Conditions: Rheumatoid Arthritis Interstitial Lung Disease
Keywords: TRAIL1 TRAIL Pirfenidone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 123
Healthy volunteers: no

Brief summary:
The purpose of this study is to to assess the safety and tolerability of pirfenidone 2403 mg/day for the treatment of RA-associated interstitial lung disease.

Detailed description:
This is a phase 2, randomized, double blind, placebo controlled trial of pirfenidone for the treatment of RA associated interstitial lung disease. Approximately 270 subjects will be randomized to receive Pirfenidone 2403 mg per day or placebo in a 1:1 ratio. The primary outcome of this study is to assess the efficacy of pirfenidone 2403 mg/day versus placebo in patients with RA associated interstitial lung disease, as defined by progression free survival over the 52 weeks of treatment. Patients will receive blinded study treatment from the time of randomization until the Week 52 Visit.

Eligible patients aged 18 to 85 years must meet 2010 ACR/EULAR criteria for RA (Aletaha, Neogi et al. 2010) as well as RA-associated ILD, as determined by imaging and, when available, lung biopsy. Patients will be required to have a % predicted FVC ≥40 and % predicted DLCO or TLCO ≥30 at screening.

The dose of study treatment will be titrated over 14 days. Patients will receive a telephone assessment at Weeks 1 and 2, and visit the clinic at Weeks 4, 8, 13, 19, 26, 39, and 52. Subjects will have a follow up phone call 28 days after completion of the study drug. Patients should complete a compliance diary between visits. If patients discontinue study treatment for any reason before the end of the study, they should continue with all scheduled study procedures through Week 52. If subjects are unable to complete the study visits as scheduled, all efforts should be made to complete an early termination visit.

The primary outcome variable of this study will be progression free survival, defined as progression free from decline in FVC of 10% or greater during the 52 week study period.

More information can be found at www.ralung.org.

Arms:
arm 1: Pirfenidone 2403 mg/d for 52 weeks arm 2: Placebo for 52 weeks

Interventions: intervention 1: Pirfenidone intervention 2: Placebo
Intervention descriptions: intervention 1: Pirfenidone three times daily (2403 mg) for 52 weeks intervention 2: Placebo three times daily for 52 weeks

Protocol document:
Prot_000.pdf: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Safety, 
Tolerability and Efficacy of Pirfenidone in Patients with Rheumatoid Arthritis 
Interstitial Lung Disease  
TRAIL1 
 
Principal Investigator 
Ivan Rosas, MD 
Pulmonary Critical Care and Sleep Medicine 
Baylor College of Medicine 
7200 Cambridge Street 
Houston, TX 77030 
Tel: (713)-798-8842 
Fax: (713) 798-2688 
Ivan.Rosas@bcm.edu 
 
 
 
 
Co-PrincipaI Investigator 
Hilary Goldberg, MD, MPH 
Pulmonary and Critical Care Medicine 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Tel: 617-732-5499 
Fax: 617-732-7421 
hjgoldberg@bwh.harvard.edu 
 
Data Coordinating Center Director  
Cathie Spino, D.Sc 
Department of Biostatistics 
School of Public Health II 
University of Michigan 
1415 Washington Heights, Rm M4507 
Ann Arbor, MI 48109-2029 
Tel: (734) 615-5469 
Fax: (734) 647-3711 
spino@med.umich.edu 
 
 
 
 
 
 


ii 
 
Grant funding provided by:   
Genentech, Inc.  
1 DNA Way 
South San Francisco, CA 94080 
 
Protocol Version Number:  v.8.0  
Protocol Version Date:  13OCT2020


TRAIL1: A Phase ll Study of Pirfenidone in Patients with RA-ILD 
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CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................... 6 
STATEMENT OF COMPLIANCE ......................................................................................................................... 8 
PROTOCOL SUMMARY ........................................................................................................................................ 9 
SUMMARY SCHEMATIC OF STUDY DESIGN ............................................................................................... 15 
1 
KEY ROLES .................................................................................................................................................. 16 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................... 17 
2.1 
 Background Information ............................................................................................................... 17 
2.1.1 
RA-ILD 
17 
2.1.2 
Nonclinical Overview Supporting Use in RA-ILD ....................................................... 18 
2.1.3 
Summary of Findings from Human Clinical Studies ................................................... 19 
2.1.3.1 
Shionogi Phase 2 Study (SP2) (Azuma et al. 2005) .................................................... 19 
2.2 
 Rationale and Study Approach ................................................................................................... 23 
2.3 
 Potential Risks and Benefits ....................................................................................................... 25 
2.3.1 
Known Potential Risks ...................................................................................... 25 
2.3.2 
Known Potential Benefits .................................................................................. 25 
3 
STUDY OBJECTIVES AND PURPOSE ................................................................................................... 25 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................... 25 
4.1 
 Description of the Study Design ................................................................................................ 25 
4.2 
 Study Endpoints ............................................................................................................................. 26 
4.2.1 
Primary Endpoint ............................................................................................... 26 
4.2.2 
Secondary Endpoints ........................................................................................ 26 
4.2.3 
Exploratory Endpoints ...................................................................................... 27 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 27 
5.1 
 Participant Inclusion Criteria ....................................................................................................... 27 
5.2 
 Participant Exclusion Criteria ..................................................................................................... 29 
5.3  
Participant Withdrawal or Termination ...................................................................................... 31 
5.3.1  
Reasons for Withdrawal or Termination .......................................................... 31 
5.3.2 
Handling of Participant Withdrawals or Termination ..................................... 31 
5.3.3 
Early Discontinuation of Study Drug ............................................................... 31 
5.3.4 
Early Termination Visit ...................................................................................... 31 
5.3.5 
Study Treatment Pre-Restart Visits ................................................................. 32 
5.3.6 
Unscheduled Visits ............................................................................................ 32 
5.3.7 
Lost to Follow-Up ............................................................................................... 32 
5.4 
 Premature Termination or Suspension of Study .................................................................... 32 
5.5 
 Approval of nintedanib (OFEV) in the United States ............................................................. 33 
6 
STUDY AGENT ............................................................................................................................................ 33 
6.1 
 Study Agent(s) and Control Description .................................................................................. 33 
6.1.1 
Source and Acquisition of Study Drugs .......................................................... 33 
6.1.2 
Study Agent Formulation, Appearance, Packaging and Labeling ................ 33 
6.1.3 
Product Storage & Stability .............................................................................. 33 


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6.1.4 
Dispensing of Study Treatment ........................................................................ 33 
6.1.5 
Pre-specified Dose Adjustment & Modifications ............................................ 34 
6.1.6 
Duration of Therapy ........................................................................................... 36 
6.1.7 
Missed Doses ..................................................................................................... 36 
6.1.8 
Interruption of Study Treatment ....................................................................... 36 
6.1.9 
Precautionary Measures ................................................................................... 36 
6.2 
 Study agent Accountability Procedures ................................................................................... 37 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................................. 37 
7.1 
 Study Procedures/Evaluations ................................................................................................... 37 
7.1.1 
Laboratory Assessments .................................................................................. 38 
7.1.2 
Clinical Assessments ........................................................................................ 39 
7.2 
 Summary of Study Schedule and Assessments .................................................................... 42 
7.2.1 
Screening Period................................................................................................ 42 
7.2.2 
Assessments During Treatment ....................................................................... 44 
7.3 
 Concomitant Medications & Treatments During the Study ................................................. 47 
7.3.1 
Concomitant Medications ................................................................................. 47 
7.3.2 
Treatment for Acute ILD Exacerbations .......................................................... 48 
7.4 
 Prohibited Medications and Treatments During the Study ................................................. 48 
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 48 
8.1 
 Specification of Safety Parameters ........................................................................................... 48 
8.2 
 Safety Data Exchange Agreement ............................................................................................. 49 
8.2.1 
Background ........................................................................................................... 49 
8.2.2 
Definitions ........................................................................................................... 49 
8.2.3 
Randomization Codes for Blinded Clinical Trials ........................................... 50 
8.2.4 
Reporting to Regulatory Authorities, Ethics Committees and Investigators50 
8.2.5 
Language ............................................................................................................ 51 
8.2.6 
Records 51 
8.3 
 AE and SAE Severity Grades and Relationship to Study Treatment ................................ 52 
8.3.1 
Adverse Event Reporting .................................................................................. 52 
8.3.2 
Serious Adverse Event Reporting .................................................................... 52 
8.3.3 
Unexpected Adverse Event Reporting ............................................................ 53 
8.3.4 
Reporting of Pregnancy .................................................................................... 54 
8.4 
 Safety Oversight ............................................................................................................................. 54 
9 
CLINICAL MONITORING ............................................................................................................................ 54 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 55 
10.1 
Randomization and Treatment Assignment ............................................................................. 55 
10.2 
Sample Size and Power Considerations ................................................................................... 55 
10.2.1 
Primary endpoint: .............................................................................................. 55 
10.2.2 
Secondary and exploratory endpoints: ........................................................... 57 
10.3 
Adverse Events ................................................................................................................................ 57 
10.4 
Statistical Analysis .......................................................................................................................... 59 
10.4.1 
Analysis Populations ......................................................................................... 59 
10.4.2   
Efficacy Analyses .............................................................................................. 59 
10.4.3 
Safety Analyses.................................................................................................. 60 
10.4.5 
Administrative Reporting .................................................................................. 60 


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10.4.6 
Trial Monitoring and Interim Analyses ............................................................ 60 
10.5 
Measures to Minimize Bias ........................................................................................................... 60 
10.5.1 
Randomization and Blinding ............................................................................ 60 
10.5.2 
Unblinding of Treatment Assignment .............................................................. 61 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 61 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 62 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 62 
13.1 
Ethical Standard .............................................................................................................................. 62 
13.2 
Institutional Review Board ............................................................................................................ 62 
13.3 
Informed Consent Process ........................................................................................................... 63 
13.4 
Delegation of Principal Investigator Responsibilities ............................................................ 63 
13.5 
Coordinating Investigator ............................................................................................................. 63 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 63 
14.1 
Retention of Documents ................................................................................................................ 63 
14.2 
Retention of Data ............................................................................................................................. 64 
14.4 
Investigator Brochure .................................................................................................................... 64 
14.5 
Case Report Forms ......................................................................................................................... 64 
14.6 
Publication and Data Sharing Policy .......................................................................................... 65 
15 
STUDY ADMINISTRATION AND OVERSIGHT ...................................................................................... 65 
15.1 
Procedure for Protocol Modification .......................................................................................... 65 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 65 
17 
COVID-19 MANAGEMENT PLAN ............................................................................................................. 65 
17.1 
SAFETY CONCERN AND MANAGEMENT OF STUDY DRUG ............................................... 66 
17.2 
IMPACT ON SCREENING AND RANDOMIZATION .................................................................. 66 
17.3 
MODIFICATIONS TO STUDY VISITS AND PROCEDURES .................................................... 66 
17.4 
SITE MONITORING .......................................................................................................................... 67 
18  LITERATURE REFERENCES.................................................................................................................... 67 
APPENDIX LIST .................................................................................................................................................... 70 
Appendix A  SCHEDULE OF STUDY ASSESSMENTS ................................................................................................. 71 
Appendix B  TRAIL1 CAPSULE DOSING FLOWCHART ............................................................................... 73 
Appendix C SAFETY REPORTING DEFINITIONS AND CONTACTS ................................................. 74 
Roche Contacts ........................................................................................................................................................ 78 
BCM Contacts ........................................................................................................................................................... 79 
Appendix D TREATMENT ASSIGNMENT NOTIFICATION LETTER ............................................................................ 80 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvate transaminase 
ANCOVA 
analysis of covariance 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
ATS 
American Thoracic Society 
BAL 
bronchoalveolar lavage 
bFGF 
basic fibroblast growth factor 
CI 
confidence interval 
CRF 
case report form 
D-12 
Dyspnea 12 questionnaire 
DCC 
Data Coordinating Center 
DLCO 
carbon monoxide diffusing capacity 
% DLCO 
percent predicted carbon monoxide diffusing capacity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ERS 
European Respiratory Society 
FDA 
(United States) Food and Drug Administration 
FEV1 
forced expiratory volume in one second 
FVC 
forced vital capacity 
%FVC 
percent predicted forced vital capacity 
GGT 
gamma-glutamyl transferase 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
HRCT 
high-resolution computed tomography 
HRQOL 
Health Related Quality of Life 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
IND 
Investigational New Drug 
IPF 
idiopathic pulmonary 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
L 
liter 
LCQ 
Leicester Cough Questionnaire 
LDH 
lactic dehydrogenase 
L/min 
liters per minute 
MedDRA 
Medical Dictionary for Regulatory Activities  
m 
meter 
MAC 
Mortality Assessment Committee  
mg 
Milligram 
mg/d 
milligrams per day 
mL 
Milliliter 
mm Hg 
millimeters of mercury  
msec 
Millisecond 
NIH 
National Institutes of Health 


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PaO2 
partial pressure of oxygen  
PDGF 
platelet-derived growth  
PF 
pulmonary fibrosis 
PFS 
progression-free survival 
PFT 
pulmonary function test 
QT interval 
time between the start of the Q wave and the end of the T wave in the heart's electrical 
cycle 
QTc 
heart-rate–corrected QT interval  
RA 
rheumatoid arthritis 
SAE 
serious adverse event  
SGRQ 
St. George’s Respiratory Questionnaire 
SLB 
surgical lung biopsy 
SmPC 
Summary of Product Characteristics 
SP2 
Shionogi Phase 2 study  
SP3 
Shionogi Phase 3 study  
SpO2 
oxygen saturation by pulse oximetry 
Study treatment 
pirfenidone or placebo equivalent 
SPF 
sun protection factor 
TLCO 
carbon monoxide transfer capacity  
TID 
three times per day 
UIP 
usual interstitial pneumonia 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia  
UV-A 
ultraviolet A (radiation) 
  
 
wk 
Week 
Sponsor  
  Brigham and Women's Hospital, Boston, MA 
Financial Support 
provided by 
Genentech, Inc / Roche 
 
 


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STATEMENT OF COMPLIANCE 
 
This trial will be conducted with Good Clinical Practice (GCP) and in accordance with the Code of 
Federal Regulations on the Protection of Human Subjects (21 CFR Part 50). The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without 
documented approval from the applicable Institutional Review Boards (IRBs), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection Training.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments.  
Principal Investigator: _________________________   
    
(Print/Type Name)  
Signed: _________________________ 
(Signature)  
 
 
 
 
 
 
 
Date:                              
 
     (MM/DD/YYYY) 
 
 


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PROTOCOL SUMMARY 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Safety, 
Tolerability and Efficacy of Pirfenidone in Patients with Rheumatoid 
Arthritis Interstitial Lung Disease 
Précis: 
A Phase 2, randomized, double blind, placebo controlled clinical trial 
designed to evaluate the efficacy and safety of administering pirfenidone or 
placebo for 52 weeks to subjects with RA-ILD. Patients meeting the 
eligibility criteria for the study will be randomized to receive either 
pirfenidone 2403 mg/d or placebo. Efficacy will be evaluated through 
interval testing of pulmonary function tests, patient reported outcomes, 
adverse events and survival.  Safety will be assessed by determining 
differences between the treatment arms for the rate of adverse events, 
serious adverse events, rates of acute exacerbation, hospitalization and all-
cause mortality. 
Objectives: 
 
To assess the efficacy and safety of pirfenidone 2403 mg/day as compared 
to placebo in patients with RA-associated interstitial lung disease.   
To explore the role of peripheral blood biomarkers in predicting disease 
progression and survival in patients with RA-associated interstitial lung 
disease. 
To explore a spectrum of validated questionnaires to assess disease specific 
PROs including overall health, and perspectives on symptoms, performance 
and quality of life. 
Endpoints 
Primary Endpoint: 
Incidence of the composite endpoint of decline from baseline in 
percent predicted FVC of 10% or greater or death during the study 
period.  
Pre-Specified Secondary Endpoints:  
1. Incidence of the composite endpoint of decline from baseline in 
percent predicted FVC of 10% or greater during the study period 
2. Frequency of progressive disease as defined by OMERACT: Relative 
decline from baseline in percent predicted FVC of ≥10%, or relative 
change from baseline in percent predicted FVC ≥ 5% and < 10%, and 
≥15% relative DLCO (Khanna, Mittoo et al. 2015) 
3. Change from baseline to end of study in absolute value of FVC 
4. Change from baseline to end of study of percent predicted FVC 
5. Slope  of  percent predicted FVC over study period 
6. Slope of absolute FVC over study period 
7. Time to decline of 10% or greater in percent predicted FVC ordeath 
over study  period 
8. Proportion of participants with all-cause mortality 
9. Proportion of participants with all-cause hospitalization 


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10. Proportion of participants with hospitalization for respiratory cause 
11. Number of respiratory exacerbations requiring hospitalizations 
12. Proportion of participants with and number of treatment-emergent 
AEs 
13. Proportion of participants with and number of treatment-emergent 
serious adverse events (SAEs) 
14. Proportion of participants with and number of treatment-
emergent/treatment-related AEs 
15. Proportion of participants with and number of treatment-
emergent/treatment-related SAEs 
16. Proportion of participants with and number of AEs leading to early 
discontinuation of study treatment 
17. Proportion of participants with and number of treatment-emergent 
death or transplant 
18. Proportion of participants with and number of treatment-emergent 
RA-ILD-related mortality 
19. Change from Baseline to end of study in dyspnea, as measured by 
the Dyspnea 12 questionnaire 
Exploratory: 
1. Change from Baseline to end of study in Disease Activity Score 
(DAS) and RAPID3 score (RA disease activity score) 
2. Change from Baseline to end of study in Routine Assessment of 
Patient Index Data 3 (RAPID3) score (RA disease activity score) 
3. Change from Baseline to end of study in Erythrocyte Sedimentation 
Rate (ESR)  
4. Change from Baseline to end of study in C-Reactive Protein (CRP)  
5. Candidate biomarker expression in the peripheral blood of patients 
with RA-ILD over the study period of treatment and the study 
follow-up period 
6. Changes from Baseline to end of study in HRCT parameters 
evaluated by quantitative functional imaging 
7. Changes from Baseline to Week 13, 26, 39 and 52 in the St. 
George’s Respiratory Questionnaire (SGRQ) 
8. Changes from Baseline to Week 13, 26 and 39 in Dyspnea 12 
questionnaire 
9. Changes from Baseline to Week 13, 26, 39 and 52 in Leicester 
Cough Questionnaire (LCQ) 
10. Changes from Baseline to Week 13, 26, 39 and 52 in the Patient 
global assessment 
11. Changes from Baseline to Week 13, 26, 39 and 52 in the Health 
assessment questionnaire 
Population: 
Approximately 270 randomized participants from recruitment sites in the 
United States, Canada, the United Kingdom and Australia, including both 
male and female patients aged 18-85 years, diagnosed with RA (according 
to revised 2010 ACR/EULAR criteria) and ILD (supported by clinically 


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indicated HRCT), without evidence or suspicion of an alternative diagnosis 
that may contribute to their interstitial lung disease. They must also meet 
all other inclusion and exclusion criteria as detailed below.  
Phase: 
Phase II 
Number of Sites 
enrolling participants: 
approximately 33  
Description of Study 
Agents: 
Study treatment is defined as either pirfenidone 2403 mg/d or placebo 
equivalent administered in divided doses three times per day (TID).   
Study treatment should be titrated over 14 days, as tolerated, to the full 
dose of 9 capsules per day (three capsules TID), as follows: 
• 
Days 1–7:  one capsule TID 
• 
Days 8–14:  two capsules TID 
• 
Days 15-21:  three capsules TID (maximum of 9 capsules daily) 
Participants will remain on a stable maintenance dose for the duration of 
the study period (Day 22 to Week 52) unless the dose is reduced to manage 
an AE. 
Genentech will supply all study medications (pirfenidone and matching 
placebo). There will be 270 capsules per bottle, which will be labeled for 
investigational use only. Pirfenidone 267-mg and placebo will be supplied in 
opaque, hard, white gelatin capsules that are visually indistinguishable. 
Study Duration: 
Approximately 4 years total study duration, sub-divided into the following 
components: 
- 30 month enrollment period  
- 12 month randomized, double-blind treatment period per patient  
- 1 month follow-up period after completion of drug therapy  
Participant Duration: 
Approximately 15 months: 
- screening = 1-2 months 
- treatment period = 12 months  
- follow-up after completion of study treatment = 1 month  
Inclusion Criteria: 
1. 
Age 18 through 85 years, inclusive, at Screening 
2. 
Probable or definite diagnosis of RA according to revised 2010 
ACR/EULAR criteria, without evidence or suspicion of an alternative 
diagnosis that may contribute to their interstitial lung disease.  
3. 
Diagnosis of ILD  
a. supported by clinically indicated HRCT, and when available surgical 
lung biopsy (SLB), prior to Screening, and 
b. presence of fibrotic abnormality affecting more than 10% of the 
lung parenchyma, with or without traction bronchiectasis or 
honeycombing, on Screening and confirmed by adjudicated HRCT 
prior to Baseline 


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4. 
No features supporting an alternative diagnosis on transbronchial 
biopsy, or SLB, if performed prior to Screening 
5. 
Attainment of the following centralized spirometry criteria (based on 
local spirometry on standardized equipment and centralized quality 
controlled): 
a. percent predicted FVC ≥ 40% at Screening 
b. change in pre-bronchodilator FVC (measured in liters) between 
Screening (Visit 1) and Baseline (Visit 2) must be a <10% relative 
difference, calculated as: 100% * [absolute value (Screening FVC – 
Baseline FVC) / Screening FVC]       
c. percent predicted DLCO or TLCO ≥ 25% at Screening 
d. Screening (Visit 1) pre-bronchodilator(BD) and Post-BD 
spirometry meets ATS quality criteria as determined by a central 
reviewer 
e. Baseline (Visit 2) Pre-BD spirometry meets ATS quality criteria as 
determined by either a site Investigator or the central reviewer 
6.      Able to understand and sign a written informed consent form 
7.      For women of childbearing potential:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or use two adequate 
methods of contraception, including at least one method with a 
failure rate of <1% per year, during the 52 week treatment period 
and for at least 118 days after the last dose of study drug.  
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, established 
and proper use of hormonal contraceptives 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. 
8.        For men who are not surgically sterile: agreement to remain 
abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating 
sperm, as defined below: 
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 study drug.   
b. Men must refrain from donating sperm during this same period. 


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Exclusion Criteria:  
1. 
Not a suitable candidate for enrollment or unlikely to comply with 
the requirements of this study, in the opinion of the investigator 
2. 
Cigarette smoking or vaping within 3 months of Screening or 
unwilling to avoid tobacco products throughout the study 
3. 
History of clinically significant environmental exposure known to 
cause pulmonary fibrosis (PF), including but not limited to drugs 
(such as amiodarone), asbestos, beryllium, radiation, and domestic 
birds 
4. 
Concurrent presence of the following conditions: 
a.  Other interstitial lung disease, related to but not limited to    
radiation, drug toxicity, sarcoidosis, hypersensitivity 
pneumonitis, or bronchiolitis obliterans organizing pneumonia 
b.  Medical history including Human Immunodeficiency Virus (HIV) 
   c.  Medical history of viral hepatitis (positive Hep A antibody in the 
 
     absence of elevated liver enzymes is not an exclusion) 
5. 
Concurrent presence of other pleuropulmonary manifestations of 
RA, including but not limited to rheumatoid nodular disease of the 
lung, pleuritis/pleural thickening, and obliterative bronchiolitis 
6. 
Post-bronchodilator FEV1/FVC  <0.65 at Screening 
7. 
Presence of pleural effusion occupying more than 20% of the 
hemithorax on Screening HRCT 
8. 
Clinical diagnosis of a second connective tissue disease or overlap 
syndrome (including but not limited to scleroderma, Sjogren’s 
polymyositis/dermatomyositis, systemic lupus erythematosus but 
excluding Raynaud’s phenomena) 
9. 
Coexistent clinically significant COPD/emphysema or asthma in the 
opinion of the site principle investigator 
10. 
Clinical evidence of active infection, including but not limited to 
bronchitis, pneumonia, sinusitis, urinary tract infection, or cellulitis. 
The infection should be resolved per PI assessment prior to 
enrollment.  Any use of antibiotics must be completed 2 weeks 
prior to the screening visit. Note that prophylactic antibiotics are 
not contraindicated or exclusionary 
11. 
Any history of malignancy diagnosed within 5 years of screening, 
other than basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or low grade cervical carcinoma, and/or low 
grade prostate cancer.  
Criteria for low grade prostate cancer: 
x Patients with suspicion for prostate cancer based on PSA and/or 
DRE should have been evaluated by urology 
x Patients with NCCN very low risk prostate cancer (· T1c and 
Grade Group 1 (Gleason 6) and PSA <10 ng/mL and Fewer than 3 
prostate biopsy fragments/cores positive, ≤50% cancer in each 
fragment/coreg and · PSA density <0.15 ng/mL/g) can be 
monitored without intervention and enrolled in study 


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x Patients with NCCN low risk prostate cancer can be  monitored 
on a case by case basis (T1-T2a and Grade Group 1 (Gleason 6) 
and · PSA <10 ng/mL) and enrolled in study. 
x All other patients should be excluded. 
12. 
History of LFT abnormalities as outlined below, or imaging, 
laboratory or other clinical information suggesting liver dysfunction, 
advanced liver disease or cirrhosis.  Evidence of hepatic impairment 
that in the opinion of the investigator could interfere with drug 
metabolism or increase the risk of the known hepatotoxicity of 
study drug.  
              Any of the following liver function abnormalities: 
a.Total bilirubin above the upper limit of normal (ULN), excluding 
patients with Gilbert’s syndrome; 
b.Aspartate or alanine aminotransferase (AST/SGOT or AST/SGPT) > 
3 X ULN; 
c. Alkaline phosphatase > 2.5 X ULN. 
13. 
History of end-stage renal disease requiring dialysis 
14. 
History of unstable or deteriorating cardiac disease, or unstable 
cardiac arrhythmia or arrhythmia requiring modification of drug 
therapy, myocardial infarction within the previous year, heart 
failure requiring hospitalization  
15. 
Any condition that, in the opinion of the investigator, might be 
significantly exacerbated by the known side effects associated with 
the administration of pirfenidone 
16. 
History of alcohol or substance abuse in the past 2 years, at the 
time of Screening 
17. 
Family or personal history of long QT syndrome 
18. 
Any of the following test criteria above specified limits: 
a. eGFR < 30 mL/min/1.73m2 
b. Electrocardiogram (ECG) with a QTc interval >500 msec at 
Screening 
19. 
Prior use of pirfenidone or known hypersensitivity to any of the 
components of study treatment 
20. 
Use of any of the following therapies within 28 days before 
Screening and during participation in the study: 
a. Investigational therapy, defined as any drug that has not been 
approved for marketing for any indication in the country of the 
participating site 
              b. Potent inhibitors of CYP1A2 (e.g. fluvoxamine, enoxacin), 
              c. Potent inducers of CYP1A2 
              d. Sildenafil (daily use). Note: intermittent use for erectile      
dysfunction is allowed 
21. 
Introduction and/or modification of dose of corticosteroids or any 
cytotoxic, immunosuppressive, or cytokine modulating or receptor 
antagonist agent for the management of pulmonary manifestations 
of RA, within 3 months of screening, is an exclusion criterion, with 
the exception of dose modification of systemic corticosteroids that 


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are maintained at or below 20 mg prednisone daily or the 
equivalent.  
 
However, introduction and/or modification of dose of corticosteroids 
or any cytotoxic, immunosuppressive, or cytokine modulating or 
receptor antagonist agent for the management of extrapulmonary 
manifestations of RA is not an exclusion criterion for enrollment. 
  
22. 
 Any use of an approved anti-fibrotic medication within 28 days of 
screening. 
 
 
SUMMARY SCHEMATIC OF STUDY DESIGN 
Visit 1 (week -8 to week 0) SCREENING 
•Obtain informed consent 
•Screen potential subjects by inclusion and exclusion criteria 
•H&P, labs, ECG, HRCT, Spirometry, DLCO, biomarkers (see study assessment calendar for details) 
 
Visit 2 (week 0) ELIGIBILITY/RANDOMIZATION 
•H&P, labs, PROs, joint count, Spirometry, biomarkers (see study assessment calendar for details) 
•Confirm eligibility and randomize patient 
•Treatment Group 1 (n=135) 
•Placebo (n=135) 
•Dispense study drug 
•AE assessment 
 
Visit 3 (week 1) TELEPHONE ASSESSMENT 
•Vital status, dosing compliance 
•Concomitant medication assessment 
•AE assessment 
 
Visit 4 (week 2) TELEPHONE ASSESSMENT 
•Vital status, dosing compliance 
•Concomitant medication assessment 
•AE assessment 
 
Visit 5 (week 4) and Visit 6 (week 8) PROTOCOL VISIT 
•H&P, labs, biomarkers (week 4 only), ECG (week 4 only) 
•Review drug compliance 
•AE assessment 
 
Visit 7 (week 13), Visit 9 (week 26) and Visit 10 (week 39) PROTOCOL VISIT / DISPENSE DRUG 
•H&P, labs, biomarkers, PROs, ECG, Spirometry 
•Dispense supply of study drug 
•AE assessment 
 
Visit 8 (week 19) LAB ASSESSMENT 


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•Liver function testing 
    •Concomitant medication assessment 
•AE assessment 
 
Visit 11 (week 52) END OF TREATMENT 
•H&P, labs, biomarkers, PROs, joint count, Spirometry, DLCO, ECG, HRCT 
    •Collect diary and unused study drug 
•AE assessment 
 
Visit 12 END OF STUDY PHONE CALL  (28 DAYS AFTER LAST DOSE OF STUDY DRUG) 
x Vital status and AE assessment 
 
PRE-RESTART VISIT  
•H&P, labs, ECG 
•AE assessment 
• Dispense supply of study drug, if required 
•Review drug compliance, dispense new diary, if required 
 
UNSCHEDULED VISIT  
x H&P, AE assessment 
x remaining elements of the visit are up to the discretion of the investigator. 
 
EARLY TERMINATION VISIT  
•H&P, labs, biomarkers, PROs, joint count ,Spirometry, DLCO, ECG, HRCT (see study assessment calendar for 
details) 
•Collect diary and unused study drug 
•AE assessment 
 
 
1 KEY ROLES 
 
Administrative Coordinating Center 
Baylor College of Medicine, Houston, 
TX  
 
 
Study Principal Investigator 
Ivan Rosas, MD 
Pulmonary Critical Care and Sleep Medicine 
Baylor College of Medicine 
7200 Cambridge Street 
Houston, TX 77030 
Tel: (713)-798-8842 
Fax: (713) 798-2688 
Ivan.Rosas@bcm.edu 
Brigham and Women’s, Boston, MA 
Co-PrincipaI Investigator 
Hilary Goldberg, MD, MPH 
Pulmonary and Critical Care Medicine 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 


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Tel: 617-732-5499 
Fax: 617-732-7421 
hjgoldberg@bwh.harvard.edu 
 
Director, HRCT Image Analysis Core 
      David Lynch, MD 
 
Director, Research Pharmacy Core 
      Josh Solomon, MD 
 
Director, Pathology Review Team 
       Bobby Padera 
 
Director, PFT Core 
      Sonye Danoff, MD, PhD 
Data Coordinating Center 
University of Michigan 
Ann Arbor, MI 
Director of Data Coordinating Center 
Cathie Spino, D.Sc. 
Associate Research Professor of Biostatistics  
Director, Statistical Analysis of Biomedical 
and Educational Research (SABER) Unit  
School of Public Health  
University of Michigan 
1415 Washington Heights, Rm M4507 
Ann Arbor, MI 48109-2029 
Tel: (734) 615-5469 
Fax: (734) 647-3711 
spino@med.umich.edu 
 
2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1  
BACKGROUND INFORMATION  
 
2.1.1 
RA-ILD 
RA is a chronic inflammatory disease that leads to joint damage, deformity, and a high rate of 
disability and unemployment (Isomaki, Mutru et al. 1975; Allebeck, Ahlbom et al. 1981; Pincus, 
Callahan et al. 1984; Wolfe, Mitchell et al. 1994; Yelin 1996; Wallberg-Jonsson, Ohman et al. 1997; 
Gabriel, Crowson et al. 1999; Guedes, Dumont-Fischer et al. 1999).  The prevalence of RA is 1-2%, with 
a 2-fold higher prevalence in women than men (Hochberg and Spector 1990; Doran, Pond et al. 2002).  
The economic burden of RA is high: direct and indirect costs in the U.S. are estimated at more than 30 
billion USD per year, respectively (Lubeck 1994).  Furthermore, the lifespan of RA patients is shortened 
by approximately 10 years (Isomaki, Mutru et al. 1975; Allebeck, Ahlbom et al. 1981; Pincus, Callahan 
et al. 1984; Wolfe, Mitchell et al. 1994; Yelin 1996; Wallberg-Jonsson, Ohman et al. 1997; Gabriel, 
Crowson et al. 1999; Guedes, Dumont-Fischer et al. 1999; Doran, Pond et al. 2002), and standardized 
mortality ratios for RA range from 1.28 to 3.0 (Wolfe, Mitchell et al. 1994).  
ILD is a common pulmonary manifestation of RA (Kim 2006).  Estimates of the prevalence of ILD vary 
based on the ascertainment technique: pulmonary function testing (PFT), chest CT or lung biopsy. 
High-resolution chest CT is more sensitive than PFTs for identifying ILD and is abnormal in 19% of an 
unselected RA population (Dawson, Fewins et al. 2001) and up to 80% of RA patients with respiratory 
symptoms (McDonagh, Greaves et al. 1994).  The most common radiographic findings on CT are 


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reticular changes including honeycombing (HC), ground glass opacities (GGO), traction bronchiectasis 
and consolidation (Cortet, Perez et al. 1997; Dawson, Fewins et al. 2001).  Pathologic evaluation on 
lung biopsy is the most sensitive assessment; ILD was present in 80% of subjects from one case series 
in which RA patients, not selected for respiratory symptoms, underwent surgical lung biopsies 
(Cervantes-Perez, Toro-Perez et al. 1980).  Among RA patients biopsied for a diagnosis of ILD, usual 
interstitial pneumonia (UIP) is the most common histopathologic pattern seen (Lamblin, Bergoin et al. 
2001), the same pattern seen in patients with idiopathic pulmonary fibrosis. This is in contrast to most 
other forms of collagen vascular associated-ILD (CVD-ILD), in which non-specific interstitial 
pneumonitis (NSIP) predominates (Lamblin, Bergoin et al. 2001).  This may account, in part, for the 
poorer prognosis associated with RA-ILD in comparison with other CVD-ILD (Lamblin, Bergoin et al. 
2001).  
Most patients develop articular symptoms of RA before lung involvement manifests, although these 
may occur simultaneously (Lee, Kim et al. 2005) or ILD may begin even before articular symptoms are 
present (Sato, Fujita et al. 2006).  The initial symptoms of RA-ILD, when present, are often non-
specific, and include dyspnea with exertion and dry cough (Kim 2006). Moreover, the symptoms of RA-
ILD overlap with symptoms of other comorbid conditions occurring in RA, such as cardiac disease, and 
may be missed in early stages due to reduced physical activity masking dyspnea.  Interstitial lung 
disease develops in a progressive fashion presumably following an unrecognized initial insult in a 
susceptible host.  The pathogenesis of the earliest phase of ILD in humans remains unknown.  A study 
which evaluated radiographic progression in a small cohort of RA patients indicated that even in 
patients with asymptomatic disease, radiographic progression by expert radiologist evaluation (ER) 
occurs in nearly 60% of patients over an 18 month period (Gochuico, Avila et al. 2008). 
Interstitial lung disease (ILD) is a significant contributor to excess mortality in patients with RA. . A long 
term, population based cohort study of ILD in RA revealed that patients with RA related ILD are at 
nearly3-fold increased risk of premature death compared to patients without this complication, a risk 
even higher than that for premature mortality due to cardiovascular disease (Bongartz et al, 2010.) A 
further longitudinal cohort study showed that RA-ILD is responsible for a significant increase in 
mortality (Young, Koduri et al. 2007). A recent national study of mortality in RA showed that nearly 
10% of the deaths in RA are attributable to ILD (Olson, Swigris et al.) consistent with a prior, single 
center study (Suzuki, Ohosone et al. 1994). Currently available treatment for RA has achieved a great 
improvement in the control of articular disease as measured by disease activity and quality of life 
instruments (van Vollenhoven 2009). Unfortunately, these benefits have not extended to RA-
associated lung disease.   
2.1.2 
Nonclinical Overview Supporting Use in RA-ILD 
The mechanism of action of pirfenidone in ILD is thought to be both anti-inflammatory and 
antifibrotic. Pirfenidone inhibits the synthesis and release of pro-inflammatory cytokines and reduces 
the accumulation of inflammatory cells in response to various stimuli (Pirfenidone Investigator’s 
Brochure, Edition 11, 2011 and Summary of Product Characteristics, 24 April 2017). Pirfenidone also 
has been shown to attenuate fibroblast proliferation, production of fibrosis-associated proteins and 
cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to 
cytokine growth factors such as transforming growth factor-beta (TGF-β) and platelet-derived growth 
factor (PDGF). 
In rat, hamster, and mouse models of bleomycin-induced lung fibrosis, prophylactic administration of 
pirfenidone reduced pulmonary fibrosis assessed by both histopathologic analysis and quantitative 
determination of collagen content. Pirfenidone treatment also reduced pulmonary edema and 


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pulmonary levels of TGF-β, basic fibroblast growth factor (bFGF), and various pro-inflammatory 
cytokines. 
Thus, both in vitro and in vivo nonclinical studies have provided evidence of reductions in fibroblast 
proliferation and collagen synthesis, decreased cellular and histologic markers of lung fibrosis, and 
reduced perturbations in lung function in animal models of fibrosis induction following administration 
of pirfenidone. 
2.1.3 
Summary of Findings from Human Clinical Studies 
A total of 15 controlled and uncontrolled clinical studies in healthy subjects and patients with IPF or 
pulmonary fibrosis (PF) have been conducted by Marnac (the original developer of pirfenidone), 
Shionogi, or InterMune. More than 1300 subjects and patients have received pirfenidone. Other 
smaller studies of pirfenidone in patients with IPF or PF conducted by independent investigators have 
been reported in the literature, with generally favorable results (Nagai et al. 2002; Raghu et al. 1999; 
Gahl et al. 2002). InterMune has conducted multiple Phase 1 studies to assess the clinical 
pharmacology and safety of pirfenidone as well as two long-term, uncontrolled safety studies that are 
currently ongoing (PIPF -002 and PIPF -012). 
The double-blind, placebo-controlled Phase 2 study conducted by Shionogi in Japan (SP2) served as 
the initial proof-of-concept study, suggesting a benefit of pirfenidone in patients with IPF. Three Phase 
3 studies were subsequently executed independently to confirm these findings, one in Japan 
(Shionogi-sponsored Phase 3 study [SP3], initiated in July 2004) and two in North America, Europe, 
and Australia (InterMune-sponsored PIPF-004 and PIPF-006, initiated in July 2006 and April 2006, 
respectively). Results from SP3, which was ongoing at the start of PIPF-004 and PIPF-006, formed the 
basis for approval of pirfenidone (Pirespa®) in Japan in October 2008. Efficacy results from these four 
trials are summarized below. 
2.1.3.1 Shionogi Phase 2 Study (SP2) (Azuma et al. 2005) 
SP2 was a multicenter, randomized, double-blind, placebo-controlled trial of pirfenidone in patients 
with a confirmed diagnosis of IPF conducted from 09 November 2000 to 30 September 2002 (Azuma 
et al. 2005). A total of 109 patients in Japan were randomized in a 2:1 ratio to receive oral pirfenidone 
(1800 mg/d) or placebo for 52 weeks. Based on a planned interim analysis at 24 weeks, the Efficacy 
and Safety Assessment Committee recommended stopping the study due to a significantly lower 
incidence of acute exacerbations, favoring pirfenidone. 
In the final analysis at 36 weeks, there was a trend toward a pirfenidone benefit in the primary 
efficacy outcome variable (mean area-above-the-curve for oxygen saturation by pulse oximetry [SpO2] 
during the 6-minute steady state exercise test [6MET], 8.12 vs. 8.23; p = 0.093). In secondary analyses, 
patients receiving pirfenidone had a reduced mean decline from Baseline in vital capacity (VC) (-0.03 L 
vs. -0.13 L; p = 0.037) and a lower rate of acute exacerbations of IPF (1.4% vs. 14.3%; p = 0.014). 
2.1.3.2 Shionogi Phase 3 Study (SP3) (Taniguchi et al. 2010) 
SP3 was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study conducted in 
Japan between 13 July 2004 and 30 August 2006 (Taniguchi et al. 2010).  A total of 275 IPF patients 
from 73 sites were randomized 2:2:1 to receive pirfenidone 1800 mg/d, placebo, or pirfenidone 1200 
mg/d for 52 weeks. Sixty-six percent of patients completed the study.  SP3 demonstrated a significant 
benefit of pirfenidone 1800 mg/d compared with placebo on the primary outcome variable of change 
from Baseline in VC at Week 52 (-90 mL vs. -160 mL; absolute difference 70 mL; relative difference 


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43.8%; p = 0.042, analysis of covariance [ANCOVA]). There was also a reduced mean decline in %VC at 
Week 52 in the pirfenidone 1800 mg/d group (-2.91% vs. -5.13%; p = 0.044, ANCOVA). 
Progression-free survival (PFS), one of two key pre-specified secondary endpoints, was prolonged in 
pirfenidone 1800 mg/d-treated patients relative to placebo (hazard ratio [HR] 0.45; 95% confidence 
interval [CI] 0.11–0.79; p = 0.028, log-rank test). In the pirfenidone 1200 mg/d treatment group, there 
was also a reduced mean decline in VC compared with placebo (-80 mL vs. -160 mL; p = 0.039, 
ANCOVA), without evidence of a dose response compared with pirfenidone 1800 mg/d. 
2.1.3.3 InterMune PIPF-004 
In PIPF-004, a multinational, Phase 3, double-blind, placebo-controlled study, 435 patients with IPF 
were randomized 2:2:1 to receive pirfenidone 2403 mg/d (n = 174), placebo (n = 174), or pirfenidone 
1197 mg/d (n = 87). Study treatment lasted from randomization until approximately 72 weeks after 
the last patient had been randomized in the study. Most patients (84%) completed the study. 
In the primary efficacy analysis, treatment with pirfenidone 2403 mg/d resulted in a statistically 
significant reduction in the mean decline from Baseline in percent predicted forced vital capacity 
(%FVC) at Week 72 compared with placebo (-8.0% vs. -12.4%; absolute difference 4.4%; relative 
difference 35.3%; p = 0.001, rank ANCOVA), as well as across all study time points using a repeated 
measures analysis (p < 0.001). In an analysis of PFS, there was a 36% reduced risk of death or disease 
progression with pirfenidone 2403 mg/d treatment at Week 72 relative to placebo (HR 0.64; 95% CI 
0.44– 0.95; p = 0.023, log-rank test), and a much lower proportion of patients with a decline of ≥10% 
in %FVC at Week 72 in the pirfenidone 2403 mg/d group (20.1% vs. 34.5%). There was no discernible 
effect of pirfenidone on other secondary efficacy endpoints. 
There was a 39% relative reduction in the risk of death in the pirfenidone 2403 mg/d group compared 
with placebo (HR 0.61; 95% CI 0.28–1.29; p = 0.191). In the analyses of on-treatment mortality, both 
the incidence of on-treatment all-cause deaths (i.e., deaths occurring between time of randomization 
and 28 days after last dose of study treatment and that of  IPF-related deaths was lower in the 
pirfenidone 2403 mg/d group than in the placebo group (10 vs. 14 deaths and 5 vs. 11 deaths, 
respectively).  Evidence of a dose response was observed with pirfenidone 1197 mg/d relative to 
pirfenidone 2403 mg/d in the analysis of the primary efficacy outcome and several secondary 
outcome variables. 
2.1.3.4 InterMune PIPF-006 
PIPF-004 and PIPF-006 studies were identical in almost all major design features; however, PIPF-006 
included two rather than three treatment groups. A total of 344 patients were randomized to receive 
pirfenidone 2403 mg/d (171 patients) or placebo(173 patients). Most patients (83%) completed the 
study. 
The primary efficacy analysis did not reach statistical significance (mean change from Baseline in %FVC 
at Week 72, -9.0% vs. -9.6%; p = 0.501, rank ANCOVA); however, there was evidence of a treatment 
effect of pirfenidone 2403 mg/d at multiple earlier time points (p < 0.001 at Week 24, p = 0.011 at 
Week 36, and p = 0.005 at Week 48). In addition, a repeated measures analysis with averaging across 
all study time points showed a reduced decline from Baseline in %FVC in pirfenidone 2403 mg/d 
patients overall (p = 0.007). Also, there was evidence of an effect of pirfenidone 2403 mg/d compared 
with placebo in the change from Baseline in 6-minute walk test (6MWT) distance at Week 24 (p = 
0.038), Week 36 (p = 0.044), Week 48 (p = 0.023), Week 60 (p = 0.014), and Week 72 (p < 0.001, rank 
ANCOVA). There was no discernable treatment effect of pirfenidone compared with placebo for the 


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endpoint of PFS (HR 0.84; 95% CI 0.58–1.22; p = 0.355) or in other secondary efficacy endpoints. There 
was no protective effect on overall survival (HR 0.95; 95% CI 0.48–1.87; p = 0.872). A total of 16 (9.4%) 
and 17 (9.8%) patients in the pirfenidone 2403 mg/d and placebo groups, respectively, died. However, 
in the analyses of on-treatment mortality, the incidence of both all-cause deaths and of RA-ILD-related 
deaths was lower in the pirfenidone 2403 mg/d group than in the placebo group (9 vs. 15 deaths and 7 
vs. 14 deaths, respectively). 
2.1.3.5 Efficacy Results Across Early Trials 
PIPF-004 and PIPF-006 
PIPF-004 and PIPF-006 were essentially identical trials by design, and pooling of their data was pre-
specified to provide a single, robust estimate of treatment effect. There was a marked reduction in the 
mean decline from Baseline in %FVC in patients receiving pirfenidone 2403 mg/d compared with 
placebo at Week 72 (p = 0.005, rank ANCOVA), with the positive treatment effect of pirfenidone 
beginning at Week 12 (p = 0.003) and sustained throughout every subsequent study time point:  Week 
24 (p < 0.001), Week 36 (p < 0.001), Week 48 (p < 0.001), and Week 60 (p < 0.001). A repeated-
measures analysis of the overall pirfenidone treatment effect on change in %FVC across all study time 
points also showed a strong benefit compared with placebo (p < 0.001). The proportion of patients 
with a decrement of ≥10% from Baseline in %FVC at Week 72, a threshold repeatedly found to predict 
mortality (Collard et al. 2003, Flaherty et al. 2003, King et al. 2005) was 30% lower in patients receiving 
pirfenidone 2403 mg/d than in patients receiving placebo (21.5% vs. 30.5%). 
In addition, treatment with pirfenidone 2403 mg/d resulted in a 26% reduction in the risk of death or 
progression of disease relative to placebo (HR 0.74; 95% CI 0.57–0.96;p = 0.025), as well as a reduced 
mean decline from Baseline in 6MWT distance at Week 72 (-52.8 m vs. -76.8 m; absolute difference of 
24 m; p < 0.001) and at all earlier study time points after Week 12. Despite the lack of adequate power 
for the outcome of survival, the risk of death in the pirfenidone 2403 mg/d group relative to placebo 
was reduced by 23% (HR 0.77; 95% CI 0.47–1.28; p = 0.315), with 7.8% and 9.8% of patients in the two 
groups dying. In the  analyses of on-treatment mortality, the incidence of all-cause death was 35% 
lower in the pirfenidone 2403 mg/d group than in the placebo group (19 vs. 29 deaths), and the 
incidence of IPF-related deaths was 52% lower in the pirfenidone 2403 mg/d group than in the 
placebo group (12 vs. 25 deaths).  
PIPF-004, PIPF-006, SP3, and SP2 
Standardized estimates of the magnitude of the treatment effect on FVC/VC were derived from PIPF-
004, PIPF-006, SP3, and SP2 to facilitate a direct comparison of study results (Figure 1-1). PIPF-004 and 
PIPF-006 analyzed change from Baseline in %FVC at time points that included Weeks 24, 36, 48, and 
72, whereas SP3 and SP2 assessed the change from Baseline in VC at time points that included Weeks 
28 and 36. SP3 also included an assessment at Week 52. The results show a high level of consistency in 
these results across time points (with the exception of Week 72) and across these studies. In addition, 
all of the meta-analysis estimates favor pirfenidone and clearly exclude no effect. At the Week 48/52 
time point, point estimates of effect are remarkably similar in the three Phase 3 studies, and the 
confidence intervals in all 3 studies exclude the null effect. 
A similar consistency in the hazard ratios for PFS was found for the 3 studies that included this 
endpoint (i.e., PIPF-004, PIPF-006, and SP3): a recent independent meta- analysis by the Cochrane 
Review (Spagnolo 2010) of these three Phase 3 trials (N = 1046) demonstrated significant 
improvement in PFS, with an overall 30% reduction in the risk of death or disease progression (HR 
0.70; 95% CI 0.56, 0.88; p = 0.002). 


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Figure 1 .  Individual Study and Meta-analysis Estimates of the Pirfenidone Treatment Effect on VC/FVC Across Time Points 
Line represents standardized treatment effect of pirfenidone vs. placebo and 95% confidence interval. The dose of pirfenidone was 2403 mg/d in PIPF-004 and 
PIPF-006 and was 1800 mg/d in SP3 and SP2. 
 


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2.1.3.6 InterMune Pooled Phase 3 Safety Data 
Safety results from the pooled PIPF-004 and PIPF-006 pirfenidone 2403 mg/d study population were 
similar to those in previous studies. Common treatment-emergent adverse events (AE) that 
occurred more frequently in the pirfenidone group than the placebo group included gastrointestinal 
disorders (nausea, diarrhea, dyspepsia, vomiting, and stomach discomfort), skin disorders (rash and 
photosensitivity reaction), anorexia, decreased appetite, fatigue, and dizziness. Although more 
pirfenidone 2403 mg/d than placebo patients had at least 1 dose reduction for at least 1 day, dose 
reductions implemented in accordance with the protocol-specified guidelines tended to be short-
lived and were typically related to transient gastrointestinal events or skin disorders. The rate of 
treatment discontinuation due to an AE in the pirfenidone 2403 mg/d group was only 6% higher 
than in the placebo group. Mild or moderate serum transaminase elevations (serum ALT or AST >3 × 
upper limit of normal [ULN]) occurred more frequently in patients treated with pirfenidone 2403 
mg/d than placebo, but they were most often effectively managed with dose modification and not 
associated with untoward clinical consequences. More extreme elevations in serum ALT or AST (>10 
× ULN) were rare in both treatment groups, and no instances of liver function abnormality meeting 
the criteria for Hy’s law occurred. 
Intermune ASCEND Trial 
In the ASCEND Trial, a multinational, Phase 3, double blind, placebo-controlled study, 555 patients 
with IPF were randomized to receive pirfenidone 2403 mg/d (n=278) or placebo (n=277).  Study 
treatment lasted from randomization until approximately 52 weeks after the last patient had been 
randomized in the study.  Most patients (94.1%) completed the study. 
In the primary efficacy analysis, treatment with pirfenidone 2403 mg/d resulted in a statistically 
significant reduction in the mean decline from Baseline in percent predicted forced vital capacity 
(%FVC) at Week 52 compared with placebo (235ml vs. 428ml; absolute difference 193ml; relative 
difference 45.1%; p <0.001, rank ANCOVA).  At week 52, the proportion of patients who had a 
decline in FVC% by 10 percentage points or had died was reduced by 47.9% in the pirfenidone group 
(16.5% vs. 31.8%). 
In the secondary efficacy analysis, pirfendone resulted in a significant between group difference in 
the 6-minute walk distance (25.9% in the pirfenidone group and 35.7% in the placebo group had a 
decrease in 6-minute walk distance of 50m or more at week 52, P=0.04) and the combined endpoint 
of reduction in risk of death or disease progression (reduced by 43% in the pirfenidone group, HR 
0.57, 95% CI 0.43 to 0.77, P<0.001).  There were no differences in dyspnea as measures by the UCSD 
SOBQ scores at week 52 or all cause mortality.  In a pooled analysis of all-cause mortality (555 
patients from ASCEND and 692 from CAPACITY), there was a reduction in the risk of death at 1 year 
by 48% (HR 0.52, 95% CI 0.31 to 0.87, P=0.01). 
2.2  
RATIONALE AND STUDY APPROACH 
RA-ILD is a life-threatening and severely debilitating disease characterized by poor survival and a lack of 
efficacious therapeutic options at the inception of this study. Results from four controlled trials, as 
described above, suggest that pirfenidone treatment is safe and well tolerated in IPF with efficacy in a 
variety of domains, including changes in lung volume (%FVC/VC) and 6MWD over time, exercise 
tolerance (change in 6MWT distance), progression-free survival time, and all-cause mortality. Thus, 


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pirfenidone may be of benefit in RA-ILD, which shares many histopathological and clinic-epidemiological 
features with IPF (including poor survival).  
Given the loss of lung volumes over time in patients with RA-ILD, this protocol is designed to evaluate 
whether pirfenidone 2403 mg/d reduces decline in FVC or mortality over 52 weeks, compared with 
placebo, in patients with RA-ILD. 
This is a multi-center, randomized, double blind, placebo-controlled trial to assess the safety and 
tolerability of pirfenidone 2403 mg/day for the treatment of RA-associated interstitial lung disease. 
The protocol eligibility criteria include a probable/definite diagnosis of RA and associated lung disease.  
These criteria must be met in patients with % predicted FVC ≥40% and % predicted DLCO ≥25% PFT 
criteria which overlap closely with eligibility criteria in prior studies demonstrating the efficacy of 
pirfenidone for the treatment of IPF. FVC and DLCO criteria have been minimally liberalized to optimize 
enrollment in the more limited population of patients with autoimmune ILD.  
The primary composite endpoint of progression-free survival represents a clinically meaningful outcome 
measure that has been demonstrated to be reliable, valid, and predictive of changes in other disease 
states (King, Bradford et al. 2014).   Exploratory endpoints include a number of, clinical, serologic and 
biomarker endpoints with the potential to serve as markers of response to therapy. 
Multiple previous authors have reported that a decrement in % FVC over 6 months, particularly if ≥ 10% 
in magnitude, is both clinically significant and highly predictive of mortality (Collard et al. 2003; Flaherty 
et al. 2003; Zappala et al. 2010). We have chosen to assess the change in % FVC over the more 
prolonged duration of 12 months (52 weeks), which is twice the 6-month duration used in many of the 
studies assessing the performance characteristics of FVC. Decrements in % FVC at 12 months have also 
been robustly associated with mortality (Collard et al. 2003; {Latsi, 2003 #4006} King et al. 2005). 
Investigators propose to to test the validity and responsiveness to change of patient reported outcomes 
in the TRAIL-1 study. Composite indices have revolutionized the drug development in rheumatology due 
to multisystem involvement of these disorders. Given the heterogeneity of rheumatic diseases, outcome 
measures show high variability across individual patients, and may even vary with time with the same 
patient. The premise of a composite index is that it will capture divergent aspects of the disease, 
including patient-reported outcomes, that are important to the patient and clinician, while reducing 
variability associated with each individual outcome measure. A composite measure is more sensitive to 
change because its precision is better than that of individual components. This precision can be achieved 
by combining measure that have modest correlation. Well-validated, widely accepted combined 
response indices are more likely to be responsive to change than individual measures, which translates 
into greater power to detect differences; facilitate drug development; and improve assessment of 
efficacy of therapeutic agents.  
Pirfenidone 2403 mg/d was the dose evaluated in studies of pirfenidone in IPF, which demonstrated 
favorable efficacy and safety results compared with placebo. 
 
 


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2.3  
POTENTIAL RISKS AND BENEFITS  
2.3.1 
Known Potential Risks 
The safety of pirfenidone has been characterized in 16 studies involving 1900 subjects and patients; 
1055 patients have received pirfenidone at a dose of 2403 mg/d or greater. Analyses of these data 
suggest that the side effects of pirfenidone are readily monitored, typically reversible, and related to 
tolerability rather than morbidity.  Drug-induced liver injury (DILI) in the form of transient and 
clinically silent elevations in transaminases, has been commonly reported and in rare cases, these 
elevations were associated with concomitant bilirubin increases. Non-serious and serious cases of 
DILI, including severe liver injury with fatal outcome, have been reported In the post marketing 
period.  Escalation of dose over the first 2 weeks, dosing with food, use of protection against sun 
exposure, prompt symptomatic management of intolerance, and monitoring of liver function tests 
during dosing are recommended to maximize tolerability. 
2.3.2 
Known Potential Benefits 
The collective data from InterMune-sponsored PIPF-004 and PIPF-006, as well as Shionogi sponsored 
SP3 and SP2 and the ASCEND Trial, provide evidence that pirfenidone provides a clinically 
meaningful benefit to patients with IPF as measured by lung function, exercise tolerance, and 
progression-free survival. 
3 STUDY OBJECTIVES AND PURPOSE 
The objectives of this study of pirfenidone in patients with RA-ILD are as follows: 
1. To assess the efficacy and safety of pirfenidone 2403 mg/day as compared to placebo in patients 
with RA-associated interstitial lung disease.   
 
2. To explore the role of peripheral blood biomarkers in predicting disease progression and survival 
in patients with RA-associated interstitial lung disease. 
 
3. To explore a spectrum of validated questionnaires to assess disease specific PROs including 
overall health, and perspectives on symptoms, performance and quality of life. 
  
4 
STUDY DESIGN AND ENDPOINTS 
4.1  
DESCRIPTION OF THE STUDY DESIGN 
This is a phase 2, randomized, double blind, placebo controlled trial of pirfenidone for the treatment of 
RA associated interstitial lung disease.  Approximately 270 subjects will be randomized to receive 
pirfenidone 2403 mg per day or placebo in a 1:1 ratio.  The primary aim of this study is to assess the 
efficacy and safety of pirfenidone 2403 mg/day versus placebo in patients with RA-associated interstitial 
lung disease.  The primary efficacy outcome is defined by a composite endpoint of decline from baseline 
in percent predicted FVC of 10% or greater or death during the 52-week treatment period.  Patients will 
receive blinded study treatment from the time of randomization until the Week 52 Visit. 


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Eligible patients aged 18 to 85 years must meet 2010 ACR/EULAR criteria for RA (Aletaha, Neogi et al. 
2010) as well as RA-associated ILD, as determined by imaging and, when available, lung biopsy. Patients 
will be required to have a percent predicted FVC ≥40% and percent predicted DLCO ≥25% at screening.  
Any patient identified for the study must discontinue all prohibited therapies for at least 28 days before 
the start of screening.  The Screening Period may last up to 56 days. 
The dose of study treatment will be titrated over 14 days. Patients will receive a telephone assessment 
at Weeks 1 and 2, and visit the clinic at Weeks 4, 8, 13, 19, 26, 39, and 52.  Patients should complete a 
treatment compliance diary between visits.  If patients discontinue study treatment for any reason 
before the end of the study, they should complete an unscheduled visit and continue with all scheduled 
study procedures through Week 52.  If subjects are unable to complete the study visits as scheduled, all 
efforts should be made to complete an early termination visit. All subjects will receive an end of study 
phone call 28 days post last dose of study drug to assess vital status and adverse events.   
4.2  
STUDY ENDPOINTS 
4.2.1 
Primary Endpoint 
The primary outcome variable of this study will be the incidence of the composite endpoint of 
decline from baseline in percent predicted FVC of 10% or greater or death during the study 
treatment period. 
 
4.2.2 
Secondary Endpoints 
Secondary outcome measures of efficacy for this study will be assessed from baseline to the 52-week 
treatment period and will include: 
1. Incidence of the composite endpoint of decline from baseline in percent predicted FVC of 10% or 
greater during the study  period.  
2. Frequency of progressive disease as defined by OMERACT:  
Relative decline from baseline in percent predicted FVC of ≥10%, or relative decline from baseline 
in percent predicted FVC ≥ 5% and < 10%, and ≥15% relative decline in DLCO predicted (Khanna, 
Mittoo et al. 2015) 
3. Change from baseline to end of study in absolute value of FVC   
4. Change from baseline to end of study of percent predicted FVC 
5. Slope  of  percent predicted FVC over study period 
6. Slope of absolute FVC over study period 
7. Time to decline of 10% or greater in percent predicted FVC or death over study period 
8. Proportion of participants with all-cause mortality 
9. Proportion of participants with all-cause hospitalization 
10. Proportion of participants with hospitalization for respiratory cause 
11. Number of respiratory exacerbations requiring hospitalizations 


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12. Proportion of participants with and number of treatment-emergent AEs 
13. Proportion of participants with and number of treatment-emergent serious adverse events (SAEs) 
14. Proportion of participants with and number of treatment-emergent/treatment-related AEs 
15. Proportion of participants with and number of treatment-emergent/treatment-related SAEs 
16. Proportion of participants with and number of AEs leading to early discontinuation of study 
treatment 
17. Proportion of participants with and number of treatment-emergent death or transplant 
18. Proportion of participants with and number of treatment-emergent RA-ILD-related mortality 
19. Change from Baseline to end of study in dyspnea, as measured by the Dyspnea 12 questionnaire 
4.2.3 
Exploratory Endpoints 
Exploratory endpoints will include the following: 
1. Change from Baseline to end of study for Disease Activity Score (DAS)  
2. Change from Baseline to end of study for RAPID3 score (RA disease activity score) 
3. Change from Baseline to end of study in Erythrocyte Sedimentation Rate (ESR)  
4. Change from Baseline to end of study in C-Reactive Protein (CRP) 
5. Candidate biomarker expression in the peripheral blood of patients with RA-ILD over the study 
period of treatment and the study follow-up period 
6. Changes from Baseline to end of study in HRCT parameters evaluated by quantitative functional 
imaging 
7. Changes from Baseline to Week 13, 26, 39 and 52 in the St. George’s Respiratory Questionnaire 
(SGRQ) 
8. Changes from Baseline to Week 13, 26, 39 and 52 in Dyspnea 12 questionnaire 
9. Changes from Baseline to Week 13, 26, 39 and 52 in Leicester Cough Questionnaire (LCQ) 
10. Changes from Baseline to Week 13, 26, 39 and 52 in the Patient global assessment 
11. Changes from Baseline to Week 13, 26, 39 and 52 in the Health assessment questionnaire 
 
5 STUDY ENROLLMENT AND WITHDRAWAL 
5.1  
PARTICIPANT INCLUSION CRITERIA 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria to be eligible for this 
study. 
Patients must fulfill all of the following criteria to be eligible for enrollment in the study:  
 
1. Age 18 through 85 years, inclusive, at Screening 


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2. Probable or definite diagnosis of RA according to revised 2010 ACR/EULAR criteria, without 
evidence or suspicion of an alternative diagnosis that may contribute to their interstitial lung 
disease.  
3. Diagnosis of ILD  
a. supported by clinically indicated HRCT, and when available, surgical lung biopsy (SLB), 
prior to Screening, and 
b. presence of fibrotic abnormality affecting more than 10% of the lung parenchyma, with 
or without traction bronchiectasis or honeycombing, on Screening and confirmed by 
adjudicated HRCT prior to Baseline 
4. No features supporting an alternative diagnosis on transbronchial biopsy, or SLB, if performed 
prior to Screening 
5. Attainment of the following centralized spirometry criteria (based on local spirometry on 
standardized equipment and centralized quality controlled): 
a. percent predicted FVC ≥ 40% at Screening 
b. change in pre-bronchodilator FVC (measured in liters) between Visit 1 (Screening) and 
Visit 2 (Randomization) must be a <10% relative difference, calculated as: 
100% * [absolute value (Visit 1 FVC – Visit 2 FVC) / Visit 1 FVC] 
c. percent predicted DLCO or TLCO ≥25 % at Screening 
d. Screening (Visit 1) pre-bronchodilator(BD) and Post-BD spirometry meets ATS quality 
criteria as determined by a central reviewer 
e. Baseline (Visit 2) Pre-BD spirometry meets ATS quality criteria as determined by the site 
Investigator or the central reviewer 
 
6. Able to understand and sign a written informed consent form.  
7. For women of childbearing potential:  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use two adequate methods of contraception, including at least one method with 
a failure rate of <1% per year, during the 52 week treatment period and for at least 118 days 
after the last dose of study drug.  
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, established and proper use of hormonal contraceptives 
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. 
8. For men who are not surgically sterile: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating sperm, as defined below: 
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  


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< 1% per year during the treatment period and for at least 118 days after the last dose 
of study drug.   
b. Men must refrain from donating sperm during this same period. 
 
5.2  
PARTICIPANT EXCLUSION CRITERIA 
1. Not a suitable candidate for enrollment or unlikely to comply with the requirements of this study, 
in the opinion of the investigator 
2. Cigarette smoking or vaping within 3 months of Screening or unwilling to avoid tobacco products 
throughout the study 
3. History of clinically significant environmental exposure known to cause pulmonary fibrosis (PF), 
including but not limited to drugs (such as amiodarone), asbestos, beryllium, radiation, and 
domestic birds 
4. Concurrent presence of the following conditions: 
a. Other interstitial lung disease, related to but not limited to radiation, drug toxicity, 
sarcoidosis, hypersensitivity pneumonitis, or bronchiolitis obliterans organizing pneumonia 
b.  Medical history including Human Immunodeficiency Virus (HIV) 
     
c.     Medical history of viral hepatitis (positive Hep A antibody in the absence of elevated liver  
 
 
enzymes is not an exclusion) 
5. Concurrent presence of other pleuropulmonary manifestations of RA, including but not limited to 
rheumatoid nodular disease of the lung, pleuritis/pleural thickening, and obliterative bronchiolitis 
6. Post-bronchodilator FEV1/FVC <0.65 at Screening 
7. Presence of pleural effusion occupying more than 20% of the hemithorax on Screening HRCT 
8. Clinical diagnosis of a second connective tissue disease or overlap syndrome (including but not 
limited to scleroderma, sjogren’s,  polymyositis/dermatomyositis, systemic lupus erythematosus 
but excluding Raynaud’s phenomena) 
9. Coexistent clinically significant COPD/emphysema or asthma in the opinion of the site principal 
investigator 
10. Clinical evidence of active infection, including but not limited to bronchitis, pneumonia, sinusitis, 
urinary tract infection, or cellulitis.  The infection should be resolved per PI assessment prior to 
enrollment.  Any use of antibiotics must be completed 2weeks prior to the screening visit. Note 
that prophylactic antibiotics are not contraindicated or exclusionary 
11. Any history of malignancy diagnosed within 5 years of screening, other than basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin, or low grade cervical carcinoma, and/or low grade 
prostate cancer.  
Criteria for low grade prostate cancer: 
x Patients with suspicion for prostate cancer based on PSA and/or DRE should have been 
evaluated by urology 
x Patients with NCCN very low risk prostate cancer (· T1c and Grade Group 1 (Gleason 6) and 
PSA <10 ng/mL and Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in 
each fragment/coreg and · PSA density <0.15 ng/mL/g) can be monitored without intervention 
and enrolled in study. 
x Patients with NCCN low risk prostate cancer can be  monitored on a case by case basis (T1-T2a 
and Grade Group 1 (Gleason 6) and · PSA <10 ng/mL) and enrolled in study. 
x All other patients should be excluded. 


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12. History of LFT abnormalities as outlined below, or imaging, laboratory or other clinical information 
suggesting liver dysfunction, advanced liver disease or cirrhosis.  Evidence of hepatic impairment 
that in the opinion of the investigator could interfere with drug metabolism or increase the risk of 
the known hepatotoxicity of study drug.  
 
Any of the following liver function abnormalities: 
a. Total bilirubin above the upper limit of normal (ULN), excluding patients with Gilbert’s 
syndrome; 
b. Aspartate or alanine aminotransferase (AST/SGOT or AST/SGPT) > 3 X ULN; 
c. Alkaline phosphatase > 2.5 X ULN. 
13. History of end-stage renal disease requiring dialysis 
14. History of unstable or deteriorating cardiac disease, or unstable cardiac arrhythmia or arrhythmia 
requiring modification of drug therapy, myocardial infarction within the previous year, heart failure 
requiring hospitalization.  
15. Any condition that, in the opinion of the investigator, might be significantly exacerbated by the 
known side effects associated with the administration of pirfenidone 
16. History of alcohol or substance abuse in the past 2 years, at the time of Screening 
17. Family or personal history of long QT syndrome 
18. Any of the following test criteria above specified limits: 
a. Estimated glomerular filtration rate <30 mL/min/1.73m2 
b. ECG with a QTc interval >500 msec at Screening 
19. Prior use of pirfenidone or known hypersensitivity to any of the components of study treatment 
20. Use of any of the following therapies within 28 days before Screening and during participation in 
the study:  
a. Investigational therapy, defined as any drug that has not been approved for marketing 
for any indication in the country of the participating site 
b. Potent inhibitors of CYP1A2(e.g. fluvoxamine, enoxacin) 
c. Potent inducers of CYP1A2. 
d. Sildenafil (daily use). Note: intermittent use for erectile dysfunction is allowed 
21. Introduction and/or modification of dose of corticosteroids or any cytotoxic, immunosuppressive, 
or cytokine modulating or receptor antagonist agent for the management of pulmonary manifestations 
of RA, within 3 months of screening, is an exclusion criterion for enrollment, with the exception of dose 
modification of systemic corticosteroids that are maintained at or below 20 mg prednisone daily or the 
equivalent.   
 


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However, introduction and/or modification of dose of corticosteroids or any cytotoxic, 
immunosuppressive, or cytokine modulating or receptor antagonist agent for the management 
of extrapulmonary manifestations of RA is not an exclusion criterion for enrollment.  
22.  Any use of an approved anti-fibrotic medication within 28 days of screening. 
 
5.3  
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.3.1  Reasons for Withdrawal or Termination 
Study treatment will be discontinued for any of the following reasons: 
x 
Unacceptable toxicity (this may include serious adverse events [SAEs] related to study 
treatment) 
x 
Participant request or withdrawal of consent 
x 
Pregnancy 
x 
Investigator discretion 
x 
Termination of study by Genentech 
x 
Lung transplantation 
 
5.3.2 
Handling of Participant Withdrawals or Termination 
It is critical to the integrity of this study that participants adhere to the visit schedule outlined in the 
protocol. As such, every reasonable effort should be made to convey the importance of remaining 
on study to the participants. Any participant discontinuing study drug (Section 5.3.3) or terminating 
participation in the study (Section 5.3.4) must be reported immediately by telephone to the medical 
monitor or designee to discuss the circumstances of the case in an effort to ensure participant safety 
and appropriate documentation of events.  
5.3.3 
Early Discontinuation of Study Drug 
Participants who discontinue study treatment before Week 52 will complete an Unscheduled Visit 
related to discontinuation of study drug and potential safety issues, as necessary. If such a visit would 
occur within +/- one week of a regularly scheduled visit at week 4-,8-,13-,26-, or 39- then the regularly 
scheduled study visit can replace an unscheduled visit, otherwise the subject should be brought in for an 
unscheduled visit.   Whenever possible, they will continue to complete all scheduled study assessments 
and procedures through Week 52. Participants who permanently discontinue study drug before Week 
52 must return unused study drug. 
 
 
5.3.4 
Early Termination Visit 
Participants who withdraw consent in writing will cease all study procedures including vital status 
assessments.  These participants will complete an Early Termination Visit (Section 7.2.2) and Visit 
12/End of Study Phone Call 28 days after the last dose of study drug, whenever possible. 
Participants may have clinically appropriate testing in preparation for lung transplantation while on 


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the study. Participants who receive a lung transplant during the study will discontinue study 
treatment and withdraw from study procedures.  These participants will also complete an Early 
Termination Visit (Section 7.2.2) and Visit 12/End of Study Phone Call 28 days after the last dose of 
study drug, whenever possible. 
 
5.3.5 
Study Treatment Pre-Restart Visits 
Participants should be encouraged to restart study treatment whenever possible and appropriate. If 
the participant has interrupted study treatment for ≥28 days, a Pre-Restart Visit is required (Section 
7.2.2). The Pre-Restart Visit will be conducted on the day study treatment is resumed. 
Participants who restart study treatment will resume the visit schedule based on their date of 
randomization. If a regularly scheduled visit (Weeks 13, 26, 39, etc.) coincides with the Pre-Restart 
Visit, then all of the elements of the regularly scheduled visit should be performed in lieu of the Pre-
Restart Visit. 
 
5.3.6 
Unscheduled Visits 
Any follow-up that is performed to monitor participant safety should be collected as an 
Unscheduled Visit (Section 7.2.2). The investigator is responsible for review of AEs/SAEs, 
concomitant medications, oxygen use, physical examination, resting oxygen saturation, vital signs, 
and weight.  The remaining elements of the visit are up to the discretion of the investigator. Any 
additional clinical laboratory assessments should be obtained through the central laboratory. 
 
5.3.7 
Lost to Follow-Up 
If a participant has missed a visit and is not responding to telephone calls from the site (all attempts 
to contact the participant should be documented), the site will need to take more aggressive action 
in locating the participant. The site should make at least two attempts to contact the participant by 
telephone and two additional attempts to contact the participant’s emergency contact. If these 
attempts are not successful, a registered letter should be sent to the last known address of the 
participant. If after all of these methods are employed and no contact with the participant results, 
the participant will be considered lost to follow-up. In this circumstance, the site should check the 
national death registries, where approved by regulatory authorities and available, to obtain vital 
status information for the database.   
 
5.4  
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
Both the Sponsor or designee and the Investigator reserve the right to terminate the study at the 
Investigator’s site, according to the terms of the study contract. The Investigator/Sponsor or 
designee should notify the IEC/IRB and relevant national competent authorities in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor or 
designee.  
The Sponsor or designee reserves the right to terminate the study overall. 
 


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5.5  
APPROVAL OF NINTEDANIB (OFEV) IN THE UNITED STATES 
 
On March 9, 2020 the U.S. Food and Drug Administration approved OFEV (nintedanib) oral capsules for 
the treatment of chronic fibrosing (scarring) interstitial lung disease (ILD), such as RA-ILD.   All US 
participants currently enrolled in the study were contacted to inform them of this new information and 
affirm their desire to continue participating in the study or not.   Neither OFEV nor Pirfendone have 
been approved for use in patient with RA-ILD in Australia, Canada, or the United Kingdom. 
 
6 STUDY AGENT 
6.1  
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 
Source and Acquisition of Study Drugs 
Genentech will supply all study medications (pirfenidone and matching placebo). There will be 270 
capsules per bottle, which will be labeled for investigational use only. Pirfenidone 267-mg and 
placebo will be supplied in opaque, hard, white gelatin capsules that are visually indistinguishable. 
 
6.1.2 
Study Agent Formulation, Appearance, Packaging and Labeling 
The contents of the pirfenidone 267-mg capsules are as follows: 
x 
Pirfenidone 82.15% 
x 
Croscarmellose sodium 8.15% 
x 
Microcrystalline cellulose 7.39% 
x 
Povidone, USP, EP 1.85% 
x 
Magnesium stearate 0.46% 
The contents of the placebo capsules are as follows: 
x 
Microcrystalline cellulose 79.99% 
x 
Pre-gel starch 19.5% 
x 
Magnesium stearate 0.5% 
x 
Bitrex 0.01% 
 
6.1.3 
Product Storage & Stability 
Study medication will be shipped to the investigational sites at ambient temperature and should be 
stored between 15 and 30° C. DO NOT FREEZE OR REFRIGERATE. Do not use beyond the expiration 
date. 
 
6.1.4 
Dispensing of Study Treatment 


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Study treatment will be dispensed to the participant every 13 weeks, but may be dispensed at other 
visits, as needed. Participants will be instructed to store study treatment at room temperature. 
Participants will be instructed to use study treatments in the order in which they are dispensed and 
that they must return all used and unused study treatment bottles. 
 
6.1.5 
Pre-specified Dose Adjustment & Modifications 
It is the responsibility of the investigator to monitor participants as frequently as clinically indicated 
for toxicities and consistent with the instructions of the package inserts for any medication used to 
treat study participants. Refer to Section 2.1 for safety data from Genentech’s Phase 3 clinical 
studies of pirfenidone. 
If a participant experiences significant side effects, treatment of symptoms and/or temporary dose 
reductions, interruptions, or discontinuation of study treatment should be considered. Investigators 
have experience of using Pirfenidone with IPF patients, however, a suggested dosing flowchart is 
attached at Appendix B.  Any such dosing modifications should be recorded in the participant diary. 
The medical monitor or designee will be available to discuss the management of AEs and dose 
modification, as needed. 
In the event of elevated liver aminotransferase tests, the recommendations in Table 1 should be 
followed. The medical monitor or designee may be contacted for further discussion, as needed.  
 
 


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Table 1. Recommended Procedures for Participants with Elevated Liver Aminotransferase Test 
Results 
 
Magnitude of Elevation in 
ALT or AST 
Recommendation 
>3 to ≤5  × ULN 
Not accompanied by 
symptoms or 
hyperbilirubinemia 
(Total bilirubin >2 × ULN) 
Exclude other causes (e.g. confounding medications). 
Monitor the patient closely, including repeat liver chemistry tests. If 
clinically appropriate, reduce or interrupt the dose (e.g., until liver 
chemistry test results are within normal limits). Once liver function 
tests are again within normal limits, Esbriet may be re-titrated to the 
recommended daily dose if tolerated. 
Liver function tests should be repeated at 1 month intervals until 
< 3 x ULN 
>3 to ≤5 × ULN 
Accompanied by  
hyperbilirubinemia 
(Total bilirubin >2 × ULN) or 
clinical signs or symptoms of 
liver injury*  
*Refer to section 6.1.19 for 
clinical signs of symptoms  
Study treatment should be permanently discontinued.  Liver 
function tests should be monitored monthly until symptoms 
resolve and bilirubin < 2 x ULN 
>5 × ULN 
Study treatment should be permanently discontinued. Liver 
function tests should be monitored monthly until < 3 x ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal 
       In the event of a QTc >500 msec, refer to Section 7.1.2 for instructions. 
With the exceptions noted above, study treatment may be restarted at the discretion of the 
investigator. For treatment interruptions of ≥28 days, a pre-restart visit is required, as outlined in 
Section 6.1.8, in addition to study treatment titration. 
Investigators should use the flowchart in Appedix B to re-titrate subjects to full dose. However if the 
subject is unable to tolerate the full dose, the subject will be maintained on the highest dose 
tolerable for the remainder of the study. Dosing changes and interruptions will be recorded.  
In participants requiring hospitalization for an acute pulmonary process of unclear etiology, the 
investigator should consider continuing study treatment, if appropriate. If the participant is 
hospitalized at an institution other than the study site, the treating physician should be encouraged 


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to discuss the participant’s management with the investigator at the earliest possible time. All 
records pertaining to the hospitalization should be obtained. 
All toxicities will be followed according to procedures in Section 8.The ultimate decision regarding 
study treatment interruption, restart, and dose modification is the responsibility of the investigator. 
For example, it is the investigator's responsibility to determine whether study treatment should be 
restarted in the setting of changing toxicity grades. Investigators are encouraged to contact the 
medical monitor or designee to discuss participant safety and dose-modification issues. 
 
6.1.6 
Duration of Therapy 
Study treatment is defined as either pirfenidone 2403 mg/d or placebo equivalent administered in 
divided doses three times per day (TID).  Each dose should be taken with food, at the same time 
each day, preferably after each meal. 
Dose Escalation Period:  Study treatment should be titrated over 14 days, as tolerated, to the full 
dose of 9 capsules per day (three capsules TID), as follows: 
• 
Days 1–7:  one capsule TID 
• 
Days 8–14:  two capsules TID 
• 
Days 15-21:  three capsules TID (maximum of 9 capsules daily) 
Stable Dosing Period:   Participants will remain on a stable maintenance dose for the duration of the 
study period (Day 22 to Week 52) unless the dose is reduced to manage an AE (see Section 6.1.5). 
Doses of more than 9 capsules per day are not recommended for any participant. 
 
6.1.7 
Missed Doses 
If participants miss a scheduled dose, that dose should be skipped. Regular dosing should resume 
with the next scheduled dose. Participants should not take any extra doses to make up for missed 
doses. 
 
6.1.8 
Interruption of Study Treatment 
Any participant with an actual or anticipated interruption of study treatment for a period of ≥28 
consecutive days will be reported by telephone to the study’s medical monitor or designee to 
discuss the circumstances of the case. Once the participant restarts study treatment, the dose may 
be re-titrated as described in Section 6.1.6. A pre-restart visit is required, as described in Section 
5.3.5. 
 
6.1.9 
Precautionary Measures 
Drug-induced liver injury (DILI) has been observed with pirfenidone. In the postmarketing period, 
non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been 
reported. Patients treated with pirfenidone had a higher incidence of ALT and/or AST elevations of 
≥3x ULN (3.7%) compared with placebo patients (0.8%). Increases in ALT and AST ≥3x ULN were 
reversible with dose modification or treatment discontinuation. 


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Measure liver function promptly in patients who report symptoms that may indicate liver injury, 
including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dosage 
modification or interruption may be necessary for liver enzyme elevations. See Table 1. 
 
Pirfenidone is causally associated with DILI, mainly in the form of transient liver enzyme elevations 
of no clinical relevance. However, clinical manifestations of DILI including cases with fatal outcome – 
possibly caused by idiosyncratic reactions to pirfenidone – have been reported in rare instances. 
Exposure to sunlight (including sunlamps and tanning beds) should be avoided or minimized during 
study treatment due to the possibility of photosensitivity reactions or rash. Participants should be 
instructed to use sunscreens that have a sun protection factor (SPF) of 50 or higher as well as 
protection against ultraviolet A (UV-A) radiation, and also to wear clothing that protects against sun 
exposure and avoid concomitant medications known to cause photosensitivity reactions, if possible. 
All doses of study treatment are to be taken with food to reduce the likelihood of gastrointestinal 
symptoms. The dose titration period of 21 days at the initiation of study treatment is designed to 
maximize tolerability. 
 
6.2  
STUDY AGENT ACCOUNTABILITY PROCEDURES 
The monitoring of the inventory of study treatment supplies may be delegated to the responsible 
pharmacist; however, the Investigator is ultimately responsible for monitoring of study treatment 
inventory. Study treatment may not be used for any purpose other than that described in the protocol. 
All study treatment must be stored in a secure place with access restricted to authorized personnel. 
Participants should return all used and unused bottles of study treatment at every visit. After drug 
accountability has been assessed and drug return has been authorized by the clinical monitor, sites may 
return all used and unused study treatment bottles to the distribution center or destroyed in 
accordance with site-specific standard operating procedures. 
All bottles of study treatment will be recorded in a Drug Accountability Log. The Investigator or designee 
will account for all study treatment received at the site, dispensed to the participants, returned by the 
participants, not used, and  destroyed. All documentation of study treatment shipments must be 
retained. 
 
7 STUDY PROCEDURES AND SCHEDULE 
7.1  
STUDY PROCEDURES/EVALUATIONS 
Informed consent must be obtained prior to Screening and before any study-mandated procedures take 
place. Study procedures are defined as laboratory tests, spirometry, lung volumes, DLCO (carbon 
monoxide transfer capacity), ECG, HRCT scan, directed history, physical examination, vital signs, height, 
weight, and any changes to existing treatment regimens. During the study, procedures and observations 
will be monitored to confirm that study requirements are being followed as outlined in Appendix A.    If 
any study procedure related to PFTs and imaging is deemed not acceptable for quality issues, the 
procedure should be repeated. 
 


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7.1.1 
Laboratory Assessments 
Routine Clinical Laboratory Tests 
The following research related assessments will be performed locally at each clinical site, according 
to Appendix A, as summarized below: 
x 
Hematology (complete blood count with platelet count and automated differential) 
x 
Serum chemistry profile (albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, total 
bilirubin, calcium, creatinine, glomerular filtration rate (eGRF), gamma-glutamyl transferase 
[GGT], glucose, potassium, sodium, BUN, uric acid and amylase) 
x 
Blood Pregnancy test for women of childbearing capacity 
x 
Serology assessments include Erythrocyte Sedimentation Rate (ESR), Rheumatoid Factor 
(RF), C-Reactive Protein (CRP), and Cyclic Citrullinated Peptide (CCP) 
 
It is the investigator’s responsibility to perform clinical laboratory assessments more frequently, if 
clinically indicated. 
 
Biomarkers in Blood 
Research laboratory studies will be conducted at Baylor College of Medicine.  Blood samples 
obtained for research studies will be shipped to Baylor College of Medicine.  Biomarker samples 
include Serum, Plasma, and RNA.  These samples will be collected according to Appendix A. Samples 
will be labeled with a unique study code and stored at the Biorepository at Baylor College of 
Medicine for future research.   
Certain biomarkers may be differentially expressed in RA-ILD and may change as a result of 
pirfenidone treatment (e.g., possibly cytokines, chemokines, microRNA expression, and other 
cellular and molecular markers of fibrosis). The blood samples that are being obtained for this study 
may help identify these biomarkers and may be used to assess their response to pirfenidone 
therapy. 
 
Genetic Polymorphisms (Assessed at  Participating Sites) 
Genetic polymorphisms have been demonstrated to alter the development and clinical course of a 
number of different diseases. The purpose of assessing genetic polymorphisms in this study is to 
understand their potential role in the pathogenesis of RA-ILD and in clinical outcomes. 
 The assessment of genetic polymorphisms will be conducted at all institutions that agree to offer 
this assessment.  Participant participation for this assessment is voluntary and declining 
participation will in no way influence eligibility for this study. Participants agreeing to participate will 
opt in on the informed consent form.  Blood samples for genetic research include DNA PAXgene 
samples.  These samples will be collected according to Appendix A. Samples will be labeled with a 
unique study code and stored at the Biorepository at Baylor College of Medicine for future research.   
 


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7.1.2 
Clinical Assessments 
 
HRCT Scans 
HRCT scans obtained before the Screening period as part of the standard of care for a participant may 
be used to confirm eligibility, provided they meet all of the image acquisition and quality criteria 
required by the central expert readers and were obtained within 3 months before the start of the 
Screening Period (see Appendix A). All HRCT digital images are to be stored on a dedicated disk or 
tape at each study center. The images will be transferred electronically to the vendor tasked with 
interpretation and archiving of the images. 
To assess for eligibility, HRCT scans will be evaluated for: 
a.  
presence and extent (to nearest 10%) of reticular abnormality, ground glass, 
honeycombing, mosaic attenuation, nodules, consolidation, emphysema, overall extent 
of fibrosis.  
 
 
b.       
Semi-quantitative estimates of extent by central reader. 
c.        Presence of traction bronchiectasis, non-traction bronchiectasis (common in RA), 
subpleural sparing, centrilobular nodularity, tree in bud, crazy paving, pleural thickening 
and/or effusion.  
 
 
d.       
Distribution of abnormalities: 
 
  
 
 
 i.     Subpleural, peribronchovascular predominance or diffuse in axial plane 
 
 
 
  
ii.    Upper lung, mid lung, lower lung predominance or diffuse in craniocaudal plane 
e.       
Radiologic pattern of abnormality: UIP, NSIP, indeterminate, mixed (Lynch DA, Godwin 
JD, Safrin S, Starko KM, Hormel P, Brown KK, et al. High-resolution computed 
tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit 
Care Med. 2005 Aug 15;172(4):488-93.) 
The HRCT scans will be reviewed by a central reader who is a radiologist with expertise in RA-ILD prior to 
randomization.  An adjudication committee will be available to assist with difficult cases. Data regarding 
the HRCT interpretation will be entered electronically into the Data Coordinating Center (DCC) database 
and incorporated into the clinical database. 
 
Surgical lung biopsy 
Surgical lung biopsy (SLB) or transbronchial biopsy, if performed, may be obtained up to 4 years before 
randomization. Data regarding the pathology findings will be entered directly into the electronic case 
report form (eCRF).  Participant eligibility will be communicated to the study site by the investigators’ 
designated vendor. 
 
 


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Spirometry and DLCO/ TLCO Measurements 
All equipment, procedures, and personnel qualifications for the assessment of lung function are based on 
the recommendations of the American Thoracic Society (ATS 2005) and will be performed and interpreted 
in accordance with published guidelines (Crapo 1994): 
Spirometry measurements will include FVC and FEV1 before and 10-15 minutes after administration of a 
bronchodilator [albuterol (or salbutamol) from a metered dose inhaler] at screening.  The remainder of 
the spirometric studies will be performed without bronchodilator administration. 
Lung volume measurements will be performed by body plethysmography and should be performed before 
or at least 30 min after the last bronchodilator puff. 
DLCO/ TLCO will be measured by determining the diffusing capacity of the lung for carbon monoxide.  
DLCO/ TLCO measurement should be performed before or at least 30 min after the last bronchodilator 
puff. 
All FVC data collected throughout the study will be evaluated by a central reader blinded to treatment 
assignment. Data for FVC and FEV1, will be entered electronically into the vendor’s database and 
incorporated into the clinical database.   DLCO/ TLCO  will be entered into the clinical database by the site.   
 
Patient Reported Outcomes 
A spectrum of validated questionnaires will be used to assessed patient related outcomes that include 
disease specific, overall health, and their perspectives on symptoms, performance and quality of life. 
These questionnaires have been endorsed by the OMERACT as the essential core set that should be 
included in the trials of Connective Tissue Disease-Interstitial Lung Disease. Domains that are advocated 
include:  1. Health Related Quality of Life (HRQOL), 2. Dyspnea, 3. Cough, 4.  Patient Global Assessment, 
and 5. Function.  
a) HRQOL instrument: St. George’s Respiratory Questionnaire (SGRQ): SGRQ, a respiratory disease-
specific HRQOL instrument that was originally developed for use in chronic obstructive pulmonary disease, 
has more recently been used in interstitial lung disease.  
b) Dyspnea: Dyspnea 12 questionnaire (D-12):  The D-12 is a unidimensional questionnaire with 12 items 
that provides a global score of breathlessness severity that incorporates both “physical” and “affective” 
aspects. The score is calculated using simple summation of the responses for each item (0 “mild” to 3 
“severe”); thus, the total score ranges from 0 to 36, with 36 representing maximal severity. It has been 
validated in Connective Tissue Disease-Interstitial Lung Disease. 
c) Cough: Leicester Cough Questionnaire (LCQ): This self-administered 19-item questionnaire for the 
quantitative assessment of symptoms of cough frequency and severity.  
d) Patient global assessment (DAS28 Section B Global Health Questionnaire): DAS28 Section B Is a single 
item visual analog scale that assesses global severity of the patient due to their disease. 
e) Function: Health assessment questionnaire (HAQ20): It is a 20-item questionnaire to assess daily 
functional disability. It is validated in RA and is universally used in clinical trials of RA. 


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f) 
RAPID3: The Routine Assessment of Patient Index Data 3 (RAPID3) is a questionnaire that has been   
validated for rheumatoid arthritis to assess patient physical function, pain, and global assessment. 
Physical Exam and Vital Signs 
A complete physical examination should be performed on the day of the visit, including all body systems 
pertinent to the participant. If clinically significant abnormalities are observed before Day 1, they should 
be reported in the participant’s medical history. If clinically significant abnormalities are observed after 
Day 1, the investigator should decide if they are new adverse events.  Vital signs for this study protocol 
include heart rate and blood pressure.  
Disease Activity Score (DAS28) 
The DAS28 will be scored by an investigator based on clinical examination including swollen and tender 
joint counts performed by the investigators and lab results (ESR and CRP), as well as patient global 
assessment score.  
 
Physician Global Assessment 
Physician Global Assessment questionnaire asks physicians to rate the patient’s overall health in the last 
week. 
Vital Status Assessments 
Vital status must be assessed at protocol-specified time points until the Follow-Up Visit, even if the 
participant cannot physically be present for the visit. Participants who chose to withdraw from study 
procedures early will be followed for vital status until Visit 12/End of Study Phone Call whenever 
possible.  
Vital status procedures are as follows: 
1. In the case of lung transplant, the date of the transplant, details of the transplant, dates of 
hospitalization, and the current vital status will be obtained 
2. In the case of participant death, the date, details, and cause of death will be obtained if possible 
3. If a participant is lost to follow-up, vital status will be ascertained through the use of Death 
Registries, where approved and available (see 5.3.7) 
Mortality Assessment Committee 
A Mortality Assessment Committee (MAC) will closely examine the details and review the relationship to 
RA-ILD for each death. Documentation regarding deaths must be requested and should include (but is not 
limited to) discharge summaries, death certificates, and autopsy reports. 
 
Adjudication of Acute Exacerbations 
An adjudication committee will be established to assess whether episodes of respiratory 
decompensation/acute exacerbation are congruent with established criteria, and their relationships to 
study treatment. 


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Electrocardiograms (ECGs) 
ECGs should be performed before bronchodilator administration or on a separate day. 
During the study, if the QTc interval is >550 msec, confirmed by a repeat ECG within 24 h, and verified by 
the study site or local cardiologist, study drug should be stopped.  If the QTc interval is between 500 and 
550 msec, confirmed by a repeat ECG within 24 hours, and verified by a study site or local cardiologist, 
study treatment should be interrupted. If an alternative explanation is identified (e.g., electrolyte 
abnormality or concomitant medication), re-initiation of study treatment may be considered by the 
investigator in consultation with the medical monitor or designee. ECG data will be incorporated into 
the clinical database. 
 
 
7.2  SUMMARY OF STUDY SCHEDULE AND ASSESSMENTS 
7.2.1 
Screening Period 
Written informed consent must be obtained before initiating any study-associated procedures or 
changes to a pre-existing treatment regimen for purposes of this study. Procedures conducted 
during screening will be used to determine the eligibility of each participant for study inclusion 
before randomization and to establish participant baseline status.  
 
Subjects who do not meet enrollment criteria at Visit 1 may be brought back to be rescreened for 
potential enrollment.  Each subject may only complete up to one rescreening visit.  The rationale to 
rescreen includes factors that may be subject to change over time such as a condition that 
subsequently resolves (e.g. infection), change in concomitant medication (e.g. dose of 
corticosteroids is stabilized or a prohibited medication has been completed/discontinued), change in 
smoking history (e.g. smoking history now greater than within 3 months of screening), spirometry 
criteria, or lab assessment criteria.  In such cases, all Visit 1 procedures will be repeated.  HRCT scans 
performed within 3 months of the start date of the screening period may be used to confirm 
eligibility. 
 
Screening (Visit 1) 
 
The Screening period (Visit 1) is defined as the time between the date of the first Screening 
procedure and Eligibility/Randomization (Visit 2) and may last up to 56 days. Screening procedures 
may be conducted on different days within the Screening period if convenient. 
The following procedures will be performed during Screening: 
1.   Written informed consent 
2.   Directed medical history/review of systems, review of AEs/SAEs, concomitant medications, 
oxygen use  


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3.   Physical examination, vital signs, resting oxygen saturation, weight, and height 
4.  Clinical laboratory assessments, including hematology, serum chemistries, serologic tests, and 
blood pregnancy test for women of childbearing capacity 
5.   ECG (obtained before bronchodilator administration or on a separate day) 
6.   Measurement of Oxygen Saturation at Rest 
7 .  Review of transbronchial biopsy or SLB, if available, to assess eligibility 
8. HRCT scan to assess eligibility 
9 .  Spirometry (FVC, FEV1) before and 10-15 minutes after bronchodilator administration 
10. Lung volumes, DLCO or TLCO obtained before or 30 minutes after bronchodilator administration 
11. Biomarkers (See Appendix A) 
 
Eligibility and Randomization (Visit 2) 
 
All Visit 2 procedures must be performed before randomization and before administration of study 
treatment.  Randomization (Visit 2) will occur no more than 56 days after the start of the Screening 
period, and study treatment should begin on the day of randomization. All results of the screening 
assessments and eligibility documentation will be submitted to study investigators or designee for 
approval at least 2 working days before the targeted randomization day. Once a participant’s 
documentation is received and the participant is confirmed to be eligible for randomization, the site 
will be instructed to randomize the participant at the end of Visit 2. 
The following procedures will be performed at Visit 2: 
Before Randomization: 
1. Directed medical history/review of systems,review of AEs/SAEs, concomitant medications, oxygen 
use 
2.  Physical examination, resting oxygen saturation, vital signs, and weight 
3. Pregnancy test for women of childbearing capacity 
4.  Biomarkers (See Appendix A)  
5. Blood samples for genetic research (DNA PAXgene samples) - Optional 
6.  Spirometry (FVC, FEV1) without bronchodilator administration 
7.  Patient Reported Outcome Questionnaires (See Appendix A) 
8. Disease Activity Score (DAS28): Swollen and Tender Joint Counts and patient global assessment 
score 
9. Confirmation of participant eligibility for study participation 


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Randomization: 
10. Randomize participant using an automated system 
After Randomization: 
11. Instruct the participant on how to titrate the dose of study treatment 
12. Dispense supply  of study treatment.  On day of randomization, first dose must be taken in clinic 
and Study Medication Accountability completed. 
13. Dispense participant diary and instruct participants on how to properly record information using 
the diary 
 
7.2.2 
Assessments During Treatment 
 
Weeks 1 and 2 (Visit 3, 4) (± 2 days) Telephone Assessment  
A telephone interview will be conducted for Vital Status Assessment, review of AEs/SAEs, concomitant 
medications, and study medication dosing.  
Weeks 4 and 8 (Visit 5, 6) (± 1 week) 
 
The following procedures will be performed at Weeks 4 and 8: 
1.   Review of AEs/SAEs, concomitant medications, oxygen use 
2.   Physical examination, resting oxygen saturation, vital signs, and weight 
3.   ECG (at Week 4 only) 
 
4.   Clinical laboratory assessments, including hematology, serum chemistries, and blood pregnancy 
test for women of childbearing capacity 
5. Study Medication Dosing review (participant diary) 
6. Biomarkers (Week 4 only) 
 
Weeks 13, 26, 39 (Visit 7, 9, 10)  (± 2 weeks) 
 
The following will be performed at Weeks 13, 26, and 39: 
1.   Review of AEs/SAEs, concomitant medications, oxygen use 
2.   Physical examination, resting oxygen saturation, vital signs, and weight 
3.   ECG  
4.   Spirometry (FVC, FEV1) without bronchodilator administration 


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5.   Clinical laboratory assessments, including hematology, serum chemistries, blood pregnancy test 
for women of childbearing capacity 
6.   Biomarkers 
7.   Patient Reported Outcome Questionnaires (See Appendix A) 
8.   Study Medication Accountability, including dispensing of study treatment 
9.   Study Medication Dosing review (participant diary) 
10.   Dispense new diary, if required. 
 
Week 19 (Visit 8) (± 1 week) 
 
The following will be performed at Week 19: 
1. Review of AEs/SAEs, concomitant medications 
 
2. Liver function testing only (AST, ALT, bilirubin, and alkaline phosphatase) 
 
Week 52 (Visit 11) (± 4 weeks) 
 
At the Week 52 Visit, the following procedures will be performed: 
1. Review of AEs/SAEs, concomitant medications, oxygen use 
2.  Physical examination, resting oxygen saturation, vital signs, and weight 
3. Clinical laboratory assessments, including hematology, serum chemistries, serologic tests, and 
blood pregnancy test for women of childbearing capacity 
4.  Biomarkers (See Appendix A) 
5. Blood samples for genetic research (DNA PAXgene samples) - Optional 
6.  Spirometry (FVC, FEV1 without bronchodilator administration) 
7.  Lung volumes, DLCO or TLCO  
8.  Patient Reported Outcome Questionnaires (See Appendix A) 
9. Study Medication Accountability, including collection of any unused study treatment 
10. Study Medication Dosing review (participant diary) 
11. HRCT scan 
12. ECG 


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13. Disease Activity Score (DAS28): Swollen and Tender Joint Counts and patient global assessment 
score 
 
Visit 12/End of Study Phone Call (28 days after last dose of study drug, ± 1 week) 
 
1. Review of AEs/SAEs 
 
2. Vital Status Assessment 
 
Early Termination Visit 
Participants who terminate participation in the study (e.g. withdraw consent in writing, receive a 
lung transplant) will discontinue study treatment, cease all study procedures, and undergo the 
assessments listed below.  These participants will also complete Visit 12/End of Study Phone Call 28 
days after the last dose of study drug. 
 
1. Review of AEs/SAEs, concomitant medications, oxygen use 
2. Physical examination, resting oxygen saturation, vital signs, and weight 
3. Clinical laboratory assessments, including hematology, serum chemistries, serologic tests, and 
blood pregnancy test for women of childbearing capacity 
4. Biomarkers (See Appendix A) 
5. Blood samples for genetic research (DNA PAXgene samples) - Optional 
6. Spirometry (FVC, FEV1 without bronchodilator administration) 
7. Lung volumes, DLCO or TLCO 
8. Patient Reported Outcome Questionnaires (See Appendix A) 
9. Study Medication Accountability, including collection of any unused study treatment 
10. Study Medication Dosing review (participant diary) 
11. HRCT scan 
12. ECG 
13. Disease Activity Score (DAS28): Swollen and Tender Joint Counts and patient global assessment 
score 
 
Study Treatment Pre-Restart Visits 
If the participant has interrupted study treatment for ≥28 days, a Pre-Restart Visit is required.  
The following procedures will be performed at the Pre-Restart Visit: 
 
1. Review of AEs/SAEs, concomitant medications, oxygen use 


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2. Physical examination, resting oxygen saturation, vital signs, and weight 
3. Clinical laboratory assessments, including hematology, serum chemistries, and blood pregnancy 
test for women of childbearing capacity 
4. ECG 
5. Study Medication Accountability, including dispensing of study treatment, if required 
6. Study Medication Dosing review (participant diary) 
7. Instruction on how to re-titrate the dose of study treatment 
8. Dispense new diary, if required 
 
Unscheduled Visits 
The following procedures are required to be performed at Unscheduled Visits to monitor participant 
safety: 
1. Review of AEs/SAEs, concomitant medications, oxygen use 
2. Physical examination, resting oxygen saturation, vital signs, and weight 
3.  Study Medication Accountability 
4. Study Medication Dosing review (participant diary) 
 
Further evaluation as part of routine clinical care would be done at the discretion of the site 
Principal Investigator.  
Participants who discontinue study drug early will complete an Unscheduled Visit.  These 
participants will then continue to complete all scheduled study assessments and procedures through 
Week 52 (Visit 11). 
 
7.3  
CONCOMITANT MEDICATIONS & TREATMENTS DURING THE STUDY 
7.3.1 
Concomitant Medications 
All of the following are considered concomitant medications, and data regarding their use must be 
collected and recorded: 
• 
Prescription drugs 
• 
Over-the-counter drugs, including vitamins, antacids, herbal and dietary supplements 
• 
Permitted therapies (see section 5.1) 
• 
Excluded therapies (see Section 7.4) 
Information on all concomitant medications will be collected until 28 days after the last dose of 
study treatment.   
 


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7.3.2 
Treatment for Acute ILD Exacerbations 
Acute ILD exacerbations should be identified in accordance with published guidelines.(Raghu, 
Collard et al. 2011)  Corticosteroids may be used at the discretion of the investigator, without dose 
restriction, for a period of up to 21 days in participants experiencing an episode of acute ILD 
exacerbation. The study drug should be continued during this time, if possible. If study treatment 
interruption/discontinuation is being considered, it must be immediately reported by telephone to 
the medical monitor or designee to discuss the circumstances of the case. 
 
7.4  
PROHIBITED MEDICATIONS AND TREATMENTS DURING THE STUDY 
Pirfenidone is metabolised by Cytochrome P450 1A2 (CYP1A2). Inhibitors of this enzyme will increase 
drug levels and inducers reduce them. Potent inhibitors and activators should be avoided. Use of 
medications with moderate and mild activator and inhibitor effects on study drug metabolism is left to 
the discretion of the site PI. 
The following medications are not permitted on this study - strong inhbitors of CYP1A2 including but not 
limited to Fluvoxamine and Enoxacin. 
The following moderate inhibitors of CYP1A2 medications should be used with caution: Amiodarone, 
Propafenone, Ciprofloxacin. Pirfenidone should be reduced to 1602 mg daily (2 capsules, 3 times a day) 
if taken with Ciprofloxacin 750mg twice daily. Special care should also be exercised if CYP1A2 inhibitors 
are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in 
the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. 
chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).  
Moderate inducers of CYP1A2 may reduce the effective dose of pirfenidone and should be used with 
caution.  
 
 
8 ASSESSMENT OF SAFETY 
8.1  
SPECIFICATION OF SAFETY PARAMETERS 
Investigators are responsible for monitoring the safety of participants who have entered this study and 
for providing appropriate medical care. In addition, the investigators are responsible for alerting 
Genentech and/or Roche or its designee to any event that seems unusual, even if the event may be 
considered an unanticipated benefit to the participant. A SAE should be reported to the medical monitor 
or designee within 24 hours after becoming aware of its occurrence via reporting in the study database. 
Investigators must report all SAEs to their governing IRB/IEC as required by local regulations and 
guidelines. 
By exercising appropriate health-care options, the investigator remains responsible for managing AEs that 
are serious or that cause the participants to withdraw before completing the study. Duration of follow-up 
and requirements for immediate SAE reporting (within 24 hours of the event) are described below. 


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8.2  
SAFETY DATA EXCHANGE AGREEMENT 
 
8.2.1 
Background 
The relevant International Conference on Harmonization (ICH) guidelines, the latest European Union 
Pharmacovigilance guidelines and applicable European Union legislation, the United States (US) 
Code of Federal Regulations, Title 21, and relevant local regulations form the basis of the 
information to be exchanged under this protocol and to be reported to the regulatory authorities, as 
applicable.  
 
8.2.2 
Definitions 
 
Single Case Management 
 
x 
Collection of Single Case Reports 
o The PI or his designee (i.e., the DCC) will collect all protocol-defined Adverse Events 
(AEs) and pregnancy reports from the Study and obtain follow-up information on 
incomplete AE and pregnancy reports. 
x 
Tracking of Safety Information 
o The PI or his designee (i.e., the DCC) will track all protocol-defined AE and pregnancy 
reports originating from the Study for the Product. The PI will also track all Serious 
Adverse Drug Reactions (SADRs) associated with other Investigational Medicinal 
Products (IMPs), (i.e., excluding the Product), as defined in the protocol.  
Exchange of Single Case Reports 
 
Serious Adverse Events (SAEs), pregnancy reports, where the participant has been exposed to 
the Product, will be sent on a MedWatch or CIOMS I form to the Roche contact via the DCC. 
Transmission of these reports (initial and follow-up) will be either electronically or by fax and 
within the timelines specified below: 
 
x 
SADRs 
Serious AE reports that are related to the Product or where the causality is assessed as 
unknown or not provided shall be transmitted to Roche via the Data Coordinating Center 
(DCC) within fifteen (15) calendar days of the awareness date. 
 
x 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Roche via the 
DCC within thirty (30) calendar days of the awareness date. 
 
x 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, any reports 
of pregnancy, where the fetus may have been exposed to the Product, shall be transmitted 
to Roche via the DCC within thirty (30) calendar days of the awareness date. Pregnancies 
will be followed-up until the outcome of the pregnancy is known, whenever possible, based 
upon due diligence taken to obtain the follow-up information. 
 


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[Note: For all reports, an acceptable format includes MedWatch or CIOMS I form, or Roche 
approved reporting forms. If the Sponsor is unable to use these formats then line-listings 
can be used as detailed in the Global: Investigator Initiated Study Safety Data Exchange 
Management (WI-0100195).]  
 
Case Transmission Verification of Single Case Reports 
 
The investigators will ensure that all single case reports have been adequately received by 
Roche, via a periodic line-listing documenting single case reports sent by the PI to Roche by the 
DCC via email in the preceding time period (e.g., monthly). 
 
Confirmation of receipt should be received within the time period mutually agreed upon. 
 
Following Case Transmission Verification, single case reports which have not been received by 
Roche shall be forwarded by the investigators (via the DCC) to Roche within five (5) calendar 
days from request by Roche. 
 
8.2.3 
Randomization Codes for Blinded Clinical Trials 
The blind will be broken for ADR reports that are serious and unexpected, unless otherwise agreed 
with applicable regulatory authorities. 
8.2.4 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
The PI will be responsible for the expedited reporting of safety reports originating from the Study to 
the regulatory authorities in those countries where it has filed a clinical trial approval, in compliance 
with local regulations. 
The PI will be responsible for the expedited reporting of safety reports originating from the Study to 
the EMA through Eudravigilance Clinical Trial Module (EVCTM).The PI will be responsible for 
expedited reporting of safety reports originating from the Study to the Ethics Committees of the 
concerned Member States, where applicable. 
The PI will be responsible for the distribution of safety information to its own investigators, where 
relevant, in accordance with local regulations. 
The PI will be responsible for the preparation of six-monthly SUSAR reports and their submission to 
investigators, regulatory authorities and Ethics Committees, where applicable.  
 
 


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Aggregate Reports 
 
x 
Development Safety Update Report 
The PI will be responsible for the preparation of a Development Safety Update Report (DSUR) 
for the Study and for the submission of the report to the regulatory authorities and Ethics 
Committees of the concerned Member States, where applicable. The PI will provide the DSUR to 
Roche as soon as reasonably possible after completion.  
Roche will forward to the PI an executive summary of the Roche DSUR upon request. The  PI 
may cross-reference the executive summary of the Roche DSUR, as applicable.  
 
x 
Other Reports 
The PI will forward quarterly listings of non-serious AEs originating from the Study to Roche. 
 
Queries 
Queries related to the Study will be answered by the PI.  However, responses to all safety 
queries from regulatory authorities or for publications will be discussed with Roche. Roche shall 
have the final say and control over safety queries relating to the Product. The PI will not answer 
such queries from regulatory authorities and other sources relating to the Product 
independently but shall redirect such queries to Roche. 
All reasonable effort will be made to ensure that deadlines for responses to urgent requests for 
information or review of data are met.  
 
Safety Crisis Management 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), 
on the conduct of the Study, may lead to labeling changes or regulatory actions that limit or 
restrict the way in which the Product is used, or where there is media involvement, the PI will 
contact Roche as soon as possible.  
 
8.2.5 
Language 
English will be used as the common language for all safety information exchanged between the 
Parties. 
8.2.6 
Records 
The PI will maintain reports and all related documentation (or true copies of these documents) for a 
time period required by the applicable laws and regulations in the territories for which they are 
responsible, taking into account the minimum archiving period worldwide. 
 
 


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8.3  
AE AND SAE SEVERITY GRADES AND RELATIONSHIP TO STUDY TREATMENT 
The seriousness of an AE should not be confused with its severity. The severity of AEs is to be graded 
according to the following guidelines: 
Grade 1–Mild: Transient or mild discomfort; no limitation in activity; no medical intervention/ 
therapy required 
Grade 2–Moderate: Mild to moderate limitation in activity; some assistance may be needed; no 
or minimal medical intervention/ therapy required 
Grade 3–Severe: Marked limitation in activity; some assistance usually required; medical 
intervention or therapy required, hospitalization possible 
Grade 4–Life Threatening: Extreme limitation in activity; significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
Grade 5-Death 
The relationship of study treatment to the AE will be determined by the investigator based on the 
following definitions: 
Not Related: Another cause of the event is most plausible; and/or clinically plausible temporal 
sequence is inconsistent with the onset of the event and the study treatment administration; 
and/or a causal relationship is considered biologically implausible. 
Possibly Related: An event that follows a reasonable temporal sequence from administration of 
the study treatment, or follows a known or expected response pattern to the suspected drug, 
but that could readily have been produced by a number of other factors. 
Probably Related: An event that follows a reasonable temporal sequence from administration of 
the study treatment, and there is a biologically plausible mechanism for study treatment causing 
or contributing to the AE and the event could not be reasonably explained by the known 
characteristics of the patient’s clinical state. In addition, the relationship may be confirmed by 
improvement of the event on stopping study treatment and reappearance of the event on 
repeated exposure to study treatment.  
8.3.1 
Adverse Event Reporting 
All AEs will be graded for severity and relevance to study agents as detailed above, and recorded 
with start dates occurring any time after informed consent is obtained until at least 7 (for non-
serious AEs or 28 days for SAEs) after the last day of study participation. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed 
for outcome information until resolution or stabilization. A record of all AEs, by study subject, will be 
recorded centrally by the DCC. 
8.3.2 
Serious Adverse Event Reporting 
All SAEs will be graded for severity and relevance to study agents as detailed above, and recorded 
with start dates occurring any time after informed consent is obtained until 28 days after the last 
day of study participation. At each study visit, the investigator will inquire about the occurrence of 
SAEs since the last visit and study participants and their significant others will be asked in advance to 


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notify the study investigators immediately regarding any hospitalization, serious change in their 
health or in the event of a death. Events will be followed for outcome information until resolution or 
stabilization.  
Regardless of whether the SAE is deemed related to use of the study agents, the data for the SAE 
must be reported with the appropriate information by the study investigators or their designee 
within 24 hours of learning of the event. In addition, new follow-up data must be reported within 24 
hours of receipt. The medical monitor or designee may be contacted at any time for immediate 
discussion regarding such an event. 
Investigators must report all SAEs to their governing IRB/IEC, as required by local regulations and 
guidelines. 
Deaths in patients who withdraw from study procedures early and continue with Vital Status 
Assessments will not be considered SAEs if the death occurs more than 28 days after last dose of 
study treatment. 
A record of all SAEs, by study subject, will be  databased by the DCC. 
8.3.3 
Unexpected Adverse Event Reporting 
All adverse events that meet the definition of an unanticipated problem should be reported to the 
local governing IRB within specific timelines as described below: The Unanticipated Problem (UP) 
report will include the following information: 
x 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
x 
A detailed description of the event, incident, experience, or outcome; 
x 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
x 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
8.3.3.1  Reporting to the IRB required within 10 working days: 
• 
Any internal or external adverse event (unanticipated problem) which meets all of the 
following criteria:  
a) Unexpected (in occurance, severity or in frequency of occurance that was not previously 
known and/or described in the approved informed consent document or other protocol 
related documents), 
b) and Related or possibly related to the research participation,  
c) and places subjects or others at greater risk of harm than was previously known or 
recognized  (i.e. a serious adverse event, a new or increased risk to subjects/others) 
8.3.3.2 Reporting within 3 working days: 
• 
An SAE, including subject death, that meet all of the following criteria: 
a) Occurred in an interventional study (i.e., involving a drug, biologic, device procedure 
and/or behavioral interventions), 
b) Unexpected, 
c) and judged to be related or possibly related to research participation 
 
 


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8.3.4 
Reporting of Pregnancy 
Pregnancies should be reported from the time the patient signs the informed consent form until the 
final study visit. Study treatment must be immediately discontinued if a patient becomes pregnant. 
Although pregnancy is not considered an SAE, all pregnancies should be reported as SAEs to the 
study sponsors. Pregnancies must be followed until termination of pregnancy or for a minimum of 6 
months after the birth of the child. 
8.4  
SAFETY OVERSIGHT 
Safety oversight will be under the direction of an external Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise in RA-ILD, the study drugs and/or clinical trials 
research including experts in Rheumatology, Pulmonary Medicine, Internal Medicine and/or Bioethics, 
and Biostatistics. The DSMB Chair will be appointed by the Study Executive Committee from among 
experts in the field who are not otherwise actively involved in the conduct of the Clinical Study or its 
reporting or analysis and who do not have an active appointment with any of the participating 
institutions. The DSMB Chair will then independently select the remainder of the Committee Members 
using similar expertise and affiliation criteria. 
Once the trial is initiated, the DSMB will review cumulative trial results to evaluate the treatment for 
adverse effects, including the review of all AEs, SAEs and UP.  The board will also monitor the 
performance of individual clinics and study performance indicators (drug monitoring and compliance, 
visit compliance, recruitment, etc.). The DSMB will meet approximiately every 6 months by 
teleconference and/or web videoconferencing for the duration of the trial and will interact directly with 
the DCC for access to study data and interim reports.  
The DSMB will be charged to provide external oversight concerning the safety and scientific integrity of 
the study for the duration of the clinical trial. Written reports will be produced that will advise study 
sites as to whether the study is approved to continue as is, specific safety and/or data management 
procedures will need to be addressed/implemented for ongoing approval, or whether the study should 
be stopped due to specific safety or ethical management concerns. 
The DCC will provide the DSMB with all of the study related information that it requires to carry out its 
directive.  
9 CLINICAL MONITORING 
Throughout the course of the study, data will be monitored for accuracy and completeness and study 
procedures will be monitored for adherence to the protocol and Good Clinical Practices (GCP). In 
addition to frequent contacts through e-mail and telephone, on-site monitoring visits will be 
coordinated by the Statistical Analysis of Biomedical and Educational Research (SABER) unit at the 
University of Michigan.  SABER (the Data Coordinating Center for this study) will be responsible for 
operational aspects and monitoring of the trial, including at least annual monitoring visits and/or 
remote source data verification.   
The clinical monitor will ensure that: 
• 
Data collected and entered into the database are verifiable against source documents for the 
participants.  The clinical monitor will need access to subject medical records and other study-related 
records needed to verify the entries on the electronic case report forms.   


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• 
Appropriate consent is obtained for each participant prior to study procedures. 
• 
The rights and well-being of participants are being protected. 
• 
The study is conducted in accordance with the currently approved protocol (including study 
treatment being used in accordance with the protocol), with any other study agreements, with GCP and 
with applicable regulatory requirements. 
• 
Study medication is properly dispensed and accounted for.  The study monitor will also perform 
drug accountability checks and review the clinical site’s regulatory document binder to assure 
completeness of documentation in all respects of clinical study conduct.   
• 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, at what 
level of detail monitoring will be performed, and the distribution of monitoring reports. 
10 STATISTICAL CONSIDERATIONS  
The objectives of the study are to assess the efficacy and safety of pirfenidone2403 mg/d compared with 
placebo in the treatment of participants with RA-ILD.  A statistical analysis plan (SAP) will be written for 
the study that contains detailed descriptions of the analyses to be performed.  The SAP will be finalized 
prior to unblinding of the data. 
 
Baseline is defined as values from assessments and testing done during the Sceening period.  
 
10.1 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Eligible participants will be screened and once determined to be eligible, informed consent will be 
obtained. Participants will then be randomized with equal probability to receive either Pirfenidone or 
placebo in a double-blinded fashion.  Treatment assignments will not be re-used; each consecutive 
randomized participant will receive the next consecutive unused treatment assignment.  The password 
protected computer text file that contains the translation of treatment labels A and B to either 
Pirfenidone or placebo will be maintained by the unblinded DCC statistician. 
 
10.2 
SAMPLE SIZE AND POWER CONSIDERATIONS 
10.2.1 Primary endpoint: 
Table 1A shows sample size calculations and Table 1B shows power that will be achieved for some 
feasible scenarios with the selected sample size.  Hypothesized estimates of treatment response in 
both placebo and pirfenidone arms were derived from the report of the Pirfenidone trial in IPF (King, 
et al., 2014.) If participants with RA-ILD are similar, then the proposed sample size of 254 
participants (127 per group) will provide 85% power to demonstrate the treatment difference in 
terms of the combined primary endpoint reached by week 52, defined as either death or a decline 
from baseline of >10 percentage points in the percent predicted FVC.  It is possible that participants 
with RA-ILD will have fewer endpoints than participants with IPF.  Table 1B and Figure 1 show that 
power will remain sufficient for several scenarios where participants have fewer endpoints, and 
showing the robustness of the power to slight deviations from the hypothesized treatment 
estimates with the selected sample size. The number of participants randomized will be 270 
because of possible loss of data due to participants dropping out before week 52 or other reasons. 


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PASS version 13 was used for power calculations (PASS 13 Power Analysis and Sample Size Software, 
2014, NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass.).    
 
Table 1: Power analysis for combined major endpoint reached by week 52, defined as either death or 
a decline from baseline of >10 percentage points in the percent predicted FVC. 
 
A. Sample Size Calculation, 5% alpha, 2-sided 
Power 
Sample Size Each 
Arm 
Total Sample 
Size 
Proportion 
Placebo 
Proportion 
Pirfenidone 
Difference 
0.80 
0.85 
0.90 
0.80 
0.85 
0.90 
141 
161 
188 
111 
127 
148 
282 
322 
376 
222 
254* 
296 
0.30 
0.30 
0.30 
0.32 
0.32 
0.32 
0.16 
0.16 
0.16 
0.16 
0.16 
0.16 
0.14 
0.14 
0.14 
0.16 
0.16 
0.16 
*  The anticipated total number of participants is 254. 
B. Possible Scenarios with fewer endpoints, 127 on each arm (254 total), 5% alpha, 2 sided. 
Proportion 
Placebo 
Proportion Pirfenidone 
Difference 
Power 
0.24 
0.08 
0.16 
0.94 
0.24 
0.10 
0.14 
0.85 
0.24 
0.11 
0.13 
0.78 
0.26 
0.08 
0.18 
0.97 
0.26 
0.10 
0.16 
0.92 
0.26 
0.12 
0.14 
0.82 
0.28 
0.12 
0.16 
0.89 
0.28 
0.13 
0.15 
0.85 
0.28 
0.14 
0.14 
0.79 
0.29 
0.13 
0.16 
0.88 
0.29 
0.14 
0.15 
0.83 
0.29 
0.15 
0.14 
0.77 
0.30 
0.14 
0.16 
0.87 
0.30 
0.15 
0.15 
0.82 
0.30 
0.16 
0.14 
0.76 
0.31 
0.15 
0.16 
0.86 
0.31 
0.16 
0.15 
0.81 
0.32 
0.15 
0.17 
0.90 
0.32 
0.16 
0.16 
0.85 


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Figure 1:
10.2.2 Secondary and exploratory endpoints:
All analyses of secondary outcomes will be exploratory.  Observed effect sizes will be useful to 
inform the design of future confirmatory trials and provide supportive information about 
consistency or lack thereof of pirfenidone on clinical outcomes. Additional exploratory analyses will 
incorporate data from Quantitative Imaging Analysis of Parenchymal Lung Abnormalities, data from 
Biomarker Analysis, and Patient Reported Assessments as described in the assessments and study 
objective sections above.
10.3
ADVERSE EVENTS
Table 2A shows the probability of observing at least one adverse event among participants randomized 
to Pirfenidone under a range of assumptions for the background adverse event rate.  The proposed 
sample size of 127 participants randomized to Pirfenidone will provide a 72% probability of observing an 
adverse event with a 1% background rate and a 99% probability of observing an adverse event that has a 
3.5% background rate.  Furthermore, with a goal of estimating an adverse event rate for this population 
with sufficient precision based on the proposed sample size, Table 2B shows that the two-sided 95% 


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confidence interval around the observed proportion will be sufficiently narrow for a range of adverse 
event rates. 
Table 2A:  Probability of observing at least one adverse event in the pirfenidone group (N=127), under a 
range of background adverse event rates.  
Background Adverse Event Rate 
Probability of Observing at Least 
One Adverse Event 
0.010 
0.72 
0.020 
0.92 
0.035 
0.99 
0.050 
1.00 
0.100 
1.00 
0.150 
1.00 
0.200 
1.00 
 
Table 2B:  Two-sided 95% confidence interval width for a range of observed adverse event proportions 
with 127 participants on Pirfenidone with complete data. 
 
Observed Proportion Confidence Interval Width Lower Limit Upper Limit 
0.025 
0.050 
0.075 
0.100 
0.125 
0.150 
0.175 
0.200 
0.064 
0.084 
0.100 
0.112 
0.122 
0.131 
0.139 
0.146 
0.006 
0.019 
0.036 
0.054 
0.073 
0.093 
0.113 
0.134 
0.069 
0.104 
0.135 
0.166 
0.195 
0.224 
0.252 
0.280 
 
 
 
 


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10.4 
STATISTICAL ANALYSIS 
10.4.1 Analysis Populations 
The intention to treat (ITT) population will include all participants randomized and will be used to 
assess primary, secondary and exploratory efficacy outcomes.  The as-treated population will 
include all randomized participants who received at least one dose of study medication and will be 
used to assess safety outcomes.  An additional secondary analysis dataset will be used to assess the 
robustness of the primary efficacy endpoint:  The per protocol dataset is defined as the ITT 
population excluding patients who are noncompliant with study medication and who have major 
protocol deviations.   
10.4.2   Efficacy Analyses 
Demographic data and baseline characteristics will be summarized by treatment arm.  The primary 
analysis population will be the ITT population. The main analysis framework will be logistic 
regression to assess treatment differences in the primary outcome, defined as either death or a 
decline from baseline of >10 percentage points in percent  predicted FVC, reached by week 52.  
Baseline for spirometry is defined as the screening visit with the assumption that values are the 
same at randomization. Baseline for other variables is defined as the randomization visit for 
variables collected at randomization, otherwise as the screening visit. The main predictor will be 
treatment arm, and covariates known to be related to the outcome and specified a priori (i.e., prior 
to database lock and unblinding), will be considered for inclusion.  The stratification factor will be 
the site. Unadjusted and adjusted odds ratios, 95% confidence intervals and Wald test p-values will 
be reported.  Similar analyses will be conducted with the listed secondary binary outcomes in 
Section 4.2.2.  An additional secondary analysis of the primary endpoint will use the Per Protocol 
population.   
Statistical analyses of the secondary outcomes that describe time-to-event will use Cox proportional 
hazards regressions using a similar approach as described above, reporting adjusted hazard ratios, 
95% confidence intervals and p-values.  Time will be measured from randomization until the event 
or until censoring.   Kaplan-Meier plots will be generated, and proportionality of hazards will be 
assessed.   
There are a number of secondary and exploratory outcome variables that are continuous, that will 
be calculated for each subject as follows:  Each change from baseline to week 52 outcome will be 
calculated as the last value minus the baseline value.  Each slope outcome will be derived from a 
linear regression of the values over the treatment period. The molecular expression outcomes will 
involve several genomic approaches to measure gene expression and protein levels with the 
purpose of identifying candidate biomarkers that differ according to treatment group. 
All continuous secondary and exploratory outcomes will be summarized and inspected for unusual 
outliers and distributional characteristics, and the treatment arms will be compared statistically 
using the nonparametric Wilcoxon rank sum test. 
Analyses of secondary and exploratory endpoints and secondary analyses of the primary endpoint 
will be reported as exploratory.   
 
 


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10.4.3 Safety Analyses 
Safety analyses will be restricted to the as-treated population and will include standard summary 
statistics and group comparisons (e.g., Chi square or Fisher’s exact test) for adverse events, as well 
as lists of participant-level data where relevant. Time-to-event analyses will also be reported for 
select safety outcomes, for example for hospitalization, transplant or death, and certain serious 
adverse events, as well as treatment-related discontinuation. Methods for count data will be used 
for certain safety outcomes to compare treatment differences in number of events, such as number 
of respiratory exacerbations for respiratory cause. 
10.4.5 Administrative Reporting 
Administrative reporting will include accrual summaries and data completeness information 
according to site, losses to follow-up, measures of data timeliness by site, and other administrative 
measures if relevant.  Administrative summaries will be pooled across treatment arms. 
 
10.4.6 Trial Monitoring and Interim Analyses 
Throughout the study, an external Data Safety Monitoring Board (DSMB) will review safety and 
administrative data periodically, according to the schedule specified in the DSMB Charter.  Open 
session reports will summarize the following types of data:  accrual, protocol deviations, data 
completeness, demographics and baseline characteristics, clinical and laboratory data, adverse 
events and other safety parameters, treatment compliance and dose modifications, reasons for 
treatment discontinuations, and causes of death. The open report will include analyses for all 
participants combined (i.e., pooled across treatment group).  The closed report will present the data 
according to treatment group in a blinded fashion.   
 
The trial is not designed to stop early for efficacy, thus preserving the 5% probability of a Type I 
error for the final analysis. The DSMB will review safety and administrative data to determine the 
safety and feasibility of continuing the trial.  There exists a possibility that the DSMB will request 
additional participant-level data and/or recommend that the study stop temporarily or permanently 
for safety concerns that are set forth in the DSMB Charter or for administrative reasons such as slow 
accrual. 
 
10.5 
MEASURES TO MINIMIZE BIAS 
10.5.1 Randomization and Blinding 
 This is a randomized, double-blind, placebo-controlled study. Neither site personnel (except for site 
research pharmacist(s) nor the participants will know which study treatment the participant is 
receiving. Pirfenidone and placebo will both be supplied in capsules that are visually 
indistinguishable. Pirfenidone and placebo packaging and labeling will be identical. 
Participants will be randomized at Visit 2 (section 7.2.1) in a 1:1 ratio to receive either pirfenidone 
2403 mg/d or placebo equivalent using automated web-based system. All randomization codes will 
be generated by a statistician independent of the trial conduct.   


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10.5.2 Unblinding of Treatment Assignment 
The Sponsor (or designee) will prepare the randomization list. All subjects, monitors, and study 
center personnel related to the study,  including the site pharmacist will be blinded to study 
treatment throughout the study. The randomization schema will be securely maintained 
electronically at the Data Coordinating Center. 
If in the event of an emergency situation when knowledge of the treatment assignment will impact 
the clinical management of the subject, the investigator will have the ability to unblind the 
treatment assignment for that subject at any time. If a subject is unblinded by the investigator, the 
Sponsor must be informed of the unblinding within 24 hrs. If the blinding is prematurely broken, it is 
the responsibility of the investigator to promptly document and explain any unblinding to the 
Sponsor. Although all subjects will receive Pirfenidone or placebo during this study, breaking of the 
blind should not occur except in the event of a medical emergency where the identity of the drug 
must be known in order to properly treat the subject, or when causality must be determined prior to 
submitting a regulatory safety report for a serious adverse event (SAE) (as defined in Section 8.2.2).  
Any unblinding event carried out in connection with submission of a regulatory safety report will be 
conducted by the Sponsor.  
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Appendix A – Schedule of Study Assessments) prior to unblinding, as knowledge of 
the treatment arm could influence subject assessment. 
Following study completion, a letter will be sent to all participants to notify them of their assigned 
treatment group. Refer to Appendix D for a draft of the treatment assignment notification letter 
that will be given to the participants.  
 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Every participating clinical site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of participants. Participating clinical sites will also obtain institutional authorization for 
external monitoring by the Data Coordinating Center and the FDA to examine (and when permitted by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety, progress, and data validity.  
Source data are defined as all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these 
original documents and data records include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, participant’s memory aids or evaluation checklists, pharmacy 
dispensing records, recorded audio tapes, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm, x-rays, and participant files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source 


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documents when the data is collected and recorded there as the primary source of information, but 
CRFs will not constitute the only form of source document information for this trial. 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
The study will be monitored by clinical study monitors to assess adherence to good clinical practice 
(GCP) and to this clinical study protocol according to a Clinical Monitoring Plan. 
The study may be audited by the sponsor’s clinical quality assurance group to assess compliance with 
GCP (including but not limited to US Food and Drug Administration (FDA) regulations, International 
Conference on Harmonisation (ICH) GCP guidelines, and other applicable regulations). Regulatory 
authorities, the IRB/IEC, and/or the sponsor’s clinical quality assurance group may request access to all 
source documents, eCRFs, and other study documentation for on-site audits or inspections. Direct 
access to these documents must be guaranteed by the Investigator, who must provide support at all 
times for these activities. 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 
ETHICAL STANDARD  
This study will be conducted in compliance with GCP as described in FDA regulations (21 CFR parts 50, 
54, 56, and 312) and the ICH document “Guideline for Good Clinical Practice, E6 (R1),” dated 10 June 
1996. These practices are consistent with the principles stated in the Declaration of Helsinki (version as 
currently endorsed by the European Medicines Evaluation Agency and the US FDA). The study will also 
be carried out in keeping with local legal and regulatory requirements. 
13.2 
INSTITUTIONAL REVIEW BOARD  
The protocol and informed consent forms that will be used must be approved by the investigator’s 
IRB/IEC before the study is initiated; documentation of this approval (i.e., a copy of the document 
showing IEC/IRB approval including the chairperson’s signature and the date of approval) must be 
provided to the sponsors or designee and made available during an inspection by the US FDA or other 
regulatory agency inspectors. 
Other investigator responsibilities regarding IEC/IRB requirements include the following: 
x 
Submit to the IEC/IRB and to study sponsor or designee for review any advertisements that will 
be used to recruit patients 
x 
During the conduct of the study, submit progress reports to the IEC/IRB, if required, and request 
x 
Re-review of the study at least once a year 
x 
Report, in writing, to the IEC/IRB any SAEs that occur during the study or SAEs reported in other 
studies using study treatment, per local IEC/IRB regulations 
x 
Inform the IEC/IRB of any changes in the protocol and obtain documented IEC/IRB approval of 
the changes 
x 
Provide the IEC/IRB with any other information it requests before or during the conduct of the 
study 
x 
Maintain a file of study-related information, including all correspondence with the IEC/IRB 
x 
Provide the IEC/IRB with a final report on the study within a time period consistent with local 
requirements 


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13.3 
INFORMED CONSENT PROCESS  
The investigator or designee is responsible for the content of the informed consent form, but the 
content must be approved by the IEC/IRB and sponsor or designee. The content of the informed consent 
must comply with FDA regulations (21 CFR 50.25) and the ICH document “Guideline for Good Clinical 
Practice, E6 (R1),” dated 10 June 1996. It should also include any additional information required by 
local laws relating to institutional review. 
The investigator is responsible for obtaining informed consent from each patient participating in the 
study. If there are any amendments to the informed consent, patients should be consented properly in a 
timely fashion. All pertinent aspects of the study must be explained to the patient before he or she signs 
the informed consent form. Informed consent must be obtained from the patient before any Screening 
activity or treatment is undertaken that is not part of routine care. This includes, but is not limited to, 
the performance of diagnostic or therapeutic procedures and the administration of the first dose of the 
study treatment. Before a patient’s participation in the study, the written informed consent form must 
be signed and personally dated by the patient or by the patient’s legally acceptable representative, and 
by the person who conducted the informed consent discussion. The investigator is responsible for 
keeping this document in a secure place. This document should not be displayed or made accessible to 
any third party except the study sponsor or designee or regulatory agency representatives. 
If a participant permanently revokes informed consent and declines further observation and Vital Status 
Assessments, then recording of study data will stop. 
13.4 
DELEGATION OF PRINCIPAL INVESTIGATOR RESPONSIBILITIES  
The investigator should ensure that all persons involved in the conduct of the study are informed about 
the protocol, protocol amendments, study procedures, and any study-related duties. The investigator is 
responsible for assuring that study site staff are properly trained and credentialed to perform any 
delegated tasks. 
13.5 
COORDINATING INVESTIGATOR  
The coordinating investigator will be one of the principal investigators on the study. The coordinating 
investigator will be responsible for signing the final clinical study report and assuring that the study has 
been executed according to the protocol. 
 
14 DATA HANDLING AND RECORD KEEPING  
14.1 
RETENTION OF DOCUMENTS 
The study-related records that must be maintained include the following: 
1. Copies of the protocol and all amendments 
2. Signed Principal Investigator Page for the protocol and all amendments 
3. Initial Approval letter(s) from and all other correspondence to and from the IEC/IRB 
4. Curricula vitae for the Principal Investigator and Sub-investigators 
5. Documentation of study treatment shipments from Genentech or designee 
6. Completed and signed dispensing records for study treatment 


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7. Documentation of unused study treatment destruction or return to Genentech or designee  
8. Signed list of all study personnel including delegation of authority for all study personnel 
9. Copy of the Investigator Brochure provided at start-up and subsequent versions for sites in the 
US. All other sites will maintain their regulatory authority’s accepted, equivalent product safety 
document (ie. Summary of Product Characteristics (SmPC). 
10. The original signed informed consent forms for each patient screened. Originals of all signed 
consent forms must be retained for all consent amendments for each randomized participant 
11. Copies of eCRFs or electronic data capture data sets for each consented participant 
12. Copies of results of all laboratory tests and other original data from which eCRF information was 
obtained as well as laboratory normal ranges and certifications, when indicated 
13. Master Patient Log 
14. Copies of all correspondence relating to this investigation 
 
14.2 
RETENTION OF DATA  
The Principal Investigator must ensure that study data are accessible to the study sponsors or their 
representatives and to FDA or other regulatory agency inspectors. All study-related records (e.g., 
research charts, eCRFs, and other study records) must be retained until disposal is authorized by the 
study sponsors, which will be no sooner than 2 years after approval of the study agent for marketing in 
an ICH region (United States, Europe) and until there are no pending or contemplated marketing 
applications in an ICH region or 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents may need to be retained for longer 
periods in some countries due to local regulatory requirements. 
 
14.4 
INVESTIGATOR BROCHURE  
The investigator will review the current version of the Investigator Brochure (IB). Sites outside of the 
U.S. may maintain their regulatory authority’s accepted, equivalent product safety document (ie. 
Summary of Product Characteristics (SmPC). It is obligatory that the investigator be familiar with all 
sections of these documents before initiation of the study. These documents will be submitted to the 
IEC/IRB. 
14.5 
CASE REPORT FORMS 
Each center will be instructed by the study sponsor or designee regarding how to record and complete 
electronic case report forms (eCRFs). Data should be recorded via eCRF as soon as possible after 
collection. 
PFT, ECG, and central laboratory data should be reviewed, initialed, and dated by the principal 
investigator or designee. Completed eCRFs are to be reviewed by the investigator to ensure accuracy, 
completeness, and legibility within 2 weeks of last participant contact unless the forms are incomplete 
because of laboratory data or medical event follow-up that is not yet available. 
 
 
 


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14.6 
PUBLICATION AND DATA SHARING POLICY 
The study grantors will share authorship with investigators and their designees in any publications 
resulting from this study. Investigational plans, protocols, and data related to this study will be treated 
as confidential information. Before submission, the study grantors must review publication or 
presentation of data or information derived from this study. 
 
15 STUDY ADMINISTRATION AND OVERSIGHT 
 
15.1 
PROCEDURE FOR PROTOCOL MODIFICATION 
Modifications which may affect the safety of the study patient, or which may alter the scope of the 
investigation, the scientific quality of the study, the study design, dosages, duration of therapy, patient 
assessments (added evaluation that poses potential risk or inconvenience to the patient), number of 
patients, and/or patient eligibility criteria, may be made only after appropriate consultation between 
the investigators, the Study Executive Committee and the DSMB. Individual sites may not alter the 
protocol without advanced consultation and approval as noted here-in. 
If the consensus is to revise the current protocol, a formal List of Changes will accompany the amended 
protocol and these will initially be submitted to the DSMB for review and until their recommendations 
for further modification have been addressed or it is approved. Once DSMB approval has been obtained, 
the revised Protocol and the List of Changes will be submitted to the FDA and to the IRBs at all 
participating clinical sites. Protocol changes will not be implemented until they have been reviewed and 
approved by all appropriate regulatory agencies and the study participants notified and/or their consent 
re-obtained if indicated by the nature of the requested change and the instructions of the FDA and/or 
responsible IRB. 
 
16 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. The study leadership has established policies 
and procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
17 COVID-19 MANAGEMENT PLAN 
 The following changes have been made to the protocol in response to current COVID-19 pandemic 
recognizing the changes to the risk to participants in the study.  
 


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17.1 
SAFETY CONCERN AND MANAGEMENT OF STUDY DRUG 
Management and dispensing of study drug 
x 
When subjects require study drugs, they should be mailed/shipped to the subject’s home after 
completion of the required remote visit or as needed.  
x 
Primary study outcome measures may need to be deferred based on changes to availability at 
individual sites during the COVID-19 pandemic.  The study investigators will address these issues 
by modifying the analysis as necessary.  
x 
Missing outcome data, which is a study deviation, should be noted in the site’s study binder as 
due to “COVID-19 Restrictions”. This will flag the reason as required for study audits.  
 
17.2 
IMPACT ON SCREENING AND RANDOMIZATION 
New enrollments to the TRAIL 1 study will be placed on hold until further notice.  This is a practical 
consideration given the growing international recommendation that all individuals at high risk, which 
include our study population, shelter in place and cease all non-essential activities.  In addition, as the 
risk for potential COVID-19 infection rises, it is not appropriate to recommend that new participants 
start therapy when the threat from this virus is immediate and the potential benefit of therapy is 
unknown.  
Each network leader can discuss with Dr. Ivan Rosas regarding the cessation of enrollment at their site.  
 
17.3 
MODIFICATIONS TO STUDY VISITS AND PROCEDURES 
Conversion to remote study visits. 
x 
Continued onsite visits are not recommended or expected at this time.  
x 
Conversion to telehealth or video conferencing visits is acceptable as is contacting subjects by 
phone to conduct study visits. In most cases, local IRBs are accepting this conversion to remote 
visits without prior approval due to the urgent need to protect subjects. 
x 
Efforts should be made to keep in contact with patients who are currently enrolled in the study 
through telemedicine and/or videoconferencing. 
 
Schedule of Study Assessments edited for COVID-19. 
x 
Visits 5 through 11 in the schedule of assessments can be converted to phone visits. There may 
be a reduction in the number of assessments, as not all will be feasible over the phone.  If 
participants cannot be present for the visit, PFTs or Physical exam cannot be performed. The 
following assessments are categorized as the “expected assessments”:  Adverse events, 
Concomitant medication review, Supplemental oxygen review, Study medication dosing, Study 
medication accountability, Weight, Resting O2 Saturation, Patient questionnaire DAS 28 GH VAS, 
Patient GA, SGRQ, HAQ20, Dyspnea-12, LCQ, RAPID3, Vital status assessment. 
x 
Monitoring of liver function testing should be continued as per protocol.  If within the first 6 
months of the study LFTs cannot be performed subjects should stop study treatment until labs 
can be obtained. Subjects are encouraged to continue the study visits.   
x 
The subject is encouraged to restart study treatment when possible and appropriate.   


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x 
If the subject has interrupted study treatment for ≥28 days, a Pre-Restart Visit is required 
(Section 7.2.2). The Pre-Restart Visit will be conducted on the day study treatment is resumed. 
Subjects who restart study treatment will resume the visit schedule based on their date of 
randomization. If a regularly scheduled visit (Weeks 13, 26, 39, etc.) coincides with the Pre-
Restart Visit, then the elements of the regularly scheduled visit as outlined above should be 
performed in lieu of the Pre-Restart Visit.  Refer to Appendix B of the protocol on page 69 for re-
titration. 
x 
Visit window for visit 11 will be extended to +/- 4 weeks 
17.4 
SITE MONITORING 
On-site monitoring visits will not be performed during COVID-19 pandemic.  DCC will perform remote 
monitoring with source data verification as outlined in section 9 of the protocol. Regular monitoring 
visits will resume after travel restrictions have been lifted.  
18  LITERATURE REFERENCES  
1. Aletaha, D., T. Neogi, et al. (2010). "2010 Rheumatoid arthritis classification criteria: an American 
College of Rheumatology/European League Against Rheumatism collaborative initiative." Arthritis 
and rheumatism 62(9): 2569-2581. 
2. Allebeck, P., A. Ahlbom, et al. (1981). "Increased mortality among persons with rheumatoid arthritis, 
but where RA does not appear on death certificate. Eleven-year follow-up of an epidemiological 
study." Scand J Rheumatol 10(4): 301-306. 
3. Bruce, B. and J. F. Fries. (2005). “The Health Assessment Questionnaire (HAQ).” Clin Exp Rheumatol 
23(5 Suppl 39): S14-8. 
4. Cervantes-Perez, P., A. H. Toro-Perez, et al. (1980). "Pulmonary involvement in rheumatoid 
arthritis." Jama 243(17): 1715-1719. 
5. Cortet, B., T. Perez, et al. (1997). "Pulmonary function tests and high resolution computed 
tomography of the lungs in patients with rheumatoid arthritis." Ann Rheum Dis 56(10): 596-600. 
6. Crapo, R. O. (1994). "Pulmonary-function testing." The New England journal of medicine 331(1): 25-
30. 
7. Dawson, J. K., H. E. Fewins, et al. (2001). "Fibrosing alveolitis in patients with rheumatoid arthritis as 
assessed by high resolution computed tomography, chest radiography, and pulmonary function 
tests." Thorax 56(8): 622-627. 
8. Doran, M. F., G. R. Pond, et al. (2002). "Trends in incidence and mortality in rheumatoid arthritis in 
Rochester, Minnesota, over a forty-year period." Arthritis Rheum 46(3): 625-631. 
9. Gabriel, S. E., C. S. Crowson, et al. (1999). "Mortality in rheumatoid arthritis: have we made an 
impact in 4 decades?" J Rheumatol 26(12): 2529-2533. 
10. Gochuico, B. R., N. A. Avila, et al. (2008). "Progressive preclinical interstitial lung disease in 
rheumatoid arthritis." Arch Intern Med 168(2): 159-166. 
11. Guedes, C., D. Dumont-Fischer, et al. (1999). "Mortality in rheumatoid arthritis." Rev Rhum Engl Ed 
66(10): 492-498. 


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12. Hochberg, M. C. and T. D. Spector (1990). "Epidemiology of rheumatoid arthritis: update." Epidemiol 
Rev 12: 247-252. 
13. Isomaki, H. A., O. Mutru, et al. (1975). "Death rate and causes of death in patients with rheumatoid 
arthritis." Scand J Rheumatol 4(4): 205-208. 
14. Khanna, D., S. Mittoo, et al. (2015). "Connective Tissue Disease-associated Interstitial Lung Diseases 
(CTD-ILD) - Report from OMERACT CTD-ILD Working Group." The Journal of rheumatology. 
15. Kim, D. S. (2006). "Interstitial lung disease in rheumatoid arthritis: recent advances." Curr Opin Pulm 
Med 12(5): 346-353. 
16. King, T. E., Jr., W. Z. Bradford, et al. (2014). "A phase 3 trial of pirfenidone in patients with idiopathic 
pulmonary fibrosis." The New England journal of medicine 370(22): 2083-2092. 
17. Latsi P.I., du Bois R.M., Nicholson A.G., et al. (2003). " Fibrotic idiopathic interstitial pneumonia: the 
prognostic value of longitudinal functional trends." Am J Resp Crit Care Med 168(5):531-7 
18. Lamblin, C., C. Bergoin, et al. (2001). "Interstitial lung diseases in collagen vascular diseases." Eur 
Respir J Suppl 32: 69s-80s. 
19. Leconte S., D. Ferrant D, et al. (2011) “Validated methods of cough assessment: a systematic review 
of the literature.” Respiration 81(2): 161-74. 
20. Lee, H. K., D. S. Kim, et al. (2005). "Histopathologic pattern and clinical features of rheumatoid 
arthritis-associated interstitial lung disease." Chest 127(6): 2019-2027. 
21. Lubeck, D. (1994). The economic impact of rheumatoid arthritis. Rheumatoid arthritis: Pathogenesis, 
assessment, outcome, and treatment. P. T. Wolfe F. New York, Marcel Dekker, Inc.: 247-259. 
22. McDonagh, J., M. Greaves, et al. (1994). "High resolution computed tomography of the lungs in 
patients with rheumatoid arthritis and interstitial lung disease." Br J Rheumatol 33(2): 118-122. 
23. Olson, A. L., J. J. Swigris, et al. "Rheumatoid arthritis-interstitial lung disease-associated mortality." 
Am J Respir Crit Care Med 183(3): 372-378. 
24. Pincus, T., L. F. Callahan, et al. (1984). "Severe functional declines, work disability, and increased 
mortality in seventy-five rheumatoid arthritis patients studied over nine years." Arthritis Rheum 
27(8): 864-872. 
25. Raghu, G., H. R. Collard, et al. (2011). "An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and management." American journal of 
respiratory and critical care medicine 183(6): 788-824. 
26. Sato, T., J. Fujita, et al. (2006). "Non-specific interstitial pneumonia; as the first clinical presentation 
of various collagen vascular disorders." Rheumatol Int 26(6): 551-555. 
27. Suzuki, A., Y. Ohosone, et al. (1994). "Cause of death in 81 autopsied patients with rheumatoid 
arthritis." J Rheumatol 21(1): 33-36. 
28. Swigris, J. J., J. Yorke, et al. (2010) “Assessing dyspnea and its impact on patients with connective 
tissue disease-related interstitial lung disease.” Respir Med 104(9): 1350-5. 
29. van Vollenhoven, R. F. (2009). "Treatment of rheumatoid arthritis: state of the art 2009." Nat Rev 
Rheumatol 5(10): 531-541. 


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30. Wallberg-Jonsson, S., M. L. Ohman, et al. (1997). "Cardiovascular morbidity and mortality in patients 
with seropositive rheumatoid arthritis in Northern Sweden." J Rheumatol 24(3): 445-451. 
31. Wolfe, F., D. M. Mitchell, et al. (1994). "The mortality of rheumatoid arthritis." Arthritis Rheum 
37(4): 481-494. 
32. Yelin, E. (1996). "The costs of rheumatoid arthritis: absolute, incremental, and marginal estimates." J 
Rheumatol Suppl 44: 47-51. 
33. Yorke J, Moosavi S, Shuldham C, et al. Quantification of dyspnoea using descriptors: Development 
and initial testing of Dyspnoea-12 Thorax. epub 8 December 2009. 
34. Young, A., G. Koduri, et al. (2007). "Mortality in rheumatoid arthritis. Increased in the early course of 
disease, in ischaemic heart disease and in pulmonary fibrosis." Rheumatology (Oxford) 46(2): 350-
357. 
 
 
 
 
 
 


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APPENDIX LIST 
 
Version 
Date 
Description 
Significant Revisions 
 
 
Appendix A - Schedule of Study 
Assessments 
 
 
 
Appendix B - Capsule Dosing 
Flowchart  
 
 
 
Appendix C- Safety Reporting 
Definitions and Contacts  
 
 
 
Appendix D- Treatment Assignment 
Notification Letter 
 
 
 
 


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Appendix A  SCHEDULE OF STUDY ASSESSMENTS  
 
 
 
 
 
 
Visit #
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Visit Description
Screening Period
Eligibility and 
Random- ization
Telephone 
Assessment
Telephone 
Assessment
Protocol Visit
Protocol Visit
Protocol Visit
Lab Assessment
Protocol Visit
Protocol Visit
Protocol Visit
End of Study Phone 
Call
Pre-Restart
Unscheduled
Early 
Termination
Week #
Week -8 to Week 0
Week 0
Week 1
Week2
Week 4
Week 8
Week 13 
Week 19
Week 26
Week 39
Week 52  
28 days after last 
dose of study drug 
required if study tx 
was interrupted 
≥28 days13
 
Visit Window
D-56 to D0
D1
± 2 days
± 2 days
± 1 week
± 1 week
± 2 weeks
± 1 week
± 2 weeks
± 2 weeks
± 1 week
± 1 week
N/A
N/A
N/A
X
X
X7
X
X7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X7
X
X
X
X
X
X
X
X
X
X
X
X
X
X7
X
X
X
X
X
X
X
X
X
X9
X
X
X
X
X
X
X
X
X12
X
X
X
X
X
X
X
X
X
X
X
X7
X
X
X
X
X
X
X
X
X
X
X7
X
X
X
X
X
X
X
X
X
X
X7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X14
X
X
X
X
X14
X
X
X7
X
X
X
X
X
X
X
X14
X
X
X7
X
X
X
X
X
X
X17
X17
X
X3
X
X
X
X
X
X
X14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Supplemental Oxygen Review
Study Assessments
Informed Consent
Medical History / Review of Systems
Adverse Event Assessment
Concomitant Med Review
DNA Paxgene17
Study Medication Dosing
Study Medication Accountability
Physical Exam
Vital Signs (heart rate and blood pressure)
Weight
Height
Lab Assessments 1
Liver Function Testing Only11
Serologic tests 10
Pregnancy Test (blood)2
Biomarkers 16 (plasma, serum, and RNA)
ECG
Resting Oxygen Saturation
Patient Questionnaires
DAS 28 GH VAS
Patient GA
Physician GA
SGRQ
HAQ20
Dyspnea-12 
Leicester Cough Questionnaire
RAPID3 


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X
X
X
X
X4
X
X18
X5
X7, 8
X8
X8
X8
X8
X8
X6
X
X
X7
X
X
X
X
10 Serologic tests include: Erythrocyte Sedimentation Rate (ESR), Rheumatoid Factor (RF), C-Reactive Protein (CRP), and Cyclic Citrullinated Peptide (CCP)
16RNA biomarker will only be collected at Visit 2(week 0) and Visit 11 (week 52) or Early Term
17 DNA PaxGene samples are collected ONLY if subject consents to the genetic component of the study
18HRCT scans performed within the past 3 months will be acceptable
Joint Count 
5FVC, FEV1 before and after bronchodilator administration 
Transbronchial biopsy or SLB (if avail)15
HRCT scan
Spirometry
Lung volumes, DLCO or TLCO  
Confirmation of Eligibility
Randomization
Vital Status Assessment
1 Lab Assessments include • Hematology (complete blood count with platelet count and automated differential) • Serum chemistry profile (albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, total bilirubin, calcium,  creatinine, glomerular filtration rate (eGRF), gamma-glutamyl transferase 
[GGT], glucose, potassium, sodium, BUN, uric acid and amylase)
2 For women of childbearing potential
3 Obtained before bronchodilator administration or on a separate day
4HRCT scans performed within 3 months of the Screening period may be used to confirm eligibility. Screening HRCT will be reviewed by a Central reader.
12instruct on re-titration of dose
13Participants who restart study treatment will resume the visit schedule based on their date of randomization. If a regularly scheduled visit (Weeks 13, 26, 39, etc.) coincides with the Pre-Restart Visit, then all of the elements of the regularly scheduled visit should be performed in lieu of the 
14The elements of the visit are up to the discretion of the investigator. 
15Surgical lung biopsy (SLB) or transbronchial biopsy, if performed, may be obtained up to 4 years before randomization
6 obtained before or 30 min after bronchodilator administration
7Must be done prior to randomization 
8without bronchodilator administration
9instruct participant on dose titration and diary usage; 1st dose must be taken in clinic on day of randomization
11Liver Function Testing Only includes: AST, ALT, bilirubin, and alkaline phosphatase


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Appendix B TRAIL1 CAPSULE DOSING FLOWCHART
Dose reduction, interruption, and discontinuation of study drug to manage adverse events will be at the 
Investigators discretion. Subjects may be re-titrated over 2 weeks, once the symptoms have subsided. 
The below flow chart is provided as guidance for re-titration. The medical monitor is also available to 
discuss dose titration and management of adverse events. 


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Appendix C SAFETY REPORTING DEFINITIONS AND CONTACTS
The definitions below are based on the International Conference on Harmonization (ICH) guidelines 
and Food and Drug Administration (FDA) regulations. The use of italic font in this section refers to 
definitions taken from ICH guidelines and/or FDA regulations. Other definitions relate to company 
specific glossaries. 
x
Adverse Drug Reaction (ADR)
In the pre-approval clinical experience or in other clinical trial experiences:
Any noxious and unintended response to a medicinal product related to any dose will be considered 
an ADR.
The phrase "responses to a medicinal product" or "associated with the use of the medication," means 
that a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out.
x
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.
x
Awareness Date
The date any Party (including employees of affiliates or agents acting on behalf of either Party), first 
has knowledge of the minimum data elements as defined by ICH E2A guideline. At the very least, the 
following data must be provided for a case to be considered as valid:
x
an identifiable reporter*
x
an identifiable patient**(i.e., either CRF number, patient/subject number, initials, gender, date 
of birth, age or age group 
x
a drug / counterfeit drug
x
an adverse event (or pregnancy)
*For AE reports from social media sources, verified contact details (e.g., email address) are considered 
an identifiable reporter.
**For reports from healthcare professionals, “a patient” is considered an identifiable patient criterion. 
The minimum data elements should be obtained initially prior to transmitting the information to the 
other Party. In the event that an AE/ADR or pregnancy report is lacking minimum data elements, this 
report should not be forwarded to the other Party until all the minimum data elements are gathered. 


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The originating Party will ensure prompt follow-up as necessary.
x
Clinical Trial/ Study
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or 
other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to 
identify any adverse reactions to one or more investigational medicinal product(s), and/or to study 
absorption, distribution, metabolism and excretion of one or more investigational product(s) with the 
object of ascertaining their safety and/or efficacy.
x
Development Safety Update Report (DSUR) 
A comprehensive, thoughtful annual review and evaluation of pertinent safety information collected 
during the reporting period related to a drug under investigation, whether marketed or not. The main 
objective of a DSUR is:
x
Assess whether the information obtained by the Sponsor during the reporting period is in accord 
with previous drug safety knowledge
x
Describe new safety issues that could have an impact on the protection of clinical trial subjects
x
Summarize the current understanding and management of identified an potential risks
x
Provide an update on the status of the clinical investigation/development program and study 
results.
x
European Medicines Agency (EMA)
The centralized European regulatory authority for the European Union (EU) member states.
x
European Economic Area (EEA)
European Union (EU) plus Iceland, Liechtenstein and Norway.
x
Expedited Safety Report
A single case report requiring submission to any regulatory authority within 7 and/or 15 calendar days.
x
Food and Drug Administration  (FDA)
US Federal Agency charged with the responsibility of enforcing the Federal Food, Drug and Cosmetic 
Laws and Regulations.
x
International conference on Harmonization (ICH)
International Conference on Harmonization of Technical Requirements for Registration on 
Pharmaceuticals for Human Use.


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Protocol # TRAIL1
13OCT2020
Page 76 of 80
x
Investigational Medicinal Product (IMP)
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical trial, including products already with a marketing authorization but used or assembled 
(formulated or packaged) in a way different from the authorized form, or when used for an 
unauthorized indication, or when used to gain further information about the authorized form.
x
Non-Serious Adverse Event
Any event that does not meet the definition of serious as defined below under SAE/SADR.
x
Product
The Roche product that is the subject of the trial/study as defined in the corresponding agreement.
x
Reference safety information (RSI)
Depending on the development and marketing status of the drug, the Reference Safety Information 
(RSI) may be one or more of the following:
x
Core Data Sheet (CDS)
x
Summary of Product Characteristics (SPC)
x
Investigator’s Brochure 
x
International Standard Prescribing Information (ISPI)
x
Local Label, e.g., United States Package Insert (USPI)
x
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR)
A serious adverse event (experience) or reaction is any untoward medical occurrence or effect that at 
any dose:
x
results in death
x
is life-threatening


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Protocol # TRAIL1
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Page 77 of 80
Note: The term "life-threatening" refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if it were 
more severe.
x
requires inpatient hospitalization or prolongation of existing hospitalization
x
results in persistent or significant disability/incapacity 
x
is a congenital anomaly/birth defect
x
is an important medical event (an event that jeopardizes the patient or may require intervention 
to prevent one of the other outcomes listed above).
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse.
Any suspected transmission via a medicinal product of an infectious agent is also considered a serious 
adverse reaction.
In certain protocols, specific arrangements may be made for SAE reporting (e.g., efficacy end points, 
study, specific events) which are not reported as SAEs to regulatory authorities during a clinical trial. 
Details of these should be documented and made known to either Party.
x
Single case reports
A document providing the most complete information related to an individual case at a certain point 
of time. An individual case is the information provided by a primary source to describe adverse events 
following the administration of one or more medicinal products to an individual patient at a particular 
point of time.
x
Six Monthly SUSAR Report
SUSAR report for an Investigational Medicinal Product (IMP) containing a listing of all SUSARs for a 
defined six monthly period providing a brief summary of any safety-related issues for that IMP. 
x
Sponsor
ICH E6:
An individual, company, institution, or organization which takes responsibility for the initiation, 
management, and/or financing of a clinical trial.


TRAIL1: A Phase ll Study of Pirfenidone in Patients with RA-ILD
Version 8.0
Protocol # TRAIL1
13OCT2020
Page 78 of 80
CFR 312.3:
A person who takes responsibility for and initiates a clinical investigation. The Sponsor may be an 
individual or pharmaceutical company, governmental agency, academic institution, private 
organization, or other organization.
x
SUSAR
Suspected Unexpected Serious Adverse Reaction.
x
Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator's Brochure for an unapproved Investigational Medicinal Product or 
package insert/summary of product characteristics for a marketed medicinal product).
Roche Contacts
Activity
Person Responsible
General Queries/  Aggregate 
Reports (e.g., DSUR, Line-
listings of Non-serious AEs)
Drug Safety Contact Line Mailbox: 
contact_line.drug_safety@roche.com
Single Case Management
Single case reports to Roche: 
Central Operations Mailbox: welwyn.pds-pc@roche.com
Fax (Clinical): +44 1707 377 967/ 373 779/ 373 793/ 390 959
Fax (Spontaneous): +44 1707 390 904
Queries on Single Case Reports/Case Transmission Verification:
Safety Operations Contact Line Mailbox: 
welwyn.contact_line_rce@roche.com
Cc:
Ivan O. Rosas
Study Principal Investigator
Baylor College of Medicine7200 Cambridge Street
Houston, TX 77030 For US IIS only:


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Protocol # TRAIL1
13OCT2020
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BCM Contacts
Activity
Person Responsible
Single Case Management, 
Safety Crisis Management, 
Aggregate Safety Reports
Ivan O. Rosas
Pulmonary Critical Care and Sleep Medicine
Baylor College of Medicine
7200 Cambridge Street
Houston, TX 77030
Tel: (713)-798-8842
Fax: (713) 798-2688
Ivan.Rosas@bcm.edu


TRAIL1: A Phase ll Study of Pirfenidone in Patients with RA-ILD
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Protocol # TRAIL1
13OCT2020
Page 80 of 80
Appendix D TREATMENT ASSIGNMENT NOTIFICATION LETTER
              __/__/__
Dear (participant name),
Thanks to the hard work and commitment of the investigators, coordinators and, study participants like 
you, the TRAIL1 study has been successfully completed. Not only did your participation contribute 
important information for testing a new treatment, but it will also continue to help us learn more about 
Rheumatoid Arthritis Interstitial Lung Disease as we perform additional analyses of the data and samples 
collected during the TRAIL1 study. 
We want to take this opportunity to tell you whether you were taking Pirfenidone or placebo during the 
TRAIL1 study. Through the randomization process, your drug assignment was __ Pirfenidone or Placebo 
___.
We will post the publications related to TRAIL1 study that describes the study results on the TRAIL1 
website once it is published. 
Once again, we would like to convey our sincere appreciation for your participation. We cannot thank 
you enough for all the time you have put into this study. We truly could not have done this without you!
Please let us know if you have any questions. 
With warmest wishes and great gratitude,
(Signatures)
________________

SAP_001.pdf: 
1 
 
TRAIL1 Statistical Analysis Plan 
 
 
TRIAL FULL TITLE 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study 
of Safety, Tolerability and Efficacy of Pirfenidone in Patients with 
Rheumatoid Arthritis Interstitial Lung Disease 
SAP VERSION 
2.0 
SAP VERSION DATE 
May 10, 2021 
PROTOCOL VERSION 
(associated with SAP) 
4.0 
TRIAL PRINCIPAL 
INVESTIGATOR 
Ivan Rosas, MD 
SAP AUTHOR(s) 
S Hurwitz, R Maurer 
 
 
 
 
 
 
 
 
 
 
 
 
 




3 
 
Contents 
Abbreviations and Definitions ................................................................................................................ 4 
Introduction ............................................................................................................................................. 6 
Scope of the Statistical Analysis Plan (SAP) .......................................................................................... 7 
Study Objectives and Endpoints ............................................................................................................. 7 
Study Objectives ................................................................................................................................. 7 
Endpoints ............................................................................................................................................ 7 
Primary Endpoint ............................................................................................................................ 7 
Secondary Endpoints....................................................................................................................... 7 
Exploratory Endpoints .................................................................................................................... 9 
Study Methods ........................................................................................................................................ 9 
General Study Design and Plan .......................................................................................................... 9 
Inclusion-Exclusion Criteria and General Study Population ............................................................ 10 
Randomization and Blinding ............................................................................................................ 10 
Study Assessments ............................................................................................................................ 10 
Definition of Baseline ....................................................................................................................... 11 
Endpoints and Relevant Variables .................................................................................................... 11 
Primary and Secondary Endpoints and Relevant Variables .......................................................... 12 
Exploratory Endpoints and Relevant Variables ............................................................................ 15 
Planned Sample Size ............................................................................................................................. 17 
Actual Sample Size ............................................................................................................................... 18 
General Analysis Considerations .......................................................................................................... 18 
Timing of Analyses ........................................................................................................................... 18 
Analysis Populations ......................................................................................................................... 19 
Intention to Treat (ITT) population (full analysis set): ................................................................. 19 
Safety population (as-treated population) ..................................................................................... 19 
Per Protocol population ................................................................................................................. 19 
Sensitivity Analyses .......................................................................................................................... 20 
Coronavirus Disease 19 (COVID-19) ............................................................................................... 20 
Covariates and Subgroups ................................................................................................................. 21 
Covariates ..................................................................................................................................... 21 
Subgroups ..................................................................................................................................... 21 
Multi-center Studies .......................................................................................................................... 21 
Missing Data ..................................................................................................................................... 22 
Time-to-event missing data ........................................................................................................... 22 


4 
 
Interim Analyses and Data Monitoring ............................................................................................. 23 
Scope of Adaptations .................................................................................................................... 23 
Practical Measures to Minimize Bias ............................................................................................ 24 
Plan for Interim and Final Analyses, and Documentation ............................................................ 24 
Multiple Testing ................................................................................................................................ 24 
Summary of Study Data ........................................................................................................................ 25 
Subject Disposition ........................................................................................................................... 25 
Protocol Deviations ........................................................................................................................... 26 
Demographic and Baseline Variables ............................................................................................... 27 
Treatment Compliance ...................................................................................................................... 27 
Treatment Exposure .......................................................................................................................... 28 
Efficacy Analyses ................................................................................................................................. 28 
Safety Analyses ..................................................................................................................................... 30 
Adverse Events ................................................................................................................................. 31 
Clinical Laboratory Evaluations ....................................................................................................... 33 
Prior and Concurrent Medications .................................................................................................... 34 
Reporting Conventions ......................................................................................................................... 34 
Unblinding ............................................................................................................................................ 34 
Quality Assurance of Statistical Programming ..................................................................................... 35 
Statistical software ................................................................................................................................ 35 
References ............................................................................................................................................. 36 
 
 
Abbreviations and Definitions 
AE 
 
Adverse event 
ANCOVA 
Analysis of covariance 
CCC 
 
Clinical Coordinating Center  
CI 
 
Confidence interval 
COVID-19 
Coronavirus Disease 19 
CRF 
 
Case report form 
CRP  
 
C-reactive protein 
DAS 
 
Disease activity score 


5 
 
DCC 
 
Data Coordinating Center 
DLCO  
Diffusing capacity of lung for carbon monoxide 
% DLCO 
Percent predicted diffusing capacity of lung for carbon monoxide 
DSMB  
Data Safety Monitoring Board 
eCRF  
Electronic case report form 
ESR  
 
Erythrocyte sedimentation rate 
FEV1  
Forced expiratory volume in one second 
FVC 
 
Forced vital capacity 
%FVC  
Percent predicted forced vital capacity 
HRCT  
High resolution computed tomography 
HRQOL 
Health Related Quality of Life 
ILD 
 
Interstitial Lung Disease 
IMP 
 
Investigational Medicinal Product 
IPF 
 
Idiopathic pulmonary fibrosis 
ITT 
 
Intention to treat 
LCQ 
 
Leicester Cough Questionnaire 
ln 
 
Natural logarithm 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
 
Milligram 
mg/d 
 
Milligrams per day 
mL 
 
Milliliter 
mm Hg  
Millimeters of mercury 
msec 
 
Millisecond 
OMERACT 
Outcome Measures in Rheumatology 
PF 
 
Pulmonary fibrosis 
PFS 
 
Progression-free survival 
PRO 
 
Patient reported outcomes 
RA 
 
Rheumatoid arthritis 


6 
 
RA-ILD  
Rheumatoid arthritis-associated interstitial lung disease  
RAPID3 
Routine Assessment of Patient Index Data 3 
SAE 
 
Serious adverse event (AE) 
SAS 
 
Statistical Analysis Software 
SGRQ  
St. George’s Respiratory Questionnaire 
SpO2  
Peripheral capillary oxygen saturation 
TLCO  
Transfer capacity of lung for carbon monoxide 
ULN 
 
Upper limit of normal 
wk 
 
Week 
 
Introduction 
Preface 
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a life-threatening and severely 
debilitating disease characterized by poor survival and a lack of efficacious therapeutic options. 
Results from previous controlled trials suggest that pirfenidone treatment is safe and well tolerated in 
idiopathic pulmonary fibrosis (IPF) with efficacy in a variety of domains that include fibrosing ILD. 
Pirfenidone may be of benefit in RA-ILD, which shares many histopathological and clinic-
epidemiological features with IPF.  Given the loss of pulmonary function over time in patients with 
RA-ILD, this protocol is designed to evaluate whether pirfenidone 2403 mg/d reduces decline in 
forced vital capacity (FVC) or mortality over 52 weeks, compared with placebo, in patients with RA-
ILD. 
 
TRAIL1 is a Phase 2, randomized, double blind, placebo controlled clinical trial designed to evaluate 
the efficacy and safety of administering pirfenidone or placebo for 52 weeks to patients with RA-ILD. 
Patients meeting the eligibility criteria for the study have been randomized to receive either 
pirfenidone 2403 mg/d or placebo. Efficacy will be evaluated through pulmonary function tests, 
patient reported outcomes (PROs), adverse events and survival. Safety will be assessed by 


7 
 
determining differences between the treatment arms for the rate of adverse events, serious adverse 
events, rates of acute exacerbation, hospitalization and all- cause mortality. 
 
Scope of the Statistical Analysis Plan (SAP) 
These analyses will assess the efficacy and safety of pirfenidone 2403 mg/day as compared with 
placebo in patients with RA-ILD. This SAP assumes familiarity with the TRAIL1 Clinical Trial 
Protocol, including amendments. In particular, the SAP is based on the planned analysis specification 
as written in the protocol Section 10 “Statistical Considerations.” Readers may consult the protocol 
for more background information on the design and conduct of the trial, and panned analyses.  
 
Study Objectives and Endpoints 
Study Objectives 
To assess the efficacy and safety of pirfenidone 2403 mg/day as compared to placebo in patients with 
RA-ILD. 
To explore the role of peripheral blood biomarkers in predicting disease progression and survival in 
patients with RA-ILD. 
To explore a spectrum of validated questionnaires to assess disease specific PROs including overall 
health, and perspectives on symptoms, performance and quality of life. 
 
Endpoints 
Primary Endpoint 
The primary outcome variable of this study is the incidence of the composite endpoint of decline 
from baseline in percent predicted FVC of 10% or greater or death during the study period.  The 
primary endpoint will be analyzed using the ITT population 
 
Secondary Endpoints 


8 
 
Secondary outcome for this study will be assessed from baseline to the end of study for each 
patient.  The following secondary outcomes will be analyzed using the ITT population: 
1. Incidence of a decline from baseline in percent predicted FVC of 10% or greater during 
the study period. 
2. Frequency of progressive disease as defined by Outcome Measures in Rheumatology 
(OMERACT):  Relative decline from baseline in percent predicted FVC of ≥10%, or 
relative change from baseline in percent predicted FVC ≥ 5% and < 10%, and ≥15% 
relative decline in diffusing capacity of lung for carbon monoxide (DLCO) (Khanna, 
Mittoo et al. 2015) 
3. Change from baseline to end of study in absolute value of FVC 
4. Change from baseline to end of study of percent predicted FVC 
5. Slope of percent predicted FVC over 52-week treatment period 
6. Slope of absolute value of FVC over study period 
7. Time to decline of 10% or greater in percent predicted FVC or death while on study 
8. Change from Baseline to end of study in dyspnea, as measured by the Dyspnea 12 
questionnaire 
The following secondary outcomes will be analyzed using the as-treated population: 
9. Proportion of participants with all-cause mortality 
10. Proportion of participants with all-cause hospitalization 
11. Proportion of participants with hospitalization for respiratory cause 
12. Number of acute exacerbations requiring hospitalizations 
13. Proportion of participants with and number of treatment-emergent adverse events (AEs) 
14. Proportion of participants with and number of treatment-emergent serious adverse 
events (SAEs) 
15. Proportion of participants with and number of treatment-emergent/treatment-related AEs 
16. Proportion of participants with and number of treatment-emergent/treatment-related SAEs 
17. Proportion of participants with and number of AEs leading to early discontinuation of 


9 
 
study treatment 
18. Proportion of participants with and number of treatment-emergent death or transplant 
19. Proportion of participants with and number of treatment-emergent RA-ILD-related 
mortality 
 
Exploratory Endpoints 
The following exploratory outcomes will be analyzed using the ITT population: 
1. Change from Baseline to end of study in Disease Activity Score (DAS)  
2. Change from baseline to end of study in Routine Assessment of Patient Index Data 3 
(RAPID3) score  
3. Change from Baseline to end of study in Erythrocyte Sedimentation Rate (ESR) 
4. Change from Baseline to end of study in C-Reactive Protein (CRP) 
5. Candidate biomarker expression in the peripheral blood of patients with RA-ILD 
over the 52 weeks of treatment. 
6. Changes from Baseline to end of study in high resolution computed tomography 
(HRCT) parameters evaluated by quantitative functional imaging 
7. Changes from Baseline to Week 13, 26, 39 and final visit in the St. 
George’s Respiratory Questionnaire (SGRQ) 
8. Changes from Baseline to Week 13, 26, 39 and final visit in Dyspnea 12 questionnaire 
9. Changes from Baseline to Week 13, 26, 39 and final visit in Leicester Cough Questionnaire 
(LCQ) 
10. Changes from Baseline to Week 13, 26, 39 and final visit in the Patient global assessment 
11. Changes from Baseline to Week 13, 26, 39 and final visit in the Health assessment 
questionnaire 
 
Study Methods 
General Study Design and Plan 


10 
 
This parallel-group double-blind randomized longitudinal study was designed to assess the superiority 
of Pirfenidone versus placebo, over a 52-week follow-up period. Patients are randomized with equal 
probability to receive Pirfenidone or placebo. After the screening visit, randomization occurs at visit 
2.  The week 52 visit is visit 11.  Adverse events are additionally queried by phone 28 days after visit 
11. 
 
Inclusion-Exclusion Criteria and General Study Population 
Eligible participants include patients age 18 through 85 years, with RA and ILD, without evidence or 
suspicion of an alternative diagnosis that may contribute to their ILD. Additional details to be found in 
the protocol. 
 
Randomization and Blinding 
After consent was obtained, participants were screened to determine eligibility.  After participants 
were determined to be eligible, they were randomized with equal probability to receive either 
Pirfenidone or placebo in a double-blinded fashion. Treatment assignment slots were not re-used; 
each consecutive randomized participant received the next consecutive unused treatment assignment 
slot. Randomization was stratified by center with random block sizes. The password protected 
computer text file that contained the translation of treatment labels A and B to either Pirfenidone or 
placebo was maintained by the unblinded DCC statistician. Details will be provided in the final study 
report. 
 
Study Assessments  
The schedule of all study assessments is in Appendix A of the protocol.  Eligibility and 
randomization take place at Visit 2. Time windows for visits are below. There is an additional phone 
visit that occurs 28 days after the last study drug dose to assess vital status and adverse events. 
 


11 
 
Visit 
Number 
Visit 
Week 
 
Target Day 
of Visit 
Visit 
Window 
1 
-8 to 0  
-56 to 0 
-56 to 0 days 
2 
0 
1 
0 
3 
1 
7 
± 2 days 
4 
2 
14 
± 2 days 
5 
4 
28 
± 1 week 
6 
8 
56 
± 1 week 
7 
13 
91 
± 2 weeks 
8 
19 
133 
± 1 week 
9 
26 
182 
± 2 weeks 
10 
39 
273 
± 2 weeks 
11* 
52 
364 
± 1 week 
* Visit 11 marks the end of the follow-up period.  Protocol amendment V8 (US/CAN/AUS) /V10 
(UK) extends the visit 11 window to ± 4 weeks due to COVID-19 laboratory closures.  
 
Definition of Baseline 
Baseline values for spirometry are defined as the screening values.  Spirometry is repeated at 
randomization to ensure stability of values, as defined in the study protocol, prior to 
randomization. Baseline is defined as screening because the screening spirometry must meet 
established criteria for quality and is done before and after bronchodilator administration.  The 
underlying true spirometry values are assumed to be the same at randomization. The absolute 
differences between the measured screening and randomization spirometry values will be summarized 
descriptively.  
 
Baseline values for patient reported outcomes are defined as the randomization visit values, and when 
unavailable, the screening or rescreening values will be used.  Baseline for other variables is defined 
as the randomization values for variables collected at randomization, otherwise it is defined as the 
screening values.  
 
Endpoints and Relevant Variables 


12 
 
Refer to separate file for list of relevant variables for each endpoint, along with relevant datasets and 
endpoint description (“TRAIL1 endpoints and dataset variable names.xlsx” and “Primary & 
Secondary Outcomes” tab.) 
 
Primary and Secondary Endpoints and Relevant Variables 
Composite endpoint of decline from baseline in percent predicted FVC of 10% or greater or 
death during study period. 
• 
FVC (percent predicted) at baseline  
• 
Last FVC (percent predicted) while on study   
Decline from baseline in percent predicted FVC is (last percent predicted FVC while on 
study) - (percent predicted FVC at baseline) 
• 
Death (yes/no) while on study  
 
Decline from baseline in percent predicted FVC of 10% or greater during study period. 
• 
FVC (% predicted) at baseline 
  
• 
Last FVC (% predicted) while on study  
 
Decline from baseline in percent predicted FVC is (last percent predicted FVC while on 
study) - (percent predicted FVC at baseline) 
 
Frequency of progressive disease as defined by OMERACT: Relative decline from baseline in percent 
predicted FVC of ≥10%, or relative decline from baseline in percent predicted FVC ≥ 5% and < 10%, 
and ≥15% relative decline from baseline in percent predicted DLCO (Khanna, Mittoo et al. 2015) 
• 
FVC (percent predicted) at baseline 
• 
Last FVC (percent predicted) while on study 
Relative decline from baseline in percent predicted FVC = [(Last FVC(percent predicted) 
– Baseline FVC (percent predicted))/Baseline FVC (percent predicted)]*100 
• 
DLCO (percent predicted) at baseline 
• 
Last DLCO (percent predicted) while on study 


13 
 
Relative decline in percent predicted DLCO = [(Last DLCO (percent predicted) – Baseline 
DLCO (percent predicted))/Baseline DLCO (percent predicted)]*100 
If DLCO (percent predicted) is missing, TLCO (percent predicted) will be substituted.  
 
Change from baseline over study period in FVC (L) 
• 
FVC (L) at baseline 
• 
Last FVC (L) while on study 
 
Change from baseline over study period of percent predicted FVC 
• 
FVC (percent predicted) at baseline  
• 
Last FVC (percent predicted) while on study 
 
Slope of percent predicted FVC over study period 
• 
All available percent predicted FVC measurements and dates while on study 
 
Slope of absolute FVC over study period 
• 
All available FVC measurements and dates while on study 
 
Time to decline of 10% or greater in percent predicted FVC at death over study period 
• 
Baseline percent predicted FVC and randomization date 
• 
All measurements of percent predicted FVC while on study and date 
• 
Death date, death indicator 
• 
Last study visit date 
 
Proportion of participants with all-cause mortality 
• 
Death date present or absent 
 


14 
 
Proportion of participants with all-cause hospitalization 
• 
Hospital admission date present or absent 
 
Proportion of participants with hospitalization for respiratory cause 
• 
Hospital admission date 
• 
Hospitalization reason 
 
Number of participants with acute exacerbations requiring hospitalizations 
• 
Hospital admission date(s)  
• 
Hospitalization reason for each admission 
 
Proportion of participants with and number of participants with treatment-emergent/treatment-
related AEs 
• 
Participants with at least one treatment emergent AE (yes/no for each  participant) where 
treatment emergent is defined as the AE onset date being greater than or equal to the date of the 
first dose of study dedication, or the randomization date if the date of the first dose of study 
medication is missing 
• 
Number of treatment-related AEs for each participant while on study 
 
Proportion of participants with and number of treatment-emergent/treatment-related SAE (a subset 
of AEs) 
• 
Participants with at least one treatment emergent SAE (yes or no for each participant) 
• 
Number of treatment-related SAEs for each participant while on study 
 
Proportion of participants with and number of AEs leading to early discontinuation of study 
treatment 
• 
Early treatment discontinuation (yes or no for each participant) 


15 
 
• 
Reason for each early treatment discontinuation 
• 
Number of AEs per participant where the action is “permanent discontinuation or withdrawn from 
study medication 
 
Proportion of participants with and number of participants with treatment-emergent death, 
transplant, and transplant then death 
• 
Cause of death 
• 
Cause of transplant 
 
Proportion of participants with and number of participants with treatment-emergent RA-ILD-related 
mortality 
• 
Cause of death 
 
Change from Baseline to Week 52 in dyspnea, as measured by the Dyspnea 12 questionnaire 
• 
Baseline Total Dyspnea 12 questionnaire score and date 
• 
Last Total Dyspnea 12 questionnaire score on study and date 
 
Exploratory Endpoints and Relevant Variables 
 
Change from Baseline to end of study period in Disease Activity Score (DAS28) and RAPID3 score 
• 
Baseline DAS (continuous, 0 to 10) 
• 
Last DAS on study (continuous, 0 to 10) on study 
• 
Baseline RAPID3 score (continuous) 
• 
Last RAPID3 score (continuous) on study 
Note: DAS28 ranges from 2 to 10, and is calculated as DAS28= (0.56*√(Tender Joint 
Count)+0.28*√(Swollen Joint Count)+0.7*ln(ESR)+0.014*(Global Health)).  The screening or 
rescreening ESR will be used for the calculation.  Cumulative and weighted RAPID3 scores will be 
used. 


16 
 
 
Change from Baseline to end of study period in Erythrocyte Sedimentation Rate (ESR) 
• 
Baseline ESR 
• 
Last ESR on study 
 
Change from Baseline to end of study period in C-Reactive Protein (CRP) 
• 
Baseline CRP 
• 
Last CRP on study 
 
Candidate biomarker expression in the peripheral blood of patients with RA-ILD over the 52 weeks of 
treatment and the study follow-up period 
• 
The exploratory analysis of candidate biomarkers will be a substudy performed at a later date. 
 
Changes from Baseline to end of study period in HRCT parameters evaluated by quantitative 
functional imaging 
• 
The quantitative parameters will be defined after the end of the trial, as exploratory analyses, and 
will include the following.  These scores are separate from the radiologist -derived scores; they 
are computer interpretation of the scans, and range from 0 to 100. 
o 
DTA fibrosis score (total fibrosis score, dta_fibrosis) 
o 
Honeycombing score (hc_score) 
o 
Reticulation (reticular abnormality, ra_score) 
o 
Ground glass abnormality score (ggo_score) 
• 
The data values that will be used: 
o Baseline HRCT quantitative measures 
o Last HRCT quantitative measures on study 
 
Changes from Baseline to Week 13, 26, 39 and final visit in the SGRQ 
• 
All measurements of SGRQ while on study, total score 


17 
 
• 
The SGRQ has 2 parts and 3 components (symptoms, activity and impacts).  Scores for each 
component range from 0 to 100 with higher scores meaning more disability.  A total score is 
calculated from component scores with a range from 0 to 100 with higher scores meaning more 
disability. 
 
Changes from Baseline to Week 13, 26, 39 and final visit in Dyspnea 12 questionnaire 
• 
All measurements of Dyspnea 12 while on study, total score 
• 
The Dyspnea 12 has 12 questions scored 0 (none) to 3 (severe).  Score are added up for total (0 to 
36) with higher scores indicating greater severity of symptoms. 
 
Changes from Baseline to Week 13, 26, 39 and final visit in LCQ 
• 
All measurements of LCQ while on study, total score 
• 
The scores are calculated as a mean for each domain and total score is found by adding the 
domain scores. 
 
Changes from Baseline to Week 13, 26, 39 and final visit in the Patient Global Assessment 
• 
All measurements of Patient Global Assessment while on study, total score 
• 
The Patient Global Assessment has 3 questions that are compared separately for change.  One 
question is scaled 0 to 10 and two questions are scaled on a likert scale. 
 
Changes from Baseline to Week 13, 26, 39 and final visit in the Health Assessment Questionnaire 
• 
All measurements of Stanford Health Assessment Questionnaire while on study and date. 
The Health Assessment Questionnaire has 8 sections scored 0 – 3. Using the highest score in 
each section, the Health Assessment Questionnaire Score is the average across all sections with 
data (see Fries, et al., 1980) 
 
 
Planned Sample Size  


18 
 
The planned sample size for this trial was 270 participants randomized with equal probability to one 
of two treatment arms. The considerations delineated in the protocol show that 254 participants with 
complete data provide at least 85% power to demonstrate the treatment arm difference in terms of the 
combined primary endpoint reached by week 52, defined as either death or a decline from baseline of 
>10 percentage points in the percent predicted FVC. The robustness of this determination under a 
variety of feasible scenarios is also demonstrated in the protocol. The planned number of participants 
randomized was 270 because of possible loss of data due to participants dropping out before week 52 
or other reasons. 
 
Actual Sample Size 
Enrolment at centers was interrupted by the COVID-19 pandemic during March, 2020.  After all 
centers were shut down for approximately three months, and after an interim DSMB meeting that 
focussed on the interruption of recruitment, a decision was made to permanently close enrolment.  
The final sample size is 123 randomized participants.  The last participant was randomized on March 
24, 2020.  
 
General Analysis Considerations 
Timing of Analyses 
 
Data cleaning will be performed throughout the enrolment period, and will continue and through the 
12-month study period of the last participant randomized.  Data cleaning will be conducted in 
conjunction with a blind data review while the study is ongoing.  The database will be locked and the 
final analysis will be performed after the last participant completes visit 12 at the end of the follow-up 
period, and after all outstanding data queries and discrepancies are resolved. This statistical analysis 
plan will be finalized before closure of the database and before any final analyses are conducted. 
Independent study monitoring will be conducted by SABER in adherence to the Good Clinical 
Practice guidelines. 


19 
 
 
Analysis Populations 
Each participant’s inclusion or exclusion status with regard to each analysis population will be 
determined prior to breaking the blind.  For relevant variables, please refer to the accompanying file 
(TRAIL1 endpoints and dataset variable names.xlsx, Analysis Population type tab.) 
Intention to Treat (ITT) population (full analysis set): 
 
Defined as all participants who were randomized.  The ITT population will be used for all primary, 
secondary, and exploratory efficacy analyses. 
Safety population (as-treated population) 
 
Defined as all randomized participants who received any study medication and who received at least 
one study medication dose. The Safety population will be used for safety-related analyses. 
Per Protocol population 
 
Defined as all randomized participants who did not deviate from the protocol, who satisfy all 
eligibility criteria, and who are compliant with study medication, determined on a per-participant 
basis by trial leadership before database lock.  The Per Protocol population will be used for sensitivity 
analyses to demonstrate robustness of the results, and for selected sub-studies to be determined.  Out 
of visit window visits do not automatically disqualify participants from the per protocol population.  If 
a visit is less than four weeks out of the window (either before or after,) then it is included in the Per 
Protocol population.  Prohibited medications will exclude participants from the Per Protocol 
population.  Medication compliance is required for inclusion in the Per Protocol population, and is 
defined elsewhere in this document as having taken at least 80% and not more than 120% of 
dispensed pills according to pill diaries.  Other protocol deviations will be discussed on a case-by-case 
basis prior to the final database lock and while all team members are blinded to treatment 
assignments. 


20 
 
Sensitivity Analyses 
To assess the robustness of the primary analysis of the primary endpoint, the following two sensitivity 
analyses will be performed.  (1) The analysis of the primary composite endpoint will be repeated 
using the Per-Protocol population.  (2)  The analysis of the primary composite endpoint will be 
repeated using an adaptation of the Per-Protocol population where the lower threshold for medication 
compliance will be reduced from 80% to 65%. 
Coronavirus Disease 19 (COVID-19) 
The effect of COVID-19 on TRAIL1 will be investigated as follows: Protocol deviations due to 
COVID-19 will be presented and visits out of window due to COVID-19 will also be identified. 
Sensitivity analyses will be determined if necessary prior to database lock, and may include the 
following: Excluding all affected participants, using time-varying covariates to identify measurements 
taken during the affected period, increasing the duration of visit windows beyond those specified in 
the protocol, setting all data in a participant’s affected period to missing and imputing values. 
(reference: Ongoing trials during COVID-19: Quantitative strategies and methodological aspects:  
Cytel, Inc. 2020.) 
 
COVID-19-related factors that have the potential to impact this trial: 
• 
COVID-19 infection resulting in voluntary or mandatory dropout 
• 
Different investigator(s) filling in 
• 
Study center closures resulting in loss to follow-up 
• 
Stopped enrollment resulting in study termination or delay 
• 
Delayed assessments and expanded protocol visit windows 
• 
Missed visits and/or assessments leading to partial data collection 
• 
Alternative data collection, phone visits, exchangeability of methods, validation  
• 
Stopping drug due to safety concerns  
• 
Stopping drug due to lack of lab monitoring 


21 
 
• 
Concomitant meds due to COVID-19, and interaction with the Investigational Medicinal 
Product (IMP) 
 
Covariates and Subgroups 
Covariates 
 
Pre-specified baseline covariates known to be related to specific endpoints will be included as 
predictors in the primary analyses.  One covariate has been pre-specified: the HRCT pattern, 
categorized as usual interstitial pneumonia (UIP)-like fibrotic pattern versus other fibrotic patterns. 
Subgroups 
 
Subgroup analyses are considered exploratory.  Subgroupings were selected for pre-specification 
where there is an expectation of differential treatment effects.  The p-value for the interaction between 
the subgroup variable and treatment arm will be reported.  Sufficient power to reject a null hypothesis 
for the interaction is not anticipated.  If the interaction (difference in the treatment effects among the 
subgroups) is judged to be clinically important, then subgroup-specific estimates of the treatment 
effect and 95% confidence intervals will be reported.  Pre-specified subgroups will include sex, race 
(white, black or African American, Asian, native Hawaiian or other pacific islander, American Indian 
or Alaska native,) and ethnicity (Hispanic or Latino.) 
 
Multi-center Studies 
In this multi-center clinical trial, to allow for center-specific effect sizes, center will serve as a random 
effect in all primary analyses comparing treatment arms.  Model fitting problems from sparse data 
may be encountered since enrolment stopped early due to COVID-19.  If that occurs, then network 
(US, Canada, UK, Australia) will serve as random effect.  As exploratory analyses, results within 
center or network will be described. 
 


22 
 
Missing Data 
Adhering to the definition of the primary outcome as either death or a decline from baseline of >10 
percentage points in percent predicted FVC, reached by week 52, all participants will be included 
in the ITT population.  Outcomes involving repeated measurements will be analyzed using mixed 
models, accommodating varying amounts of follow-up data among participants.  The statistical 
models allow for missing data, assuming they are missing at random. Even participants with only 
one post-baseline assessment can be included, and can therefore contribute to variance estimation.  
It is reasonable to assume that missing data due to COVID-19 center closures are missing at 
random. The statistical model assumes that participants who prematurely discontinue study 
participation would have behaved similarly to those who remained in the study.  The mixed effect 
model for repeated measures analyses allows for form-level missing data, assuming they are 
missing at random. Item-level data for PROs will be handled according to the instructions provided 
by the instrument developer.   
 
Sensitivity analyses using alternative assumptions will be conducted to investigate the potential 
effect of missing data on the results of the primary analysis. One such analysis will exclude 
participants with less than six months of follow-up.  It is conceivable that one arm, such as the 
active drug arm, may have more early discontinuations and/or more missing data than the other 
arm.  The extent of missing data will be reported overall and by treatment arm, and quantified for 
key primary and secondary endpoints, with a graphical representation. Reasons for treatment 
discontinuation and for study discontinuation will be reported. Because missing data arising from 
the temporary closure of centers due to the COVID-19 pandemic is assumed to be missing at 
random, treatment arm comparisons will be valid. Where covariates are missing, a value of 0 will 
be imputed, along with a missing-indicator variable for the covariate as an additional covariate in 
the regression model (White, Thompson, 2005). 
Time-to-event missing data 
 


23 
 
In the analyses of the time-to-event endpoints, missing or incomplete data will be managed by 
censoring at the last date recorded without the event.  In the case of partially missing dates, the 
following imputation will be done:  
1. If day is missing, then imputed day will be the 15th of the month.  
2. If day and month are missing, they will be imputed by inference from the participant’s 
other visit dates. 
3. If year is missing, it will be imputed by inference from participant’s other visit dates. 
 
Interim Analyses and Data Monitoring 
This phase II clinical trial was not designed to stop early for efficacy in order to preserve the 5% 
probability of a Type I error for the final analysis.  Throughout the study, an external Data Safety 
Monitoring Board (DSMB) reviewed safety and administrative data periodically, according to the 
schedule specified in the DSMB Charter, to determine the safety and feasibility of continuing the trial.  
Open session reports summarized the following types of data: accrual, protocol deviations, data 
completeness, demographics and baseline characteristics, clinical and laboratory data, adverse events 
and other safety parameters, treatment compliance and dose modifications, reasons for treatment 
discontinuations, and causes of death. The open report included analyses with all participants 
combined (i.e., pooled across treatment group). The closed report presented the data according to 
treatment group in a blinded fashion. The DSMB could request additional participant-level data 
and/or recommend that the study stop temporarily or permanently for safety concerns that are set forth 
in the DSMB Charter, or for administrative reasons such as slow accrual.  An interim DSMB meeting 
was convened on June 1, 2020 that focussed on the ongoing COVID-19 pandemic, and the potential 
permanent discontinuation of enrolment.   
 
Scope of Adaptations 
Serious safety concerns could lead to a Data Safety Monitoring Board (DSMB) recommendation to 
temporarily stop the trial pending additional information, or to permanently stop the trial.  Issues with 


24 
 
slow accrual could lead to a recommendation to stop the trial or to expand recruitment with marketing 
efforts and/or by adding centers, for example.  The unprecedented COVID-19 pandemic precipitated 
the permanent discontinuation of enrolment. 
 
Practical Measures to Minimize Bias 
Any level of unblinding, either of individual participants or of treatment estimates, could induce 
biases. Therefore, all study personnel were blinded throughout the study, seeing only pooled 
summaries, with the exception of the Data Coordinating Center (DCC) statisticians producing the 
DSMB closed reports and the Clinical Coordinating Center (CCC) statisticians producing the final 
analysis after the data lock.  To minimize bias during the trial before the data lock, the treatment arms 
had masked labels such as “A” and “B.”  Individual participant treatment assignments were not 
known unless there was a safety concern where knowledge of treatment assignment determined 
patient care. 
 
Plan for Interim and Final Analyses, and Documentation 
● The DCC statisticians will perform interim analyses for DSMB periodic reports 
● The DCC statisticians and the DSMB members will see the DSMB analyses broken down by 
masked treatment arm 
● A decision to stop or modify the trial will be provided to the sponsor and investigators 
● The CCC statisticians will perform final analyses. 
 
Snapshots of the data available at each interim analysis will be preserved, as will all documentation of 
analysis plans, programming code and reporting provided at each interim.  
 
Multiple Testing 
As this is a Phase II trial with only one single pre-specified primary endpoint, adjustment for multiple 
testing in the analyses is not planned for the primary endpoint or for the hypothesis-generating 


25 
 
secondary endpoints.  In the exploration of the pre-specified subgroups, estimates of effect and 95% 
confidence intervals will be reported with an accompanying statement regarding multiplicity and the 
exploratory nature of the subgroup analyses.  
 
Summary of Study Data 
All continuous variables will be summarized using the following descriptive statistics: n (non-
missing sample size), mean, standard deviation, median, minimum, and maximum. The frequency 
and percentages (based on participants’ non-missing values for each particular variable) of 
observed levels will be reported for all categorical measures.  In general, all data will be listed, 
treatment, and participant, and when appropriate by visit number within participant. Age will 
additionally be summarized by pre-specified age groups.  Selected other continuous variables, that 
are specified before the database lock, will be additionally summarized using categories. 
 
All summary tables will be structured with a column for each treatment in the order (Placebo, 
Pirfenidone) and will be annotated with the total population size relevant to that table/treatment.  
The number of missing observations will be reported. 
 
Summary tables of baseline characteristics will be based on the ITT population.  Summary tables 
of adverse events will be based on the As Treated population.  Summary tables of outcomes will 
be presented for the ITT population, with the primary endpoint also being presented using the Per 
Protocol population. 
 
Subject Disposition 
Please refer to the accompanying spreadsheet for forms and variable names (TRAIL1 endpoints and 
dataset variable names.xlsx, Subject Disposition tab.) 
The consort diagram will be presented. 


26 
 
http://www.consort-statement.org/consort-statement/flow-diagram 
The number of participants reaching the milestones in the trial will show the number screened, 
randomized, and reaching each visit, or study close, and the number dropped out and for what reasons 
(death, toxicity, treatment failure, withdrew consent).  A crosstabulation will show the accrual by 
quarter and by network and center.  A listing of participant discontinuation from study medication 
will be presented for all randomized participants. Frequency counts and percentages of all participants 
providing informed consent, randomized/enrolled, completing and discontinuing from the study and 
study treatment will be presented according to treatment arm and overall. A summary of 
discontinuations will also be presented by visit. The proportion who discontinued the study early will 
be compared using chi-square test in the ITT population.  The proportion who stopped treatment early 
on each arm will be compared using chi-square test in the as-treated population. 
 
Protocol Deviations 
Important protocol deviations will be listed for all participant providing consent.   
1. Those who entered the study even though they did not satisfy the entry criteria.  
2. Those who developed withdrawal criteria during the study but were not withdrawn:  Patients 
with visit dates out of visit window will be included in the ITT population and the per 
protocol population.   
3. Randomized participants who report taking excluded medications will be included in the ITT 
population only. 
Protocol deviations will be summarised by center and grouped into the following categories:  
 
• 
Informed consent deviation  
 
 
 
• 
Study procedure not completed (laboratory, serology, liver enzymes, ecg, biomarkers, patient 
reported outcome questionnaire, physician global assessment, hrct, diffusion capacity/lung 
volumes, physical exam, oxygen saturation) 
 
• 
Study procedure performed incorrectly   
 
 
• 
Eligibility violation (FVC ≤40%, change in FVC >10%, FEV1/FVC ratio <0.7, spirometry 
quality not met, eGFR out of range) 
 


27 
 
• 
Study medication dose error/not taken as prescribed error  
 
 
 
• 
Prohibited medication (Nintedanib)  
 
 
 
• 
Visit or procedure performed out of window  
 
 
 
• 
Missed visit  
 
 
 
• 
Other (incorrect equipment, incorrect/missing drug diary, additional/duplicate procedure, 
procedure/visit done over multiple days, study medication dispensed at incorrect visit, wrong 
medication (clofazimine), extra blood drawn) 
 
 
 
Demographic and Baseline Variables 
Summarization by treatment arm will include mean, standard deviation, median, minimum, maximum 
for continuous variables, and the number and percent for binary and ordinal variables. The age at 
randomization will be use in analyses.  The following is a list of the demographic and baseline 
variables, recorded at, or shortly, before Randomization or first treatment administration: 
• 
Age (Years)  
• 
Age group  
o 18 to 35 years   
o >35 to 55 years  
o >55 to 75 years  
o >75 years  
 
• 
Sex 
• 
Ethnicity 
• 
Percent predicted FVC at Screening (Pre-Bronchodilator) as 100*FVC/FVCpredicted 
• 
Relative Change in Pre-Bronchodilator FVC between Screening and Baseline  
• 
Percent predicted DLCO at Screening (Note that TLCO in SI units × 2.987 = DLCO) 
o DLCO corrected for Hg 
• 
Number (%) with Either DLCO or TLCO Provided at Screening 
 
Treatment Compliance 


28 
 
Pill diaries will be used to determine compliance. The large number of unreturned pill bottles due to 
COVID-19 and participant non-compliance is the reason that pill counts will not be used.  
Compliance is defined as the number of pills taken (based on participant reporting in diaries) divided 
by the number prescribed. Compliance will be summarized and presented in descriptive statistics 
that include the sample size, mean, standard deviation, median, min, and max.   For missing 
medication time period dates, we will assume the time period is contiguous with the next or the 
previous time period.  Time periods with missing pill numbers prescribed and/or taken will be 
excluded from the calculation. Participants will be categorized as compliant if at least 80% and not 
more than 120% of prescribed pills are reported to have been taken.   The proportion of participants 
who are compliant will also be presented for each treatment arm. 
 
Treatment Exposure 
Treatment exposure is defined as the time measured in days from when the participant receives 
the first study drug until the participant either discontinues from treatment or completes the 
treatment period as planned.  The duration of treatment exposure will be listed and summarized 
by treatment group for the ITT population. Summary statistics will include mean per participant 
exposure in days, standard deviation, median, min, and max.  
 
Efficacy Analyses 
All efficacy variables will be listed by participant within study center. Data will be summarized 
by treatment arm using descriptive statistics (N, Mean, Standard Deviation, Minimum, and 
Maximum) for continuous efficacy variables.  Number and percent will be presented for 
categorical efficacy variables. Columns will be Placebo and Pirfenidone.  The primary efficacy 
population will be the ITT population, where all randomized participants are included according 
to their randomized treatment arm.  
 
The primary efficacy analysis for this trial has a binary composite outcome.  (A) Patients will be 


29 
 
categorized based on their decline since baseline in percent predicted FVC of 10% or greater 
during study period.  (B) Patients will also be categorized based on death during study period.  
The composite primary endpoint is the occurrence of either (A) or (B) during the study period.  
Comparisons between treatment arms will be performed using a mixed effect logistic regression 
model, adjusting for the continuous fixed covariate baseline percent predicted FVC and the fixed 
binary covariate HRCT pattern. Treatment arm will be an independent fixed effect and study 
center will be a random effect in the analysis (Kahn, 2014). The likelihood-ratio test will be used 
to test for differences between treatment arms.  Treatment arm will be tested at a 2-sided 5% 
significance level. The components of the primary endpoint will be similarly analyzed. 
 
The adjusted odd ratios together with 95% confidence interval and p-value will be used to 
quantify the effect of treatment, comparing pirfenidone with placebo as the reference. The 
data will be coded such that an odds ratio less than 1.0 will indicate that pirfenidone is 
protective.  Assumptions for models will be assessed by examining the plots for the residual 
values.  If data sparseness causes model fitting problems, the model will be simplified by 
using study network instead of study center as a random effect and/or eliminating the random 
center (or network) effect.  
 
The longitudinal continuous efficacy endpoints will be presented graphically and numerically.  
The analysis will use a restricted maximum likelihood-based repeated measures approach with a 
random slope and intercept model.  Visit will be analyzed as weeks since baseline. The analysis 
will include the fixed, categorical effect of treatment arm, fixed continuous effect of visit, and the 
treatment arm-by-visit interaction. The baseline value will be included as a fixed covariate.  
Random effects will be included for participant response and for both visit and intercept.  An 
unstructured covariance structure will be used to model the within-participant errors.  If this 
analysis fails to converge, the other structures that will be tested will include spatial power 
because visits are unevenly spaced, and compound symmetry. The covariance structure 
converging to the best fit, as determined by Akaike’s information criterion, will be used as the 


30 
 
primary analysis.   The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom and adjust standard errors.  The analysis will use all measurements obtained 
over the 52-week study period, including those from patients who had discontinued study 
medication.  The model allows for missing data assuming missing at random. If model 
optimization does not converge, then the random effect will be removed.  Significance tests will 
be based on least squares means using a two-sided α = 0.05 with two-sided 95% confidence 
interval. The primary treatment comparison of slopes will be assessed through the treatment-by-
visit interaction coefficient. Assumptions for models will be assessed by examining plots of the 
residual values. 
 
Analyses of time-to-event outcomes will be performed using mixed effect proportional hazards 
regression modelling with treatment arm as main effect, and with study center as random effect. 
The analysis will include the fixed categorical effects of treatment arm and baseline HRCT 
pattern category.  For time-to-event analyses involving spirometry, the baseline value will also be 
a covariate. The censoring date will be the earlier of the end of study period date or the date the 
participant was last observed without the event.  The actual dates, rather than visit number will be 
used to calculate time to event, and time will be expressed in weeks. The proportional hazards 
assumption will be assessed using Kaplan Meier plots and Schoenfeld residuals.  A time 
dependent covariate will be added if proportionality is not supported.  The treatment arm 
difference will be tested at the 2-sided 5% significance level. The adjusted hazard ratio and 95% 
confidence interval for the hazard ratio will be reported.  The data will be coded such that for 
death and for endpoints that indicate a decline in function, a hazard ratio less than 1.0 will 
indicate that pirfenidone is protective.  Breslow’s method for handling ties will be used.  
 
Safety Analyses 
The analysis population for the safety analyses will be the As-Treated population.  Safety data will be 
described as follows. 


31 
 
● The sort order of listings will be the participant number within randomized treatment arm. 
● Summary information will be grouped according to randomized treatment arm. 
● Continuous data will be summarized using descriptive statistics (median, minimum, 
maximum, mean, standard deviation and number with non-missing data.) 
● Categorical data that is not ordered will be summarized with frequencies, percents, and 
number with non-missing data.  
● When calculating the incidence of adverse events, or any sub-classification thereof by 
treatment, time period, severity, etc., each participant will only be counted once and any 
repetitions will be ignored; the denominator will be the total population size. 
 
Per ClinicalTrial.gov reporting requirements, three tables summarizing adverse events are required: 
● All-Cause Mortality:  A table of all anticipated and unanticipated deaths due to any cause, 
with number and frequency of such events in each arm/group of the trial. 
● SAEs: A table of all anticipated and unanticipated serious adverse events, grouped by organ 
system, with number and frequency of such events in each arm of the trial. 
● Other (Not Including Serious) AEs: A table of anticipated and unanticipated events (not 
included in the serious adverse event table) that exceed an incidence rate of 5% on either arm 
of the trial, grouped by organ system, with number of such events in each arm/ of the trial. 
 
Adverse Events 
An AE is any untoward medical event associated with the use of a drug in humans, whether or 
not it is considered related to a drug. Adverse events will be coded from the actual term described 
by the investigator using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs are events that first occur or increase in severity after the first study 
drug dose. In case of repeated events in participants, the proportions on each treatment arm will use 
the number of participants as the denominator, and the number of participants with at least one event 
as the numerator, so each participants will be counted once.  Incidence of AEs by treatment arm will 


32 
 
be compared using chi square tests. 
 
AEs will be summarized by treatment arm, overall and by system organ class, severity, and 
relationship to study drug. 
 
The following body systems will be summarized according to treatment arm: 
• 
Any Treatment-Emergent AEs 
• 
Blood and Lymphatic System Disorders 
• 
Cardiac Disorders 
• 
Ear and Labyrinth Disorders 
• 
Eye Disorders 
• 
Gastrointestinal Disorders 
• 
General Disorders 
• 
Hepatobiliary Disorders 
• 
Immune System Disorders 
• 
Infections and Infestations 
• 
Injury, Poisoning and Procedural Complications 
• 
Metabolism and Nutrition Disorders 
• 
Musculoskeletal and Connective Tissue Disorders 
• 
Nervous System Disorders 
• 
Psychiatric Disorders 
• 
Renal and Urinary Disorders 
• 
Reproductive System and Breast Disorders 
• 
Respiratory, Thoracic and Mediastinal Disorders 
• 
Skin and Subcutaneous Tissue Disorders 
• 
Surgical and Medical Procedures 
 


33 
 
AE listings will be sorted by treatment arm, then participant ID, and will include the following: 
• 
Treatment Emergent (yes/no) 
• 
AE # for the participant 
• 
AE Primary Category 
• 
AE Event Term 
• 
AE Start Date 
• 
AE Stop Date 
• 
Days from Start of Study Medication 
• 
Severity Grade 
• 
Expected? 
• 
Relationship to Study Drug 
• 
Study Drug Action Taken 
• 
Outcome 
 
Deaths, Serious AEs and other Significant AEs 
Separate summaries will be provided for deaths, serious AEs, and other AEs by treatment arm. Tables 
will include the number and percent.  Summaries will be shown for the number of events and the 
number of patients experiencing the event. Frequency of SAEs by treatment arm will be compared 
using chi square tests. 
 
Clinical Laboratory Evaluations 
Normal ranges for each study center will be tabulated.  Scheduled laboratory tests will be 
summarized. Unscheduled follow-up tests performed for medical or safety concerns, will be listed 
only. Test results will be presented using shift tables, showing the change in laboratory values from 
baseline to each subsequent visit.  Accompanying scatter plots and line plots will have a different 
symbol or color for each treatment arm.  All summary analyses will be conducted by treatment group 
using the as-treated population.  


34 
 
 
Descriptive statistics will be presented by treatment group and visit week for the laboratory 
measurements.  Continuous laboratory measures will also be compared to reference ranges to 
determine whether they are abnormally high, low, or normal. The incidence and percent of high, low 
and normal values will be listed for each of the treatment arms. For subjective (qualitative) laboratory 
assessments, count and percent of normal and abnormal values will be presented. For laboratory 
values that are entered as outside the detectible range for a laboratory, the midpoint of the 
undetectable range will be used for analyses and nonparametric analyses will be performed. 
 
Prior and Concurrent Medications 
Concomitant medication is defined as any medication a participant has received concurrently with 
study treatment.  Prior Medication is defined as any medication or therapies initiated prior to date of 
first dose of study drug. Medications that are started prior to the date of first dose of study drug and 
continue after the first dose of drug are considered to be both prior and concomitant medications.   
 
Reporting Conventions 
P-values ≥ 0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) will 
be reported to 3 significant digits.  
 
Unblinding  
Study Center Level Unblinding:  A minimum number of personnel will see the randomization 
table and treatment assignments before the study is complete. The treatment assignments will be 


35 
 
blinded to participants and investigators until the end of the study.  Emergency un-blinding for 
AEs may be performed ONLY if the participant’s well-being requires knowledge of the 
participant’s treatment assignment.  The investigator should make every effort to contact the study 
team prior to un-blinding a participant’s treatment assignment.   
 
Sponsor/Trial Level Unblinding:  The study team will remain blinded to treatment assignments 
until all participants have completed the study and the database has been finalized and locked for 
analysis. 
 
Quality Assurance of Statistical Programming 
Programs and anonymized datasets will be stored on a server at Brigham and Women’s Hospital that 
has nightly back-up.  To provide high quality code that is understandable, and allows reproduction of 
the analysis the following will be explicitly stated: 
● Author  
● Date of writing  
● Description of the code’s purpose, e.g. to create the analytic dataset, to analyze the primary 
outcome variable, etc. 
● List of steps or strategy to achieve purpose of code 
● References to inputs and outputs  
● Reference to any parent code file that runs the child code file  
● Population to be used in a table or figure will be explicitly set at the start of a block of code 
that computes the output. 
 
Statistical software  
Statistical analyses will be performed using SAS version 9.4 (Cary, North Carolina.)  Supplemental 
graphics may be generated using JMP, Stata, and/or Excel. 
 


36 
 
 
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