Multicenter, International, Double-blind, Two-Arm, Randomized, Placebo-controlled Phase II Trial of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing ILD
Phase: PHASE2
Conditions: Lung Diseases, Interstitial
Sponsor: Hoffmann-La Roche

 
Official Title: 
 
MULTICENTER, INTERNATIONAL, DOUBLE-BLIND, TWO-ARM, 
RANDOMIZED, PLACEBO-CONTROLLED PHASE II TRIAL OF 
PIRFENIDONE IN PATIENTS WITH UNCLASSIFIABLE 
PROGRESSIVE FIBROSING ILD 
NCT Number: 
NCT03099187 
Document Date: 
Protocol Version 3: 28-June-2018 
 
 

PROTOCOL AMENDMENT APPROVAL
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especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) 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 — F. Hoffmann-La Roche Ltd
Protocol MA39189, Version 3.0
PROTOCOL
TITLE:
MULTICENTER, INTERNATIONAL, DOUBLE-
BLIND, TWO-ARM, RANDOMIZED, PLACEBO-
CONTROLLED PHASE II TRIAL OF PIRFENIDONE
IN PATIENTS WITH UNCLASSIFIABLE 
PROGRESSIVE FIBROSING ILD
PROTOCOL NUMBER:
MA39189
VERSION NUMBER:
3.0
EUDRACT NUMBER:
2016-002744-17
IND NUMBER:
67284
TEST PRODUCT:
Pirfenidone (RO0220912)
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1.0:  15 November 2016
DATE AMENDED:
Version 2.0: 03 March 2017
Version 3.0:  See electronic date stamp below
 
28-Jun-2018 12:58:04
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Pirfenidone — F. Hoffmann-La Roche Ltd
2/Protocol MA39189, Version 3.0
PROTOCOL AMENDMENT No. 2.0, PROTOCOL VERSION 3.0:
RATIONALE
Protocol version 2.0 has been amended mainly in order to provide additional guidance 
on trial specific procedures. Changes to the protocol including the rationale for each 
change are listed below. 

Synopsis (Target Population) and Protocol Section 4.1 (Patients) of the protocol 
have been amended in order to provide guidance on conditions for allowing the re-
screening of patients.

Protocol Section 4.5.5 (FVC) has been amended to provide guidance on when to use 
a short-acting bronchodilator prior to on-site spirometry for patients who are routinely 
treated with such medication. 

Protocol Sections 4.5.9 (Electrocardiograms) and 5.1.1.8 (Management of Increases 
in QT Interval) have been amended to provide more clear guidance for ECGs and 
the management of increases in QT interval. 

Protocol Section 4.5.10 (Patient-Reported Outcomes) has been amended as the 
timing for the completion of the Patient-Reported Outcomes is independent of the 
administration time of the trial treatment. 

Protocol Section 4.6.1 (Patient Discontinuation) has been amended to include lung 
transplantation during the trial as a reason for patient discontinuation.

Schedule of Assessments has been amended to reflect the changes made to the 
body of the protocol and also to provide further trial-specific guidance.
Additional minor changes have been made to improve clarity and consistency. New 
information is shown in italics and deletions to text are shown as strikethrough. This 
amendment represents cumulative changes to protocol version 2.0.

Pirfenidone —F. Hoffmann-La Roche Ltd
3/Protocol MA39189, Version 3.0
PROTOCOL AMENDMENT No. 2.0, PROTOCOL VERSION 3.0:
SUMMARY OF CHANGES
GLOBAL CHANGES
Protocol version 2.0 (3 March 2017) has been amended in order to provide further 
guidance on trial specific procedures.  
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes made to the protocol, 
where applicable.
SECTION: Target Population
Reason for change: Text has been added to provide guidance on conditions allowing 
for the re-screening of patients.  
Added text:
Re-screening may be considered for patients who do not show sufficient disease 
deterioration in accordance to the protocol at the time of the initial screening. Re-
screening is permitted if there is strong evidence of clinical worsening based on the 
Investigator’s judgement and only upon receipt of official approval from the Study 
Management Team. In such cases, re-screening may be performed after a minimum of 
4-weeks lapse from the initial screening date.
PROTOCOL
SECTION 4.1:  Patients
Reason for change: Text has been added to provide guidance and conditions allowing 
for the re-screening of patients.  
Added text: 
Re-screening may be considered for patients who do not show sufficient disease 
deterioration in accordance to the protocol at the time of the initial screening. Re-
screening is permitted if there is strong evidence of clinical worsening based on the 
Investigator’s judgement and only upon receipt of official approval from the Study 
Management Team. In such cases, re-screening may be performed after a minimum of 
4-weeks lapse from the initial screening date.

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4/Protocol MA39189, Version 3.0
SECTION 4.5.5:  FVC
Reason for change: Text has been added in order to provide additional guidance on 
the use of short-acting bronchodilator prior to spirometry.
Added text: 
If a patient is routinely treated with a short-acting bronchodilator (for example albuterol, 
salbutamol), the bronchodilator should be taken approximately 30 minutes prior to the 
on-site spirometry.
SECTION 4.5.9:  Electrocardiograms
Reason for change: Text amended in order to replace a general guidance with specific 
requirements provided in section 5.1.1.8.
Amended text: 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper copies of ECG tracings will be kept as part of the patient's permanent 
trial file at the site. Digital recordings will be stored at site. The following should be 
recorded in the appropriate eCRF: heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and the QTcF based on the machine readings of the individual 
ECG tracings. Any morphologic waveform changes or other ECG abnormalities must be 
documented on the eCRF. If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory. Refer to section 5.1.1.8 for details on 
protocol management of increases in QT interval.
If at a particular post dose time point the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs. The Medical Monitor should be notified. Standard of care treatment 
may be instituted at the discretion of the investigator. A decision on trial treatment 
discontinuation should be made, as described in Section 4.6.1. The investigator should 
also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co medications known to prolong the QT interval, and severe 
bradycardia).
SECTION 4.5.10:  Patient-Reported Outcomes

Reason for change: Text has been amended as the timing for the completion of the 
Patient-Reported Outcomes is independent of the administration time for the trial 
treatment. 

Pirfenidone —F. Hoffmann-La Roche Ltd
5/Protocol MA39189, Version 3.0
Amended text: 
PRO data will be collected via questionnaires to document the treatment effect and to 
evaluate the benefit of pirfenidone. The questionnaires, translated into the local 
language as required, will be completed in their entirety at specified time points during 
the trial (see Appendix 1) To ensure instrument validity and that data standards meet 
health authority requirements, questionnaires will be self-administered before the patient 
receives any information on disease status, and prior to the performance of non-PRO 
assessments, and prior to the administration of trial treatment, unless otherwise 
specified.
SECTION 4.6.1:  Patient Discontinuation
Reason for change: Text has been amended in order to include lung transplantation as 
reason for patient’s discontinuation from the trial.
Added text:

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 trial

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, defined as non-adherence with the dosing regimen, 
including the dose-titration guidance for starting trial treatment

Lung transplantation
Patients who undergo lung transplantation during the trial will be discontinued at the time 
of hospitalization for transplantation.
SECTION 5.1.1.8:  Management of Increases in QT Interval
Reason for change: Text has been amended in order to provide more clear guidance 
on the management of increases in QT interval.
Amended text: 
In the event of a QTcF interval >550 ms or an increase from baseline of >60 ms, a 
repeat ECG must be obtained within 24 hours. If the QTcF finding is confirmed by the 
repeat ECG and verified by the site (trial center) or local cardiologist, pirfenidone
treatment should be discontinued and the patient should be withdrawn from the trial.
In the event of a QTcF interval of >500 550 ms or an increase from baseline of 
31-60 ms, a repeat ECG must be obtained within 24 hours. If the QTcF finding is 
confirmed by the repeat ECG and verified by the site (trial center) or local cardiologist, 
pirfenidone treatment should be discontinued and a decision on trial treatment 
discontinuation should be made, as described in Section 4.6.1 interrupted.[…]

Pirfenidone —F. Hoffmann-La Roche Ltd
6/Protocol MA39189, Version 3.0
SECTION 5.4.4:  Reporting Requirements for Cases of Pirfenidone Accidental 
Overdose, Medication Error, Drug Abuse, or Drug Misuse
Reason for change: Text has been amended in order to include new requirements for 
safety reporting related to overdose, medication error, drug abuse, or drug misuse.
Added text:
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:
•
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose
•
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose
•
Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of the drug.
•
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm
•
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse could involve 
the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately 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 hours after learning of the event; see Section 5.4.2).  For Pirfenidone, 
adverse events associated with special situations should be recorded as described 
below for each situation:
•
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.
•
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug abuse 
is not suspected, check the "Drug misuse" box.
•
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.
•
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Pirfenidone —F. Hoffmann-La Roche Ltd
7/Protocol MA39189, Version 3.0
•
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.
•
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.
•
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.
•
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with Pirfenidone, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:
•
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.
•
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.
•
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.
•
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication error" 
boxes.  Enter a description of the error in the additional case details.
•
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of the 
error in the additional case details.
•
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.
•
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" boxes.
•
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.
•
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

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8/Protocol MA39189, Version 3.0
•
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" box.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
APPENDIX 1:  Schedule of Assessments
Guidance Text
Reason for change: Guidance text amended as the timing of the trial visit assessments 
is independent of the administration time for the trial treatment. 
Amended text:
Notes: all assessments should be performed within 7 days of the scheduled visit, unless 
otherwise specified. On treatment days, all assessments should be performed prior to 
dosing, unless otherwise specified.
Foot Note C
Reason for change: Guidance text amended as during the first 6 months of the 12-
month open-label period, trial visits are conducted on a monthly basis. 
Amended text:
c  After completion of the double-blind treatment period and the Follow-up Visit at Week 
28, the Sponsor will offer the possibility to the patients to receive open-label pirfenidone 
within the trial protocol in a safety follow-up period of up to 12 months. During the 12-
month safety follow-up period, initially, patients will be evaluated at monthly visits for the 
first 6 months. At the end of the first 6 months, patients will be evaluated at each site 
visit occurring approximately every 3 months until the end of the safety follow-up period.
During the safety follow up period, the patients should be evaluated by the investigator 
approximately every 3 months. […]
Foot Note Q
Reason for change: Guidance text amended as the timing of the trial visit assessments 
is independent of the administration time for the trial treatment.
Amended text:
q  Questionnaires will be self-administered prior to the patient receiving any information 
on disease status and, prior to the performance of non-PRO assessments, and prior to 
the administration of trial treatment. […]
Foot Note U
Reason for change: Guidance text added for patients who discontinue the trial between 
weeks 24 and 28 and which visit assessments should be conducted as the final visit.

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9/Protocol MA39189, Version 3.0
Amended text:
U If a patient discontinues the trial between weeks 24 and 28, final assessments 
according to the Follow-up visit for week 28 should be performed.

Pirfenidone — F. Hoffmann-La Roche Ltd
10/Protocol MA39189, Version 3.0
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
MULTICENTER, INTERNATIONAL, DOUBLE-
BLIND, TWO-ARM, RANDOMIZED, PLACEBO-
CONTROLLED PHASE II TRIAL OF PIRFENIDONE
IN PATIENTS WITH UNCLASSIFIABLE 
PROGRESSIVE FIBROSING ILD
PROTOCOL NUMBER:
MA39189
VERSION NUMBER:
3.0
EUDRACT NUMBER:
2016-002744-17
IND NUMBER:
67284
TEST PRODUCT:
Pirfenidone (RO0220912)
MEDICAL MONITOR:
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 site contact.

Pirfenidone — F. Hoffmann-La Roche Ltd
11/Protocol MA39189, Version 3.0
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS.................................................................................... 16
1.
BACKGROUND.......................................................................................... 26
1.1
BACKGROUND ON UNCLASSIFIABLE 
INTERSTITIAL LUNG DISEASE .......................................... 26
1.2
BACKGROUND ON PIRFENIDONE .................................... 26
1.3
TRIAL RATIONALE AND BENEFIT-RISK 
ASSESSMENT...................................................................... 28
2.
OBJECTIVES AND ENDPOINTS............................................................... 29
3.
TRIAL DESIGN........................................................................................... 30
3.1
DESCRIPTION OF THE TRIAL ............................................ 30
3.2
END OF TRIAL AND LENGTH OF TRIAL............................ 33
3.3
RATIONALE FOR TRIAL DESIGN....................................... 34
3.3.1
Rationale for Pirfenidone Dose and Schedule.................. 34
3.3.2
Rationale for Patient Population ........................................ 34
3.3.3
Rationale for Control Group ............................................... 35
3.3.4
Rationale for Concomitant MMF Therapy.......................... 35
3.3.5
Rationale for Biomarker Assessments.............................. 36
3.3.6
Rationale for Disease Response–based 
Endpoints 36
3.3.7
Rationale for PRO Assessments........................................ 37
4.
MATERIALS AND METHODS ................................................................... 37
4.1
PATIENTS............................................................................. 37
4.1.1
Inclusion Criteria ................................................................. 37
4.1.2
Exclusion Criteria ................................................................ 38
4.2
METHOD OF TREATMENT ASSIGNMENT AND 
BLINDING ............................................................................. 40
4.3
TRIAL TREATMENT............................................................. 41
4.3.1
Formulation, Packaging, and Handling ............................. 41
4.3.2
Dosage, Administration, and Compliance......................... 41

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4.3.3
Investigational Medicinal Product 
Accountability........................................................................................ 42
4.3.4
Continued Access to Pirfenidone ...................................... 42
4.4
CONCOMITANT THERAPY AND PROHIBITED 
FOOD .................................................................................... 44
4.4.1
Permitted Therapy............................................................... 44
4.4.2
Prohibited Therapy.............................................................. 44
4.4.3
Prohibited Food................................................................... 46
4.4.4
Additional Restrictions ....................................................... 46
4.5
TRIAL ASSESSMENTS........................................................ 46
4.5.1
Informed Consent Forms and Screening Log................... 46
4.5.2
Medical History and Demographic Data ............................ 46
4.5.3
Physical Examinations........................................................ 46
4.5.4
Vital Signs ............................................................................ 47
4.5.5
FVC ....................................................................................... 47
4.5.6
Handheld Spirometry .......................................................... 47
4.5.7
Other Trial Assessments .................................................... 48
4.5.8
Laboratory and Biomarker Samples .................................. 48
4.5.9
Electrocardiograms............................................................. 49
4.5.10
Patient-Reported Outcomes ............................................... 49
4.5.11
Optional Samples for Research Biosample 
Repository.............................................................................................. 50
4.6
PATIENT, TREATMENT, TRIAL, AND SITE 
DISCONTINUATION ............................................................. 52
4.6.1
Patient Discontinuation....................................................... 52
4.6.2
Trial Treatment Discontinuation......................................... 53
4.6.3
Trial and Site Discontinuation............................................ 53
5.
ASSESSMENT OF SAFETY ...................................................................... 54
5.1
SAFETY PLAN...................................................................... 54
5.1.1
Risks Associated with Pirfenidone .................................... 54
5.1.2
Management of Patients Who Experience 
Specific Adverse Events ....................................................................... 57
5.2
SAFETY PARAMETERS AND DEFINITIONS...................... 58
5.2.1
Adverse Events.................................................................... 58

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5.2.2
Serious Adverse Events (Immediately 
Reportable to the Sponsor)................................................................... 58
5.2.3
Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor)............................................ 59
5.3
METHODS AND TIMING FOR CAPTURING 
AND ASSESSING SAFETY PARAMETERS........................ 59
5.3.1
Adverse Event Reporting Period........................................ 60
5.3.2
Eliciting Adverse Event Information .................................. 60
5.3.3
Assessment of Severity of Adverse Events...................... 60
5.3.4
Assessment of Causality of Adverse Events.................... 61
5.3.5
Procedures for Recording Adverse Events....................... 61
5.4
IMMEDIATE REPORTING REQUIREMENTS 
FROM INVESTIGATOR TO SPONSOR ............................... 67
5.4.1
Emergency Medical Contacts............................................. 67
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest.................................. 68
5.4.3
Reporting Requirements for Pregnancies......................... 68
5.4.4
Reporting Requirements for Cases of 
Pirfenidone Accidental Overdose, Medication Error, 
Drug Abuse, or Drug Misuse ................................................................ 70
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE 
EVENTS ................................................................................ 72
5.5.1
Investigator Follow-Up........................................................ 72
5.5.2
Sponsor Follow-Up.............................................................. 72
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD ........................... 72
5.7
EXPEDITED REPORTING TO HEALTH 
AUTHORITIES, INVESTIGATORS, 
INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES......................................................... 72
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 73
6.1
DETERMINATION OF SAMPLE SIZE.................................. 73
6.2
SUMMARIES OF CONDUCT OF TRIAL .............................. 74
6.3
SUMMARIES OF DEMOGRAPHIC AND 
BASELINE CHARACTERISTICS ......................................... 74
6.4
EFFICACY ANALYSES ........................................................ 74

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6.4.1
Primary Efficacy Endpoint.................................................. 74
6.4.2
Secondary Efficacy Endpoints ........................................... 75
6.5
SAFETY ANALYSES............................................................ 76
6.6
EXPLORATORY ANALYSES............................................... 77
6.7
INTERIM ANALYSIS............................................................. 77
6.7.1
Optional Interim Analysis ................................................... 77
7.
DATA COLLECTION AND MANAGEMENT .............................................. 77
7.1
DATA QUALITY ASSURANCE ............................................ 77
7.2
ELECTRONIC CASE REPORT FORMS............................... 78
7.3
SOURCE DATA DOCUMENTATION.................................... 78
7.4
USE OF COMPUTERIZED SYSTEMS.................................. 79
7.5
RETENTION OF RECORDS................................................. 79
8.
ETHICAL CONSIDERATIONS ................................................................... 80
8.1
COMPLIANCE WITH LAWS AND 
REGULATIONS .................................................................... 80
8.2
INFORMED CONSENT......................................................... 80
8.3
INSTITUTIONAL REVIEW BOARD OR 
ETHICS COMMITTEE........................................................... 81
8.4
CONFIDENTIALITY .............................................................. 81
8.5
FINANCIAL DISCLOSURE................................................... 82
9.
TRIAL DOCUMENTATION, MONITORING, AND 
ADMINISTRATION..................................................................................... 82
9.1
TRIAL DOCUMENTATION ................................................... 82
9.2
PROTOCOL DEVIATIONS ................................................... 82
9.3
SITE INSPECTIONS ............................................................. 83
9.4
ADMINISTRATIVE STRUCTURE ......................................... 83
9.5
PUBLICATION OF DATA AND PROTECTION 
OF TRADE SECRETS .......................................................... 83
9.6
PROTOCOL AMENDMENTS................................................ 84
10. REFERENCES ........................................................................................... 85

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PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
5.4.4
Reporting Requirements for Cases of Pirfenidone 
Accidental Overdose, Medication Error, Drug Abuse, or Drug 
Misuse
70
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 29
Table 2
Titration Schedule....................................................................... 31
Table 3
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Pirfenidone................................... 57
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 60
LIST OF FIGURES
Figure 1
Trial Schema............................................................................... 32
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................... 88
Appendix 2
Patient-Reported Outcome Questionnaires ................................ 93

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PROTOCOL SYNOPSIS
TITLE:
MULTICENTER, INTERNATIONAL, DOUBLE-BLIND, TWO-
ARM, RANDOMIZED, PLACEBO-CONTROLLED PHASE II 
TRIAL OF PIRFENIDONE IN PATIENTS WITH 
UNCLASSIFIABLE PROGRESSIVE FIBROSING ILD
PROTOCOL 
NUMBER:
MA39189
VERSION NUMBER:
3.0
EUDRACT NUMBER:
2016-002744-17
IND NUMBER:
67284
TEST PRODUCT:
Pirfenidone (RO0220912)
PHASE:
II
INDICATION:
Fibrotic interstitial lung disease of unknown origin
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This trial will evaluate the efficacy and safety of pirfenidone in patients with fibrosing 
interstitial lung disease (ILD) who cannot be classified with moderate or high 
confidence into any other category of fibrosing ILD by multidisciplinary team (MDT) 
review (“unclassifiable” ILD).
Efficacy Objective
The primary efficacy objective for this trial is to evaluate the effect of pirfenidone vs. 
placebo on lung function parameters on the basis of the following endpoint:

Rate of decline in forced vital capacity (FVC) measured in mL by daily handheld 
spirometer over the 24-week double-blind treatment period.
Safety Objective
The safety objective for this trial is to evaluate the safety of pirfenidone vs. placebo on 
the basis of the following endpoints:

Nature, frequency, severity, and timing of treatment-emergent adverse events

Dose reductions and treatment interruptions

Clinical laboratory test results

12-lead electrocardiograms (ECGs)

Withdrawals from trial treatment or trial discontinuations.
Exploratory Objective
One exploratory objective for this trial is to evaluate the role of MMF (mycophenolate 
mofetil/sodium or mycophenolic acid) treatment in ILD on the basis of the following 
endpoint:

Efficacy and safety data from subgroups of patients who did or did not receive 
MMF treatment.

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In addition, exploratory biomarkers associated with fibrosis and ILD will be evaluated in 
plasma, serum, and whole blood ribonucleic acid (RNA) and deoxyribonucleic acid 
(DNA) samples.
Trial Design
Description of Trial
This is a multicenter, international, double-blind, two-arm, randomized, placebo-
controlled Phase II trial in patients with fibrosing ILD who cannot be classified with 
moderate or high confidence into any other category of fibrosing ILD by MDT review 
(“unclassifiable ILD”). Patients will be randomized in a 1:1 ratio, on a double-blind basis 
using a stratified algorithm, to receive either pirfenidone (801 mg three times daily [TID]) 
or placebo. The randomized patients will be stratified by concomitant MMF treatment 
(yes/no), the presence/absence of interstitial pneumonia with autoimmune features 
(IPAF) as defined by the MDT.
Most established MDTs have access to clinical, radiologic, and pathology expertise, 
and should have a sufficient case load of ILDs per year. Access to rheumatology 
expertise will be at the discretion of the MDT.
In total, approximately 90 clinical centers (sites) in Australia, Europe, the Middle East, 
and North America are expected to enroll approximately 250 patients. Patients who are 
withdrawn from the trial will not be replaced. The trial design is represented in Figure 1.
After discussing the risks and benefits of the trial with the investigator and providing 
informed consent, patients will be required to taper and/or discontinue all prohibited 
medications (Section 4.4.2) in the 28 days prior to the start of screening during the 
washout period. If a prohibited medication must be tapered, the process must start 
early enough so that the patient discontinues the medication in the 28 days prior to the 
start of screening. After completing the washout period, patients will enter screening, 
which lasts up to 21 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.
At the end of screening, patients will be randomized (Day 1) to receive either 
pirfenidone or placebo (1:1 ratio).
Following treatment initiation, the daily dosage will be titrated to the full dosage of nine 
capsules per day over a 14-day period as outlined in Table 2 . After the titration period, 
trial treatment will continue through Week 24 and monitoring will be conducted by trial
visits. Patients should remain on a stable maintenance dose for the duration of the 
treatment period unless the dose is reduced or dosing is interrupted to manage an 
adverse event (see Section 5.1.1). Any patient with an actual or anticipated interruption 
of trial treatment for a period of ≥28 consecutive days will be reported by telephone to 
Roche‘s medical monitor or designee to discuss the circumstances of the case. Once 
the patient restarts trial treatment, the dose must be re-titrated over 14 days as 
described in Table 2 . A Follow-up Visit will occur 28 days after the end of the 24-week 
double-blind treatment period.
After completion of the double-blind treatment period and the Follow-up Visit at 
Week 28, the Sponsor will offer the possibility to the patients to receive open-label 
pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. 
During the safety follow up period, the patients should be evaluated by the investigator 
initially at monthly visits during the first 6 months and subsequently at each visit 
occurring approximately every 3 months thereafter. A final Follow-up Visit will be 
performed at the end of the safety period, 28 days after the last open-label dose.

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Table 1       Titration Schedule
Treatment Days
Dosage
Days 1 through 7
One capsule three times daily with meals
Days 8 through 14
Two capsules three times daily with meals
Day 15 onwards
Three capsules three times daily with meals
The Sponsor will provide trial treatment on a double-blind basis. The design that will be 
utilized in this trial is shown in Figure 1.
Figure 1
Trial Schema
1 Patients will be required to taper and/or discontinue all prohibited medications in the 28 days 
prior to the start of screening during the washout period. Patients not taking a prohibited 
medication will forgo the washout period and directly enter screening.
2 Informed consent must be documented before any trial-specific screening procedure is 
performed, and may be obtained either at the Washout or Screening Visits.
3 After completion of the double-blind treatment period and the Follow-up Visit at Week 28, the 
Sponsor will offer the possibility to the patients to receive open-label pirfenidone within the trial 
protocol in a safety follow-up period of up to 12 months. A final Follow-up Visit will be performed 
at the end of the safety period, 28 days after the last open-label dose.
D=Day; ICF=informed consent form
The primary objective of this trial is to evaluate the efficacy of pirfenidone vs. placebo 
on lung function parameters by examining the rate of decline in FVC (measured in mL). 
A handheld spirometry device will be used by the patient to measure daily FVC at 
home. Confirmatory site (trial center) based FVC measurements will be conducted 
every 4 weeks (see Schedule of Assessments; Appendix 1). Blood samples will be 
obtained from patients in order to analyze clinical laboratory values and biomarkers.
Number of Patients
Approximately 250 patients with unclassifiable fibrosing ILD will be enrolled in this trial.

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Target Population
Inclusion Criteria
Patients must meet the following criteria for trial entry:
1. Signed Informed Consent Form
2. Age 18–85 years
3. Able to comply with the trial protocol, according to the investigator’s judgment
4. Confirmed fibrosing ILD which, following MDT review, cannot be classified with 
either high or moderate confidence as a specific idiopathic interstitial 
pneumonia or other defined ILD (e.g. chronic hypersensitivity or connective 
tissue disease-ILD [CTD-ILD])
5. Progressive disease as considered by the investigator using the following 
definition:
a. Patient deterioration within the last 6 months, which is defined as:
i.
A rate of decline in FVC >5% OR
ii.
Significant symptomatic worsening not due to cardiac, pulmonary, 
vascular, or other causes.
6. Extent of fibrosis >10% on high-resolution computed tomography (HRCT; visual 
scoring) within the last 12 months
7. FVC 45% of predicted value
8. Diffusing capacity of the lung for carbon monoxide (DLco) 30% of predicted 
value
9. Forced expiratory volume in 1 second (FEV1)/FVC ratio 0.7
10. 6-minute walk distance (6MWD) 150 meters
11. For women of childbearing potential: agreement to remain abstinent (refrain 
from heterosexual intercourse) or use a 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 trial treatment:
a. A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal 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)
b. Examples of contraceptive methods with a failure rate of <1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives 
including those that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices
c. 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.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) 
or use contraceptive measures, and agreement to refrain from donating sperm, 
as defined below:
a. 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  trial treatment. 
Men must refrain from donating sperm during this same period
b. 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 trial treatment to avoid exposing the embryo

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c. 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.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from trial entry:
1. Diagnosis with moderate or high confidence of nonspecific interstitial 
pneumonia (NSIP) and any ILD with an identifiable cause such as CTD-ILD, 
chronic hypersensitivity pneumonitis (cHP), or others
2. Diagnosis of idiopathic pulmonary fibrosis (IPF) independent of the confidence 
level
3. History of unstable angina or myocardial infarction during the previous 
6 months
4. Pregnant or lactating, or intending to become pregnant during the trial
5. A positive urine pregnancy test, which was confirmed with a positive serum 
pregnancy test. Women with a confirmed pregnancy will be excluded from trial 
participation and must discontinue trial treatment
6. Treatment with high dose systemic corticosteroids (i.e., >15 mg/d of 
prednisolone or equivalent), or any immunosuppressant other than MMF, at any 
time at least 4 weeks prior to screening. Patients being treated with MMF 
should be on a stable dose that is expected to remain stable throughout the trial 
and was started at least 3 months prior to screening
7. Patients previously treated with pirfenidone or nintedanib
8. Patients treated with N-acetyl-cysteine (NAC) for fibrotic lung disease, at any 
time within the 4 weeks of the screening period
9. Drug treatment for any type of pulmonary hypertension (e.g. sildenafil, 
endothelin receptor antagonist [ERA], etc.)
10. Participation in a trial of an investigational medical product within the last 
4 weeks
11. Significant co-existent emphysema (extent greater than extent of fibrosis on 
HRCT within the last 12 months)
12. Significant other organ co-morbidity including hepatic or renal impairment
13. Previous intolerance or allergy to the trial treatment
14. Pregnant patients, or women of child-bearing potential, not using a reliable 
contraceptive method
15. Unable to provide informed written consent
16. Predicted life expectancy <12 months or on an active transplant waiting list
17. Use of any tobacco product in the 12 weeks prior to the start of screening, or 
any unwillingness to abstain from their use through to the Follow-up Visit
18. Illicit drug or alcohol abuse within 12 months prior to screening, according to the 
investigator’s judgment
19. Planned major surgery during the trial
20. Hypersensitivity to the active substance or to any of the excipients of 
pirfenidone
21. History of angioedema
22. Concomitant use of fluvoxamine
23. Clinical evidence of any active infection which according to the investigator’s 
judgment may interfere with trial conduct, measurement of pulmonary function, 
or impact the course of the ILD

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24. Any history of hepatic impairment, elevation of transaminase enzymes, or the 
confirmation of any of the following liver function test (LFT) criteria above the 
specified limits:
a. Total bilirubin above the upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >1.5 × ULN
c.
Alkaline phosphatase >2.0 × ULN.
25. Creatinine clearance <30 mL/min, calculated using the Cockcroft-Gault formula
26. Any serious medical condition, clinically significant abnormality on an ECG at 
screening, or laboratory test results (hematology, serum chemistry, and 
urinalysis) that, in the opinion of the investigator, may pose an additional risk to 
the patient following the administration of trial treatment
27. An 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.
Re-screening may be considered for patients who do not show sufficient disease 
deterioration in accordance to the protocol at the time of the initial screening. Re-
screening is permitted if there is strong evidence of clinical worsening based on the 
Investigator’s judgement and only upon receipt of official approval from the Study 
Management Team. In such cases, re-screening may be performed after a minimum of 
4-weeks lapse from the initial screening date.
End of Trial and Length of Trial
After completion of the double-blind treatment period and the Follow-up Visit at 
Week 28, the Sponsor will offer the possibility to the patients to receive open-label 
pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. The 
end of the clinical trial is defined as the date when the last patient, last visit (LPLV) 
occurs or the date at which the last data point which is required for the statistical 
analysis is received, whichever is the later date. For this trial, LPLV will occur when the 
last patient has completed the final safety Follow-up Visit, 28 days after the final open-
label dose, or when the last data point is collected in the safety follow-period.
For each patient the total length of the trial is expected to be up to a maximum of 
91 weeks. The trial duration includes the washout period of up to 4 weeks, the 
screening period of up to 3 weeks, the double-blind treatment period of 24 weeks, the 
follow-up period of 4 weeks, the open-label safety follow-up period up to 12 months 
(52 weeks) and a final safety Follow-up Visit 4 weeks after the last dose.
Investigational Medicinal Products
Pirfenidone and Placebo
Pirfenidone and placebo will be supplied by the Sponsor as 267 mg capsules in a 
bottle. For information on the formulation and handling of pirfenidone, see the 
Investigator's Brochure or local prescribing information for pirfenidone.
Placebo will be supplied by the Sponsor in the form of capsules with identical 
appearance and size as the pirfenidone capsule. The placebo capsules will contain 
microcrystalline cellulose.
Statistical Methods
Primary Analysis
The primary efficacy objective for this trial is to evaluate the efficacy of pirfenidone vs. 
placebo on lung function parameters on the basis of rate of decline in FVC in mL 

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measured by handheld spirometry over the 24-week double-blind treatment period (see 
Section 2).
The primary analysis will be based on the intent-to-treat (ITT) population. Patients who 
discontinue treatment prematurely will be analyzed based on the available data. No 
imputation method will be applied.
The primary analysis of the primary endpoint will compare the mean FVC decline in 
each treatment arm using a student’s t-test with a two-sided significance level α=0.05. 
The mean FVC decline for each treatment arm will be calculated using the estimated 
FVC decline for each individual patient. The individual FVC decline will be estimated by 
applying a linear regression model to all data points collected during the 24-week 
double-blind treatment period.
Determination of Sample Size
The purpose of this trial is hypothesis generation regarding the efficacy of pirfenidone 
vs. placebo on lung function parameters on the basis of rate of decline in FVC, as 
measured by daily handheld spirometry.
A total sample size of approximately 250 patients is planned, and patients will be 
randomized in a 1:1 ratio. The randomization will be stratified by concomitant MMF 
treatment (yes/no), the presence/absence of IPAF as defined by the MDT.
The planned sample size is based on the statistical hypothesis of the primary endpoint 
and assumes 80% power and a two-sided significance level of 5% using a student’s t-
test. It is assumed, after inspection of historical data, that FVC decline in the placebo 
arm is 85 mL with a common standard deviation of 70 mL, which can be reduced to 
60 mL with a common standard deviation of 70 mL in the pirfenidone arm. In this 
scenario, 125 patients per treatment arm are needed to detect this treatment effect with 
80% power.
Interim Analyses
There are no planned interim efficacy analyses for this trial. Safety interim analyses will 
be performed at least three times during the trial, at approximately 6, 12, and 18 
months after the start of recruitment.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
6MWD
6-minute walk distance
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BID
two times daily
BTPS
body temperature and pressure saturated with water 
vapor
BUN
blood urea nitrogen
CAPACITY
Clinical Studies Assessing Pirfenidone in idiopathic 
pulmonary fibrosis: Research of Efficacy and Safety 
Outcomes
cHP
chronic hypersensitivity pneumonitis
CI
confidence interval
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CTD
connective tissue disease
CYP
cytochrome P450
DLco
diffusing capacity of the lung for carbon monoxide
DNA
deoxyribonucleic acid
DSMB
Data and Safety Monitoring Board
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EEA
European Economic Area
ERA
endothelin receptor antagonist
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
GERD
gastroesophageal reflux disease
HIPAA
Health Insurance Portability and Accountability Act
HRCT
high-resolution computed tomography
ICH
International Conference on Harmonisation
iDMC
independent Data Monitoring Committee
IL
interleukin

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Abbreviation
Definition
ILD
interstitial lung disease
IMP
investigational medicinal product
IND
Investigational New Drug
IPAF
interstitial pneumonia with autoimmune features
IPF
idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ITT
intent-to-treat
IxRS
interactive voice or web-based response system
LDH
lactate dehydrogenase
LFT
liver function test
LOTUSS
An open-Label, randOmized, Phase 2 sTUdy of the 
safety and tolerability of pirfenidone when administered 
to patients with Systemic Sclerosis−related interstitial 
lung disease
LPLV
last patient, last visit
MDT
multidisciplinary team
MedDRA
Medical Dictionary for Regulatory Activities
MMF
mycophenolate mofetil/sodium or mycophenolic acid 
NAC
N-acetyl-cysteine
NCI
National Cancer Institute
NGS
next-generation sequencing
NSIP
nonspecific interstitial pneumonia
PDGF
platelet-derived growth factor
PFS
progression-free survival
PRO
patient-reported outcome
QTcF
QT interval corrected using Fridericia’s formula
RBC
red blood cell
RBR
Research Biosample Repository
RNA
ribonucleic acid
SAP
Statistical Analysis Plan
SGRQ
St. George's Respiratory Questionnaire
SOBQ
Shortness of Breath Questionnaire
SOC
System Organ Class
SSc
systemic sclerosis
TGF
transforming growth factor
TID
three times daily
UCSD
University of California, San Diego
UIP
usual interstitial pneumonia

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Abbreviation
Definition
ULN
upper limit of normal
US
United States
VC
vital capacity
WBC
white blood cell
WGS
whole genome sequencing

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1.
BACKGROUND
1.1
BACKGROUND ON UNCLASSIFIABLE INTERSTITIAL LUNG 
DISEASE
The proper classification of interstitial lung diseases (ILDs) requires multidisciplinary 
expertise with input from various clinical experts, including pulmonologists, thoracic 
radiologists, and lung pathologists (Ryerson et al. 2013). Despite this coordinated effort, 
approximately 15% of all patients evaluated by multidisciplinary teams (MDTs) cannot 
ultimately be classified according to their fibrosing ILD (Skolnik and Ryerson 2016). 
Classification cannot be achieved in these patients due to nonspecific or conflicting 
clinical, radiological, or histopathological findings, or because patients are unable or 
unwilling to undergo certain, in particular invasive, diagnostic procedures (Cottin and 
Wells 2013; Ryerson et al. 2013).
Unclassiﬁable ILD represents a heterogeneous collection of undiagnosed ﬁbrosing ILDs, 
which have a prognosis between idiopathic pulmonary fibrosis (IPF) and other non-IPF 
fibrosing ILDs (Ryerson et al. 2013). Patients also display clinical features typical of both 
IPF, dominated by fibrotic changes to lung architecture, and other non-IPF ILDs (i.e., 
chronic hypersensitivity pneumonitis [cHP], idiopathic nonspecific interstitial pneumonia
[NSIP], connective tissue disease-ILD [CTD-ILD]), in which inflammatory processes 
predominate. The fibrotic features of IPF include the patchy involvement of lung 
parenchyma by fibrosis/architectural distortion, honeycombing in a predominantly 
subpleural/paraseptal distribution, and the presence of fibroblast foci (Spagnolo et al. 
2012). Owing to the heterogeneous nature of the disease, the choice of 
pharmacotherapy for unclassifiable ILD is unquestionably complex (Skolnik and Ryerson 
2016). Treatment usage is complicated by both a lack of direct evidence in this patient 
population and by clinical data that indicate that different therapeutic strategies need to 
be employed in patients with IPF compared with patients with other fibrotic ILDs (Raghu 
et al. 2012; Skolnik and Ryerson 2016). Therefore it is not currently possible to use one 
specific therapy in all patients with unclassiﬁable ILD and each patient must be treated 
on a case-by-case basis (Skolnik and Ryerson 2016).
Although no specific therapy has been universally recommended to treat patients with 
unclassiﬁable ILD, immunomodulatory treatments such as mycophenolate mofetil (MMF) 
have been used by several authors to treat the diverse spectrum of ILD (Fischer et al. 
2013; Panopoulos et al. 2013; Tzouvelekis et al. 2012).
1.2
BACKGROUND ON PIRFENIDONE
Pirfenidone is an orally active, small molecule (molecular weight: 185.2 g/mol) that has 
been shown to exert both antifibrotic and anti-inflammatory properties in a variety of
animal models and in vitro systems. The broad antifibrotic activity of pirfenidone across 
organ systems has been demonstrated in more than 20 animal studies utilizing various 
models that examined liver, heart, kidney, and lung fibrosis (Schaefer et al. 2011). 
Studies involving bleomycin-induced pulmonary fibrosis models found that pirfenidone 

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reduced visible lung pathology, lung tissue hydroxyproline content, edema (wet-to-dry 
lung weight), as well as the histological fibrotic score (Oku et al. 2008; Takeda et al. 
2014). Additionally, pirfenidone administration significantly suppressed bleomycin-
induced increases in interleukin- (IL)-1β, IL-6, monocyte chemoattractant protein-1, and 
IL-12p40 in these models (Oku et al. 2008).
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); promoted the release of collagenase from 
fibroblasts; and reduced the accumulation of certain extracellular matrix components, in 
particular collagen (EMA 2010).
Taken together, the preclinical cell-based studies and the investigations involving animal 
fibrosis models provide evidence that pirfenidone reduces levels of profibrotic growth 
factors and cytokines, lessens collagen deposition, and reduces interstitial fibrosis. All of 
these factors are known to be physiological elements which are to dysregulated in IPF 
(Clarke et al. 2013; Ryu et al. 2014; Todd et al. 2012).
Following on from the promising findings obtained in the extensive pre-clinical program, 
several clinical trials were conducted to investigate the efficacy and safety of pirfenidone 
in patients with IPF. A proof-of-concept study in 107 patients with IPF found that 
treatment with pirfenidone improved vital capacity (VC) and prevented acute 
exacerbation of IPF during the 9 months of follow-up (Azuma et al. 2005). Although 
significant adverse events were associated with pirfenidone, treatment adherence was 
similar between the pirfenidone and placebo groups. In fact, the study was aborted early 
on the basis of recommendations from the Data and Safety Monitoring Board (DSMB) in 
favor of pirfenidone treatment over placebo. Building on the results of this study, the 
Clinical Studies Assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of 
Efficacy and Safety Outcomes (CAPACITY) program included two similar multinational 
Phase III trials and was designed to confirm the effects of pirfenidone on reducing the 
decline in lung function (Noble et al. 2011). Pirfenidone significantly reduced the decline 
in forced vital capacity (FVC) in one study (Study 004), although the difference between 
pirfenidone and placebo in FVC change was not significant at Week 72 in the other trial 
(Study 006). Patients in the pirfenidone group experienced higher rates of several 
adverse events, including nausea, rash, and vomiting, although fewer overall and deaths 
related to IPF occurred in the pirfenidone group. Agreeing with the results of Study 004, 
a further Phase III study in 275 Japanese patients found that treatment with pirfenidone 
decreased the rate of decline in VC and increased the progression-free survival (PFS) 
time over 52 weeks (Taniguchi et al. 2010). Owing to the discrepancies between the 
results of the three Phase III trials, a further subsequent trial was initiated to confirm the 
beneficial effect of pirfenidone on disease progression in patients with IPF (King Jr. et al. 
2014). This trial enrolled 555 patients with IPF and found that pirfenidone reduced 
disease progression, as reflected by reduced declines in lung function and exercise 

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tolerance, and improved PFS. Pirfenidone treatment was also associated with an 
acceptable side-effect profile and fewer deaths compared with placebo.
Following on the positive clinical results achieved, pirfenidone was approved in a 267 mg 
capsule dosage form for the treatment of IPF in the United States (US), and for the 
treatment of mild to moderate IPF in the European Economic Area (EEA) and Canada 
(Esbriet SmPC 2015; Health Canada 2016; US FDA 2015). The recommended daily 
maintenance dose in patients with IPF is 2403 mg/d, administered as three 267 mg 
capsules (801 mg) three times daily (TID) with food, at the same times each day (Esbriet 
SmPC 2015; US FDA 2015).
Refer to pirfenidone Investigator's Brochure or local prescribing information for 
pirfenidone for details on nonclinical and clinical studies.
1.3
TRIAL RATIONALE AND BENEFIT-RISK ASSESSMENT
No approved treatments are available for the 15% of patients with ILD who have 
unclassifiable disease. Rather, therapeutic management is based on the most probable 
diagnosis after multidisciplinary discussions and consideration of the expected disease 
behavior (Antoniou et al. 2014). The data for pirfenidone in IPF are sufficiently 
encouraging (Section 1.2) to hypothesize that a beneficial clinical effect would also be 
observed with this agent in patients with unclassifiable fibrosing ILD.
There are several key areas for uncertainty in the assessment of the benefit-risk profile 
for pirfenidone in the unclassifiable ILD patient population. Fibrosing ILD might have a 
different natural history compared with IPF and the efficacy of pirfenidone treatment may 
be different in patients with unclassifiable ILD compared with patients with IPF.
MMF may have an effect on the disease course of patients with unclassifiable ILD, in 
particular patients with interstitial pneumonia with autoimmune features (IPAF). Patients 
may be receiving treatment with MMF as a concomitant therapy at the start of the trial 
and therefore the patient population in this trial will be stratified according to use of MMF 
(MMF treatment includes mycophenolate mofetil/sodium or mycophenolic acid). Patients 
receiving MMF concomitant therapy at the start of the trial are allowed to continue with 
this treatment throughout the study including the 24-week double-blind and 12-month 
safety follow-up periods. A similar approach had been used previously in a study of the 
safety and tolerability of pirfenidone in patients with systemic sclerosis−related ILD (SSc-
ILD; an open-Label, randOmized, Phase 2 sTUdy of the safety and tolerability of 
pirfenidone when administered to patients with Systemic Sclerosis−related interstitial 
lung disease [LOTUSS]) (Khanna et al. 2016). The results of this trial also include data 
concerning the use of MMF as concomitant treatment with pirfenidone. The conclusion 
from this trial was that MMF, which was taken concomitantly with pirfenidone by 63.5% 
of patients, did not appear to affect the tolerability of pirfenidone and no particular safety 
concerns were noted following the combined use of MMF and pirfenidone.

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washout period. If a prohibited medication must be tapered, the process must start early 
enough so that the patient discontinues the medication in the 28 days prior to the start of 
screening. After completing the washout period, patients will enter screening, which lasts 
up to 21 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.
At the end of screening, patients will be randomized (Day 1) to receive either pirfenidone 
or placebo (1:1 ratio).
Following treatment initiation, the daily dosage will be titrated to the full dosage of nine 
capsules per day over a 14-day period as outlined in Table 2 . After the titration period, 
trial treatment will continue through Week 24 and monitoring will be conducted by site 
visits. Patients should remain on a stable maintenance dose for the duration of the 
treatment period unless the dose is reduced or dosing is interrupted to manage an 
adverse event (see Section 5.1.1). Any patient with an actual or anticipated interruption 
of trial treatment for a period of ≥28 consecutive days will be reported by telephone to 
Roche‘s medical monitor or designee to discuss the circumstances of the case. Once 
the patient restarts trial treatment, the dose must be re-titrated over 14 days as 
described in Table 2 . A Follow-up Visit will occur 28 days after the end of the 24-week 
double-blind treatment period.
After completion of the double-blind treatment period and the Follow-up Visit at Week 28, 
the Sponsor will offer the possibility to the patients to receive open-label pirfenidone 
within the trial protocol in a safety follow-up period of up to 12 months. During the safety
follow-up period, the patients should be evaluated by the investigator approximately 
every 3 months. A final Follow-up Visit will be performed at the end of the safety period, 
28 days after the last open-label dose.
Table 2Titration Schedule
Treatment Days
Dosage
Days 1 through 7
One capsule three times daily with meals
Days 8 through 14
Two capsules three times daily with meals
Day 15 onwards
Three capsules three times daily with meals
The Sponsor will provide trial treatment on a double-blind basis. The design that will be 
utilized in this trial is shown in Figure 1 .

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Figure 1
Trial Schema
1 Patients will be required to taper and/or discontinue all prohibited medications in the 28 days 
prior to the start of screening during the washout period. Patients not taking a prohibited 
medication will forgo the washout period and directly enter screening.
2 Informed consent must be documented before any trial-specific screening procedure is 
performed, and may be obtained either at the Washout or Screening Visits.
3 After completion of the double-blind treatment period and the Follow-up Visit at Week 28, the 
Sponsor will offer the possibility to the patients to receive open-label pirfenidone within the trial 
protocol in a safety follow-up period of up to 12 months. A final Follow-up Visit will be performed 
at the end of the safety period, 28 days after the last open-label dose.
D=Day; ICF=informed consent form
The primary objective of this trial is to evaluate the efficacy of pirfenidone vs. placebo on 
lung function parameters by examining the rate of decline in FVC (measured in mL). A 
handheld spirometry device will be used by the patient to measure daily FVC at home. 
Confirmatory site (trial center) based FVC measurements will be conducted every 
4 weeks (see Schedule of Assessments; Appendix 1). Blood samples will be obtained 
from patients in order to analyze clinical laboratory values and biomarkers.
The secondary objective for this trial is to evaluate the efficacy of pirfenidone vs. placebo 
on other functional parameters, outcomes, and patient-reported outcomes (PROs). Part 
of this objective will involve measuring the changes in FVC and comparing the results 
with baseline findings. In addition, the changes from baseline to the end of the 24-week 
double-blind treatment period will be investigated for several parameters, including 
percent predicted diffusing capacity of the lung for carbon monoxide (DLco), 6-minute 
walk distance (6MWD), University of California, San Diego-Shortness of Breath 
Questionnaire (UCSD-SOBQ) score, Leicester Cough Questionnaire, cough visual 
analog scale, and total and sub-scores of the St. George's Respiratory Questionnaire 
(SGRQ; see Appendix 2 and the Study Manual for further information). All of these 
assessments will be conducted at baseline, Week 12, Week 24, and at the Early 
Treatment Discontinuation Visit (see Schedule of Assessments; Appendix 1). PFS will 
also be evaluated as part of this trial, which is defined as the time to the first occurrence 
of a >10% absolute decline in percent predicted FVC (measured during a clinic visit), 
a >50 m decline of 6MWD, or death. An alternative definition of PFS, that is the time to 

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the first occurrence of a >10% relative decline in FVC (measured during a clinic visit), 
non-elective respiratory hospitalization, or death, will also be evaluated. Further 
analyses will investigate the incidences of non-elective respiratory and all cause 
hospitalization, time to death from any cause, and time to death from respiratory 
diseases.
The safety objective for this trial involves evaluating the safety of pirfenidone in 
comparison with placebo. In order to achieve this objective, the nature, frequency, 
severity, and timing of treatment-emergent adverse events will be documented. Dose 
reductions and treatment interruptions and withdrawals from trial treatment or trial 
discontinuations will also be evaluated. Clinical laboratory assessments and 
electrocardiograms (ECGs) will be collected as per the Schedule of Assessments 
(Appendix 1).
The exploratory objectives for this trial are to evaluate the role of MMF treatment in ILD 
and to investigate potential biomarkers associated with fibrosis and ILD. To achieve the 
MMF objective, patients will be stratified according to whether they received treatment 
with MMF. The efficacy and safety data will be analyzed according to this stratification. 
For the biomarker objective, an investigation will be conducted with the aim of 
determining the impact of pirfenidone on exploratory inflammatory and fibrotic 
biomarkers. Transcriptomic and proteomic profiling of markers associated with the 
molecular pathways and cellular processes of lung injury and fibrosis will be measured.
An independent Data Monitoring Committee (iDMC) will review safety data and advise 
on trial conduct at least three times during the trial. A first meeting is planned 6 months 
after start of recruitment, and subsequently at 12 and 18 months. Additional ad hoc 
meetings or data reviews can be requested at any time by the iDMC or the Sponsor, if 
warranted. The iDMC will be an independent body who will recommend to continue, 
modify or stop the trial at each meeting. The procedures that will be used by the iDMC 
will be detailed in an iDMC charter.
3.2
END OF TRIAL AND LENGTH OF TRIAL
After completion of the double-blind treatment period and the Follow-up Visit at Week 28, 
the Sponsor will offer the possibility to the patients to receive open-label pirfenidone 
within the trial protocol in a safety follow-up period of up to 12 months. The end of the 
clinical trial is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point which is required for the statistical analysis is received, 
whichever is the later date. For this trial, LPLV will occur when the last patient has 
completed the final safety Follow-up Visit, 28 days after the final open-label dose, or 
when the last data point is collected in the safety follow-period. 
For each patient the total length of the trial is expected to be up to a maximum of 
91 weeks. The trial duration includes the washout period of up to 4 weeks, the screening 
period of up to 3 weeks, the double-blind treatment period of 24 weeks, the follow-up 

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period of 4 weeks, the open-label safety follow-up period up to 12 months (52 weeks) 
and a final safety Follow-up Visit 4 weeks after the last dose.
3.3
RATIONALE FOR TRIAL DESIGN
3.3.1
Rationale for Pirfenidone Dose and Schedule
In this trial, pirfenidone will be administered at a daily dose of 2403 mg. This dose will be 
administered orally in the form of three 267 mg capsules (801 mg) TID with food, at the 
same times each day. This dosing schedule is the same as the clinically recommended 
daily maintenance dose for patients with IPF (Esbriet SmPC 2015; US FDA 2015).
For each patient, the double-blind trial treatment period will last 24 weeks. Previous 
clinical studies have demonstrated that clinically significant differences in mean FVC 
changes from baseline have been observed in pirfenidone-treated compared with 
placebo-treated patients over this time frame (Noble et al. 2011). It is therefore assumed 
that this treatment period will be sufficient to observe any statistically significant 
differences in the primary endpoint. Moreover, recent data suggest that daily FVC 
measurements may be more sensitive to detect significant declines in lung function 
(Russell et al. 2016). The enrolled patients are therefore required to conduct daily 
spirometry assessments.
3.3.2
Rationale for Patient Population
No approved treatments are currently available to treat patients with ILD who have 
unclassifiable disease. Therefore, there is an unmet need to develop effective and well 
tolerated therapies for the treatment of patients with ILD.
Patients will be assigned to the category “unclassifiable ILD” if the participating 
investigator’s MDT cannot assign a case of fibrosing ILD with moderate or high 
confidence to any category of fibrosing ILD. As patients who fulfil the proposed research 
classification criteria for IPAF do not have CTD-ILD or other defined form of ILD, they will 
also be included within the unclassifiable ILD category. The MDT will use the available 
clinical, radiologic, or pathological evidence (with the involvement of rheumatology 
expertise at the discretion of the MDT team) to attempt to diagnose the patient with a 
category of fibrosing ILD (e.g., IPF, CTD-ILD, NSIP, cHP, or ILDs caused by 
occupational exposure or drugs). In the absence of a surgical lung biopsy or 
transbronchial lung cryobiopsy, the investigator must state the reason a biopsy was not 
performed. The available clinical, radiologic, or pathologic evidence used by the MDT 
will be documented in the electronic Case Report Form (eCRF). In this context, the 
levels of confidence are defined as follows:

High confidence: a specific diagnosis is highly likely (i.e., usual interstitial pneumonia
[UIP] pattern on high-resolution computed tomography [HRCT] in the case of IPF)

Moderate confidence: the MDT arrives at a “working diagnosis” of a particular ILD 
which is sufficient to lead to a specific therapeutic strategy (i.e. antifibrotic therapy in 
the case of IPF, immunosuppressive therapy in the case of CTD-ILD)

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
Low confidence: the MDT may have a suspicion of a particular ILD but considers the 
available evidence insufficient to inform therapeutic strategy.
The following, non-exhaustive, list of patient populations will therefore be eligible for 
enrollment:

Patients with “unclassifiable ILD”

Patients fulfilling research classification criteria for IPAF (Fischer et al. 2015)

Patients with a low confidence diagnosis of NSIP, cHP, CTD-ILD, etc.
Patients diagnosed with any fibrosing or non-fibrosing ILD with high or moderate 
confidence will be excluded from the trial. Patients with IPF, irrespective of the level of 
confidence of diagnosis, cannot be included in the trial.
3.3.3
Rationale for Control Group
No approved treatments are available for the patients with ILD who have unclassifiable 
disease, and no controlled clinical trials have been performed to date in this patient 
population. In the absence of any clinically recognized comparator, patients in the 
control group will receive placebo treatment during the 24-week double-blind treatment 
period.
3.3.4
Rationale for Concomitant MMF Therapy
In this trial, patients may be receiving concomitant therapy with MMF (MMF treatment 
includes mycophenolate mofetil/sodium or mycophenolic acid) when the trial starts. As 
MMF may have an effect on the disease course of unclassifiable ILD, patients will be 
stratified according to whether they received concomitant MMF treatment during the trial 
(see Section 3.1). In the LOTUSS trial, which included patients with SSc-ILD, all patients 
who were enrolled on the basis of a stable dose of allowable SSc medication, could 
receive treatment with MMF. In this trial, the maximum allowed dose of MMF was 1.5g 
two times daily (BID), but the dosage was otherwise left to the discretion of the 
investigator. For the current trial, a similar treatment approach will be used. MMF will be 
used at a stable dose of up to 1.5g (or equivalent) BID that should be kept constant 
unless safety considerations require dose reduction, dose interruption, or stopping MMF 
altogether. Patients enrolled without MMF treatment should not start MMF during the 
blinded treatment period.
MMF was chosen as the permitted concomitant therapy as it is a potential treatment 
choice in patients who have secondary interstitial lung fibrosis related to autoimmune 
disease (Chartrand et al. 2016, Fischer et al. 2013, Khanna et al. 2016, Volkman et al. 
2016). In addition, MMF is used in patients with autoimmune fibrosis of an unknown 
etiology. 
Recruitment into the trial would be limited, if concomitant MMF treatment was not 
permitted for patients who are receiving therapeutic benefit from this treatment. Allowing 

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MMF as concomitant therapy also enables the clinical community to gather further 
information on the safety of MMF in this patient population.
3.3.5
Rationale for Biomarker Assessments
Certain biomarkers may be differentially expressed in patients with unclassifiable ILD 
and may change as a result of 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 trial may help identify the 
serum and plasma proteins or blood ribonucleic acid (RNA) biomarkers related to 
disease progression and/or may be used to assess their response to pirfenidone therapy. 
Transcriptomic and protein markers associated with the molecular pathways and cellular 
processes of lung injury and fibrosis will be measured. This may include, but is not 
restricted to, measurement of CCL18, MMP7, CXCL13, and COMP.
Serum, plasma, and whole blood (for RNA analysis) samples will be acquired at baseline, 
Week 4, Week 12, Week 24, and at the Early Treatment Discontinuation Visit (see the 
Schedule of Assessments; Appendix 1).
Optional Research Biosample Repository (RBR) whole blood samples for 
deoxyribonucleic acid (DNA) extraction, described in Section 4.5.8 of the protocol, will 
also be collected at baseline to examine genetic polymorphisms and their potential role 
in the pathogenesis and associated clinical outcomes of unclassifiable ILD. Patient 
participation for this assessment is voluntary and declining participation to collect 
biomarker data will not influence eligibility for this trial.
3.3.6
Rationale for Disease Response–based Endpoints
The primary objective of this trial is to evaluate the efficacy of pirfenidone vs. placebo on 
lung function parameters by examining the rate of decline in FVC measured in mL. FVC 
will be measured daily using a handheld spirometer by the patient and every 4 weeks at 
the site (see Schedule of Assessments; Appendix 1) during the 24-week double-blind 
treatment period. Changes in FVC have been examined in several different clinical 
studies which enrolled patients with unclassifiable ILD (Leung et al. 2015; Ryerson et al. 
2013; Solomon et al. 2013), and are generally accepted as a valid measure of disease 
course in patients with ILD.
Other disease response-based parameters that will be examined in this trial include 
predicted DLco, 6MWD, UCSD-SOBQ, Leicester Cough Questionnaire, cough visual 
analog scale, and total and subscores of the SGRQ (see Appendix 2). All of these 
parameters have been used extensively as disease response-based parameters in 
studies involving similar patient populations (Jones et al. 2011; Key et al. 2010; Ryerson 
et al. 2014; Swigris et al. 2010, 2012).

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3.3.7
Rationale for PRO Assessments
Several PRO assessments will be conducted in this trial, including the UCSD-SOBQ, the 
Leicester Cough Questionnaire, the cough visual analog scale, and the SGRQ (see 
Appendix 2 and the Study Manual for further information). All of these assessments have 
been used extensively as PRO measures in studies involving similar patient populations 
(Jones et al. 2011; Key et al. 2010; Ryerson et al. 2014; Swigris et al. 2010, 2012). No 
bias is assumed in the results of these assessments.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 250 patients with unclassifiable fibrosing ILD will be enrolled in this trial.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for trial entry:
1.
Signed Informed Consent Form
2.
Age 18–85 years
3.
Able to comply with the trial protocol, according to the investigator’s judgment
4.
Confirmed fibrosing ILD which, following MDT review, cannot be classified with 
either high or moderate confidence as a specific idiopathic interstitial pneumonia or 
other defined ILD (e.g. chronic hypersensitivity or connective tissue disease-ILD 
[CTD-ILD])
5.
Progressive disease as considered by the investigator using the following definition:
a. Patient deterioration within the last 6 months, which is defined as:
i.
A rate of decline in FVC >5% OR
ii.
Significant symptomatic worsening not due to cardiac, pulmonary, 
vascular, or other causes.
6.
Extent of fibrosis >10% on high-resolution computed tomography (HRCT; visual 
scoring) within the last 12 months
7.
FVC ≥45% of predicted value
8.
Diffusing capacity of the lung for carbon monoxide (DLco) ≥30% of predicted value
9.
Forced expiratory volume in 1 second (FEV1)/FVC ratio ≥0.7
10. 6-minute walk distance (6MWD) ≥150 meters
11. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% 
per year during the treatment period and for at least58 days after the last dose of 
trial treatment:
a. A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state 
(12 continuous months of amenorrhea with no identified cause other 

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than menopause), and has not undergone surgical sterilization (removal 
of ovaries and/or uterus)
b. Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives 
including those that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices
c.
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.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
a. 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 trial treatment. Men must refrain 
from donating sperm during this same period
b. 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 trial treatment to avoid exposing the embryo
c.
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.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from trial entry:
1.
Diagnosis with moderate or high confidence of nonspecific interstitial pneumonia
(NSIP) and any ILD with an identifiable cause such as CTD-ILD, chronic 
hypersensitivity pneumonitis (cHP), or others
2.
Diagnosis of idiopathic pulmonary fibrosis (IPF) independent of the confidence level
3.
History of unstable angina or myocardial infarction during the previous 6 months
4.
Pregnant or lactating, or intending to become pregnant during the trial
5.
A positive urine pregnancy test, which was confirmed with a positive serum 
pregnancy test. Women with a confirmed pregnancy will be excluded from trial 
participation and must discontinue trial treatment
6.
Treatment with high dose systemic corticosteroids (i.e., >15 mg/d of prednisolone or 
equivalent), or any immunosuppressant other than MMF, at least 4 weeks prior to 
screening. Patients being treated with MMF should be on a stable dose that is 

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expected to remain stable throughout the trial and was started at least 3 months 
prior to screening
7.
Patients previously treated with pirfenidone or nintedanib
8.
Patients treated with N-acetyl-cysteine (NAC) for fibrotic lung disease, at any time 
within the 4 weeks of the screening period
9.
Drug treatment for any type of pulmonary hypertension (e.g. sildenafil, endothelin 
receptor antagonist [ERA], etc.)
10. Participation in a trial of an investigational medicinal product within the last 4 weeks
11. Significant co-existent emphysema (extent greater than extent of fibrosis on HRCT 
within the last 12 months)
12. Significant other organ co-morbidity including hepatic or renal impairment
13. Previous intolerance or allergy to the trial treatment
14. Pregnant patients, or women of child-bearing potential, not using a reliable 
contraceptive method
15. Unable to provide informed written consent
16. Predicted life expectancy <12 months or on an active transplant waiting list
17. Use of any tobacco product in the 12 weeks prior to the start of screening, or any 
unwillingness to abstain from their use through to the Follow-up Visit
18. Illicit drug or alcohol abuse within 12 months prior to screening, according to the 
investigator’s judgment
19. Planned major surgery during the trial
20. Hypersensitivity to the active substance or to any of the excipients of pirfenidone
21. History of angioedema
22. Concomitant use of fluvoxamine
23. Clinical evidence of any active infection which according to the investigator’s 
judgment may interfere with trial conduct, measurement of pulmonary function, or 
impact the course of the ILD
24. Any history of hepatic impairment, elevation of transaminase enzymes, or the 
confirmation of any of the following liver function test (LFT) criteria above the 
specified limits:
a. Total bilirubin above the upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >1.5 × ULN
c.
Alkaline phosphatase >2.0 × ULN.
25. Creatinine clearance <30 mL/min, calculated using the Cockcroft-Gault formula
26. Any serious medical condition, clinically significant abnormality on an ECG at 
screening, or laboratory test results (hematology, serum chemistry, and urinalysis) 

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that, in the opinion of the investigator, may pose an additional risk to the patient 
following the administration of trial treatment
27. An 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.
Re-screening may be considered for patients who do not show sufficient disease 
deterioration in accordance to the protocol at the time of the initial screening. Re-
screening is permitted if there is strong evidence of clinical worsening based on the 
Investigator’s judgement and only upon receipt of official approval from the Study 
Management Team. In such cases, re-screening may be performed after a minimum of 
4-weeks lapse from the initial screening date.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Patients will be randomized 1:1 to receive either pirfenidone versus 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 concomitant
MMF treatment (yes/no), the presence/absence of IPAF as defined by the MDT.
To maintain the double-blind nature of the trial, the pirfenidone and placebo treatments 
will be identical in appearance (see Section 4.3.1.1).
The investigational site personnel and the patients will be blinded to treatment 
assignment following randomization. The iDMC and any personnel performing any 
interim analysis (as applicable) will be unblinded to the treatment throughout the trial.
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event 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. The 
investigator should document and provide an explanation for any premature unblinding 
(e.g., accidental unblinding, unblinding due to a serious adverse event).
Unblinding should not necessarily result in the withdrawal of a patient from the trial. After 
unblinding, the patient will be withdrawn from the 24-week double-blind treatment period. 
If the unblinding was based on the investigator’s safety concerns and reveals that the 
patient had been treated with pirfenidone, the patient will be withdrawn from the trial. In 
this case, the patient will attend the Early Treatment Discontinuation Visit and thus end 
his/her participation in the trial. However, if unblinding reveals that the patient had not 
been treated with pirfenidone and that the investigator has no further safety concerns, 
then the patient may be offered the option to continue into the 12-month open-label 
pirfenidone safety follow-up period. In this case, the patient will attend the Early 
Treatment Discontinuation Visit (+ 28 days after the last dose of the double-blind 

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treatment) and on the same day begin his/her participation in the 12-month open-label 
pirfenidone safety follow-up period.
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 trial treatment.
4.3
TRIAL TREATMENT
The investigational medicinal product (IMP) for this trial is pirfenidone.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Pirfenidone and Placebo
Pirfenidone and placebo will be supplied by the Sponsor as 267 mg capsules in a bottle.
For information on the formulation and handling of pirfenidone, see the Investigator's 
Brochure or local prescribing information for pirfenidone.
The chemical name of pirfenidone is 5-methyl-1-phenyl-2-1(H)-pyridone.
Pirfenidone (pirfenidone 267 mg) will be supplied as white, hard gelatin capsules.
Each pirfenidone capsule contains 267 mg of pirfenidone, and the following inactive 
ingredients:

Capsule content: microcrystalline cellulose, croscarmellose sodium, povidone, and 
magnesium stearate

Capsule shell: gelatin and titanium dioxide.
Pirfenidone should be stored according to the IMP label and the bottle should be tightly 
closed.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Pirfenidone and Placebo
In this trial, pirfenidone will be administered at a daily dose of 2403 mg. This dose will be 
administered orally in the form of three 267 mg capsules (801 mg) TID with food, at the 
same times each day.
Patients will initially take one capsule TID with meals. Following treatment initiation, the 
daily dosage will be titrated to the full dosage of nine capsules per day over a 14-day 
period as outlined in Table 2
. Temporary dosage reduction, treatment interruption, or
discontinuation should be considered in order to effectively manage any treatment-
emergent adverse reactions. Guidelines for dosage modification and treatment 
interruption or discontinuation are provided in Section 5.1.1.

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Any overdose or incorrect administration of trial treatment should be noted on the 
Study Drug Administration eCRF. Adverse events associated with an overdose or 
incorrect administration of trial treatment should be recorded on the Adverse Event 
eCRF. Section 5.3.5.11 summarizes available safety data related to overdosing of 
pirfenidone.
Placebo will be supplied by the Sponsor in the form of capsules with identical 
appearance and size as the pirfenidone capsule. The placebo capsules will contain 
microcrystalline cellulose.
Patients will be asked to take the IMP according to site instructions. IMP accountability 
will be performed at the next site visit.
4.3.2.2
Dose Modification/Restarting Treatment
Patients should remain on a stable maintenance dose for the duration of the treatment
period unless the dose is reduced or dosing is interrupted to manage an adverse event 
(see Section 5.1.1). Any patient with an actual or anticipated interruption of trial 
treatment for a period of ≥ 28 consecutive days will be reported by telephone to Roche‘s 
medical monitor or designee to discuss the circumstances of the case. Once the patient 
restarts trial treatment, the dose must be re-titrated over 14 days as described in Table 2
.
4.3.3
Investigational Medicinal Product Accountability
The IMP required for completion of this trial (pirfenidone) will be provided by the Sponsor. 
The trial 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 trial site according to the trial site’s institutional 
standard operating procedure 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 the IMP received at, dispensed from, returned to, and disposed of by 
the trial site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Pirfenidone
After completion of the double-blind treatment period, the Sponsor will offer the possibility 
to the patients to receive continued access to pirfenidone in a safety follow-up period of 
up to 12 months, within this clinical trial protocol. A final Follow-up Visit will be performed 
at the end of the safety period, 28 days after the last open-label dose.
At the end of the 24-week double-blind treatment period, in order to maintain blinding, all 
patients will discontinue treatment over a 28-day period and return for the Follow-up Visit. 

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For patients who could benefit from participating in the 12-month safety follow-up period, 
according to the investigator’s judgment, open-label pirfenidone will be started on the 28-
day Follow-up Visit, using the titration schedule in Table 2
. During the 12-month 
safety follow-up period, initially, patients will be evaluated at monthly visits for the first 6 
months. At the end of the first 6 months, patients will be evaluated at each site visit 
occurring approximately every 3 months until the end of the safety follow-up period. In 
addition, at the end of the first 6 months, patients will perform home pregnancy tests at 
each month where there is no site visit. Patients will be provided with home pregnancy 
test kits and will be instructed to contact the site immediately should the test result be 
positive. In such cases, the patient must visit the site for a confirmatory serum pregnancy 
test. Refer to Schedule of Assessments for the assessments to be performed during this 
safety follow-up period (Appendix 1). The dose of pirfenidone used during the safety 
follow-up period is in accordance to section 4.3.2.1.
Following the end of the 12-month safety follow-up period, the Sponsor will offer post-
trial access to the trial treatment (pirfenidone), free of charge, to eligible patients in 
accordance with the Roche Global Policy on Continued Access to IMP, as outlined 
below.
A patient will be eligible to receive Pirfenidone (Esbriet®) after completing the trial if all of 
the following conditions are met:

The patient has a life-threatening or severe medical condition and requires continued 
trial 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 Pirfenidone (Esbriet®) after completing the trial if 
any of the following conditions are met:

Pirfenidone (Esbriet®) 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 
would not otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of Pirfenidone (Esbriet®)or data 
suggest that Pirfenidone (Esbriet®)is not effective for unclassifiable ILD

The Sponsor has safety concerns regarding Pirfenidone (Esbriet®)as treatment for 
unclassifiable ILD

Provision of Pirfenidone (Esbriet®)is not permitted under the laws and regulations of 
the patient's country.
The Roche Global Policy on Continued Access to IMP is available at the following Web 
site:
http://www.roche.com/policy continued access to investigational medicines.pdf

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4.4
CONCOMITANT THERAPY AND PROHIBITED FOOD
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 the washout period until 28 days after the last dose of trial treatment. All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.1
Permitted Therapy
All protocol-allowed medications taken by the patient for concomitant disease(s) should 
be continued as necessary during the trial and be recorded on the eCRF. Treatments 
prescribed to patients should be adapted according to the local standard of care practice.
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the trial and should be tapered and/or 
discontinued in the 28 days prior to screening:

Investigational therapy other than trial treatment

High dose systemic corticosteroids (15 mg/d of prednisolone or equivalent) for longer 
than 28 days

Immunosuppressive therapies (e.g. azathioprine)

Treatment with NAC for fibrotic lung disease, at any time within the 4 weeks of the 
screening period; intermittent use of NAC for other conditions is permitted

Fluvoxamine and other cytochrome P450 1A2 (CYP1A2) inhibitors

CYP1A2 inducers.
If down titration of prohibited therapy is required, it must be done during the 28-day 
washout period.
4.4.2.1
Corticosteroids
Pirfenidone should not be used in combination with high-dose corticosteroids 
(>15 mg/day) for periods longer than 28 days. Co-administration of pirfenidone with 
lower doses of corticosteroids is at the discretion of the investigator.
4.4.2.2
Fluvoxamine and Other CYP1A2 Inhibitors
In a Phase I study, the co-administration of pirfenidone and fluvoxamine (a strong 
inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, 
and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers 
(Esbriet SmPC 2015). Pirfenidone is therefore contraindicated in patients who are 
receiving concomitant fluvoxamine. Fluvoxamine treatment should be discontinued prior 
to the initiation of pirfenidone therapy and avoided during therapy due to the reduced 
clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or 
more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 
2C19, and 2D6) should be avoided during pirfenidone treatment.

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In vitro and in vivo extrapolations have indicated that strong and selective inhibitors of 
CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by 
approximately 2 to 4-fold (Esbriet SmPC 2015). If concomitant use of pirfenidone with a 
strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of pirfenidone 
should be reduced to 801 mg daily (one capsule TID).
Co-administration of pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of 
CYP1A2) increased the exposure to pirfenidone by 81% (Esbriet SmPC 2015). If 
ciprofloxacin at a dose of 750 mg BID cannot be avoided, the dose of pirfenidone should 
be reduced to 1602 mg daily (two capsules TID). Pirfenidone should be used with 
caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. 
Pirfenidone should also be used with caution in patients treated with other moderate 
inhibitors of CYP1A2 (e.g. amiodarone, propafenone).
Caution should be exercised if CYP1A2 inhibitors are being used concomitantly with 
pirfenidone and potent inhibitors of one or more of the other CYP isoenzymes involved in 
the metabolism of pirfenidone (Esbriet SmPC 2015). These isoenzymes include 
CYP2C9 (inhibitors include amiodarone and fluconazole), CYP2C19 (inhibitors include 
chloramphenicol), and CYP2D6 (inhibitors include fluoxetine and paroxetine).
4.4.2.3
CYP1A2 Inducers
Concomitant use of strong inducers of CYP1A2 should be avoided during pirfenidone 
therapy following the results of a Phase I interaction study that found that pirfenidone 
exposure was 50% lower in smokers compared with non-smokers (Esbriet SmPC 2015). 
Smoking induces the CYP1A2 isoenzyme. Patients should therefore be encouraged to 
discontinue the use of strong inducers of CYP1A2 and to stop smoking before and 
during treatment with pirfenidone.
In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may 
theoretically result in a lowering of pirfenidone plasma levels (Esbriet SmPC 2015).
Co-administration of pirfenidone with medicinal products that act as potent inducers of 
both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone 
(e.g., rifampicin) may result in significant lowering of pirfenidone plasma levels (Esbriet 
SmPC 2015). These medicinal products should therefore be avoided whenever possible.
4.4.2.4
Other Medications
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 strongly inhibits or induces CYP1A2. In addition, the investigator should 
contact the Medical Monitor if questions arise regarding specific medications not listed 
above.

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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 from the start of screening through 
to the Follow-up visit. 
4.4.4
Additional Restrictions
The use of any tobacco product will be prohibited from 12 weeks prior to the start of 
screening through to the Follow-up Visit. 
4.5
TRIAL ASSESSMENTS 
Please see Appendix 1 for the Schedule of Assessments to be performed during the trial.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the trial must be obtained before performing 
any trial-related procedures. Informed Consent Forms for enrolled patients and for 
patients who are not subsequently enrolled will be maintained at the trial site.
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.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant respiratory diseases (asthma, chronic 
obstructive pulmonary disease, and pneumonia), 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 from the washout period until 28 days after the last 
dose of trial treatment will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination will be performed at screening and will include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems. Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.

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At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations will be performed (see the Schedule of Assessments; Appendix 1). 
Changes from baseline abnormalities should be recorded in patient notes. New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature. All 
vital sign measurements are to be obtained prior to any blood draws scheduled at the 
same time.
4.5.5
FVC
FVC is defined as the maximal volume of gas that can be exhaled following full 
inhalation by exhaling as forcefully and rapidly as possible. FVC has been an 
established measure of pulmonary function in patients with IPF for many decades (du 
Bois et al. 2011). Longitudinal changes in serial measures of lung volume are a widely 
accepted reflection of disease progression in patients with IPF and a commonly used 
primary endpoint in therapeutic studies.
If a patient is routinely treated with a short-acting bronchodilator (for example albuterol, 
salbutamol), the bronchodilator should be taken approximately 30 minutes prior to the 
on-site spirometry.
4.5.6
Handheld Spirometry
Patients will perform a single spirometry reading at approximately the same time each 
day. For this purpose, trial participants will be provided with a portable handheld Micro 
spirometer (
, England). The Micro spirometer measures FEV1 and FVC 
by means of a turbine volume transducer and provides a digital read out registered in 
liters at body temperature and pressure saturated with water vapor (BTPS). Each 
spirometer will be factory calibrated. Patients will be given 60 minutes dedicated 
instruction on how to undertake spirometry at the Screening Visit. Patients will be asked 
to use the device during the screening period and will be subsequently retrained at the 
Baseline Visit. Additional refresher training will be provided after 1 month. 
As the primary endpoint of this trial is to determine the rate of decline in FVC measured 
by daily handheld spirometer, further support to effectively use this device will be 
provided to the patients. The Sponsor will select a healthcare company that will be 
responsible for providing home nursing services for the participating sites. The vendor is 
responsible for ensuring that all home nursing professionals are licensed, qualified, and 
in good standing, as per applicable regulations, and that appropriate background checks 
have been performed.

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Sites will communicate directly with the vendor in their country when patients have 
entered the trial. The trained nursing professional will conduct the visit at the patient’s 
home or at another suitable location in order to provide handling evaluations and quality 
assurance for the daily spirometer assessments. The expected number of home visits is 
stated in the Schedule of Assessments (Appendix 1).
4.5.7
Other Trial Assessments
Further information on the other assessments (e.g., FVC, DLco, 6MWD, UCSD-SOBQ, 
Leicester Cough Questionnaire, cough visual analog scale, and SGRQ) that will be 
conducted as part of this trial can be found in Appendix 2 and the Study Manual.
4.5.8
Laboratory and Biomarker Samples
All of the laboratory tests will be conducted by the trial site’s local laboratory. Biomarker 
samples will first be sent to a central laboratory and then to outsourced contract 
research organizations (CROs) or the Sponsor for testing.
The following laboratory and biomarker samples will be collected:

Hematology: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, 
hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells)

Chemistry panel (serum or plasma): sodium, potassium, chloride, bicarbonate, 
glucose, blood urea nitrogen (BUN) or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric 
acid, lactate dehydrogenase (LDH)

Pregnancy test:

All women of childbearing potential will have a serum pregnancy test at screening. 
Urine pregnancy tests will be performed at specified subsequent visits. If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.

Blood samples for exploratory research on biomarkers (see Appendix 1).
Exploratory biomarker research may include, but will not be limited to CCL18, MMP7, 
CXCL13, and COMP.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Whole blood, plasma, and serum samples collected for biomarker analyses will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

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When a patient withdraws from the trial, 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.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.9
Electrocardiograms
Single ECG recordings will be obtained at specified time points, as outlined in the 
Schedule of Assessments (see Appendix 1), and may be obtained at unscheduled time 
points as indicated.
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. ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes. 
All ECGs, when possible, should be obtained prior to other procedures scheduled at the 
same time (e.g., vital sign measurements, blood draws). 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.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper copies of ECG tracings will be kept as part of the patient's permanent 
trial file at the site. Digital recordings will be stored at site. The following should be 
recorded in the appropriate eCRF: heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and the QTcF based on the machine readings of the individual 
ECG tracings. Any morphologic waveform changes or other ECG abnormalities must be 
documented on the eCRF. If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory. Refer to section 5.1.1.8 for details on 
protocol management of increases in QT interval.
4.5.10
Patient-Reported Outcomes
Several PRO assessments will be conducted in this trial, including the UCSD-SOBQ, the 
Leicester Cough Questionnaire, the cough visual analog scale, and the SGRQ (see 
Appendix 2). The impact of potential bias on these outcomes will not be investigated.
PRO data will be collected via questionnaires to document the treatment effect and to 
evaluate the benefit of pirfenidone. The questionnaires, translated into the local 
language as required, will be completed in their entirety at specified time points during 
the trial (see Appendix 1). To ensure instrument validity and that data standards meet 
health authority requirements, questionnaires will be self-administered before the patient 

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receives any information on disease status and prior to the performance of non-PRO 
assessments, unless otherwise specified.
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays.
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.11) will not be 
applicable at that site.
4.5.11.3
Sample Collection
The following samples will be collected for research purposes, including, but not limited 
to, research on biomarkers related to pirfenidone or unclassifiable ILD:

Leftover plasma, serum, and whole blood RNA (PAX gene) samples

RBR whole blood for DNA extraction
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations, somatic mutations via whole genome sequencing 
(WGS), next-generation sequencing (NGS), or other genomic analysis methods.

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Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this trial, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this trial but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted. However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.11.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens 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.
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to trial investigators or patients unless required 
by law. The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on trial data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR. Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period. A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens. 
Patients who decline to participate will not provide a separate signature.

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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason. If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Patient 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF. The patient will be 
provided with instructions on how to withdraw consent after the trial is closed. A patient's 
withdrawal from this trial does not, by itself, constitute withdrawal of specimens from the 
RBR. Likewise, a patient's withdrawal from the RBR does not constitute withdrawal from 
this trial.
4.5.11.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form. Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor. The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
PATIENT, TREATMENT, TRIAL, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the trial at any time for any reason. In 
addition, the investigator has the right to withdraw a patient from the trial at any time. 
Reasons for withdrawal from the trial 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 trial

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, defined as non-adherence with the dosing regimen, 
including the dose-titration guidance for starting trial treatment

Lung transplantation

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Patients who undergo lung transplantation during the trial will be discontinued at the time 
of hospitalization for transplantation.
Every effort should be made to obtain information on patients who withdraw from the trial. 
The primary reason for withdrawal from the trial 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 trial will not be replaced.
4.6.2
Trial Treatment Discontinuation
Patients must discontinue trial treatment if they experience any of the following:

Pregnancy

Hepatic or renal impairment

LFT elevations that require discontinuation

Angioedema
The primary reason for early trial treatment discontinuation should be documented on 
the appropriate eCRF. Patients who discontinue trial treatment prematurely will not be 
replaced.
4.6.3
Trial and Site Discontinuation
The Sponsor has the right to terminate this trial at any time. Reasons for terminating the 
trial 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 trial.
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 trial activity (i.e., all patients have completed the trial and all obligations have 
been fulfilled)

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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Pirfenidone is approved for the treatment of IPF in the US, and for the treatment of mild 
to moderate IPF in the EEA and Canada (Esbriet SmPC 2015; Health Canada 2016; US 
FDA 2015). However, the efficacy and safety of pirfenidone in patients with 
unclassifiable ILD has not been fully elucidated. The safety plan for patients in this trial is 
based on clinical experience with pirfenidone in completed and ongoing studies 
predominately involving patients with IPF. The anticipated important safety risks for 
pirfenidone are outlined below. Please refer to the pirfenidone Investigator's Brochure for 
a complete summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in this trial. 
Eligibility criteria have been designed to exclude patients at higher risk for toxicities. 
Patients will undergo safety monitoring during the trial, 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.
An iDMC will review safety data and advise on trial conduct (see Section 3.1). The 
procedures that will be used by the iDMC will be detailed in an iDMC charter.
5.1.1
Risks Associated with Pirfenidone
Treatment with pirfenidone was consistent with the known safety profile and generally 
well tolerated in patients who received treatment in the clinical development program.
Almost all patients experienced an adverse event (99.0% in the pirfenidone 2403 mg/day 
group and 97.9% in the placebo group). The most common adverse events in the 
pirfenidone group were GI events (nausea, diarrhea, dyspepsia, vomiting, 
gastroesophageal reflux disease [GERD], and constipation), respiratory-related events 
(cough, dyspnea, IPF, upper respiratory tract infection, nasopharyngitis, bronchitis, and
sinusitis), fatigue, decreased weight, anorexia, back pain, arthralgia, headache, 
dizziness, insomnia, rash, and photosensitivity reactions.
5.1.1.1
Hepatic Function
Elevations in ALT and AST >3 × ULN have been reported in patients receiving therapy 
with pirfenidone. Rarely, these have been associated with concomitant elevations in 
bilirubin. LFTs (ALT, AST, and bilirubin) should be conducted prior to the initiation of 
treatment with pirfenidone and subsequently at monthly intervals for the first 6 months. 
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
. See Sections 5.4.2.11 and 6.4.1 of the Investigator’s Brochure for more details.

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Patients with clinically significant hepatic impairment will be excluded from this trial (see 
Section 4.1.2).
5.1.1.2
Gastrointestinal effects
Gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, GERD, and abdominal
pain have been more frequently reported in the pirfenidone treatment groups than in the 
placebo groups. Dose reduction or interruption for gastrointestinal events was required in
18.5% of patients in the pirfenidone 2403 mg/day group compared with 5.8% of patients
in the placebo group. In addition, 2.2% of patients in the pirfenidone 2403 mg/day group 
discontinued treatment due to a gastrointestinal event, as compared with 1.0% of patients
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. See Sections 5.4.2.10 and 6.4.1 of the 
Investigator’s Brochure for more details.
The incidence of gastrointestinal events was higher early in the course of pirfenidone 
treatment (with the highest incidence occurring during the initial 3 months) and usually 
decreased over time.
5.1.1.3
Photosensitivity Reaction or Rash
Exposure to direct sunlight (including sunlamps) should be avoided or minimized during 
treatment with pirfenidone (see Investigator’s Brochure for more details). 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 any symptoms of photosensitivity reaction or rash. 
Dose adjustments or temporary treatment discontinuation may be necessary for 
photosensitivity reaction or rash. See Sections 5.4.2.13 and 6.4.1 of the Investigator’s 
Brochure for more details.
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. Patients with angioedema should be managed 
according to standard of care. Pirfenidone should not be used in patients with a history 
of angioedema due to pirfenidone treatment. See Sections 5.4.2.16 and 6.4.1 of the 
Investigator’s Brochure for more details.
5.1.1.5
Dizziness
In the pooled Phase 3 analysis (PIPF-004/006/016), dizziness was reported for a larger 
proportion of pirfenidone patients than placebo patients (18.0% pirfenidone vs. 11.4% 
placebo), and the majority of pirfenidone patients who reported dizziness first did so 

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during the initial 3 months of treatment (72/112, 64.3%). Two (0.3%) pirfenidone patients 
and one (0.2%) placebo patient had Grade 3 dizziness. There were no Grade 4 events, 
serious adverse events, hospitalizations, treatment discontinuations, or deaths for 
dizziness in either group. See Sections 5.4.2.9 and 6.4.1 of the Investigator’s Brochure 
for more details.
An analysis of the relationship between dizziness and subsequent falls revealed that six 
of 112 (5.4%) pirfenidone patients who reported dizziness experienced a fall at some 
time after the first report of dizziness.
5.1.1.6
Fatigue
In the pooled Phase 3 analysis (PIPF-004/006/016), fatigue was reported for 26.0% of 
pirfenidone patients and 19.1% of placebo patients. The majority of pirfenidone patients 
who reported fatigue first did so during the initial 9 months of treatment (127/162, 78.4%), 
with 81/162 (50.0%), experiencing it within the first month. In the pirfenidone group, 1.1% 
of patients had a Grade 3 event; there were no Grade 4 events, serious adverse events, 
hospitalizations, treatment discontinuations, or deaths. In the placebo group, 0.8% of 
patients had a Grade 3 event, one (0.2%) patient had a serious adverse event, and one 
(0.2%) patient was hospitalized for fatigue; there were no Grade 4 events, deaths, or 
treatment discontinuations. See Section 6.4.1 of the Investigator’s Brochure for more 
details.
5.1.1.7
Weight loss
In the pooled Phase 3 analysis (PIPF-004/006/016), the adverse event of weight 
decrease was reported for a larger proportion of pirfenidone patients than placebo 
patients (10.1% pirfenidone vs. 5.4% placebo), and the majority of pirfenidone patients 
who reported an adverse event of weight decrease first did so during the initial 6 months 
of treatment (39/63, 61.9%). In the pirfenidone group, two (0.3%) patients had Grade 3 
adverse events, one (0.2%) patient had a serious adverse event, and five (0.8%) 
patients discontinued trial treatment for this adverse event; there were no Grade 4 
events, hospitalizations, or deaths. In the placebo group, one (0.2%) patient had a 
serious adverse event and was hospitalized; there were no Grade 3 or 4 events, deaths, 
or treatment discontinuations for this adverse event. See Sections 5.4.2.14 and 6.4.1 of 
the Investigator’s Brochure for more details.
5.1.1.8
Management of Increases in QT Interval
In the event of a QTcF interval of >500 ms or an increase from baseline of >60 ms, a 
repeat ECG must be obtained within 24 hours. If the QTcF finding is confirmed by the 
repeat ECG and verified by the site (trial center) or local cardiologist, pirfenidone
treatment should be discontinued and a decision on trial treatment discontinuation 
should be made, as described in Section 4.6.1.. If an alternative explanation is identified 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, and 

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severe bradycardia) and the abnormality resolves, restarting trial treatment should be 
considered by the investigator in consultation with the Medical Monitor or designee. If 
the investigator, in consultation with the Medical Monitor or designee, considers it 
clinically appropriate to recommence trial treatment, treatment should be restarted as 
described in Table 2 .
5.1.2
Management of Patients Who Experience Specific Adverse 
Events
Guidelines for management of specific adverse events are outlined in Table 3
.
Table 3Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Pirfenidone
Event
Action to Be Taken
Elevated aminotransferase 
results

For patients with a >3 to <5 × ULN increase in ALT or AST levels 
without hyperbilirubinemia:

Discontinue confounding medications

Monitor the patient closely, including repeating liver 
chemistry tests

Maintain the full daily 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 if well tolerated.

For patients with a >3 to <5 × ULN increase in ALT or AST levels 
with symptoms or hyperbilirubinemia:

Discontinue pirfenidone and do not rechallenge the patient.

For patients with a >5 × ULN increase in ALT or AST levels:

Trial treatment should be permanently discontinued.
Gastrointestinal disorders

Dose modifications may be necessary in some cases of 
gastrointestinal adverse reactions.

Taking pirfenidone with food is recommended.
Photosensitivity reaction 
and rash

Exposure to direct sunlight (including sunlamps) should be 
avoided or minimized during treatment with pirfenidone.

Instruct patients to:

Wear clothing that protects against sun exposure

Avoid other medicinal products that cause photosensitivity

Report symptoms of photosensitivity reaction or rash.

Adjust dose or temporarily discontinue treatment (if necessary).

Use an effective sunblock on a daily basis.
Angioedema

Immediately discontinue treatment.

Manage patients according to standard of care.

Pirfenidone should not be used in patients with a history of 
angioedema.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal

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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
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 trial.
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, an adverse event is any 
untoward medical occurrence in a clinical investigation patient 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 trial treatment or concomitant 
treatment or discontinuation from trial treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of trial 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)
o
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)

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
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
trial treatment

Is a significant medical event according to 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 to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 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 hours 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 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). Adverse events of special interest for this trial 
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 trial treatment, 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 trial treatment 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 Sections 5.45.6.

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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).
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 trial personnel, will be recorded in 
the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of trial treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see 
Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of trial treatment, all adverse events will be reported until 28 days after 
the last dose of trial treatment (Follow-up Visit).
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 time points. 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 (v4.0) 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.
Table 4Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE

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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=National Cancer Institute; CTCAE=Common Terminology Criteria for Adverse Events.
Note: based on the most recent version of NCI CTCAE (v4.0), 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 trial treatment, indicating "yes" or "no" 
accordingly. The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of trial treatment

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of trial treatment, or reintroduction of trial treatment (as applicable)

Known association of the event with the trial treatment 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
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.

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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 time points. 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 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF. If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions). The Adverse Event eCRF should be updated by 

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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 time points 
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 trial treatment (e.g., dosage modification, treatment 
interruption, or early treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant according to 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).
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 trial treatment (e.g., dosage modification, treatment 
interruption, or early treatment discontinuation)

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
Results in a medical intervention or a change in concomitant therapy

Is clinically significant according to 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 hours 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
For this protocol, mortality from any cause and mortality from respiratory diseases are 
included as efficacy endpoints. Mortality is also included as part of the PFS efficacy 
endpoint. Deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1) that are attributed by the investigator solely to progression of 
unclassifiable ILD should be recorded on the Death Attributed to Progressive Disease 
eCRF. All other on-trial deaths, regardless of relationship to trial treatment, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor (see 
Section 5.4.2). The iDMC will monitor the frequency of deaths in this trial.
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. 

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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 
pre-existing heart disease, within 1 hour after the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours 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.
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Pre-existing Medical Conditions
A pre-existing medical condition is one that is present at the Screening Visit for this trial. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the trial. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the pre-existing condition has changed by including applicable descriptors (e.g., 
"more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Unclassifiable ILD
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events. These data will be 
captured as efficacy assessment data only. In most cases, the expected pattern of 
progression will be based on ≥10% relative decline in FVC or a >50 m decline in 6MWD. 
In rare cases, the determination of clinical progression will be based on symptomatic 
deterioration or a decline in DLco of ≥15%. However, every effort should be made to 
document progression through use of objective criteria. If there is any uncertainty as to 
whether an event is due to disease progression, it should be reported as an adverse 
event.
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.
The following hospitalization scenarios are not considered to be adverse events:

Hospitalization for respite care

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
Hospitalization for a pre-existing condition, provided that all of the following criteria 
are met:

The hospitalization was planned prior to the trial or was scheduled during the trial 
when elective surgery became necessary because of the expected normal 
progression of the disease

The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying ILD
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 trial 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 trial treatment 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 hours after 
learning of the event; see Section 5.4.2).
There is limited clinical experience with regards to overdose with pirfenidone. Multiple
doses of pirfenidone up to a dose of 4806 mg/day (six 267 mg capsules TID) have been 
administered to healthy adult volunteers over a 12-day dose escalation period. Adverse
reactions were mild, transient, and consistent with the most frequently reported adverse
reactions for pirfenidone.
In the event of a suspected overdose, supportive medical care should be provided
including monitoring of vital signs and close observation of the clinical status of the
patient.
No deaths occurred in dogs that received single oral doses of pirfenidone up to 
1000 mg/kg (approximately 11 times the maximum recommended daily dose in adults on 
a mg/m2 basis). Clinical signs included vomiting, weakness of limbs, hypoactivity,
salivation, mydriasis, shivering, and abnormal vocalization. The maximum nonlethal
dose in rats was 500 mg/kg (approximately two times the maximum recommended daily
dose in adults on a mg/m2 basis). Clinical signs in rats included decrease in locomotor
activity, bradypnea, lacrimation, salivation, ptosis, mydriasis, prone position, lateral
position, and hypothermia.

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5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from 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 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to trial treatment:

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)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours 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 IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for all sites
Medical Monitor/Roche Medical Responsible:
 (Primary)
Mobile Telephone No.:
Medical Monitor/Roche Medical Responsible:
 (Secondary)
Mobile Telephone No.:
Alternate Medical Monitor Contact Information for all sites
Roche Medical Responsible:
Telephone No.:

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Mobile Telephone No.:
To ensure the safety of trial 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 individual (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 hours 
per day, 7 days per week. Toll-free numbers for the Help Desk, as well as Medical 
Monitor and Medical Responsible individual 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 Trial Treatment Initiation
After informed consent has been obtained but prior to initiation of trial treatment, only 
serious adverse events caused by a protocol-mandated intervention 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 hours 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 Trial Treatment Initiation
After initiation of trial treatment, serious adverse events and adverse events of special 
interest will be reported until 28 days after the last dose of trial treatment. Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
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 by 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 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
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 serious adverse events that occur ≥28 days after the last dose 
of trial treatment 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 trial or within 58 days after the last dose 

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of trial treatment. A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 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 trial 
treatment 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 trial or within 
118 days after the last dose of trial treatment. A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours 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 trial treatment. 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.
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 hours 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 trial 
treatment or the female partner of a male patient exposed to trial treatment 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 hours after learning of the 
event; see Section 5.4.2).

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5.4.4
Reporting Requirements for Cases of Pirfenidone Accidental 
Overdose, Medication Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately 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 hours after learning of the event; see Section 5.4.2).  For 
Pirfenidone, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

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
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with Pirfenidone, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.

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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 trial treatment or trial-related 
procedures until a final outcome can be reported.
During the treatment 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 trial 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
After the end of the adverse event reporting period (defined as 28 days after the last 
dose of trial treatment), all deaths, regardless of cause, should be reported through use 
of the Long-Term Survival Follow-Up eCRF. In addition, if the investigator becomes 
aware of a serious adverse event that is believed to be related to prior trial treatment, the 
event should be reported through use of the Adverse Event eCRF.
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:
Pirfenidone Investigator's Brochure.
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the trial with the severity and frequency reported in the applicable 
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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
Certain adverse events are anticipated to occur in the trial population at some frequency 
independent of trial treatment exposure and will be excluded from expedited reporting. 
These anticipated events include, but are not limited to, the following:

Cough

Dyspnea

Hypoxemia

Lung crepitations
The iDMC will monitor the incidence of the above-listed anticipated events during the 
trial. An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities.
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 the treatment groups as randomized.
The safety population is defined as all treated patients (at least one drug intake of 
pirfenidone or placebo). Patients in the safety population will be assigned to treatment 
groups according to the treatment they received.
6.1
DETERMINATION OF SAMPLE SIZE
The purpose of this trial is hypothesis generation regarding the efficacy of pirfenidone vs. 
placebo on lung function parameters on the basis of rate of decline in FVC, as measured 
by daily handheld spirometry.
A total sample size of approximately 250 patients is planned, and patients will be 
randomized in a 1:1 ratio. The randomization will be stratified by concomitant MMF 
treatment (yes/no), the presence/absence of IPAF as defined by the MDT.
The planned sample size is based on the statistical hypothesis of the primary endpoint 
and assumes 80% power and a two-sided significance level of 5% using a student’s t-
test. It is assumed, after inspection of historical data, that FVC decline in the placebo 
arm is 85 mL with a common standard deviation of 70 mL, which can be reduced to 
60 mL with a common standard deviation of 70 mL in the pirfenidone arm. In this 
scenario, 125 patients per treatment arm are needed to detect this treatment effect with 
80% power.
These assumptions are based upon the following considerations: in IPF, the annual rate 
of decline of FVC is approximately 200 mL. Owing to the fact that patients with 
unclassifiable ILD have rates of disease progression in the range of patients with IPF, 

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albeit with a lower mortality rate (Ryerson et al. 2013), a similar decline rate of 
200 mL/year, equivalent to a 100 mL decline over a treatment period of 24 weeks, can 
be expected. However, a yet unknown proportion of patients in this trial will be treated 
concomitantly with MMF. In a previous study of CTD-ILD (Fischer et al. 2013), MMF was 
found to have beneficial effects on lung functions in these patients. While CTD-ILD is a 
distinct entity from the current trial population, both conditions may share some 
autoimmune features. Therefore assuming a smaller FVC decline of 85 mL in the 
placebo arm compared with 60 mL in the pirfenidone arm over the 24-week double-blind 
treatment period appears justified. In addition, the potential confounding effect of 
concomitant MMF therapy in these patients justifies stratification to ensure equal 
distribution of patients who receive and do not receive treatment with MMF.
6.2
SUMMARIES OF CONDUCT OF TRIAL
Patient enrollment, trial treatment administration, and reasons for early treatment 
discontinuation and trial discontinuation will be summarized for all enrolled patients. In 
addition, protocol deviations and eligibility violations will be summarized by frequency 
tables.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographics and baseline characteristics, such as age, sex, and race, will be 
summarized by treatment arm using means or medians for continuous variables and 
proportions for categorical variables as well as appropriate measures of variability. 
Medical history will be tabulated by treatment arm. Summary of concomitant medications 
will be displayed by treatment arm 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 trial is to evaluate the efficacy of pirfenidone vs. 
placebo on lung function parameters on the basis of rate of decline in FVC in mL 
measured by handheld spirometry over the 24-week double-blind treatment period (see 
Section 2).
The primary analysis will be based on the ITT population. Patients who discontinue 
treatment prematurely will be analyzed based on the available data. No imputation 
method will be applied.
The primary analysis of the primary endpoint will compare the mean FVC decline in each 
treatment arm using a student’s t-test with a two-sided significance level α=0.05. The 
mean FVC decline for each treatment arm will be calculated using the estimated FVC 
decline for each individual patient. The individual FVC decline will be estimated by 

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applying a linear regression model to all data points collected during the 24-week 
double-blind treatment period.
6.4.2
Secondary Efficacy Endpoints
For secondary endpoints, all data from baseline (Day 1) until Week 24 will be taken into 
account for the statistical analysis. In a similar manner to the primary endpoint data, 
patients who discontinue early will be analyzed based on the data collected until 
withdrawal.
The secondary efficacy objective for this trial is to evaluate the efficacy of pirfenidone 
compared with placebo on the basis of the following endpoints:

The decline of FVC in mL measured by spirometry during site (clinic) visits will be 
compared between the treatment arms in the same fashion as described for the 
primary endpoint

Change in percent predicted FVC measured by spirometry during site visits will be 
compared between the treatment arms using a rank analysis of covariance
(ANCOVA). Change from baseline will be used as an outcome variable and 
standardized rank baseline value will be used as a covariate

Categorical changes in FVC of >5% and >10% will be compared between the 
treatment arms using a Cochran-Mantel-Haenszel test stratified by geographic 
region, concomitant MMF medication use, and the presence/absence of IPAF as 
defined by the MDT

Change in percent predicted DLco will be compared between the treatment arms 
using a rank ANCOVA. Change from baseline will be used as an outcome variable 
and standardized rank baseline value will be used as a covariate

The change in 6MWD will be analyzed using a rank ANCOVA model. The 6MWD 
recorded at 24 weeks will be used as an outcome variable and standardized rank 
baseline 6MWD will be used as a covariate

The change in UCSD-SOBQ score will be analyzed using a rank ANCOVA model. 
The UCSD-SOBQ score recorded at 24 weeks will be used as an outcome variable 
and standardized rank baseline UCSD-SOBQ score will be used as a covariate

The change in Leicester Cough Questionnaire score will be analyzed using a rank 
ANCOVA model. The Leicester Cough Questionnaire score recorded at 24 weeks 
will be used as the outcome variable and standardized rank baseline Leicester 
Cough Questionnaire score will be used as a covariate

The change in cough visual analog scale will be analyzed using a rank ANCOVA 
model. The result recorded at 24 weeks will be used as the outcome variable and 
the standardized rank baseline result will be used as a covariate

The change in total and sub-scores of the SGRQ will be analyzed using a rank 
ANCOVA model. The scores recorded at 24 weeks will be used as outcome 
variables and the standardized rank baseline scores will be used as covariates

All-cause non-elective hospitalization and respiratory non-elective hospitalization will 
be analyzed using Kaplan-Meier techniques and the two treatment arms will be 

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compared with a log-rank test. In addition, hazard ratios and corresponding 95% 
confidence interval (CI) will be calculated by applying Cox-proportional hazard 
models

The incidence of investigator reported acute exacerbations in the two treatment 
arms will be compared with Fisher’s exact test

PFS, defined as the time to the first occurrence of a >10% absolute decline in 
percent predicted FVC, a >50 m decline of 6MWD, 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

An alternative definition of PFS, namely the time to the first occurrence of a >10% 
relative decline in FVC, non-elective respiratory hospitalization, or death, 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

Time to death from any cause and time to death from respiratory diseases 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.
For all secondary endpoints p-values will be reported in a descriptive fashion. No 
multiplicity adjustments for statistical testing will be done.
6.5
SAFETY ANALYSES
The safety analyses will include all randomized patients who received at least one dose 
of trial treatment, with patients grouped according to treatment received. 
The safety objective for this trial is to evaluate the safety of pirfenidone vs. placebo (see 
Section 2).
The safety analysis will involve investigating the nature, frequency, severity, and timing 
of treatment-emergent adverse events. The specific parameters that will be investigated 
include all adverse events, adverse events Grade ≥3 according to the NCI CTCAE 
version 4.0, adverse events of special interest, and serious adverse events. The primary 
interest in this trial will be adverse events Grade ≥3 related to pirfenidone or placebo.
Prior to the first administration, only serious adverse events caused by a protocol-
mandated intervention will be recorded. These adverse events will be listed.
The incidence, type, and severity of adverse events will be summarized according to the 
primary System Organ Class (SOC) and within each SOC, by the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term.
Adverse events Grade ≥3, adverse events of special interest, and serious adverse 
events will be analyzed in a similar way to all adverse events.

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Descriptive statistics will be presented for dose reductions and treatment interruptions. 
Adverse events leading to treatment interruption or dose reduction will also be 
summarized.
Laboratory parameters including hematology and the chemistry panel will be presented 
in shift tables of NCI-CTCAE version 4.0 grade at baseline versus worst grade during 
treatment period. The laboratory parameters will presented according to means, 
standard deviation, minimum, and maximum. Selected laboratory parameters will be 
also graphically presented over time.
The results from the 12-lead ECGs will be summarized and presented.
The number of patients who withdraw from pirfenidone or placebo treatment with 
corresponding reason for withdrawal will be summarized and listed. The discontinuation 
from trial data will be also summarized and listed.
6.6
EXPLORATORY ANALYSES
The exploratory objectives for this trial are to evaluate the role of MMF treatment in ILD 
and to investigate potential biomarkers associated with fibrosis and ILD (see Section 2).
For the MMF objective, efficacy and safety data will be investigated by means of a 
subgroup analyses that stratifies patients according to whether they received MMF 
treatment. The conduct of these analyses will be described in detail in the Statistical 
Analysis Plan (SAP).
For the biomarker objective, assessments of the exploratory biomarkers and their 
relationship with drug responses will be described in a separate analysis plan.
6.7
INTERIM ANALYSIS
6.7.1
Optional Interim Analysis
There are no planned interim efficacy analyses for this trial.
Safety interim analyses will be performed at least three times during the trial, at 
approximately 6, 12, and 18 months after the start of recruitment.
Efficacy data will only be provided if requested by the iDMC.
Further details on the function and logistics of the iDMC will be provided in the iDMC 
Charter.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will supply eCRF specifications for this trial. A CRO will be responsible for 
data management of this trial, including quality checking of the data. Data entered 

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manually will be collected via EDC through use of eCRFs. Sites will be responsible for 
data entry into the EDC system. In the event of discrepant data, the CRO will request 
data clarification from the sites, which the sites will resolve electronically in the EDC 
system.
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.
The Sponsor will perform oversight of the data management of this trial, including 
approval of the CRO’s data management plans and specifications. Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. 
System backups for data stored at the CRO and records retention for the trial data will 
be consistent with the CRO’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.
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 trial, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the trial records. 
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Trial 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 site charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 

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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 trial 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 trial site must also allow inspection 
by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a trial site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
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 trial and the distribution of IMP, 
including eCRFs, 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 trial 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.

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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This trial 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 trial will comply with the requirements of the ICH 
E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). If the US participates in this trial, studies conducted in the US or 
under a US Investigational New Drug (IND) application will comply with US Food and 
Drug Administration (FDA) regulations and applicable local, state, and federal laws. 
Studies conducted in the European Union or EEA will comply with the European Union 
Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Biomarker 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 approved 
IRB/EC 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 
consent at any time for any reason. 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 trial. 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 trial.
The Consent Forms should be revised whenever there are changes to trial 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 trial. For any updated or revised Consent 

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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 trial.
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 trial file or in the site file and must be available for verification by trial 
monitors at any time.
If sites in the US participate in this trial, each Consent Form may also include patient 
authorization to allow use and disclosure of personal health information in compliance 
with the US Health Insurance Portability and Accountability Act (HIPAA) of 1996. If the 
site utilizes a separate Authorization Form for patient authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply, except that IRB review and 
approval may not be required per trial site policies.
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 trial 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 trial 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 trial file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
trial 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 trial is confidential and may be disclosed to 
third parties only as permitted by the Informed Consent Form (or separate authorization 

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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.
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to trial investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Roche policy on trial data publication (see 
Section 9.5).
Data generated by this trial 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 trial 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 trial and for 1 year after completion of the trial (trial completion is expected 
to occur approximately 84 weeks after the last patient is enrolled and receives their first 
dose of trial treatment).
9.
TRIAL DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
TRIAL DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the trial 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 trial, the investigator will receive the 
patient data, including an audit trail containing a complete record of all changes to the 
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.

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9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of trial data, patients’ medical records, and eCRFs. The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this trial.
9.4
ADMINISTRATIVE STRUCTURE
An iDMC will review safety data and advise on trial conduct (see Section 3.1). The 
procedures that will be used by the iDMC will be detailed in an iDMC charter. The IxRS 
system will be used to conduct the randomization process (see Section 4.2) and to 
confirm the shipment condition and content of the IMPs (see Section 4.3.3). A CRO will 
be responsible for data management of this trial (see Section 7.1).
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 trial results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following Web site: 
http://www.roche.com/dam/jcr:1c46aa73-cea0-4b9b-8eaa-
e9a788ed021b/en/roche global policy on sharing of clinical study information.pdf
The results of this trial 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 
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 

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the trial 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 trial 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.
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Appendix 1 Schedule of Assessments
Washout a
Screening
Double-blind treatment
Early treatment 
discontinuation b
Follow-
upu
Additional 
safety follow-
up c
Additional 
safety 
follow-up 
final visit
Day
Week
–50 to –22
–21 to –1
Randomization
1
1
28
4
56
8
84
12
112
16
140
20
168
24
196
28
up to 12 
months
up to 12 
months 
plus 28 
days
Window (days, unless 
otherwise stated)
5 5
5
5
5
5
5  b
5
5
5
Treatment Period 
Visit
1
2
3
4
5
6
7
Month 1 to 6: 
Monthly visits
Month 7 to12: 
Approximately 
every 
3 months
Informed consent d,e
x
x
Review Eligibility 
Criteria
x
Demographic data e
x
x
General medical 
history and baseline 
conditions e
x
x
Vital signs f
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
Height
x
Complete physical 
examination g
x
x
x
x

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Washout a
Screening
Double-blind treatment
Early treatment 
discontinuation b
Follow-
upu
Additional 
safety follow-
up c
Additional 
safety 
follow-up 
final visit
Day
Week
–50 to –22
–21 to –1
Randomization
1
1
28
4
56
8
84
12
112
16
140
20
168
24
196
28
up to 12 
months
up to 12 
months 
plus 28 
days
Window (days, unless 
otherwise stated)
5 5
5
5
5
5
5  b
5
5
5
Treatment Period 
Visit
1
2
3
4
5
6
7
Month 1 to 6: 
Monthly visits
Month 7 to12: 
Approximately 
every 
3 months
ECG h
x
x
x
x
x
x
Hematology i
x
x
x
x
x
Chemistry j
x
x
x
x k
x
x k
x k
x
x
xk
Pregnancy test l
x
x
x
x
x
x
x
x
x
x
Trial treatment
administration
x
x
x
x
x
x
x m
x
Spirometry (FVC, 
FEV1)
x
x
x
x
x
x
x
x
x
Daily spirometry 
(handheld device) n,o
x
x
x
x
x
x
x
x
x
DLco
x
x
x
x
x
6MWD p
x
x
x
x
x
Leicester Cough 
Questionnaire q
x
x
x
x
UCSD-SOBQ q
x
x
x
x

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Washout a
Screening
Double-blind treatment
Early treatment 
discontinuation b
Follow-
upu
Additional 
safety follow-
up c
Additional 
safety 
follow-up 
final visit
Day
Week
–50 to –22
–21 to –1
Randomization
1
1
28
4
56
8
84
12
112
16
140
20
168
24
196
28
up to 12 
months
up to 12 
months 
plus 28 
days
Window (days, unless 
otherwise stated)
5 5
5
5
5
5
5  b
5
5
5
Treatment Period 
Visit
1
2
3
4
5
6
7
Month 1 to 6: 
Monthly visits
Month 7 to12: 
Approximately 
every 
3 months
SGRQ q
x
x
x
x
Cough visual analog 
score q
x
x
x
x
Serum for biomarker 
assessments
x
x
x
x
x
Plasma for biomarker 
assessments
x
x
x
x
x
Whole blood for PAX
gene biomarker 
assessment
x
x
x
x
x
Concomitant 
medications r
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events s
x
x
x
x
x
x
x
x
x
x
x
x
Whole blood sample 
for RBR (optional) t
x

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6MWD=6-minute walk distance; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; DLco=diffusing 
capacity of the lung for carbon monoxide; ECG=electrocardiogram; eCRF=electronic case report form; FEV1=forced expiratory volume in 1 second; 
FVC=forced vital capacity; IMP=investigational medicinal product; LDH=lactate dehydrogenase; LFT=liver function test; PRO=patient-reported 
outcome; RBC=red blood cell; RBR=Research Biosample Repository; SGRQ=St. George's Respiratory Questionnaire; SOBQ=Shortness of Breath 
Questionnaire; UCSD=University of California, San Diego; WBC=white blood cell
Notes: all assessments should be performed within 7 days of the scheduled visit, unless otherwise specified. 
a Patients will be required to taper and/or discontinue all prohibited medications in the 28 days prior to the start of screening during the washout 
period. Patients not taking a prohibited medication will forgo the washout period and directly enter screening.
b Patients who discontinue trial treatment prematurely will return to the site (clinic) for an Early Treatment Discontinuation Visit 28 (5) days after 
the last dose of the double-blind treatment, thus ending their participation in the trial. For patients who end their participation in the double-blind 
treatment period due to unblinding, they may be offered to continue into the open-label period according to the investigator’s judgment. These 
patients will attend the Early Treatment Discontinuation Visit (28 (5) days after the last dose of the double-blind treatment) and on the same 
day begin their participation in the 12-month open-label pirfenidone safety follow-up period.
c After completion of the double-blind treatment period and the Follow-up Visit at Week 28, the Sponsor will offer the possibility to the patients to 
receive open-label pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. During the 12-month safety follow-up 
period, initially, patients will be evaluated at monthly visits for the first 6 months. At the end of the first 6 months, patients will be evaluated at 
each site visit occurring approximately every 3 months until the end of the safety follow-up period.. A final Follow-up Visit will be performed at the 
end of the safety period, 28 (5) days after the last open-label dose.
d Informed consent must be documented before any trial-specific screening procedure is performed, and may be obtained either at the Washout or 
Screening Visits.
e Any procedures that were not completed during washout, must be completed at the Screening Visit.
f
Includes respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature. 
Abnormalities observed at baseline should be recorded on the General Medical History and Baseline Conditions eCRF. At subsequent visits, 
new or worsened clinically significant abnormalities should be recorded on the Adverse Event eCRF. All vital sign measurements are to be 
obtained prior to any blood draws scheduled at the same time.
g Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems. Abnormalities observed at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF. At subsequent visits, new or worsened clinically significant abnormalities should be recorded on the Adverse 
Event eCRF.
h All ECGs are to be obtained prior to other procedures scheduled at the same time.
i
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
j
Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH.

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k Only LFTs (AST, ALT, bilirubin, and alkaline phosphatase) will be conducted at these visits. During the Safety Follow-up period, LFTs will be 
performed every month during the first 6 months and subsequently at each visit occurring approximately every 3 months thereafter, until the end 
of this period.
l
All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at the specified 
subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. During the Safety Follow-up period, urine 
pregnancy tests will be performed every month during the first 6 months at each site visit. Urine pregnancy tests will continue to be performed on 
a monthly basis during the remainder of the Safety Follow-up period with patients performing the test at home (using kits provided by the site) 
during months where there is no site visit and at each site visit occurring approximately every 3 months. Patients will be instructed to contact the 
site immediately in case the result of the home pregnancy test is positive. In such cases, the patient must visit the site for a confirmatory serum 
pregnancy test.
m Open-label treatment with pirfenidone will be started at this visit, if the patient requests continued treatment with pirfenidone.
n Handheld spirometry will be conducted by the patient every day in a seated position.
o To provide handling evaluations and quality assurance for the daily spirometer assessments, nursing visits to the patient’s home (or at another 
suitable location) will occur at least three times during the trial, namely between Weeks 1 and 4, between Weeks 8 and 12, and between 
Weeks 16 and 20. Additional home nursing visits may be conducted according to the investigator’s judgment.
p   6-Minute Walk Distance (6MWD) is used to evaluate the functional capacity of patients with lung disease.
q Questionnaires will be self-administered prior to the patient receiving any information on disease status and prior to the performance of non-PRO 
assessments. Refer to Appendix 2 for copies of the questionnaires and a brief description.
r
Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient from the washout period until 28 days after the last dose of trial treatment.
s After informed consent has been obtained but prior to initiation of trial treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of trial treatment, all adverse events will be reported until 28 days after the last dose of trial 
treatment. After this period, all deaths, regardless of cause, should be reported. In addition, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior trial treatment (see Section 5.6). 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 
trial treatment or trial-related procedures until a final outcome can be reported.
t
Not applicable for a site that has not been granted approval for RBR sampling.
u  If a patient discontinues the trial between weeks 24 and 28, final assessments according to the Follow-up visit for week 28 should be performed.

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Appendix 2 Patient-Reported Outcome Questionnaires
The Leicester Cough Questionnaire is a patient-reported questionnaire evaluating the 
impact of cough on quality of life. The questionnaire comprises 19 items and takes 5 to 
10 minutes to complete. Each item assesses symptoms, or the impact of symptoms, 
over the last 2 weeks on a seven-point Likert scale. Scores in three domains (physical, 
psychological and social) are calculated as a mean for each domain (range 1 to 7). A 
total score (range 3 to 21) is also calculated by adding the domain scores together. 
Higher scores indicate better quality of life.
LEICESTER COUGH QUESTIONNAIRE
This questionnaire is designed to assess the impact of your cough on various aspects of your life. Read each question 
carefully and answer by CIRCLING the response that best applies to you. Please answer ALL questions, as honestly as 
you can. 
1. In the last 2 weeks, have you had chest or stomach pains as a result of your cough?
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
2. In the last 2 weeks, have you been bothered by phlegm production when you cough?
1
2
3
4
5
6
7
Every time
Most times
Several times
Sometimes
Occasionally
Rarely
Never
3. In the last 2 weeks, have you been tired because of your cough?
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
4. In the last 2 weeks, have you felt in control of your cough?
1
2
3
4
5
6
7
None of the time
Hardly any of the 
time
A little of the time
Some of the time
A lot of the time
Most of the time
All of the time
5. How often during the last 2 weeks have you felt embarrassed by your coughing?
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
6. In the last 2 weeks, my cough has made me feel anxious
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
7. In the last 2 weeks, my cough has interfered with my job, or other daily tasks
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
8. In the last 2 weeks, I felt that my cough interfered with the overall enjoyment of my life
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
9. In the last 2 weeks, exposure to paints or fumes has made me cough
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
10.In the last 2 weeks, has your cough disturbed your sleep?
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
11.In the last 2 weeks, how many times a day have you had coughing fits?
1
2
3
4
5
6
7
All of the time 
(continuously)
Most times during 
the day
Several times during 
the day
Sometimes during 
the day
Occasionally through 
the day
Rarely
None
12.In the last 2 weeks, my cough has made me feel frustrated
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
13.In the last 2 weeks, my cough has made me feel fed up

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94/Protocol MA39189, Version 3.0
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
14.In the last 2 weeks, have you suffered from a hoarse voice as a result of your cough?
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
15.In the last 2 weeks, have you had a lot of energy?
1
2
3
4
5
6
7
None of the time
Hardly any of the 
time
A little of the time
Some of the time
A lot of the time
Most of the time
All of the time
16.In the last 2 weeks, have you worried that your cough may indicate a serious illness?
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
17.In the last 2 weeks, have you been concerned that other people think something is wrong with you because of your 
cough?
1
2
3
4
5
6
7
All of the time
Most of the time
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
18.In the last 2 weeks, my cough has interrupted conversations or telephone calls
1
2
3
4
5
6
7
Every time
Most times
A lot of the time
Some of the time
A little of the time
Hardly any of the 
time
None of the time
19.In the last 2 weeks, I feel that my cough has annoyed my partner, family or friends
1
2
3
4
5
6
7
Every time I cough
Most times when 
I cough
Several times when 
I cough
Sometimes when 
I cough
Occasionally when 
I cough
Rarely
Never
Thank you for completing this questionnaire.

Pirfenidone — F. Hoffmann-La Roche Ltd
95/Protocol MA39189, Version 3.0
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.
When I do, or if I were to do, the following tasks, I would rate 
my breathlessness as:
0
None at all
1
2
3
4
Severe
5
Maximum or unable to do because of 
breathlessness
1.
Brushing my teeth...................................................0
1
2 
4
5
Harry has felt moderately short of breath during the past 7 days while brushing his teeth 
and so circles a three for this activity.

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2.
Mowing the lawn ....................................................0
1
2
3
4 
Anne has never mowed the lawn before but estimates that she would have been too 
breathless to do this activity during the past 7 days. She circles a five for this activity.
When I do, or if I were to do, the following tasks, I would rate 
my breathlessness as:
0
None at all
1
2
3
4
Severe
5
Maximum or unable to do because of 
breathlessness
1.
At rest.........................................................................0
1
2
3
4
5
2.
Walking on a level at my own pace...........................0
1
2
3
4
5
3.
Walking on a level with others my age......................0
1
2
3
4
5
4.
Walking up a hill........................................................0
1
2
3
4
5
5.
Walking up stairs .......................................................0
1
2
3
4
5
6.
While eating...............................................................0
1
2
3
4
5
7.
Standing up from a chair............................................0
1
2
3
4
5
8.
Brushing my teeth......................................................0
1
2
3
4
5
9.
Shaving and/or brushing my hair...............................0
1
2
3
4
5

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10.
Showering/bathing.....................................................0
1
2
3
4
5
When I do, or if I were to do, the following tasks, I would rate 
my breathlessness as:
0
None at all
1
2
3
4
Severe
5
Maximum or unable to do because of 
breathlessness
11.
Dressing .....................................................................0
1
2
3
4
5
12.
Picking things up and tidying up a room ...................0
1
2
3
4
5
13.
Doing the dishes.........................................................0
1
2
3
4
5
14.
Sweeping/vacuuming.................................................0
1
2
3
4
5
15.
Making the bed ..........................................................0
1
2
3
4
5
16.
Shopping ....................................................................0
1
2
3
4
5
17.
Doing laundry ............................................................0
1
2
3
4
5
18.
Washing the car..........................................................0
1
2
3
4
5
19.
Mowing the lawn .......................................................0
1
2
3
4
5
20.
Watering the lawn......................................................0
1
2
3
4
5
21.
Sexual activities .........................................................0
1
2
3
4
5

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0
None at all
1
2
3
4
Severe
5
Maximum or unable to do because of 
breathlessness
How much do the following limit you in your daily life?
22.
Shortness of breath.....................................................0
1
2
3
4
5
23.
Fear of "hurting myself" by overexertion ..................0
1
2
3
4
5
24.
Fear of shortness of breath.........................................0
1
2
3
4
5
The St. George’s Respiratory Questionnaire (SGRQ) is an index designed to measure 
and quantify health-related health status in patients with chronic airflow limitations.

Pirfenidone — F. Hoffmann-La Roche Ltd
99/Protocol MA39189, Version 3.0

Pirfenidone — F. Hoffmann-La Roche Ltd
100/Protocol MA39189, Version 3.0

Pirfenidone — F. Hoffmann-La Roche Ltd
101/Protocol MA39189, Version 3.0

Pirfenidone — F. Hoffmann-La Roche Ltd
102/Protocol MA39189, Version 3.0

Pirfenidone — F. Hoffmann-La Roche Ltd
103/Protocol MA39189, Version 3.0

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105/Protocol MA39189, Version 3.0
Cough Visual Analogue Scale (VAS)
This visual analogue scale is designed to help us learn about the severity of your cough. 
This scale is 100mm (10cm) in length. 
During the last week, how do you rate the severity of your cough; 0mm representing no 
cough and 100mm representing the worst cough ever? Please indicate the severity of 
your cough by placing an X on the line.