Conditions: Lung Diseases, Interstitial
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 253
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of pirfenidone in participants 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).

Detailed description:
Study participants will be randomised to receive 801 mg pirfenidone or placebo three times daily for 24 weeks. The efficacy of pirfenidone versus placebo will be assessed by daily measurement of forced vital capacity using a handheld spirometer over the treatment period. Additionally, the study will assess the efficacy and safety of pirfenidone with and without concomitant mycophenolate mofetil treatment and in study participants with or without interstitial pneumonia with autoimmune features (IPAF). All study participants who attend the follow-up visit at Week 28 will be offered the opportunity to receive open-label pirfenidone within the trial protocol. In order to maintain blinding of the controlled period of the study, all study participants will discontinue treatment by Week 24 and return for a follow-up visit 4 weeks later. Study participants eligible to participate in the single-arm 12-month extension will be initiated on open-label pirfenidone during this visit (re-starting the dose titration from one capsule three times daily \[TID\]). During the long-term extension period, study participants will be monitored for safety, initially at monthly visits during the first 6 months and thereafter approximately every 3 months. A final follow-up visit will take place 4 weeks after the last dose of pirfenidone is taken.

Arms:
arm 1: Participants will receive pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. arm 2: Participants will receive matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

Interventions: intervention 1: Pirfenidone intervention 2: Placebo
Intervention descriptions: intervention 1: Pirfenidone 267 mg capsules three times in a day. intervention 2: Matching placebo capsules three times in a day.

Protocol document:
Prot_002.pdf: 
 
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.


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


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


Pirfenidone — F. Hoffmann-La Roche Ltd
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.


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


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


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


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101/Protocol MA39189, Version 3.0


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


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


Pirfenidone — F. Hoffmann-La Roche Ltd
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.

SAP_003.pdf: 
 
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: SAP Version 3: 20-July-2020 
 
 


Pirfenidone and sildenafil/placebo — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
STATISTICAL ANALYSIS PLAN
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
STUDY DRUG:
Pirfenidone (RO0220912)
VERSION NUMBER:
Version 3.0 17-July-2020
IND NUMBER:
67284
Eudract Number:
2016-002744-17
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
(Clinipace)
 (Clinipace)
 (F. Hoffmann-La Roche Ltd) 
DATE FINAL:
17 July 2020
Date and Time(UTC)        Reason for Signing                              Name
20-Jul-2020 08:57:11
Company Signatory


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
The following changes were made compared to the first version of the SAP:
Version
Date
Change 
number
Change description
2
08-Oct-2018
1
Clarification related to the aim and timeline of the primary 
analysis and final analysis of the study are included under 
section Outcome Measures.
2
08-Oct-2018
2
Week 28 is included in all descriptive efficacy tables.
2
08-Oct-2018
3
The safety follow-up period definition is changed as stated 
in section On-treatment Assessments (12-Month Safety 
Follow-up Period).
2
08-Oct-2018
4
Disposition is updated in section Patient Disposition.
2
08-Oct-2018
5
Details were added in order to analyze valid daily 
spirometry data in section Demographic and Baseline 
Characteristics.
2
08-Oct-2018
6
Additional analyses needed in the safety follow-up period 
based on safety follow-up population are presented under 
section Safety Follow-up analyses. 
2
08-Oct-2018
7
Safety follow-up visits were included under section Visit 
Windows. 
2
08-Oct-2018
8
Listings of stratification factors, separated types of adverse 
events and pregnancy data were removed from the 
corresponding sections.
3
18-Jun-2020
9
Categorical change of 5% and 10% for home FVC 
measurements deleted because of implausible data 
collected
3
18-Jun-2020
10
Restrict analysis of oxygen requirements to patients who 
had oxygen requirements
3
18-Jun-2020
11
Add information about sensitivity analyses performed for 
home FVC measurements in section Sensitivity Analyses
3
18-Jun-2020
12
Add correlation analysis for home FVC and site FVC 
measurements (Additional analyses after FDA feedback), 
see Exploratory Efficacy Endpoints
3
18-Jun-2020
13
Mixed model analysis added for home spirometry and site 
spirometry as sensitivity analysis in section Sensitivity 
Analyses


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
3
18-Jun-2020
14
Subgroup analysis for biopsy taken before randomization 
(yes/no) added
3
18-Jun-2020
15
Tipping point analysis added for various assumptions to 
impute missing values in section Sensitivity Analyses for 
missing data
3
18-Jun-2020
16
Safety tables added to compare study data with phase III 
studies in section Adverse events


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
TABLE OF CONTENTS
1.
BACKGROUND .......................................................................................... 11
2.
STUDY DESIGN......................................................................................... 11
2.1
Protocol Synopsis.................................................................. 12
2.2
Outcome Measures ............................................................... 12
2.2.1
Primary Efficacy Outcome Measures .................................... 13
2.2.2
Secondary Efficacy Outcome Measures................................ 13
2.2.3
Exploratory Efficacy Outcome Measures............................... 14
2.2.4
Safety Outcome Measures .................................................... 14
2.3
Determination of Sample Size ............................................... 14
2.4
Interim Analysis ..................................................................... 15
3.
STUDY CONDUCT..................................................................................... 15
3.1
Randomization, BLINDING AND UNBLINDING 
PROCEDURES ..................................................................... 15
3.2
Independent Review Facility.................................................. 15
3.3
Data Monitoring ..................................................................... 16
4.
STATISTICAL METHODS .......................................................................... 16
4.1
Analysis Populations ............................................................. 16
4.1.1
Intent-to-treat Population ....................................................... 16
4.1.2
Per Protocol Population......................................................... 16
4.1.3
Safety Population .................................................................. 16
4.1.4
Safety Follow-up Population.................................................. 17
4.2
Trial Periods, Observation and analysis times....................... 17
4.2.1
Study Days ............................................................................ 17
4.2.2
Baseline and Screening Observations................................... 18
4.2.3
On-treatment Assessments for Efficacy Analyses 
(Double-blind Treatment Period).............................................................. 18
4.2.4
On-treatment Assessments for Safety Analyses 
(Double-blind Treatment Period).............................................................. 18


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
4.2.5
On-treatment Assessments (12-Month Safety 
Follow-up Period)..................................................................................... 18
4.2.6
Cut-off points ......................................................................... 19
4.3
Analysis of Treatment arm Comparability.............................. 19
4.4
Analysis of Study Conduct..................................................... 19
4.4.1
Patient Disposition................................................................. 19
4.4.2
Major Protocol Deviations...................................................... 21
4.4.3
Demographic and Baseline Characteristics........................... 21
4.4.4
Previous and Concomitant Medication .................................. 24
4.4.5
Daily Spirometry (Handheld Device)...................................... 25
4.4.6
Compliance............................................................................ 25
4.5
Efficacy Analysis.................................................................... 25
4.5.1
Primary Efficacy Endpoints.................................................... 26
4.5.2
Reassessment of quality of home spirometry........................ 27
4.5.3
Secondary Efficacy Endpoints............................................... 27
4.5.4
Exploratory Efficacy Endpoints.............................................. 30
4.5.5
Analyses of Patient-Reported Outcomes............................... 31
4.5.6
Sensitivity Analyses............................................................... 33
4.5.7
Subgroup Analyses ............................................................... 34
4.5.8
Sensitivity Analyses for missing data..................................... 34
4.5.8.1
Fixed missing imputation based on Placebo 
distribution.......................................................................................... 34
4.5.8.2
Fixed missing imputation between Q1 and Q3 of 
Placebo distribution ............................................................................ 35
4.5.8.3
Tipping point analysis with shifts .......................................... 36
4.6
Safety Analyses..................................................................... 37
4.6.1
Exposure of Study Medication............................................... 38
4.6.1.1
Treatment duration............................................................... 38
4.6.1.2
Doses and Dose modifications or interruptions .................... 38
4.6.2
Adverse Events ..................................................................... 39


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
4.6.3
Deaths ................................................................................... 42
4.6.4
Laboratory Data..................................................................... 43
4.6.5
Vital Signs.............................................................................. 44
4.6.6
ECG....................................................................................... 44
4.7
Safety Follow-up analyses..................................................... 44
4.8
Missing Data.......................................................................... 45
4.9
Visit Windows ........................................................................ 47
4.10
Interim Analyses .................................................................... 48
4.11
Biomarker Analyses............................................................... 48
REFERENCES................................................................................................... 50


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
LIST OF TABLES
Table 1
Definition of Baseline and Screening Observations .................... 18
Table 2
Visit Windows.............................................................................. 47
LIST OF APPENDICES
APPENDIX 1
PROTOCOL SYNOPSIS ...................................................... 51
APPENDIX 2
  SCHEDULE OF ASSESSMENTS ....................................... 59
APPENDIX 3
PRO QUESTIONNAIRES..................................................... 67


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
LIST OF ABBREVIATIONS
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
BP 
blood pressure 
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 
CSP
clinical study protocol
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 
GCP 
Good Clinical Practice 
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 


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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
LFT 
lactate dehydrogenase 
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 mycophenolate acid 
NAC 
N-acetyl-cysteine 
NCI
National Cancer Institute 
NGS 
next-generation sequencing 
NSIP
nonspecific interstitial pneumonia 
PDGF 
platelet-derived growth factor 
PDMS
protocol deviation management system
PFS 
progression-free survival 
PFTs 
pulmonary function tests 
PRO 
patient-reported outcome 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cells 
RBR
Research Biosample Repository 
RNA 
ribonucleic acid 
RoW
Rest of the World
SAE
Serious adverse event
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SGRQ 
St. George’s Respiratory Questionnaire 
SOBQ
Shortness of Breath Questionnaire
SOC
System Organ Class 
SOP 
standard operating procedure 
SpO2
oxyhemoglobin saturation at rest
SQRT
Square root


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
SSc
systemic sclerosis 
TEAE
treatment-emergent adverse event
TGF
transforming growth factor 
TID 
three times daily 
UCSD
University of California, San Diego 
UIP
usual interstitial pneumonia 
ULN 
upper limit of normal 
US 
United States 
VAS
Visual Analogue Scale
VC 
vital capacity 
WBC 
white blood cells 
WGS
whole genome sequencing 


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
1.
BACKGROUND
As described in section 1.3 of Clinical Study Protocol (CSP) version 2.0 dated 3 March 
2017, no approved treatments are available for the 15% of patients with interstitial lung
disease (ILD) who have unclassifiable disease. 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 idiopathic 
pulmonary fibrosis (IPF) are sufficiently encouraging 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 (Esbriet®) 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. 
Mycophenolate mofetil/sodium or mycophenolic acid (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. 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.
2.
STUDY DESIGN
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 multidisciplinary 
team (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 TID) 
or placebo. The randomized patients will be stratified by concomitant MMF treatment 
(yes/no), the presence/absence of IPAF as defined by 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. 


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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 CSP) 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 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. 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 
CSP 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. 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, 
patients will be given the opportunity to receive open-label pirfenidone within a safety 
follow-up period of up to 12 months of the 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. 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.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1 and the Schedule of Assessments in Appendix 2
For additional details, please see the CSP Version 3, 28 June 2018 (and its Appendices).
2.2
OUTCOME MEASURES
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). 
The primary analysis of the primary and secondary efficacy outcome measures of this 
study is planned to be performed when the last patient reached the date of the last 
follow-up visit after end of the double-blind treatment period.


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2.2.1
Primary Efficacy Outcome Measures
The primary efficacy objective for this trial is to evaluate the effect of pirfenidone vs. 
placebo on lung function parameters on the basis of Forced Vital Capacity (FVC) 
measurements. FVC will be measured daily by the patients by use of a handheld 
spirometry.
The primary efficacy endpoint is defined as:

rate of decline in FVC in mL measured by daily handheld spirometer over the 24-
week double-blind treatment period. 
2.2.2
Secondary Efficacy Outcome Measures
The secondary efficacy objective for this trial is to evaluate the efficacy of pirfenidone 
compared with placebo from baseline until Week 24 on other functional parameters, 
outcomes, and patient reported outcomes (PROs).
The following endpoints will be analyzed:

Change in percent predicted FVC and in mL measured by spirometry during 
clinic visits

Categorical change in FVC of >5% (absolute change in percent predicted and 
relative change in mL), measured by spirometry during clinic visits

Categorical change in FVC of >10% (absolute change in percent predicted and 
relative change in mL), measured by spirometry during clinic visits

Change in percent predicted diffusing capacity of the lung for carbon monoxide
(DLco)

Change in (6-minute walk distance) 6MWD in meters

Change in University of California, San Diego Shortness of Breath Questionnaire
(UCSD-SOBQ) score

Change in score in Leicester Cough Questionnaire

Change in cough visual analog scale

Change in total and sub-scores of the St. George's Respiratory Questionnaire
(SGRQ)

Non-elective hospitalization, both respiratory and all cause

Incidence of, and time to first, investigator-reported acute exacerbations 

Progression free survival (PFS), 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

PFS, alternatively defined as the time to the first occurrence of a >10% relative 
decline in FVC (measured during a clinic visit), non-elective respiratory 
hospitalization, or death

Time to death from any cause


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
Time to death from respiratory diseases
2.2.3
Exploratory Efficacy Outcome Measures
One exploratory objective for this trial is to evaluate the role of mycophenolate 
mofetil/sodium or mycophenolic acid (MMF) treatment in ILD and to evaluate potential 
biomarkers associated with fibrosis and ILD.
The exploratory endpoints associated are:

Efficacy and safety data from subgroups of patients who did or did not receive 
MMF treatment

Biomarker data from plasma, serum, and whole blood ribonucleic acid (RNA) and 
deoxyribonucleic acid (DNA) samples
2.2.4
Safety Outcome Measures
The safety objective for this trial is to evaluate the safety of pirfenidone vs. placebo by 
investigating the following endpoints: 

Nature, frequency, severity, and timing of treatment-emergent adverse events

Dose reductions and treatment interruptions

Clinical laboratory test results

12-lead ECGs

Withdrawals from trial treatment or trial discontinuations
All analyses with regard to the safety outcome measures will be performed from the date 
of first randomized treatment intake until 28 days after the last positive dose during the 
double-blind randomized treatment period.
2.3
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 


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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, 
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.
2.4
INTERIM ANALYSIS
There are no planned interim efficacy analyses for this trial. 
3.
STUDY CONDUCT
The study conduct is described in Section 2.
3.1
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES
Patients will be randomized 1:1 to receive either pirfenidone or 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 arm, 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 CSP 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.
3.2
INDEPENDENT REVIEW FACILITY
An independent review of home spirometry date (FVC (mL)) took place after it was 
recognized that the data collected for the primary analysis of this study was jeopardized 
by incorrect readings of the device and implausible values were collected due to 
technical issues. A new data set is available now after doing the reread of the FVC data 
and will be analyzed together with the previous data set collected to investigate the 
impact of the new data on the statistical results of this endpoint.


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More details are provided in section 4.5.2.
3.3
DATA MONITORING
An independent Data Monitoring Committee (iDMC) will review safety data and advice
on study conduct at least three times during the study. Efficacy data will only be provided 
if requested by the iDMC. A first meeting is planned 6 months after start of recruitment, 
and subsequently at 12 and 18 months. Details on procedures and safety review by the 
iDMC are described within an iDMC charter.
4.
STATISTICAL METHODS
Categorical data will be summarized using frequencies and percentages (including a 
category for missing, if appropriate). Percentages will be based on the number of 
patients in each treatment arm for the analysis population, if not otherwise specified.
Continuous endpoints will be summarized using descriptive statistics (mean, standard 
deviation, minimum, 25th and 75th quartiles, median, and maximum). 
Where data will be summarized over time, the following timepoints will be presented as 
applicable: Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 
28 (if applicable) and early discontinuation visit.
Data analysis of data collected during the 12-month safety follow-up period will be 
described in section 4.7.
Where applicable other analysis methods will be specified below.
4.1
ANALYSIS POPULATIONS
4.1.1
Intent-to-treat Population
The intent-to-treat (ITT) population is defined as all randomized patients. Patients in the 
ITT population will be assigned to treatment arm as randomized (planned treatment).
The ITT population is the primary analysis population for all efficacy analyses. The time 
period for all efficacy analyses is defined from date of randomization until the treatment 
completion date of the double-blind treatment period or the date of early discontinuation 
collected on the early treatment discontinuation eCRF page in case a patient does not 
complete the planned 24 weeks of double-blind treatment.
4.1.2
Per Protocol Population
Not applicable.
4.1.3
Safety Population
The safety population is defined as all patients with at least one intake of pirfenidone or 
placebo, i.e. at least one record in the drug-log of the double-blind period with a non-
zero dose. Patients in the safety population will be assigned to treatment arm according 
to the actual treatment they received.


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4.1.4
Safety Follow-up Population
For the 12-month safety follow-up period, the safety follow-up population will be defined 
as all patients who have received at least one dose of pirfenidone after the randomized 
treatment end plus 28 days.
Safety analyses for the 12-month follow-up period will be performed from the date of the 
first pirfenidone drug intake during safety follow-up period up to the study 
completion/discontinuation visit.
4.2
TRIAL PERIODS, OBSERVATION AND ANALYSIS TIMES
Where durations are to be calculated (e.g. treatment duration), these will be derived
based on the interval in days (end date – start date + 1) and converted to months and 
years if needed, using 30.4375 and 365.25, respectively, as denominator if not otherwise 
specified.
For the investigational medicinal product (IMP) exposure, treatments administered from 
the date of first randomized pirfenidone/placebo treatment up to the date of completion 
of double-blind treatment or date of early treatment discontinuation, will be regarded. 
For drug safety, analyses will be restricted to AEs or assessments that occurred from the 
first day of randomized treatment until the date of last positive dose of randomized 
treatment plus 28 days.
Safety analyses for the 12-month follow-up period will be performed using the time 
window from the safety follow-up period start up to the study completion/discontinuation 
visit.
4.2.1
Study Days
Study days will be defined as the number of days since randomization, and is calculated 
as:

Study day = Assessment date – randomization date + 1, for assessments on or 
after the randomization date.

Study day = Assessment date – randomization date, for assessments before the 
randomization date.
The day of randomization will be study day 1.


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4.2.2
Baseline and Screening Observations
Table 1
Definition of Baseline and Screening Observations
Definition
Baseline data
Baseline is defined as the last valid assessment prior to first intake of 
randomized study drug (pirfenidone/placebo).
This may not be the same as the Day 1 (Week 1) visit as per eCRF. In 
case that Day 1 (Week 1) visit data is missing and the randomized 
treatment is given, data from the screening period will be used as 
baseline. In addition, if randomized treatment is not given then 
baseline will be defined as the last valid assessment collected either 
screening or day 1.
Generally, it is assumed that measurements referring to the Day 1 
(Week 1) visit have been performed before randomized study drug 
(pirfenidone/placebo) was given.
Adverse events occurring on the date of first randomized 
pirfenidone/placebo treatment will not be considered baseline, but 
treatment-emergent.
Screening data
Screening measurements are all the measurements performed before 
the randomization date.
4.2.3
On-treatment Assessments for Efficacy Analyses (Double-blind 
Treatment Period)
For efficacy analyses, on-treatment assessments will be the assessments performed on 
or after the randomization date until the double-blind treatment completion or 
discontinuation date.
4.2.4
On-treatment Assessments for Safety Analyses (Double-blind 
Treatment Period)
For safety analyses, on-treatment assessments will be the assessments performed on or 
after the first dose of randomized pirfenidone/placebo date until the last positive dose of 
randomized treatment plus 28 days.
4.2.5
On-treatment Assessments (12-Month Safety Follow-up Period)
Details of all data recorded during the 12-month safety follow-up period will be presented. 
This period starts on the day of the first positive dose of pirfenidone after the 28 days 
follow-up visit for patients who completed the double-blind treatment period without 
being discontinued the study. The safety follow-up period ends with the study 
completion/discontinuation visit, with a maximum duration of 12 months plus 28 days. 


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Safety follow-up analyses will be presented separately from double-blind treatment 
phase ones.
4.2.6
Cut-off points
The clinical cut-off for the primary analysis will occur when the last patient has 
completed the final safety Follow-up Visit, 28 days after the double-blind treatment 
period.
There will be a second cut-off for the final analysis when all patients have completed the 
12-month safety follow-up 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)
plus 28 days and a final safety Follow-up Visit 4 weeks after the last dose.
4.3
ANALYSIS OF TREATMENT ARM COMPARABILITY
To ensure the comparability of the treatment arm, the randomization will be stratified by 
the availability of a previous MMF treatment (yes/no) and the presence/absence of IPAF 
as defined by MDT to ensure an equal distribution of patients.
These stratification factors will be included in the analysis of the primary endpoint as a 
sensitivity analysis. Please refer to the corresponding section 4.4.5 for further details.
Outputs for concordance between the stratification factors by eCRF and by IxRS will 
also be presented.
4.4
ANALYSIS OF STUDY CONDUCT
Unless otherwise specified, all analyses described in this section will be performed on 
the ITT population, presenting data by treatment arm.
4.4.1
Patient Disposition
An overview on patient disposition, showing number and percentages of patients 
enrolled, screened, failed screening, randomized, treated, completed or early 
discontinued the double-blind treatment period, patients entering the 12-month safety 
follow-up period and their current status (ongoing, completion, discontinued) in that 
period will be provided. For patients who have early discontinued the double-blind 
treatment period or the study, frequencies of reasons for early discontinuation will be 
provided. A listing with all the patient disposition data will be also presented.
The following definitions will be used:

Patients randomized: All patients who have been randomized to receive either 
pirfenidone or placebo, i.e. have a randomization date.


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
Patients randomized and not treated: all randomized patients who have not received 
at least one dose of the randomized treatment.

Patients randomized and treated: all randomized patients who have received at least 
one dose of the randomized treatment.

Patients randomized and treated with sufficient post-baseline efficacy data: all 
randomized patients who have received at least one dose of the randomized 
treatment and have at least one post-baseline assessment of FVC (mL).

Completion of double-blind treatment period: eCRF question “Did the patient 
complete course of double-blind treatment?” is ticked “Yes” (eCRF form “Double-
blind treatment Completion/Early Discontinuation”).

Early discontinuation (non-completion) of double-blind treatment period: eCRF 
question “Did the patient complete course of double-blind treatment?” is ticked “No” 
(eCRF form “Double-blind treatment Completion/Early Discontinuation”).

Early discontinuation (non-completion) of study: eCRF question “Did the subject 
early discountinue from the study?” is ticked “Yes” (eCRF form “Study 
Completion/Early Discontinuation”) for patients who discontinued double-blind 
treatment period.

Status during the 12-month safety follow-up (entered, ongoing, completed). 
Completers are defined as those patients that have filled the study 
completion/discontinuation form. Otherwise, the patient is considered ongoing in the 
safety follow-up phase.

Completion of study: eCRF question “Did the subject complete the study?” is ticked 
“Yes” (eCRF form “Study Completion/Early Discontinuation”) 

Early discontinuation (non-completion) of study: eCRF question “Did the subject 
early discountinue from the study?” is ticked “Yes” (eCRF form “Study 
Completion/Early Discontinuation”)
An overview on patients’ enrolment will be provided based on the randomized subjects 
by country and center separately for the pirfenidone and placebo arm.
Kaplan-Meier (KM) plots for time to treatment discontinuation will be provided for all 
randomized patients and by randomized arm, based on the date subject completed or 
early discontinued from double-blind treatment period, as per eCRF. If the patient 
completed the treatment without treatment discontinuation, then it will be censored to the 
date of treatment completion. 
In addition, KM plots for time to study discontinuation will be presented for all 
randomized patients by arm, based on the study discontinuation date. If the patient 
completed the study as planned per protocol, then the patient will be censored to the 
study completion date.


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In addition, a consort diagram with some of the categories above will be presented.
4.4.2
Major Protocol Deviations
Major protocol deviations and eligibility violations will be summarized by frequency 
tables and all patients with protocol deviations will be listed. Protocol deviations will be 
collected in the protocol deviation management system (PDMS), reviewed by the 
medical monitors. All deviations provided in that dataset will be considered as major 
protocol deviations.
4.4.3
Demographic and Baseline Characteristics
Baseline and disease characteristics such as demographics, medical history and
tobacco use history will be summarized by descriptive statistics or frequency tables for 
each treatment arm.
Demographics
The following demographic characteristics will be summarized by treatment arm: 

Age (years): as entered in the eCRF at the screening visit.

Age categories: <65, and ≥ 65.

Age categories: <45, ≥45 to <65 years, ≥65 to <85 years, and ≥ 85 years.

Gender: Male/Female.

Race: White, American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, Unknown. In case that more than one race 
will be ticked, a concatenated variable, containing all races will be presented (e.g. 
Asian/White).

Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown.

Weight (kg) at baseline

Height (cm) at baseline

BMI (kg/m2) at baseline. BMI will be calculated as: weight(kg) / (height(m))2

Female reproductive status: childbearing potential without contraceptive protection, 
Childbearing potential with contraceptive protection, surgically sterilized, 
Postmenopausal, Pre-menarchal, Non childbearing potential.
Data on female reproductive status will be presented descriptively.
Demographic data will be also listed. 


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Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), version 20.1 or higher and will be summarized presenting numbers and 
frequencies by primary System Organ Class (SOC) and Preferred Term (PT) by 
treatment arm. If patients have more than one disease within a SOC or PT they will be 
counted only once for the respective SOC or PT.
A listing with past and ongoing medical history data from the washout period will be 
presented.
Tobacco use history 
The history of tobacco use will be summarized by treatment arm with the following 
characteristics: 

Tobacco use history (never, current, previous)

Nicotine exposure (pack-years), smokers only
Numbers and percentages of patients will be provided for tobacco use history. Nicotine 
exposure will be summarized descriptively.
Diagnosis and time from uILD Diagnosis
Frequencies and percentages will be presented for the uILD category collected into the 
eCRF page MDT/Diagnosis (Eligibility).
The time in months since the original uILD diagnosis will be calculated as 
Date of randomization – Date of ILD diagnosis and will be summarized descriptively by 
randomized treatment arm. The number and percentage of patients with a historical 
high-resolution computed tomography and with a historical surgical lung biopsy will also 
be presented. 
Descriptive statistics of the time from most recent historical high-resolution computed 
tomography (months) and historical surgical lung biopsy will be presented. As above, the 
date of randomization will be used as reference date for calculation of duration.
Stratification Factors
The number and percentage of patients that fall into each of the four groups based on 
the two stratification factors: Concomitant MMF treatment (yes/no), and the 
presence/absence of IPAF as defined by the MDT will be presented by treatment arm. 
Baseline Site Spirometry Test
The values recorded for the baseline assessments of the site spirometry tests were the 
following:


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
Forced vital capacity (FVC) (L and % predicted)  

Forced expiratory volume in 1 second (FEV1) (L and % predicted)

FEV1 (L) / FVC (L) ratio (1)

Carbon monoxide diffusing capacity (DLco) (% predicted)
Descriptive statistics will be provided for these parameters separately for treatment arm. 
Historical Spirometry Test
The number and percentage of patients who performed spirometry test (FVC, DLco, 
FEV1, and FEV1/FVC ratio) in the past will be provided. The most recent assessment
before the Screening visit will be collected:

Hemoglobin corrected DLco (mmol/min/kPa and %)

DLco/Va (KCO) (mL/min/mmHg/L and % predicted)

FVC (L and % predicted)  

FEV1 (L and % predicted)

FEV1(L)/FVC(L) ratio (1)
These historical spirometry test parameters will be summarized using descriptive 
statistics by treatment arm. Both, absolute and percent predicted values will be 
presented. Frequencies and percentages will be presented for the high-resolution 
computed tomography and the surgical lung biopsy.
Baseline 6-minute walk distance (6MWD)
The 6MWD is used to evaluate the functional capacity of patients with lung disease. The 
6MWD measures the distance a patient is able to walk quickly on a flat, hard surface in a 
period of 6 minutes.
The number and percentage of patients that 

Performed the 6-minute walking test (yes/no), 

Rested for at least 10 minutes (yes/no), 

Stopped the test before 6 minutes (yes/no), 

Required O2 (yes/no)
at the baseline visit will be summarized by randomized treatment group.  


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The values of the parameters recorded for the 6MWD test are:

Vital signs (Heart rate (beats/min), systolic blood pressure (mmHg), diastolic 
pressure (mmHg)) (before the test, at the end of the test)

Distance walked (m), 

Oxyhemoglobin saturation (SPO2) (before the test (at rest), at the end of the test), 

Oxygen (O2) requirements (L) for patients who received oxygen (at the end of the 
test)
will be summarized descriptively by treatment arm. 
4.4.4
Previous and Concomitant Medication
Previous and concomitant medications will be presented based on the safety population.
Post medications administrated during the safety follow-up period will be presented 
based on the safety follow-up population.
Previous and concomitant medications are non-study medications. Concomitant therapy 
includes any medication used by a patient from the washout period until 28 days after 
the last dose of trial treatment. The previous and concomitant medication will be coded 
using the Genentech (GNE) drug dictionary. This is a proprietary Roche Dictionary which 
is used to code concomitant medications in the Trial Management System (TMS) coding 
tool. The Standardized Medication Name (CMDECOD), which is the medication generic 
or combination generic as defined by the Drug Thesaurus (proprietary Genentech/Roche 
dictionary), and the Medication Class (CMCLAS), which is the primary medication class 
as defined by the Drug Thersaurus, will be used for the analyses.
Therapies will be classified as previous or concomitant as follows:
Previous: If the medication start date is prior to start of double-blind treatment,
Concomitant: If medication is taken at any time between the start of double-blind 
treatment and 28 days after last positive dose of randomized treatment. 
Post (safety follow-up): If the medication is taken more than 28 days after the last 
positive dose of randomized treatment.
The number and frequency of previous and concomitant medications taken by patients 
in the two treatment arms will be presented by Medication Class and Standardized 
Medication Name. If patients receive more than one drug within a Medication Class or 
Standardized Medication Name they will be counted only once for the respective 
Medication Class or Standardized Medication Name. 




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The primary analysis of the primary efficacy endpoint of this study is planned to be 
performed when the last patient reached the date of the last follow-up visit after end of 
the double-blind treatment period (clinical cut-off date).
4.5.1
Primary Efficacy Endpoints
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 spirometer over the 24-week double-blind treatment period. 
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 for the primary endpoint. 
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 estimated FVC decline for individual patients will 
be obtained by applying a linear regression model to all data points collected during the 
24-week double-blind treatment period:
where
= the FVC measurements (mL) of patient i on day t, with i=1,…,N and t=1,…,T, 
being N the total number of patients randomized and T the total number of days with 
assessment.
= study day t of patient i
= intercept and slope of the individual linear regression of patient i
The time-adjusted decline for patient i is then obtained by estimating the patients’ 
individual difference in predicted values between baseline and week 24 from the linear 
regression.
In a further step, the time-adjusted mean FVC decline is estimated by calculating the 
mean over all individual time-adjusted declines of all patients by treatment arm.
A summary table displaying the mean FVC decline together with two-sided 95% 
confidence intervals based on percentiles of the t-distribution will be provided by 
treatment arm. The mean FVC decline in each treatment arm will be compared using a 
student’s t-test with a two-sided significance level α=0.05. Additionally, a two sample 
Wilcoxon test will be used for treatment comparison. Results of this test are of 
descriptive nature only.   
The same analyses will be done by restricting the FVC decline values:
-
Including patients with at least 3 site spirometry measurements


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-
excluding patients with a predicted FVC decline below -1000 mL
-
or above 1000 mL
-
excluding values with a difference +/-50% from corresponding baseline site 
spirometry
Mean FVC declines and results from Student’ s t-test by subgroups (for definition see 
4.5.6) will be displayed in a forest plot.
As a sensitivity analysis to the primary analysis, the time-adjusted mean FVC decline will 
be estimated by a repeated measures mixed model with patient effects fitted as random 
and day of measurement and treatment fitted as fixed effects. Please refer to Section 
4.5.6 for further details.
A detailed description of SAS code to be used for the repeated measures mixed model 
is provided together with the respective table shell.
4.5.2
Reassessment of quality of home spirometry
Due to the nature of the home FVC measurements resulting in a highly skewed 
distribution with high unexpected variability and a number of measurements resulting in 
physiologically implausible values the home spirometry data was reassessed by an 
independent and blinded group of experts.
The reassessment of home spirometry data resulted in a flag with 2 categories:
130 = acceptable, 110 = not acceptable.
A comparison between the quality assessments before and after update will be
presented by a concordance analysis. In this analysis old assessments with “BOR” are 
tabulated as non-acceptable quality.
The compliance of home spirometry data will also be assessed by analyzing the number 
of gaps in daily measurements.
4.5.3
Secondary Efficacy Endpoints
For secondary endpoints, all data from baseline 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 date of withdrawal
from treatment. 
The secondary efficacy objective for this trial is to evaluate the efficacy of pirfenidone 
compared with placebo on the basis of the following endpoints: 

Descriptive statistics for values and changes from baseline over time of all 
spirometry test parameters will be presented.


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
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. A Wilcoxon tests was not planned for this endpoint.

Mean FVC declines and results from Student’ s t-test by subgroups (for definition 
see 4.5.6) will be displayed in a forest plot.

In addition the decline of FVC in mL measured by spirometry during site (clinic) 
visits will be compared between the treatment arms using a repeated measures 
mixed effects model. Please refer to Section 4.5.6 for further details.

The absolute change in percent predicted FVC measured by spirometry during 
site visits at week 24 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 (mL) measured during site (clinic) visits of >5% and 
>10% will be compared between the treatment arms using a Cochran-Mantel-
Haenszel test stratified by concomitant MMF medication use (Yes/No), and the 
presence/absence of IPAF as defined by the MDT

Absolute change from baseline to week 24 in percent predicted DLco will be 
compared between the treatment arms using a rank ANCOVA. Change from 
baseline to week 24 will be used as an outcome variable and standardized rank 
baseline value will be used as a covariate
o A summary table presenting the values of DLco (%) and its change from 
baseline will be presented over time and by treatment arm.

The absolute 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
o A summary table presenting the 6MWD parameters and their change from 
baseline will be presented over time and by treatment arm.

The absolute change in UCSD-SOBQ total score will be analyzed using a rank 
ANCOVA model. The UCSD-SOBQ total 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 Please see Section 4.5.5 for further details.

The absolute change in Leicester Cough Questionnaire total score will be 
analyzed using a rank ANCOVA model. The Leicester Cough Questionnaire total 
score recorded at 24 weeks will be used as the outcome variable and 
standardized rank baseline Leicester Cough Questionnaire total score will be 
used as a covariate. Please see Section 4.5.5 for further details.


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
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. Please see 
Section 4.5.5 for further details.

The change in total 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. Please see Section 
4.5.5 for further details.

The time from randomization to the first occurrence of all-cause non-elective 
hospitalization and respiratory non-elective hospitalization will be analyzed using 
Kaplan-Meier (KM) techniques:
o KM plots of time to first occurrence of the different events will be provided 
by treatment arm. Frequencies and percentages of patients with events 
and patients censored will be provided. Descriptive statistics of KM 
estimates of the time to first occurrence (weeks) will be presented.
o Log-rank tests based on the time to the first event will be used to compare 
the two treatment arms.
o Hazard ratios and corresponding 95% CI will be calculated by applying 
Cox-proportional hazard models in which the four groups from the two 
randomization stratification factors are included in the model.

The incidence of investigator reported acute exacerbations in the two treatment 
arms will be compared with Fisher’s exact test.
o Incidence of, and time to first, investigator-reported acute exacerbations 

Progression free survival (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:
o KM plots of time to first occurrence of the combined primary efficacy 
endpoint will be provided by treatment arm. 
o Frequencies and percentages of patients with events and patients 
censored will be provided. Descriptive statistics of KM estimates of PFS 
(weeks) will be presented.
o The PFS of two randomized treatment arms will be compared with a log-
rank test. 
o Hazard ratios and corresponding 95% CI will be calculated by applying 
Cox-proportional hazard models.

An alternative definition of PFS (also in weeks), 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 as 


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defined for the point above; 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
assessed by the SOC “Respiratory, thoracic and mediastinal disorders” (in weeks) 
will be analyzed using Kaplan-Meier techniques as defined above; 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.
4.5.4
Exploratory Efficacy Endpoints
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.
For the MMF objective, primary and selected secondary endpoints will be investigated 
by means of a subgroup analyses that stratifies patients according to whether they 
received MMF treatment. In addition, the overall safety summary will be presented by 
this subgroup. The selected secondary endpoints are:

Deaths from any cause and respiratory disease-related

Hospitalizations from any cause and respiratory disease-related
The analysis of these exploratory efficacy endpoints by subgroup are defined under 
section Section 4.5.6.
The mean FVC decline in each treatment arm will be calculated as in the primary 
analysis for the subgroups of patients that received MMF treatment and compared using 
a student’s t-test. 
Other exploratory efficacy endpoints are discussed in the sensitivity and subgroup 
sections (see Section 4.5.6 and Section 4.5.7, respectively). 
Moreover, additional categorical analyses for the percent predicted DLco and 6MWD will 
be presented as exploratory:

Categorical change of >15% absolute decline from baseline to week 24 in 
percent predicted DLco will be compared between the treatment arms using a 
logistic regression.

Categorical change of >50% absolute decline from baseline to week 24 in 6MWD
(m) will be compared between the treatment arms using a logistic regression.


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For the biomarker objective, assessments of the exploratory biomarkers and their 
relationship with drug responses will be described in a separate analysis plan.
A correlation analysis of individual patient slopes estimated by linear regression models 
between those obtained for home spirometry and site spirometry were performed to 
assess the concordance of the data obtained by the two methods.
4.5.5
Analyses of 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.
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. 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, 
unless otherwise specified.
St. George´s Respiratory Questionnaire (SGRQ)
The St. George’s Respiratory Questionnaire (SGRQ) is an index designed to measure 
and quantifies health-related health status in patients with chronic airflow limitations. The 
SGRQ is a 50-item questionnaire, addressing the frequency of respiratory symptoms 
(items 1 – 8), the patient’s current state (sections 9 – 16). From the 50 items a total 
score, as well as three component scores (Symptoms, Activities, Impacts) will be derived. 
The total score ranges from 0, presenting the best possible health status to 100, 
presenting the worst possible health status.
The change in SGRQ total score will be of primary interest when assessing health-
related quality of life (HRQoL).
The analysis of PROs assessed by SGRQ total score and by SGRQ component scores 
for symptoms, activity, and impacts will be analyzed as follows:

The absolute score values and changes from baseline for the total and each sub-
score will be presented descriptively over time by treatment arm.

Changes from baseline to week 24 or early discontinuation visit will be compared 
between the treatment arms using a rank ANCOVA with change from baseline as 
outcome variable and standardized rank baseline value as covariate. This analysis 
will be done only for the total score.
The SGRQ and the details for calculating the score can be found in Appendix 3.


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The University of California, San Diego-Shortness of Breath Questionnaire 
(UCSD-SOBQ) 
The University of California, San Diego-Shortness of Breath Questionnaire (UCSD-
SOBQ) is a symptom-specific, 24-item, patient-self-administered questionnaire that 
assesses shortness of breath while doing a variety of activities of daily living. Each of the 
24 activities are rated on how dyspnea affects the activity on a 6-point scale: 0 = None at 
all to 5 = Maximal or unable to do because of breathlessness. The scores will be 
summarized to a total score, ranging from 0 – 120.
The total score of the UCSD SOBQ will be summarized as follows:

The absolute total scores and changes from baseline will be presented descriptively 
over time by treatment arm.

Changes from baseline to week 24 or early discontinuation visit will be compared 
between the treatment arms using a rank ANCOVA with change from baseline as 
outcome variable and standardized rank baseline value as covariate. 
Additional details on the UCSD SOBQ can be found in Appendix 3
The Leicester Cough Questionnaire
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.
The total score and the physical, psychological and social domain scores of the 
Leicester Cough Questionnaire will be analyzed as follows:

The scores and changes from baseline will be presented descriptively over time by 
treatment arm.

Changes from baseline to week 24 or early discontinuation visit will be compared 
between the treatment arms using a rank ANCOVA with change from baseline as 
outcome variable and standardized rank baseline value as covariate. This analysis 
will be done only for the total score.
Details on calculating the domain scores can be found in Appendix 3
The Cough VAS
This visual analogue scale is designed to help us learn about the severity of your cough. 
This scale is 100mm (10cm) in length. 


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The cough VAS score will be summarized descriptively by visit and treatment arm. The 
change in cough VAS will be analyzed using a rank ANCOVA model. The change in 
VAS score for cough recorded at 24 weeks will be used as the outcome variable and the 
standardized rank baseline result will be used as a covariate. Please refer to Appendix 3
for further details.
4.5.6
Sensitivity Analyses
As a sensitivity analysis to the primary analysis, the time-adjusted mean FVC decline will 
be estimated a random slope and intercept linear regression model, with an absolute 
change in FVC (mL) as the outcome variable assuming linear decline in lung function 
over time. The model includes random coefficients for slope and intercept and fixed 
effect terms for treatment, and covariates to be selected as described below. The 
statistical model is defined as follows:
Yijk = (α + ai) + (γ + βsTk + gi) tij + βg Cov1i + βa Cov2i + εij
o
Yijk is the value measured for ith patient at time j in treatment group k 
o
tij is the time of measurements for ith patient at study day j 
o
Tk =0 if patient in Placebo group and Tk=1 is patient in Pirfenidone
o
βs is the effect of Pirfenidone on the slope
o
α and γ are elements of the intercept and slope respectively ai and gi are random 
specific components of the intercept and slope for the ith patient 
o
βg , βa  are patient specific demographics’ coefficients (strata)
o
Cov1i, Cov2i are covariates to be included for the ith patient
o
εij is the random error for ith patient at time j
o
ai and gi are assumed to be normally distributed with mean 0 and arbitrary 
covariance matrix
o
εij are assumed to be independent and normally distributed with mean 0 and 
variance σε2
o
Within patient errors follow a random coefficient regression model with random 
effect for intercept and slope
o
An unstructured variance-covariance structure will be used to model the within 
patient measurements
o
The variance-covariance matrix, modeled to estimate the inter-individual 
variability is considered to have a Variance-Components structure
The model will be applied by adding the stratification factors MMF treatment and IPAF 
as covariates to the home spirometry data, once taking into account the old and once 
the new quality flag.
The same model with and without adding the stratification factors as covariates will be 
applied to the key secondary endpoint of site-measured FVC (mL).


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4.5.7
Subgroup Analyses
Subgroup analyses will be conducted for the exploratory endpoint, as described in 
Section 4.5.4. The following subgroups will be based on:

The four groups resulting from combinations of the two stratification factors:
o Concomitant MMF treatment (yes/no)
o Presence/absence of IPAF as defined by the MDT

Gender: Male, Female

Age (years): <65 years, ≥ 65 years

Percent predicted FVC at Baseline: <65%, ≥65% to < 80%, ≥80%

Percent predicted DLco at Baseline: <35%, ≥35%

Body weight: <60 kg, ≥60 kg

Previous Biopsy (yes/no)
4.5.8
Sensitivity Analyses for missing data
The robustness of the primary method of estimation described above will be explored by 
a series of sensitivity estimators based on varying assumptions underlying the multiple 
imputation strategy. 
As the primary analysis for this study was performed in March 2019 the number of 
patients with missing FVC values at week 24 are known. No data was collected after 
treatment discontinuation.
3 different approaches will be used to evaluate the robustness of the analysis of the 
secondary endpoint to the missing at random (MAR) assumption.
Due to the low number, deaths and other intercurrent events have not been considered 
in the multiple imputation analysis.
4.5.8.1
Fixed missing imputation based on Placebo distribution
To evaluate the robustness of the analysis of the second endpoint to the missing at 
random (MAR) assumption missing data of both treatment groups will be imputed by 
descriptive statistics derived from the distribution of the placebo group. For each visit the 
following descriptive statistics of FVC (mL) will be calculated from the placebo group 
only: lower quartile, median, upper quartile.


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For each of the 2 treatment groups 3 datasets with imputed missing values will be 
created:

Missing values imputed by median of placebo group for the respective visit 

Missing values imputed by lower quartile of placebo group for the respective visit 

Missing values imputed by upper quartile of placebo group for the respective visit 
Then, within each of the 9 possible combinations of datasets two analyses will be 
performed:
The mean FVC decline in the treatment arms will be compared using a student’s t-test. 
The mean FVC decline for each treatment arm will be calculated using the estimated 
FVC decline for each individual patient, which will be obtained by applying a linear 
regression model to the data over time of the respective patient.
The decline in FVC (mL) at week 24 will be estimated from a random slope and intercept 
model. This model will include fixed effects for treatment, the stratifying variables 
concomitant use of MMF and presence/absence of IPAF and treatment-by time-
interaction. Random effects will be included for both time and intercept. 
The difference between treatment groups will be calculated together with the 
corresponding p-value.
A table will present the results from the two analyses: estimates for the placebo group, 
pirfenidone group and the comparison pirfenidone versus placebo together with the 
respective p-value for each of the 9 combinations of imputed values. 
4.5.8.2
Fixed missing imputation between Q1 and Q3 of Placebo 
distribution
In another approach to evaluate the robustness of the analysis of the second endpoint to 
the missing at random (MAR) assumption a tipping point sensitivity analysis will be 
performed, where missing data of both treatment groups will be imputed by values 
derived from the range between lower and upper quartile (Q1 – Q3) in the Placebo 
group at each visit. The aim of the tipping point approach is to assess how severe 
departures from MAR could be in order to reverse conclusions from the analysis of 
secondary endpoint under different assumptions for the decline after withdrawal of the 
randomized treatment.
100 datasets with imputed values will be created for each treatment group. For the first 
dataset missing values in the respective treatment group will be imputed by the lower 
quartile (Q1) of placebo group within each visit. In the second dataset, the missing 
values will be imputed by Q1 plus the amount of 0.01 x (Q3 – Q1). The value added to 
Q1 will be increased within each subsequent dataset by another amount of 0.01 x (Q3-
Q1), so that in the last of the 100 dataset the amount of Q3 from the placebo group will 
be imputed for missing values. 


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Then, for each of the 10000 combinations of datasets the decline in FVC (mL) at week 
24 will be estimated from a random slope model This model will include fixed effects for  
the stratifying variables concomitant use of MMF and presence/absence of IPAF and 
treatment-by time-interaction. Random effects will be included for both time and intercept. 
The difference between treatment groups will be calculated together with the respective 
p-value.
A heat map displaying positive and negative outcome based on the p-values for the 
comparison pirfenidone versus placebo with green and red colors (green: < 0.05, red: > 
0.05) will be provided to illustrate the outcome of this analysis graphically. The 
robustness of the results will be discussed based on the magnitude of deviations from 
MAR required to change the results. 
4.5.8.3
Tipping point analysis with shifts 
An additional approach is to evaluate the robustness of the analysis of the secondary 
endpoint to the missing at random (MAR) assumption by performing a tipping point 
sensitivity analysis using the Multiple Delta Adjustment Method. 
As a first step non-monotone missing data will be imputed 100 times using MCMC 
(Markov Chain Monte Carlo) to generate 100 data sets of longitudinal spirometry data 
(FVC [mL]) with monotone missingness pattern (PROC MI). Such a missingness pattern 
is the pre-requisite for subsequently applying sequential imputation and means that once 
a patient has a missing FVC value at a particular time point, FVC values at all 
subsequent time points also have missing values. The seed in PROC MI number will be 
set to 1234. 
Once the monotone missing pattern has been created, the tipping point analysis for the 
longitudinal FVC data will be based on the Multiple Delta Adjustment Method. Data in 
each of the 100 generated datasets with the monotone missingness pattern will be 
imputed once by using sequential regression. A delta adjustment will be added to each 
imputed value. The value of each delta adjustment will be given by shift parameters S1
and S2 for the 2 treatments. 
For patients with more than one monotone missing visit, multiple adjustments must be 
applied and since the imputation method is sequential, the effect of the adjustments is 
cumulative. S1 and S2 therefore represent the slope of a linear adjustment over time. 
This step will be repeated for a variety of combinations of S1 and S2. 
For each combination of shift values S1 and S2 the 100 complete data sets will be 
analyzed using the statistical model as described above. The estimate of treatment 
difference at week 24 will be derived. Rubin’s rules (16) will be used to combine the 
results from the analyses for each pair of S1 and S2 (PROC MIIANALYZE). Point 
estimates for the comparison pirfenidone versus placebo and respective p-values will be 
reported for selected combinations of S1 and S2 in a cross-table. 
The following combinations of S1 and S2 will be applied:


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• S1 (Pirfenidone): -130, -125,-120,-115,-110,-105,-100,-95,-90,-85,-80,-75,-70,-65,-60,-
55,-50,-45,-40,-35,-30,-25,-20,-15,-10,-5,0,  5, 10
• S2 (Placebo): -40,-35,-30,-25,-20,-15,-10,-5,0,  5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 
60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120.
A heat map displaying positive and negative outcome based on the p-values for the 
comparison pirfenidone versus placebo with green and red colors (green: < 0.05, red: > 
0.05) will be provided to illustrate the outcome of this analysis graphically. The 
robustness of the results will be discussed based on the magnitude of deviations from 
MAR required to change the results (Rubin, 1987). Pharmacokinetic and 
Pharmacodynamic Analyses
No pharmacokinetic or pharmacodynamic analyses are planned for this study.
4.6
SAFETY ANALYSES
All safety analyses of data from the double-blind treatment period will be based on the 
safety population, i.e., the safety population will include all randomized patients who 
received at least one dose of trial treatment, with patients grouped according to 
treatment received. Safety data from the follow-up period will be summarized based on 
the safety follow-up population.
The safety objective for this trial is to evaluate the safety of pirfenidone vs. placebo.
No formal statistical testing will be performed for safety parameters. 
Data collected during the 12-month safety follow-up will be analyzed separately (see 
section 4.7).
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 4.03, 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) version 20.1 or higher 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 modifications and treatment interruptions.
Adverse events leading to treatment interruption or dose modification will also be 
summarized. 
Laboratory parameters including hematology and the chemistry panel will be presented 
in shift tables of NCI-CTCAE version 4.03 grade at baseline vs. worst grade during 
treatment period. The laboratory parameters will be presented according to means, 
standard deviation, minimum, and maximum. Selected laboratory parameters will be 
also graphically presented over time. Liver abnormalities for the parameters total 
bilirubin, alkaline phosphatase, ALAT (SGPT) and ASAT (SGOT)) will be also presented.
The results from the 12-lead ECGs will be summarized and presented. 
4.6.1
Exposure of Study Medication
All analyses described in this section refer to the data collected in the drug-log for the 
double-blind randomized treatment period. Unknown doses will be excluded from the 
exposure analyses. 
4.6.1.1 Treatment duration
Summaries of dosing, treatment duration, dose interruptions or reductions during the 
randomized double-blind treatment period will be provided for each treatment arm
separately.
The overall treatment duration (weeks), including and excluding dose interruptions, will 
be summarized descriptively by treatment arm. The overall treatment duration including 
dose interruptions will be defined as follows:
[Date of last positive dose of randomized treatment received (pirfenidone/placebo) – date of 
first intake of randomized treatment) + 1)] / 7.
The overall treatment duration excluding dose interruptions will be derived from the 
treatment administration panels using the time windows described above, considering 
only days on treatment. i.e. positive dose.
Details on treatment administration, reductions or interruptions will be listed.
4.6.1.2 Doses and Dose modifications or interruptions
The total dose (mg), the average daily dose (mg/d) and the last dose administered (mg/d)
will be presented descriptively for each of the study treatments. 
The average daily dose will be calculated by summing up the number of capsules taken, 
divided by the overall treatment duration including dose interruptions as defined above. 
Numbers and proportions of patients with at least one dose modification, or drug 
interruption, will be presented for each treatment arm separately. Numbers and 
proportions of patients with 1, 2, 3 or more dose modifications, or treatment interruptions, 
will be given.


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The total number of dose modifications, reductions or treatment interruptions, will be 
presented together with numbers and frequencies of reasons for dose modification,
reduction or treatment interruption.
Dose modifications, reductions or treatment interruptions will be presented as given in 
the drug logs dose strength and number of capsules taken.
In addition, dose intensity will be analyzed descriptively by treatment arm over time. For 
calculation of dose intensities, the time from first administration of randomized treatment
to the end date of randomized treatment will be considered. The following formula will be 
used for calculation:
Dose intensity (DI) = (total dose received / total dose planned)*100.
4.6.2
Adverse Events
Verbatim descriptions of adverse events (AEs) will be mapped to a preferred term (PT) 
and system organ class (SOC) using the Medical Dictionary for Regulatory Agencies
(MedDRA®). MedDRA version 20.1 or above and related SMQ lists will be used for 
coding.
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03. For AEs of varying severity, the 
most severe grade as documented on the eCRF will be used in the summaries. An AE 
will be considered severe if the most extreme grade will be larger or equal to 3.
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. All 
adverse events will be reported until 28 days after the last dose of study drug. After this 
period, the Investigator should report any SAEs that are believed to be related to prior 
study drug treatment.
For safety analysis of the double-blind treatment period treatment-emergent adverse 
events (TEAEs) will be defined as:

AEs that started or worsened on or after first intake of randomized treatment until last 
positive dose of randomized treatment + 28 days
Adverse events that are reported after informed consent but before the first intake of 
randomized treatment will be considered as non-treatment-emergent AEs. These might 
include AEs that occur during the screening period.
Post-treatment AEs are not expected to occur, but will be defined as AEs that are 
reported more than 28 days after the last dose of randomized treatment for patients who
do not enter the 12-month safety follow-up period. Those AEs will be listed.


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The analysis of AEs within the framework of the primary study analysis will focus on 
treatment-emergent AEs (TEAE). 
An overview of patient safety profile will present the number and proportion of patients in 
each treatment arm experiencing:

Any and any related treatment-emergent adverse events (TEAE)

Any and any related serious treatment-emergent adverse events (serious TEAE)

Any and any related severe treatment-emergent adverse events (TEAEs ≥ Grade 3)

Any and any related TEAE of special interest (AESI). 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: [ALT or AST >3 x ULN + total bilirubin >2 x ULN] 

Any and any related hepatic side effects: elevations in ALT and AST >3 × ULN at 
the same timepoint in the study.

Any and any related gastrointestinal (GI) disorder (MedDRA SOC: GI Disorders)

Any and any related photosensitivity (MedDRA Preferred terms Nodular rash, 
Photodermatosis, Photosensitivity reaction, Pruritus, Pruritus generalized). Potential 
updates in those terms will be needed in case the MedDRA version changes.

Any and any related rash (MedDRA Preferred terms Rash, Rash erythematous, 
Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, 
Solar dermatitis, Solar urticarial, , Sunburn, Erythema, Dry skin). Potential updates in 
those terms will be needed in case the MedDRA version changes.

Angioedema (MedDRA preferred term Angioedema).

Dizziness (MedDRA preferred term Dizziness).

Fatigue (MedDRA preferred term Fatigue).

Weight loss (MedDRA preferred term Weight loss).

Increase 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. 

Any and any related TEAE leading to death

Any and any related TEAE leading to treatment discontinuation


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
Any grade 3-4 laboratory liver test results
o ASAT (SGOT) results
o ALAT (SGPT) results
o alkaline phosphatase results
o total bilirubin results 
The incidence of TEAEs, related TEAEs, non-serious TEAEs, serious TEAEs, related 
serious TEAEs, grade 3-5 TEAEs and TEAEs leading to treatment discontinuation, dose 
modification or death will be summarized by treatment arm, by system organ class (SOC)
and preferred term (PT) on the basis of the safety population. Frequencies and 
percentages of patients experiencing (at least) one event in the respective category will 
be presented by decreasing frequencies. If patients have more than one AE within a 
SOC or PT they will be counted only once for the respective SOC or PT. Additionally the 
total numbers of TEAEs will be provided for each SOC and overall.
Similar summary presentations will be provided for the incidence of TEAEs leading to 
dose reduction and drug interruption and TEAEs leading to hospitalization.
Non serious Treatment-emergent Adverse Events with >5% frequency will be also 
presented by SOC and PT. In addition, Serious Treatment-emergent Adverse Events, 
Fatal serious TEAEs and serious TEAEs related to pirfenidone or placebo will be 
presented in the same table by SOC and PT.
A summary table presenting the numbers and frequency of patients with TEAEs by most
extreme CTCAE Grade (Grade 1, Grade 2, Grade 3, Grade 4 and Grade 5) will be 
provided for each SOC and PT by treatment arm. In case the most extreme intensity is 
missing, it will be replaced by the initial intensity. If both most extreme and initial intensity 
are missing, the AE will be included in the Grade ≥3 category and a category for 
“missing” will be added. 
Further, Kaplan-Meier curves for time to onset of first adverse event of the most relevant 
related TEAEs will be provided by treatment arm when the number of events are enough 
to do the analyses. These will include the following PTs or groups of AEs: Nausea, 
Diarrhoea, Weight decreased, Fatigue, Decreased appetite, and photosensitivity, or rash. 
In addition, the analysis will be done for the SOC GI.
All adverse event data will be listed by patient number and study day of onset including a 
flag variable for identifying the period of the event (double-blind treatment period or 
safety follow-up period). If the AE does not belong to any of the periods, the period flag 
will be missing.
In addition, for regulatory purpose two additional tables will be provided:


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Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Frequency of adverse drug reactions occurring in patients treated with Esbriet 
(Pirfenidone) in clinical trials
TEAEs from day 1 of dosing until 168 days for MA39189 will be compared with the data 
from the phase III studies CAPACITY1 and 2 and ASCEND (restricted to first 168 days 
after first dose). The frequency of patients with related AEs (ADR) will be presented by 
System Organ Class and will be classified by their occurrences into
-
Very common ((>=10% incidence rate)
-
common ((>= 1% to <10% incidence rate)
-
uncommon (>= 0.1% to <1% incidence rate)
-
rare (>= 0.01% to <0.1% incidence rate)
Patients who withdrew from treatment during first 168 days of dosing will be censored at 
day of withdrawal for this analysis. 
Rates of Adverse events per 100 patient years 
TEAEs and SAEs from day 1 of dosing until 168 days for MA39189 will be compared 
with the data from the registrational phase III studies in IPF patients CAPACITY1 and 2 
and ASCEND (restricted to first 168 days after first dose). The following parameters will 
be displayed in this analysis:
-
duration of study in patient years (PY), calculated as sum of all patient’s 
observation times).
-
number of patients with at least one event, 
-
number of all events, defined as all AEs from all patients with onset date 
during observation time period
-
rate of events per 100 PYs observation time, calculated as [number of 
events/duration] * 100
-
95% CI for this rate with 
oLower limit = 100*[number of events – z1-α/2 * SQRT(number of 
events)]/duration
oUpper limit = 100*[number of events + z1-α/2 * SQRT(number of 
events)]/duration
where z1-α/2 is the 1-α/2 quantile of the standard normal distribution.
Patients who withdrew from treatment during first 168 days of dosing will be 
censored at day of withdrawal for this analysis. The analysis will be repeated for all 
TEAEs/SAEs from first day of dosing until 28 days of last dose, irrespective of the 
different study durations for MA39189 versus the phase III studies.
4.6.3
Deaths
Numbers and frequencies of deaths during double-blind period occurring until 28 days 
after the last dose of double-blind treatment will be presented by treatment arm. Deaths 
occurring more than 28 days after last dose for patients who did not enter the safety-
follow-up period will also be presented separately.


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All information associated with deaths collected in eCRF panel on study discontinuation 
will be listed. A flag variable will be included in the listing specifying the study period 
when the death occurred.
4.6.4
Laboratory Data
All of the laboratory tests will be conducted by the trial site’s local laboratory.
All parameters will be graded according to NCI CTCAE (CTEP 2010), version 4.03, if 
applicable. Laboratory parameters that cannot be graded according to the corresponding 
NCI CTCAE version 4.03 will be assessed with respect to normal range (low, normal, 
high).
Laboratory parameters including hematology and the chemistry panel will be presented 
in shift tables of NCI-CTCAE version 4.03 grade at baseline versus worst grade during 
randomized double-blind treatment period. The laboratory parameters will be presented 
according to means, standard deviation, minimum, and maximum. Selected laboratory 
parameters will be also graphically presented over time. 
The following laboratory 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).
Clinical laboratory values will be presented separately for CTCAE-gradable and non-
CTCAE gradable parameters by laboratory panel (hematology, serum chemistry). For 
laboratory analyses, visits will be assigned to visit windows as described in Section 4.10.
This will also be valid for possible unscheduled visits. In case that multiple evaluable 
assessments occur within the same visit, the nearest to midpoints value will be used for 
analyses.
The following summaries will be prepared:
For each laboratory parameter, descriptive statistics of laboratory values at each 
scheduled visit (derived as described above), and absolute changes from baseline to 
post-baseline will be presented by treatment arm.
Shift tables presenting categorical changes in CTCAE grade from baseline to worst 
grade recorded during the double-blind period, in the indicated direction, will be provided 
for CTCAE-gradable parameters by treatment arm. If no CTCAE grade is available for a 
specific laboratory variable, shift tables will present worst changes with respect to normal 
range category (low, normal, high).


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Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Liver abnormalities (total bilirubin, alkaline phosphatase, ALAT (SGPT), ASAT (SGOT)) 
of Grade 3 and 4 will be presented showing numbers and percentages of patients for 
each parameter separately. Line graphs of liver parameters will be provided.
4.6.5
Vital Signs
Vital signs will include measurements of respiratory rate (breaths/min), pulse rate 
(beats/min), and systolic and diastolic blood pressures (mmHg) while the patient is in a 
seated position, temperature (C) and weight (kg). Vital signs will be assigned to visit 
windows as per Section 4.10. Descriptive statistics will be used to summarize vital signs
data at baseline and at each scheduled post-baseline visit, and for the absolute change 
from baseline to each scheduled post-baseline visit by treatment arm during double-blind 
period.
4.6.6
ECG
Single ECG recordings will be obtained at specified time points, as outlined in the 
Schedule of Assessments (see Appendix 2), and may be obtained at unscheduled time 
points as indicated.
The following should be recorded in the appropriate eCRF: heart rate (beats/min), RR 
interval (msec), QRS interval (msec), PR duration (msec), uncorrected QT interval
(msec), 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.
QTcF values of the safety population will be assigned to the following intervals: < 500 ms, 
500–550 ms, and > 550 ms. Numbers and percentages of patients with their maximum 
QTcF interval category will be summarized by treatment arm over time. Absolute 
changes from the Baseline to each post-baseline visit in QTcF values will be categorized 
to < 31 ms, 31–60 ms, and > 60 ms. Numbers and percentages of patients in each 
category will be presented by treatment arm for each post-baseline visit or treatment 
discontinuation. Planned visits will be used for presentations.
Descriptive statistics for heart rate, RR interval, QRS interval, PR duration, uncorrected 
QT interval, and the QTcF will be presented for each visit by treatment arm.
A listing containing ECG data will be presented.
4.7
SAFETY FOLLOW-UP ANALYSES
Data collected during the safety- follow-up period will be analyzed in the following way.
Adverse events during the 12-month safety follow-up period for pirfenidone treatment will 
be defined as:

AEs that started or worsened on or after the date of safety follow-up period start until 
the end of the safety follow-up.


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Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
The safety follow-up population will be used for these analyses. 
Summary tables for the incidence of AEs, related AEs, serious AEs, related serious AEs, 
severe AEs and severe related AEs will be summarized by system organ class (SOC) 
and preferred term (PT). Frequencies and percentages of patients experiencing (at least) 
one event in the respective category will be presented by decreasing frequencies. If 
patients have more than one AE within a SOC or PT they will be counted only once for 
the respective SOC or PT. Additionally, the total numbers of AEs will be provided for 
each SOC and overall. As with the end of the double-blind treatment period, an overview 
of safety will also be presented.
Pirfenidone exposure during safety-follow-up will be analyzed in a similar fashion as 
described in Section 4.7.1 with regard to treatment duration and amount of drug intake.
Data of laboratory assessments (AST, ALT, bilirubin, and alkaline phosphatase) and vital 
signs during safety-follow-up period will be analyzed in a similar fashion as described in 
Section  4.7.4 and Section 4.7.5 .
Data will be presented by randomized treatment labeled as ‘Randomized Pirfenidone’ 
and ‘Randomized Placebo’.
4.8
MISSING DATA
With exception of the tipping point analysis described in section 4.5.8, missing data will 
not be imputed. Other exceptions will be made for the data related to adverse events 
and concomitant medications as described below.
For adverse events, missing start dates will only be imputed for determination of whether 
the adverse event is considered to be treatment-emergent or not.
Incomplete or missing onset dates will be imputed to the earliest date possible (using 
any reliable portions of the onset date that are available). The onset day is considered 
unreliable if the month or year portions of the date are missing. 
In case the month portion of the AE start date is missing, the AE start date will be 
imputed to the earliest day possible by using the following principles:

If Treatment Start Date is missing, then the AE Start Date will be imputed as 01-
01-YYYY or the earliest date regarding signature of informed consent, screening 
date or randomization date, whichever is the later one

When the Treatment Start Date is not missing, and the years of AE Start Date 
and Treatment Start Date coincide, the AE onset date will be set to the 
Treatment Start Date

When the Treatment Start Date is not missing, and the years of the AE Start 
Date and the Treatment Start Date do not coincide, then the AE Start Date will be 
imputed as 01-01-YYYY or the earliest date regarding signature of informed 
consent, screening date or randomization date, whichever is the later one


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Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
In case the day portion of the AE Start Date is missing, the AE Start Date will be imputed 
to the earliest day possible as follows:

If the Treatment Start Date is missing, then the AE Start Date will be imputed as 
01-MMM-YYYY or the earliest date regarding signature of informed consent, 
screening date or randomization date, whichever is the later one

When the treatment date is not missing, and the years and months from the AE 
Start Date and the Treatment Start Date coincide, the AE onset date will be set to 
the Treatment Start Date

When the Treatment Start Date is not missing, and AE Start Date is after the 
Treatment Start Date according to the given year or month, then the AE Start 
Date will be imputed as 01-MMM-YYYY 
If the AE stop date is missing, then the event will be assumed to be ongoing and a stop 
date will not be imputed. 
In the case the treatment end date is missing and it cannot be judged whether the event 
occurred during the period of Treatment Start Date to Treatment End Date plus 28 days, 
the AE will be considered treatment-emergent as long as it is not flagged as prior AE.
For imputation and handling of missing intensity or relationship to study medication, 
please see Section 4.7.2.
All other missing or incomplete adverse event data will be left as missing.
For concomitant medications, missing start or end dates will only be imputed to 
determine whether the medication is considered to be prior, on-treatment, post-treatment.
In general if only the day is missing from the start date then the missing day will be 
imputed as 01-MMM-YYYY unless the month is the same month as the start of study 
medication in which case the missing date will be imputed as the treatment start date.
If both the day and month are missing from the start date then the start date will be 
imputed as 01-JAN-YYYY.
If both the day and month are missing from the start date year is the same as treatment 
start date then the start date will be imputed as ‘treatment start date’, but if the year is 
after treatment start date, the start date will be imputed as 01-JAN-YYYY.
If the day, month and year are all missing from the start date then the start date will be 
imputed as 01-JAN for the year in which the patient was recruited to the study.
If the day, month and year are all missing from the start date then the start date will be 
imputed as ‘treatment start date’.


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If an incomplete stop date has both the year and month present, the day will be imputed 
as the last day of the month or date of discontinuation/death.
If the AE is ongoing at time of primary analysis, concomitant medication will be 
summarized for the double-blind treatment period and safety follow-up.
4.9
VISIT WINDOWS
Visit windows for double-blind treatment period will be applied to vital signs and 
laboratory data and the derived visits will be used in the by-visit summarizations. If
multiple observations fall within the same visit window, the observation with the nearest 
to midpoint value will be used in the analysis, if not stated otherwise. If subjects 
discontinue from the double-blind treatment period early the data will be assigned to the 
early discontinuation visit. The date of early discontinuation will be considered as the 
target date. 
The “Baseline” visit is a derived data point to identify baseline values which are used to 
calculate the change from baseline values. Baseline is defined in Section 4.2.2.
The End of Treatment [EOT] visit will either be a copy of early discontinuation records for 
patients who prematurely discontinued double-blind treatment period or Week 24 
records for patients who completed the double-blind treatment period.
Table 2
Visit Windows 
Analysis Visit [AVISITN]
Target Day
Analysis Window (scheduled Study Days)
Baseline [0]
1
Last valid assessment prior to first intake 
of randomized study drug 
(pirfenidone/placebo).
Generally, it is assumed that 
measurements referring to the Day 1 
(Week 1) visit have been performed before 
randomized study drug 
(pirfenidone/placebo) was given.
Week 4 [4]
28
One day after first dose of randomized 
treatment to 42
Week 8 [8]
56
43 to 70
Week 12 [12]
84
71 to 98
Week 16 [16]
112
99 to 126
Week 20 [20]
140
127 to 154
Week 24 [24]  
168
155 to a maximum of 195 if the patient did 
not early discontinued.


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Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Early discontinuation [25]
Not applicable
As occurred 
End of treatment (EOT) 
[26]
Not applicable
As occurred 
Follow-up visit (FUP1) [27]
Not applicable
As occurred
Safety follow-up 
visits(SFUP) [28]
Not applicable
As occurred:
Month 1 to 6: Monthly visits
Month 7 to12: Approximately every 3 
months
Additional Safety follow-up 
visit [29]
Not applicable
As occurred:
up to 12 months plus 28 days
4.10
INTERIM ANALYSES
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.
No formal interim analyses for efficacy are planned.
4.11
BIOMARKER ANALYSES
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 2).
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.


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Biomarkers associated with fibrosis and ILD will be evaluated in plasma, serum, and 
whole blood ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) samples.
Analyses on biomarker data will not be in the scope of this SAP, but will be planned and 
described separately.


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Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and 
tolerability of pirfenidone in patients with scleroderma-associated interstitial lung 
disease: the LOTUSS trial. J Rheumatol 2016;epub.
Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary 
fibrosis. An international working group report. Am J Respir Crit Care Med 
2016;194:265–75.
Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable 
interstitial lung disease. Eur Respir J 2013;42:750–7.
Fischer A, Brown KK, du Bois RM, et al. Mycophenolate mofetil improves lung function 
in connective tissue disease-associated interstitial lung disease. J Rheumatol 
2013;40:640–6.
Eakin EG, Resnikoff PM, Prewitt LM, et al. Validation of a new dyspnea measure: the 
UCSD Shortness of Breath Questionnaire. University of California, San Diego. Chest.
1998 Mar;113(3):619-24.
Ries AL, Minimally clinically important difference for the UCSD Shortness of Breath 
Questionnaire, Borg Scale, and Visual Analog Scale. COPD. 2005 Mar;2(1):105-10. 
Rubin, DB. Multiple Imputation for Nonresponse in Surveys New York John Wiley and 
Sons 1987 
Jones PW, Quirk FH, Baveystock CM, The St George's Respiratory Questionnaire. 
Respir Med. 1991 Sep;85 Suppl B:25-31; discussion 33-7. 
Nishimura K, Tsukino M, Hajiro T, Health-related quality of life in patients with chronic 
obstructive pulmonary disease. Curr Opin Pulm Med. 1998 Mar;4(2):107-15. 
St. George’s Respiratory Questionnaire: http://www.healthstatus.sgul.ac.uk/sgrq
S S Birring, B Prudon, A J Carr, S J Singh, M D L Morgan, I D Pavord, Development of a 
symptom specific health status measure for patients with chronic cough: Leicester 
Cough Questionnaire (LCQ). Thorax 2003;58:339-343.


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Appendix 1
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.


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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.
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 
Appendix 3
PRO Questionnaires
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 of the CSP) 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. 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. 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 


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
dose must be re-titrated over 14 days. 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.
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 Appendix 3
PRO Questionnaires
below.
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


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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 2). 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.
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


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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.
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)


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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) 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 


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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 
measured by handheld spirometry over the 24-week double-blind treatment period.
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.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Appendix 2
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
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


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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
Month 1 to 6: 
Monthly visits
Month 7 to12: 
Approximately 
every 
3 months
Weight
x
x
x
Height
x
Complete physical 
examination g
x
x
x
x
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


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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
Month 1 to 6: 
Monthly visits
Month 7 to12: 
Approximately 
every 
3 months
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


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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
Month 1 to 6: 
Monthly visits
Month 7 to12: 
Approximately 
every 
3 months
UCSD-SOBQ q
x
x
x
x
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


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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
Month 1 to 6: 
Monthly visits
Month 7 to12: 
Approximately 
every 
3 months
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


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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.
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.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
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. 
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. 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.
a.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Appendix 3
PRO Questionnaires
Leicester Cough Questionnaire


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Scoring
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.
The scores from each of the following questions are added together to provide the mean score 
for each domain:
1. Physical: 1, 2, 3, 9, 10, 11, 14, 15   
2. Psychological: 4, 5, 6, 12, 13, 16, 17
3. Social: 7, 8, 18, 19
Domain scores: total score from items in domain/number of items in domain (range 1–7).
Total scores: addition of domain scores (range 3–21).


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
UCSD-SOBQ
The University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) is a 
symptom-specific, 24-item, patient-self-administered questionnaire that assesses shortness of 
breath while doing a variety of activities of daily living. 
UCSD MEDICAL CENTER
PULMONARY REHABILITATION PROGRAM
SHORTNESS-OF-BREATH QUESTIONNAIRE
© 1995 The Regents of the University of California
Please rate the breathlessness you experience when you do, or if you were to do, each of the 
following tasks. Do not skip any items. If you’ve never performed a task, or no longer perform 
it, give your best estimate of the breathlessness you would experience while doing that activity. 
Please review the two sample questions below before turning the page to begin the 
questionnaire. 


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Scoring
Twenty one items assess the severity of shortness of breath during specific activities associated 
with daily living if patients do not routinely perform the activity, they are asked to estimate the 
degree of shortness of breath anticipated. Three additional items ask about limitations due to: 
shortness of breath, fear of harm from overexertion and fear of shortness of breath.
Each of the 24 activities are rated on how dyspnea affects the activity on a 6-point scale: 
0 = None at all to 5 = Maximal or unable to do because of breathlessness
The scores from all 24 questions are totalled to provide a score in the range 0 – 120.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
SGRQ
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
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
STRUCTURE OF SGRQ
The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in 
patients with diseases of airways obstruction.
Part 1 (Questions 1-8) addresses the frequency of respiratory symptoms. It is not designed to 
be a precise epidemiological tool, but to assess the patient’s perception of their recent 
respiratory problems.
Part 2 (Sections 9-16) addresses the patient’s current state (i.e. how they are these days).
The Activity score measures disturbances to daily physical activity. The Impacts score covers a 
range of disturbances of psycho-social function. Validation studies for the original SGRQ 
showed that this component relates in part to respiratory symptoms, but it also correlates quite 


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
strongly with exercise performance (6-minute walk test), breathlessness in daily life (MRC 
breathlessness score) and disturbances of mood (anxiety and depression). The Impacts score 
is, therefore, the broadest component of the questionnaires, covering the whole range of 
disturbances that respiratory patients experience in their lives.
Three component scores are calculated for the SGRQ
Symptoms – concerned with the effect of respiratory symptoms their frequency and severity
Activity concerned with activities that cause or are limited by breathlessness
Impacts covers a range of aspects concerned with social functioning and psychological 
disturbances resulting from airway disease.
Total score summaries the impact of disease on overall health status.  Scores are expressed as 
a percentage of overall impairment where 100 represents worst possible health status and 0 
indicates best possible health status.
SGRQ SCORES IN HEALTHY SUBJECTS
Means (95% confidence intervals) for SGRQ scores in normal subjects with no history of
respiratory disease
N
Age-years
FEV1 as 
% 
predicted
Symptoms 
score
Activity 
score
Impacts 
Score
Total 
Score
72
46  (17 - 80)
95 (91-
99)
12 (9-15)
9 (7-12)
2 (1-3)
6 (5-7)


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Scoring 
Questions 1 – 7 The eCRF screens should be set up so that where a patient has ticked a box, a 
value of 1 is entered for the appropriate question.  By default, the empty boxes are entered as 0. 
Where a patient has missed a question the cells on the spreadsheet are left blank. Example: 
Response = 1c, ‘Over the last year I have coughed a few days a month’. A value of 1 is entered 
for 1c and a value of 0 is entered for 1a, 1b, 1d and 1e. If no tick was present for question 1 then 
1a to 1e would be left blank.
Question 8 Where a patient has ticked ‘Yes’ to having a worse wheeze in the morning, a value of 
1 is entered for the appropriate question. All other responses are entered as 0. Example: Do you 
have a wheeze? = ‘Yes’ and Worse in the morning = ‘Yes’. then response to question 8 = 1.  Do 
you have a wheeze? = ‘Yes’ and Worse in the morning = ‘No’. Or, Do you have a wheeze? = 
‘No’. then response to question 8=0.
Questions 9, 10 & 17 Where a patient has ticked a box, a value of 1 is entered for the
appropriate question. The empty boxes are entered as 0. Where a patient has missed the 
question the cells on the spreadsheet are left blank. Example: Response = 10a, ‘My chest 
trouble made me stop work’. A value of 1 is entered for 10a and a value of 0 is entered for 10b 
and 10c. If no tick was present for question 10, then 10a to 10c would be left blank.
Questions 11 – 16 Where a patient has ticked ‘True’ a value of 1 is entered for the appropriate 
question and where a patient has ticked ‘False’ a value of 0 is entered. Where a patient has 
missed a question the cell on the spreadsheet is left blank.
Example: 15a = ‘True’ then 15a = 1.
14c = ‘False’ then 14c = 0.
13h = missing then 13h is left blank
In response to question 14, if a patient is not receiving medication, enter the responses as zero, 
otherwise the calculator will read the values as missing.
Missing Questions
There should not be any missing items in the questionnaire, but the SGRQ can have up to 24% 
of missing items in the questionnaire. If more than 24% of items are missing the scores will be 
missing.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
ITEM WEIGHTS
Once the questions have been answered the following weights are applied to the individual 
responses 
PART 1
Over the past 3 months, I have coughed:
Most 
days/week
Several days/ 
week
A few days a 
month
Only with chest 
infections 
Not at all
80.6
63.2
29.3
28.1
0.0
Over the past 3 months, I have brought up phlegm (sputum):
Most 
days/week
Several days/ 
week
A few days a 
month
Only with chest 
infections 
Not at all
76.8
60.0
34.0
30.2
0.0
3) Over the past 3 months, I have had shortness of breath:
Most 
days/week
Several days/ 
week
A few days a 
month
Only with chest 
infections 
Not at all
87.2
71.4
43.7
35.7
0.0
4) Over the past 3 months, I have had attacks of wheezing:
Most 
days/week
Several days/ 
week
A few days a 
month
Only with chest 
infections 
Not at all
86.2
71.40
45.6
36.4
0.0
5) During the past 3 months, how many severe or very bad unpleasant attacks of chest trouble 
have you had?


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
More than three
3  attacks
2 attacks
1 attack
None
86.7
73.5
60.3
44.2
0.0
6) How long did the worst attack of chest trouble last?
a week or more
3 or more days
1 or 2 days 
Less than a day
None
89.7
73.5
58.8
41.9
0.0


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
7) Over the past 3 months, in an average week, how many good days (with little chest trouble) 
have you had?
No good days
1 or 2 good 
days
3 or 4 good 
days
Nearly every 
day
Every day
93.3
76.6
61.5
15.4
0.0
8) If you have a wheeze, is it worse in the morning?
No
Yes
0.0
62.0
PART 2
The weights in Part 2 are also applied to the individual responses to each question. The worse 
the impact the higher the weight. This means that weights are not applied sequentially in the 
order that the response is given. 
9) How would you describe your chest condition?
The most important problem I have 
83 .2
Causes me quite a lot of problems 
82.5
Causes me a few problems 
34.6
Causes no problem 
0.0
10) If you have ever had paid employment?
My chest trouble made me stop work
88.9


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
My chest trouble interferes with my work or made me change my work
77.6
My chest trouble does not affect my work
0.0
11) Questions about what activities usually make you feel breathless.
Sitting or lying still  
90.6
Getting washed or dressed  
82.8
Walking around the home  
80.2
Walking outside on the level  
81.4
Walking up a flight of stairs  
76.1
Walking up hills  
75.1
Playing sports or games  
72.1


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
12) More questions about your cough and breathlessness.
My cough hurts 
81.1
My cough makes me tired 
79.1
I get breathless when I talk 
84.5
I get breathless when I bend over 
76.8
My cough or breathing disturbs my sleep 
87.9
I get exhausted easily 
84.0
13) Questions about other effects your chest trouble may have on you.
My cough or breathing is embarrassing in public 
74.1
My chest trouble is a nuisance to my family, friends or neighbours 
79.1
I get afraid or panic when I cannot get my breath 
87.7
I feel that I am not in control of my chest problem 
90.1
I do not expect my chest to get any better 
82.3
I have become frail or an invalid because of my chest 
89.9
Exercise is not safe for me 
75.7
Everything seems too much of an effort 
84.5
14) Questions about your medication.
My medication does not help me very much  
88.2


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
I get embarrassed using my medication in public  
53.9
I have unpleasant side effects from my medication  
81.1
My medication interferes with my life a lot  
70.3
15) Questions about how activities may be affected by your breathing.
I take a long time to get washed or dressed  
74.2
I cannot take a bath or shower, or I take a long time  
81.0
I walk more slowly than other people, or I stop for rests  
71.7
Jobs such as housework take a long time, or I have to stop for rests  
70.6
If I walk up one flight of stairs, I have to go slowly or stop  
71.6
If I hurry or walk fast, I have to stop or slow down  
72.3
My breathing makes it difficult to do things such as walk up hills, carry things up stairs, 
light gardening such as weeding, dance, play bowls or play golf  
74.5
My breathing makes it difficult to do things such as carry heavy loads, dig the garden 
or shovel snow, jog or walk at 5 miles per hour, play tennis or swim 
71.4
My breathing makes it difficult to do things such as very heavy manual work, run, 
cycle,swim fast or play competitive sports 
63.5


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
16) We would like to know how your chest trouble usually affects your daily life.
I cannot play sports or games  
64.8
I cannot go out for entertainment or recreation  
79.8
I cannot go out of the house to do the shopping  
81.0
I cannot do housework  
79.1
I cannot move far from my bed or chair  
94.0
17) Tick the statement which you think best describes how your chest affects you.
It does not stop me doing anything I would like to do  
0.0
It stops me doing one or two things I would like to do  
42.0
It stops me doing most of the things I would like to do  
84.2
It stops me doing everything I would like to do 
96.7
SCORING ALGORITHM
Three component scores are calculated: Symptoms; Activity; Impacts
One Total score is also calculated.
PRINCIPLE OF CALCULATION
Each questionnaire response has a unique empirically derived 'weight'. The lowest possible 
weight is zero and the highest is 100.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Each component of the questionnaire is scored separately in three steps:
i. The weights for all items with a positive response are summed.
ii The weights for missed items are deducted from the maximum possible weight for
each component. The weights for all missed items are deducted from the maximum
possible weight for the Total score.
iii. The score is calculated by dividing the summed weights by the adjusted maximum
possible weight for that component and expressing the result as a percentage :
Score = 100 x Summed weights from positive items in that component
Sum of weights for all items in that component
The Total score is calculated in similar way:
Score = 100 x Summed weights from positive items in the questionnaire
Sum of weights for all items in the questionnaire
Sum of maximum possible weights for each component and Total:
Symptoms 662.5
Activity 1209.1
Impacts 2117.8
Total 3989.4
(Note: these are the maximum possible weights that could be obtained for the worst possible 
state of the patient).


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
It will be noted that the questionnaire requests a single response to questions 1-7, 9-10 and 17. 
If multiple responses are given to one of these questions then averaging the weights for the 
positive responses for that question are acceptable
SYMPTOMS COMPONENT
This is calculated from the summed weights for the positive responses to questions 1-8.
ACTIVITY COMPONENT
This is calculated from the summed weights for the positive responses to questions 11 and 15.
IMPACTS COMPONENT
This is calculated from the summed weights for the positive responses to questions 9-10, 12- 14 
and 16-17.
TOTAL SCORE
The Total score is calculated by summing all positive responses in the questionnaire and
expressing the result as a percentage of the total weight for the questionnaire 
HANDLING MISSED ITEMS
There should not be any missed items but if there are missing items  the scores should be 
calculated using the following rules:
following should be used: The following method is recommended for missing items:
Symptoms


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
The Symptoms component will tolerate a maximum of 2 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Symptoms component (662.5) and from 
the Total weight (3989.4).


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Activity
The Activity component will tolerate a maximum of 4 missed items. The weight for the
missed item is subtracted from the total possible weight for the Activity component (1209.1) and 
from the Total weight (3989.4).
Impacts
The Impacts component will tolerate a maximum of 6 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Impacts component (2117.8) and from 
the Total weight (3989.4).
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.


Pirfenidone — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MA39189, Version 3.0, 17-July-2020
Cough Visual Analogue Scale (VAS)
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.


Pirfenidone — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
1 
 
STATISTICAL ANALYSIS PLAN 
 
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 
STUDY DRUG: 
Pirfenidone (RO0220912) 
VERSION NUMBER: 
Version 2.0 Final 29-Oct-2018 
IND NUMBER: 
67284 
Eudract Number: 
2016-002744-17 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
; 
 (F. Hoffmann-La Roche Ltd)  
DATE FINAL: 
29 October 2018 
 




 
Pirfenidone — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
3 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
The following changes were made compared to the first version of the SAP: 
Version 
Date 
Change 
number 
Change description 
2 
08-Oct-2018
1 
Clarification related to the aim and timeline of the primary 
analysis and final analysis of the study are included under 
section Outcome Measures. 
2 
08-Oct-2018
2 
Week 28 is included in all descriptive efficacy tables. 
2 
08-Oct-2018
3 
The safety follow-up period definition is changed as stated 
in section On-treatment Assessments (12-Month Safety 
Follow-up Period). 
2 
08-Oct-2018
4 
Disposition is updated in section Patient Disposition. 
2 
08-Oct-2018
5 
Details were added in order to analyze valid daily spirometry 
data in section Demographic and Baseline Characteristics. 
2 
08-Oct-2018
6 
Additional analyses needed in the safety follow-up period 
based on safety follow-up population are presented under 
section Safety Follow-up analyses.  
2 
08-Oct-2018
7 
Safety follow-up visits were included under section Visit 
Windows.  
2 
08-Oct-2018
8 
Listings of stratification factors, separated types of adverse 
events and pregnancy data were removed from the 
corresponding sections. 
2 
29-Oct-2018
9 
Post-medications during safety follow-up period are adapted 
as per new period definition in section Previous and 
Concomitant Medication. 
 


 
Pirfenidone — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
4 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE .............................................................................................. 2 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1. 
BACKGROUND .......................................................................................... 11 
2. 
STUDY DESIGN ......................................................................................... 11 
2.1 
Protocol Synopsis .................................................................. 12 
2.2 
Outcome Measures ............................................................... 12 
2.2.1 
Primary Efficacy Outcome Measures .................................... 13 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 13 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 14 
2.2.4 
Safety Outcome Measures .................................................... 14 
2.3 
Determination of Sample Size ............................................... 14 
2.4 
Interim Analysis ..................................................................... 15 
3. 
STUDY CONDUCT ..................................................................................... 15 
3.1 
Randomization, BLINDING AND UNBLINDING 
PROCEDURES ..................................................................... 15 
3.2 
Independent Review Facility .................................................. 15 
3.3 
Data Monitoring ..................................................................... 15 
4. 
STATISTICAL METHODS .......................................................................... 16 
4.1 
Analysis Populations ............................................................. 16 
4.1.1 
Intent-to-treat Population ....................................................... 16 
4.1.2 
Per Protocol Population ......................................................... 16 
4.1.3 
Safety Population .................................................................. 16 
4.1.4 
Safety Follow-up Population .................................................. 16 
4.2 
Trial Periods, Observation and analysis times ....................... 17 
4.2.1 
Study Days ............................................................................ 17 
4.2.2 
Baseline and Screening Observations ................................... 17 


 
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Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
5 
 
4.2.3 
On-treatment Assessments for Efficacy Analyses 
(Double-blind Treatment Period) .............................................................. 18 
4.2.4 
On-treatment Assessments for Safety Analyses 
(Double-blind Treatment Period) .............................................................. 18 
4.2.5 
On-treatment Assessments (12-Month Safety 
Follow-up Period) ..................................................................................... 18 
4.2.6 
Cut-off points ......................................................................... 18 
4.3 
Analysis of Treatment arm Comparability .............................. 19 
4.4 
Analysis of Study Conduct ..................................................... 19 
4.4.1 
Patient Disposition ................................................................. 19 
4.4.2 
Major Protocol Deviations ...................................................... 21 
4.4.3 
Demographic and Baseline Characteristics ........................... 21 
4.4.4 
Previous and Concomitant Medication .................................. 24 
4.4.5 
Compliance ............................................................................ 25 
4.5 
Efficacy Analysis .................................................................... 25 
4.5.1 
Primary Efficacy Endpoints .................................................... 26 
4.5.2 
Secondary Efficacy Endpoints ............................................... 27 
4.5.3 
Exploratory Efficacy Endpoints .............................................. 29 
4.5.4 
Analyses of Patient-Reported Outcomes ............................... 30 
4.5.5 
Sensitivity Analyses ............................................................... 32 
4.5.6 
Subgroup Analyses ............................................................... 32 
4.6 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 33 
4.7 
Safety Analyses ..................................................................... 33 
4.7.1 
Exposure of Study Medication ............................................... 34 
4.7.1.1 Treatment duration ............................................................... 34 
4.7.1.2 Doses and Dose modifications or interruptions .................... 34 
4.7.2 
Adverse Events ..................................................................... 35 
4.7.3 
Deaths ................................................................................... 38 
4.7.4 
Laboratory Data ..................................................................... 38 
4.7.5 
Vital Signs .............................................................................. 39 


 
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Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
6 
 
4.7.6 
ECG ....................................................................................... 39 
4.8 
Safety Follow-up analyses ..................................................... 39 
4.9 
Missing Data .......................................................................... 40 
4.10 
Visit Windows ........................................................................ 42 
4.11 
Interim Analyses .................................................................... 43 
4.12 
Biomarker Analyses ............................................................... 43 
REFERENCES ................................................................................................... 45 
 


 
Pirfenidone — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
7 
 
 
 
LIST OF TABLES 
Table 1 
Definition of Baseline and Screening Observations .................... 17 
Table 2 
Visit Windows .............................................................................. 42 
 
 
LIST OF APPENDICES 
APPENDIX 1 
 PROTOCOL SYNOPSIS ...................................................... 46 
APPENDIX 2        SCHEDULE OF ASSESSMENTS ......................................... 54 
APPENDIX 3        PATIENT REPORTED OUTCOME 
QUESTIONNAIRE ...................................................................................... 62 
 


 
Pirfenidone — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
8 
 
 
LIST OF ABBREVIATIONS 
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 
BP  
blood pressure  
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  
CSP 
clinical study protocol 
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  
GCP  
Good Clinical Practice  
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  


 
Pirfenidone — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
9 
 
IL  
interleukin  
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 
LFT  
lactate dehydrogenase  
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 mycophenolate acid  
NAC  
N-acetyl-cysteine  
NCI 
National Cancer Institute  
NGS  
next-generation sequencing  
NSIP 
nonspecific interstitial pneumonia  
PDGF  
platelet-derived growth factor  
PDMS 
protocol deviation management system 
PFS  
progression-free survival  
PFTs  
pulmonary function tests  
PRO  
patient-reported outcome  
QTcF  
QT interval corrected using Fridericia’s formula  
RBC  
red blood cells  
RBR 
Research Biosample Repository  
RNA  
ribonucleic acid  
RoW 
Rest of the World 
SAP  
Statistical Analysis Plan  
SBP  
systolic blood pressure  
SGRQ  
St. George’s Respiratory Questionnaire  
SOBQ 
Shortness of Breath Questionnaire 
SOC 
System Organ Class  
SOP  
standard operating procedure  
SpO2 
oxyhemoglobin saturation at rest 


 
Pirfenidone — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA39189, Version 2.0, 29-Oct-2018 
 
 
10 
 
SSc 
systemic sclerosis  
TGF 
transforming growth factor  
TID  
three times daily  
UCSD 
University of California, San Diego  
UIP 
usual interstitial pneumonia  
ULN  
upper limit of normal  
US  
United States  
VAS 
Visual Analogue Scale 
VC  
vital capacity  
WBC  
white blood cells  
WGS 
whole genome sequencing  


 
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1. 
BACKGROUND 
As described in the Clinical Study Protocol (CSP) Section 1.3, no approved treatments 
are available for the 15% of patients with interstitial lung disease (ILD) who have 
unclassifiable disease. 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 idiopathic pulmonary fibrosis 
(IPF) are sufficiently encouraging 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 (Esbriet®) 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.  
Mycophenolate mofetil/sodium or mycophenolic acid (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. 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. 
2. 
STUDY DESIGN 
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 multidisciplinary 
team (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 TID) 
or placebo. The randomized patients will be stratified by concomitant MMF treatment 
(yes/no), the presence/absence of IPAF as defined by 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.  


 
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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 CSP) 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 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. 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 
CSP 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. 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, 
patients will be given the opportunity to receive open-label pirfenidone within a safety 
follow-up period of up to 12 months of the 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. 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. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1 and the Schedule of Assessments in Appendix 2 
For additional details, please see the CSP Version 3, 28 June 2018 (and its Appendices). 
2.2 
OUTCOME MEASURES 
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).  
The primary analysis of the primary and secondary efficacy outcome measures of this 
study is planned to be performed when the last patient reached the date of the last 
follow-up visit after end of the double-blind treatment period. 
 


 
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2.2.1 
Primary Efficacy Outcome Measures 
The primary efficacy objective for this trial is to evaluate the effect of pirfenidone vs. 
placebo on lung function parameters on the basis of Forced Vital Capacity (FVC) 
measurements. FVC will be measured daily by the patients by use of a handheld 
spirometer. 
The primary efficacy endpoint is defined as: 
• 
rate of decline in FVC in mL measured by daily handheld spirometry over the 24-
week double-blind treatment period.  
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy objective for this trial is to evaluate the efficacy of pirfenidone 
compared with placebo from baseline until Week 24 on other functional parameters, 
outcomes, and patient reported outcomes (PROs). 
The following endpoints will be analyzed: 
• 
Change in percent predicted FVC and in mL measured by spirometry during 
clinic visits 
• 
Categorical change in FVC of >5% (absolute change in percent predicted and 
relative change in mL), measured both by daily spirometry as well as by 
spirometry during clinic visits 
• 
Categorical change in FVC of >10% (absolute change in percent predicted and 
relative change in mL), measured both by daily spirometry as well as by 
spirometry during clinic visits 
• 
Change in percent predicted diffusing capacity of the lung for carbon monoxide 
(DLco) 
• 
Change in (6-minute walk distance) 6MWD in meters 
• 
Change in University of California, San Diego Shortness of Breath Questionnaire 
(UCSD-SOBQ) score 
• 
Change in score in Leicester Cough Questionnaire 
• 
Change in cough visual analog scale 
• 
Change in total and sub-scores of the St. George's Respiratory Questionnaire 
(SGRQ) 
• 
Non-elective hospitalization, both respiratory and all cause 
• 
Incidence of, and time to first, investigator-reported acute exacerbations  
• 
Progression free survival (PFS), 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 
• 
PFS, alternatively defined as the time to the first occurrence of a >10% relative 
decline in FVC (measured during a clinic visit), non-elective respiratory 
hospitalization, or death 


 
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• 
Time to death from any cause 
• 
Time to death from respiratory diseases 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
One exploratory objective for this trial is to evaluate the role of mycophenolate 
mofetil/sodium or mycophenolic acid (MMF) treatment in ILD and to evaluate potential 
biomarkers associated with fibrosis and ILD.  
The exploratory endpoints associated are: 
• 
Efficacy and safety data from subgroups of patients who did or did not receive 
MMF treatment 
• 
Biomarker data from plasma, serum, and whole blood ribonucleic acid (RNA) and 
deoxyribonucleic acid (DNA) samples 
  
2.2.4 
Safety Outcome Measures 
The safety objective for this trial is to evaluate the safety of pirfenidone vs. placebo by 
investigating the following endpoints:  
• 
Nature, frequency, severity, and timing of treatment-emergent adverse events 
• 
Dose reductions and treatment interruptions 
• 
Clinical laboratory test results 
• 
12-lead ECGs 
• 
Withdrawals from trial treatment or trial discontinuations 
All analyses with regard to the safety outcome measures will be performed from the date 
of first randomized treatment intake until 28 days after the last positive dose during the 
double-blind randomized treatment period. 
2.3 
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 


 
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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, 
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. 
2.4 
INTERIM ANALYSIS 
There are no planned interim efficacy analyses for this trial.  
3. 
STUDY CONDUCT 
The study conduct is described in Section 2. 
3.1 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES 
Patients will be randomized 1:1 to receive either pirfenidone or 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 arm, 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 CSP 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. 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 
3.3 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will review safety data and advice 
on study conduct at least three times during the study. Efficacy data will only be provided 
if requested by the iDMC. A first meeting is planned 6 months after start of recruitment, 


 
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and subsequently at 12 and 18 months. Details on procedures and safety review by the 
iDMC are described within an iDMC charter. 
4. 
STATISTICAL METHODS 
Categorical data will be summarized using frequencies and percentages (including a 
category for missing, if appropriate). Percentages will be based on the number of 
patients in each treatment arm for the analysis population, if not otherwise specified. 
Continuous endpoints will be summarized using descriptive statistics (mean, standard 
deviation, minimum, 25th and 75th quartiles, median, and maximum).  
Where data will be summarized over time, the following timepoints will be presented as 
applicable: Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 
28 (if applicable) and early discontinuation visit. 
Data analysis of data collected during the 12-month safety follow-up period will be 
described in section 4.8. 
Where applicable other analysis methods will be specified below.   
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-treat Population 
The intent-to-treat (ITT) population is defined as all randomized patients. Patients in the 
ITT population will be assigned to treatment arm as randomized (planned treatment). 
The ITT population is the primary analysis population for all efficacy analyses. The time 
period for all efficacy analyses is defined from date of randomization until the treatment 
completion date of the double-blind treatment period or the date of early discontinuation 
collected on the early treatment discontinuation eCRF page in case a patient does not 
complete the planned 24 weeks of double-blind treatment. 
4.1.2 
Per Protocol Population 
Not applicable. 
4.1.3 
Safety Population 
The safety population is defined as all patients with at least one intake of pirfenidone or 
placebo, i.e. at least one record in the drug-log of the double-blind period with a non-
zero dose.. Patients in the safety population will be assigned to treatment arm according 
to the actual treatment they received. 
4.1.4 
Safety Follow-up Population 
For the 12-month safety follow-up period, the safety follow-up population will be defined 
as all patients who have received at least one dose of pirfenidone after the randomized 
treatment end plus 28 days. 


 
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Safety analyses for the 12-month follow-up period will be performed from the date of the 
first pirfenidone drug intake during safety follow-up period up to the study 
completion/discontinuation visit. 
4.2 
TRIAL PERIODS, OBSERVATION AND ANALYSIS TIMES 
Where durations are to be calculated (e.g. treatment duration), these will be derived 
based on the interval in days (end date – start date + 1) and converted to months and 
years if needed, using 30.4375 and 365.25, respectively, as denominator if not otherwise 
specified.  
For the investigational medicinal product (IMP) exposure, treatments administered from 
the date of first randomized pirfenidone/placebo treatment up to the date of completion 
of double-blind treatment or date of early treatment discontinuation, will be regarded.  
For drug safety, analyses will be restricted to AEs or assessments that occurred from the 
first day of randomized treatment until the date of last positive dose of randomized 
treatment plus 28 days. 
Safety analyses for the 12-month follow-up period will be performed using the time 
window from the safety follow-up period start up to the study completion/discontinuation 
visit. 
4.2.1 
Study Days 
Study days will be defined as the number of days since randomization, and is calculated 
as: 
• 
Study day = Assessment date – randomization date + 1, for assessments on or 
after the randomization date. 
• 
Study day = Assessment date – randomization date, for assessments before the 
randomization date. 
The day of randomization will be study day 1.  
4.2.2 
Baseline and Screening Observations 
Table 1 
Definition of Baseline and Screening Observations 
 
Definition 
Baseline data 
Baseline is defined as the last valid assessment prior to first intake of 
randomized study drug (pirfenidone/placebo). 
This may not be the same as the Day 1 (Week 1) visit as per eCRF. In 
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treatment is given, data from the screening period will be used as 
baseline. In addition, if randomized treatment is not given then 
baseline will be defined as the last valid assessment collected either 
screening or day 1. 
Generally, it is assumed that measurements referring to the Day 1 
(Week 1) visit have been performed before randomized study drug 
(pirfenidone/placebo) was given. 
Adverse events occurring on the date of first randomized 
pirfenidone/placebo treatment will not be considered baseline, but 
treatment-emergent. 
Screening data 
Screening measurements are all the measurements performed before 
the randomization date. 
 
4.2.3 
On-treatment Assessments for Efficacy Analyses (Double-blind 
Treatment Period) 
For efficacy analyses, on-treatment assessments will be the assessments performed on 
or after the randomization date until the double-blind treatment completion or 
discontinuation date. 
4.2.4 
On-treatment Assessments for Safety Analyses (Double-blind 
Treatment Period) 
For safety analyses, on-treatment assessments will be the assessments performed on or 
after the first dose of randomized pirfenidone/placebo date until the last positive dose of 
randomized treatment plus 28 days. 
4.2.5 
On-treatment Assessments (12-Month Safety Follow-up Period) 
Details of all data  recorded during the 12-month safety follow-up period will be 
presented. This period starts  on the day of the first positive dose of pirfenidone on or 
after the 28 days follow-up visit  for patients who completed the double-blind treatment 
period without being discontinued the study. The safety follow-up period ends with the 
study completion/discontinuation visit, with a maximum duration of 12 months plus 28 
days. Safety follow-up analyses will be presented separately from double-blind treatment 
phase ones. 
4.2.6 
Cut-off points 
The clinical cut-off for the primary analysis will occur when the last patient has 
completed the final safety Follow-up Visit, 28 days after the double-blind treatment 
period. 
There will be a second cut-off for the final analysis when all patients have completed the 
12-month safety follow-up period.  


 
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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) 
plus 28 days and a final safety Follow-up Visit 4 weeks after the last dose. 
4.3 
ANALYSIS OF TREATMENT ARM COMPARABILITY 
To ensure the comparability of the treatment arm, the randomization will be stratified by 
the availability of a previous MMF treatment (yes/no) and the presence/absence of IPAF 
as defined by MDT to ensure an equal distribution of patients. 
These stratification factors will be included in the analysis of the primary endpoint as a 
sensitivity analysis. Please refer to the corresponding section 4.4.5 for further details. 
Outputs for concordance between the stratification factors by eCRF and by IxRS will 
also be presented.  
4.4 
ANALYSIS OF STUDY CONDUCT 
Unless otherwise specified, all analyses described in this section will be performed on 
the ITT population, presenting data by treatment arm. 
4.4.1 
Patient Disposition 
An overview on patient disposition, showing number and percentages of patients 
enrolled, screened, failed screening, randomized, treated, completed or early 
discontinued the double-blind treatment period, patients entering the 12-month safety 
follow-up period and their current status (ongoing, completion, discontinued) in that 
period will be provided. For patients who have early discontinued the double-blind 
treatment period or the study, frequencies of reasons for early discontinuation will be 
provided. A listing with all the patient disposition data will be also presented. 
 
The following definitions will be used: 
 
• 
Patients randomized: All patients who have been randomized to receive either 
pirfenidone or placebo, i.e. have a randomization date. 
• 
Patients randomized and not treated: all randomized patients who have not received 
at least one dose of the randomized treatment. 
• 
Patients randomized and treated: all randomized patients who have received at least 
one dose of the randomized treatment. 
• 
Patients randomized and treated with sufficient post-baseline efficacy data: all 
randomized patients who have received at least one dose of the randomized 
treatment and have at least one post-baseline assessment of FVC (mL). 


 
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• 
Completion of double-blind treatment period: eCRF question “Did the patient 
complete course of double-blind treatment?” is ticked “Yes” (eCRF form “Double-
blind treatment Completion/Early Discontinuation”). 
• 
Early discontinuation (non-completion) of double-blind treatment period: eCRF 
question “Did the patient complete course of double-blind treatment?” is ticked “No” 
(eCRF form “Double-blind treatment Completion/Early Discontinuation”). 
• 
Early discontinuation (non-completion) of study: eCRF question “Did the subject 
early discountinue from the study?” is ticked “Yes” (eCRF form “Study 
Completion/Early Discontinuation”) for patients who discontinued double-blind 
treatment period. 
• 
Early discontinuation (non-completion) of study: eCRF question “Did the subject 
early discountinue from the study?” is ticked “Yes” (eCRF form “Study 
Completion/Early Discontinuation”) for patients who completed double-blind 
treatment period and did not enter 12-month safety follow-up period. 
• 
Status during the 12-month safety follow-up (entered, ongoing, completed). 
Completers are defined as those patients that have filled the study 
completion/discontinuation form. Otherwise, the patient is considered ongoing in the 
safety follow-up phase. 
• 
Completion of study: eCRF question “Did the subject complete the study?” is ticked 
“Yes” (eCRF form “Study Completion/Early Discontinuation”)  
• 
Early discontinuation (non-completion) of study: eCRF question “Did the subject 
early discountinue from the study?” is ticked “Yes” (eCRF form “Study 
Completion/Early Discontinuation”)  
An overview on patients’ enrolment will be provided based on the randomized subjects 
by country and center separately for the pirfenidone and placebo arm. 
Kaplan-Meier (KM) plots for time to treatment discontinuation will be provided for all 
randomized patients and by randomized arm, based on the date subject completed or 
early discontinued from double-blind treatment period, as per eCRF. If the patient 
completed the treatment without treatment discontinuation, then it will be censored to the 
date of treatment completion.  
In addition, KM plots for time to study discontinuation will be presented for all 
randomized patients by arm, based on the study discontinuation date. If the patient 
completed the study as planned per protocol, then the patient will be censored to the 
study completion date. 
In addition, a consort diagram with some of the categories above will be presented. 


 
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4.4.2 
Major Protocol Deviations 
Major protocol deviations and eligibility violations will be summarized by frequency 
tables and all patients with protocol deviations will be listed. Protocol deviations will be 
collected in the protocol deviation management system (PDMS), reviewed by the 
medical monitors, and will be provided in a SAS dataset via the Biometrics Computing 
Environment (BCE). All deviations provided in that dataset will be considered as major 
protocol deviations.  
4.4.3 
Demographic and Baseline Characteristics 
Baseline and disease characteristics such as demographics, medical history and 
tobacco use history will be summarized by descriptive statistics or frequency tables for 
each treatment arm.  
Demographics 
The following demographic characteristics will be summarized by treatment arm:  
• 
Age (years): as entered in the eCRF at the screening visit. 
• 
Age categories: <65, and ≥ 65. 
• 
Age categories: <45, ≥45 to <65 years, ≥65 to <85 years, and ≥ 85 years. 
• 
Gender: Male/Female.  
• 
Race: White, American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, Unknown. In case that more than one race 
will be ticked, a concatenated variable, containing all races will be presented (e.g. 
Asian/White). 
• 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown. 
• 
Weight (kg) at baseline 
• 
Height (cm) at baseline 
• 
BMI (kg/m2) at baseline. BMI will be calculated as: weight(kg) / (height(m))2 
• 
Female reproductive status: childbearing potential without contraceptive protection, 
Childbearing potential with contraceptive protection, surgically sterilized, 
Postmenopausal, Pre-menarchal, Non childbearing potential. 
Data on female reproductive status will be presented descriptively. 
Demographic data will be also listed.  
Medical History 


 
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Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), version 20.1 or higher and will be summarized presenting numbers and 
frequencies by primary System Organ Class (SOC) and Preferred Term (PT) by 
treatment arm. If patients have more than one disease within a SOC or PT they will be 
counted only once for the respective SOC or PT.  
A listing with past and ongoing medical history data from the washout period will be 
presented. 
Tobacco use history  
The history of tobacco use will be summarized by treatment arm with the following 
characteristics:  
• 
Tobacco use history (never, current, previous) 
• 
Nicotine exposure (pack-years), smokers only 
Numbers and percentages of patients will be provided for tobacco use history. Nicotine 
exposure will be summarized descriptively. 
Diagnosis and time from uILD Diagnosis 
Frequencies and percentages will be presented for the uILD category collected into the 
eCRF page MDT/Diagnosis (Eligibility). 
The time in months since the original uILD diagnosis will be calculated as  
Date of randomization – Date of ILD diagnosis and will be summarized descriptively by 
randomized treatment arm. The number and percentage of patients with a historical 
high-resolution computed tomography and with a historical surgical lung biopsy will also 
be presented.  
Descriptive statistics of the time from most recent historical high-resolution computed 
tomography (months) and historical surgical lung biopsy will be presented. As above, the 
date of randomization will be used as reference date for calculation of duration. 
Stratification Factors 
The number and percentage of patients that fall into each of the four groups based on 
the two stratification factors: Concomitant MMF treatment (yes/no), and the 
presence/absence of IPAF as defined by the MDT will be presented by treatment arm.  
Baseline Spirometry Test 
The values recorded for the baseline assessments of the spirometry tests were the 
following: 




 
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FVC (mL) will be measured daily with a handheld device. 
Descriptive statistics of the baseline site measurements will be provided for these 
parameters separately by treatment arm together with the efficacy results. 
Baseline 6-minute walk distance (6MWD) 
The 6MWD is used to evaluate the functional capacity of patients with lung disease. The 
6MWD measures the distance a patient is able to walk quickly on a flat, hard surface in a 
period of 6 minutes.  
 
The number and percentage of patients that  
• 
Performed the 6-minute walking test (yes/no),  
• 
Rested for at least 10 minutes (yes/no),  
• 
Stopped the test before 6 minutes (yes/no),  
• 
Required O2 (yes/no) 
at the baseline visit will be summarized by randomized treatment group.   
 
The values of the parameters recorded for the 6MWD test are: 
  
• 
Vital signs (Heart rate (beats/min), systolic blood pressure (mmHg), diastolic 
pressure (mmHg)) (before the test, at the end of the test) 
• 
Distance walked (m),  
• 
Oxyhemoglobin saturation (SPO2) (before the test (at rest), at the end of the test),  
• 
Oxygen (O2) requirements (L) (at the end of the test) 
will be summarized descriptively by treatment arm.  
 
4.4.4 
Previous and Concomitant Medication 
Previous and concomitant medications will be presented based on the safety population. 
Post medications administrated during the safety follow-up period will be presented 
based on the safety follow-up population. 
Previous and concomitant medications are non-study medications. Concomitant therapy 
includes any medication used by a patient from the washout period until 28 days after 
the last dose of trial treatment. The previous and concomitant medication will be coded 
using the Genentech (GNE) drug dictionary. This is a proprietary Roche Dictionary which 
is used to code concomitant medications in the Trial Management System (TMS) coding 
tool. The Standardized Medication Name (CMDECOD), which is the medication generic 


 
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or combination generic as defined by the Drug Thesaurus (proprietary Genentech/Roche 
dictionary), and the Medication Class (CMCLAS), which is the primary medication class 
as defined by the Drug Thersaurus, will be used for the analyses. 
Therapies will be classified as previous or concomitant as follows: 
Previous: If the medication start date is prior to start of double-blind treatment, 
Concomitant: If medication is taken at anytime between the start of double-blind 
treatment and 28 days after last positive dose of randomized treatment.  
Post (safety follow-up): if the medication is taken during the safety follow-up period, i.e., 
on or after the first dose of open-label pirfenidone. 
The number and frequency of previous and concomitant medications taken by patients 
in the two treatment arms will be presented by Medication Class and Standardized 
Medication Name. If patients receive more than one drug within a Medication Class or 
Standardized Medication Name they will be counted only once for the respective 
Medication Class or Standardized Medication Name.  
A separated table will be presented for post medications during the safety follow-up 
period. 
All medications will be listed identifying the previous/concomitant and post medications.  
The missing imputation rules for the medication dates are described under section 4.8. 
4.4.5 
Compliance 
With respect to the home-based daily measurements compliance of patients will be 
investigated. It will be analyzed if gaps of measurements occur over time. A gap is 
thereby defined as 7 or more than 7 consecutive days of missing measurements or non-
accepted (borderline accepted or rejected) quality blows. A summary table displaying 
number of patients with gaps in daily measurements, number of gaps and duration of 
gaps will be provided by treatment arm for data from handheld spirometer.  
4.5 
EFFICACY ANALYSIS 
The primary and secondary efficacy analyses will include all patients in ITT population, 
with patients grouped according to their assigned treatment. 
The primary analysis of the primary efficacy endpoint of this study is planned to be 
performed when the last patient reached the date of the last follow-up visit after end of 
the double-blind treatment period (clinical cut-off date). 


 
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4.5.1 
Primary Efficacy Endpoints 
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 spirometer over the 24-week double-blind treatment period. 
The primary null hypothesis (H0) is that the mean FVC decline for both treatments is 
equal: 
 
H0: µ1 = µ2, 
 
where µ1 denotes the mean FVC decline for patients receiving Pirfenidone, and µ2 
denotes the mean FVC decline for patients receiving Placebo. 
 
The primary alternative hypothesis (H1) is that the mean FVC decline for both 
treatments is not equal: 
 
H1: µ1 ≠ µ2 
  
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 for the primary endpoint.  
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 estimated FVC decline for individual 
patients will be obtained by applying a linear regression model to all data points 
collected during the 24-week double-blind treatment period: 
 
where 
 
 = the FVC measurements (mL) of patient i on day t, with i=1,…,N and t=1,…,T, 
being N the total number of patients randomized and T the total number of days with 
assessment. 
 = study day t of patient i 
 = intercept and slope of the individual linear regression of patient i 
The time-adjusted decline for patient i is then obtained by estimating the patients’ 
individual difference in predicted values between baseline and week 24 from the linear 
regression. 


 
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In a further step, the time-adjusted mean FVC decline is estimated by calculating the 
mean over all individual time-adjusted declines of all patients by treatment arm. 
A summary table displaying the mean FVC decline together with two-sided 95% 
confidence intervals based on percentiles of the t-distribution will be provided by 
treatment arm. The mean FVC decline in each treatment arm will be compared using a 
student’s t-test with a two-sided significance level α=0.05 
As a sensitivity analysis to the primary analysis, the time-adjusted mean FVC decline will 
be estimated by a repeated measures mixed model with patient effects fitted as random 
and day of measurement and treatment fitted as fixed effects. Please refer to Section 
4.5.5 for further details. 
A detailed description of SAS code to be used for the repeated measures mixed model 
is provided together with the respective table shell. 
4.5.2 
Secondary Efficacy Endpoints 
For secondary endpoints, all data from baseline 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:  
• 
Descriptive statistics for values and changes from baseline over time of all 
spirometry test parameters will be presented. 
• 
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  
• 
The absolute change in percent predicted FVC measured by spirometry during 
site visits at week 24 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 concomitant 
MMF medication use (Yes/No), and the presence/absence of IPAF as defined by 
the MDT 
• 
Absolute change from baseline to week 24 in percent predicted DLco will be 
compared between the treatment arms using a rank ANCOVA. Change from 
baseline to week 24 will be used as an outcome variable and standardized rank 
baseline value will be used as a covariate 


 
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o A summary table presenting the values of DLco (%) and its change from 
baseline will be presented over time and by treatment arm. 
• 
The absolute 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 
o A summary table presenting the 6MWD parameters and their change from 
baseline will be presented over time and by treatment arm. 
• 
The absolute change in UCSD-SOBQ total score will be analyzed using a rank 
ANCOVA model. The UCSD-SOBQ total 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 Please see section 4.5.4 for further details. 
• 
The absolute change in Leicester Cough Questionnaire total score will be 
analyzed using a rank ANCOVA model. The Leicester Cough Questionnaire total 
score recorded at 24 weeks will be used as the outcome variable and 
standardized rank baseline Leicester Cough Questionnaire total score will be 
used as a covariate. Please see section 4.5.4 for further details. 
• 
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. Please see 
section 4.5.4 for further details. 
• 
The change in total 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. Please see section 
4.5.4 for further details. 
• 
The time from randomization to the first occurrence of all-cause non-elective 
hospitalization and respiratory non-elective hospitalization will be analyzed using 
Kaplan-Meier (KM) techniques: 
o KM plots of time to first occurrence of the different events will be provided 
by treatment arm. Frequencies and percentages of patients with events 
and patients censored will be provided. Descriptive statistics of KM 
estimates of the time to first occurrence (weeks) will be presented. 
o Log-rank tests based on the time to the first event will be used to compare 
the two treatment arms. 
o Hazard ratios and corresponding 95% CI will be calculated by applying 
Cox-proportional hazard models in which the four groups from the two 
randomization stratification factors are included in the model. 
• 
The incidence of investigator reported acute exacerbations in the two treatment 
arms will be compared with Fisher’s exact test. 
o Incidence of, and time to first, investigator-reported acute exacerbations  


 
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• 
Progression free survival (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: 
o KM plots of time to first occurrence of the combined primary efficacy 
endpoint will be provided by treatment arm.  
o Frequencies and percentages of patients with events and patients 
censored will be provided. Descriptive statistics of KM estimates of PFS 
(weeks) will be presented. 
o The PFS of two randomized treatment arms will be compared with a log-
rank test.  
o Hazard ratios and corresponding 95% CI will be calculated by applying 
Cox-proportional hazard models. 
• 
An alternative definition of PFS (also in weeks), 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 as 
defined for the point above; 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 
assessed by the SOC “Respiratory, thoracic and mediastinal disorders” (in weeks) 
will be analyzed using Kaplan-Meier techniques as defined above; 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.  
4.5.3 
Exploratory Efficacy Endpoints 
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. 
For the MMF objective, primary and selected secondary endpoints will be investigated 
by means of a subgroup analyses that stratifies patients according to whether they 
received MMF treatment. In addition, the overall safety summary will be presented by 
this subgroup. The selected secondary endpoints are: 
• 
Deaths from any cause and respiratory disease-related 
• 
Hospitalizations from any cause and respiratory disease-related 
 


 
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The analysis of these exploratory efficacy endpoints by subgroup are defined under 
section Section 4.5.6. 
The mean FVC decline in each treatment arm will be calculated as in the primary 
analysis for the subgroups of patients that received MMF treatment and compared using 
a student’s t-test with a two-sided significance level α=0.05. Exploratory efficacy 
endpoints are discussed in the sensitivity and subgroup sections (see Section 4.5.5 and 
Section 4.5.6, respectively).  
 
Moreover, additional categorical analyses for the percent predicted DLco and 6MWD will 
be presented as exploratory: 
• 
Categorical change of >15% absolute decline from baseline to week 24 in 
percent predicted DLco will be compared between the treatment arms using a 
logistic regression. 
• 
Categorical change of >50% absolute decline from baseline to week 24 in 6MWD 
(m) will be compared between the treatment arms using a logistic regression. 
For the biomarker objective, assessments of the exploratory biomarkers and their 
relationship with drug responses will be described in a separate analysis plan. 
4.5.4 
Analyses of 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. 
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. 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, 
unless otherwise specified. 
St. George´s Respiratory Questionnaire (SGRQ) 
The St. George’s Respiratory Questionnaire (SGRQ) is an index designed to measure 
and quantifies health-related health status in patients with chronic airflow limitations. The 
SGRQ is a 50-item questionnaire, addressing the frequency of respiratory symptoms 
(items 1 – 8), the patient’s current state (sections 9 – 16). From the 50 items a total 
score, as well as three component scores (Symptoms, Activities, Impacts) will be derived. 
The total score ranges from 0, presenting the best possible health status to 100, 
presenting the worst possible health status. 
The change in SGRQ total score will be of primary interest when assessing health-
related quality of life (HRQoL). 


 
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The analysis of PROs assessed by SGRQ total score and by SGRQ component scores 
for symptoms, activity, and impacts will be analyzed as follows: 
• 
The absolute score values and changes from baseline for the total and each sub-
score will be presented descriptively over time by treatment arm. 
• 
Changes from baseline to week 24 or early discontinuation visit will be compared 
between the treatment arms using a rank ANCOVA with change from baseline as 
outcome variable and standardized rank baseline value as covariate. This analysis 
will be done only for the total score. 
The SGRQ and the details for calculating the score can be found in Appendix 3. 
The University of California, San Diego-Shortness of Breath Questionnaire 
(UCSD-SOBQ)  
The University of California, San Diego-Shortness of Breath Questionnaire (UCSD-
SOBQ) is a symptom-specific, 24-item, patient-self-administered questionnaire that 
assesses shortness of breath while doing a variety of activities of daily living. Each of the 
24 activities are rated on how dyspnea affects the activity on a 6-point scale: 0 = None at 
all to 5 = Maximal or unable to do because of breathlessness. The scores will be 
summarized to a total score, ranging from 0 – 120. 
The total score of the UCSD SOBQ will be summarized as follows: 
• 
The absolute total scores and changes from baseline will be presented descriptively 
over time by treatment arm. 
• 
Changes from baseline to week 24 or early discontinuation visit will be compared 
between the treatment arms using a rank ANCOVA with change from baseline as 
outcome variable and standardized rank baseline value as covariate.  
Additional details on the UCSD SOBQ can be found in Appendix 3 
The Leicester Cough Questionnaire  
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. 
The total score and the physical, psychological and social domain scores of the 
Leicester Cough Questionnaire will be analyzed as follows: 


 
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• 
The scores and changes from baseline will be presented descriptively over time by 
treatment arm. 
• 
Changes from baseline to week 24 or early discontinuation visit will be compared 
between the treatment arms using a rank ANCOVA with change from baseline as 
outcome variable and standardized rank baseline value as covariate. This analysis 
will be done only for the total score. 
Details on calculating the domain scores can be found in Appendix 3 
The Cough VAS 
This visual analogue scale is designed to help us learn about the severity of your cough. 
This scale is 100mm (10cm) in length.  
The cough VAS score will be summarized descriptively by visit and treatment arm. The 
change in cough VAS will be analyzed using a rank ANCOVA model. The change in 
VAS score for cough recorded at 24 weeks will be used as the outcome variable and the 
standardized rank baseline result will be used as a covariate. Please refer to Appendix 3 
for further details. 
4.5.5 
Sensitivity Analyses 
As a sensitivity analysis to the primary analysis, the time-adjusted mean FVC decline will 
be estimated by a repeated measures mixed model with patient effects fitted as random 
and day of measurement and treatment fitted as fixed effects. Corresponding model 
estimates will be tabulated. 
A second model adding the stratification factors as covariates will be also presented. 
Additional covariates such as gender, age and height that are used to determine FVC % 
predicted will be examined as well. 
Additionally, the impact of different assumptions with respect to the variance-covariance 
matrix underlying the repeated measures mixed model will be investigated.  
4.5.6 
Subgroup Analyses 
Subgroup analyses will be conducted for the exploratory endpoint, as described in 
Section 4.5.3. The following subgroups will be based on: 
• 
The four groups resulting from combinations of the two stratification factors: 
o Concomitant MMF treatment (yes/no) 
o Presence/absence of IPAF as defined by the MDT 
• 
Gender: Male, Female 


 
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• 
Age (years): <65 years, ≥ 65 years 
• 
Percent predicted FVC at Baseline: <65%, ≥65% to < 80%, ≥80% 
 
• 
Percent predicted DLco at Baseline: <35%, ≥35% 
• 
Body weight: <60 kg, ≥60 kg 
4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
No pharmacokinetic or pharmacodynamic analyses are planned for this study. 
4.7 
SAFETY ANALYSES 
All safety analyses of data from the double-blind treatment period will be based on the 
safety population, i.e., the safety population will include all randomized patients who 
received at least one dose of trial treatment, with patients grouped according to 
treatment received. Safety data from the follow-up period will be summarized based on 
the safety follow-up population. 
The safety objective for this trial is to evaluate the safety of pirfenidone vs. placebo. 
No formal statistical testing will be performed for safety parameters.  
Data collected during the 12-month safety follow-up will be analyzed separately (see 
section 4.8). 
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 4.03, 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) version 20.1 or higher 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. 
Descriptive statistics will be presented for dose modifications and treatment interruptions. 
Adverse events leading to treatment interruption or dose modification will also be 
summarized.  


 
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Laboratory parameters including hematology and the chemistry panel will be presented 
in shift tables of NCI-CTCAE version 4.03 grade at baseline vs. worst grade during 
treatment period. The laboratory parameters will be presented according to means, 
standard deviation, minimum, and maximum. Selected laboratory parameters will be 
also graphically presented over time. Liver abnormalities for the parameters total 
bilirubin, alkaline phosphatase, ALAT (SGPT) and ASAT (SGOT)) will be also presented. 
The results from the 12-lead ECGs will be summarized and presented.  
4.7.1 
Exposure of Study Medication 
All analyses described in this section refer to the data collected in the drug-log for the 
double-blind randomized treatment period. Unknown doses will be excluded from the 
exposure analyses.  
 
4.7.1.1 Treatment duration 
Summaries of dosing, treatment duration, dose interruptions or reductions during the 
randomized double-blind treatment period will be provided for each treatment arm 
separately. 
The overall treatment duration (weeks), including and excluding dose interruptions, will 
be summarized descriptively by treatment arm. The overall treatment duration including 
dose interruptions will be defined as follows: 
[Date of last positive dose of randomized treatment received (pirfenidone/placebo) – date of 
first intake of randomized treatment) + 1)] / 7. 
The overall treatment duration excluding dose interruptions will be derived from the 
treatment administration panels using the time windows described above, considering 
only days on treatment. i.e. positive dose. 
Details on treatment administration, reductions or interruptions will be listed. 
4.7.1.2 Doses and Dose modifications or interruptions 
The total dose (mg), the average daily dose (mg/d) and the last dose administered (mg/d) 
will be presented descriptively for each of the study treatments.  
The average daily dose will be calculated by summing up the number of capsules taken, 
divided by the overall treatment duration including dose interruptions as defined above.  
Numbers and proportions of patients with at least one dose modification, or drug 
interruption, will be presented for each treatment arm separately. Numbers and 
proportions of patients with 1, 2, 3 or more dose modifications, or treatment interruptions, 
will be given.  


 
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The total number of dose modifications, reductions or treatment interruptions, will be 
presented together with numbers and frequencies of reasons for dose modification, 
reduction or treatment interruption. 
Dose modifications, reductions or treatment interruptions will be presented as given in 
the drug logs dose strength and number of capsules taken. 
In addition, dose intensity will be analyzed descriptively by treatment arm over time. For 
calculation of dose intensities, the time from first administration of randomized treatment 
to the end date of randomized treatment will be considered. The following formula will be 
used for calculation: 
Dose intensity (DI) = (total dose received / total dose planned)*100. 
4.7.2 
Adverse Events 
Verbatim descriptions of adverse events (AEs) will be mapped to a preferred term (PT) 
and system organ class (SOC) using the Medical Dictionary for Regulatory Agencies 
(MedDRA®). MedDRA version 20.1 or above and related SMQ lists will be used for 
coding. 
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03. For AEs of varying severity, the 
most severe grade as documented on the eCRF will be used in the summaries. An AE 
will be considered severe if the most extreme grade will be larger or equal to 3. 
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. All 
adverse events will be reported until 28 days after the last dose of study drug. After this 
period, the Investigator should report any SAEs that are believed to be related to prior 
study drug treatment. 
For safety analysis of the double-blind treatment period treatment-emergent adverse 
events (TEAEs) will be defined as: 
• 
AEs that started or worsened on or after first intake of randomized treatment until last 
positive dose of randomized treatment + 28 days 
Adverse events that are reported after informed consent but before the first intake of 
randomized treatment will be considered as non-treatment-emergent AEs. These might 
include AEs that occur during the screening period. 
Post-treatment AEs are not expected to occur, but will be defined as AEs that are 
reported more than 28 days after the last dose of randomized treatment for patients who 
do not enter the 12-month safety follow-up period. Those AEs will be listed. 


 
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The analysis of AEs within the framework of the primary study analysis will focus on 
treatment-emergent AEs (TEAE).  
An overview of patient safety profile will present the number and proportion of patients in 
each treatment arm experiencing:  
• 
Any and any related treatment-emergent adverse events (TEAE) 
• 
Any and any related serious treatment-emergent adverse events (serious TEAE) 
• 
Any and any related severe treatment-emergent adverse events (TEAEs ≥ Grade 3) 
• 
Any and any related TEAE of special interest (AESI). 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:  [ALT or AST >3 x ULN + total bilirubin >2 x ULN]  
• 
 Any and any related hepatic side effects: elevations in ALT and AST >3 × ULN at 
the same timepoint in the study. 
• 
Any and any related gastrointestinal (GI) disorder (MedDRA SOC: GI Disorders) 
• 
Any and any related photosensitivity (MedDRA Preferred terms Photodermatosis, 
Photosensitivity reaction, Pruritus, Pruritus allergic, Pruritus generalized). Potential 
updates in those terms will be needed in case the MedDRA version changes. 
• 
Any and any related rash (MedDRA Preferred terms Nodular rash, Rash, Rash 
erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash 
papular, Rash pruritic, Rash follicular, Exfoliative Rash, Solar dermatitis, Solar 
urticarial, Sunburn, Erythema, Dry skin). Potential updates in those terms will be 
needed in case the MedDRA version changes. 
• 
Angioedema (MedDRA preferred term Angioedema). 
• 
Dizziness (MedDRA preferred term Dizziness). 
• 
Fatigue (MedDRA preferred term Fatigue). 
• 
Weight loss (MedDRA preferred term Weight loss). 
• 
Increase 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.  
• 
Any and any related TEAE leading to death 


 
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• 
Any and any related TEAE leading to treatment discontinuation 
• 
Any grade 3-4 laboratory liver test results 
o ASAT (SGOT) results 
o ALAT (SGPT) results 
o alkaline phosphatase results 
o total bilirubin results  
The incidence of TEAEs, related TEAEs, non-serious TEAEs, serious TEAEs, related 
serious TEAEs, grade 3-5 TEAEs and TEAEs leading to treatment discontinuation, dose 
modification or death will be summarized by treatment arm, by system organ class (SOC) 
and preferred term (PT) on the basis of the safety population. Frequencies and 
percentages of patients experiencing (at least) one event in the respective category will 
be presented by decreasing frequencies. If patients have more than one AE within a 
SOC or PT they will be counted only once for the respective SOC or PT. Additionally the 
total numbers of TEAEs will be provided for each SOC and overall. 
Similar summary presentations will be provided for the incidence of TEAEs leading to 
dose reduction and drug interruption and TEAEs leading to hospitalization. 
Non serious Treatment-emergent Adverse Events with >5% frequency will be also 
presented by SOC and PT. In addition, Serious Treatment-emergent Adverse Events, 
Fatal serious TEAEs and serious TEAEs related to pirfenidone or placebo will be 
presented in the same table by SOC and PT. 
A summary table presenting the numbers and frequency of patients with TEAEs by most 
extreme CTCAE Grade (Grade 1, Grade 2, Grade 3, Grade 4 and Grade 5) will be 
provided for each SOC and PT by treatment arm. In case the most extreme intensity is 
missing, it will be replaced by the initial intensity. If both most extreme and initial intensity 
are missing, the AE will be included in the Grade ≥3 category and a category for 
“missing” will be added.  
Further, Kaplan-Meier curves for time to onset of first adverse event of the most relevant 
related TEAEs will be provided by treatment arm when the number of events are enough 
to do the analyses. These will include the following PTs or groups of AEs: Nausea, 
Diarrhoea, Weight decreased, Fatigue, Decreased appetite, and photosensitivity, or rash. 
In addition, the analysis will be done for the SOC GI. 
All adverse event data will be listed by patient number and study day of onset including a 
flag variable for identifying the period of the event (double-blind treatment period or 
safety follow-up period). If the AE does not belong to any of the perods, the period flag 
will be missing.  


 
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4.7.3 
Deaths 
Numbers and frequencies of deaths and of deaths occurring within 28 days after the last 
dose of double-blind treatment will be presented by treatment arm.  
All information associated with deaths collected in eCRF panel on study discontinuation 
will be listed. A flag variable will be included in the listing specifying the study period 
when the death occurred. 
4.7.4 
Laboratory Data 
All of the laboratory tests will be conducted by the trial site’s local laboratory. 
All parameters will be graded according to NCI CTCAE (CTEP 2010), version 4.03, if 
applicable. Laboratory parameters that cannot be graded according to the corresponding 
NCI CTCAE version 4.03 will be assessed with respect to normal range (low, normal, 
high). 
Laboratory parameters including hematology and the chemistry panel will be presented 
in shift tables of NCI-CTCAE version 4.03 grade at baseline versus worst grade during 
randomized double-blind treatment period. The laboratory parameters will be presented 
according to means, standard deviation, minimum, and maximum. Selected laboratory 
parameters will be also graphically presented over time.  
The following laboratory 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). 
Clinical laboratory values will be presented separately for CTCAE-gradable and non-
CTCAE gradable parameters by laboratory panel (hematology, serum chemistry). For 
laboratory analyses, visits will be assigned to visit windows as described in Section 4.9. 
This will also be valid for possible unscheduled visits. In case that multiple evaluable 
assessments occur within the same visit, the nearest to midpoints value will be used for 
analyses. 
The following summaries will be prepared: 
For each laboratory parameter, descriptive statistics of laboratory values at each 
scheduled visit (derived as described above), and absolute changes from baseline to 
post-baseline will be presented by treatment arm. 


 
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Shift tables presenting categorical changes in CTCAE grade from baseline to worst 
grade recorded during the double blind period, in the indicated direction, will be provided 
for CTCAE-gradable parameters by treatment arm. If no CTCAE grade is available for a 
specific laboratory variable, shift tables will present worst changes with respect to normal 
range category (low, normal, high). 
Liver abnormalities (total bilirubin, alkaline phosphatase, ALAT (SGPT), ASAT (SGOT)) 
of Grade 3 and 4 will be presented showing numbers and percentages of patients for 
each parameter separately. Line graphs of liver parameters will be provided. 
4.7.5 
Vital Signs 
Vital signs will include measurements of respiratory rate (breaths/min), pulse rate 
(beats/min), and systolic and diastolic blood pressures (mmHg) while the patient is in a 
seated position, temperature (C) and weight (kg). Vital signs will be assigned to visit 
windows as per Section 4.9. Descriptive statistics will be used to summarize vital signs 
data at baseline and at each scheduled post-baseline visit, and for the absolute change 
from baseline to each scheduled post-baseline visit by treatment arm during double-blind 
period.  
4.7.6 
ECG 
Single ECG recordings will be obtained at specified time points, as outlined in the 
Schedule of Assessments (see Appendix 2), and may be obtained at unscheduled time 
points as indicated. 
The following should be recorded in the appropriate eCRF: heart rate (beats/min), RR 
interval (msec), QRS interval (msec), PR duration (msec), uncorrected QT interval 
(msec), 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. 
QTcF values of the safety population will be assigned to the following intervals: < 500 ms, 
500–550 ms, and > 550 ms. Numbers and percentages of patients with their maximum 
QTcF interval category will be summarized by treatment arm over time. Absolute 
changes from the Baseline to each post-baseline visit in QTcF values will be categorized 
to < 31 ms, 31–60 ms, and > 60 ms. Numbers and percentages of patients in each 
category will be presented by treatment arm for each post-baseline visit or treatment 
discontinuation. Planned visits will be used for presentations. 
 
Descriptive statistics for heart rate, RR interval, QRS interval, PR duration, uncorrected 
QT interval, and the QTcF will be presented for each visit by treatment arm. 
A listing containing ECG data will be presented. 
4.8 
SAFETY FOLLOW-UP ANALYSES 
Data collected during the safety- follow-up period will be analyzed in the following way. 


 
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Adverse events during the 12-month safety follow-up period for pirfenidone treatment will 
be defined as: 
• 
AEs that started or worsened on or after the date of safety follow-up period start until 
the end of the safety follow-up. 
The safety follow-up population will be used for these analyses.  
Summary tables for the incidence of AEs, related AEs, serious AEs, related serious AEs, 
severe AEs and severe related AEs will be summarized by system organ class (SOC) 
and preferred term (PT). Frequencies and percentages of patients experiencing (at least) 
one event in the respective category will be presented by decreasing frequencies. If 
patients have more than one AE within a SOC or PT they will be counted only once for 
the respective SOC or PT. Additionally, the total numbers of AEs will be provided for 
each SOC and overall. As with the end of the double-blind treatment period, an overview 
of safety will also be presented. 
Pirfenidone exposure during safety-follow-up will be analyzed in a similar fashion as 
described in section 4.7.1 with regard to treatment duration and amount of drug intake. 
Data of laboratory assessments (AST, ALT, bilirubin, and alkaline phosphatase) and vital 
signs during safety-follow-up period will be analyzed in a similar fashion as described in 
section 4.7.4 and 4.7.5. 
Data will be presented by randomized treatment labeled as ‘Randomized Pirfenidone’ 
and ‘Randomized Placebo’. 
4.9 
MISSING DATA 
In general, missing data will not be imputed. Exceptions will be made for the data related 
to adverse events and concomitant medications as described below. 
For adverse events, missing start dates will only be imputed for determination of whether 
the adverse event is considered to be treatment-emergent or not. 
Incomplete or missing onset dates will be imputed to the earliest date possible (using 
any reliable portions of the onset date that are available). The onset day is considered 
unreliable if the month or year portions of the date are missing.  
In case the month portion of the AE start date is missing, the AE start date will be 
imputed to the earliest day possible by using the following principles: 
• 
If Treatment Start Date is missing, then the AE Start Date will be imputed as 01-
01-YYYY or the earliest date regarding signature of informed consent, screening 
date or randomization date, whichever is the later one 
• 
When the Treatment Start Date is not missing,  and the years of AE Start Date 
and Treatment Start Date coincide, the AE onset date will be set to the 
Treatment Start Date 


 
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• 
When the Treatment Start Date is not missing, and the years of the AE Start 
Date and the Treatment Start Date do not coincide, then the AE Start Date will be 
imputed as 01-01-YYYY or the earliest date regarding signature of informed 
consent, screening date or randomization date, whichever is the later one 
In case the day portion of the AE Start Date is missing, the AE Start Date will be imputed 
to the earliest day possible as follows: 
• 
If the Treatment Start Date is missing, then the AE Start Date will be imputed as 
01-MMM-YYYY or the earliest date regarding signature of informed consent, 
screening date or randomization date, whichever is the later one 
• 
When the treatment date is not missing, and the years and months from the AE 
Start Date and the Treatment Start Date coincide, the AE onset date will be set to 
the Treatment Start Date 
• 
When the Treatment Start Date is not missing, and AE Start Date is after the 
Treatment Start Date according to the given year or month, then the AE Start 
Date will be imputed as 01-MMM-YYYY  
If the AE stop date is missing, then the event will be assumed to be ongoing and a stop 
date will not be imputed.  
In the case the treatment end date is missing and it cannot be judged whether the event 
occurred during the period of Treatment Start Date to Treatment End Date plus 28 days, 
the AE will be considered treatment-emergent as long as it is not flagged as prior AE. 
For imputation and handling of missing intensity or relationship to study medication, 
please see Section 4.7.2. 
All other missing or incomplete adverse event data will be left as missing. 
For concomitant medications, missing start or end dates will only be imputed to 
determine whether the medication is considered to be prior, on-treatment, post-treatment.  
In general if only the day is missing from the start date then the missing day will be 
imputed as 01-MMM-YYYY unless the month is the same month as the start of study 
medication in which case the missing date will be imputed as the treatment start date. 
If both the day and month are missing from the start date then the start date will be 
imputed as 01-JAN-YYYY. 
If both the day and month are missing from the start date year is the same as treatment 
start date then the start date will be imputed as ‘treatment start date’, but if the year is 
after treatment start date, the start date will be imputed as 01-JAN-YYYY. 
If the day, month and year are all missing from the start date then the start date will be 
imputed as 01-JAN for the year in which the patient was recruited to the study. 


 
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If the day, month and year are all missing from the start date then the start date will be 
imputed as ‘treatment start date’. 
If an incomplete stop date has both the year and month present, the day will be imputed 
as the last day of the month or date of discontinuation/death. 
If the AE is ongoing at time of primary analysis, concomitant medication will be 
summarized for the double-blind treatment period and safety follow-up. 
4.10 
VISIT WINDOWS 
Visit windows for double-blind treatment period will be applied to vital signs and 
laboratory data and the derived visits will be used in the by-visit summarizations. If 
multiple observations fall within the same visit window, the observation with the nearest 
to midpoint value will be used in the analysis, if not stated otherwise. If subjects 
discontinue from the double-blind treatment period early the data will be assigned to the 
early discontinuation visit. The date of early discontinuation will be considered as the 
target date.  
The “Baseline” visit is a derived data point to identify baseline values which are used to 
calculate the change from baseline values. Baseline is defined in section 4.2.2 
The End of Treatment [EOT] visit will either be a copy of early discontinuation records for 
patients who prematurely discontinued double-blind treatment period or Week 24 
records for patients who completed the double-blind treatment period. 
Table 2 
Visit Windows  
Analysis Visit [AVISITN] 
Target Day 
Analysis Window (scheduled Study Days) 
Baseline [0] 
1 
Last valid assessment prior to first intake 
of randomized study drug 
(pirfenidone/placebo). 
Generally, it is assumed that 
measurements referring to the Day 1 
(Week 1) visit have been performed before 
randomized study drug 
(pirfenidone/placebo) was given. 
Week 4 [4] 
28 
One day after first dose of randomized 
treatment to 42 
Week 8 [8] 
56 
43 to 70 
Week 12 [12] 
84 
71 to 98 
Week 16 [16] 
112 
99 to 126 
Week 20 [20] 
140 
127 to 154 


 
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Week 24 [24]   
168 
155 to a maximum of 195 if the patient did 
not early discontinued. 
Early discontinuation [25] 
Not applicable 
As occurred  
End of treatment (EOT) 
[26] 
Not applicable 
As occurred  
Follow-up visit (FUP1) [27]
Not applicable 
As occurred 
Safety follow-up 
visits(SFUP) [28] 
Not applicable 
As occurred: 
Month 1 to 6: Monthly visits 
Month 7 to12: Approximately every 3 
months 
Additional Safety follow-up 
visit [29] 
Not applicable 
As occurred: 
up to 12 months plus 28 days 
 
4.11 
INTERIM ANALYSES 
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. 
No formal interim analyses for efficacy are planned. 
4.12 
BIOMARKER ANALYSES 
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 2). 
Optional Research Biosample Repository (RBR) whole blood samples for 
deoxyribonucleic acid (DNA) extraction, described in Section 4.5.8 of the protocol, will 


 
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also be collected at baseline to examine genetic polymorphisms and their potential role 
in the pathogenesis and associated clinical outcomes of unclassifiable ILD. 
Biomarkers associated with fibrosis and ILD will be evaluated in plasma, serum, and 
whole blood ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) samples. 
Analyses on biomarker data will not be in the scope of this SAP, but will be planned and 
described separately. 


 
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REFERENCES 
Antoniou KM, Margaritopoulos GA, Tomassetti S, Bonella F, Costabel U, Poletti V. 
Interstitial lung disease. Eur Respir Rev 2014;23:40–54. 
Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and 
tolerability of pirfenidone in patients with scleroderma-associated interstitial lung 
disease: the LOTUSS trial. J Rheumatol 2016;epub. 
Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary 
fibrosis. An international working group report. Am J Respir Crit Care Med 
2016;194:265–75. 
Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable 
interstitial lung disease. Eur Respir J 2013;42:750–7. 
Fischer A, Brown KK, du Bois RM, et al. Mycophenolate mofetil improves lung function 
in connective tissue disease-associated interstitial lung disease. J Rheumatol 
2013;40:640–6. 
Eakin EG, Resnikoff PM, Prewitt LM, et al. Validation of a new dyspnea measure: the 
UCSD Shortness of Breath Questionnaire. University of California, San Diego. Chest. 
1998 Mar;113(3):619-24. 
Ries AL, Minimally clinically important difference for the UCSD Shortness of Breath 
Questionnaire, Borg Scale, and Visual Analog Scale. COPD. 2005 Mar;2(1):105-10.  
Jones PW, Quirk FH, Baveystock CM, The St George's Respiratory Questionnaire. 
Respir Med. 1991 Sep;85 Suppl B:25-31; discussion 33-7.  
Nishimura K, Tsukino M, Hajiro T, Health-related quality of life in patients with chronic 
obstructive pulmonary disease. Curr Opin Pulm Med. 1998 Mar;4(2):107-15.  
St. George’s Respiratory Questionnaire: http://www.healthstatus.sgul.ac.uk/sgrq 
 
S S Birring, B Prudon, A J Carr, S J Singh, M D L Morgan, I D Pavord, Development of a 
symptom specific health status measure for patients with chronic cough: Leicester 
Cough Questionnaire (LCQ). Thorax 2003;58:339-343. 
 
 
 
 
 


 
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Appendix 1 
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. 


 
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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. 
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 
Appendix 3 
Patient Reported Outcome Questionnaire 
 
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 of the CSP) 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. 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. 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 


 
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dose must be re-titrated over 14 days. 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. 
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 Appendix 3 
Patient Reported Outcome Questionnaire 
 below. 
 
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 


 
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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 2). 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. 
 
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 


 
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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. 
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. 
 
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 
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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) 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 


 
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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 
measured by handheld spirometry over the 24-week double-blind treatment period. 
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. 


 
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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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Appendix 2 
 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 
 
 
 
 
 
 
 
 
 
 
 


 
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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 
 
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 
 
 
 
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 
 


 
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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 
 
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 
 
 
 


 
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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 
 
UCSD-SOBQ q 
 
 
x 
 
 
x 
 
 
x 
x 
 
 
 
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 
 
 
 


 
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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 
 
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. 


 
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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. 
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. 


 
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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.  
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. 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. 
 
 
 
a. 
 


 
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Appendix 3 
Patient Reported Outcome Questionnaire 
Leicester Cough Questionnaire 
 


 
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Scoring 
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. 
The scores from each of the following questions are added together to provide the mean score 
for each domain: 
1. Physical: 1, 2, 3, 9, 10, 11, 14, 15    
2. Psychological: 4, 5, 6, 12, 13, 16, 17 
3. Social: 7, 8, 18, 19 
Domain scores: total score from items in domain/number of items in domain (range 1–7). 
Total scores: addition of domain scores (range 3–21). 


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


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


 
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SGRQ 
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. 
 


 
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STRUCTURE OF SGRQ 
The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in 
patients with diseases of airways obstruction. 
Part 1 (Questions 1-8) addresses the frequency of respiratory symptoms. It is not designed to 
be a precise epidemiological tool, but to assess the patient’s perception of their recent 
respiratory problems. 
Part 2 (Sections 9-16) addresses the patient’s current state (i.e. how they are these days). 
The Activity score measures disturbances to daily physical activity. The Impacts score covers a 
range of disturbances of psycho-social function. Validation studies for the original SGRQ 
showed that this component relates in part to respiratory symptoms, but it also correlates quite 


 
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strongly with exercise performance (6-minute walk test), breathlessness in daily life (MRC 
breathlessness score) and disturbances of mood (anxiety and depression). The Impacts score 
is, therefore, the broadest component of the questionnaires, covering the whole range of 
disturbances that respiratory patients experience in their lives. 
Three component scores are calculated for the SGRQ 
Symptoms – concerned with the effect of respiratory symptoms their frequency and severity 
Activity concerned with activities that cause or are limited by breathlessness 
Impacts covers a range of aspects concerned with social functioning and psychological 
disturbances resulting from airway disease. 
Total score summaries the impact of disease on overall health status.  Scores are expressed as 
a percentage of overall impairment where 100 represents worst possible health status and 0 
indicates best possible health status. 
SGRQ SCORES IN HEALTHY SUBJECTS 
Means (95% confidence intervals) for SGRQ scores in normal subjects with no history of 
respiratory disease 
N 
Age-years 
FEV1 as 
% 
predicted 
Symptoms 
score 
Activity 
score 
Impacts 
Score 
Total 
Score 
72 
46  (17 - 80) 
95 (91- 
99) 
12 (9-15) 
9 (7-12) 
2 (1-3) 
6 (5-7) 
 


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


 
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ITEM WEIGHTS 
Once the questions have been answered the following weights are applied to the individual 
responses  
PART 1 
Over the past 3 months, I have coughed: 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
80.6 
63.2 
29.3 
28.1 
0.0 
 
Over the past 3 months, I have brought up phlegm (sputum): 
 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
76.8 
60.0 
34.0 
30.2 
0.0 
 
3) Over the past 3 months, I have had shortness of breath: 
 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
87.2 
71.4 
43.7 
35.7 
0.0 
 
4) Over the past 3 months, I have had attacks of wheezing: 
 
Most 
days/week 
Several days/ 
week 
A few days a 
month 
 Only with chest 
infections  
Not at all 
86.2 
71.40 
45.6 
36.4 
0.0 
 


 
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5) During the past 3 months, how many severe or very bad unpleasant attacks of chest trouble 
have you had? 
 
More than three
3  attacks 
2 attacks 
 1 attack 
None 
86.7 
73.5 
60.3 
44.2 
0.0 
 
6) How long did the worst attack of chest trouble last? 
 
a week or more 
3 or more days 
1 or 2 days  
Less than a day
None 
89.7 
73.5 
58.8 
41.9 
0.0 
 


 
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7) Over the past 3 months, in an average week, how many good days (with little chest trouble) 
have you had? 
 
No good days 
1 or 2 good 
days 
3 or 4 good 
days 
Nearly every 
day 
Every day 
93.3 
76.6 
61.5 
15.4 
0.0 
 
8) If you have a wheeze, is it worse in the morning? 
 
No 
Yes 
0.0 
62.0 
 
PART 2 
The weights in Part 2 are also applied to the individual responses to each question. The worse 
the impact the higher the weight. This means that weights are not applied sequentially in the 
order that the response is given.  
9) How would you describe your chest condition? 
 
The most important problem I have  
 
83 .2
Causes me quite a lot of problems   
  
82.5 
Causes me a few problems  
 
 
 
34.6 
Causes no problem   
 
 
 
  
0.0 
 
10) If you have ever had paid employment? 
 
My chest trouble made me stop work 
 
 
88.9 


 
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My chest trouble interferes with my work or made me change my work 
77.6 
My chest trouble does not affect my work 
 
 
0.0 
 
11) Questions about what activities usually make you feel breathless. 
 
Sitting or lying still   
90.6 
Getting washed or dressed   
82.8 
Walking around the home   
80.2 
Walking outside on the level   
81.4 
Walking up a flight of stairs   
76.1 
Walking up hills   
75.1 
Playing sports or games   
72.1 
 


 
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12) More questions about your cough and breathlessness. 
 
My cough hurts  
81.1 
My cough makes me tired  
79.1 
I get breathless when I talk  
84.5 
I get breathless when I bend over  
76.8 
My cough or breathing disturbs my sleep  
87.9 
I get exhausted easily  
84.0 
 
13) Questions about other effects your chest trouble may have on you. 
 
My cough or breathing is embarrassing in public  
74.1 
My chest trouble is a nuisance to my family, friends or neighbours  
79.1 
I get afraid or panic when I cannot get my breath  
87.7 
I feel that I am not in control of my chest problem  
90.1 
I do not expect my chest to get any better  
82.3 
I have become frail or an invalid because of my chest  
89.9 
Exercise is not safe for me  
75.7 
Everything seems too much of an effort  
84.5 
 
14) Questions about your medication. 
 
My medication does not help me very much   
88.2 


 
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I get embarrassed using my medication in public   
53.9 
I have unpleasant side effects from my medication   
81.1 
My medication interferes with my life a lot   
70.3 
 
15) Questions about how activities may be affected by your breathing. 
 
I take a long time to get washed or dressed   
74.2 
I cannot take a bath or shower, or I take a long time   
81.0 
I walk more slowly than other people, or I stop for rests   
71.7 
Jobs such as housework take a long time, or I have to stop for rests   
70.6 
If I walk up one flight of stairs, I have to go slowly or stop   
71.6 
If I hurry or walk fast, I have to stop or slow down   
72.3 
My breathing makes it difficult to do things such as walk up hills, carry things up stairs, 
light gardening such as weeding, dance, play bowls or play golf   
74.5 
My breathing makes it difficult to do things such as carry heavy loads, dig the garden 
or shovel snow, jog or walk at 5 miles per hour, play tennis or swim  
71.4 
My breathing makes it difficult to do things such as very heavy manual work, run, 
cycle,swim fast or play competitive sports  
63.5 
 


 
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16) We would like to know how your chest trouble usually affects your daily life. 
 
I cannot play sports or games   
64.8 
I cannot go out for entertainment or recreation   
79.8 
I cannot go out of the house to do the shopping   
81.0 
I cannot do housework   
79.1 
I cannot move far from my bed or chair   
94.0 
 
17) Tick the statement which you think best describes how your chest affects you. 
 
It does not stop me doing anything I would like to do   
0.0 
 It stops me doing one or two things I would like to do   
42.0 
It stops me doing most of the things I would like to do   
84.2 
It stops me doing everything I would like to do  
96.7 
 
SCORING ALGORITHM 
Three component scores are calculated: Symptoms; Activity; Impacts 
One Total score is also calculated. 
 
PRINCIPLE OF CALCULATION 
 
Each questionnaire response has a unique empirically derived 'weight'. The lowest possible 
weight is zero and the highest is 100. 
 


 
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Each component of the questionnaire is scored separately in three steps: 
i. The weights for all items with a positive response are summed. 
 
ii The weights for missed items are deducted from the maximum possible weight for 
each component. The weights for all missed items are deducted from the maximum 
possible weight for the Total score. 
 
iii. The score is calculated by dividing the summed weights by the adjusted maximum 
possible weight for that component and expressing the result as a percentage : 
Score = 100 x Summed weights from positive items in that component 
Sum of weights for all items in that component 
 
The Total score is calculated in similar way: 
Score = 100 x Summed weights from positive items in the questionnaire 
Sum of weights for all items in the questionnaire 
 
Sum of maximum possible weights for each component and Total: 
 
Symptoms 662.5 
Activity 1209.1 
Impacts 2117.8 
Total 3989.4 
(Note: these are the maximum possible weights that could be obtained for the worst possible 
state of the patient). 
 


 
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It will be noted that the questionnaire requests a single response to questions 1-7, 9-10 and 17. 
If multiple responses are given to one of these questions then averaging the weights for the 
positive responses for that question are acceptable 
 
SYMPTOMS COMPONENT 
This is calculated from the summed weights for the positive responses to questions 1-8. 
 
ACTIVITY COMPONENT 
This is calculated from the summed weights for the positive responses to questions 11 and 15. 
 
IMPACTS COMPONENT 
This is calculated from the summed weights for the positive responses to questions 9-10, 12- 14 
and 16-17. 
 
TOTAL SCORE 
The Total score is calculated by summing all positive responses in the questionnaire and 
expressing the result as a percentage of the total weight for the questionnaire  
 
HANDLING MISSED ITEMS 
There should not be any missed items but if there are missing items  the scores should be 
calculated using the following rules: 
 following should be used: The following method is recommended for missing items: 
 
Symptoms 


 
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The Symptoms component will tolerate a maximum of 2 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Symptoms component (662.5) and from 
the Total weight (3989.4). 


 
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Activity 
The Activity component will tolerate a maximum of 4 missed items. The weight for the 
missed item is subtracted from the total possible weight for the Activity component (1209.1) and 
from the Total weight (3989.4). 
Impacts 
The Impacts component will tolerate a maximum of 6 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Impacts component (2117.8) and from 
the Total weight (3989.4). 
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. 
 


 
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Cough Visual Analogue Scale (VAS) 
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.