be imputed for determination of whether 
the adverse event is considered to be treatment-emergent or not. 
Incomplete or missing onset dates will be imputed to the earliest date possible (using 
any reliable portions of the onset date that are available). The onset day is considered 
unreliable if the month or year portions of the date are missing.  


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In case the month portion of the AE start date is missing, the AE start date will be 
imputed to the earliest day possible by using the following principles: 
• 
If treatment start date is missing, then the AE start date will be imputed as 01-01-
YYYY or the earliest date regarding signature of informed consent, screening 
date or randomization date, whichever is the later one. 
• 
When the treatment start date is not missing, and the years of AE Start Date and 
treatment start date coincide, the AE onset date will be set to the treatment start 
date. 
• 
When the treatment start date is not missing, and the years of the AE start date 
and the treatment start date do not coincide, then the AE start date will be 
imputed as 01-01-YYYY or the earliest date regarding signature of informed 
consent, screening date or randomization date, whichever is the later one. 
In case the day portion of the AE start date is missing, the AE start date will be imputed 
to the earliest day possible as follows: 
• 
If the treatment start date is missing, then the AE start date will be imputed as 
01-MMM-YYYY or the earliest date regarding signature of informed consent, 
screening date or randomization date, whichever is the later one. 
• 
When the treatment date is not missing, and the years and months from the AE 
start date and the treatment start date coincide, the AE onset date will be set to 
the treatment start date. 
• 
When the treatment start date is not missing, and AE start date is after the 
treatment start date according to the given year or month, then the AE start date 
will be imputed as 01-MMM-YYYY. 
If the AE stop date is missing, then the event will be assumed to be ongoing and a stop 
date will not be imputed.  
In the case the treatment end date is missing and it cannot be judged whether the event 
occurred during the period of treatment start date to treatment end date plus 28 days, 
the AE will be considered treatment-emergent. 
For imputation and handling of missing intensity or relationship to study medication, 
please see Section 4.7.4. 
All other missing or incomplete adverse event data will be left as missing. 


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For concomitant medications, missing start or end dates will only be imputed to 
determine whether the medication is considered to be prior, on-treatment, post-
treatment.  
For previous pirfenidone treatment, recorded in the concomitant medication eCRF that 
started before informed consent, missing month and day for the start year will be 
imputed with July 1st of the respective year. If the day is unknown, the 15th of the 
respective month will be imputed. Imputations will only be used for calculation of 
duration of previous pirfenidone treatment.  
In general, if only the day is missing from the start date then the missing day will be 
imputed as 01-MMM-YYYY unless the month is the same month as the start of study 
medication in which case the missing date will be imputed as the treatment start date. 
If both the day and month are missing from the start date year is the same as treatment 
start date then the start date will be imputed as ‘treatment start date’, but if the if the year 
is after treatment start date, the start date will be imputed as 01-JAN-YYYY. 
If the day, month and year are all missing from the start date then the start date will be 
imputed as 01-JAN for the year in which the patient was recruited to the study. 
If an incomplete stop date has both the year and month present, the day will be imputed 
as the last day of the month or date of discontinuation/death. 
If the event is ongoing at time of primary analysis, concomitant medication will be 
summarized for the double-blind treatment period and safety follow-up. 
4.10 
VISIT WINDOWS 
To ensure that recorded data are summarized at appropriate intervals, visit windows will 
be applied and the derived visits will be used in the by-visit summarizations. If multiple 
observations fall within the same visit window, the observation with the value nearest to 
midpoint will be used in the analysis. If subjects discontinue from the study early the data 
will be assigned to the early discontinuation visit.  
The “Baseline” visit is a derived data point to identify baseline values which are used to 
calculate the change from baseline values. Baseline is defined in section 4.2.2. 
Table 2 
Visit Windows for 6MWT, laboratory data, vital signs, WHO functional 
class (Assessments made at every planned visit) 
Analysis Visit [AVISITN] 
Target Day 
Analysis Window (scheduled Study 
Days)   


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Baseline [0] 
1 
Last valid assessment prior to first 
intake of randomized study drug 
(sildenafil/placebo). 
Generally, it is assumed that 
measurements referring to the Day 1 
(Week 1) visit have been performed 
before randomized study drug 
(sildenafil/placebo) was given. 
Week 3 [3] 
22 
One day after first dose of 
randomized treatment to 33  (17 to 
27)          
Week 6 [6] 
45 
34 to 67  (40 to 50)          
Week 12 [12] 
90 
68 to 112 (85 to 90)          
Week 19 [19]  
135 
113 to 157 (130 to 140)      
Week 26 [26] 
180 
158 to 202 (175 to 185)      
Week 32 [32] 
225 
203 to 247 (220 to 230)      
Week 39 [39] 
270 
248 to 292 (265 to 275)      
Week 45 [45] 
315 
293 to 340 (310 to 329)      
Week 52 [52]  
365 
341 to maximum of 392  
Early discontinuation from 
double-blind  period [53] 
Not applicable 
As occurred 
Follow-up visit  
393 
Vital signs only: as occurred 
 
 Table 3 Visit Windows for ECG, ECHO and weight data 
Analysis Visit [AVISITN] 
Target Day 
Analysis Window (scheduled Study 
Days)   
Baseline [0] 
1 
Last valid assessment prior to first 
intake of randomized study drug 
(sildenafil/placebo). 
Generally, it is assumed that 
measurements referring to the Day 1 
(Week 1) visit have been performed 
before randomized study drug 
(sildenafil/placebo) was given. 
Week 26 [26] 
180 
One day after first dose of 
randomized treatment to 272 (175 to 
185)      
Week 52 [52]  
365 
273 to maximum of 392  


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Early discontinuation [53] 
Not applicable 
As occurred  
Follow-up visit  
393 
Weight only: as occurred 
 
Table 4 Visit Windows for Borg scale, DLCo, spriometry tests and GAP score 
Analysis Visit [AVISITN] 
Target Day 
Analysis Window (scheduled Study 
Days)   
Baseline [0] 
1 
Last valid assessment prior to first 
intake of randomized study drug 
(sildenafil/placebo). 
Generally, it is assumed that 
measurements referring to the Day 1 
(Week 1) visit have been performed 
before randomized study drug 
(sildenafil/placebo) was given. 
Week 12 [12] 
90 
One day after first dose of 
randomized treatment to 135 (85 to 
90)          
Week 26 [26] 
180 
136 to 225 (175 to 185)      
Week 39 [39] 
270 
226 to 315 (265 to 275)      
Week 52 [52]  
365 
316 to maximum of 392  
Early discontinuation [53] 
Not applicable 
As occurred 
 
Table 5 Visit Windows for NT-ProBNP, CRP, aldosterone and urinalysis 
Analysis Visit [AVISITN] 
Target Day 
Analysis Window (scheduled Study 
Days)   
Baseline [0] 
1 
Last valid assessment prior to first 
intake of randomized study drug 
(sildenafil/placebo). 
Generally, it is assumed that 
measurements referring to the Day 1 
(Week 1) visit have been performed 
before randomized study drug 
(sildenafil/placebo) was given. 
Week 1 [1] 
1 
First dose of randomized treatment. 
Week 12 [12] 
90 
One day after first dose of 
randomized treatment  to 135 (85 to 
90)          
Week 26 [26] 
180 
136 to 272 (175 to 185)      


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Week 52 [52]  
365 
273 to maximum of 392  
Early discontinuation [53] 
Not applicable 
As occurred 
 
Table 6 Visit Windows for SGRQ and UCSD SOBQ 
Analysis Visit [AVISITN] 
Target Day 
Analysis Window (scheduled Study 
Days)   
Baseline [0] 
1 
Last valid assessment prior to first 
intake of randomized study drug 
(sildenafil/placebo). 
Generally, it is assumed that 
measurements referring to the Day 1 
(Week 1) visit have been performed 
before randomized study drug 
(sildenafil/placebo) was given. 
Week 12 [12] 
90 
One day after first dose of 
randomized treatment to 135 (85 to 
90)          
Week 26 [26] 
180 
136 to 225 (175 to 185)      
Week 39 [39] 
270 
226 to 315 (265 to 275)      
Week 52 [52]  
365 
316 to maximum of 392  
Early discontinuation [53] 
Not applicable 
As occurred 
 
4.11 
 INTERIM ANALYSES 
Throughout the study, an external independent Data Monitoring Board (iDMC) will 
review individual SAE reports and laboratory toxicities. The iDMC will meet regularly 
(approximately every 3 months) to review safety data (and efficacy, if requested) as 
described in the iDMC charter and advise on the study conduct.    
The iDMC may recommend that the Sponsor stop the study for safety concerns set forth 
in the iDMC Charter. Additional ad hoc meetings or data review can be requested by the 
iDMC or Sponsor, if warranted. Additional information is provided in the iDMC Charter.  
No formal interim analyses for efficacy are planned. 
4.12 
 BIOMARKER ANALYSES (OPTIONAL) 
Genomic, transcriptomic and proteomic profiling of markers associated with the 
molecular pathways and cellular processes of lung injury and fibrosis will be measured. 
Certain biomarkers may be differentially expressed in patients with advanced IPF and 
risk of Group 3 PH on pirfenidone treatment (e.g., possibly cytokines, chemokines and 


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other cellular and molecular markers of lung injury and fibrosis). The blood biomarker 
samples may help identify those serum and plasma proteins or blood ribonucleic acid 
(RNA) biomarkers related to disease progression. 
Analyses on biomarker data will not be in the scope of this SAP, but will be planned and 
described separately. 
 
 


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5. 
REFERENCES 
Galie N, Humbert M, Vachieryc J-L, et al. ESC/ERS Guidelines for the diagnosis and 
treatment of pulmonary hypertension. Eur Heart J 2015;ehv317 67-119. 
Wuyts W, Antoniou KM, Borensztain K, et al. Combination therapy: the future of 
management for idiopathic pulmonary fibrosis? Lancet Resp Med 2014: 2(11): 933–42. 
Simonneau, MD, Gatzoulis MA, Adatia I, et al. Updated Clinical Classification of 
Pulmonary Hypertension. Journal of the American College of Cardiology 2013;Vol 62, 
No. 25, Suppl D  
Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez 
FJ; IPFnet Investigators. Sildenafi l Preserves Exercise Capacity in Patients With 
Idiopathic Pulmonary Fibrosis and Right-sided Ventricular Dysfunction Han et al. Chest. 
2013 Jun;143(6):1699-1708. doi: 10.1378/chest.12-1594. 
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: 
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management. Am J Respir Crit Care Med 2011;183:788–824. 
Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, 
Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A Controlled Trial of Sildenafil 
in Advanced Idiopathic Pulmonary Fibrosis. N Engl J Med 2010;363:620-8. 
Lettieri CJ, Nathan SD, Barnett SD, et al. Prevalence and outcomes of pulmonary 
arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006;126:746-
752. 
Hallstrand TS, Boitano LJ, Johnson WC, et al. The timed walk test as a measure of 
severity and survival in idiopathic pulmonary fibrosis. Eur Respir J 2005;25:96–103. 
Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with 
idiopathic pulmonary fibrosis. Chest 2005;128(4):2393-9. 
Ries AL. Minimally clinically important difference for the UCSD Shortness of Breath 
Questionnaire, Borg Scale, and Visual Analog Scale. 2005 Mar;2(1):105-10.  
Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil foe treatment of lung fibrosis and 
pulmonary hypertension: a randomised controlled trial. Lancet 2002;360(9337):895-900. 
Prewitt LM, Ries AL, Kaplan RM. Validation of a new dyspnea measure: the UCSD 
Shortness of Breath Questionnaire. University of California, San Diego. 1998 
Mar;113(3):619-24.  


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51 
 
Nishimura K, Tsukino M, Hajiro T. Health-related quality of life in patients with chronic 
obstructive pulmonary disease. 1998 Mar;4(2):107-15.  
Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. 1991 
Sep;85 Suppl B:25-31; discussion 33-7.  
St. George’s Respiratory Questionnaire 
http://www.healthstatus.sgul.ac.uk/sgrq 
Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary 
fibrosis. An International Working Group Report. Am J Respir Crit Care Med 
2016;194:265–75. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1  
Schedule of Assessments 
Day 
Week 
Washouta 
Screeningb 
Double blind treatment phase 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up (FU) 
Additional 
safety FUi 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Informed 
Consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
and Baseline 
Conditions 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain and 
Review 
Historical 
PFTs, HRCT*, 
Surgical Lung 
Biopsy, and 
RHC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Excl-
usion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up 
Additional 
safety FU 
i, 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Approx. 
every 3 
months 
Spirometry 
post broncho-
dilator (FVC, 
FEV1, FEV1/ 
FVC) d 
 
X 
X d1 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
DLCO e 
 
X 
X e1 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
6MWT and 
SpO2 (resting, 
nadir, and end 
of test) f 
 
X 
Xf 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Borg scale 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
WHO 
Functional 
Class 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NT-proBNP, 
CRP, 
aldosterone 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Urinalysis 
 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Urine 
Pregnancy 
Test g 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up  
Additional 
safety FU i, 
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Serum 
Pregnancy 
Test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
ECHO 
 
X h 
X h1 
 
 
 
 
X 
 
 
 
X 
X 
 
 
SGRQ 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
UCSD SOBQ 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Serum and 
plasma for 
optional 
biomarker 
assessment 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
PAXgene for 
optional 
biomarker 
assessment 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
optional DNA 
biomarker 
assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Adverse 
Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 
Week 
Washouta 
Screeningb 
Double blind Treatment 
Early Study 
Withdrawal/
Study Treat. 
Discontinua
tion 
Follow-
Up 
Additional 
safety FU i,  
up to 11 
months 
-57 to -29 
 28 to -1  
 
1 
W1 
22 
W3 
45 
W6 
90 
W12 
135 
W19 
180 
W26 
225 
W32 
270 
W39 
315 
W45 
365 
W52 
393 
(Window, 
days) 
 
 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
 
Treatment 
Period Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Approx. 
every 3 
months 
Review Dosing 
Adherence 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review Patient 
Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense/ 
Collect Patient 
Diary 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Dispense 
Wallet Card 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pirfenidone 
treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X j 
Dispense 
Sildenafil/ 
Placebo and 
Explain Dosing 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect Unused 
Sildenafil/ 
Placebo and 
Empty Bottles 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
6MWT = 6-minute walk test; DLCO =  pulmonary diffusion capacity; ECG = electrocardiogram; ECHO = echocardiography; NT-proBNP = N-terminal 
pro-brain natriuretic peptide; RHC = right-heart catheterization; SGRQ = Saint George's Respiratory Questionnaire; UCSD SOBQ = University of 
California San Diego Shortness of Breath questionnaire; SpO2 = oxyhemoglobin saturation. 


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______________________________________________________________________________________________ 
* Collect from randomized patients the most recent HRCTs performed prior to entering the study  
a Patients taking prohibited medications at the time of consent must, after consent, discontinue the prohibited medications 28 days prior to the 
start of Screening (Day -57 to -29). If a prohibited medication must be tapered, tapering will be followed by discontinuation, and the 
discontinuation should last at least 28 days (washout period) before the start of screening.  Patients that do not require Washout proceed directly 
to Screening.  In addition, a run-in period will be provided for countries where patients will not be able to take pirfenidone for 12 weeks due to 
reimbursement issues.  After signing the ICF, the 12-week run-in pirfenidone supply will be provided by the Sponsor.   
b The Screening Period of up to 28 days may comprise one or more visits for the convenience of the patient. 
c Written informed consent will be obtained prior to any study procedures, either prior to Washout or if not applicable, prior to Screening. 
d Spirometry will be performed only post-bronchodilator.  Reference equations for spirometric indices will be provided in the Procedure Manual. 
d1 Should Spirometry at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening 
Spirometry can be used as baseline 
e The reported DLCO will be corrected for the current hemoglobin level, using reference equations. 
e1 Should DLCO at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening DLCO 
can be used as baseline 
f The 6MWT will be performed once at each visit highlighted.  At Baseline, it will be performed twice and the better of the two 6MWD values will be 
reported.  Please refer to the 6MWT Procedure Manual. 
g If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
h ECHO assessment at screening is not required for eligible patients based on RHC criteria.  
h1 Should the ECHO at screening collect all information required at Visit 1 and the patient is eligible and randomized in ≤14 days, the screening 
ECHO can be used as baseline 
i The sponsor will offer the possibility to the patients to receive pirfenidone within the study protocol up to a 11 months safety follow up.  During 
this interval the patients should be evaluated approximately every three months. 
j During the additional safety FU, data related to the pirfenidone administration will not be collected on the CRF.    
 


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Decline  
15-25%?
Appendix 2  
Endpoint Decision process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6MWD 
Decline 
> 25%? 
Respiratory-related  
non-elective hospitalization,  
or all-cause mortality?
No 
 
N
o 
 
N
o 
Compared with 
baseline: 
SpO2 worse? Or 
Maximum Borg scale 
worse ?Or  
increased O2?  
              No 
Yes 
Yes 
 
Y
e
s 
Y
e
s 
 
Combined 
Endpoint = Yes 
 
Combined 
Endpoint = No 


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Appendix 3 
MedDRA Browser Basket: Esbriet – Potential Hy’s Law AEGT 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated total 
bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by Hy's law).  
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin  2  ULN 
• 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
Description 
AEGT to identify cases of potential Hy's Law: 50 Terms 
 
Created Date              11-May-2016  
 
By User FLOODC 
Last Modified Date 
03-Nov-2016  
 
By User MOHANS5 
Last Reviewed Date 04-Nov-2016  
 
By User coyagonr 
 
Included MedDRA Preferred Terms 
 
 
 
Liver injury 
 
Bilirubin conjugated increased 
 
Urine bilirubin increased 
 
Hepatobiliary disease 
 
Jaundice 
 
Transaminases abnormal 
 
Subacute hepatic failure 
 
Aspartate aminotransferase increased 
 
Cholestatic liver injury 
 
Bilirubin conjugated abnormal 
 
Mixed liver injury 
 
Hyperbilirubinaemia 
 
Drug-induced liver injury 
 
Hepatic enzyme abnormal 
 
Blood alkaline phosphatase abnormal 
 
Gamma-glutamyltransferase increased 
 
Hepatic failure 
 
Acute hepatic failure 
 
Blood alkaline phosphatase increased 
 
Hepatic enzyme increased 
 
Aspartate aminotransferase abnormal 
 
Biopsy liver abnormal 
 
Liver function test increased 
 
Liver function test abnormal 
 


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Blood bilirubin increased 
 
Jaundice hepatocellular 
 
Hepatitis 
 
Alanine aminotransferase abnormal 
 
Hepatitis fulminant 
 
Hepatitis cholestatic 
 
Hepatitis acute 
 
Acute yellow liver atrophy 
 
Cholestasis 
 
Blood bilirubin unconjugated increased 
 
Prothrombin time ratio increased 
 
Chronic hepatitis 
 
Prothrombin time abnormal 
 
Hepatic infiltration eosinophilic 
 
Hepatic function abnormal 
 
Prothrombin time prolonged 
 
Hepatotoxicity 
 
Hepatitis toxic 
 
Transaminases increased 
 
Blood bilirubin abnormal 
 
Prothrombin time ratio abnormal 
 
Liver disorder 
 
Alanine aminotransferase increased 
 
Hepatic necrosis 
 
Gamma-glutamyltransferase abnormal 
 
Hepatocellular injury 
 
MedDRA Version 19.1 used. 
 
Note: The same terms are required for MedDRA version 21.1. They will be reviewed and 
adapted the higher MedDRA versions. 
 
 


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Appendix 4  
Calculation of GAP Index Categories 
Calculation of GAP Score 
The GAP score and staging system is based on four baseline characteristics, gender, age, %FVC 
at baseline and %DLco at baseline. If any of the four baseline characteristics is missing then the 
GAP score is missing. 
Table 7  
GAP Index and Staging System 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This definition follows the descriptions used in the Pirfenidone 2014 Resubmission Efficacy 
Update (RISE). 
• 
GAP Index Stage I:   Total Points: 0 to 3 
• 
GAP Index Stage II:  Total Points: 4 to 5 
• 
GAP Index Stage III: Total Points: 6 to 8 
 
In order to prevent possible issues with unexpected data formats, the following changes to the 
above definitions will be performed in this study: 
 
 
 
 
 
 
 
 
Variable name from 
ADSL 
Predictor 
Points 
Gender (G) 
SEX 
Female 
0 
Male 
1 
Age (A) 
AGERAND 
Age <=60 
0 
60<Age=<65 
1 
Age >65 
2 
Physiology (P) 
FVCBL 
FVC >75 
0 
50<=FVC<=75 
1 
FVC<50 
2 
DLCOBL 
DLCO>55 
0 
36<=DLCO<=55 
1 
DLCO<36 
2 
Cannot Perform 
3 
 
Variable name from 
ADIESL 
Predictor 
Points 
Age (A) 
AGERAND 
Age < 61 
0 
61<=Age=<65 
1 
Age >65 
2 
 
 
 
 


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Appendix 5  
UCSD-SOBQ 
The University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) is a 
symptom-specific, 24-item, patient-self-administered questionnaire that assesses shortness of 
breath while doing a variety of activities of daily living.  
UCSD MEDICAL CENTER 
PULMONARY REHABILITATION PROGRAM 
SHORTNESS-OF-BREATH QUESTIONNAIRE 
© 1995 The Regents of the University of California 
Please rate the breathlessness you experience when you do, or if you were to do, each of the 
following tasks. Do not skip any items. If you’ve never performed a task, or no longer perform 
it, give your best estimate of the breathlessness you would experience while doing that activity. 
Please review the two sample questions below before turning the page to begin the 
questionnaire. 
 


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Scoring 
Twenty one items assess the severity of shortness of breath during specific activities associated 
with daily living if patients do not routinely perform the activity, they are asked to estimate the 
degree of shortness of breath anticipated. Three additional items ask about limitations due to: 
shortness of breath, fear of harm from overexertion and fear of shortness of breath. 
 
Each of the 24 activities are rated on how dyspnea affects the activity on a 6-point scale:  
0 = None at all to 5 = Maximal or unable to do because of breathlessness 
 
The scores from all 24 questions are totalled to provide a score in the range 0 – 120. 
 
 


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Appendix 6  
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ) 
The St. George’s Respiratory Questionnaire (SGRQ) is an index designed to measure and 
quantifies health-related health status in patients with chronic airflow limitations. 
 


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Appendix 7 
Scoring Algorithm: SGRQ 
STRUCTURE OF SGRQ 
 
The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in 
patients with diseases of airways obstruction. 
 
Part 1 (Questions 1-8) addresses the frequency of respiratory symptoms. It is not designed to 
be a precise epidemiological tool, but to assess the patient’s perception of their recent 
respiratory problems. 
 
Part 2 (Sections 9-16) addresses the patient’s current state (i.e. how they are these days). 
The Activity score measures disturbances to daily physical activity. The Impacts score 
covers a range of disturbances of psycho-social function. Validation studies for the original 
SGRQ showed that this component relates in part to respiratory symptoms, but it also correlates 
quite strongly with exercise performance (6-minute walking test), breathlessness in daily life 
(MRC breathlessness score) and disturbances of mood (anxiety and depression). The Impacts 
score is, therefore, the broadest component of the questionnaires, covering the whole range of 
disturbances that respiratory patients experience in their lives. 
 
Three component scores are calculated for the SGRQ 
Symptoms – concerned with the effect of respiratory symptoms their frequency and severity 
Activity concerned with activities that cause or are limited by breathlessness 
Impacts covers a range of aspects concerned with social functioning and psychological 
disturbances resulting from airway disease. 
Total score summaries the impact of disease on overall health status.  Scores are expressed as 
a percentage of overall impairment where 100 represents worst possible health status and 0 
indicates best possible health status . 
SGRQ SCORES IN HEALTHY PATIENTS 
 
 
 
Means (95% confidence intervals) for SGRQ scores in normal patients with no history of 
respiratory disease 
 
N 
Age-years 
FEV1 as 
% 
predicted 
Symptoms 
score 
Activity 
score 
Impacts 
Score 
Total 
Score 
72 
46  (17 - 80) 
95 (91- 
99) 
12 (9-15) 
9 (7-12) 
2 (1-3) 
6 (5-7) 
 


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Scoring  
Questions 1 – 7  The eCRF screens should be set up so that where a patient has ticked a box, a 
value of 1 is entered for the appropriate question.  By default, the empty boxes are entered as 0. 
Where a patient has missed a question the cells on the spreadsheet are left blank. Example: 
Response = 1c, ‘Over the last year I have coughed a few days a month’. A value of 1 is entered 
for 1c and a value of 0 is entered for 1a, 1b, 1d and 1e. If no tick was present for question 1 then 
1a to 1e would be left blank. 
 
Question 8 Where a patient has ticked ‘Yes’ to having a worse wheeze in the morning, a value of 
1 is entered for the appropriate question. All other responses are entered as 0. Example: Do you 
have a wheeze? = ‘Yes’ and Worse in the morning = ‘Yes’. then response to question 8 = 1.  Do 
you have a wheeze? = ‘Yes’ and Worse in the morning = ‘No’. Or, Do you have a wheeze? = 
‘No’. then response to question 8=0. 
 
Questions 9, 10 & 17 Where a patient has ticked a box, a value of 1 is entered for the 
appropriate question. The empty boxes are entered as 0. Where a patient has missed the 
question the cells on the spreadsheet are left blank. Example: Response = 10a, ‘My chest 
trouble made me stop work’. A value of 1 is entered for 10a and a value of 0 is entered for 10b 
and 10c. If no tick was present for question 10, then 10a to 10c would be left blank. 
 
Questions 11 – 16 Where a patient has ticked ‘True’ a value of 1 is entered for the 
appropriate question and where a patient has ticked ‘False’ a value of 0 is entered. Where a 
patient has missed a question the cell on the spreadsheet is left blank. 
 
Example: 15a = ‘True’ then 15a = 1. 
14c = ‘False’ then 14c = 0. 
13h = missing then 13h is left blank 
In response to question 14, if a patient is not receiving medication, enter the responses as zero, 
otherwise the calculator will read the values as missing. 
 
Missing Questions 
There should not be any missing items in the questionnaire,  but the SGRQ can have up to 24% 
of missing items in the questionnaire. If more than 24% of items are missing the scores will be 
missing. 


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ITEM WEIGHTS 
 
Once the questions have been answered the following weights are applied to the individual 
responses. 
 
PART 1 
Over the past 3 months, I have coughed: 
 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
80.6 
63.2 
29.3 
28.1 
0.0 
 
Over the past 3 months, I have brought up phlegm (sputum): 
 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
76.8 
60.0 
34.0 
30.2 
0.0 
 
3) Over the past 3 months, I have had shortness of breath: 
 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
87.2 
71.4 
43.7 
35.7 
0.0 
 
4) Over the past 3 months, I have had attacks of wheezing: 
 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
86.2 
71.40 
45.6 
36.4 
0.0 
 
5) During the past 3 months, how many severe or very bad unpleasant attacks of chest trouble 
have you had? 
 
More than three 3  attacks 
2 attacks 
 1 attack 
None 
86.7 
73.5 
60.3 
44.2 
0.0 
 
6) How long did the worst attack of chest trouble last? 
a week or more 
3 or more days 
1 or 2 days  
Less than a day None 
89.7 
73.5 
58.8 
41.9 
0.0 
 
7) Over the past 3 months, in an average week, how many good days (with little chest trouble) 
have you had? 
No good days 
1 or 2 good 
days 
3 or 4 good 
days 
Nearly every 
day 
Every day 
93.3 
76.6 
61.5 
15.4 
0.0 
 
8) If you have a wheeze, is it worse in the morning? 
No 
Yes 
0.0 
62.0 


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PART 2 
The weights in Part 2 are also applied to the individual responses to each question. The worse 
the impact the higher the weight. This means that weights are not applied sequentially in the 
order that the response is given.  
 
9) How would you describe your chest condition? 
 
The most important problem I have  
 
83 .2 
Causes me quite a lot of problems   
  
82.5 
Causes me a few problems  
 
 
 
34.6 
Causes no problem   
 
 
 
  
0.0 
 
 
10) If you have ever had paid employment? 
 
My chest trouble made me stop work 
 
 
88.9 
My chest trouble interferes with my work or made me change my work 
77.6 
My chest trouble does not affect my work 
 
 
0.0 
 
11) Questions about what activities usually make you feel breathless. 
 
Sitting or lying still   
90.6 
Getting washed or dressed   
82.8 
Walking around the home   
80.2 
Walking outside on the level   
81.4 
Walking up a flight of stairs   
76.1 
Walking up hills   
75.1 
Playing sports or games   
72.1 
 
12) More questions about your cough and breathlessness. 
 
My cough hurts  
81.1 
My cough makes me tired  
79.1 
I get breathless when I talk  
84.5 
I get breathless when I bend over  
76.8 
My cough or breathing disturbs my sleep  
87.9 
I get exhausted easily  
84.0 
 
13) Questions about other effects your chest trouble may have on you. 
 
My cough or breathing is embarrassing in public  
74.1 
My chest trouble is a nuisance to my family, friends or neighbours  
79.1 
I get afraid or panic when I cannot get my breath  
87.7 
I feel that I am not in control of my chest problem  
90.1 
I do not expect my chest to get any better  
82.3 
I have become frail or an invalid because of my chest  
89.9 
Exercise is not safe for me  
75.7 
Everything seems too much of an effort  
84.5 
 
 


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14) Questions about your medication. 
 
My medication does not help me very much   
88.2 
I get embarrassed using my medication in public   
53.9 
I have unpleasant side effects from my medication   
81.1 
My medication interferes with my life a lot   
70.3 
 
15) Questions about how activities may be affected by your breathing. 
 
I take a long time to get washed or dressed   
74.2 
I cannot take a bath or shower, or I take a long time   
81.0 
I walk more slowly than other people, or I stop for rests   
71.7 
Jobs such as housework take a long time, or I have to stop for rests   
70.6 
If I walk up one flight of stairs, I have to go slowly or stop   
71.6 
If I hurry or walk fast, I have to stop or slow down   
72.3 
My breathing makes it difficult to do things such as walk up hills, carry things up stairs, 
light gardening such as weeding, dance, play bowls or play golf   
74.5 
My breathing makes it difficult to do things such as carry heavy loads, dig the garden 
or shovel snow, jog or walk at 5 miles per hour, play tennis or swim  
71.4 
My breathing makes it difficult to do things such as very heavy manual work, run, 
cycle,swim fast or play competitive sports  
63.5 
 
16) We would like to know how your chest trouble usually affects your daily life. 
 
I cannot play sports or games   
64.8 
I cannot go out for entertainment or recreation   
79.8 
I cannot go out of the house to do the shopping   
81.0 
I cannot do housework   
79.1 
I cannot move far from my bed or chair   
94.0 
 
17) Tick the statement which you think best describes how your chest affects you. 
 
It does not stop me doing anything I would like to do   
0.0 
 It stops me doing one or two things I would like to do   
42.0 
It stops me doing most of the things I would like to do   
84.2 
It stops me doing everything I would like to do  
96.7 
 
 
 
 


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SCORING ALGORITHM 
Three component scores are calculated: Symptoms; Activity; Impacts 
One Total score is also calculated. 
 
PRINCIPLE OF CALCULATION 
 
Each questionnaire response has a unique empirically derived 'weight'. The lowest possible 
weight is zero and the highest is 100. 
 
Each component of the questionnaire is scored separately in three steps: 
i. The weights for all items with a positive response are summed. 
 
 
ii The weights for missed items are deducted from the maximum possible weight for 
each component. The weights for all missed items are deducted from the maximum 
possible weight for the Total score. 
 
iii. The score is calculated by dividing the summed weights by the adjusted maximum 
possible weight for that component and expressing the result as a percentage : 
Score = 100 x Summed weights from positive items in that component 
Sum of weights for all items in that component 
 
The Total score is calculated in similar way: 
Score = 100 x Summed weights from positive items in the questionnaire 
Sum of weights for all items in the questionnaire 
 
Sum of maximum possible weights for each component and Total: 
 
 
Symptoms 662.5 
Activity 1209.1 
Impacts 2117.8 
Total 3989.4 
 
(Note: these are the maximum possible weights that could be obtained for the worst possible 
state of the patient). 
It will be noted that the questionnaire requests a single response to questions 1-7, 9-10 and 17. 
If multiple responses are given to one of these questions then averaging the weights for the 
positive responses for that question are acceptable 
 
SYMPTOMS COMPONENT 
This is calculated from the summed weights for the positive responses to questions 1-8. 
 
ACTIVITY COMPONENT 
This is calculated from the summed weights for the positive responses to questions 11 and 15. 
 
IMPACTS COMPONENT 
This is calculated from the summed weights for the positive responses to questions 9-10, 12- 14 
and 16-17. 
 
 


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TOTAL SCORE 
The Total score is calculated by summing all positive responses in the questionnaire and 
expressing the result as a percentage of the total weight for the questionnaire  
 
HANDLING MISSED ITEMS 
There should not be any missed items but if there are missing items the scores should be 
calculated using the following method which is recommended for missing items: 
 
Symptoms 
The Symptoms component will tolerate a maximum of 2 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Symptoms component (662.5) and from 
the Total weight (3989.4). 
 
Activity 
The Activity component will tolerate a maximum of 4 missed items. The weight for the 
missed item is subtracted from the total possible weight for the Activity component (1209.1) and 
from the Total weight (3989.4). 
 
Impacts 
The Impacts component will tolerate a maximum of 6 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Impacts component (2117.8) and from 
the Total weight (3989.4). 
 
 


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Appendix 8 
Acute exacerbations