Clinical trial NCT03221257
Conditions: Scleroderma, Systemic Interstitial Lung Disease
Sponsor: Michael Roth
Start date: 2017-11-28; Completion date: 2022-06-13
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase II multi-center, double-blind, parallel group, randomized and placebo-controlled clinical trial addressing the treatment of patients with active and symptomatic Scleroderma-related interstitial lung disease (SSc-ILD).

Detailed description:
A Phase II multi-center, double-blind, parallel group, randomized and placebo-controlled clinical trial addressing the treatment of patients with active and symptomatic Scleroderma-related interstitial lung disease (SSc-ILD). Patients who are either treatment naive or only recently started treatment (\</= 6 months of prior treatment) will be randomized in a 1:1 assignment to receive either oral mycophenolate mofetil (MMF) and a placebo (Plac) or a combination of oral MMF and oral pirfenidone (PFD), with both regimens administered for 18 months. The primary hypothesis is that the rapid onset and anti-fibrotic effects of PFD, which have been observed in the treatment of Idiopathic Pulmonary Fibrosis (IPF), will complement the delayed antiinflammatory and immunosuppressive effects of MMF, to produce a significantly more rapid and/or greater improvement in lung function over time than occurs in patients receiving control therapy with MMF and Plac.

Arms: arm 1: Participants will receive Placebo (Plac) as add-on to a background therapy of Mycophenolate Mofetil (MMF). arm 2: Participants will receive Pirfenidone (PFD) as add-on to a background therapy of Mycophenolate Mofetil (MMF).
Interventions: intervention 1: Pirfenidone (PFD) intervention 2: Placebo (Plac) intervention 3: Mycophenolate Mofetil (MMF)
Intervention descriptions: intervention 1: Participants will receive PFD titrated up to a target dose of 801 mg taken three times daily as tolerated (3-step titration occurring at 2 week intervals). intervention 2: Participants will receive a Plac, matched to resemble PFD, titrated up to a target dose of 801 mg taken three times daily as tolerated (3-step titration occurring at 2 week intervals). intervention 3: Participants will receive MMF titrated up to a target dose of 1500 mg taken twice daily as tolerated (4-step titration occurring at monthly intervals).

Protocol documents:
Prot_ICF_000.pdf: 
Scleroderma Lung Study III (SLS III): 
Combining the anti-fibrotic effects of pirfenidone (PFD) 
with mycophenolate (MMF) for treating scleroderma-
related interstitial lung disease 
Protocol Identifying Number: UCLA-SLS3 
 
Principal Investigator  
Michael D. Roth, M.D. 
Division of Pulmonary & Critical Care 
Department of Medicine, 43-229 CHS 
David Geffen School of Medicine/UCLA 
Los Angeles, CA 90095-1690 
Tel: (310) 206-7389 
Fax: (310) 206-5088 
mroth@mednet.ucla.edu 
 
Co-Principal Investigator  
Dinesh Khanna, M.D., M.Sc.  
Division of Rheumatology 
Dept. of Internal Medicine, Suite 7C27 
Univ. of Michigan School of Medicine 
300 North Ingalls Street, SPC 5422 
Ann Arbor, MI  48109 
 
Tel: (734) 232-2104  
 
Fax: (734) 763-5761 
khannad@med.umich.edu 
 
Data Coordinating Center Director / Principal Statistician 
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 
 
 
IND:  
IND# 135848 
Michael D. Roth, M.D. 
 
 
 
David Geffen School of Medicine/UCLA 
 
Financial support for an Investigator-Initiated Study provided by:   
 
Genentech, Inc.  
1 DNA Way 
South San Francisco, CA 94080 
 
Protocol Version Number:  v.2.5 
Protocol Version Date: 11/17/2021 


ii 
 
 
List of Participating Clinical Sites as of June 30, 2020: 
(15 to 25 participating sites anticipated) 
Site # Institution 
Location 
1 
Boston University, School of Medicine  
Boston, MA 
2 
David Geffen School of Medicine at UCLA* 
Los Angeles, CA 
3 
Georgetown University School of Medicine  
Washington, DC 
4 
Harvard Medical School, Brigham & Women’s Hospital 
Boston, MA 
5 
Hospital for Special Surgery, New York 
New York, NY 
6 
Johns Hopkins University School of Medicine  
Baltimore, MD 
7 
Medical University of South Carolina 
Charleston, SC 
8 
Northwestern University Feinberg School of Medicine 
Chicago, IL 
9 
Rutgers Robert Wood Johnson Medical School  
New Brunswick, NJ 
10 
University of California, San Francisco, School of Medicine 
San Francisco, CA 
11 
University of Colorado Denver 
Denver, CO 
12 
University of Michigan Medical School**  
Ann Arbor, MI  
13 
University of Minnesota Medical School 
Minneapolis, MN 
14 
University of Pittsburgh 
Pittsburgh, PA 
15 
University of Texas Medical School at Houston 
Houston, TX 
16 
University of Utah School of Medicine 
Salt Lake City, UT 
17 
University of Washington School of Medicine 
Seattle, WA 
20 
University of Indiana Heatlh 
Indianapolis, IN 
 
*Also serves as Clinical Coordinating Center  
**Also serves as Data Coordinating Center  
 
 


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Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................................................. 1 
STATEMENT OF COMPLIANCE ................................................................................................................................. 4 
PROTOCOL SUMMARY .............................................................................................................................................. 5 
SUMMARY SCHEMATIC OF STUDY DESIGN ......................................................................................................... 10 
SUMMARY TABLE OF STUDY VISITS AND ASSESSMENTS ................................................................................. 11 
1 
KEY ROLES ......................................................................................................................................................... 12 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE.................................... 16 
2.1  Background Information ............................................................................................................... 16 
2.1.1 Prevalence & Course of SSC-ILD & the Need for New Treatments .......................................... 16 
2.1.2 Effectiveness of Immune Suppression for the Treatment of SSc-ILD ...................................... 17 
2.1.3 The Importance of Addressing Fibrosis in Addition to Inflammation ...................................... 20 
2.1.4 Pirfenidone: a Drug of Interest for Treating the Fibrotic Aspect of SSc-ILD ............................ 22 
2.1.5 The Documented Efficacy of Pirfenidone for the Treatment of IPF ........................................ 23 
2.1.6 The Feasibility of Combining PFD with MMF for the Treatment of SSc-ILD ............................ 25 
2.2  Rationale and Study Approach ...................................................................................................... 26 
2.3  Potential Risks and Benefits .......................................................................................................... 28 
2.3.1 Known Potential Risks .............................................................................................................. 28 
2.3.2 Known Potential Benefits ........................................................................................................ 41 
3 
STUDY OBJECTIVES AND PURPOSE ............................................................................................................... 41 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................................. 42 
4.1  Description of the Study Design .................................................................................................... 42 
4.2.1 Primary Endpoint 
…………….. ............................................................................................... 42 
4.2.2 Secondary Endpoints …… ......................................................................................................... 42 
4.2.3 Other Important Endpoints ..................................................................................................... 43 
4.2.4 Exploratory Endpoints .............................................................................................................. 44 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................................. 44 
5.1  Participant Inclusion Criteria ......................................................................................................... 44 
5.2  Participant Exclusion Criteria ........................................................................................................ 45 
5.3  Discontinuing Drug Treatment or Complete Withdrawal from the Study .................................... 48 
5.3.1  Reasons for Discontinuing Drug Treatment or Withdrawing from Study ............................... 48 
5.3.2 Definition and Handling of Treatment Failures ....................................................................... 48 
5.3.3 Handling of Premature Participant Withdrawals ..................................................................... 49 
5.4  Premature Termination or Suspension of Study ........................................................................... 49 
6 
STUDY AGENT ................................................................................................................................................... 50 
6.1  Study Agent(s) and Control Description ........................................................................................ 50 
6.1.1 Source and Acquisition of Study Drugs .................................................................................... 50 
6.1.2 Study Agent Formulation, Appearance, Packaging and Labeling ............................................ 50 
6.1.3 Product Storage & Stability ...................................................................................................... 52 
6.1.4 Route, Administration, Titration Schedule and Target Dose ................................................... 52 


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6.1.5 Pre-specified Dose Adjustment & Modifications ..................................................................... 53 
6.1.6 Duration of Therapy ………….. .................................................................................................. 58 
6.1.7 Tracking of Dose and Drug Compliance ................................................................................... 58 
6.2  Study agent Accountability Procedures ........................................................................................ 59 
6.2.1 Responsibilities of the Central Pharmacy Core ........................................................................ 59 
6.2.2 Responsibilities of the Clinical Site Pharmacy.......................................................................... 59 
6.2.3 Site Investigator Responsibility ................................................................................................ 59 
6.2.4 Monitoring & Compliance Oversight by the Data Coordinating Center .................................. 59 
7 
STUDY PROCEDURES AND SCHEDULE .......................................................................................................... 59 
7.1  Study Procedures/Evaluations ...................................................................................................... 59 
7.1.1 Study Specific Procedures ........................................................................................................ 60 
7.1.2 Standard of Care Study Procedures ......................................................................................... 64 
7.2  Study Schedule .............................................................................................................................. 65 
7.2.1 Screening Visits (Study Day -90 through 0; Screening Visit #1&2) .......................................... 65 
7.2.2 Enrollment/Baseline Visit (Study Day 0; Visit #1) .................................................................... 66 
7.2.3 Follow-up Visits (Months 0.5-18, Study Visits #2-21) .............................................................. 67 
7.2.4 Final Phone Follow-up Visit / Early Termination Final Phone Visit .......................................... 68 
7.2.5 Follow-up for Participants who Prematurely Discontinue  Study Drug Treatment or who 
Completely Withdraw from the Study ..................................................................................... 68 
7.2.6 Unscheduled Visits for Additional Safety Monitoring ............................................................. 69 
7.2.7 Long-term Follow-up ….. .......................................................................................................... 69 
7.3  Summary of Study Schedule and Assessments ............................................................................. 69 
7.4  Concomitant Medications & Treatments During the Study .......................................................... 71 
7.5  Prohibited Medications and Treatments During the Study .......................................................... 71 
7.5.1 Prohibited Medications & Treatments with DMARD Activity.................................................. 71 
7.5.2 Prohibited Medications & Treatments that may Increase Immune Suppression Risk ............ 71 
7.5.3 Prohibited Medications that may Interfere with Study Drug Absorption/Metabolism .......... 72 
7.5.3 Restrictions on Medications with Other Adverse Interactions ................................................ 72 
7.6  Prophylactic Medications, Treatments, and Procedures .............................................................. 73 
8 
ASSESSMENT OF SAFETY ................................................................................................................................ 73 
8.1  Specification of Safety Parameters ............................................................................................... 73 
8.1.1 Definition of Adverse Events (AEs) .......................................................................................... 73 
8.1.2 Definition of Serious Adverse Events (SAEs) ............................................................................ 74 
8.1.3 Definition of Unanticipated Problems (UP – unexpected AEs & Problems) ............................ 74 
8.2  Classification of an Adverse Event ................................................................................................ 75 
8.2.1 Severity of Event 
…. ........................................................................................................... 75 
8.2.2 Relationship to Study Drug .................................................................................................... 755 
8.2.3 Expectedness 
… ............................................................................................................ 76 
8.2.4 AE of Special Interest …… ......................................................................................................... 76 
8.3  Adverse Event Reporting ............................................................................................................... 76 
8.3.1 Adverse Event Reporting ......................................................................................................... 77 


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8.3.2 Serious Adverse Event Reporting ............................................................................................. 77 
8.3.3 Unexpected Adverse Event/Problem (UP) Reporting .............................................................. 78 
8.3.4 Reporting of Pregnancy ........................................................................................................... 78 
8.3.5 Reporting of Post-Study Adverse Events ................................................................................. 79 
8.4  Study Halting Rules ........................................................................................................................ 79 
8.5  Safety Oversight ............................................................................................................................ 79 
8.5.1 Morbidity and Mortality Committee ....................................................................................... 79 
9 
CLINICAL MONITORING .................................................................................................................................. 80 
10 STATISTICAL CONSIDERATIONS .................................................................................................................... 81 
10.1 Statistical and Analytical Plans ....................................................................................................... 81 
10.2 Statistical Hypotheses .................................................................................................................... 81 
10.3 Analysis Datasets ............................................................................................................................ 81 
10.4 Description of Statistical Methods ................................................................................................. 82 
10.4.1 General Approach 
…. ........................................................................................................... 82 
10.4.2 Analysis of the Primary Efficacy Endpoint ............................................................................... 82 
10.4.3 Analysis of the Secondary Endpoints and Exploratory Outcomes ........................................... 83 
10.4.4 Safety Analyses 
…. ........................................................................................................... 84 
10.4.5 Adherence & Retention Analyses ............................................................................................ 84 
10.4.6 Baseline Descriptive Statistics .................................................................................................. 84 
10.4.7 Planned Interim Analyses ........................................................................................................ 84 
10.4.8 Additional Sub-Group Analyses ............................................................................................... 85 
10.4.9 Multiple Comparison/Multiplicity Analyses ............................................................................ 85 
10.4.10  Tabulation of Individual Response Data ................................................................................ 85 
10.4.11   Exploratory Analyses ............................................................................................................. 85 
10.5 Sample Size..................................................................................................................................... 85 
10.5.1 Introduction & Background to Sample Size Determination .................................................... 85 
10.5.2 Assumptions 
…. ........................................................................................................... 86 
10.5.3 Defining the Primary Study Outcome ...................................................................................... 87 
10.5.4 Clinical Trial Scenarios & Simulations to Estimate Study Power in Treatment Naïve Patients 87 
10.5.5 Impact of a Mixed Population of Treatment Naïve and Previously-treated Patients on the 
Estimate of Study Power .......................................................................................................... 89 
10.6 Measures to Minimize Bias ............................................................................................................ 93 
10.6.1 Enrollment/Randomization/Masking Procedures ................................................................... 93 
10.6.2 Evaluation of Success of Blinding ............................................................................................. 93 
10.6.3 Breaking the Study Blind/Participant Code ............................................................................. 93 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................................................. 94 
12 QUALITY ASSURANCE AND QUALITY CONTROL ......................................................................................... 95 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS .............................................................................................. 95 
13.1 Ethical Standard ............................................................................................................................. 95 
13.2 Institutional Review Board ............................................................................................................. 95 
13.3 Informed Consent Process ............................................................................................................. 96 


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13.4 Sample Informed Consent Language ............................................................................................. 96 
13.5 Participant and Data Confidentiality ............................................................................................ 112 
13.6 Future Use of Stored Data and Specimens .................................................................................. 112 
14 DATA HANDLING AND RECORD KEEPING ................................................................................................. 112 
14.1 Data Collection and Management Responsibilities ..................................................................... 112 
14.2 Study Records Retention .............................................................................................................. 113 
14.3 Protocol Deviations ...................................................................................................................... 113 
14.4 Publication and Data Sharing Policy ............................................................................................. 113 
15 STUDY ADMINISTRATION AND OVERSIGHT ............................................................................................. 114 
15.1 Study Leadership .......................................................................................................................... 114 
15.1.1 UCLA Administrative & Contracting Core .................................................................................. 115 
15.1.2 Data Coordinating Center (DCC) ............................................................................................ 116 
15.1.3 Executive Committee ………………………………………………………………………………………………………. 116 
15.1.4 Steering Committee …………………. .......................................................................................... 117 
15.1.5 Data & Safety Monitoring Board (DSMB) .............................................................................. 117 
15.1.6 Study Cores …………………………………………………………………………………………………………………….. 118 
15.2 Procedure for Protocol Modification ........................................................................................... 119 
16 CONFLICT OF INTEREST POLICY ................................................................................................................... 119 
16.1 Compliance with 21 CFR part 54 .................................................................................................. 119 
16.1.1 Disclosable Financial Interests & Arrangements under 21 CFR part 54 ................................ 119 
16.1.2 Completion of Forms FDA 3455 & 3454 under 21 CFR part 54 ............................................. 120 
16.2 Compliance with Local State and University Regulations & Policy .............................................. 121 
17 
 EMERGENCY DISASTER/ PANDEMIC MANAGEMENT PLAN ........................................................................ 119 
17.1 Modifications to inclusion and exclusion criteria ........................................................................ 119 
17.2 Determination of risk and options for management of study drugs ........................................... 119 
17.2.1 Risk assignment during covid-19 pandemic ........................................................................... 119 
17.2.2 Options for management of study drugs during covid-19 pandemic .................................... 120 
17.2.3 Dispensing of study drugs during covid-19 pandemic ........................................................... 120 
17.3 Impact of the emergency on screening and randomization ........................................................ 119 
17.4 Allowable modifications to study visits and procedures ............................................................. 119 
17.4.1 Conversion from in person to remote study visits ................................................................ 119 
17.4.2 Components of study visits that can be carried out remotely .............................................. 120 
17.4.3 Components of study visits that cannot be carried out remotely ......................................... 120 
17.5 Revised site monitoring ................................................................................................................... 121 
18  LITERATURE REFERENCES ............................................................................................................................. 125 
APPENDIX LIST ........................................................................................................................................................ 125 
 
 
 


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
1 
LIST OF ABBREVIATIONS 
 
AE  
Adverse Event 
ACR 
American College of Rheumatology 
ADL 
Activities of daily living 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance  
AST 
Aspartate Aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
BID 
Twice daily 
BDI 
Baseline Mahler Modified Dyspnea Index 
BAL 
Bronchoalveolar lavage 
BUN 
Blood Urea Nitrogen 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum concentration 
CMP 
Clinical monitoring plan 
CMV 
Cytolomegalovirus 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF  
Case Report Form 
CRISS 
Combined Response index in Systemic Sclerosis 
CTCAE 
Common Terminology Criteria for Adverse Events V4.03-2010 
CYC 
Cyclophosphamide 
CYP 
Cytochrome P450 
DCC  
Data Coordinating Center 
DLCO 
Single-Breath Diffusing Capacity of the Lung for Carbon Monoxide 
DLCO-Hb-% 
DLCO, adjusted for age, height, gender and hemoglobin 
DMARD 
Disease-modifying antirheumatic drug 
DSMB  
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
ERS 
European Respiratory Society 
EULAR 
European League Against Rheumatism 
FEV1 
Forced Expiratory Volume in the first second 
FDA 
Food and Drug Administration 
FVC 
Forced vital capacity 
FVC-% 
Forced vital capacity as a percentage of the age-, height-, gender- and race-adjusted 
predicted value 
GERD 
Gastroesophageal reflux disease 
GCP 
Good Clinical Practice 
GGO 
Ground glass opacification 


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
2 
GLP  
Good Laboratory Practices 
GMP  
Good Manufacturing Practices 
H&P 
History and physical 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIPAA  
Health Insurance Portability and Accountability Act 
HRCT 
High resolution computerized tomography 
HRCT-TLC 
HRCT-measured total lung capacity at maximum inspiration 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
IFN-γ 
Interferon-gamma 
ILD 
Interstitial lung disease 
IND  
Investigational New Drug Application 
IPF 
Idiopathic pulmonary fibrosis 
IRB  
Investigational Review Board 
JC 
Polyomavirus JC 
LCQ 
Leicester Cough Questionnaire 
LFTs 
Liver function test 
MCP-1 
Macrophage chemotactic protein-1 
MCTM 
Markov Chain Transition Matrix 
mITT 
Modified intention to treat 
MPA 
Mycophenolic acid 
MPAG 
phenolic glucuronide metabolite of MPA 
MMF 
Mycophenolate mofetil; same as CellCept 
MMP 
Matrix metalloproteinase 
MOP 
Manual of Procedures 
mRSS 
Modified Rodnan Skin Score 
NIH  
National Institutes of Health 
NSIP 
Non-specific interstitial pneumonia 
OHRP  
Office for Human Research Protections 
PAH 
Pulmonary arterial hypertension 
PDGF 
Platelet derived growth factor 
PFD 
Pirfenidone; same as Esbriet 
PFT 
Pulmonary function test 
PI  
Principal Investigator 
Plac 
Placebo 
PML 
Progressive multifocal leukoencephalopathy associated with JC virus 
PP 
Per protocol 
PPI 
Proton pump inhibitors 
PRCA 
Pure Red Cell Aplasia 
PRO 
Patient Reported Outcome 
PROMIS-29 
Patient-reported outcomes measurement information system 29-item health profile 
PVAN 
Polyomavirus associated nephropathy 
QA 
Quality Assurance 
QC 
Quality Control 


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
3 
QGG 
Quantitative ground glass 
QHC 
Quantitative honeycomb change 
QIA 
Quantitative image analysis 
QILD-LM 
Quantitative interstitial lung disease score in the lobe of maximal involvement 
QILD-WL 
Quantitative interstitial lung disease score in the whole lung 
QLF-LM 
Quantitative lung fibrosis score in the lobe of maximal involvement 
QLF-WL 
Quantitative lung fibrosis score in the whole lung 
SABER 
Statistical Analysis of Biomedical and Educational Research Unit 
SAE  
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SGRQ 
St. George's Respiratory Questionnaire 
SHAQ 
Scleroderma Health Assessment Questionnaire 
SLS 
Scleroderma Lung Study 
SMC  
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP  
Standard Operating Procedure 
SSc 
Scleroderma (same as Systemic Sclerosis) 
SSc-lc 
Scleroderma with limited cutaneous features 
SSc-dc 
Scleroderma with diffuse cutaneous features 
SSc-ILD 
Scleroderma-related interstitial lung disease 
TDI 
Transitional Mahler Modified Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
TGF-β1 
Transforming growth factor beta-1 
TID 
Three times daily 
UCLA SCTC 
GIT 2.0 
University of California, Los Angeles, Scleroderma Clinical Trials Consortium 
Gastrointestinal Scale 
UIP 
Usual interstitial pneumonia 
ULN 
Upper limit of normal 
UP  
Unanticipated Problem 
US  
United States 
WBC 
White blood cell 
 
 
 


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
4 
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:  
Michael D. Roth, M.D.   
(Print/Type Name)  
Signed:  
 
 
__________________________________________________________________________ 
(Signature)  
 
Date:   11/17/2021  (version 2.5)    


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
5 
 
 
PROTOCOL SUMMARY 
Title: 
SCLERODERMA LUNG STUDY III (SLS III) 
Précis: 
A Phase II multi-center, double-blind, parallel group, randomized and 
placebo-controlled clinical trial addressing the treatment of patients with 
active and symptomatic Scleroderma-related interstitial lung disease (SSc-
ILD). 150 patients who are either treatment naïve or only recently started 
treatment (<6 mo of prior treatment with a potentially disease-modifying 
therapy) will be randomized in a 1:1 assignment to receive either oral 
mycophenolate mofetil (MMF) and a placebo (Plac) or a combination of 
oral MMF and oral pirfenidone (PFD), with both regimens administered for 
18 months. The primary assessment will be the change from baseline over 
the 18 month treatment period, as measured at 3-month intervals, in the 
course of the Forced Vital Capacity measured as a percentage of the age-, 
height-, gender- and race-adjusted predicted value (FVC-%). Key secondary 
outcomes will include changes over time in dyspnea, skin score, diffusing 
capacity and high resolution computerized tomography (HRCT) measures 
of interstitial lung disease ILD). Tolerability and toxicity of the two 
treatments will also be assessed.  
Objectives: 
 
Primary Hypothesis:  
The primary hypothesis is that the rapid onset and anti-fibrotic effects 
of PFD, which have been observed in the treatment of Idiopathic 
Pulmonary Fibrosis (IPF), will complement the delayed anti-
inflammatory and immunosuppressive effects of MMF, to produce a 
significantly more rapid and/or greater improvement in lung function 
over time than occurs in patients receiving control therapy with MMF 
and Plac. 
A secondary objective is to demonstrate that combination therapy 
with PFD and MMF is well tolerated, in comparison to MMF alone, and 
not associated with limiting toxicity that impacts on the overall 
treatment effect.  
Endpoints 
Primary Endpoint: 
The primary endpoint is the change from baseline, measured at 3-
month intervals, in the mean forced vital capacity (represented as the 
percentage of the age-, height-, gender- and race-adjusted predicted 
value,  i.e. FVC-%) over the course of the 18-month double-blind 
treatment period.   
Pre-specified Secondary Endpoints: 
1. The change from baseline to 18 months, measured at 3-month 
intervals, in the following disease measures: 
• 
Single-breath diffusing capacity for carbon monoxide (DLCO), 
calculated as a percent of the age-, height-, gender-, race- and 
hemoglobin-adjusted predicted value (DLCOHb-%).  


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
6 
• 
Modified Rodnan Skin Score (mRSS).  
• 
Transitional Mahler Modified Dyspnea Index (TDI). 
• 
Patient Reported Outcomes (PROs), which provide subjective 
measures of dyspnea and quality of life based on patient 
responses to standardized patient questionnaires. 
2. The change from baseline to 18 months in HRCT measures of SSc-
ILD: 
• 
Quantitative lung fibrosis score in the whole lung (QLF-WL).  
• 
Quantitative lung fibrosis score in the lobe of maximal 
involvement (QLF-LM).  
• 
Quantitative interstitial lung disease score in the whole lung 
(QILD-WL).  
• 
Quantitative interstitial lung disease score in the lobe of 
maximal involvement (QILD-LM). 
• 
Total lung capacity at maximum inspiration (HRCT-TLC) 
3. Differences in the frequency distribution of individual patient 
responses when grouped into defined intervals of improvement or 
worsening (defined by the change in an outcome measure from 
baseline to 18 months) for the following outcome measures: 
• 
Forced vital capacity (represented as the percentage of the 
age-, height-, gender- and race-adjusted predicted value,  i.e. 
FVC-%) 
• 
Single-breath diffusing capacity for carbon monoxide (DLCO), 
calculated as a percent of the age, height, gender and 
hemoglobin adjusted predicted value (DLCOHb-%).  
• 
Modified Rodnan Skin Score (mRSS).  
• 
Transitional Mahler Modified Dyspnea Index (TDI) 
4. The time (in months) required for each treatment arm to achieve a 
3.0% or greater improvement from baseline in the FVC-% over the 
18-month treatment period. 
5. A threshold analysis based on the percentage of subjects in each 
treatment arm achieving greater than a 5% improvement in FVC-% 
over the 18-month treatment period. 
6. Tolerability and toxicity of MMF+Plac versus MMF+PFD over the 
course of 18 months. 
Population: 
150 randomized participants from recruitment sites in the United States, 
including both male and female patients of an age >18 years, diagnosed 
with systemic scleroderma (SSc) as defined by the 2013 American College 
of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 
classification criteria, who demonstrate evidence of active restrictive lung 
disease by pulmonary function testing, symptomatic dyspnea and any 
evidence of ground glass opacification (GGO) on baseline thoracic HRCT, 
and who meet the study definition of being either treatment naïve or 
recently started on treatment (<6 mo of prior treatment with a potentially 
disease-modifying therapy) and all other inclusion & exclusion criteria as 
detailed below. 


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
7 
Phase: 
Phase II 
Number of Sites 
enrolling participants: 
Between 15 to 25 participating clinical sites 
Please see Section 1, Key Roles, for a current list of participating sites 
Description of Study 
Agents: 
1. Mycophenolate Mofetil (MMF) 
Manufactured by: Teva Pharmaceuticals, Inc (Generic) 
Oral Route 
250 mg capsules 
Target Dose:  
1500 mg twice daily as tolerated with a 4-step titration at monthly 
intervals  
a) 500 mg (two capsules) twice daily (BID) for 4 weeks 
b) 1000 mg (four capsules) BID for 4 weeks 
c) 1250 mg (five capsules) BID for 4 weeks 
d) 1500 mg (six capsules) BID for remainder of study as 
tolerated. 
2. Pirfenidone (PFD), same as Esbriet® 
Manufactured by:  Genentech, Inc. 
Oral Route 
267 mg capsules. 
Target Dose:  
801 mg three times daily as tolerated with a 3-step titration at 2 
week intervals: 
a) 267 mg (one capsule) three times daily (TID) for 2 weeks 
b) 534 mg (two capsules) TID for 2 weeks 
c) 801 mg (three capsules) TID for remainder of study as 
tolerated. 
3. Placebo (Plac), matching to the PFD capsules 
Manufactured by:  Genentech, Inc. 
Oral Route 
267 mg capsules. 
Target Dose:  
801 mg three times daily as tolerated with a 3-step titration at 2 
week intervals: 
a) 267 mg (one capsule) three times daily (TID) for 2 weeks 
b) 534 mg (two capsules) TID for 2 weeks 
c) 801 mg (three capsules) TID for remainder of study as 
tolerated. 
Study Duration: 
Approximately 4 years total study duration, sub-divided into the following 
components: 
a. 24 month enrollment period  
b. 18-month randomized, double-blind treatment period per patient  
c. 1 month follow-up period after completion of drug therapy  
d. 6 month primary analysis period 
Participant Duration: 
20-22 month subject participation period made up of the following 
components: 


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- screening = 1-3 months 
- randomized, double-blind treatment period = 18 months 
- final follow-up period after completion of drug therapy = 1 month 
Inclusion Criteria: 
1.  Age >18 yrs 
2.  Scleroderma as determined by the 2013 ACR/EULAR classification 
criteria. 
3.  Grade ≥2 on the Magnitude of Task component of the Mahler Modified 
Dyspnea Index  
(Becomes short of breath with moderate or average tasks such as 
walking up a gradual hill, climbing less than three flights of stairs, or 
carrying a light load on the level.  
4.  FVC-% of ≤85% at screening. 
5.  Onset of the first non-Raynaud manifestation of SSc within the prior 84 
months. 
6.  Presence of any GGO on thoracic HRCT  
7.   Repeat FVC-% at the baseline visit within 10% of the FVC-% value 
measured at screening. If these criteria are not met, a repeat FVC-% 
may be obtained within 7 days and the subject may qualify for 
randomization if the repeat FVC-% agrees within 10% of the FVC-% 
obtained at screening. 
Exclusion Criteria: 
1.   Disease features supporting the primary diagnosis of another 
connective tissue disease such as rheumatoid arthritis, systemic lupus 
erythematosus or mixed connective tissue disease (Features consistent 
with a secondary Sjogren syndrome or scleroderma-associated 
myopathy will be allowed).  
2.   FVC-% of <45% at either screening or baseline. 
3.   FEV1/FVC ratio <0.65 at either screening or baseline. 
4.   DLCOHb-% of <30% at screening or <25% at baseline.  
a)  All participants with a DLCOHb-% between 30 to 40% must have 
pulmonary artery pressures documented by either echocardiogram, 
right heart catheterization or magnetic resonance imaging in order to 
be considered for inclusion. 
5.   Diagnosis of clinically significant resting pulmonary hypertension 
requiring treatment or mild pulmonary hypertension requiring 
treatment with more than one oral medication as ascertained prior to 
study evaluation or as part of a standard of care clinical assessment 
performed outside of the study protocol. 
6.   Evidence of uncontrolled congestive heart failure, unstable ischemic 
heart disease, history of complicated pulmonary embolism impacting 
on heart or lung function, or unstable cardiac arrhythmia requiring 
chronic anticoagulation. 
7.   Clinically significant abnormalities on HRCT not attributable to SSc  
8.   Hematologic abnormality at screening including:  


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a) Leukopenia (white blood cells [WBC] <4.0x103/µl)  
b) Thrombocytopenia (platelet count <120.0x103/µl) 
c) Clinically significant anemia [Hemoglobin (Hgb) <10.0 g/dl] 
 
Participants with an identified and correctable etiology may be eligible 
if repeat testing within the maximal 90-day screening period meets all 
criteria. 
9.   A diagnosis of chronic liver disease or abnormal baseline liver function 
test (LFTs) or total bilirubin that are >2.0 x upper normal limit 
10.  Serum creatinine >2.0mg/dl 
11. History of recurrent aspiration, uncontrolled heartburn, or 
gastroesophageal reflux disease (GERD) with a reflux scale score of 
>1.00 as determined by a UCLA Scleroderma Clinical Trial Consortium 
Gastrointestinal Scale (UCLA SCTC GIT), Version 2.0.  
Participants with uncontrolled heartburn or GERD that is amenable to 
medical management may be eligible if repeat testing within the 
maximal 90-day screening period meets this criteria. 
12. Known achalasia, esophageal stricture or esophageal dysfunction 
sufficient to limit the ability to swallow medication.  
13. Pregnancy (documented by serum pregnancy test) and/or breast 
feeding 
14. If of child bearing potential (a female participant < 55 years of age who 
has not been postmenopausal for ≥ 5 years or who has not had a 
bilateral salpingectomy, hysterectomy and/or oophorectomy), failure 
to employ two reliable means of contraception which may include 
surgical sterilization, barrier methods, spermicidals, intrauterine 
devices, and/or hormonal contraception, unless the participant 
chooses abstinence (to avoid heterosexual intercourse completely.) If a 
subject chooses abstinence, then a second reliable means of 
contraception is not needed.   
15. Prior use of potential disease modifying antirheumatic drugs (DMARDs) 
according to the following exposure rules: 
a)  Use of oral cyclophosphamide (CYC), MMF, azathioprine or other 
oral or short half-life DMARDs (as detailed in Section 7.5.1a) for 
more than 6 months in the past year as determined at the time of 
the initial screening visit. 
b)  Treatment with more than three intravenous doses of CYC, one 
treatment course of Rituximab or other intravenous or injectable 
DMARDs (as detailed in Section 7.5.1b) in the past year. 
c)  More distant h/o treatment with a DMARD is allowed as long as the 
patient has a new diagnosis/new episode of active SSc-ILD since 
stopping that treatment and meets the criteria noted in 15a or 15b.  
16. Use of CYC, MMF, azathioprine, Rituximab or other DMARD (as 
detailed in Section 7.5.1a&b) in the 30 days prior to the baseline visit 


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unless the patient is on MMF and the responsible physician indicates 
that continued use is in the best clinical interest of the patient. 
17. Active infection (lung, ulcers or elsewhere) whose management would 
be compromised by immunosuppression. 
18. Other serious concomitant medical illness (e.g., active malignancy 
within the past 5 years other than surgically-removed local skin cancer 
such as a basal cell carcinoma), chronic debilitating illness (other than 
SSc), unreliability or drug abuse that might compromise the patient’s 
participation in the trial. 
19. Current use, or use within the 30 days prior to their baseline visit, of 
prednisone (or equivalent) in doses >10 mg/day. 
20. Smoking of cigars, pipes, or cigarettes during the past 6 months. 
21. Use of contraindicated medications, including medications with 
putative disease-modifying properties that do not meet the exposure 
limits described in Exclusion Criteria #15 and #16, moderate or strong 
inhibitors of cytochrome P450 (CYP) isozyme 1A2 (CYP1A2) (note 
ciprofloxacin allowed up to a dose of 500 mg twice daily), and 
moderate inducers of CYP1A2 (such as tobacco smoke, or phenytoin). 
See Section 7.5 for complete list. 
 
 
SUMMARY SCHEMATIC OF STUDY DESIGN 
 


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SUMMARY TABLE OF STUDY VISITS AND ASSESSMENTS** 
 
 
Screen 
 
Randomized Double-blind Phase 
 
Exit visit* 
Visit # 
 
S1 
S2 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
 
V22 
Month on Study 
(Month = 28 days) 
 
Sc-1 
Sc-2 
 
0 
 
0.5 (14 
days) 
±7d 
1 (28 
days) 
±7d 
1.5 (42 
days) 
±7d 
2 (56 
days) 
±10d 
3 (84 
days) 
±10d 
4 (112 
days) 
±10d 
5 (140 
days) 
±10d 
6 (168 
days) 
±10d 
7 (196 
days) 
±10d 
8 (224 
days) 
±10d 
9 (252 
days) 
±10d 
10 (280 
days) 
±10d 
11 (308 
days) 
±10d 
12 (336 
days) 
±14d 
13 (364 
days) 
±10d 
14 (392 
days) 
±10d 
15 (420 
days) 
±14d 
16 (448 
days) 
±10d 
17 (476 
days) 
±10d 
18 (504 
days) 
±14d 
 
Month 19 (532 
days)  
±10d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone contact 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
On-Site Visit 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Complete H&P 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
F/u SSc-H&P  
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Vital signs 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
mRSS 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Study Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
Medications 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense meds 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Drug reconciliation 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Mahler BDI/TDI  
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
SGRQ 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
SHAQ, PROMIS-29, 
UCLA SCTC GIT, 
CRISS, LCQ, Global 
Assessments 
 
UCLA 
SCTC 
GIT 
 
 
X 
(except 
CRISS) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
LABS: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - CBC, diff, plat  
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
  - Metabolic/liver 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
  - Serum Preg+ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - Urine Preg+ 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HRCT 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Spiro/DLCO 
 
X 
 
 
X‡ 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biorepository  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
‡Screen and Baseline FVC value must be within an absolute difference in percent-predicted of 10% - may repeat within 7 days if not and proceed to enroll if criteria met 
+For women of childbearing potential, initial serum pregnancy testing will be carried out with subsequent urine testing at each visit using test kits provided by the study. 
*Exit visit will also be carried out within 30 days (±10d) of early termination/withdrawal from the protocol. All subjects who terminate/withdraw early will be encouraged to return for the outcome 
assessments as detailed above for the 12 month (V15) and 18 month (V21) visits. 
**Refer to Protocol Section 17.0 (EMERGENCY DISASTER/ PANDEMIC MANAGEMENT PLAN) for allowed adjustments in the event of a disaster/pandemic that disrupts patient or institutional access. 


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1 KEY ROLES 
Study Roles and Participating Sites as of February 18, 2020 
Administrative Coordinating 
Center 
David Geffen School of Medicine  
at UCLA 
Los Angeles, CA 90095-1690  
 
 
 
Study Principal Investigator 
Michael D. Roth, M.D. 
Professor, Pulmonary and Critical Care 
Vice-Chair for Clinical Research Compliance 
Department of Medicine, 43-229 CHS 
David Geffen School of Medicine at UCLA 
Los Angeles, CA 90095-1690  
Tel: (310)206-7389;  Fax: (310) 206-5088  
mroth@mednet.ucla.edu 
 
Director, HRCT Quantitative Image Analysis (QIA) Core 
Jonathan G. Goldin, M.D., Ph.D. 
Professor of Radiology & Biomedical Physics Program 
Executive Chief of Clinical Care, Dept. of Radiology 
David Geffen School of Medicine at UCLA 
Los Angeles, CA 90095-1690  
Tel: (424) 259-8719;  Fax: (424) 259-6521 
jgoldin@mednet.ucla.edu 
 
Director, UCLA Research Pharmacy Core 
Christina S. Shin, Pharm.D. 
Investigational Drug Pharmacist 
Investigational Drug Section 
Ronald Reagan-UCLA Medical Center Pharmaceutical Services 
757 Westwood Plaza Room, Room# B-504G 
Tel: (310) 267-8522;  Fax: (310) 267-3652 
csshin@mednet.ucla.edu 
 
Director, UCLA Pulmonary Function Quality Assurance Core 
Eric Kleerup, M.D. 
Clinical Professor of Pulmonary & Critical Care 
Department of Medicine, 37-131 CHS 
David Geffen School of Medicine at UCLA 
Los Angeles, CA 90095-1690  
Tel: (310) 794-6593 
ekleerup@mednet.ucla.edu 
Data Coordinating Center 
University of Michigan 
Ann Arbor, MI 48109-2029  
Principal Statistician & 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 


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spino@med.umich.edu 
 
Co-Principal Investigator 
Dinesh Khanna, MD, MSc  
Division of Rheumatology 
University of Michigan School of Medicine 
300 North Ingalls Street, SPC 5422  
Ann Arbor, MI  48109  
Tel: (734) 232-2104;  Fax: (734) 763-5761 
khannad@med.umich.edu 
17 Participating Clinical Sites 
1. Boston University, School of Medicine  
Marcin Trojanowski, MD 
Principal Investigator  
Division of Rheumatology 
Department of Medicine 
Tel: (617) 638-7460 
trojanma@bu.edu 
 
2. David Geffen School of Medicine at UCLA 
S. Samuel Weigt, M.D. 
Principal Investigator 
Division of Pulmonary & Critical Care 
Department of Medicine  
Tel: (310) 794-1996 
sweigt@mednet.ucla.edu 
 
3. Georgetown University School of Medicine 
Virginia Steen, M.D. 
Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (202) 444-6210 
steenv@georgetown.edu 
 
4. Harvard / Brigham and Women’s Hospital 
Paul Dellaripa, M.D.  
Principal Investigator 
Division of Rheumatology, Immunology and 
AllergyDepartment of Medicine  
Tel: (617) 732-5548 
pdellaripa@bwh.harvard.edu 
 
5. Hospital for Special Surgery  
Jessica  Gordon, M.D.  
Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (212) 606-1351 
gordonJ@hss.edu 
 
6. Johns Hopkins University School of Medicine 
Laura Hummers, M.D.  


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Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (410) 550-6819 
lhummers@jhmi.edu 
 
7. Medical University of South Carolina 
Richard Silver, M.D.  
Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (843) 792-3484 
silverr@musc.edu 
 
8. Northwestern University Feinberg School of Medicine 
Jane Dematte-D’Amico, M.D.  
Principal Investigator 
Division of Pulmonary & Critical Care 
Department of Medicine  
Tel: (312) 695-1879 
j-dematte@northwestern.edu 
 
9. Rutgers Robert Wood Johnson Medical School 
Vivien Hsu, M.D.   
Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (732) 418-8484 
hsuvm@rwjms.rutgers.edu 
 
10. University of California San Francisco 
Jeffrey Golden, M.D.   
Principal Investigator 
Division of Pulmonary & Critical Care 
Department of Medicine  
Tel: (415) 353-2935 
jeff.golden@ucsf.edu 
 
11. University of Colorado Denver 
Joyce S. Lee, M.D.  
Principal Investigator 
Division of Pulmonary Sciences and Critical Care 
MedicineDepartment of Medicine  
Tel: (855) 586 4824; 
joyce.lee@cuanschutz.edu  
 
12. University of Michigan Medical School 
Vivek Nagaraja, MBBS  
Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (734) 936-9539 


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nagarajv@med.umich.edu 
 
13. University of Minnesota Medical School 
Hyun Kim, M.D.  
Principal Investigator 
Division of Pulmonary & Critical Care 
Department of Medicine  
Tel: (612) 626-6127 
kimxx015@umn.edu 
 
14. University of Pittsburgh 
Robyn T Domsic, M.D.  
Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (412) 648-4814 
rtd4@pitt.edu 
 
15. University of Texas Medical School at Houston  
Maureen Mayes, M.D.  
Principal Investigator 
Division of Rheumatology 
Department of Medicine  
Tel: (713) 500-6905 
Maureen.D.Mayes@uth.tmc.edu  
 
16. University of Utah School of Medicine  
Mary Beth Scholand, M.D.  
Principal Investigator 
Division of Pulmonary & Critical Care 
Department of Medicine  
Tel: (801) 581-7806 
Scholand@genetics.utah.edu 
 
17. University of Washington School of Medicine  
Ganesh Raghu, MD  
Principal Investigator 
Division of Pulmonary & Critical Care 
Department of Medicine  
Tel: (206) 598-6190 
graghu@uw.edu 
 
20. University of Indiana Health 
Ryan Boente, MD  
Principal Investigator 
Division of Pulmonary & Critical Care 
Department of Medicine  
Tel: (317) 278-0064 
rboente@iu.edu 
 
 
 


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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
 
BACKGROUND INFORMATION  
 
2.1.1 Prevalence & Course of SSC-ILD & the Need for New Treatments 
Systemic scleroderma (Systemic Sclerosis, SSc) is an autoimmune rheumatologic disorder 
characterized by the overproduction of auto-antibodies, tissue inflammation with small vessel 
vasculopathy, activation of tissue fibroblasts, and the deposition of extracellular matrix within skin 
and other defined organ sites including the lungs (55). It falls within the Food and Drug 
Administration's (FDA) designation of a rare disease, with estimates of the prevalence in the United 
States ranging between 40,000 to 165,000 overall cases (3). Although relatively rare, its impact is 
magnified by the fact that it primarily affects patients at middle-age, produces debilitating morbidity 
that can involve many organ systems, and is associated with significant mortality. Ten-year survival 
rates have recently been estimated at 65-70% (48).  
Of patients with SSc, up to 74% have some evidence of interstitial fibrosis at the time of autopsy (9) 
and progressive interstitial lung disease (ILD) occurs in approximately 40% of patients. SSc-related 
ILD (SSc-ILD) has emerged as a leading overall cause of disease-related deaths as summarized in a 
report by Nikpour and Baran (Table 2.1.1a; 38,54). 
 
Table 2.1.1a. 
Causes of death in SSc: results from the University of Pittsburgh SSc cohort (54) and 
the EUSTAR registry (48) as reproduced from the report by Nikpour & Baron, 2014 (38) 
 
ILD, interstitial lung disease; PAH, pulmonary arterial hypertension, SSc, systemic sclerosis  
aCause of death not assigned at the time of publication 
bAmong 5860 patients at risk; although there were 283 deaths, death questionnaires were completed in 234 
patients for whom data are summarized in this table 
cAmong 221 patients at risk 
dAmong 1508 patients at risk  
SSc-ILD usually emerges early during the inflammatory phase of the disease and rapidly transitions 
to the local deposition of collagen and destructive tissue changes (40,57). In fact, when the average 
annual decline in lung function was mapped out over time in a large cohort of 889 SSc patients, the 


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greatest decrease in lung function was found to occur early, within the first few years after 
diagnosis, after which time further decline was rather limited (Figure 2.1.1a/b; 46). The median 
survival for patients with SSc-ILD is in the range of 5-8 years and the extent of pulmonary 
involvement has repeatedly been found to correlate in an independent manner as a risk factor 
predicting time to death (16,35,38,46-47).  
 
Figure 2.1.1a (above, left). Mean loss of percent vital capacity occurring over 2-year time periods in 55 
patients whose initial pulmonary function tests (PFTs) were performed during the first 5 years of 
scleroderma symptoms. (adapted from ref 46). 
Figure 1b. (above, right) Percent cumulative survival rate from onset of disease in patients grouped 
according to their lowest forced vital capacity. Those with severe restrictive lung disease had the worst 
prognosis (p<0.01). (adapted from ref 46). 
 
Based on such information, a strong argument can be made that the identification of SSc-ILD and 
targeted early interventions that reduce or reverse the impact of lung inflammatory and fibrosis 
have the potential to significantly reduce patient morbidity and mortality. 
 
2.1.2 Effectiveness of Immune Suppression for the Treatment of SSc-ILD 
SSc-ILD is characterized by a combination of interstitial and alveolar inflammation, vascular injury 
with endothelial activation/apoptosis, and evidence of activation of fibroblasts and pro-fibrotic 
signaling cascades (56). Based on the proposed linkage between inflammation and fibrosis, 
immunosuppression was initially investigated as the treatment of choice in Scleroderma Lung Study 
I (SLS I; 51). One-hundred fifty-eight (158) patients with SSc-ILD were randomized into a placebo-
controlled double-blind trial to evaluate a 1-year treatment with oral cyclophosphamide (CYC) on 
the course of forced vital capacity as a percentage of the age-, height-, gender- and race-adjusted 
predicted value (FVC-%) and several secondary outcomes. There was a modest but statistically-
significant difference between the treatment arms at the 12-month primary outcome (51) which 
continued to increase over time until a maximal treatment effect was observed at 18 months; 6 
months after stopping immunosuppressive therapy (50, Figure 2.1.2a). At this point, using a 
longitudinal statistical model and a modified intention to treat (m-ITT) approach to take into 
account all available data, the average improvement in absolute FVC-% was 2.67% comparing the 
lung function in the active treatment arm to that in the placebo (Plac) group (p=0.0107). SLS I was 
the first randomized controlled trial to demonstrate that SSc-ILD responds to immunosuppression 
with placebo-adjusted improvements in pulmonary function as well as associated improvements in 


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the patient's perception of dyspnea, objective measurements of skin disease, and health-related 
quality of life (HRQoL) when compared to an untreated control arm (26,50-51). 
Figure 2.1.2a  (below). Time course from 6 to 24 months of mean values (+SE) for the FVC-% of 
participants in the Plac and CYC treatment groups of the SLS I study determined using a longitudinal 
model that adjusted for baseline % predicted values, maximal high-resolution computed tomography–
scored fibrosis, and non-ignorable missing data. Numbers of patients in each treatment group at each visit 
are shown, along with the P values for the between-treatment differences obtained from Huber’s robust 
regression analysis with multiple imputation 
. 
Similar results were observed with the use of intravenous CYC in the Fibrosing Alveolitis in 
Scleroderma Trial (FAST study) carried out in the United Kingdom (19). While the overall magnitude 
of the response to CYC has been considered modest in these studies, a subset analysis of the SLS I 
patients suggested that distinct subsets of “responders” and “non-responders” might be 
prospectively identified based on the extent of interstitial disease on chest high resolution 
computerized tomography (HRCT) imaging and/or the extent of skin disease (44). When results from 
SLS I were retrospectively stratified based on these criteria, the average treatment effect in the 
responder population was approximately a 5 point difference at 12 months and a 10 point 
difference at 18 months with respect to the FVC-% (Figure 2.1.2b). Approximately one-half of the 
overall treatment effect in this responder population could be attributed to the ongoing 
deterioration that occurs in subjects treated with placebo, while the other one-half of the treatment 
response appeared to represent a significant improvement over time in subjects who were on active 
CYC therapy. In contrast, subjects identified as non-responders by this approach remained relatively 
stable with little deterioration if on placebo and little, if any, benefit from CYC (Figure 2.1.2c). 
Figure 2.1.2b (left) and 2c (right). Time-trend curves. The changes in FVC-% from baseline to 18 months 
(adjusted for baseline FVC-%) are plotted for the cyclophosphamide (CYC) and placebo (Plac) arms (mean 
+SEM). The number of subjects (N) at each time-point and the p-value comparing groups is presented. (A) 
There was a small but significant difference between the treatment arms at 18 months when results were 
plotted for all patients. (B) Dividing the study population into Responder and Non-responder subsets 
resulted in two distinct plots with a highly-significant treatment effect from 9 to 18 months occurring only 
in the Responder population. 


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In Scleroderma Lung Study II, a two year course of daily oral mycophenolate mofetil (MMF) was 
evaluated as an alternative to one year of daily oral CYC (followed by placebo in the second year). 
The goals were to evaluate whether MMF, an alternative immunosuppressant, would induce clinical 
responses, extend the duration of the treatment effect, and produce a longer lasting outcome with 
less toxicity (bone marrow suppression, hemorrhagic cystitis or malignancies) than CYC (14,42). The 
primary outcome from the SLS II trial confirmed that both MMF and CYC significantly improved lung 
function compared to that at baseline with no difference between the study arms (52, Figure 
2.1.2d/e). 
 
 
Figure 2.1.2d (left).  Absolute change in FVC-% 
from baseline by treatment arm. Estimates of the 
absolute changes in mean FVC-% in the two 
treatment arms at three month intervals from 
baseline to 24 months were calculated using a 
pre-specified joint longitudinal model that linked 
a linear mixed-effects model with a cause-specific 
hazards model and took into account the time to 
cause-specific drop-out, treatment failure and/or 
death. 95% confidence intervals for the estimates 
are shown for the data at 6, 12, 18 and 24 
months. 
Figure 2.1.2e  (right). A number of patients who 
received at least one dose of study medication 
prematurely withdrew or were withdrawn from 
study treatment at various times during the study 
due to adverse events, noncompliance, loss to 
follow-up or having met the protocol- definition 
of treatment failure. As an overall measure of 
tolerability, time to withdrawal from the study 
medication or treatment failure was significantly 
shorter in the CYC arm (p=0.019; log rank test) 
and consistent with the hypothesis that MMF is 
better tolerated and associated with less dose-


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limiting toxicity. 
As hypothesized, MMF was also better tolerated with respect to the time to treatment failure or 
drug discontinuation (p=0.019; log rant test; Figure 2.1.2e) and its use was associated with fewer 
episodes of protocol-defined levels of anemia (CYC = 26; MMF = 18), leukopenia (CYC = 51; MMF = 
5), neutropenia (CYC = 7; MMF = 3) and thrombocytopenia (CYC = 7; MMF = 0).  
In order to better understand the modeled outcomes, frequency distribution histograms were 
prepared from the un-modeled outcome data in which the subject-by-subject change in FVC-% from 
baseline to 24 months were plotted for the two treatment arms in increments of a 5% improvement 
or worsening from baseline (Figure 2.1.2f). Very similar to outcomes portrayed by the joint model, 
the overall change (+SE) in FVC-% averaged 3.0+1.2 for the CYC arm and 3.3+1.1 for the MMF arm. 
The majority of subjects in both arms had improving FVC-% values over time (64.7% for CYC, 71.7% 
for MMF) and no significant difference was identified between treatments (p=0.55; Fisher’s exact 
test). Of the 34 patients in the CYC arm and the 38 patients in the MMF arm with a positive change 
over time, the average (±SE) improvement was a 7.1±0.7 and 7.5± 0.9 change in FVC-%, respectively. 
Of the 17 patients in the CYC arm and the 15 patients in the MMF arm whose FVC-% declined over 
24 months, the average (±SE) decrement was a 6.0±1.6 and 6.4±1.6 change in FVC-%, respectively. 
We noted that the majority of subjects who experienced decrements in lung function belonged to 
the subset in either arm that had stopped drug treatment prematurely.  Similar to the observations 
from the SLS I study, values for the mRSS decreased (i.e. improved) in 73.6 % of subjects on CYC and 
71.7 % of subjects on MMF, with most of these improvements being by ≥5 units. Mahler’s 
Transitional Dyspnea Index (TDI) values increased (i.e. improved) by at least 1 unit in 59 % of 
subjects on CYC and 47.5% % of subjects on MMF, with most of these improvements being by ≥3 
units in both arms. In most cases these individual improvements exceeded the minimal clinically 
important changes that have been described for both of these endpoints (22,25,52). 
Figure 2.1.2f.  Raw 
unmodeled data from all 
subjects completing the 24 
month evaluation, regardless 
of whether they stayed on 
drug therapy or withdrew 
prematurely from the 
treatment phase of the 
protocol, was used to 
construct a frequency 
distribution of changes from 
baseline in FVC-% at 24 
months, by treatment arm. 
 
 
The relatively equivalent efficacy and improved tolerability of MMF, as compared to CYC, make a 
strong clinical argument for its use as the preferred immunosuppressive medication for SSc-ILD 
(10,52). 
 
2.1.3 The Importance of Addressing Fibrosis in Addition to Inflammation 
In addition to confirming the important role of inflammation and auto-immunity in driving SSc-ILD, 
the Scleroderma Lung Study also identified the extent of fibrotic interstitial lung changes on baseline 


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HRCT, i.e. linear reticular markings, as an important predictor of progressive lung destruction and 
treatment-related improvement in SSc-ILD (44). The important role of lung fibrotic changes on 
disease progression and mortality has also been observed in a number or retrospective and 
longitudinal studies (35,58).  These observations prompted us to examine HRCT-based evidence of 
disease progression in patients who participated in the SLS I study. Quantitative computer aided 
HRCT measurements of fibrosis, ground glass changes and honeycomb changes were compared at 
baseline to scans performed after 12 months in the patients assigned to the Plac Arm (Figure 2.1.3a; 
28). By far, the most frequently observed transition from one type of lung involvement to another 
related to the development of fibrotic reticulation and honeycomb changes (cumulative probability 
0.29) while the progression to a ground glass appearance, usually associated with worsening 
inflammation, was infrequent (cumulative probability 0.04). 
 
Figure 2.1.3a.  A Markov Chain Transition Matrix 
(MCTM) was prepared for the patients participating 
in the Placebo Arm of the SLS I study based on 
quantitative computer aided image analysis of 
HRCT scans obtained on the same patients at 
baseline and again at 12 months. Means and 
standard deviations of the probability of 
transitioning from one pattern to another (straight 
arrows) or of remaining the same pattern (curved 
arrows near a circle) are shown for the most severe 
zone of disease involvement in each patient. Note 
that the most common transition from one type of 
disease finding to another related to the transition 
of both existing ground glass changes into fibrotic 
and honeycomb changes or the change from what 
appeared to be normal lung to fibrotic and 
honeycomb changes. 
These observations further strengthen the linkage between fibrosis and progressive SSc-ILD. While 
SSc-ILD is most often thought of as a form of non-specific interstitial pneumonia (NSIP), 
differentiating it from the usual interstitial pneumonia (UIP) that occurs in Idiopathic Pulmonary 
Fibrosis (IPF), the work of Bouros et al. (6, Table 2.1.3a/b) makes a convincing argument that it is 
best characterized as fibrotic rather than cellular NSIP. In contrast to other rheumatologic diseases 
associated with ILD where cellular NSIP and lymphocytic infiltration appear to predominate, SSc-ILD 
demonstrates significant fibrosis combined with infiltration by neutrophils and eosinophils. 
Table 2.1.3a. Histopathologic diagnosis, according to type of scleroderma and duration of 
exertional dyspnea. (adapted from ref 6) 


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Table 2.1.3b. Bronchoalveolar lavage cell (BAL) differential (median, range) in usual interstitial 
pneumonia/end-stage lung disease, non-specific interstitial pneumonia, with data given 
separately for cellular and fibrotic non-specific interstitial pneumonia. (adapted from ref 6) 
In addition to this pathologic and CT evidence of fibrosis, there has been considerable effort at 
mapping the biologic environment associated with progressive SSc-ILD through the study of serum, 
plasma, peripheral blood, BAL fluid and lung tissue obtained from patients and in animal models. A 
number of these findings support the role of a pro-fibrotic environment. In some of the earliest 
studies, BAL obtained from the lungs of SSc-ILD patients were noted to have significantly higher 
levels of platelet derived growth factor (PDGF) and transforming growth factor beta-1 (TGF-β1) than 
BAL obtained from controls and these factors stimulated the proliferation of myofibroblasts (32). 
Baroni et al (4), identified autoantibodies from the serum of scleroderma patients that targeted and 
activated the PDGF receptor, resulting in collagen production and the generation of a myofibroblast 
phenotype. Thrombin levels are also increased in BAL fluid from patients with SSc-ILD and can 
induce profibrotic cytokines, growth factors, and extracellular matrix production associated with a 
myofibroblast phenotype, a key feature of fibrotic lung disease (1,14). Increased numbers of 
circulating fibrocytes – bone marrow-derived fibroblast precursors that have been reported in the 
circulation of patients with IPF, especially in the setting of acute exacerbation, are also observed in 
patients with SSc (4).  Similarly, gene arrays and cytokine profiling have repeatedly identified the 
activation of related pro-fibrotic pathways in SSc-ILD patients including TGF-β1, collagens, 
interferon-gamma (IFN-γ) receptor, matrix metalloproteinase -7 (MMP-7), macrophage chemotactic 
protein-1 (MCP-1), and others as recently reviewed by Fan and associates (13).  
Collectively, there is strong and clear evidence of the important role of pro-fibrotic signaling and 
active fibrosis in the pathogenesis of SSc-ILD. 
 
2.1.4 Pirfenidone: a Drug of Interest for Treating the Fibrotic Aspect of SSc-ILD 
PFD, currently marketed under the trade name Esbriet®, is an anti-inflammatory and anti-fibrotic 
drug that was approved by the FDA in 2014 for the treatment of IPF. PFD is a low molecular weight 
non-peptide molecule and biologically active when taken by the oral route (12). In vitro, PFD inhibits 
release of pro fibrotic factors by activated fibroblasts and macrophages while concurrently 
suppressing activation of pro-inflammatory factors. It reduces lung damage in animal models of 
pulmonary fibrosis and in human clinical trials it significantly reduces the rate of decline of lung 
function in patients with IPF (29,49). 


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Despite the success of cytotoxic therapy in resolving inflammation and preventing the progression 
of lung disease, it is not clear that this approach adequately addresses the considerable fibrosis that 
already exist in patients at the time of diagnosis or the fact that disease progression continues for 
several months after starting immunosuppression. As the majority of functional lung deterioration 
and fibrotic changes occur within the first few years of SSc-ILD, the delayed response to cytotoxic 
therapy is of particular concern.  
In contrast to the slow onset of activity observed when CYC and MMF are used to treat SSc-ILD (50-
52), PFD exhibits a relatively rapid onset of anti-fibrotic activity in patients with IPF (29). In IPF, the 
course of disease progression in patients on PFD and those on placebo begin to separate within the 
first few months and follow divergent trajectories over time (see Figure 2.1.4a).  
Figure 2.1.4a: Time course of the response to 
PFD in patients with IPF. The mean change 
from baseline in FVC (in ml) is plotted against 
time for the entire 52 weeks of therapy with 
PFD versus Plac. Using a ranked ANCOVA 
analysis, treatment with PFD resulted in a 
significant between-group difference in the 
primary end point, the change from baseline 
to week 52 in the percentage of the predicted 
FVC (P<0.001). The treatment effect was 
evident by week 13 and increased throughout 
the duration of the trial. The mean decline 
from baseline in FVC was 235 ml in the PFD 
group and 428 ml in the Plac group (absolute 
difference, 193 ml; relative difference, 45.1%; 
P<0.001). (Adapted from ref# 29)  
 
 
This rapid effect, if it occurs in SSc-ILD, should complement the slower onset of action associated 
with cytotoxic therapy alone. As can be seen from SLS I data (see Figures 2.1.2a-b), patients on Plac 
show progressive deterioration over the first year and significant improvement from CYC was not 
observed until at least 6-9 months into therapy.  A nearly identical pattern, with a delayed onset of 
the treatment effect, was observed with the use of MMF in SLS II (see Figure 2.1.2d). In addition, 
given its different mechanism of action, the hope is that PFD might produce at least additive effects 
with respect to the ultimate improvement in lung function. Preliminary toxicity and tolerability 
testing has already been carried out in patients with SSc-ILD (20) and suggest that PFD is reasonably 
tolerated when given alone and in patients who are on concurrent therapy with MMF. Given these 
differences in the rapidity of onset and mechanisms of action, we hypothesize that studies 
combining PFD and MMF should focus on outcome measures that address both the time to an 
observed improvement in lung function and the overall magnitude of the improvement.  
 
2.1.5 The Documented Efficacy of Pirfenidone for the Treatment of IPF 
Three randomized, double-blind, placebo-controlled Phase 3 studies evaluating PFD in patients with 
IPF have been conducted (PIPF-004, PIPF-006, and PIPF-016). A complete outcome summary 
detailing the findings from these studies is provided in the Esbriet Investigational Drug Brochure 
(11). The major findings are presented here as a brief summary. 
2.1.5.1 Primary Study Endpoints in the treatment of IPF with PFD. 


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In the pooled Phase 3 analysis (PIPF-004/006/016) of the primary endpoint, there was a clear 
effect of treatment with PFD in reducing the decline in percent predicted FVC compared with 
placebo (p < 0.0001, ANCOVA; Figure 2.1.5a, adapted from ref #11, Investigational brochure).  
 
 
Figure 2.1.5a Percent Predicted FVC: Cumulative Distribution of Change from baseline to Month 12 in 
Pooled Phase 3 Studies (adapted from ref #11, Investigational Brochure) 
 
There was a relative reduction of 43.8% in the proportion of patients with decline in percent 
predicted FVC > 10% or death from Baseline at Month 12 in the PFD group compared with the 
placebo group, as well as a 59.3% relative increase in the proportion with no decline in percent 
predicted FVC (Figure 2.1.5b).  
 
 
Figure 2.1.5b Percent Predicted FVC: Proportion of patients with decline of > 10% to Month 12 in 
Pooled Phase 3 Studies 
 


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2.1.4.1 Key Secondary Endpoints in the treatment of IPF with PFD. 
In the pooled Phase 3 analysis (PIPF-004/006/016) of key secondary endpoints, a beneficial 
effect of PFD on exercise tolerance was seen, represented by a statistically significantly lower 
decline from Baseline to Month 12 in the 6-minute walk test (6MWT) distance in the pirfenidone 
group compared with the placebo group (p = 0.0004) (11). There was also a 38% relative 
reduction in the risk of disease progression or death at Month 12 in pirfenidone-treated patients 
compared with placebo-treated patients (hazard ratio [HR] 0.62; 95% CI, 0.51 - 0.75; p < 0.0001) 
(11). In the mortality analysis, a 48% relative reduction in the risk of death from any cause 
favoring PFD was seen (HR 0.52; 95% CI, 0.31 -0.87; p =0.0107, log-rank test) (11). A smaller 
proportion of PFD-treated patients died compared with placebo-treated patients (3.5% vs. 6.7%, 
respectively) (11). 
 
2.1.6 The Feasibility of Combining PFD with MMF for the Treatment of SSc-ILD 
Directly relevant to this proposal, patients with SSc-ILD were randomized 1:1 in an initial safety and 
tolerability trial in patients with SSc-ILD (LOTUSS study, 20) to receive PFD when titrated from 
starting to final dose over a 2 week interval (one arm) vs a 4 week interval (second arm). Titration 
started at a dose of 801 mg/day and increased up to a maintenance dose of 2403 mg/day. Patients 
received PFD for 16 weeks in total and both treatment naïve patients and those already on other 
therapies, including treatment with MMF or CYC, were included in a stratified design. This design 
allowed an evaluation of whether the titration interval resulted in a difference in safety and 
tolerability and whether or not there were obvious differences when administered to treatment 
naïve patients or as an add-on therapy in combination with some form of immunosuppressive 
therapy. This trial Assessments included treatment-emergent AEs (TEAEs) and exploratory disease 
outcomes. Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients 
reported TEAEs during the titration vs maintenance period consistent with the known pattern of 
TEAEs described when PFD has been used for the treatment of IPF. The most commonly reported 
TEAEs were also consistent with those observed for PFD when used in the treatment of IPF (nausea, 
headache, fatigue) and the frequency and type of TEAEs were similar regardless of titration schedule 
(Table 2.1.6a).  
Table 2.1.6a. Summary of TEAEs in the LOTUSS Study. 
 


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However, more patients discontinued treatment due to TEAEs in the 2- vs 4-week titration group (5 
vs 1, respectively); all discontinuation events occurred >3 weeks after reaching the full dose of 
pirfenidone. MMF, taken by 63.5% of patients in addition to PFD, did not appear to affect 
tolerability in the stratified analysis. Exploratory disease outcomes remained largely unchanged. 
The tolerability profile of PFD in this preliminary study of SSc-ILD was therefore considered to be 
similar to that in IPF. Tolerability was not affected by titration length or concomitant MMF, although 
more subjects prematurely discontinued therapy in the 2 week titration as compared to the 4 week 
titration, leading to the hypothesis that tolerability might be improved when a slower titration is 
employed. The findings support the clinical feasibility of evaluating PFD when combined with MMF in 
future clinical trials in patients with SSc-ILD. 
 
2.2 
 
RATIONALE AND STUDY APPROACH 
Scleroderma Lung Study III proposes to investigate a new combination therapy for patients with SSc-ILD 
that will combine the established effects of immunosuppression, as mediated by MMF, with the anti-
fibrotic effects of PFD. The primary hypothesis is that the rapid onset and anti-fibrotic activity of PFD, 
which have been observed in the treatment of IPF, will complement the delayed anti-inflammatory and 
immunosuppressive effects of MMF, to produce a significantly more rapid and/or greater improvement 
in lung function over time than occurs in patients receiving control therapy with MMF (and Plac) alone. 
A secondary objective is to demonstrate that combination therapy with PFD and MMF is well tolerated, 
in comparison to MMF alone, and not associated with limiting toxicity that impacts on the overall 
treatment effect. 
There are several important concepts that collectively provide a strong rationale for the proposed study:   
First, SSc is a devastating disease in which pulmonary manifestations are the most frequent cause of 
morbidity and mortality (9,38,54). Studies focused on the development of new treatments for SSc-ILD 
have the potential to make a significant impact on the lives of SSc patients.  
Second, SSc-ILD is a rare condition with estimates of the prevalence in the United States ranging 
between 40,000 to 165,000 overall cases (3), and falls within the Food and Drug Administration's (FDA) 
designation of a "rare disease" for which there are limited FDA-approved therapies. Studies that focus 
on novel clinical approaches to treatment are considered a high priority.  


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Third, the SLS Investigators and the collaborative infrastructure that they have developed represent a 
well-established resource for carrying out clinical studies targeting the treatment of SSc-ILD. The 
identification and participation by centers of excellence in SSc-ILD, the collaborative interaction that 
occurs between pulmonologists and rheumatologists in the generation and conduct of the research, and 
the integration of key ancillary resources such as CT imaging and translational biology, all represent 
unique strengths of the SLS Investigators that are not likely to be reproduced elsewhere (10,26-27,50-
52).  
Fourth, while SLS I and II focused on establishing the benefits of cytotoxic therapy (utilizing CYC and/or 
MMF) for SSc-ILD, the improvements in lung function remain modest and it is reasonable to speculate 
that a combination therapy, which addresses perceived limitations in the use of cytotoxic therapy, might 
enhance the treatment effect to a level that is universally appreciated as efficacious.  
Fifth, given that the predominant pathology in SSc-ILD is a fibrotic form of NSIP (6), the addition of an 
anti-fibrotic drug like PFD with proven efficacy in the treatment of IPF appears logical (2,29,36,39,43).  
Sixth, as it can take up to 6 months of cytotoxic therapy before responses are apparent, during which 
time lung disease may progress (51-52), it is rational to add a drug like PFD that has a rapid onset of 
action that might ameliorate the ongoing decline in lung that occurs for months after starting MMF. This 
is particularly relevant when the most active decline in lung function is known to occur early in the 
course of the disease (46).  
Seventh, given that MMF and PFD act by different mechanisms, it is reasonable to hypothesize that their 
combined use might produce additive or synergistic effects on lung function.  
Eighth, as demonstrated in the LOTUSS study (20), it is expected that PFD is safe to administer to 
patients with SSc-ILD and can be used in conjunction with MMF with an acceptable tolerability and 
toxicity profile.  
As a result of all of these considerations, we have designed SLS III as a two-arm Phase II clinical trial in 
which all patients will receive background therapy with MMF as the best tolerated cytotoxic therapy 
with documented clinical impact on the course of FVC-% over time (10,52). The inclusion and exclusion 
criteria, outcome measures, visit schedules and analysis approaches that have been developed and 
refined in the SLS I and SLS II studies will be carried forward, with only minor modification, and thereby 
provide a solid basis for the SLS III protocol. Treatment will last 18 months: the time associated with 
maximal response to cytotoxic therapy as defined in SLS I and II (10,50). In addition, patients will receive 
either PFD or matching Plac in a randomized double-blinded manner in order to objectively evaluate 
whether combination therapy produces a superior outcome when compared to cytotoxic therapy alone. 
The primary outcome will focus on the change from baseline in the mean forced vital capacity, 
measured as the percentage of the age-, height-, gender- and race-adjusted predicted value (FVC-%) 
over the course of the 18-month double-blind treatment period.  FVC-% will be measured at baseline 
(pre-treatment) and then quarterly after treatment begins during the entire double-blind treatment 
period (i.e., months 3, 6, 9, 12, 15 and 18).  A number of secondary outcomes are defined, following the 
logic and models developed in the SLS I and II studies. Given that the trajectories of the primary 
endpoint are expected to differ because of the mechanisms of action (and the time course of action) of 
the two treatment modalities, a longitudinal analysis approach incorporating all time points will be 
employed.  Specifically, the endpoint will be analyzed using a linear mixed model with participant-month 
in the study (3, 6, 9, 12, 15 and 18) as the unit of analysis and the change from baseline in FVC-% as the 
outcome, with terms for treatment group, baseline FVC-%month and the interaction of treatment group 
with month used as fixed covariates.  Study participant will be treated as a random effect to account for 
the correlation of outcomes over time within a participant.  The model generates adjusted estimates of 


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change from baseline in the FVC-% for each treatment group and month, and an F-test will be used to 
test the hypothesis that the mean change from baseline during the treatment period differs between 
the two treatment groups.  
 
2.3 
 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 Known Potential Risks 
Two active drugs in oral capsule form will be administered to patients and include Mycophenolate 
Mofetil (MMF; Generic, Teva Pharmaceuticals, Inc.) and Pirfenidone (PFD; same as Esbriet®, 
Genentech, Inc.).  They are both FDA approved medications for other related medical indications, 
but neither is currently approved by the FDA for use in the treatment of SSc-ILD. MMF is approved 
for use as an immunosuppressant in solid organ transplantation (cardiac, hepatic and renal) at doses 
up to 1.5 g twice daily and for the treatment of Lupus nephritis, an autoimmune manifestation of 
systemic lupus erythematosus, in the dose range of 1 to 3 g daily. PFD is currently approved for the 
treatment of IPF at a recommended dose of 801 mg (3 capsules of 267 mg each) 3 times daily. They 
will be administered in this study at doses that fall within these FDA-defined dosing ranges but as 
experimental therapy for SSc-ILD. 
This section will summarize their known risks, when applicable, from the FDA-approved package 
inserts. In addition, details are provided regarding observed adverse events when used in clinical 
investigations that were closely related to those proposed by this protocol. Letters authorizing 
cross-filing to existing FDA data from a pharmaceutical manufacturer of these drugs is also provided 
in support of this protocol and the related IND filing.  An inactive placebo capsule (Plac; matching to 
PFD, Genentech, Inc.) will also be administered to study participants but will not be considered 
further in this section. 
2.3.1.1  
Mycophenolate Mofetil 
2.3.1.1.1 
Black Box Warnings: 
a) Embryofetal Toxicity.  Use during pregnancy is associated with increased risks of first 
trimester pregnancy loss and congenital malformations. Females of reproductive 
potential (FRP) must be counseled regarding pregnancy prevention and planning. 
b) Malignancies And Serious Infections. Immunosuppression may lead to increased 
susceptibility to infection and possible development of lymphoma.  Only physicians 
experienced in immunosuppressive therapy and  management of renal, cardiac or 
hepatic transplant patients should prescribe MMF. Patients receiving the drug should be 
managed in facilities equipped and staffed with adequate laboratory and supportive 
medical resources. The   physician   responsible for maintenance therapy should have 
complete information requisite for the follow-up of the patient. 
2.3.1.1.2 
Contraindications: 
Allergic reactions to MMF have been observed; therefore, MMF is contraindicated in 
patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any 
component of the drug product.  
2.3.1.1.3 
Warnings and Precautions: 
a) Embryofetal Toxicity. MMF can cause fetal harm when administered to a pregnant  
female. Use of MMF during pregnancy is associated with an increased risk of first 


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trimester pregnancy loss and an increased risk of congenital malformations, especially 
external ear and other facial abnormalities including cleft lip and palate, and anomalies 
of the distal limbs, heart, esophagus, kidney and nervous system. 
b) Pregnancy Exposure Prevention and Planning. Females of reproductive potential must 
be made aware of the increased risk of first trimester pregnancy loss and congenital 
malformations and must be counseled regarding pregnancy prevention and planning. 
c) Lymphoma and Malignancy.  Patients receiving immunosuppressive regimens involving 
combinations of drugs, including MMF, as part of an immunosuppressive regimen are at 
increased risk of developing lymphomas and other malignancies, particularly of the skin. 
The risk appears to be related to the intensity and duration of immunosuppression 
rather than to the use of any specific agent. As usual for patients with increased risk for 
skin cancer, exposure to sunlight and UV light should be limited by wearing protective 
clothing and using a sunscreen with a high protection factor. Lymphoproliferative 
disease or lymphoma developed in 0.4% to 1% of patients receiving MMF (2 g or 3 g) 
with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and 
hepatic transplant patients. In pediatric patients, no other malignancies besides 
lymphoproliferative disorder (2/148 patients) have been observed. 
d) Serious Infections.  Patients receiving immunosuppressants, including MMF, are at 
increased risk of developing bacterial, fungal, protozoal and new or reactivated viral 
infections, including opportunistic infections. These infections may lead to serious, 
including fatal, outcomes. Because of the danger of oversuppression of the immune 
system which can increase susceptibility to infection, combination immunosuppressant 
therapy should be used with caution. 
e) New or Reactivated Viral Infections.  Polyomavirus associated nephropathy (PVAN), JC 
virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus 
(CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been 
reported in patients treated with immunosuppressants, including MMF. Reduction in 
immunosuppression should be considered for patients who develop evidence of new or 
reactivated viral infections. Physicians should also consider the risk that reduced 
immunosuppression represents to the functioning allograft. 
PVAN, especially due to BK virus infection, is associated with serious outcomes, 
including deteriorating renal function and renal graft loss. Patient monitoring may help 
detect patients at risk for PVAN. 
PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, 
cognitive deficiencies, and ataxia. Risk factors for PML include treatment with 
immunosuppressant therapies and impairment of immune function. In 
immunosuppressed patients, physicians should consider PML in the differential 
diagnosis in patients reporting neurological symptoms and consultation with a 
neurologist should be considered as clinically indicated. 
The risk of CMV viremia and CMV disease is highest among transplant recipients 
seronegative for CMV at time of transplant who receive a graft from a CMV seropositive 
donor. Therapeutic approaches to limiting CMV disease exist and should be routinely 
provided. Patient monitoring may help detect patients at risk for CMV disease.  
Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring 
infected patients for clinical and laboratory signs of active HBV or HCV infection is 
recommended. 


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f) Neutropenia.  Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 103/μL] 
developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic 
transplant patients receiving MMF 3 g daily (see ADVERSE REACTIONS). Patients 
receiving MMF should be monitored for neutropenia. The development of neutropenia 
may be related to MMF itself, concomitant medications, viral infections, or some 
combination of these causes. If neutropenia develops (ANC <1.3 x 103/μL), dosing with 
MMF should be interrupted or the dose reduced, appropriate diagnostic tests 
performed, and the patient managed appropriately. Neutropenia has been observed 
most frequently in the period from 31 to 180 days posttransplant in patients treated for 
prevention of renal, cardiac, and hepatic rejection. Patients receiving MMF should be 
instructed to report immediately any evidence of infection, unexpected bruising, 
bleeding or any other manifestation of bone marrow depression. 
g) Pure Red Cell Aplasia (PRCA).  Cases of pure red cell aplasia (PRCA) have been reported 
in patients treated with MMF in combination with other immunosuppressive agents. 
The mechanism for MMF induced PRCA is unknown; the relative contribution of other 
immunosuppressants and their combinations in an immunosuppression regimen are 
also unknown. In some cases, PRCA was found to be reversible with dose reduction 
orcessation of MMF therapy. In transplant patients, however, reduced 
immunosuppression may place the graft at risk. 
h) Gastrointestinal Disorders.  Gastrointestinal bleeding (requiring hospitalization) has 
been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic 
transplant patients treated with MMF 3 g daily. In pediatric renal transplant patients, 
5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed. 
Gastrointestinal perforations have rarely been observed. Most patients receiving MMF 
were also receiving other drugs known to be associated with these complications. 
Patients with active peptic ulcer disease were excluded from enrollment in studies with 
MMF. Because MMF has been associated with an increased incidence of digestive 
system adverse events, including infrequent cases of gastrointestinal tract ulceration, 
hemorrhage, and perforation, MMF should be administered with caution in patients 
with active serious digestive system disease. 
i) 
Concomitant Medications.  It is recommended that MMF not be administered 
concomitantly with azathioprine because both have the potential to cause bone marrow 
suppression and such concomitant administration has not been studied clinically. In 
view of the significant reduction in the AUC of mycophenolic acid (MPA) by 
cholestyramine, caution should be used in the concomitant administration of MMF with 
drugs that interfere with enterohepatic recirculation because of the potential to reduce 
the efficacy of MMF. 
j) 
Patients with HGPRT Deficiency.  MMF is an inosine monophosphate dehydrogenase 
inhibitor; therefore it should be avoided in patients with rare hereditary deficiency of 
hypoxanthine-guanine phosphoribosyl-transferase  such as Lesch-Nyhan and Kelley-
Seegmiller syndrome.  
k) Immunizations.  During treatment with MMF, the use of live attenuated vaccines should 
be avoided and patients should be advised that vaccinations may be less effective. 
l) 
Drug Interactions.  Drug interaction studies with MMF have been conducted with 
acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, 
sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug 
interaction studies have not been conducted with other drugs that may be commonly 


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administered to renal, cardiac or hepatic transplant patients. MMF has not been 
administered concomitantly with azathioprine. 
• 
Acyclovir.  Coadministration of MMF (1 g) and acyclovir (800 mg) to 12 healthy 
volunteers resulted in no significant change in MPA AUC and Cmax. However, the 
phenolic glucuronide metabolite of MPA (MPAG) and acyclovir plasma AUCs were 
increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are 
increased in the presence of renal impairment, as are acyclovir concentrations, the 
potential exists for MMF and acyclovir or its prodrug (eg, valacyclovir) to compete 
for tubular secretion, further increasing the concentrations of both drugs. 
• 
Antacids With Magnesium and Aluminum Hydroxides.  Absorption of a single dose 
of MMF (2 g) was decreased when administered to ten rheumatoid arthritis patients 
also taking Maalox® TC (10 mL qid). The Cmax and AUC(0-24h) for MPA were 33% 
and 17% lower, respectively, than when MMF was administered alone under fasting 
conditions. MMF may be administered to patients who are also taking antacids 
containing magnesium and aluminum hydroxides; however, it is recommended that 
MMF and the antacid not be administered simultaneously. 
• 
Proton Pump Inhibitors (PPIs).  Coadministration of proton pump inhibitors (PPIs; 
e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple 
doses to transplant patients receiving MMF has been reported to reduce the 
exposure to MPA. An approximate reduction of 30 to 70% in the Cmax and 25% to 
35% in the AUC of MPA has been observed, possibly due to a decrease in MPA 
solubility at an increased gastric pH. The clinical impact of reduced MPA exposure 
on organ rejection has not been established in transplant patients receiving PPIs and 
MMF. Because clinical relevance has not been established, PPIs should be used with 
caution when coadministered to transplant patients being treated with MMF. 
• 
Cholestyramine.  Following single-dose administration of 1.5 g MMF to 12 healthy 
volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased 
approximately 40%. This decrease is consistent with interruption of enterohepatic 
recirculation which may be due to binding of recirculating MPAG with 
cholestyramine in the intestine. Some degree of enterohepatic recirculation is also 
anticipated following intravenous administration of MMF. Therefore, MMF is not 
recommended to be given with cholestyramine or other agents that may interfere 
with enterohepatic recirculation. 
• 
Cyclosporine. Cyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 
415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of 
mycophenolate mofetil in 10 stable renal transplant patients. The mean (±SD) 
AUC(0-12h) and Cmax of cyclosporine after 14 days of multiple doses of MMF were 
3290 (±822) ng·h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) 
ng·h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of MMF. 
Cyclosporine A interferes with MPA enterohepatic recirculation. In renal transplant 
patients, mean MPA exposure (AUC0-12h) was approximately 30-50% greater when 
mycophenolate mofetil is administered without cyclosporine compared with when 
mycophenolate mofetil is coadministered with cyclosporine. This interaction is due 
to cyclosporine inhibition of multidrug-resistance-associated protein 2  transporter 
in the biliary tract, thereby preventing the excretion of MPAG into the bile that 
would lead to enterohepatic recirculation of MPA. This information should be taken 
into consideration when MMF is used without cyclosporine; changes in MPA 
exposure should be expected when switching patients from cyclosporine A to one of 


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the immunosuppressants which do not interfere with MPA’s enterohepatic cycle 
(e.g., tacrolimus; belatacept). 
• 
Telmisartan.  Concommitant administration of telmisartan and MMF resulted in an 
approximately 30% decrease in MPA concentrations. Telmisartan changes MPA’s 
elimination by enhancing peroxisome proliferator-activated receptor gamma 
expression, which in turn results in an enhanced UGT1A9 expression and activity. 
• 
Ganciclovir.  Following single-dose administration to 12 stable renal transplant 
patients, no pharmacokinetic interaction was observed between MMF (1.5 g) and 
intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) 
were 54.3 (±19.0) μg·h/mL and 11.5 (±1.8) μg/mL, respectively, after 
coadministration of the two drugs, compared to 51.0 (±17.0) μg·h/mL and 10.6 
(±2.0) μg/mL, respectively, after administration of intravenous ganciclovir alone. The 
mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) 
μg·h/mL and 27.8 (±13.9) μg/mL, respectively, compared to values of 80.3 (±16.4) 
μg·h/mL and 30.9 (±11.2) μg/mL, respectively, after administration of 
mycophenolate mofetil alone. Because MPAG plasma concentrations are increased 
in the presence of renal impairment, as are ganciclovir concentrations, the two 
drugs will compete for tubular secretion and thus further increases in 
concentrations of both drugs may occur. In patients with renal impairment in which 
MMF and ganciclovir or its prodrug (eg, valganciclovir) are coadministered, patients 
should be monitored carefully. 
• 
Oral Contraceptives.  A study of coadministration of MMF (1 g bid) and combined 
oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and 
levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 
0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual 
cycles. Mean AUC(0-24h) was similar for ethinylestradiol and 3-keto desogestrel; 
however, mean levonorgestrel AUC(0-24h) significantly decreased by about 15%. 
There was large inter-patient variability (%CV in the range of 60% to 70%) in the 
data, especially for ethinylestradiol. Mean serum levels of LH, FSH and progesterone 
were not significantly affected. MMF may not have any influence on the ovulation-
suppressing action of the studied oral contraceptives. It is recommended to 
coadminister MMF with hormonal contraceptives (eg, birth control pill, transdermal 
patch, vaginal ring, injection, and implant) with caution and additional barrier 
contraceptive methods must be used. 
• 
Sevelamer.  Concomitant administration of sevelamer and MMF in adult and 
pediatric patients decreased the mean MPA Cmax and AUC0-12h by 36% and 26% 
respectively. This data suggest that sevelamer and other calcium free phosphate 
binders should not be administered simultaneously with MMF. Alternatively, it is 
recommended that sevelamer and other calcium free phosphate binders 
preferentially could be given 2 hours after MMF intake to minimize the impact on 
the absorption of MPA. 
• 
Trimethoprim/sulfamethoxazole. Following single-dose administration of MMF (1.5 
g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 
mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of 
MPA was observed. The mean (±SD) AUC and Cmax of MPA after concomitant 
administration were 75.2 (±19.8) μg·h/mL and 34.0 (±6.6) μg/mL, respectively, 
compared to 79.2 (±27.9) μg·h/mL and 34.2 (±10.7) μg/mL, respectively, after 
administration of MMF alone. 


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• 
Norfloxacin and Metronidazole.  Following single-dose administration of MMF (1 g) 
to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin 
and metronidazole, the mean MPA AUC0-48h was significantly reduced by 33% 
compared to the administration of MMF alone (p<0.05). Therefore, MMF is not 
recommended to be given with the combination of norfloxacin and metronidazole. 
There was no significant effect on mean MPA AUC0-48h when MMF was 
concomitantly administered with norfloxacin or metronidazole separately. The 
mean (±SD) MPA AUC0-48h after coadministration of MMF with norfloxacin or 
metronidazole separately was 48.3 (±24) μg·h/mL and 42.7 (±23) μg·h/mL, 
respectively, compared with 56.2 (±24) μg·h/mL after administration of MMF alone. 
• 
Ciprofloxacin and Amoxicillin plus Clavulanic Acid.  A total of 64 MMF-treated renal 
transplant recipients received either oral ciprofloxacin 500 mg bid or amoxicillin plus 
clavulanic acid 375 mg tid for 7 or at least 14 days. Approximately 50% reductions in 
median trough MPA concentrations (predose) from baseline (MMF alone) were 
observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus 
clavulanic acid. These reductions in trough MPA concentrations tended to diminish 
within 14 days of antibiotic therapy and ceased within 3 days after discontinuation 
of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced 
reduction in glucuronidase-possessing enteric organisms leading to a decrease in 
enterohepatic recirculation of MPA. The change in trough level may not accurately 
represent changes in overall MPA exposure; therefore, clinical relevance of these 
observations is unclear. 
• 
Rifampin.  In a single heart-lung transplant patient, after correction for dose, a 67% 
decrease in MPA exposure (AUC0-12h) has been observed with concomitant 
administration of MMF and rifampin. Therefore, MMF is not recommended to be 
given with rifampin concomitantly unless the benefit outweighs the risk. 
• 
Other Interactions. The measured value for renal clearance of MPAG indicates 
removal occurs by renal tubular secretion as well as glomerular filtration. Consistent 
with this, coadministration of probenecid, a known inhibitor of tubular secretion, 
with MMF in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold 
increase in plasma MPA AUC. Thus, other drugs known to undergo renal tubular 
secretion may compete with MPAG and thereby raise plasma concentrations of 
MPAG or the other drug undergoing tubular secretion. Drugs that alter the 
gastrointestinal flora may interact with MMF by disrupting enterohepatic 
recirculation. Interference of MPAG hydrolysis may lead to less MPA available for 
absorption. 
2.3.1.1.4 
Adverse Events:  
The principal adverse events reported during the administration of MMF include diarrhea, 
leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of 
infections eg, opportunistic infection. Elderly patients (≥65 years), particularly those who are 
receiving MMF as part of a combination immunosuppressive regimen, may be at increased 
risk of certain infections (including CMV tissue invasive disease) and possibly gastrointestinal 
hemorrhage and pulmonary edema, compared to younger individuals. 
Adverse event profiles reported in the packaging insert for MMF are those described for 
solid organ transplant recipients who were treated with MMF as one of many treatments 
administered following surgical organ transplantation. By definition, these patients had 


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recent major surgery, end-stage organ failure for one or more organ systems, variable 
degrees of recipient organ tissue type mismatch, and were receiving combination 
immunosuppression with one or more concurrent medications. The relevance of these 
reports to the administration of MMF to patients with autoimmune disease such as SSc, in 
the absence of organ system failure and concurrent immunosuppressive therapy, is 
unknown.  
Information that is more relevant to the patient population and intended use described in 
this protocol comes from SLS II, where patients with SSc-ILD with similar characteristics 
were randomized to receive either oral CYC for one year followed by Plac for a second year 
(N=73) or a two year course of oral MMF (N=69). Adverse event data comparing these two 
study groups is summarized as follows: 
a) Protocol defined and managed adverse events (AEs). According to the protocol, five 
specific types of adverse events were pre-defined as likely to be related to the 
administration of study drugs and to warrant protocol-defined management. 
• Anemia = Hgb <10.0 g/dl or <9.0 g/dl for those with Hgb <11.0 g/dl at enrollment 
• Leukopenia = WBC <2.5x103/µl 
• Neutropenia = neutrophil count <1.0x103/µl 
• Thrombocytopenia = Platelet count <100.0x103/µl 
• Hematuria = >25 Red blood cells (or 10-15 range on more than one routine urine 
analysis) in absence of a urinary tract infection or menses 
These protocol-defined AEs were tracked and recorded for all subjects until the time they 
either completed the study or withdrew or were withdrawn from active participation. The 
development of protocol-defined AEs from the SLS II study are summarized below by 
treatment arm. 
Table 2.3.1.1.4a. Protocol-defined and managed adverse events reported for SLS II  
 
†p<0.05, Fisher’s exact test comparing the number of patients experiencing AE 
(some patients had more than one AE event).  
The following conclusions were drawn from this data: 
i.  Anemia and Leukopenia were the dominant causes of protocol-defined AEs 
during treatment with MMF, accounting for 23/29 reported events. 
ii.  Absolute neutropenia, while a common occurance in patients receiving CYC, 
occured only rarely in those receiving MMF (4.3% of patients randomized to the 
MMF arm) and at rates reported when MMF is used for other indications. 


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 iii.  Thrombocytopenia, which occurs during the administration of CYC, was not 
observed in the MMF arm. 
b) All adverse events by system or disease category. All AEs, categorized by system or 
disease category, were tracked and recorded for all study subjects until the time they 
either completed the study or withdrew or were withdrawn from active participation. 
Recorded AEs from the SLS II study are summarized below by treatment arm and 
according to the frequency of occurance (least to most frequent). 
Table 2.3.1.1.4b. All adverse events summarized by category and study arm 
Category 
Number of Reported AE 
Number of Patients with AE 
Total 
CYC 
MMF 
Total 
CYC 
MMF 
N 
N (% of AE) 
N (% of AE) 
N 
N (% of 
randomized) 
N (% of 
randomized) 
Cancer (including skin) 
6 
2 (33.3) 
4 (66.7) 
6 
2 (2.7) 
4 (5.8) 
Immune System 
Disorders 
6 
4 (66.7) 
2 (33.3) 
6 
4 (5.5) 
2 (2.9) 
Vision and Hearing 
10 
8 (80.0) 
2 (20.0) 
8 
6 (8.2) 
2 (2.9) 
Hepatobiliary Disorders 
12 
6 (50.0) 
6 (50.0) 
10 
4 (5.5) 
6 (8.7) 
Surgical & Medical 
Procedures 
17 
6 (35.3) 
11 (64.7) 
11 
5 (6.8) 
6 (8.7) 
Psychiatric Disorders 
22 
10 (45.5) 
12 (54.5) 
19 
9 (12.3) 
10 (14.5) 
Injury, Poisoning & 
Procedural 
Complications 
25 
15 (60.0) 
10 (40.0) 
18 
10 (13.7) 
8 (11.6) 
Nervous System 
Disorders 
31 
9 (29.0) 
22 (71.0) 
21 
9 (12.3) 
12 (17.4) 
Reproductive System & 
Breast Disorders 
36 
17 (47.2) 
19 (52.8) 
27 
12 (16.4) 
15 (21.7) 
Metabolism & Nutrition 
Disorders* 
40 
24 (60.0) 
16 (40.0) 
33 
22 (30.1) 
11 (15.9) 
Vascular Disorders 
66 
33 (50.0) 
33 (50.0) 
41 
22 (30.1) 
19 (27.5) 
Cardiac Disorders 
67 
32 (47.8) 
35 (52.2) 
39 
21 (28.8) 
18 (26.1) 
Renal & Urinary 
Disorders 
93 
44 (47.3) 
49 (53.7) 
53 
27 (37.0) 
26 (37.7) 
General Disorders 
146 
85 (58.2) 
61 (41.8) 
64 
33 (45.2) 
31 (45.0) 
Skin & Subcutaneous 
Tissue Disorders 
174 
92 (52.9) 
82 (47.1) 
78 
43 (58.9) 
35 (50.7) 


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Category 
Number of Reported AE 
Number of Patients with AE 
Total 
CYC 
MMF 
Total 
CYC 
MMF 
N 
N (% of AE) 
N (% of AE) 
N 
N (% of 
randomized) 
N (% of 
randomized) 
Musculoskeletal & 
Connective Tissue 
Disorders 
181 
102 (56.4) 
79 (43.6) 
68 
34 (46.6) 
34 (49.3) 
Blood & Lymphatic 
System Disorders*  
199 
149 (74.9) 
50 (25.1) 
67 
47 (64.4) 
20 (29.0) 
Respiratory, Thoracic & 
Mediastinal Disorders 
223 
102 (45.7) 
121 (54.3) 
91 
45 (61.6) 
46 (66.7) 
Gastrointestinal 
Disorders 
260 
115 (44.2)   
145 (55.8) 
87 
40 (54.8) 
47 (68.1) 
Infections & Infestations 
290 
139 (47.9) 
151 (52.1) 
109 
57 (78.1) 
52 (75.4) 
Total 
1904 
994 (52.2) 
910 (47.8) 
139 
71 
68  
*p<0.05, Fisher’s exact test comparing the number of patients experiencing AEs. 
The following conclusions were drawn from this data: 
i.  The distribution of AEs is similar to that observed in the SLS I study with the  5 most 
common AE categories including infections, GI disorders, respiratory and thoracic, 
blood and lymphatic, and musculoskeletal and connective tissue.  
ii.   While there were no significant differences between arms with respect to either the 
total # of AEs or the total # of patients with AEs, there was an unequal distribution 
between study arms with respect to two categories; blood and lymphatic disorders 
and metabolism and nutrition disorders. In each case, fewer events were observed 
in the patients treated with MMF as compared to those treated with CYC, 
supporting the overall conclusion from SLS II that treatment with oral MMF appears 
better tolerated than treatment with oral CYC.  
iii. When broken down further, it was determined that the difference between groups 
for blood and lympatic disorders was primarily driven by significant differences in 
the number of patients experiencing leukocpenia and thrombocytopenia - 
reinforcing the findings from the recording of protocol-defined events noted above. 
iv. When broken down further, no statistically significant difference between groups 
was identified for individual categories within the subset of metabolism and 
nutrition disorders. The only notable numerical imbalance (although not statistically 
significant) being for the category of weight loss, which occured more frequently in 
patients receiving CYC. 
c. Severe Adverse Events. All SAEs, categorized by system or disease category, were 
tracked and recorded for all study subjects. In addition, all SAE documentation was 
reviewed by an independent Morbidity and Mortality Committee composed of one 
rheumatologist, one pulmonologist and one general internal medicine specialist, who 
determined the relatedness of the SAE according to the study protocol (related to study 


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treatment, related to underlying disease, related to other causes or related to unknown 
causes).  
Table 2.3.1.1.4c-1. Serious adverse events reported for SLS II.  
Category 
# of Patients 
# of SAEs 
MMF 
CYC 
Cancer 
3 
3 
2 
1 
Renal/Bladder 
2 
2 
1 
1 
Syncope/ Seizures 
2 
3 
3 
0 
Hematologic 
3 
3 
1 
2 
Miscellaneous 
6 
6 
5 
1 
Gastrointestinal 
6 
7 
2 
5 
Musculoskeletal/ Skin 
6 
7 
4 
3 
Respiratory Infection 
9 
9 
2 
7 
Respiratory 
12 
18 
12 
6 
Cardiac 
16 
20 
10 
10 
TOTAL 
65 
78 
42 
36 
• Cancer cases included lymphoma and adenocarcinoma of the lung (2 cases) 
• Renal/Bladder cases included one renal crisis with stroke and one bladder lesion with hematuria 
• Hematologic cases included anemia (2 cases) and a blood clot (1 case)  
• Miscellaneous cases included an assault, sulfa allergy, weight loss, and elective surgeries  
• Gastrointestinal cases included dysphagia/vomiting, gastroenteritis, bile duct obstruction, and 
scleroderma bowel.  
• Musculoskeletal/skin cases included arthritis, fractures, elbow pain/ulcer, and infected bursa with 
abscess  
• Respiratory infections included influenza, bronchitis and pneumonia 
• Respiratory cases included progressive dyspnea, respiratory failure, severe hypoxemia, progressive 
ILD, and shortness of breath 
• Cardiac cases included heart failure, palpitations, arrhythmias, chest pain/pressure, pericarditis, 
cardiac cath, ischemic heart disease, and non-infective nodule on mitral valve 
 
Table 2.3.1.1.4c-2. Relatedness of Serious Adverse Events reported for SLS II.  
 
The following conclusions were drawn from this data: 
i.  SAEs occurred slightly more frequently in the MMF group than the CYC group 
(n=42 vs36), whereas numerically more SAEs in the CYC group (n=8) than in the 


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MMF group (n=3) were deemed by the Morbidity and Mortality Committee to 
be related to the study drug. No statistically significant differences were noted 
between treatment arms. 
ii. Relatively equal numbers of serious adverse events were attributed to systemic 
sclerosis itself (16 in each group) or to other causes (MMF [n=11] vs CYC [n=14}.  
iii. While a numerically greater number of Respiratory SAE’s were observed in the 
MMF Arm (12) than the CYC Arm (6), only 4 were determined by the morbidity 
and mortality committee to be possibly or probably due to drug and three of 
these occurred in the CYC arm. 
 
2.3.1.2  
Pirfenidone 
2.3.1.2.1 
Black Box Warnings: 
None   
2.3.1.2.2 
Contraindications: 
None 
2.3.1.2.3 
Warnings: 
a) Elevated Liver Enzymes and drug-induced liver injury. Increases in Alanine 
Aminotransferase (ALT),  Aspartate Aminotransferase (AST) and bilirubin elevations 
have been reported in patients treated with PFD including cases of drug-induced liver 
injury. In postmarketing reporting, non-serious and serious cases of drug-induced liver 
injury, including severe liver injury with fatal outcome. Patients treated with PFD 2403 
mg/day in the three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥3 
× ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations ≥10 × ULN in ALT 
or AST occurred in 0.3% of patients in the PFD 2403 mg/day group and in 0.2% of 
patients in the placebo group. Increases in ALT and AST ≥3 × ULN were reversible with 
dose modification or treatment discontinuation. Conduct liver function tests (ALT, AST, 
and bilirubin) prior to the initiation of therapy with PFD in all patients, then monthly for 
the first 6 months, every 3 months thereafter, and as clinically indicated. Measure liver 
function tests promptly in patients who report symptoms that may indicate liver injury, 
including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 
Dosage modifications or interruption may be necessary for liver enzyme elevations 
b) Photosensitivity Reaction or Rash.  Patients treated with PFD 2403 mg/day in the three 
Phase 3 studies had a higher incidence of photosensitivity reactions (9%) compared with 
patients treated with placebo (1%). The majority of the photosensitivity reactions 
occurred during the initial 6 months. Instruct patients to avoid or minimize exposure to 
sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing 
that protects against sun exposure. Additionally, instruct patients to avoid concomitant 
medications known to cause photosensitivity. Dosage reduction or discontinuation may 
be necessary in some cases of photosensitivity reaction or rash. 
c) Gastrointestinal Disorders.  In the clinical studies, gastrointestinal events of nausea, 
diarrhea, dyspepsia, vomiting, gastro-esophageal reflux disease, and abdominal pain 
were more frequently reported by patients in the PFD treatment groups than in those 
taking placebo. Dosage reduction or interruption for gastrointestinal events was 
required in 18.5% of patients in the 2403 mg/day group, as compared to 5.8% of 
patients in the placebo group; 2.2% of patients in the PFD 2403 mg/day group 


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discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the 
placebo group. The most common (>2%) gastrointestinal events that led to dosage 
reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. The incidence 
of gastrointestinal events was highest early in the course of treatment (with highest 
incidence occurring during the initial 3 months) and decreased over time. Dosage 
modifications may be necessary in some cases of gastrointestinal adverse reactions. 
2.3.1.2.4 
Adverse Events reported during the treatment of IPF:  
Adverse reactions related to Liver Enzyme Elevations, Photosensitivity Reaction or Rash, and 
Gastrointestinal Disorders represent the principal adverse reactions associated with the 
administration of PFD and have already been described in the Warnings section above and 
are detailed in the Investigational Brochure (11). 
The safety of PFD has been evaluated in more than 1400 subjects with over 170 subjects 
exposed to PFD for more than 5 years in clinical trials. PFD was studied in 3 randomized, 
double-blind, placebo-controlled trials (Studies 1, 2, and 3) in which a total of 623 patients 
received 2403 mg/day of PFD and 624 patients received placebo. Subjects ages ranged from 
40 to 80 years (mean age of 67 years). Most patients were male (74%) and Caucasian (95%). 
The mean duration of exposure to PFD was 62 weeks (range: 2 to 118 weeks) in these 3 
trials. 
At the recommended dosage of 2403 mg/day, 14.6% of patients on PFD compared to 9.6% 
on placebo permanently discontinued treatment because of an adverse event. The most 
common (>1%) adverse reactions leading to discontinuation were rash and nausea. The 
most common (>3%) adverse reactions leading to dosage reduction or interruption were 
rash, nausea, diarrhea, and photosensitivity reaction. 
The most common adverse reactions with an incidence of ≥10% and more frequent in the 
PFD than placebo treatment group are listed in Table 2.3.1.2.4a (adapted from ref #12).  
Table 2.3.1.2.4a. Adverse reactions occurring in ≥10% of PFD (ESBRIET)-treated patients 
and more commonly than placebo in studies 1, 2, and 3 (adapted from ref #12). 
 
 


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Adverse reactions occurring in ≥5 to <10% of PFD-treated patients and more commonly 
than placebo are photosensitivity reaction (9% vs. 1%), decreased appetite (8% vs. 3%), 
pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6% vs. 2%), and non-cardiac chest 
pain (5% vs. 4%). 
In addition to adverse reactions identified from clinical trials the following adverse 
reactions have been identified during postapproval use of PFD. Because these reactions 
are reported voluntarily from a population of uncertain size, it is not always possible to 
reliably estimate their frequency. 
a) Blood and Lymphatic System Disorders: Agranulocytosis 
b) Immune System Disorders: Angioedema 
c) Hepatobiliary Disorders: Bilirubin increased in combination with increases of 
ALT and AST 
2.3.1.2.5 
Adverse Events reported during the treatment of SSc-ILD:  
Directly relevant to this proposal, patients with SSc-ILD were treated in a multinational, 
open-label, randomized, parallel-group safety and tolerability trial (LOTUSS study; 11,20) 
and received PFD when titrated from starting to final dose over a 2 week interval (one arm) 
vs a 4 week interval (second arm). Titration started at a dose of 801 mg/day and increased 
up to a maintenance dose of 2403 mg/day. Patients received PFD for 16 weeks and the 
population included both treatment naïve patients and those already on other therapies, 
including treatment with MMF or CYC, in a stratified design. Most AEs were mild or 
moderate and resolved without sequelae; severe AEs were reported in 19%, most 
commonly fatigue, diarrhea, and nausea and consistent with the experience in IPF. Similarly, 
all of the most commonly reported (>10%) AEs have been seen in pirfenidone IPF studies. 
The AE system organ class (SOC) with the greatest incidence was gastrointestinal disorders, 
with nausea, diarrhea, vomiting, GERD, dyspepsia, constipation, and stomach discomfort 
each occurring in >10% of patients. GI events were mostly mild or moderate and none led to 
study treatment discontinuation.  
AEs of interest in this study (events known or suspected to be associated with PFD 
administration and occurring in organs or systems already affected in patients with 
scleroderma) were nausea (49.2%), vomiting (28.6%), and skin events: rash (20.6%), 
photosensitivity reaction (6.3%), erythema (4.8%), and follicular rash (1.6%). Almost all of 
these events were mild or moderate and considered related to study treatment.  Three 
patients (4.8%) had SAEs (bronchitis, small intestinal obstruction, and pulmonary 
hypertension/interstitial lung disease [PAH/ILD]); all but the PAH/ILD events resolved. No 
deaths occurred during this study. There were no clinically relevant abnormal findings in 
clinical laboratory tests including liver function tests (LFT), vital signs, body weight, or ECGs. 
 
2.3.1.3  
Approaches to reduce risks associated with study drugs 
Due to the frequent and sometimes serious risks associated with the two study drugs, specific 
measures have been instituted to minimize these risks and improve the risk:benefit ratio for 
participants. First, while neither drug is approved for the treatment of SSc-ILD, they are 
approved for related conditions and will be used within the dosage range and with the 
accumulated knowledge of their effectiveness and potential toxicity gained from their 
prescribed uses. In addition, based on past experience with the administration of 
immunosuppressive therapies to patients with SSc-ILD, the inclusion and exclusion criteria have 
been selected to enrich for subjects most-likely to benefit from therapy (see Inclusion Criteria) 


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and to avoid those subjects who are less-likely to benefit or more likely to experience 
treatment-related toxicity (see Exclusion Criteria). Concurrent medications that adversely 
interact with the study drugs or with the potential adverse effects of the study drugs will be 
excluded. Pregnancy status will be carefully evaluated, institution of appropriate precautions 
verified in participants of childbearing potential, and pregnancy status monitored throughout 
the study. In addition, frequent and routine laboratory monitoring will be carried out 
throughout the entire study protocol. The Clinical Investigator is responsible for reviewing and 
acting on toxicity data in accordance with a protocol-defined action plan. The Clinical 
Investigator will be guided in the management of study drugs by detailed protocols for 
modifying drug dosing in the event of specific adverse events. In view of a recent FDA warning 
concerning the occurrence of progressive multifocal leukoencephalopathy in subjects receiving 
MMF (always in conjunction with other immunosuppressive therapy), subjects in SLS II will be 
monitored closely for evidence of any neurologic symptoms or findings suggestive of the early 
development of progressive multifocal leukoencephalopathy, such as apathy, confusion, 
cognitive deficiencies, ataxia or hemiparesis. 
 
2.3.2 Known Potential Benefits 
The two active drugs that will be employed to treat patients in this protocol, MMF and PFD, are both 
FDA approved treatments for medical conditions that are related to but not known to be the same 
as SSc-ILD. Neither is currently approved by the FDA for use in the treatment of SSc-ILD and 
therefore both are considered experimental in this respect. MMF is approved by the FDA for use as 
an immunosuppressant in solid organ transplantation and for the treatment of another type of 
autoimmune disease with end-organ dysfunction, Lupus nephritis. As presented in Section 2.1 on 
Background Information, the recent publication of primary outcome results from the SLS II study 
provides striking evidence that lung function, dyspnea and skin disease all improve over time in 
patients treated with MMF, which is in contrast to the known progression of disease that occurs 
without treatment (10,50-52), suggesting that it has a disease modifying effect and supporting its 
ongoing clinical evaluation as a potential treatment for SSc-ILD. PFD is currently approved for the 
treatment of IPF and as presented in Section 2.1 on  Background Information, SSc-ILD shares some 
of the important features of IPF, providing a strong rationale for its evaluation as a potential 
therapy. However, at this point in time, there is no direct clinical evidence regarding the efficacy of 
PFD for the treatment of SSc-ILD. 
 
 
3 STUDY OBJECTIVES AND PURPOSE 
 
The primary purpose for this Phase II clinical investigation is to determine the relative efficacy and safety 
of combining two drugs with different mechanisms of action, PFD and MMF, for the treatment of 
Scleroderma-related ILD.  
It is hypothesized that the rapid onset and anti-fibrotic activity of PFD, which have been observed in the 
treatment of IPF, will complement the delayed anti-inflammatory and immunosuppressive effects of 
MMF, to produce a significantly more rapid and/or greater improvement in lung function over time than 
occurs in patients receiving control therapy with MMFand Plac.  
The Primary Objective is therefore to assess the impact of combined PFD and MMF, as compared to 
treatment with MMF alone (i.e combined with Plac), on the overall course of lung function over an 18-
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A secondary objective is to demonstrate that combination therapy with PFD and MMF is well tolerated, 
in comparison to MMF alone, and not associated with limiting toxicity that impacts on the overall 
treatment effect. 
 
4 STUDY DESIGN AND ENDPOINTS 
 
4.1 
 
DESCRIPTION OF THE STUDY DESIGN 
 
The SLS III study is designed as a Phase II multi-center, double-blind, parallel group, randomized and 
placebo-controlled clinical trial addressing the treatment of patients with active and symptomatic SSc-
ILD. Enrollment will occur at 15 to 20 participating academic clinical centers within the United States. 
150 patients who are either treatment-naïve or only recently started on treatment (<6 mo of prior 
treatment with a potentially disease-modifying therapy) will be randomized in a 1:1 assignment to 
receive either oral MMF and Plac (acting as a control arm) or a combination of oral MMF and oral PFD 
(acting as an experimental arm), with both regimens administered for 18 months. The target dose for 
MMF will be 1,500 mg twice daily as tolerated, starting with 500 mg twice daily and proceding with a 4-
step titration at monthly intervals until a maximal tolerated dose or the target dose is achieved for each 
patient. The target dose for PFD will be 801 mg three times daily as tolerated, starting with 267 mg 
three-times daily and proceding with a 3-step titration at 2 week intervals until a maximal tolerated 
dose or the target dose is achieved for each patient. The length of therapy, 18 months, was established 
based on prior studies with immunosuppressive therapy alone, which demonstrated that 18 months 
represents the time required to achieve a peak treatment response. The primary outcomes will include 
physiologic measures of lung function, HRCT imaging measures of lung inflammatory and fibrotic 
changes, dyspnea, assessments of skin inflammation and thickening, and patient reported measures of 
symptoms and quality of life.  Tolerability and toxicity of the two treatments will also be assessed. 
 
4.2.1 Primary Endpoint 
The primary endpoint is the change from baseline, measured at 3-month intervals, in the mean 
forced vital capacity (represented as the percentage of the age-, height-, gender- and race-adjusted 
predicted value,  i.e. FVC-%) over the course of the 18-month double-blind treatment period.   
 
4.2.2 Secondary Endpoints 
4.2.2.1 The change from baseline to 18 months, measured at 3-month intervals, in single-breath 
diffusing capacity for carbon monoxide (DLCO), calculated as a percent of the age-, height-, 
gender-, race- and hemoglobin-adjusted predicted value (DLCOHb-%).  
4.2.2.2 The change from baseline to 18 months, measured at 3-month intervals, in the Modified 
Rodnan Skin Score (mRSS).  
4.2.2.3 The change from baseline to 18 months, measured at 3-month intervals, in dyspnea, as 
measured by the Baseline and Transition Dyspnea Index (BDI and TDI, respectively.)  
4.2.2.4 The change from baseline to 18 months, measured at 3-month or 6-month intervals, in 
Patient Reported Outcomes (PROs), which provide subjective measures of dyspnea and quality 
of life based on patient responses to standardized patient questionnaires which include: 
a) St. George Respiratory Questionnaire (SGRQ); 3 month intervals 


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b) Health assessment questionnaire modified for scleroderma (SHAQ); 6 month intervals 
c) Patient-reported outcomes measurement information system 29-item health profile 
(PROMIS-29 version 2.0); 6 month intervals 
4.2.2.5 The change from baseline to 18 months in quantitative HRCT measures of SSc-ILD which 
specifically include: 
a) Quantitative lung fibrosis score in the whole lung (QLF-WL).  
b) Quantitative lung fibrosis score in the lobe of maximal involvement (QLF-LM).  
c) Quantitative interstitial lung disease score in the whole lung (QILD-WL).  
d) Quantitative interstitial lung disease score in the lobe of maximal involvement (QILD-
LM). 
e) Total lung capacity at maximum inspiration (HRCT-TLC) 
4.2.2.6 Differences in the frequency distribution of individual patient responses when grouped into 
defined intervals of improvement or worsening (defined by the change in an outcome measure 
from baseline to 18 months) for the following outcome measures: 
a) Forced vital capacity (represented as the percentage of the age-, height-, gender- and 
race-adjusted predicted value,  i.e. FVC-%) 
b) Single-breath diffusing capacity for carbon monoxide (DLCO), calculated as a percent of 
the age, height, gender-, race- and hemoglobin-adjusted predicted value (DLCOHb-%).  
c) Modified Rodnan Skin Score (mRSS).  
d) Transitional Mahler Modified Dyspnea Index (TDI) 
4.2.2.7 The time (in months) required for each treatment arm to achieve a 3.0% or greater 
improvement from baseline in the FVC-% over the 18-month treatment period. 
4.2.2.8 A threshold analysis based on the percentage of subjects in each treatment arm achieving 
greater than a 5% improvement from baseline in FVC-% over the 18-month treatment period. 
4.2.2.9 Tolerability and toxicity of combined MMF and Plac vs MMF and PFD over the course of 18 
months. 
 
4.2.3 Other Important Endpoints 
4.2.3.1 Physician and Patient Global Assessments 
a) Physician global assessment of patient’s “overall health” in the past week on a Likert 
scale; 6 month intervals  
b) Physician transition questions comparing patient’s i) overall health and ii) lung 
involvement to that at the baseline visit; 6 month intervals 
c) Patient global assessment of “overall health” in the past week on a Likert scale; 6 
month intervals  
d) Patient transition questions comparing their i) overall health and ii) lung involvement to 
that at the baseline visit; 6 month intervals 
4.2.3.2 UCLA Scleroderma Clinical Trial Consortium GIT 2.0 (UCLA SCTC GIT 2.0); 6 month intervals 
4.2.3.3 Leicester Cough Questionnaire (LCQ); 6 month intervals 
 
 
 


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4.2.4 Exploratory Endpoints 
Exploratory endpoints will include the following: 
4.2.4.1 Identification of baseline features that predict treatment responsiveness, disease 
progression and the course of lung and skin disease over time.  
4.2.4.2 Identification of biomarkers that predict disease features, treatment responsiveness, 
disease progression and the course of lung and skin disease over time. 
4.2.4.3 Composite outcome measures that distinguish early and late treatment responses 
4.2.4.4  Performance of CRISS index at 6, 12 and 18-months 
 
5 STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
 
PARTICIPANT INCLUSION CRITERIA 
In order to be eligible for randomization as a study patient, an individual must meet all of the following 
inclusion criteria. Notes are included, as needed, to provide additional explanation and/or background 
rationale for selected criteria (see bullet points). Patients will provide consent prior to the screening and 
screening is included as part of the consent process. Note that the screening occurs in stages in order to 
limit unnecessary testing: 
Screening criteria that must be met prior to moving forward to HRCT imaging 
5.1.1 Age >18 yrs 
5.1.2   
Scleroderma as determined by the 2013 ACR/EULAR classification criteria. 
5.1.3   
Grade ≥2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index 
(Becomes short of breath with moderate or average tasks such as walking up a gradual hill, 
climbing less than three flights of stairs, or carrying a light load on the level.  
5.1.4   
FVC-% of ≤85% at screening. 
• 
NOTE: Inter-test variability for FVC-% can range up to 10% and therefore some 
participants with an FVC-% between 80-85% at screening might exceed an FVC-% of 85% 
when testing is repeated at the baseline. 
• 
NOTE: The acceptable reproducibility of the FVC-% at baseline will be governed by 
inclusion criteria #7 detailed in Section 5.1.7 below. 
5.1.5   
Onset of the first non-Raynaud manifestation of SSc within the prior 84 months. 
• 
This criteria is based on the natural history SSc-ILD which is known to be more 
progressive early after the onset of scleroderma and become less active over time.  
 
Screening HRCT imaging   
5.1.6   
Presence of any ground glass opacification (any GGO) on thoracic HRCT  
• 
This criteria defines a population with active and measurable parenchymal lung 
involvement. 
 
Final screening criteria fulfilled at Baseline Visit, but prior to randomization 
5.1.7    Repeat FVC-% at the baseline visit within 10% of the FVC-% value measured at screening. If 


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these criteria are not met, a repeat FVC-% may be obtained within 7 days and the subject 
may qualify for randomization if the repeat FVC-% agrees within 10% of the FVC-% obtained 
at screening. 
 
5.2 
 
PARTICIPANT EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study.  
The majority of exclusion criteria are assessed at screening, unless explicitly stated.  Notes are included, 
as needed, to provide additional explanation and/or background rationale for selected criteria (see 
bullet points).  
5.2.1 
Disease features supporting the primary diagnosis of another connective tissue disease such 
as rheumatoid arthritis, systemic lupus erythematosus or mixed connective tissue disease 
(Features consistent with a secondary Sjogren syndrome or scleroderma-associated 
myopathy will be allowed).  
5.2.2    FVC-% <45% at either screening or baseline. 
• 
to avoid severe, probably irreparable disease associated with higher morbidity 
5.2.3    FEV1/FVC ratio <0.65 at either screening or baseline. 
• 
to avoid concurrent and clinically-significant obstructive lung disease which can increase 
the risk for infection, need for corticosteroid therapy, and interferes with use of 
spirometry as outcome measure 
5.2.4    DLCOHb-% of <30% at screening or <25% at baseline. 
a)   All participants with a DLCOHb-% between 30 to 40% must have pulmonary artery 
pressures documented by either echocardiogram, right heart catheterization or 
magnetic resonance imaging in order to be considered for inclusion. 
• 
the risk for concurrent scleroderma-related pulmonary vascular disease is increased in 
patients with higher FVC/DLCO ratios, warranting additional testing before including 
such subjects in the study. 
• 
In order to account for normal test-to-test variability, subjects with an acceptable 
DLCOHb-% of between 30% to 40% at screening, with no evidence of clinically significant 
pulmonary hypertension, will remain eligible at their baseline measurement as long as 
the DLCOHb-% is >25% predicted.  
5.2.5    Diagnosis of clinically significant resting pulmonary hypertension or mild pulmonary 
hypertension requiring treatment with more than one oral medication as ascertained prior 
to study evaluation or as part of a standard of care clinical assessment performed outside of 
the study protocol. 
• 
to avoid concurrent scleroderma-related pulmonary vascular disease that could alter 
primary and secondary outcome measures in a manner independent of the effect of the 
investigational drugs. 
• 
The presence of mild pulmonary hypertension, identified as either an estimated right 
ventricular systolic pressure of </=40 mmHg on echocardiogram or mean systolic 
pulmonary artery pressure of </=30 mmhg on right heart catheterization is acceptable 
for inclusion in the study if there are no signs of right heart dysfunction and treatment 


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includes no more than one oral PAH medication. 
5.2.6    Evidence of uncontrolled congestive heart failure, unstable ischemic heart disease, history 
of complicated pulmonary embolism impacting on heart or lung function, or unstable 
cardiac arrhythmia requiring chronic anticoagulation. 
• 
to avoid undiagnosed scleroderma cardiomyopathy and unstable patients whose 
concurrent disease might impact on the measured study outcomes. 
5.2.7    Clinically significant abnormalities on HRCT not attributable to SSc   
• 
e.g., lung mass, cavitary lesion, airspace consolidation, mediastinal adenopathy, etc. 
5.2.8    Hematologic abnormality at screening including:  
a)  Leukopenia (white blood cells [WBC] <4.0x103/µl)  
b)  Thrombocytopenia (platelet count <120.0x103/µl) 
c)  Clinically significant anemia [Hemoglobin (Hgb) <10.0 g/dl] 
 
Participants with an identified and correctable etiology may be eligible if repeat testing 
within the maximal 90-day screening period meets all criteria. 
• 
to avoid persistent bone marrow abnormalities or bleeding that would complicate 
detection and treatment of a primary side effect of MMF therapy. 
5.2.9    A diagnosis of chronic liver disease or abnormal baseline liver function test (LFTs) or total 
bilirubin that are >2.0 x upper normal limit. 
5.2.10 
Serum creatinine >2.0mg/dl 
5.2.11  History of recurrent aspiration, uncontrolled heartburn, or gastroesophageal reflux disease 
with a reflux scale score of >1.00 as determined by a UCLA Scleroderma Clinical Trial 
Consortium Gastrointestinal Scale (UCLA SCTC GIT), Version 2.0.  
Participants with uncontrolled heartburn or GERD that is amenable to medical management 
may be eligible if repeat testing within the maximal 90-day screening period meets this 
criteria. 
• 
both medications can exhibit significant GI toxicity and it would be inappropriate to 
include patients already exhibiting clinically significant and uncontrolled GI symptoms. 
5.2.12  Known achalasia, esophageal stricture or esophageal dysfunction sufficient to limit the 
ability to swallow medication.  
• 
this trial requires that patients take a large number of capsules at frequent intervals 
throughout the day and these conditions represent significant obstacles to compliance. 
5.2.13  Pregnancy (documented by serum pregnancy test) and/or breast feeding 
5.2.14  If of child bearing potential (a female participant < 55 years of age who has not been 
postmenopausal for ≥ 5 years or who has not had a bilataeral salpingectomy, hysterectomy 
and/or oophorectomy), failure to employ two reliable means of contraception which may 
include   surgical sterilization, barrier methods, spermicidals, intrauterine devices, and/or 
hormonal contraception, unless the participant chooses abstinence (to avoid heterosexual 
intercourse completely).  If a subject chooses abstinence, then a second reliable means of 
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5.2.15  Prior use of potential disease modifying antirheumatic drugs (DMARDs) according to the 
following exposure rules: 
a)  Use of oral cyclophosphamide (CYC), MMF, azathioprine or other oral or short half-life 
DMARDs (as detailed in Section 7.5.1a) for more than 6 months in the past year, as 
determined at the time of the initial screening visit. 
b)  Treatment with more than three intravenous doses of CYC, more than one course of 
Rituximab or other intravenous or injectable DMARDs (as detailed in Section 7.5.1b) in 
the past year. 
c) ) More distant h/o treatment with a DMARD is allowed as long as the patient has a new 
diagnosis/new episode of active SSc-ILD since stopping that treatment and meets the 
criteria noted in 15a or 15b. 
• 
these criteria have been adopted as the cut-off for enrolling treatment naïve 
patients as we are particularly focused on the contribution of early treatment on the 
study outcomes. 
5.2.16  Use of CYC, MMF, azathioprine, Rituximab or other DMARD (as detailed in Section 7.5.1a&b)  
in the 30 days prior to the baseline visit unless the patient is on MMF and the responsible 
physician indicates that continued use is in the best clinical interest of the patient.  
• 
the study focuses on treatment-naïve patients (as defined above) and a wash-out period 
from pre-study drugs with potential DMARD activity will help to clarify the contribution 
of early exposure to PFD on the treatment outcome. 
• 
subjects who meet all other criteria, but have been on limited therapy with MMF and 
decide to participate, will be assessed by the responsible study physician to determine 
whether it is in the patient’s best clinical interest to stop MMF and complete a 30-day 
washout period or to continue on pre-study drug therapy until the time of 
randomization. 
5.2.17  Active infection (lung, ulcers or elsewhere) whose management would be compromised by 
immunosuppression. 
5.2.18  Other serious concomitant medical illness (e.g., active malignancy within the past 5 years 
other than surgically-removed local skin cancer such as a basal cell carcinoma), chronic 
debilitating illness (other than SSc), unreliability or drug abuse that might compromise the 
patient’s participation in the trial. 
5.2.19  Current use, or use within the 30 days prior to their baseline visit, of prednisone (or 
equivalent) in doses >10 mg/day. 
• 
to avoid increased drug toxicity due to combined immunosuppression. 
• 
subjects who meet all other criteria, but have been on higher doses of prednisone, will 
be allowed to decrease their prednisone (or equivalent) dose and proceed to the 
baseline visit at the completion of the 30-day washout. 
5.2.20  Smoking of cigars, pipes, or cigarettes during the past 6 months.  
• 
to avoid the increased risk of pulmonary complications and variation in lung function that 
would be independent from the primary study objectives. 
5.2.21  Use of contraindicated medications, including medications with putative disease-modifying 
properties that do not meet the exposure limits described in Exclusion Criteria #15 and #16, 
moderate or strong inhibitors of cytochrome P450 (CYP) isozyme 1A2 (CYP1A2) (note 


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ciprofloxacin allowed up to a dose of 500 mg twice daily), and moderate inducers of CYP1A2 
(such as tobacco smoke or phenytoin). See Section 7.5 for complete list. 
 
A study eligibility form will be completed at the end of screening and baseline (i.e., prior to 
randomization) to assure that all criteria have been met before a subject is eligible for randomization. 
 
5.3 
 
DISCONTINUING DRUG TREATMENT OR COMPLETE WITHDRAWAL FROM THE 
STUDY 
Patients participating in this study may discontinue active drug treatment but continue with follow-up. 
They may also completely withdraw from the study (i.e. drop out; end their participation entirely). 
 
5.3.1  Reasons for Discontinuing Drug Treatment or Withdrawing from Study 
Patients participating in this study may discontinue active drug treatment or completely withdraw 
from the study (or their participation terminated) for the following anticipated reasons.  
5.3.1.1 Ongoing participation in this research study is voluntary and patients may discontinue active 
drug treatment or completely withdraw from the study at any time without an identified 
cause or the need for explanation.  
5.3.1.2 Patients may also discontinue or be removed from active drug treatment due toadverse 
events (AEs), laboratory abnormality, or other medical condition or situation such that 
continued use of one or both of the study drugs is not considered to be in their best 
interest. 
5.3.1.3 Patients who become pregnant and/or start breast feeding; which are  absolute 
contraindications to continued therapy,  will be required to stop active drug therapy. 
5.3.1.4 Patients who meet the pre-defined criteria for a “Treatment Failure” (see Section 5.3.2) will 
be withdrawn from the active drug treatment . 
 
5.3.2 Definition and Handling of Treatment Failures 
Subjects who, after >3 months of study, demonstrate an absolute fall in FVC-% of ≥ 15% from their 
baseline determination will be classified as “treatment failures” (e.g., an initial FVC-% of 75% would 
need to drop to ≤60% to be classified as a treatment failure). A treatment failure will also be 
defined, after >3 months of study, when the FVC-% falls below a lower limit of <35%, regardless of 
the absolute change from baseline (e.g., an initial FVC-% between 45% and 49% that declines to 
≤35%). To meet these definitions, subjects must have two FVC-% measurements greater than 15 
days apart, both showing an absolute decrement of  ≥15% from baseline and/or a FVC-% of ≤ 35%. 
Subjects with treatment failures will be withdrawn from active drug treatment (both PFD/Plac and 
MMF). The clinical management of treatment failures will be at the discretion of the patient and 
their treating physician. The study blind will not be broken unless the treating physician is convinced 
that unblinding is required in order to appropriately treat the patient and their request is reviewed 
and agreed to by the Executive Committee. Subjects who fail treatment will be encouraged to return 
for key outcome determinations at 12 and 18 months, at which time any medication prescribed by 
their treating physician since leaving the study will be recorded in addition to other required 
assessments for the 12 and 18-month visits. 
 


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5.3.3 Handling of Premature Participant Withdrawals 
Should a participant prematurely discontinue  all active drug treatment for any reason, he/she will 
be asked to return for key outcome determinations at 12 and 18 months. Their clinical management 
during the intervals between these visits will be at the discretion of the patient and their treating 
physician. At the 12 and 18 month visits, any medication prescribed by their treating physician since 
discontinuing study drug treatment will be recorded in addition to other required assessments for 
the 12 and 18-month visits. The participant will also be asked to participate in an exit visit, either by 
phone or in person, to document the reason for withdrawal and the status of the participant at the 
time of the withdrawal. Should the participant die, the cause of death will be determined and 
recorded if possible. This additional data will be utilized in the statistical analysis of the primary and 
secondary study outcomes as defined by the statistical plan.  
If only PFD/Plac is prematurely discontinued, and the participant continues to take MMF according 
to the protocol, then they will continue their participation in all study visits according to the normal 
study protocol. 
If MMF is prematurely discontinued, the participant must stop the PFD/Plac study medication as 
well and will be asked to return for key outcome determinations at 12 and 18 months. Their clinical 
management during the intervals between these visits will be at the discretion of the patient and 
their treating physician. At the 12 and 18 month visits, any medication prescribed by their treating 
physician since discontinuing study drug treatment will be recorded in addition to other required 
assessments for the 12 and 18-month visits. 
Participants who completely withdraw from the study (drop out; end their participation entirely) will 
be asked to participate in an exit visit, either by phone or in person, to document the reason for 
withdrawal and the status of the participant at the time of the withdrawal. Should the participant 
die, the cause of death will be determined and recorded if possible.  
 
5.4 
 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
The investigators and/or sponsor reserve the right to terminate the study at any time. If this becomes 
necessary, appropriate procedures for continuing long-term follow-up and assuring the adequate 
treatment and safety of the participating subjects will be arranged after review and approval by the 
study sponsors, Institutional Review Boards and the FDA. 
The DSMB will also provide external oversight concerning the safety and scientific integrity of the study 
for the duration of the clinical trial.  The DSMB will review the progress of the study toward meeting 
enrollment goals, adverse and serious adverse event profiles, and study outcome measures at regular 
intervals to occur at least twice annually.  The DSMB may recommend at any time that the study should 
be terminated due to drug toxicity, patient safety, poor compliance and/or futility considerations. In 
such cases, their recommendations will be reviewed and discussed with the Executive Committee, which 
will make a final determination.   
 
 
 


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6 STUDY AGENT 
 
6.1 
 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 Source and Acquisition of Study Drugs 
The Investigational Drug Section, Department of Pharmaceutical Services, University of California 
Los Angeles (UCLA) Ronald Reagan Medical Center will serve as the Pharmacy Core, providing 
centralized drug procurement, accountability and distribution for all study drugs (MMF, PFD) and 
the Plac. 
6.1.1.3 Mycophenolate Mofetil (MMF) will be purchased from a generic vendor, Teva 
Pharmaceuticals, Inc., or other generic vendor authorized to market by the FDA 
In the event that the commercial drug supply from Teva is insufficient to meet the needs of 
the study at any point in time, MMF will be acquired from an alternative manufacturer 
approved by the FDA to produce and sell equivalent 250 mg capsules. Participating study 
sites and impacted patients will be advised of any change in appearance of the capsules, 
bottles and labeling without other required change to the Protocol. 
6.1.1.2 Pirfenidone (PFD) will be shipped directly by the manufacturer, Genentech, Inc., to the 
UCLA Pharmacy Core. 
6.1.1.3 Placebo (Plac), formulated to match PFD and manufactured by Genentech, Inc., will be 
shipped directly to the UCLA Pharmacy Core. 
 
6.1.2 Study Agent Formulation, Appearance, Packaging and Labeling 
All study agents used in this protocol will be provided in sealed and clearly identified bottles from 
their respective manufacturers and stored by the UCLA Pharmacy Core for distribution to the 
participating clinical site research pharmacies without modification or relabeling.  
On-site, at the Clinical Site Research Pharmacy, patient specific labeling will be added to the existing 
MMF bottles when supplied as 500 capsule bottles from the manufacturer. Alternatively, when 
supplied as 100 capsule bottles, bottles derived from the same lot will be transferred at the time of 
dispensing into a single generic bottle to produce bottles of 500 capsule each. In such cases, labels 
containing both drug information and patient specific identification and instructions will be applied. 
Use of existing bottles is not a concern for this study drug as it will be provided in an open-label 
format to study participants. However, in order to maintain the blind and avoid disclosure due to 
the manufacturer labeling, capsules from individual bottles of PFD and Plac must be transferred at 
the time of prescription into new generic bottles and fresh labels attached by the site pharmacy. In 
addition to patient specific labeling information, the information from the study label will be 
replicated except that the contents will indicate capsules that contain either “267 mg of PFD or 
matching Plac”. 
6.1.2.1 Mycophenolate Mofetil (MMF)  
Formulation and strength:  
Size 1 hard opaque gelatin capsules containing 250 mg 
Appearance:  
 Opaque capsules, Blue and Orange  
 (Teva example, coloring will vary by manufacturer) 
Packaging:  
 Supplied in Bottles of either 100 capsules (NDC 0093-7334-01) or 500 
capsules (NDC 0093-7334-05) with barcodes and labels  


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 (Teva example, labeling will vary by manufacturer)
 
 
 
6.1.2.2 Pirfenidone (PFD)  
Formulation and strength:  
Size 1 hard opaque gelatin capsules containing 267 mg  
Appearance:   
Opaque, White 
Packaging:   
Labeled for investigational use only, marked as Pirfenidone on bottle 
Supplied in Bottles of 270 capsues with labeling as follows: 
 
6.1.2.3 Placebo (Plac)  
Formulation and strength:  Size 1 hard opaque gelatin capsules containing 267 mg  
Appearance:  
Opaque, White 
Packaging:   
Labeled for investigational use only, marked as Plac on bottle 
Supplied in Bottles of 270 capsues with labeling as follows: 


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6.1.3 Product Storage & Stability 
Prefilled and sealed bottles will be shipped from the manufacturers with labeled expiration dates; 
beyond which they will not be used in the study. MMF capsules will be stored at room temperature; 
defined as between 68°F (20°C) to 77°F ( 25°C). PFD and Plac capsules will also be stored at room 
temperature; defined in this case as between 68°F (20°C) to 86°F ( 30°C). Brief excursions in 
temperature allotted for shipping and handling. 
 
6.1.4 Route, Administration, Titration Schedule and Target Dose 
6.1.4.1 Drug:   
MMF: 250 mg hard gelatin capsules 
 Route: 
Oral, taken without food and at least one hour prior to taking a PPI.  
  
 
Titration Schedule and Target Dose (as tolerated):  
Dose 
# of Capsules 
Schedule 
Dose Duration 
500 mg 
2 
Twice daily 
4 weeks 
1000 mg 
4 
Twice daily 
4 weeks 
1250 mg 
5 
Twice daily 
4 weeks 
1500 mg 
6 
Twice daily 
Duration of study 
Randomized patients who were on pre-study treatment with MMF, and for whom it was 
determined that they should continue on treatment without a 30-day washout period, will 
be evaluated by the responsible study physician and start their MMF study drug titration at 
one of the following doses: 
a)  if their pre-study dose matches one of the levels indicated above and they are tolerating 
the dose, they may be started at the same dose level. This dose level should be 
administered for the initial 4 weeks of the study and then titrated as indicated by the 
table above. 
b)  if their pre-study dose does not match one of the levels indicated above, they may start 
at the level that is closest to but does not exceed their pre-study dose. They will 
continue on that dose for the initial 4 weeks of the study and then have drug titrated as 
indicated by the table above. 
c)  at the discretion of the responsible study physician, the study patient may be started at 
a dose that is lower than their pre-study dosing if it is determined to be in the best 


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clinical interest of the patient. They will continue on that dose for the initial 4 weeks of 
the study and then have drug titrated as indicated by the table above. 
 
6.1.4.2 Drug:   
PFD: 267 mg hard gelatin capsules 
 Route: 
Oral, taken with food  
  
 
Titration Schedule and Target Dose (as tolerated):  
Dose 
# of Capsules 
Schedule 
Dose Duration 
267 mg 
1 
Three times daily 
2 weeks 
534 mg 
2 
Three times daily 
2 weeks 
801 mg 
3 
Three times daily 
Duration of study 
 
6.1.4.3 Drug:   
Plac: 267 mg hard gelatin capsules 
 Route: 
Oral, taken with meals  
  
Titration Schedule and Target Dose (as tolerated):  
Dose 
# of Capsules 
Schedule 
Dose Duration 
267 mg 
1 
Three times daily 
2 weeks 
534 mg 
2 
Three times daily 
2 weeks 
801 mg 
3 
Three times daily 
Duration of study 
 
6.1.5 Pre-specified Dose Adjustment & Modifications 
The toxicity profiles for MMF and PFD are well established as outlined in Section 2.3 and drug 
discontinuation and/or dose modification should be managed in a manner consistent with the 
following criteria in order to provide a nearly uniform response to pre-defined toxicity at all centers. 
However, in clinical situations that fall outside of these parameters and if warranted based on good 
clinical practice, a site investigator may independently modify drug dosing as needed to assure 
patient safety. If such a change is required, the reasons for the deviation are to be documented and 
the Executive Committee notified within 3 days. Medications that are contraindicated while on 
treatment with the study drugs are detailed separately in Section 7.5. 
In the event that one study drug is permanently discontinued due to tolerability, adverse event or 
other medical consideration, then continued use of the remaining study drug will be according to 
the following pre-specified management:  
• 
If only PFD/Plac is permanently discontinued, the participant may continue to take MMF 
according to the protocol and continue their participation in all study visits according to the 
normal protocol-defined schedule of events.   
• 
If MMF is prematurely discontinued, the participant must stop the PFD/Plac study 
medication as well and will be asked to return for key outcome determinations at 12 and 18 
months as detailed in Section 5.3.3 ( Handling of Premature Participant Withdrawals). 
6.1.5.1 Pre-specified dose adjustments for MMF.  
The following abnormalities and laboratory test monitoring results require study drug 
adjustment, either temporary (until normalization) or permanent, as indicated by the nature 
of the event, its severity and/or course of resolution upon discontinuation of therapy. 
a) Allergic reaction associated with the administration of MMF. 


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Dose Management: Study drug will be stopped and subject withdrawn from study. 
b) Evidence of clinically significant Bone Marrow Suppression including any one or more of 
the following 
- WBC <2.5x103/µl 
- Absolute neutrophil count <1.0x103/µl 
- Platelet count <100.0x103/µl 
- Hemoglobin < 10.0 gm/dl or a drop in hemoglobin to < 9.0 gm/dl if the baseline 
hemoglobin was < 11.0 gm/dl 
Dose Management: Management as follows: 
• 
Hold study drug until there is a stabilization of the hematologic abnormality at a 
value above the toxicity threshold levels indicated above. In addition, if other 
causes of noted reductions are identified (e.g., gastrointestinal bleeding), they 
should be treated and stabilized before restarting on study drug. 
• 
Once threshold levels are exceeded (an indication of recovery), MMF will be 
reintroduced at a daily dose of 1000 mg (500 mg twice daily doses) and inceased 
by 500 mg (one 250 mg capsule for each of the twice daily doses) every two 
weeks.  At the discretion of the clinical site investigator, after taking into 
account whether the study drug was likely or probably related to the adverse 
event, the final maintenance dose may be either the last regular dose of MMF 
taken by the patient or one capsule per-dose less (500 mg/day less).  
• 
In the event of repeat toxicity, the same cycle should be repeated except with 
the intention of achieving a maintenance dose equal to 1000 mg/day less for 
MMF.  
c) Documentation of gastrointestinal ulcer, bleeding or abdominal emergency.  
Dose Management: Management as follows: 
• 
Hold study drug until there is a clinically stable resolution of the problem. In 
addition, if other causes of noted conditions are identified (e.g., polyps, 
diverticulitis, untreated peptic ulcer disease), they should be treated and 
stabilized before restarting on study drug. 
• 
Once a stable recovery occurs, as judged by the clinical site investigator, MMF 
will be reintroduced at a daily dose of 1000 mg (500 mg twice daily doses) and 
inceased by 500 mg (one 250 mg capsule for each of the twice daily doses) 
every two weeks.  At the discretion of the clinical site investigator, after taking 
into account whether the study drug was likely or probably related to the 
adverse event, the final maintenance dose may be either the last regular dose of 
MMF taken by the patient or one capsule per-dose less (500 mg/day less).  
• 
In the event of repeat toxicity, the same cycle should be repeated except with 
the intention of achieving a maintenance dose equal to 1000 mg/day less for 
MMF.  
d) Pregnancy or initiation of breastfeeding. 
Dose Management: Study drug will be permanently discontinued and subject withdrawn 
from study. 
e) Serum creatinine > 2.0 mg/dl or estimated GFR to < 40 ml/min/1.73 m2 (corrected) in 
the absence of other etiology. 


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Dose Management: Hold study drug until there is a clinically stable resolution of the 
problem. In addition, if other causes of noted conditions are identified (e.g., 
medications, dehydration, etc.), they should be treated and stabilized before restarting 
on study drug. If there is no improvement, the study drug will be stopped and subject 
withdrawn from study. 
f) Ongoing infection whose management would be significantly compromised by 
continued drug-associated immunosuppression or any hospitalization, surgery or 
infection requiring antibiotic therapy where the immununosuppressive effects of MMF 
are determined by the clinical site investigator to likely complicate the patient’s 
response to therapy. 
Dose Management: Hold study drug until the potential interaction with the medical 
condition in question has resolved. Once the patient is stable, the study drug can be 
restarted without dose modification. 
g) Development of a proven malignancy other than basal cell cancer of the skin or cervical 
carcinoma in situ removed entirely by excisional biopsy or surgical resection. 
Dose Management: Study drug will be permanently discontinued and subject withdrawn 
from study. 
h) Any adverse event felt by the investigator to be possibly or probably related to the 
administration of MMF and of a clinical significance sufficient to warrant holding or 
discontinuing drug.  
Dose Management: Management as follows: 
• 
Hold study drug until there is a clinically stable resolution of the problem. In 
addition, if other causes of noted conditions are identified, they should be 
treated and stabilized before restarting on study drug. 
• 
Once a stable recovery occurs, as judged by the clinical site investigator, MMF 
will be reintroduced at a daily dose of 1000 mg (500 mg twice daily doses) and 
inceased by 500 mg (one 250 mg capsule for each of the twice daily doses) 
every two weeks.  At the discretion of the clinical site investigator, after taking 
into account whether the study drug was likely or probably related to the 
adverse event, the final maintenance dose may be either the last regular dose of 
MMF taken by the patient or one capsule per-dose less (500 mg/day less).  
• 
In the event of repeat toxicity, the same cycle should be repeated except with 
the intention of achieving a maintenance dose equal to 1000 mg/day less for 
MMF.  
• 
Alternatively, for less severe or dangerous adverse events (e.g., dyspepsia) not 
responding to concomitant medications: the study drugs may be discontinued at 
the discretion of the clinical site investigator until the adverse event disappears. 
At that point the subject can be restarted at one-half of the original dose. The 
subject can return to the full dose of MMF after 2 weeks or 500 mg less (one 
capsule less for each of the twice daily doses) as clinically indicated. All such 
discretionary plans for adjusting study drug dosing should be approved within 3 
days of initiation by the Executive Committee.  
i) 
Unresolved toxicity or inability to tolerate therapy with MMF for >60 days.  
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from the treatment phase of the study. 
 
6.1.5.2 Pre-specified dose adjustments for PFD/Plac.  
The following abnormalities and laboratory test monitoring results require study drug 
adjustment, either temporary (until normalization) or permanent, as indicated by the nature 
of the event, its severity and/or course of resolution upon discontinuation of therapy. 
a) For liver enzyme elevations in a patient who exhibits >2 but <3x the upper limit of 
normal (ULN) for ALT and/or AST without clinical symptoms or hyperbilirubinemia after 
starting PFD/Plac therapy.  
Dose Management: Management as follows: 
• Any confounding medications that might increase liver function tests should be 
discontinued and any other potential causes identified and treated. 
• Liver function tests should be performed at 7-14 day intervals to monitor. 
• 
Continue the current dose of study drug and then choose one of the following 
two managments based on the follow-up liver function test results: 
i. 
If liver function tests worsen to >3X ULN, then follow recommendations 
as noted in b), c) or d) below. 
ii. 
If liver function tests are stable or show improvement (or continued 
improvement) on repeat testing in 7-14 days, then the study drug 
should be continued at the current dose.  
b) For liver enzyme elevations in a patient who exhibits >3 but ≤5 × the ULN for ALT and/or 
AST without clinical symptoms or hyperbilirubinemia after starting PFD/Plac therapy.  
Dose Management: Management as follows: 
• 
Any confounding medications that might increase liver function tests should be 
discontinued and any other potential causes identified and treated. 
• 
Liver function tests should be performed at 7-14 day intervals to monitor as 
needed based on resulting laboratory and clinical findings. 
• 
Choose one of the following two managments based on the results of repeat 
liver function testing: 
iii. 
If liver function tests worsen (but still do not exceed 5 x ULN) on repeat 
testing in 7-14 days despite addressing any confounding medications or 
causes, then the study drug should be held until liver function tests have 
decreased to <2X normal.  PFD/Plac should then be re-started at one 
capsule three times daily, re-titrated using the original study titration 
protocol (see Section 6.1.4.3) and increased up to the full dosage as 
tolerated. 
iv. 
If liver function tests are stable or show improvement (or continued 
improvement) on repeat testing in 7-14 days, then the study drug may 
be handled using one of two options at the discretion of the clinical site 
investigator: 
- continue at the current dosage without interruption and continue to 
monitor at 7-14 day intervals. 
- reduce the PFD/Plac dose by 1 capsule for each of the three times 
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c) For liver enzyme elevations in a patient who exhibits >3 but ≤5 × ULN for ALT and/or AST 
that is accompanied by clinical symptoms or hyperbilirubinemia after starting PFD/Plac 
therapy.  
Dose Management: Study drug will be permanently discontinued and subject withdrawn 
from study. 
d) For liver enzyme elevations in a patient who exhibits >5 × ULN for ALT and/or AST after 
starting PFD/Plac therapy.  
Dose Management: Study drug will be permanently discontinued and subject withdrawn 
from study. 
e) For gastrointestinal symptoms that are of sufficient clinical importance to warrant drug 
dose adjustment (typically involving nausea, diarrhea, vomiting, and dyspepsia), the 
patient should take the following steps, if not already in place and clinically indicated, 
prior to considering dose management: 
• 
Take the study medication with food. 
• 
Spread the dose throughout the meal rather than taking all capsules at once.  
• 
Add appropriate pharmacologic therapy to control acid and dysmotility.  
Dose Management:. 
• 
Reduce PFD/Plac dose by 1 capsule for each of the three times daily doses and if 
symptoms improve/resolve, can increase back to the original dosing after 2 
weeks as tolerated. If the higher dose is still not tolerated, then 1 capsule less 
for each of the three times daily doses can be continued. 
• 
Reduce PFD/Plac dose by 1 capsule for each of the three times daily doses and if 
symptoms do not improve, the study drug should be held until the potential 
interaction with the medical condition in question has resolved. Once the 
patient is stable, the study drug can be re-started and titrated according to the 
original schedule as tolerated. 
f) For photosensitivity skin reactions or rash that do not respond to UVA/UVB sunscreen, 
sun avoidance, and/or the use of over the counter topical corticosteroid creams, and are 
of sufficient clinical importance to warrant drug dose adjustment.  
Management:. 
• 
Reduce PFD/Plac dose by 1 capsule for each of the three times daily doses and if 
symptoms improve/resolve, can increase back to the original dosing after 2 
weeks as tolerated. If the higher dose is still not tolerated, then 1 capsule less 
for each of the three times daily doses can be continued.  
• 
Reduce PFD/Plac dose by 1 capsule for each of the three times daily doses and if 
symptoms do not improve, the study drug should be held until the potential 
interaction with the medical condition in question has resolved. Once the 
patient is stable, the study drug can be re-started and titrated according to the 
original schedule as tolerated. 
g) An infection whose management requires the use for Ciprofloxacin at a dose of 750 mg 
twice daily (or other fluoroquinolone at high dose) for 2 weeks or less will require a dose 
adjustment for PFD/Plac. 
• 
During the course of antibiotic treatment, the daily dose of PFD/Plac should be 
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(patients on 3 capsules should reduce to 2, while patients on 2 capsules should 
reduce to 1). 
h) Any adverse event felt by the investigator to be possibly or probably related to the 
administration of PFD/Plac and of a clinical significance sufficient to warrant adjusting or 
discontinuing drug.  
Dose Management: Management as follows: 
• 
Reduce PFD/Plac dose by 1 capsue for each of the three times daily doses and if 
symptoms improve/resolve, can increase back to the original dosing after 2 
weeks as tolerated. If the higher dose is still not tolerated, then 1 capsule less 
for each of the three times daily doses can be continued as the maximally 
tolerated treatment dose. 
• 
Alternatively, at the discretion of the site investigator, the study drugs may be 
held at the discretion of the clinical investigator until the adverse event 
disappears. PFD/Plac should then be re-started and using the standard titration 
protocol increased to the full dosage as tolerated. 
i) 
Unresolved toxicity or inability to tolerate therapy with PFD/Plac for >60 days.  
Dose Management: Study drug will be permanently discontinued and subject withdrawn 
from the treatment phase of the study. 
 
6.1.6 Duration of Therapy 
The intended duration of therapy for all study drugs is 18 months. 
 
6.1.7 Tracking of Dose and Drug Compliance 
The protocol proposes several challenges to effective drug administration due to the combination of 
two therapies administered according to different schedules, with different titration protocols, and 
with multiple capsules required for each dose. Compliance is further challenged by differences in 
whether the drugs are taken with or without food.   
As a result of these challenges, specific attention will be focused on the use of study aides to 
promote the correct timing, amount and administration of the study drugs. The following 
procedures will be used to promote patient compliance and allow drug compliance monitoring. 
6.1.7.1 Patient aides to promote compliance: 
a) Wallet-size Study Drug Identification Cards will be prepared at each study visit that describe 
the current dose and schedule of each drug to be taken during the coming study interval 
until the next scheduled visit. 
b) Study Drug Administration Calendars with daily check-boxes will be generated for patients 
at each study visit to map out and record each dose of each study drug when taken. 
c) “One-Week Drug Dispensers” will be provided to the patients and they will be taught how to 
fill them at each visit, and at home on a weekly basis, so that medications are easily and 
reliably dispensed without having to count out capsules and remember each dose. Two 
dispensers will be provided: a) a twice daily dispenser for MMF and b) a three-times daily 
dispenser for PFD/Plac. 
d)  An SLS III Study Bag will be provided to subjects and they will be instructed to put all study 
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calendars, etc.) and carry it with them to/from every clinic visit. 
6.1.7.2 Study approaches promoting the monitoring of drug compliance:  
a) Individual drug inventory records will be kept for each patient, recording number of bottles 
and capsules dispense and the number returned at the next visit. 
b) Mandatory pill/capsule counts of unused medication will be required at each visit and 
reconciled with the patients drug usage calendar. 
 
6.2 
 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
 
6.2.1 Responsibilities of the Central Pharmacy Core 
The UCLA Pharmacy Core will be responsible for maintaining a central log of all drug purchased and 
received, that in storage, and that distributed to every participating clinical site. The Pharmacy Core 
will be responsible for reordering and restocking of drug inventory and for timely distribution to all 
participating sites to assure that study needs never lapse. They will also be responsible for tracking 
lot expiration and replacement.  
 
6.2.2 Responsibilities of the Clinical Site Pharmacy 
The dispensing pharmacy at each site will maintain an independent drug accountability log for all 
shipments from the UCLA Pharmacy Core that will act as an automatic drug reconciliation control for 
the Core Pharmacy. In addition, logs will be maintained to track each bottle dispensed, the date, 
number of capsules and study recipient.  
 
6.2.3 Site Investigator Responsibility 
The site team will maintain a drug accountability log for each study patient to document subject 
number, visit number, date medication dispensed, number of bottles and bottle ID, number of 
capsules dispensed at each visit and the number counted as remaining at the subsequent visit. All 
used bottles will be returned and stored on site until an inventory control is carried out by the study 
monitor.  
 
6.2.4 Monitoring & Compliance Oversight by the Data Coordinating Center 
The Data Coordinating Center will utilize an online recording and reconcilliation system to track 
these three inventory sources and acurately track and verify the status of all study drugs. Errors and 
discrepencies between the different reporting sources will be reconciled as part of the individual site 
monitoring process carried out by the DCC. Compliance will be calculated for each visit and for each 
subject from the information supplied in this manner. 
 
7 STUDY PROCEDURES AND SCHEDULE 
 
7.1 
 
STUDY PROCEDURES/EVALUATIONS 
In the event of an emergency that disrupts patient or institutional access and usual study care, such as 
an unexpected disaster or pandemic, refer to Protocol Section 17.0 (EMERGENCY DISASTER/ PANDEMIC 
MANAGEMENT PLAN) for allowable adjustments to the study procedures and schedule that may be 
invoked as dictated by the nature of the emergency. 


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7.1.1 Study Specific Procedures 
7.1.1.1 Spirometry. Spirometry will be performed under the direction of the pulmonology 
investigator at each site and carried out by either certified pulmonary function technologists 
(National Board of Respiratory Care) or experienced staff that meet American Thoracic 
Society (ATS) recommendations (15). All spirometry equipment and procedures will conform 
to the most recently published standards of the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) Task Force (34,41). Forced expiratory maneuvers will be 
performed at least in triplicate with the minimal requirement that three maneuvers are 
“acceptable” and that two of these maneuvers meet end-of-test and repeatability criteria 
for FVC and Forced Expiratory Volume in the first second (FEV1). Printouts of all data and 
curves will be sent to the Pulmonary Function Core at UCLA for central quality control 
monitoring with individual optimization and re-training for study specific requirements at 
each site if required to assure standardized and reproducible measurements. Spirometry 
results will be expressed both as measured values and as a percentage of gender-specific 
predicted values using the regression equations of Hankinson (17) for spirometry. For 
spirometry, the race-specific regression equations of Hankinson (17) will be used for African-
Americans and Mexican-Americans and normal referenced values multiplied by 0.88 for 
Asians (17a). Spirometry measurements will be performed at entry (screening), just prior to 
initiation of study medication (baseline) and every 3 months for the entire 18 months of the 
study.   
In the event that a participant has already completed spirometry testing within 30 days of 
Screening Visit #1 and the testing meets all eligibility criteria, it may be used in lieu of 
repeating  the spirometry measurements at Screening Visit #1.  In order to be considered 
eligible, the testing must have been performed at the same facility that will be used during 
the study, the full spirometry data set must be available for review and it must pass a 
Quality Assurance review by the Pulmonary Function Core at UCLA.   
7.1.1.2 Single-breath diffusing capacity for carbon monoxide (DLCO) and DLCO adjusted for 
hemoglobin (DLCOHb). DLCO measurements will be performed in accordance with 
published ATS/ERS guidelines using equipment and testing techniques that meet ATS/ERS 
requirements (33).  At least 2 acceptable tests that meet repeatability criteria (33) will be 
performed and the mean DLCO value (uncorrected for Hgb) from acceptable measurements 
reported. Other reported values will include the inspired vital capacity, which must be 
within 10% of the expiratory Vital Capacity, and the alveolar volume. DLCO will then be 
corrected for hemoglobin that will be measured at the corresponding study visit as part of 
the blood monitoring and reported as DLCOHb. DLCO and DLCOHb will be expressed both as 
measured values and as a percentage of gender-specific predicted values (DLCO-% and 
DLCOHb-%) using the regression equations of Neas (37). The race-specific equations of Neas 
et al. (53) will also be used for calculation of the predicted values of DLCO for African-
Americans. DLCO measurements will be performed at entry (screening), just prior to 
initiation of study medication (baseline) and every 3 months for the entire 18 months of the 
study.   
In the event that a participant has already completed DLCO testing within 30 days of the 
Screening Visit #1 and the testing meets all eligibility criteria, it may be used in lieu of 
repeating  the DLCO measurements at Screening Visit #1.  In order to be considered eligible, 
the testing must have been performed at the same facility that will be used during the 


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study, the full DLCO data set must be available for review and it must pass a Quality 
Assurance review by the Pulmonary Function Core at UCLA.   
7.1.1.3 Thoracic HRCT with Quantitative Image Analysis. Thoracic HRCT will be performed using a 
standardized volume acquisition protocol developed by the UCLA Imaging Core with 1-1.5 
mm slice thicknesses acquired contiguously.  Multidetector CT scanners with 16 to 64 
channel scanners will be used at each site to minimize breath-hold times (4-6 seconds).  The 
subject will be imaged prone and at suspended end-inspiration (HRCT-TLC). Technologists 
will be trained to coach maximal inspiratory breath-hold from the subject and will instruct 
them to “Take your biggest breath in until you feel your lungs are completely full, in the 
same way you do in the lung function laboratory, and then signal when you feel completely 
full and hold your breath.” Subjects will be instructed how to signal when their lungs are 
completely full and the technologists will again remind them to hold their breath for the 
entire scan. Digitalized imaging data collected during the scan is transferred from the clinical 
site to the UCLA HRCT QIA Core using HIPAA compliant electronic transfer protocols and 
stored on a dedicated server with built-in encryption security and automated backup in 
place.  
Within the UCLA HRCT QIA Core, scans are reconstructed and entered into a quantitative 
image workstation to produce quantitative scores. The imaging analysis process consists of 
three steps: (1) semi-automated lung segmentation which requires approval by a 
radiologist; (2) execution of an automated classification model that classifies pixels into 
fibrotic, ground glass, honeycomb and normal lung patterns within the segmented whole 
lung region; and (3) division of the entire lung into anatomical lobes. HRCT scores for 
quantitative lung fibrosis (QLF), quantitative ground glass opacifications (QGG) and 
quantitative honeycomb changes (QHC) are determined separately from the percentage of 
overall pixels in which the classified abnormal pattern comprised reticular opacity with 
architectural distortion (QLF), hazy parenchymal opacity through which normal lung 
markings were visible in the absence of reticular opacity or architectural distortion (QGG) or 
clustered air-filled cysts with dense walls (QHC), respectively. The quantitative ILD (QILD) 
score represents the sum of all abnormally classified scores (QLF+QGG+QHC). Scores are 
then summated for the whole lung (WL; e.g. QLF-WL) which includes all pixels within both 
lungs, and for the lobe of maximal involvement (LM; e.g. QLF-LM). These approaches have 
been well standardized and reported for the evaluation of SSc-ILD, with documented 
changes in response to immunosuppression with both cyclophosphamide and MMF (27-
28,52). Total lung capacity will also be determined from the image analysis protocol and is 
known to be highly correlated with plethysmographic measures of total intrathoracic gas 
volume measured by spirometric techniques. Defined CT outcome measures will therefore 
include at a minimum: 
a) Quantitative lung fibrosis score in the whole lung (QLF-WL).  
b) Quantitative lung fibrosis score in the lobe of maximal involvement (QLF-LM).  
c) Quantitative ground glass opacification score in the whole lung (QGG-WL).  
d) Quantitative ground glass opacification score in the lobe of maximal involvement 
(QGG-LM). 
e) Quantitative honeycomb change score in the whole lung (QHC-WL).  
f) Quantitative honeycomb change score in the lobe of maximal involvement (QHC-
LM). 
g) Quantitative interstitial lung disease score in the whole lung (QILD-WL).  


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h) Quantitative interstitial lung disease score in the lobe of maximal involvement 
(QILD-LM). 
i) 
Total lung capacity at maximum inspiration (HRCT-TLC) 
The UCLA HRCT QIA core will screen the thoracic HRCT performed during screening for 
specific abnormalities that may lead to exclusion from the trial including, but are not 
limited: pulmonary nodules/masses, bronchiectasis, evidence of active infection, lobar or 
segmental collapse, and/or mediastinal/hilar mass(es) or nodes. Scans with abnormal 
findings will be reported to the site investigators and reconstructed images obtained at the 
local site will be available for review by clinical radiologists at the site outside of the 
responsibility of the study protocol. 
A radiation physicist from the UCLA HRCT QIA Core will initially assess the equipment and 
perform standardization protocols using phantom image results obtained at each site prior 
to the initiation of clinical testing. Site equipment will be programmed with the study-
specific protocols to assure safety and reproducibility. The estimated radiation dose that 
subjects will receive as a result of the proposed CT scans is ~120 millirem, or 2.4% of the 
5,000 millirem annual limit allowed radiation workers.  Subjects will receive a total of two 
HRCT scans over the course of the entire 18-month study, for a total radiation exposure of 
240 millirem. 
In the event that a participant has recently undergone an HRCT scan of the chest that was 
performed outside of the study, but within the required time window prior to 
randomization (< 60 days), it may be considered as a potential substitute for the official 
screening HRCT. To be eligible for such use, the digitalized imaging data collected during the 
scan must be transferred from the clinical site to the UCLA HRCT QIA Core using HIPAA 
compliant electronic transfer protocols as already noted. A review will be carried out to 
determine whether it was performed in a manner consistent with the key requirements for 
a full study scan performed at TLC, whether the image quality is adequate for assessing 
required inclusion and exclusion criteria, and whether digital image analysis can be 
adequately performed to yield required study outcome data as already described. If the 
scan is determined to be adequate by the UCLA HRCT QIA Core then it will be submitted for 
assessment in lieu of repeating the scan and exposing the patient to additional radiation. If 
it is determined that the scan is not adequate by these criteria, the patient may decide 
whether to proceed with a full protocol-defined HRCT in order to continue with the study 
screening.  
7.1.1.4 Mahler Baseline and Transitional Dyspnea Index. The paper version of Mahler’s Baseline 
Dyspneic Index (BDI) will be administered to subjects by a trained interviewer at the time of 
the baseline visit and the Translational Dyspneic Index (TDI) will be administered to subjects 
by a trained interviewer every 3 months thereafter. The interviewer will have an advanced 
understanding of dyspnea in respiratory disease and training in how to ask questions and 
select, based on information provided by the patient, from pre-defined test responses.  If at 
all possible, the same person will conduct all evaluations for a given patient. The TDI has 
proven to be a sensitive measure of treatment response in both SLS I and II studies (25,51).  
7.1.1.5 Skin thickness and function scores. Skin thickness score will be quantified using the 
modified Rodnan measurement method (mRSS), with a scale that ranges from 0 (no skin 
involvement) to a maximum of 51. Clinical assessment of skin thickness will be made in each 
of 17 body areas with 0-3 score (0 = normal; 1= mild thickness; 2 = moderate; 3 = severe 
thickness). Documented coefficient of variation is 12% for intra-observer reliability and 25% 


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for inter-observer variability (7-8).  Skin thickness scores have been found to significantly 
improve when therapy with cyclophosphamide was compared to placebo in SLS I (50-51) 
and similar improvements in response to MMF were confirmed in SLS II which likely 
contribute to the overall treatment effect (52). The capacity for PFD to enhance the effects 
of therapy with MMF on skin disease in patients with SSc is currently unknown and will be 
specifically evaluated as a component of this study using the mRSS assessment. The mRSS 
will be performed at baseline and at 3 month intervals throughout the study and should be 
carried out by the same investigator (if at all possible). 
7.1.1.6 Composite end point. Combined Response index in Systemic Sclerosis (CRISS). CRISS, a 
combined outcome index to assess treatment responses in SSc, was developed through an 
iterative process combining expert consensus conferences and data-driven approaches, and 
was recently validated as a therapeutic outcome measure (21). This composite index is a 2-
step process where step 1 assesses clinically meaningful decline in cardio-pulmonary-renal 
involvement and step 2 assesses changes in mRSS, FVC-%, patient global assessment, 
physician global assessment, and HAQ DI (from the SHAQ) as a combined outcome measure. 
It will be assessed at 6-, 12, and 18 month period. 
7.1.1.7 Physician and Patient Global Assessment. The Physician Global Assessment employs a 0-10 
likert scale to assess the patient’s “overall health” in the past 1 week. The single-item 
question is anchored from 0 (excellent health) to 10 (extremely poor). In addition, the 
physician will assess changes in the patient’s overall health and lung involvement by 
transition questions: Compared to the baseline visit, how would you rate your patient’s i) 
overall health and ii) overall lung involvement: much better, a little better, no change, a little 
worse, much worse. Using a similar approach the Patient Global Assessment employs a 0-10 
likert scale for the patient to assess their overall health in the past 1 week. The single-item 
question is anchored from 0 (excellent health) to 10 (extremely poor). In addition, the 
patient will assess changes in the patient’s overall health and lung involvement by transition 
questions: Compared to your baseline visit, how would you rate your i) overall health and ii) 
overall lung involvement: much better, a little better, no change, a little worse, much worse. 
Global Assessments will be administered at baseline (no transition component) and every 6 
months thereafter. 
7.1.1.8 Patient Reported Outcomes (PROs) in the form of patient responses to standardized 
patient questionnaires. 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 (Complete questionnaire can be found in 
Appendix A): 
a) 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.  It will be 
self-administered at baseline and every 3 months thereafter. This instrument, although 
not specifically designed for SSc, has recently been validated in SSc-ILD (5). It has been 
shown to be correlated inversely with FVC and directly with HRCT and exercise 
performance and to perform better in relation to exercise capacity and lung imaging 
than other non-respiratory-specific questionnaires for the evaluation of HRQoL in SSc-
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b) Health assessment questionnaire modified for scleroderma (SHAQ): The SHAQ will be 
administered at baseline and every 6 months thereafter. The SHAQ was shown to be 
favorably responsive to CYC therapy in SLS I (26). 
c) Patient-reported outcomes measurement information system 29-item health profile 
(PROMIS-29). The National Institutes of Health Patient-Reported Outcomes 
Measurement Information System (PROMIS) roadmap initiative utilized a cooperative 
group approach to develop and standardize item banks to measure patient-reported 
outcomes relevant across medical conditions. The resulting PROMIS-29 instrument 
provides assessment scales for Physical Functioning, Anxiety, Depression, Fatigue, Pain 
Interference, Sleep Disturbance and Impact on Social Roles, and has been validated to 
measure health status outcomes in patients with SSc while requiring limited time to 
repeat (average <2 min) (18). It will be administered at baseline and every 6 months 
thereafter. 
d) UCLA Scleroderma Clinical Trial Consortium GIT 2.0. The UCLA SCTC GIT is a validated 36-
item, self-reported measure assessing bowel involvement, symptoms and related 
emotional well-being, and social functioning administered at baseline, 6 months, 12 
months, 18 months (23-24).  A modified version, including only questions #1-8, will be 
used at screening to determine study eligibility as related to the extent of GI symptoms. 
e) Leicester Cough Questionnaire (LCQ): This self-administered 19-item questionnaire for 
the quantitative assessment of symptoms of cough frequency and severity will be 
completed at baseline and every 6 months (30). This will be supplemented with a 
ranking of cough severity, frequency, and sputum production using a simple likert scale 
(42,53). 
7.1.1.9 Blood collection for the Biological Specimen Repository. Blood samples will be serially 
collected from each study patient prior to (baseline), during (at 12 months) and at the 
completion of therapy (18 months). These samples will be immediately processed on site 
into serum, plasma, buffy coat and whole blood RNA samples (PAXgene RNA collection) 
according to a standard protocol, labeled and temporarily stored at the site at < -70°C prior 
to batch shipping to a central repository for long-term storage. The Bio-specimen Repository 
will reside at the University of California, Los Angeles, where a master inventory will be kept 
of all samples. The Executive Committee will oversee all requests (both internal and external 
to the study) to access these samples for ancillary biological studies directed toward the 
understanding of scleroderma, SSc-ILD, and the treatment protocol. 
7.1.1.10 Study drug reconciliation. A drug inventory is kept for every patient and contains the date, 
lot number, bottle number, type (MMF vs PFD/Plac) and number of capsules released to the 
patient. Patients are also provided with a medication calendar to complete and bring back at 
each visit and are required to return with all bottles of study drug that are in their 
possession regardless of whether they are opened, in use or empty. Bottle and pill counts 
will occur at each visit and information recorded on the drug inventory. 
7.1.1.11 Assessment of adverse events.  As detailed in Section 8 
 
7.1.2 Standard of Care Study Procedures 
7.1.2.1 Complete medical history and physical examination. A complete medical history and 
physical exam covering details related to the patient’s history of scleroderma, their entire 
medical history with a review of systems, and their current physical findings will be 


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performed during the initial screening visit and at 12 months. This will include a review of 
pertinent medical records provided by the patient and/or their referring physicians. 
7.1.2.2 Focused Interval history and examination. A review of current symptoms, medications, 
physical findings and any changes noted by the patient or a physician since a prior visit will 
be performed at baseline, monthly for the first 6 months and then every 3 months.  
7.1.2.3 Vital signs. Vital signs will include: pulse, blood pressure, respiratory rate,  temperature (oC), 
weight (kg), and SpO2 by pulse oximetry will be performed at initial screening, baseline , 
monthly for the first 6 months and then every 3 months.  Height (cm) will only be done at 
screening.   
7.1.2.4 Toxicity Monitoring with Blood Tests. A comprehensive set of laboratory results performed 
on a current blood sample to evaluate any toxicity or adverse events associated with 
Scleroderma or its treatment with the study drugs. Blood tests will include: comprehensive 
metabolic panel (to include serum electrolytes, BUN, Cr, glucose, albumin, ALT, AST, alkaline 
phosphatase, bilirubin, total protein) and a complete blood count with differential (to 
include WBC, Hgb, hematocrit, platelet count, and cellular differential count including 
absolute neutrophil count). Monitoring will occur at initial screening, monthly for the first 6 
months and then every 3 months.   
In the event that a participant has had all required laboratory tests completed within 30 
days of the Screening Visit #1, the results may substitute for the official screening laboratory 
tests.   
7.1.2.5 Pregnancy Testing. An initial serum pregnancy test at screening and subsequent monitoring 
with urine pregnancy testing to be performed on all female participants of child-bearing 
potential at baseline, monthly for the first 6 months and then every 3 months. 
 
7.2 
 STUDY SCHEDULE 
The complete schedule for study visits is detailed below and summarized in the subsequent Study Flow 
Diagram (Figure 7.3a) and Table of Study Visits (see below Schedule of Events, Table 7.3a).  
In the event of an emergency that disrupts patient or institutional access and usual study care, such as 
an unexpected disaster or pandemic, refer to Protocol Section 17.0 (EMERGENCY DISASTER/ PANDEMIC 
MANAGEMENT PLAN) for allowable adjustments to the study procedures and schedule that may be 
invoked as dictated by the nature of the emergency. 
7.2.1 Screening Visits (Study Day -90 through 0; Screening Visit #1&2) 
In order to be eligible for randomization, patients must proceed through a series of screening steps. 
At Screening Visit #1, a preliminary evaluation is performed and if eligibility criteria are met the 
patient will proceed to the screening HRCT scan (Screening Visit #2) to assess for the presence of 
any ground glass opacity and to exclude concurrent findings of concern that may require additional 
evaluation or exclude the patient from further participation.  If all inclusion and exclusion criteria are 
met, the patient will proceed to the baseline evaluation where a final check of pulmonary function 
and pregnancy testing is required to meet randomization criteria: 
7.2.1.1 Screening Visit #1. (preferably within 60 d, but no earlier than 90 d prior to randomization) 
a. Patient provides written informed consent and research HIPAA authorization prior to 
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b. A review of existing medical records and tests, provided by the patient or referring 
physician, is performed to document the history of scleroderma and general medical 
history. 
c. Vital signs obtained. 
d. The patient undergoes a complete medical history and physical examination. 
e. Review of concomitant medications including all medications taken within past 3 
months and any prior use of medications detailed in Section 7.5.1 (Prohibited 
Medications & Treatments with Potential Disease Modifying Effects).  
f. Pulmonary function testing for spirometry and diffusing capacity will be completed 
unless acceptable testing has been completed within 30 days of the screening visit and 
approved in advance by the Pulmonary Function Core at UCLA. 
g. A limited subset of the UCLA SCTC GIT questionnaire (including only Questions #1-8) is 
completed by the participant 
h. The patient has blood drawn for monitoring blood tests and serum pregnancy test (if 
applicable). 
7.2.1.2 Screening Visit #2. (may not be completed until results from screening visit #1 confirm 
potential eligibility, must be completed within 60 days of randomization) 
a) Thoracic HRCT with visual review for the presence of entry and exclusion criteria and 
with Quantitative Image Analysis 
7.2.2 Enrollment/Baseline Visit (Study Day 0; Visit #1) 
Subjects who meet all defined inclusion and exclusion criteria (up to this point) will be asked to 
return for the baseline visit. This will preferably occur within 60 days of their initial screening 
evaluation, but must occur within 90 days of their initial evaluation.  For subjects who have not met 
study enrollment criteria, their participation will end and they will not proceed. The following 
studies will take place at the baseline visit. 
a) A focused interval history and examination will be performed.  
b) Vital signs obtained. 
c) Review of concomitant medications  
d) Pulmonary function testing for spirometry and diffusing capacity will be completed.  
e) Urine pregnancy test performed (if indicated) 
f) Patient Reported Outcomes (PROs) in the form of patient responses to standardized patient 
questionnaires (SGRQ; SHAQ; PROMIS-29; UCLA SCTC GIT;  LCQ). 
g) Complete the Mahler Baseline Dyspnea Index. 
h) An assessment of skin thickness and function scores (mRSS) 
i) 
Patient and Physician Global Assessments (no transition questions) 
j) 
Blood collection for the Biological Specimen Repository 
If the repeat FVC-% fails to be within 10% of the value obtained at screening or is not > 45% and ≤ 
85%, the subject will be offered one opportunity to repeat testing within 7 days. If they choose not 
to repeat testing or if the repeat testing remains outside of the required range, their participation in 
the study will end. 
If the subject meets the repeat FVC-% inclusion criteria, and assuming that pregnancy testing is 
negative if required, the site coordinator will complete the online eligibility case report form and 
login to the electronic web-based randomization application to randomize the participant.  
Once randomization has occurred, the UCLA Pharmacy Core or the designated site Pharmacy, will 
confirm the drug and bottle assignment. In conjunction with a prescription signed by the Clinical Site 


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investigator, study drugs will be dispensed according to established protocol. Randomization will 
occur via the Data Coordinating Center and result in a notification of study assignment group to the 
UCLA Pharmacy Core and the Site Pharmacy. Study drug (PFD/Plac) will be released in a double-
blinded manner and neither the study investigators or staff, or the patient, will know the treatment 
assignment.  
7.2.3 Follow-up Visits (Months 0.5-18, Study Visits #2-21) 
There are a number of potential side effects of the study drugs that may be detected only through 
regular follow-up and blood testing monitoring. Given the nature of the study drugs, good clinical 
practice will require study visits for the purpose of monitoring every month for the first 6 months 
and every 3 months thereafter until drug therapy is completed at month 18. In addition to this 
clinical monitoring, outcome assessments are scheduled to occur every 3 to 6 months throughout 
the duration of the study. Finally, additional contact will be maintained with the subjects through 
regularly scheduled phone contacts to assure that drug titration and dosing, changes in health and 
adverse events are adequately tracked and recorded.  
7.2.3.1 Regular Follow-up Visits (Months 1 through 18; Visits 3, 5-9, 12, 15, 18, 21). 
Regular follow-up visits include a combination of toxicity monitoring and outcome 
assessments. Not all assessments are performed at each visit. Therefore, after each task 
listed below, a list of visit numbers (and corresponding month on study drug) is included to 
indicate when the task will be performed. Each visit must be completed within a specified 
time window with respect to the protocol defined follow-up date: Visit #3 = +7d; Visits #5-9 
and 12 = +10 d; Visit #15, 18, 21 = +14d. 
a) A focused interval history and examination will be performed.  
[Visit # 3 (month 1), 5-9 (months 2-6), 12 (month 9), 18 (month 15), 21 (month 18)] 
b) Vital signs obtained. 
[Visit # 3 (month 1), 5-9 (months 2-6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
c) Assessment of adverse events 
[Visit # 3 (month 1), 5-9 (months 2-6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
d) Review of concomitant medications  
e) Study drug reconciliation 
[Visit # 3 (month 1), 5-9 (months 2-6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
f) Study drug dispensing 
[Visit # 3 (month 1), 5-9 (months 2-6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
g) Toxicity monitoring with blood tests. 
[Visit # 3 (month 1), 5-9 (months 2-6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
h) Urine pregnancy test performed (if indicated) 
[Visit # 3 (month 1), 5-9 (months 2-6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
i) 
Pulmonary function testing for spirometry and diffusing capacity will be completed.  
[Visit #6 (month 3), 9 (months 6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
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j) 
Patient Reported Outcomes (PROs) in the form of patient responses to standardized 
patient questionnaires  
• SGRQ  
[Visit #6 (month 3), 9 (month 6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
• 
SHAQ; PROMIS-29; UCLA SCTC GIT; CRISS; LCQ 
[Visit #9 (month 6), 15 (month 12), 21 (month 18)] 
k) Complete the Mahler Transitional Dyspnea Index. 
[Visit #6 (month 3), 9 (months 6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
l) 
An assessment of skin thickness and function scores (mRSS) 
[Visit #6 (month 3), 9 (months 6), 12 (month 9), 15 (month 12), 18 (month 15), 21 
(month 18)] 
m) Physician and Patient Global Assessments. 
[Visit #9 (month 6), 15 (month 12), 21 (month 18)] 
7.2.3.2 Additional Assessments at the 12-Month & 18 Month Visit (Visit #15 and 21). 
a) In addition to testing completed at the Regular Follow-up Visits described above, the 
following will take place at the 12 Month Visit: 
• Blood collection for the Biological Specimen Repository 
• The patient undergoes a complete medical history and physical examination. 
b) In addition to testing completed at the Regular Follow-up Visits described above, the 
following will take place at the 18 Month Visit: 
• 
Blood collection for the Biological Specimen Repository 
Thoracic HRCT with Quantitative Image Analysis  
7.2.3.3 Phone Follow-up Visits.  
Month 0.5 (Visit #2); Month 1.5 (Visit #4); Months 7-8 (Visit #10-11); Months 10-11 (Visit 
#13-14); Months 13-14 (Visit #16-17); Months 16-17 (Visits 19-20) 
(Visit windows +7d for Visits 2 & 4; +10d for all others)  
a) Focused interval history 
b) Assessment of adverse events 
c) Review of Concomitant medications  
d) Study drug reconciliation (focused review of current dose and changes since last visit, 
missed doses, remaining supply)    
7.2.4 Final Phone Follow-up Visit / Early Termination Final Phone Visit 
Month 19 (Visit #22) or within 30 days of completely withdrawing from study   
(Visit window +10d) 
a) Focused interval history 
b) Assessment of adverse events 
c) Review of medications and alternative treatments (if premature termination visit)  
d) Reasons for leaving study (if premature termination visit) 
7.2.5 Follow-up for Participants who Prematurely Discontinue  Study Drug Treatment or who 
Completely Withdraw from the Study 
Should a participant prematurely discontinue all study drugs he/she will be asked to return for the 
key outcome determinations at 12 and 18 months, as detailed above. In addition, at that time, any 
medication prescribed by their treating physician since discontinuing study drugs will be recorded. 


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The participant will also be asked to participate in an exit visit as detailed in 7.2.4 above. Should the 
participant die, the cause of death will be determined and recorded if possible. 
In the event that one study drug is permanently discontinued due to tolerability, adverse event or 
other medical consideration, then continued use of the remaining study drug will be according to 
the following pre-specified management:  
• If only PFD/Plac is permanently discontinued, the participant may continue to take MMF 
according to the protocol and continue their participation in all study visits according to the 
normal protocol-defined schedule of events.   
• If MMF is prematurely discontinued, the participant must stop the PFD/Plac study 
medication as well and will be asked to return for key outcome determinations at 12 and 18 
months as detailed in Section 5.3.3 ( Handling of Premature Participant Withdrawals) 
7.2.6 Unscheduled Visits for Additional Safety Monitoring 
As detailed in Protocol Section 8 on Safety, patients who experience defined adverse events that 
require additional safety monitoring will be asked to return at defined intervals for additional 
follow-up and blood test monitoring (if indicated). It is estimated that routine laboratory safety 
monitoring may be required every 1-2 weeks until the side effect is resolved or until a proper dose 
of medication is identified. 
7.2.7 Long-term Follow-up 
On a voluntary basis, as a component of the consent process, participants will be asked whether 
they are willing (or not) to be contacted on an annual basis for up to 5 years after completing the 
study protocol at which time they would be asked to provide an update regarding their health 
status, symptoms related to their scleroderma and to describe any other treatments that they might 
have received for this condition.  
 
7.3   SUMMARY OF STUDY SCHEDULE AND ASSESSMENTS 
Figure 7.3a Study Schedule Flow Diagram 
 


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Table 7.3a: Table of Study Visits & Assessments  
SCREENING AND INITIAL 6 MONTHS 
Type of Visit: 
Screen 
Baseline 
Phone 
Regular 
Phone 
Regular Regular Regular Regular Regular 
Visit #: 
S1-2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study Month: 
 
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
Assessments 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signs** 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Reconciliation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Lung function testing 
X 
X 
 
 
 
 
X 
 
 
X 
Blood Test Monitoring 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Questionnaires 
UCLA 
SCTC GIT 
X 
 
 
 
 
X 
 
 
X 
HRCT scan of chest 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test* 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Blood for Bio-Repository 
 
X 
 
 
 
 
 
 
 
 
* For women who are able to become pregnant; require a blood test at screening then urine testing. 
** Only need height at screening. 
 
MONTHS 7 – 19 & EXTRA VISITS 
Type of Visit: 
Phone 
Regular 
Phone 
One 
Year 
Phone 
Regular 
Phone 
18 
Month 
Final 
Phone 
Extra 
Visit #: 
10-11 
12 
13-14 
15 
16-17 
18 
19-20 
21 
22 
 
Study Month: 
7, 8 
9 
10, 11 
12 
13, 14 
15 
16, 17 
18 
19 
Yrs 2-5 
Assessments 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
 
X 
 
X 
 
X 
 
X 
 
 
Vital signs** 
 
X 
 
X 
 
X 
 
X 
 
 
Concurrent Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Reconciliation 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lung function testing 
 
X 
 
X 
 
X 
 
X 
 
 
Blood test monitoring 
 
X 
X 
 
X 
 
X 
 
 
Questionnaires 
X 
 
X 
 
X 
 
X 
 
 
HRCT scan of chest 
 
 
 
X 
 
 
Pregnancy test* 
 
X 
 
X 
 
X 
 
X 
 
 
Blood for BioRepository 
 
 
X 
 
 
 
X 
 
 
* For women who are able to become pregnant; require a blood test at screening then urine testing. 
** Only need height at screening. 


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7.4 
 
CONCOMITANT MEDICATIONS & TREATMENTS DURING THE STUDY 
All concomitant prescription, over-the-counter and non-prescription medications taken during study 
participation will be recorded on the case report forms (CRFs) and checked for compatibility with the 
study drugs as defined in Section 7.5.  
 
 
7.5 
 
PROHIBITED MEDICATIONS AND TREATMENTS DURING THE STUDY 
 
7.5.1 Prohibited Medications & Treatments with DMARD Activity 
Medications from the following list, and their biosimilars, are prohibited and may not be taken prior 
to screening in amounts (or for time intervals) that exceed allowable limits as detailed in Exclusion 
Criteria #15 and #16. They may not be taken while participating in the active drug treatment phase 
of this study (except for MMF and PFD when specifically administered as study drugs according to 
the study protocol). 
Prior use of these medications must be consistent with Exclusion Criteria #15 
a) Oral or short half-life drugs with potential DMARD activity 
• Anakinra 
• Apremilast 
• Azathioprine  
• Baricitinib  
• Cyclophosphamide oral 
• Cyclosporine  
• Dasatinib  
• Imatinib  
• Leflunomide  
• Methotrexate 
• Mycophenolate mofetil 
• Nilotinib 
• Nintedanib  
• Pirfenidone 
• Pomalidomide  
• Rilonacept  
• Tacrolimus 
• Tofacitinib 
  
b) Intravenous or injectable drugs with potential DMARD activity 
• Abatacept 
• Adalimumab  
• Alemtuzumab 
• Belimumab 
• Canakinumab 
• Certolizumab 
• Cyclophosphamide IV  
• Etanercept 
• Guselkumab 
• Golimumab 
• Infliximab 
• Ixekizumab 
• Rituximab 
• Sarilumab 
• Secukinumab 
• Tocilizumab 
• Ustekinumab 
 
7.5.2 Prohibited Medications & Treatments that may Increase Immune Suppression Risk 
a) Prednisone >10mg/day (or equivalent corticosteroid). 
NOTE: a brief pulse of prednisone to <30 mg/day that lasts no more that 7 days before 
returning to a dose of < 10 mg is permissible if indicated for a temporary intercurrent 
medical condition. 
a) Live vaccines administered within 30 days of, or after randomization including:                                                       
• 
Bacillus of Calemett and Guerin (BCG) Vaccine 
• 
Measles Virus 
• 
Mumps 


Scleroderma Lung Study III                                           [Confidential] 
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• 
Polio Virus  
• 
Rotovirus  
 
  
• 
Rubella   
 
 
 
 
• 
Small pox  
• 
Typhoid  
• 
Varicella Virus                            
 
• 
Yellow Fever                   
• 
Live influenza vaccine                                             
 
7.5.3 Prohibited Medications that may Interfere with Study Drug Absorption/Metabolism 
a) Antacids containing Magnesium and Aluminum Hydroxides should not be taken together (at 
the same time) with MMF due to their impact on the absorption of MMF. 
NOTE: Antacids may be used, but should not be taken within 2 hrs of MMF. 
b) Proton Pump Inhibitors (PPIs) should not be taken together (at the same time) with MMF 
due to their impact on the absorption of MMF. 
NOTE: PPIs may be used, but should not be taken within 2 hrs of MMF. 
c) Sevelamer and other calcium free phosphate binders should not be taken together (at the 
same time) with MMF due to their impact on the absorption of MMF. 
NOTE: Calcium free phosphate may be used, but should not be taken within 2 hrs of 
MMF. 
b) Cholestyramine should not be taken due to interference with enterohepatic recirculation of 
MMF 
c) Cyclosprine should not be taken due to interference with enterohepatic recirculation of 
MMF 
d) Norfloxacin and Metronidazole should not be taken together as a combination therapy 
while on therapy with MMF due to interference with serum levels of MMF 
e) Ciprofloxacin and/or Amoxicillin plus Clavulanic Acid may temporarily interfere with the 
enterohepatic recirculation of MMF producing temporary reductions in serum MMF levels.  
NOTE: Temporary use for 2 weeks or less is of unclear significance but sustained use of 
these antibiotics is not recommended. 
f) Ciprofloxacin and other Fluoroquinolones which are moderate inhibitors of CYP1A2 may 
interfere with the metabolism of PFD, significantly increasing drug exposure. 
NOTE: Use of Ciprofloxacin at a maximal dose of 500 mg twice daily for up to two weeks 
is allowed. 
NOTE: If temporary use for Ciprofloxacin at a dose of 750 mg twice daily (or other 
fluoroquinolone at high dose) is required for 2 weeks or less, the daily dose of PFD 
should be reduced by 1 capsule three times a day during the period of concommitent 
use (patients on 3 capsules should reduce to 2, while patients on 2 capsules should 
reduce to 1) 
g) Rifampin may temporarily interfere with serum levels of MMF.  
NOTE: Temporary use for 2 weeks or less is of unclear significance but sustained use of 
these antibiotics is not recommended. 
h) Fluvoxamine, enoxacin or other strong CYP1A2 inhibitors should not be taken due to their 
impact on the metabolism of PFD, which can significantly increase drug exposure 
i) 
Smoking, which is a strong inducer of CYP1A2, is not allowed during the study 
 
7.5.4 Restrictions on Medications with Other Adverse Interactions 


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a) Hormonal contraceptives may not be effective during administration of MMF due to 
interactions with drug metabolism and a second type of contraception must be used to 
participate in study if one of the following hormonal contraceptive is used: 
• 
Levongogrestrel 
• 
Norethindrone 
• 
Mestranol 
• 
Norgestrel 
• 
Ethinyl estradiol 
• 
Etonogrestrel 
b) Use of tanning beds or medical phototherapy that includes UV light exposure are 
contraindicated during the use of PFD due to their impact on photosensitivity reactions. 
 
7.6 
 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 
Prophylactic use of topical sunblock agents: PFD is associated with photosensitivity. In addition to 
advising patients to wear protective clothing, hats, and avoid extended sun (or tanning light) exposure, 
they will be advised to use over the counter sunblock as a prophylactic therapy if sun exposure is 
anticipated. 
Prophylactic consumption of PFD with food: Patients are advised to take PFD with food to help 
decrease gastrointestinal side effects. 
 
8 ASSESSMENT OF SAFETY 
 
8.1 
 
SPECIFICATION OF SAFETY PARAMETERS 
Safety parameters will include frequency of events and/or incidence of study subjects experiencing 
events, by study arm for the following: 
a) Study-defined Treatment failures 
b) Study-defined Treatment emergent AEs of Special Interest 
c) All treatment emergent AEs, total and by organ system classification  
d) All treatment related AEs, total and by organ system classification  
e) All treatment emergent SAEs, total and by organ system classification  
f) All treatment related SAEs, total and by organ system classification  
g) All treatment emergent deaths 
h) All treatment-emergent AEs and SAEs that result in discontinuation of treatment 
i) 
Time to treatment failure, treatment emergent AEs and SAEs that result in discontinuation of 
treatment, and death 
 
8.1.1 Definition of Adverse Events (AEs) 
Adverse event means any untoward medical occurrence, such as an abnormal laboratory finding, 
physical sign, symptom, or diagnosis of a disease state, that is temporally associated with the use of 
an interventional treatment or procedure in a human subject regardless of whether or not it is 
considered intervention-related [consistent with 21 CFR 312.32 (a)]. 
8.1.1.1 Treatment-emergent AEs (TEAEs): 


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TEAEs are those that start or worsen after the start of study treatment and up to 7 days (for AEs) 
and 30 days (for serious AEs) after the last dose of study treatment. This AE definition would 
include the following: 
• 
Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of the study treatment administration 
• 
Complications resulting from protocol-mandated procedures 
• 
AEs occurring as a result of product withdrawal, abuse or overdose 
• 
A change in a laboratory variable if considered by the investigator to be clinically significant 
or if it is caused (or should have caused) the investigator to reduce or discontinue the use of 
the product or initiate a non-protocol therapy or procedure 
8.1.1.2  AEs of Special  Interest:   
AEs of Special Interest represent a specific subset of all AEs and are defined by the study 
protocol based on two distinct features: 1) their likely association with the investigational 
drug(s), and 2) the presence of pre-specified study drug management guidelines that are to be 
followed when the AE occurs.  
 
8.1.2 Definition of Serious Adverse Events (SAEs) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator 
or sponsor, it results in any of the following outcomes:  
• 
Death,  
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• 
A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. [Consistent with 21 CFR 312.32 (a)] 
 
8.1.3 Definition of Unanticipated Problems (UP – unexpected AEs & Problems) 
An AE or suspected adverse reaction is considered "unanticipated" if it is not listed or characterized 
in the Package Insert or in the current Investigator Brochure or is not listed at the specificity or 
severity that has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or elsewhere in the 
current application, as amended. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 


Scleroderma Lung Study III                                           [Confidential] 
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from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. [Consistent with 21 CFR 312.32 (a)] 
 
8.2 
 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 Severity of Event 
The intensity of all AEs will be graded using a five-point grading scale in which the following 
descriptions of severity will apply. Note that for some AEs, Grades 4 and/or 5 may not be applicable. 
In those cases only 3 different grades (Grade 1-3) are to be considered: 
 
8.2.1.1 
Grade 1: 
“Mild”; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
8.2.1.2 
Grade 2: 
“Moderate”; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
8.2.1.3 
Grade 3: 
“Severe”; medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL**. 
8.2.1.4 
Grade 4: 
 “Life-threatening consequences”; urgent intervention indicated. 
8.2.1.5 
Grade 5: 
“Death related to AE”. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
8.2.2 Relationship to Study Drug 
For all collected AEs, the clinician who examines and evaluates the participant will determine the 
AE’s causality based on temporal relationship and his/her clinical judgment. A binary assessment 
(related/not related) will be made and take into consideration the natural history of the underlying 
disease, concurrent illness, concomitant therapy, study-related procedures, accidents, and other 
external factors. While the relationship to the study drug (related/not related) is part of the 
documentation process, it is not a factor in determining what is or is not reported in the study. All 
AEs are recorded regardless of relatedness. 
8.2.2.1 Related 
The AE is known to occur with the study agent, there is a 
reasonable possibility that the study agent caused the AE, or there 
is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study agent and the AE. An AE can 
be deemed related even if other factors may have contributed to 
the event. 
8.2.2.2 Not Related 
There is not a reasonable possibility that the administration of the 
study agent caused the event, there is no temporal relationship 
between the study agent and event onset, or an alternate etiology 
has been established or appears to provide a plausible explanation 


Scleroderma Lung Study III                                           [Confidential] 
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(e.g. the participant’s clinical condition, underlying disease or 
concomitant treatments). 
 
8.2.3 Expectedness 
For all SAEs, the Clinical Site Principal Investigator, in consultation with a designated Medical 
Monitor whenever possible, will be responsible for determining whether the SAE is expected or 
unexpected using the definition from section 8.1.3 above. 
 
8.2.4 AE of Special Interest 
AEs meeting the following criteria will be classified and reported as AEs of Special Interest in 
addition to their inclusion in the overall frequency and incidence of AEs.   
• 
Leukopenia, defined as WBC <2.5x103/µl of blood 
• 
Neutropenia, defined as an absolute neutrophil count < 1.0x103/µl of blood  
• 
Clinically significant anemia, defined as blood hemoglobin < 10.0 gm/dl or a drop in 
hemoglobin to < 9.0 gm/dl if the baseline hemoglobin was < 11.0 gm/dl 
• 
Liver enzyme elevations that exceed 3× the upper limit of normal (ULN) ALT and/or AST. 
• 
New onset or worsening of existing gastrointestinal symptoms that do not respond to 
medical management and are of sufficient clinical importance to warrant drug dose 
adjustment (including nausea, diarrhea, vomiting, and dyspepsia). 
• 
Documentation of gastrointestinal ulcer, gastrointestinal bleeding or abdominal emergency 
• 
Infection requiring hospitalization, intravenous antibiotics, or judged as requiring the 
withdrawal of immune suppression for effective treatment. 
• 
New or reactivated viral infections including PVAN, JC virus associated PML, CMV infections, 
reactivation of HBV or HCV. 
• 
Photosensitivity skin reactions that do not respond to sunscreen, avoidance, and as-needed 
use of over the counter topical creams, and are of sufficient clinical importance to warrant 
drug dose adjustment. 
• 
Development of a proven malignancy other than basal cell cancer of the skin or cervical 
carcinoma in situ removed entirely by biopsy. 
• 
Angioedema 
 
8.3 
 
ADVERSE EVENT REPORTING 
A consistent methodology for eliciting AEs will be used at all subject evaluation time points that includes 
open-ended questions such as:  
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?”  
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate CRF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while 


Scleroderma Lung Study III                                           [Confidential] 
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on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study (in frequency, severity or character), it will be recorded as an AE and a descriptor 
will be used as a modifier term to convey that it relates to a pre-existing condition that has changed (e.g. 
“more frequent headaches”). UPs will be recorded in the data collection system throughout the study. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
The Principal Investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and to Genentech, Inc. in 
accordance with CFR 312.32 (IND Safety Reports).  
 
8.3.1 Adverse Event Reporting 
All AEs will be mapped to system organ classes (SOC) using preferred MedDRA SOC terms, graded 
for severity and relationship to study drugs as detailed above, and recorded with start dates 
occurring any time after informed consent is obtained until at least 7 days (for non-serious AEs) or 
30 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 and preferred SOC 
terms will be recorded centrally by the DCC. 
 
8.3.2 Serious Adverse Event Reporting 
All SAEs will be mapped to system organ classes (SOC) using preferred MedDRA SOC terms, graded 
for severity and relationship to study drugs as detailed above, and recorded with start dates 
occurring any time after informed consent is obtained until 30 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 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, with stop dates recorded for resolution.  
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 to 
the Data Coordinating Center within 24 hours of learning of the event. In addition, new follow-up 
data must be reported within 24 hours of receipt. The designated study medical monitor or 
designee may be contacted at any time for immediate discussion regarding such an event. 
Hospitalizations for the following reason, which are not related to an AE, do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions. 
Deaths occurring in patients who have withdrawn from the active treatment phase of the study will 
not be considered SAEs if the death occurs more than 30 days after last dose of study treatment. 
When recording a death, the event or condition that caused or contributed to the fatal outcome 


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should be reported as the single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, the report will be identified as an “Unexplained Death”. 
Investigators must report all SAEs to their governing IRB/IEC, as required by local regulations and 
guidelines. 
A record of all SAEs, by study subject and preferred SOC terms will be recorded centrally by the DCC. 
 
8.3.3 Unexpected Adverse Event/Problem (UP) Reporting 
All adverse events that meet the definition of an UP should be reported to the local governing IRB 
within specific timelines as described below: The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken orare 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 (UP) 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 
 
8.3.4 Reporting of Pregnancy 
a) Pregnancies should be reported from the time the patient signs the informed consent 
until 30 days after the last dose of study drug. Study treatment must be immediately 
discontinued if a patient becomes pregnant. Although pregnancy is not considered an 
SAE, a report should be completed and expeditiously submitted to the DCC and to 
Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also 
occur.Abortion, whether accidental, therapeutic, or spontaneous, should always be 
classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to the study drug 
should be reported as an SAE.  
 


Scleroderma Lung Study III                                           [Confidential] 
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8.3.5 Reporting of Post-Study Adverse Events 
SAEs occurring more than 30 days after a subject has completed or discontinued study participation, 
if reported to a study investigator and attributed to prior study drug exposure, will be reported as an 
SAE to Genentech, Inc.  Any investigator who becomes aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female subject who participated in 
the study, will report such event as an SAE to Genentech. 
 
8.4 
 
STUDY HALTING RULES  
The investigators and/or sponsor reserve the right to terminate the study at any time. If this becomes 
necessary, appropriate procedures for continuing long-term follow-up and assuring the adequate 
treatment and safety of the participating subjects will be arranged after review and approval by the 
study sponsor, Institutional Review Boards and the FDA. 
The appointed DSMB will also provide external oversight concerning the safety and scientific integrity of 
the study for the duration of the clinical trial.  The DSMB will review the progress of the study toward 
meeting enrollment goals, adverse and serious adverse event profiles, and study outcome measures at 
regular intervals to occur at least twice annually.  The DSMB may recommend at any time that the study 
should be terminated due to drug toxicity, patient safety, poor compliance and/or futility 
considerations. In such cases, their recommendations will be reviewed and discussed with the Executive 
Committee, which will make a final determination.  
 
8.5 
 
SAFETY OVERSIGHT 
Safety oversight will be under the direction of a 3-member External Data and Safety Monitoring Board 
(DSMB, See Section 15.1.5) composed of individuals with the appropriate expertise in SSc-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 a salaried appointment with any of 
the participating institutions. The DSMB Chair will then recommend the remainder of the Committee 
Members for consideration by the study Executive Committee using similar expertise and affiliation 
criteria. 
The DSMB will review the protocol and recommend modifications with respect to monitoring, safety and 
outcome assessments that will be addressed by the study prior to the onset of clinical activity.  Once the 
trial is initiated, the DSMB will review cumulative trial results to evaluate the treatment for beneficial 
and 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 every 6 months by teleconference and/or web 
videoconferencing for the duration of the trial and will interact directly with the Data Coordinating 
Center for access to study data and interim reports, and with the Executive Committee regarding any 
recommendations for procedural changes, study modifications or management of perceived safety or 
data integrity issues.  
 
8.5.1 Morbidity and Mortality Committee 


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A separate Morbidity and Mortality Review Committee (MMRC) will be appointed by the Executive 
Committee and consist of the Medical Monitor and two invited members who are not otherwise 
involved in the research.  The composition of the MMRC will include at least one member 
specializing in pulmonary medicine and one in rheumatology. The purpose of this committee will be 
to review all reported SAEs (as detailed in Sections 8.1 to 8.3) and provide an independent and 
blinded determination as to: 
a) The proximate cause of the SAE.  
b) Relationship of the SAE to the study drug as detailed in Section 8.2.2. 
c) The expectedness of the SAE as defined in Section 8.1.3. 
Individual SAE case reports will be reviewed as they occur by an identified medical monitor who will 
assure that all relevant material has been collected and, in consultation with the reporting site 
investigator, that the determination of the proximate cause, relationship to the study drug and 
determination of expectedness are consistent with the documentation and reporting guidelines.  
Independent reviews by the MMRC will occur retrospectively, in batches, at a time when the records 
for a group of 12-20 SAEs are ready for review or at the conclusion of the study if less than 12 SAEs 
are recorded.  Each member of the MMRC will independently review cases and provide a 
determination. No further review will be required when all reviewers agree as to the relationship of 
the SAE to the study drug and the expectedness. Cases in which reviewers disagree on these 
determinations will be discussed at a MMRC teleconference and a final determination reported as 
either a consensus opinion (when all three reviewers agree after discussion) or a majority opinion 
(indicating the majority opinion of two out of three reviewers). The MMRC findings will represent the 
final study determination with respect to reporting SAE outcomes. 
 
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.   
• 
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. 


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• 
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  
 
10.1 STATISTICAL AND ANALYTICAL PLANS 
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. 
 
10.2 STATISTICAL HYPOTHESES 
The primary hypothesis is that the rapid onset and anti-fibrotic effects of PFD, which have been 
observed in the treatment of Idiopathic Pulmonary Fibrosis (IPF), will complement the delayed anti-
inflammatory and immunosuppressive effects of MMF, to produce a significantly more rapid and/or 
greater improvement in lung function over time than occurs in patients receiving control therapy with 
MMF (and Plac) alone.  Statistically, the following null and alternative hypotheses will test the 
superiority of the combination of PFD+MMF versus MMF+Plac in improving the change from baseline in 
mean forced vital capacity (as a percentage of the age-, height-, gender- and race-adjusted predicted 
value, indicated as FEV-%) over the course of the 18-month double-blind treatment period (primary 
endpoint): 
 
 
H0:  ΔPFD+MMF = ΔMMF+Plac 
HA:  ΔPFD+MMF ≠ ΔMMF+Plac 
where Δ reflects the adjusted mean change from baseline trajectory over the 18-month treatment 
period.    
 
10.3 ANALYSIS DATASETS 
Several analysis sets will be used in analyses: 
• 
The main population for efficacy will be the modified intention-to-treat population (m-ITT), defined 
as all participants randomized, receiving at least one dose of study medication, and having at least 
one post-baseline efficacy assessment. Subjects will be analyzed by assigned treatment.  
• 
A second analysis set will be used to assess the robustness of the primary and key secondary 
conclusions in the subset of participants in the m-ITT analysis set who complied with the protocol 
sufficiently to ensure that these data would be likely to represent the effect of treatment according 
to the underlying scientific model.  The Per Protocol (PP) analysis set will consist of all subjects in the 
m-ITT population who do not have a major protocol violation, inclusive of violation of entry criteria.  
• 
The Safety Population is defined as all participants who are randomized and receive at least one 
dose of the study medication.  The Safety Population will be used for all safety analyses.  Subjects 
will be analyzed by assigned treatment. 


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10.4 DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 
General Approach 
The design of this randomized controlled study is a parallel-group, two treatment, placebo-
controlled investigation of pirfenodine vs placebo in participants receiving mycophenolate.  
Continuous variables will be summarized using descriptive statistics including n, mean, median, 
standard deviation, range (e.g., minimum and maximum).  Qualitative variables will be summarized 
using counts and percentages.  Summaries will be provided by treatment group and overall.  Unless 
otherwise specified, statistical analyses will be performed using SAS Version 9 or higher.  Where 
appropriate, statistical tests will be conducted at the 0.05 significance level using two-tailed tests 
and p-values will be reported.  
 
10.4.2 
Analysis of the Primary Efficacy Endpoint 
The primary endpoint is change from baseline in the mean forced vital capacity, measured as the 
percentage of the age-, height-, gender- and race-adjusted predicted value (FVC-%) over the course 
of the 18-month treatment period, as reported quarterly (i.e., months 3, 6, 9, 12, 15 and 18). Given 
that the trajectories of the primary endpoint are expected to differ because of the mechanisms of 
action of the two treatment modalities, a longitudinal approach incorporating all time points will be 
employed.  Specifically, the endpoint will be analyzed using a linear mixed model with participant-
month in the study (3, 6, 9, 12, 15, 18) as the unit of analysis and the change from baseline in FVC-% 
as the outcome, with terms for baseline FVC-%, treatment group, month, the interaction of month 
(x) treatment group, and prior MMF therapy (stratification factor: naïve, >0 to <3 months, and >3 
months to 6 months), as fixed covariates.  Study participant will be treated as a random effect to 
account for the correlation of outcomes over time within a participant.  The model generates 
adjusted estimates of change from baseline in the FVC-% for each treatment group and month, and 
an F-test will be used to test the hypothesis that the mean change from baseline during the 
treatment period differs between the two treatment groups.  The model-based adjusted mean 
change from baseline in FVC-% will be presented graphically by treatment group by study month, 
with 95% confidence intervals (CIs) provided at each month. 
The primary analysis of the primary efficacy endpoint will use the m-ITT analysis set.  Appropriate 
non-linear parametric or non-parametric tests may be applied if the assumptions of the model are 
not satisfied.  Details will be presented in the SAP. 
To assess the robustness of treatment effects, a secondary analysis of the primary efficacy endpoint 
will be performed using the PP analysis set.  In addition, two separate a priori analyses will be 
conducted using the model described above with the m-ITT analysis set:  one with baseline CT 
fibrosis scores as a covariate, and one with baseline mRSS as a covariate. 
Sensitivity analyses will be performed to assess how subjects who withdrew may affect conclusions 
of the analysis.  In particular, our primary analytic approach assumes a missing-at-random 
mechanism (45) and one sensitivity analysis will employ a nonignorable model.  With nonignorable 
missingness, the stochastic process that generates missingness is explicitly modeled.  We will jointly 
model the longitudinal measures with the missing data mechanism using a pattern mixture model 
(31).  Depending on the extent and pattern of missingness, other simpler sensitivity analyses may be 
used:  for example, change from baseline to the end of treatment for subjects completing the study 


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(completers) may be analyzed using an analysis of variance model.  The model will include the same 
covariates that are included in the primary mixed effects analysis.   
In addition to the assessment of the overall trajectory of pulmonary response which integrates the 
timing of the onset of response and the overall magnitude of effect at 18 months, we will evaluate 
the individual components of this response.  Using the same model as for the primary endpoint, we 
will assess the change point for response to evaluate the onset of response for the two treatment 
groups, and the change from baseline to month 18 to evaluate the overall magnitude of effect at the 
end of the treatment period. 
In addition, frequency distributions of changes from baseline to 18 months in FVC-% will be 
presented by treatment group to describe observed (i.e., not model-based) estimates of treatment 
effects for the m-ITT analysis set, for those who completed 18 months of treatment and those who 
prematurely discontinued treatment. Additional analyses may be performed to assess more 
granular changes in treatment adherence (e.g., premature discontinuation of study treatment prior 
to 3, 6, 9, 12, 15 and 18 months) depending upon the observed extent and timing of 
discontinuation.   
 
10.4.3 
Analysis of the Secondary Endpoints and Exploratory Outcomes 
10.4.3.1 
Analyses of Secondary Endpoints.   
There are three categories of secondary outcomes: 
1. Continuous outcomes such as change from baseline in mRSS, QLF-max and QILD-lung 
from HRCT, hemoglobin-adjusted DLCOHb-%, PROs, and compliance with pill 
administration during the treatment period; 
2. Dichotomous outcomes such as the proportion of subjects who report improvement on 
the TDI at 18 months during the treatment period.   
3. Time (in months) required for each treatment arm to achieve a 3.0% or greater 
improvement from baseline in the FVC-% over the 18-month treatment period. 
Continuous secondary outcomes will be compared between treatment groups using the same 
methods as described for the primary analysis of the primary endpoint.  For dichotomous 
secondary outcomes, logistic or Poisson regression will be used with treatment group, site, and 
prior MMF therapy (stratification factor: naïve, >0 to <3 months and >3 months to 6 months) 
included as covariates.  For these dichotomous models, odds ratios (for logistic models) or 
relative risks (for Poisson models), with corresponding 95% CIs, will be presented; p-values for 
the test of treatment differences will also be presented.  For time to event outcomes, Kaplan-
Meier methods will be used to graphically present treatment differences; median time to event 
with 95% CIs and stratified (by prior MMF therapy) log-rank test p-values will be presented.  The 
m-ITT analysis set will be used in the analyses of secondary endpoints. 
In addition, the graphical descriptive approach described above to summarize the frequency 
distributions of changes from baseline to 18 months will be provided for key secondary 
endpoints (to be detailed in the SAP). 
10.4.3.2 
Analyses of Exploratory Outcomes.   
Comparable methods as described above for primary and secondary outcomes will be used for 
the exploratory aims described in Section 4.2.3.  For example, identification of baseline features 
that predicted treatment responsiveness, disease progression and course of lung and skin 


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disease over time will employ the appropriate models with the baseline covariate and 
potentially the interaction of treatment and baseline as covariates.  Separate models would be 
assessed for each outcome and baseline.  Biomarker identification would be handled similarly.  
The identification of composite outcome measures that distinguish early and late treatment 
responses will be detailed in the SAP.  These analyses will be considered exploratory and 
hypothesis-generating. 
 
10.4.4 
Safety Analyses 
Safety analyses will be performed on the Safety analysis set.  Safety data, including frequency of 
events and proportion of participants experiencing events described in section 8.1, clinical 
laboratory tests, vital signs, and physical examinations, will be summarized descriptively overall and 
by treatment group.  For categorical safety outcomes, numbers and percentages will be used.  For 
continuous safety outcomes, number, mean, standard deviation, median, interquartile range, 
minimum and maximum will be used to summarize changes from baseline to each study visit in 
laboratory tests and vital signs.  Percent change from baseline will be added for laboratory values as 
outlined in the SAP.  The primary organ system associated with each adverse event will be coded by 
the medical monitor.  Kaplan-Meier methods will be used to summarize graphically the time to 
treatment failure, treatment emergent AEs and SAEs that result in discontinuation of treatment, and 
death. 
 
10.4.5 
Adherence & Retention Analyses 
Participant disposition will be summarized descriptively.  The number and percentage of participants 
randomized, completed, and withdrawing, along with reasons for withdrawal, will be tabulated 
overall, and by treatment group.  The number of participants in each analysis population will be 
reported.  Other disposition and study conduct information, including major protocol violations will 
be summarized.  Duration of the study follow-up will be summarized overall and by treatment 
group. 
Compliance with study medication will be assessed and summarized, including the proportion of 
participants who adhered to study treatment at each study visit, the median duration of adherence 
to study treatment and the proportion of participants who permanently discontinued study 
medication by reason for treatment permanent discontinuation, overall and by treatment group.   
 
10.4.6 
Baseline Descriptive Statistics 
Prior to analysis, the two treatment groups will be compared descriptively with respect to 
demographic and baseline variables (e.g., age, race, FVC-%, mRSS).  No statistical tests will be used 
to compare the treatment groups.   
 
10.4.7 
Planned Interim Analyses 
10.4.7.1 
Safety Review 
Safety outcomes will be presented at each DSMB meeting.  These include number of and 
proportion of subjects with SAEs (including segregation of those involving deaths), treatment-
emergent AEs, AEs of Special Interest, discontinuation of study medication due to AEs, and 


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protocol-defined treatment failures.  These presentations will be descriptive, with no formal 
inferential methods used.  Given that these study medications have been approved for other 
indications, their safety profile has been well characterized.  Thus, no specific rules for halting 
study enrollment or study interventions for safety are specified; however, the DSMB may 
request formal inferential testing to assess the risk-benefit profile of these study medications in 
this study population. 
10.4.7.2 
Efficacy Review 
No interim analysis is planned. 
 
10.4.8 
Additional Sub-Group Analyses 
No other sub-group analyses (other than those described above for the primary and secondary 
efficacy endpoints) are planned.   
 
10.4.9 
Multiple Comparison/Multiplicity Analyses 
No adjustments for multiplicity are planned since there is one primary analysis of the primary 
endpoint at the end of the study.  Secondary analyses of the primary endpoint and analyses of the 
secondary endpoints serve to assess the robustness of the results and consistency of treatment 
effect on clinical outcomes important in this disease. 
 
10.4.10 Tabulation of Individual Response Data 
SAEs, deaths, and AEs resulting in discontinuation of study medication will be tabulated for 
participants who experience these events. 
 
10.4.11 Exploratory Analyses 
Additional analyses may be performed to explore both safety and efficacy measures collected in this 
study.  The precise methods and analyses will be determined after the database is locked and the 
blind is broken.  Thus all such analyses will be interpreted cautiously and not used for formal 
inference, although inferential statistics may be used as part of the data summary.   
 
10.5 SAMPLE SIZE 
 
10.5.1 
Introduction & Background to Sample Size Determination 
An initial sample size target of 150 participants (up to 190 consented and screened subjects to 
achieve 75 randomized per treatment group) was identified based on recent clinical trial experience 
and logistical considerations including the number of clinical centers with appropriate leadership 
and infrastructure to be considered as state of the art for treating SSc-ILD.  Statistical analysis, using 
a clinical trials simulation approach, was then employed to estimate the power to detect various 
treatment effects on the primary endpoint with a two-sided Type I error of 5% and an 18-month 
attrition estimate of 24%.   
Data from the SLS I and II clinical trials (44,50-52) were used to estimate the baseline characteristics 
of the proposed study population and their response over time to treatment with MMF, including 
the impact of prior treatment with MMF (occurring prior to study randomization), on the predicted 


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course of lung function changes over time. Note that SLS III will employ essentially the same patient 
recruiting centers and investigators as those that participated in the prior studies (with some new 
additions) and that the enrollment criteria have been relatively conserved over time to assure 
reproducibility. Furthermore, both the control arm and experimental arm of the proposed study will 
be treated with a course of cytotoxic therapy that is essentially identical to that reported from the 
SLS I and II studies.  For the impact of PFD, safety and tolerability data from the LOTUSS trial (20) 
and outcome data from studies in which PFD was used to treat IPF (12-13) were considered 
informative. 
 
10.5.2 
Assumptions 
Based on these available data, the following assumptions were used to generate clinical outcome 
scenarios for the potential response of FVC-% over time for both the control arm (MMF+Plac) and 
the experimental arm (MMF+PFD) of SLS III:  
1)  Data from SLS I and II were used as the best available data to estimate the standard 
deviation of the FVC-% values at different times in the study and the mean change in FVC-% 
at 3, 6, 9, 12, 15 and 18 months were assumed to follow a multivariate normal distribution, 
with equivalent variances in the two treatment groups. 
2) In the same manner, data from the II study was used to inform the estimated impact of prior 
therapy with MMF, occurring prior to randomization, on the expected mean change in FVC-
% and the variance of the FVC-% values at different times after randomization. 
3)  We measured the correlation structure over time for repeated measurement of the FVC-% 
in individual subjects participating in the SLS I study and applied that to the prediction of 
outcomes for SLS III. As one might assume, correlation between measurements taken at 
closer intervals is greater than measurements taken farther apart and from SLS I data the 
correlations among outcomes 3 months apart was 0.866, 6 months apart was 0.834, and 9 
months apart was 0.802.   
4) Treatment with cytotoxic therapy (MMF or CYC) is associated with an initial period of 
deteriorating lung function during the first 3-6 months of treatment that appears due to the 
required titration of cytotoxic medication over several months and the relatively slow 
clearing of existing immune mediators that drive inflammation and tissue destruction.  This 
initial loss of lung function can average from -0.25% to -2.5%. 
5)  After an initial 3-6 month period that is associated with a relative decline of lung function, 
continued treatment with cytotoxic therapy is associated with a relative improvement in 
lung function over time that ranges from approximately +2.0 to +3.0% at 12 months and 
from approximately +3.0 to +5.0% at 18 months.  
6)  These time-dependent treatment response features, with an initial decline and delayed 
improvement, have a direct impact on the predicted course of the FVC-% over time in 
subjects who present to the study after several months of prior MMF therapy. The 
percentage of patients on cytotoxic therapy prior to randomization, and the length of prior 
treatment, need to be accounted for in predicting the overall course and magnitude of the 
change in FVC-% over time.  
7) In contrast to the delayed effects of MMF, use of PFD for the treatment of IPF is associated 
with a rapid onset that slows the decline in lung function and is seen as early as 3 months.  


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8)  In addition, given that the mechanisms of action for MMF and PFD are fundamentally 
different, it is reasonable to speculate that combination therapy (MMF+PFD) will have an 
overall impact on lung function at 18 months that is superior to either agent alone. 
 
10.5.3 
Defining the Primary Study Outcome 
The primary aim of the study is to compare the impact of combining PFD and MMF in the 
experimental arm with that of MMF plus Plac in the control arm on pulmonary function during the 
18-month double-blind period.  The primary endpoint is change from baseline in the mean forced 
vital capacity, measured as the percentage of the age-, height-, gender- and race-adjusted predicted 
value (FVC-%) over the course of the 18-month double-blind treatment period.  FVC is measured at 
baseline (pre-treatment) and then quarterly after treatment begins during the treatment period 
(i.e., months 3, 6, 9, 12, 15 and 18).  Participants are required to have FVC-% ≤ 85% at screening.   
 
10.5.4 
Clinical Trial Scenarios and Simulations to Estimate Study Power in Treatment Naïve 
Patients 
Two outcome scenarios were considered based on the two potential mechanisms of action by which 
the addition of PFD might improve the response to treatment with MMF alone. Both scenarios 
assume that the average response pattern to MMF alone (the control arm) would approximate the 
average response pattern to cytotoxic therapy observed from SLS II. In that study, the overall 
improvement from baseline in the FVC-% was approximately 3.0% at the 12 month time point and 
4.25% at 18 months. Two different response scenarios were then proposed to represent the range 
of possible responses in patients treated with combined MMF+PFD (the experimental arm).  
• 
In Scenario 1, it is assumed that treatment with PFD is associated with an early slowing of the 
decline in lung function normally observed during the first 3-6 months of cytotoxic therapy and 
that there is only a small additive effect of PFD to the later improvement in lung function. The 
collective result is a 2.5% greater response to treatment at 12 months in the experimental 
versus control arms and this difference between the groups remains the same for the duration 
of the 18-month study. 
• 
In Scenario 2, it is assumed that treatment with PFD is associated with both an early slowing of 
the decline in lung function and a definite additive effect on the overall improvement in FVC-% 
that continues throughout the entire treatment period.  The collective result is a 3.125% greater 
response to treatment at 12 months in the experimental versus control arms which continues to 
slowly increase to a final 3.25% difference between the two groups at 18 months. 
Figure 10.5.4.  Hypothesized Response Trajectories over the 18-Month Double-Blind Treatment 
Period by Treatment Group with two scenarios considered, all participants naïve to therapy.  


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The power to detect a response based on each Scenario was then calculated by carrying out 1,000 
clinical trials simulations for each scenario in SAS 9.4, using a linear mixed model with participant-
month in the study (3, 6, 9, 12, 15 and 18) as the unit of analysis and the change from baseline in 
FVC-% as the outcome, with terms for treatment group, baseline FVC-%, month and the interaction 
of treatment group with month as a fixed covariate and participant as a random effect to account 
for the correlation of outcomes over time within a participant.  (This is a simplification of the model 
used for the primary analysis of the primary endpoint described above.)  We used a compound 
symmetry variance-covariance structure.  The average power is calculated as the number of 
simulations where the F-test used to test the hypothesis that the mean change from baseline during 
the double-blind treatment period differs between the two treatment groups is rejected (p<0.05) 
divided by the number of simulations.  95% CIs for power are calculated based on the exact binomial 
proportion. 
Table 10.5.4.  Power to detect differences in the response pattern from baseline to 18 months for 
the primary outcome (change in FVC-%) when comparing the course of change in lung function over 
time for the MMF+PFD arm and the MMF+Plac arm according to the two proposed outcome 
scenarios. Results assume a 5% two-sided type I error and are provided for three different sample 
sizes (N = 75/arm; 70/arm and 65/arm) 
Assumptions: 
-  Drop-out rates, variances and data inter-correlations presented below are derived from SLS I and 
II data and assumed to be identical for the two defined scenarios 
-  A 5% two-sided type I error is assumed 
-  The difference in the outcome measure between treatment arms (relative difference in the 
change from baseline in absolute FVC %-predicted) for each scenario was estimated based on the 
hypothetical response to PFD proposed for each scenario as detailed in Figure 10.5.4. 
Scenario 1 Difference 
between treatment 
arms (FVC-%) 
Scenario 2 Difference 
between treatment 
arms (FVC-%) 
Dropout 
(Cumulative %) 
SD Estimate 
 
Assumed Correlations 
(AR1): 
Mo   3:     0.5 
Mo   6:     1.375 
Mo   9:     2.25 
Mo 12:     2.5 
Mo   3:     0.75 
Mo   6:     1.75 
Mo   9:     3.0 
Mo 12:     3.125 
Mo   3:  6.5% 
Mo   6:   13% 
Mo   9:   17% 
Mo 12:   20% 
Mo   3:   4.1 
Mo   6:   5.1 
Mo   9:   6.2 
Mo 12:   6.9 
3-mo intervals:    0.866 
6-mo intervals:    0.834 
9-mo intervals:    0.802 
12-mo intervals:  0.790 


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Mo 15:     2.5 
Mo 18:     2.5 
Mo 15:     3.25 
Mo 18:     3.25 
Mo 15:   23% 
Mo 18:   24% 
Mo 15:   6.2 
Mo 18:   6.2 
15-mo intervals:  0.780 
Power Calculations Scenario 1: 
Evaluation of Statistical Power by sample size, adjusting for drop outs over time, based on 1000 
clinical trial outcome simulations: 
N per arm at 
baseline 
N per arm 
at 18 mo 
Estimated 
Statistical Power 
95% Lower Bound of 
Statistical Power 
95% Upper Bound of 
Statistical Power 
75 
57 
82.3% 
79.8% 
84.6% 
70 
53 
78.6% 
75.9% 
81.1% 
65 
49 
76.3% 
73.5% 
78.9% 
Power Calculations Scenario 2: 
Evaluation of Statistical Power by sample size, adjusting for drop outs over time, based on 1000 
clinical trial outcome simulations: 
N per arm at 
baseline 
N per arm 
at 18 mo 
Estimated 
Statistical Power 
95% Lower Bound of 
Statistical Power 
95% Upper Bound of 
Statistical Power 
75 
57 
95.6% 
94.1% 
96.8% 
70 
53 
92.6% 
90.8% 
94.2% 
65 
49 
91.8% 
89.9% 
93.4% 
Note that with the given m-ITT design, the linear mixed effects model will actually include data from 
all subjects who have at least a baseline and one follow-up measure of FVC-%. In this setting, even 
with an overall 24% attrition by the end of 18 months, it is estimated that 83% of the maximal 
possible study outcome data points (assuming no attrition) would be included in the analysis.   
According to Scenario 1, which is strictly based on the documented capacity for PFD to slow the rate 
of decline of lung function in patients with IPF who are not receiving any other treatment, a sample 
size of 75 patients per treatment arm is required to obtain a minimum power of 80% (i.e.,  80% is 
within the 95% CI for this prediction).  If PFD has novel effects when combined with MMF so that it 
both reduces the rate of lung decline and works in concert with MMF to improve overall lung 
function (i.e., Scenario 2), then the predicted outcome will be much more reliably detected and a 
smaller sample size would be sufficient.   
 
10.5.5 
Impact of a Mixed Population of Treatment Naïve and Previously-treated Patients on the 
Estimate of Study Power 
Having established adequate estimates of study power in a population of treatment naïve patients, 
the clinical trial Scenarios were then adjusted to assess the impact of a mixed starting population of 
patients in which some of the participants are treatment naïve and others have been on prior 
treatment with MMF (or DMARD with similar activity) for a period of 3, 6 or 9 months. Additional 
assumptions associated with these modified Scenarios include: 
1) The mean change in FVC-% over a given 3-month interval and the corresponding impact on the 
standard deviation of the FVC-% measurement will always reflect the total time that a patient 
has been on therapy, including therapy that was administered before randomization and 
therapy that was administered following randomization.  


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2) The treatment effect is measured as the change from baseline, in which baseline is determined 
at the time of randomization (baseline visit). The baseline FVC-% measurement therefore 
establishes the zero reference value for evaluating change over time in response to the time 
that a patient is on the protocol.  In this setting, patients who have been on 3 months or more 
of MMF will not be expected to experience the initial decline in lung function that occurs when 
enrolling treatment naïve patients. 
3) As one of the hypothesized benefits of starting PFD and MMF at the same time in treatment 
naïve patients is the prevention of an early decline in lung function, there is a relative 
treatment penalty in the predicted PFD+MMF arm when patients have been on prior therapy 
with MMF. This results in less and less separation between the course of the two treatment 
arms as the length of time on prior MMF increases. This impact must be accounted for when 
modeling treatment outcomes and predicting study power. 
 
Figure 10.5.5.  Hypothesized Response Trajectories over the 18-Month Double-Blind Treatment 
Period by Treatment Group for Scenario 2 based on length of time on MMF therapy prior to 
randomization. 
 
The power to detect a response according to Scenario 2, when taking into account the length of 
prior treatment with MMF (naïve, 3 mo, 6 mo and 9 mo strata) and the percentage of subjects 
within each of these strata, was then calculated by carrying out 1,000 clinical trials simulations for 
each situation in SAS 9.4 as already described. We varied the proportion of patients from 100% 
naïve down to 50% naïve, with the distribution across the prior treatment with MMF strata varied as 
described below. Estimates of the differences between treatment arms and the standard deviation 


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for the measurements at a given time were adjusted according to the scenario curves shown in 
Figure 10.5.5. 
 
Table 10.5.5.  Power to detect differences in the response pattern from baseline to 18 months for 
the primary outcome (change in FVC-%) when comparing the course of change in lung function over 
time for the MMF+PFD arm and the MMF+Plac arm according to Scenario 2 with different mixtures 
of treatment naïve patients and those who were on prior MMF therapy for 3, 6 or 9 months as 
indicated. Results assume a 5% two-sided type I error and are provided for three different sample 
sizes (N = 75/arm; 70/arm and 65/arm) 
 
a. Scenario 2: N = 75 per arm 
% per stratum  
(length of prior MMF) 
Estimated statistical power based on 
1000 clinical trial outcome simulations  
Naive 
3 mo 
6 mo 
9 mo 
Power 
95% Lower 
Bound  
95% Upper 
Bound  
1.00 
0.00 
 
 
95.6% 
94.1% 
96.8% 
0.80 
0.20 
 
 
93.8% 
92.1% 
95.2% 
0.75 
0.25 
 
 
92.2% 
90.4% 
93.8% 
0.70 
0.30 
 
 
90.8% 
88.8% 
92.5% 
0.60 
0.40 
 
 
90.5% 
88.5% 
92.2% 
0.50 
0.50 
 
 
86.1% 
83.8% 
88.2% 
0.80 
0.10 
0.10 
 
91.4% 
89.5% 
93.1% 
0.70 
0.20 
0.10 
 
89.5% 
87.4% 
91.3% 
0.70 
0.10 
0.20 
 
90.2% 
88.2% 
92.0% 
0.60 
0.30 
0.10 
 
89.0% 
86.9% 
90.9% 
0.60 
0.20 
0.20 
 
88.2% 
86.0% 
90.1% 
0.60 
0.10 
0.30 
 
85.2% 
82.8% 
87.3% 
0.50 
0.40 
0.10 
 
84.7% 
82.3% 
86.9% 
0.50 
0.30 
0.20 
 
82.7% 
80.2% 
85.0% 
0.50 
0.20 
0.30 
 
82.7% 
80.2% 
85.0% 
0.50 
0.10 
0.40 
 
79.7% 
77.1% 
82.2% 
0.70 
0.10 
0.10 
0.10 
86.4% 
84.1% 
88.5% 
0.60 
0.20 
0.10 
0.10 
86.2% 
83.9% 
88.3% 
0.60 
0.10 
0.20 
0.10 
83.7% 
81.3% 
85.9% 
0.50 
0.30 
0.10 
0.10 
79.9% 
77.3% 
82.3% 
0.50 
0.20 
0.20 
0.10 
79.3% 
76.7% 
81.8% 
 
b. Scenario 2: N = 70 per arm 


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% per stratum  
(length of prior MMF) 
Estimated statistical power based on 
1000 clinical trial outcome simulations  
Naive 
3 mo 
6 mo 
9 mo 
Power 
95% Lower 
Bound  
95% Upper 
Bound  
1.00 
0.00 
 
 
91.8% 
89.9% 
93.4% 
0.80 
0.20 
 
 
91.3% 
89.4% 
93.0% 
0.70 
0.30 
 
 
88.1% 
85.9% 
90.0% 
0.60 
0.40 
 
 
86.0% 
83.7% 
88.1% 
0.50 
0.50 
 
 
84.6% 
82.2% 
86.8% 
0.80 
0.10 
0.10 
 
89.4% 
87.3% 
91.2% 
0.70 
0.20 
0.10 
 
88.7% 
86.6% 
90.6% 
0.70 
0.10 
0.20 
 
85.6% 
83.3% 
87.7% 
0.60 
0.30 
0.10 
 
85.7% 
83.4% 
87.8% 
0.60 
0.20 
0.20 
 
82.9% 
80.4% 
85.2% 
0.60 
0.10 
0.30 
 
81.5% 
79.0% 
83.9% 
0.50 
0.40 
0.10 
 
83.0% 
80.5% 
85.3% 
0.50 
0.30 
0.20 
 
81.5% 
79.0% 
83.9% 
0.50 
0.20 
0.30 
 
79.9% 
77.3% 
82.3% 
0.50 
0.10 
0.40 
 
79.9% 
77.3% 
82.3% 
 
c. Scenario 2: N = 65 per arm 
% per stratum  
(length of prior MMF) 
Estimated statistical power based on 
1000 clinical trial outcome simulations  
Naive 
3 mo 
6 mo 
9 mo 
Power 
95% Lower 
Bound  
95% Upper 
Bound  
1.00 
0.00 
 
 
91.8% 
89.9% 
93.4% 
0.80 
0.20 
 
 
88.2% 
86.0% 
90.1% 
0.70 
0.30 
 
 
85.5% 
83.2% 
87.6% 
0.60 
0.40 
 
 
81.4% 
78.9% 
83.8% 
0.50 
0.50 
 
 
79.7% 
77.1% 
82.2% 
0.80 
0.10 
0.10 
 
87.1% 
84.9% 
89.1% 
0.70 
0.20 
0.10 
 
85.5% 
83.2% 
87.6% 
0.70 
0.10 
0.20 
 
83.2% 
80.7% 
85.5% 
0.60 
0.30 
0.10 
 
78.4% 
75.7% 
80.9% 
0.60 
0.20 
0.20 
 
77.5% 
74.8% 
80.0% 
 
According to these predictions for Clinical Trial Scenario 2, representing the primary outcome to be 
investigated, the study is adequately powered (80% power or greater) to detect a difference 
between the two treatment arms when the sample size is 150 and the patient population contains at 
least 50% treatment naïve patients. If the remaining 50% of enrolled patients are limited to no more 


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than 6 months of prior therapy with MMF, then adequate power is maintained across the entire 
range of anticipated distributions between subjects with up to 3 mo of prior therapy and those with 
between 3 to 6 mo of prior therapy.  
 
As a result, the target study population will consist of at least 50% of patients who are treatment 
naïve and up to 50% of patients who recently started on therapy within 6 months of entering the 
study (as detailed in Table 10.5.5 above). With this mixture of patients, the power remains adequate 
even if only 70 patients are enrolled in each arm (total randomization 140 patients), providing 
optimal flexibility for the enrollment phase of the study. 
 
When a similar statistical approach is applied to Clinical Trial Scenario 1, in which only a small 
additive effect of PFD is modeled in addition the the underlying treatment response to MMF, the 
power to detect a difference between the two treatment arms is adequate (80% power or greater) 
when the sample size is 150 and the patient population contains at least 75% treatment naïve 
patients.  When the percentage of treatment naïve patients is reduced to 50%, the predicted power 
is at best 75% (assumes % per stratum of 50% naïve, 40% 3 mo, 10% 6 mo). 
 
10.6 MEASURES TO MINIMIZE BIAS 
 
10.6.1 
Enrollment/Randomization/Masking Procedures 
This study will use randomization and masking as two of the cardinal principles of clinical trials to 
minimize bias. 
Randomization.  Participants will be randomized after all screening assessments have been 
completed and the investigator has verified that eligibility criteria have been met.  At the time of 
randomization, participants will be assigned a unique randomization number; no participant may 
begin treatment prior to randomization.  Eligible participants will be randomized to PFD+MMF or 
MMF+Plac in a 1:1 manner, stratified by clinical site (pooled into 4 groups) and prior MMF exposure 
(naïve, >0 to <3 months, and >3 months to <6 months).  Randomization to the different strata will be 
capped if necessary to maintain at least 50% of randomized subjects within the treatment naïve 
strata (no prior therapy with MMF or DMARD) in order to maintain adequate power (as detailed in 
Section 10.5). The DCC will prepare the randomization schedule, using computer-generated block 
randomization with the block size(s) known only by the DCC.  A secure web-based application will be 
built that will be used by the coordinators to enter participant information (e.g., participant ID, 
stratification factor) and to obtain the randomization number.  The information can be printed and 
sent and/or emailed directly to the site pharmacists.  Participants who withdraw from the study 
prior to completion of the treatment period will not be replaced.   
Blinding.   This is a double-blind study.  The study staff (except for select staff at the Data 
Coordinating Center and Research Pharmacists) and the participant are blinded to the treatment 
assignment.   
 
10.6.2 
Evaluation of Success of Blinding 
Not applicable. 
 
10.6.3 
Breaking the Study Blind/Participant Code 


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Blinding is critical to the integrity of this clinical study. All participants will receive MMF in an open-
label manner and blinding pertains only to their assignment to either PFD or matching placebo. 
There are two identified situations in which unblinding to identify the investigational drug will be 
considered.  
10.6.3.1  
Unblinding associated with protocol-defined Treatment Failure. 
As detailed in Section 5.3.2, subjects who meet criteria for a protocol-defined treatment failure 
will be withdrawn from both PFD/Plac and MFF (i.e., the active drug treatment phase of the 
trial) and their clinical management transfered to an identified treating physician at the 
discretion of the patient. The study blind will not be broken unless the treating physician is 
convinced that unblinding is required in order to appropriately treat the patient and their 
request is reviewed and agreed to as compelling by the Executive Committee.  
10.6.3.2 
Unblinding associated with emergent medical necessity. 
In addition, in the event of a medical emergency in which knowledge of the investigational 
product is deemed critical to the participant's management, the blind for that participant may 
be broken.  Before breaking the blind of an individual participant’s treatment, the investigator 
should have determined that the information is necessary, i.e., that it will alter the participant’s 
immediate management. Unless time is of the essence due to the emergency nature of the 
participant's medical condition, any request for unblinding must be reviewed and agreed to as 
compelling by the Executive Committee. However, the investigator holds sole responsibility for 
the decision to unblind in case of emergency.  
In many cases, particularly when the emergency is not investigational product-related, the 
problem may be properly managed by assuming that the participant is receiving active product 
without the need for unblinding. Should unblinding of a study participant be necessary because 
of an emergency, the site personnel will login to the password-protected electronic database 
application (developed and maintained by the DCC) that will provide the treatment assignment.  
Audit procedures will ensure that the name of the individual associated with the login will be 
communicated to the DCC.  As an additional safety measure, the personnel at the clinical sites 
will be provided with telephone numbers to contact the DCC and/or Pharmacy personnel having 
access to the treatment assignment on a 24-7 basis. If unblinding occurs, it is the responsibility 
of the investigator to promptly document and explain any unblinding and the circumstances 
that led to it will be reviewed by the study Executive Committee.   
 
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 Sponsor, 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 


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transcriptions certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfildm 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 
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 
DCC staff will prepare data management and clinical monitoring plans. The clinical monitoring plan will 
detail procedures to assess accuracy of the database relative to source documents, as well as site 
adherence to regulatory and study procedures. Emphasis will be placed on the process of consenting 
subjects, compliance with regulatory requirements and study protocol, values of key endpoints, and 
identification of SAEs that may not have been reported. The data management plan will describe the 
front-and back-end edit checks, as well as forms tracking procedures, that will be implemented to 
ensure timely and high-quality data collection.  It will also define the periodic reports that will be shared 
with site coordinators and PIs that summarize site performance.  The clinical monitoring and data 
management procedures will be consistent with the International Conference on Harmonisation (ICH 
E6) standards for Good Clinical Practice (GCPs). 
Quality Assurance monitoring for essential study procedures and outcomes will be handled by the Core 
Programs including the Pulmonary Function Core, Radiology Core, Pharmacy Core and the Biorepository 
Core.  These Core programs will prepare independent manuals of operation and assume responsibility to 
inventory and monitor quality features of every study performed. Core inventory and quality assurance 
reports will be prepared in advance of and included as a component of each DSMB review.  
Monitoring of Protocol Compliance will be carried out as detailed in Section 9.0 on Clinical Monitoring 
under the direction of the DCC according to a defined Clinical Monitoring Plan. The Executive Committee 
will meet at least twice monthly to review site monitoring reports as they become available, enrollment 
and retention reports, interval AEs and SAEs, drug compliance, protocol compliance including interval 
study withdrawals and treatment failures, delinquincy reports, regulatory status updates, and interval 
reports from the Core Programs as available.  
 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 ETHICAL STANDARD  
The investigators will ensure that the study is conducted in accord with the principles of “Good Clinical 
Practice” and in full conformance with the FDA standards for human subject research as codified in 21 
CFR part 312 (Responsibility of Sponsors and Investigators), 21 CFR part 50 (Protection of Human 
Subjects), and 21 CFR part 56 (Institutional Review Boards), as well as in a manner compliant with 
Federal HIPAA Guidelines. 
 
13.2 INSTITUTIONAL REVIEW BOARD  
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form by 
the responsible IRB having jurisdiction over each clinical site form must be obtained before any 


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participant is enrolled at that site. Any amendment to the protocol will require review and approval by 
the IRB of record for each site before the changes are implemented to the study. All changes to the 
consent form will be IRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented. 
 
13.3 INFORMED CONSENT PROCESS  
It is the responsibility of the named investigators at each participating clinical study site to assure that all 
study participants undergo an appropriate process of written informed consent that has been reviewed 
and approved by their local Institutional Review Board. The investigators will inform all subjects as to 
the nature, aims, duration, potential hazards, and procedures to be performed during the study and that 
his/her medical records and study-related documents may be reviewed by the FDA, NIH or sponsoring 
companies in a manner designed to protect their confidentiality.  This protocol must receive approval by 
the Institutional Review Board at each participating site prior to implementation of the study at that 
site. Investigators must also disclose to participants any existing conflicts of interest and explain that 
patients are completely free to refuse to enter the study or to withdraw from it at any time without 
prejudice to their medical care.  The protocol will be discussed in detail with all potentially eligible 
patients and the essential components of the informed consent process personally confirmed by a 
responsible investigator before the consent is signed and countersigned. The participant will sign the 
informed consent document prior to any procedures being done specifically for the study. All revisions 
of the protocol must be reviewed by the IRB and reflected in the consent form. Patients will receive 
copies of all consent documents and HIPAA forms for their records and these documents will detail 
emergency contact numbers for the study and independent reporting numbers for the local IRB in the 
event that they have any concerns or questions about the process of consent or the handling of human 
subjects. 
 
13.4 SAMPLE INFORMED CONSENT LANGUAGE  
______________________________________________________________________________________________ 
 
DAVID GEFFEN SCHOOL OF MEDICINE AT 
THE UNIVERSITY OF CALIFORNIA LOS ANGELES 
 
CONSENT TO PARTICIPATE IN RESEARCH 
 
 
 
UCLA Site Principal Investigator: S. Samuel Weigt, M.D. 
Coordinating Center Principal Investigator: Michael D. Roth, M.D 
 
INTRODUCTION 
StudyTitle:  
Scleroderma Lung Study III (SLS 3): Combining the anti-fibrotic effects of 
pirfenidone (PFD) with mycophenolate (MMF) for treating scleroderma-
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S. Samuel Weigt, M.D., who is the Principal Investigator responsible for the UCLA site and Michael D. 
Roth, M.D., who is the Principal Investigator for the overall research study, and their associates from the 
Pulmonary and Rheumatology Divisions of the Department of Medicine at the University of California, Los 
Angeles, are conducting a research study. 
The researchers will explain this study to you. Research studies are voluntary and include only people 
who choose to take part. Please take your time about deciding whether to participate in this study. 
Before deciding: 
• 
You can discuss this study with friends and family. 
• 
You can also discuss it with your health care doctor or request a second opinion. 
• 
If you have any questions, you can ask the researchers for more information before deciding to 
participate. 
The research team is asking you to participate in this study because you are at least 18 years of age, 
have been diagnosed with Scleroderma (also called Systemic Sclerosis), your disease is felt to have been 
active for less than 7 years, and there are signs that you have lung involvement that includes shortness 
of breath and abnormal lung tests.  
 
WHY IS THIS STUDY BEING DONE?  
This research will use a double-blinded design (meaning that neither you nor the treating doctors will 
know which treatment you are on) to compare the safety and effectiveness of two experimental drug 
treatments for Scleroderma-related lung disease.  One treatment involves taking mycophenolate as the 
only study drug along with a placebo (a sugar capsule that looks the same as pirfenidone). The other 
treatment involves taking a combination of mycophenolate along with pirfenidone.   
This research is designed to test whether combining pirfenidone and mycophenolate will result in a 
more rapid and possibly greater improvement in lung function than occurs when mycophenolate is used 
alone. While both of these drugs have been approved by the U.S. Food and Drug Administration (FDA) to 
treat other medical conditions, neither drug has been FDA-approved for the treatment of scleroderma-
related lung disease.   
This study is being funded in part by Genentech, Inc. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
This study will enroll 150 patients with Scleroderma-related lung disease at research centers nationwide 
with the expectation that up to 20 will take part at the UCLA site.   
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS STUDY?  
 
Before you begin the study: Screening 
In order to determine if you are eligible for the study you will need to undergo a two-part screening 
process.  
In the first part of the screening, a routine medical history and physical examination will be performed. 
You should bring medical records for review of your history as you would for any new medical 
evaluation. A blood sample will be drawn from your arm to check your blood counts, liver and kidney 
tests.  If you recently completed blood tests (within the past 30 days) you should bring a copy of these 
results with you and, if they meet the requirements of the study, you may not need another blood draw.  
Unless already completed within the prior 30 days and considered to meet the needs of the study, you  


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will undergo breathing tests to measure how deep of a breath you can take, how easily you can blow 
out air from the lungs, and how well your lungs work at taking up gas into the bloodstream.  A brief 
questionnaire detailing any gastrointestinal symptoms will be completed. 
If you appear to qualify for the study based on the first stage of screening, then you will be asked to 
complete the second part of the screening and undergo a high resolution computerized x-ray 
examination of the lungs (chest HRCT scan). If you recently completed a chest HRCT scan (within the 
past 45 days) you should advise the study physician as it can be considered in place of completing 
another scan. If it is found to meet all of the required study criteria the study physician will advise you of 
this and a repeat chest HRCT scan performed specifically for the study will not be necessary. Otherwise, 
to complete this test you will lie still on a table that moves into a large donut-shaped machine and you 
will be asked to take a full deep breath and hold your breath at certain times. A computer will then 
provide us with very detailed images of your lungs. The process will take 30 minutes to an hour, and can 
take place on the same or a different day than the rest of your Screening visit.  
The final determination regarding whether you are eligible will not be made until you return for the first 
baseline visit. 
Before you begin the study: Washing-out other medications 
If you appear to qualify for the study based on results from the screening described above and you are 
currently (or within the past 30 days) taking either one of the study drugs (mycophenolate or 
pirfenidone) or another medication that might also act as a treatment for scleroderma-related lung 
disease (the research team will let you know), then you may need to stop these treatments and let their 
effects wash-out from your system. While a period of at 30 days off these medications is routinely 
recommended before randomization to one of the study treatment arms, the study physician will review 
the details related to your medical condition and help determine whether stopping the pre-study 
medication or continuing on it is recommended. The decision will be based on what is considered to be 
in your best interests after considering your history, lab findings and the potential risks and benefits. 
During the study: 
If you take part in this study, the researcher(s) will assign you to one of the treatment groups, ask you to 
undergo several procedures, and you will need to return for a number of study visits and procedures 
over the course of the next 19 months. The details are described below and a chart summarizing each 
procedure and each visit is included on the last page of this consent. 
 
Baseline Visit (Visit 1, Month 0) 
You will return to the clinic within 90 days of your first screening visit for Visit 1. At this visit, 
the following will take place: 
• 
You will review any changes in your health or medication with the study doctor, and answer 
questions about your symptoms. 
• 
You will complete a set of health questionnaires regarding your shortness of breath, your 
ability to function, how short of breath you are, symptoms of cough, and how you rate your 
quality of life in respect to scleroderma and your lung problems. These questionnaires will 
take 20-30 minutes to complete. You have the right to refuse to answer any question you do 
not wish to answer. 
• 
You will also complete a questionnaire addressing any gastrointestinal symptoms you may 
be experiencing (such as nausea or constipation). This questionnaire will take about 10 
minutes to complete. You have the right to refuse to answer any question you do not wish 


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to answer. 
• 
You will undergo pulmonary function tests similar to those performed during the screening. 
• 
You will give a blood sample (approximately 2-3 tablespoons drawn from a vein in your arm) 
that will be stored in a repository for use in several different types of research tests 
designed to provide information about the causes of scleroderma and the mechanisms by 
which it involves the skin and the lungs. 
• 
You will have a pregnancy test if you are a woman who is able to become pregnant. 
If it is determined that you are eligible for the study, you will be randomly assigned to one of the 
study groups indicated below and given medication to take home with you. Because some test 
results may not be available immediately, the determination of eligibility might not occur the day of 
your visit. If this is the case, the medication will be mailed to you or you can come to the clinic to 
pick it up. 
 
Treatment Group Assignment 
If you qualify, you will be randomly assigned (like the flip of a coin) to one of the following 
two groups: 
• Mycophenolate, up to a target dose of 1.5 gram twice daily, as tolerated, plus placebo 
capsules. 
• Mycophenolate, up to a target dose of 1.5 gram twice daily, as tolerated, plus pirfenidone, 
administered up to a target dose of 801 mg three times daily as tolerated. 
‘Target dose’ means that we will aim to have all participants in each group on this dose of the 
drug. However, different people react differently to drugs, so we may have to adjust the dose 
for some participants. You have an equal (50/50) chance of being in either group.  Some participants 
will receive placebo capsules instead of pirfenidone.  A placebo is a pill that looks like the study drug 
but contains no active medication. The placebo will make it so that neither you nor the study doctor 
will know which study group you are in. However, this information can be obtained if there is an 
emergency or if it is necessary to know for your health. You won’t start the study taking the target 
doses; rather your dose will be titrated up (slowly increased) to the indicated doses but it may be 
held or continued at a lower dose if you do not tolerate. People in the mycophenolate plus 
pirfenidone group will receive two active drugs without a placebo.  
 
Regular Follow-up Visits (Visits 3, 5-9, 12, 15, 18, 21)  
Blood and Urine Testing 
There are a number of potential side effects of the study drugs that may be detected only through 
regular blood testing. Therefore, you will be required to attend a clinic to give regular blood (1 ½ - 3 
½ teaspoons) for routine lab tests and urine for pregnancy testing, if applicable, throughout the 
study. These samples will be collected every month for the first 6 months and every 3 months 
thereafter. Based on your tolerance of the medication and the results of this laboratory testing, 
your dosage of medication may be adjusted and it is possible that additional blood testing might be 
required to monitor more closely. 
Other Monitoring and Assessments 
During each of these regular follow-up visits you will also see a study doctor and the study staff so 
that other monitoring and outcome assessments can take place. Each assessment will not 
necessarily be completed at each visit, so the timing for each one is indicated below. 


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• 
You will review any changes in your health or medication with the study doctor, and answer 
questions about your symptoms.  
- This will occur at every visit (Visits 3, 5-9, 12, 15, 18, 21). 
• 
You will have a targeted physical exam in order to assess the extent of your scleroderma.  
- This will occur at every visit (Visits 3, 5-9, 12, 15, 18, 21). 
• 
You will be asked to maintain a study medication calendar and keep all of the bottles of 
study drugs that are supplied to you. You will need to bring the completed calendar and all 
bottles and containers of medication, whether completely or partially used (or not used at 
all) to every visit. A study coordinator will review the calendar and your use of medications 
at every visit. 
- These will be checked at every visit (Visits 3, 5-9, 12, 15, 18, 21). 
• 
You will complete breathing tests to measure how deep of a breath you can take, how easily 
you can blow out air from the lungs, and how well your lungs work at taking up oxygen into 
the bloodstream.  
- This testing will occur at 3 month intervals (Visits 6, 9, 12, 15, 18, 21). Breathing tests 
will take approximately 30-45 minutes to complete.  
• 
You will complete health-related questionnaires.  
- Questionnaires directly assessing your breathing and the impact of shortness of breath 
on your activity will need to be completed at 3 month intervals (Visits 6, 9, 12, 15, 18, 
21). These questionnaires will take 10-20 minutes to complete. You have the right to 
refuse to answer any question you do not wish to answer.  
- Questionnaires regarding your ability to function, symptoms of cough, any 
gastrointestinal symptoms, and how you rate your quality of life in respect to your 
scleroderma will need to be completed at 6 month intervals (Visits 9, 15, 21). These 
questionnaires will take 10-20 minutes to complete. You have the right to refuse to 
answer any question you do not wish to answer. 
Interval Phone Visits (Visits 2, 4, 10-11, 13-14, 16-17, 19-20) 
Some of the regular monitoring for this study will occur over the phone and will not require that you 
present to the clinic (or study center) for an in-person visit. At a pre-arranged date and time, the 
study team will contact you to obtain information about how you are doing, ask you whether any 
changes to your health or use of medications has occurred, ask you to report any side effects or 
adverse health events, and to review the use of your study drugs.  
Extra Follow-up Safety Visits (if needed) 
If you should get a side effect that requires adjustment to your dose of study medication, you may 
be required to attend the clinic to provide blood samples for routine lab safety tests every 1-2 weeks 
until the side effect is resolved or until a proper dose of medication is identified. 
Visit 15 (Month 12 = 336 days, +/- 14 days) 
In addition to testing completed at the Regular Follow-up Visits described above, the following will 
take place: 
• 
You will give a blood sample (approximately 2-3 tablespoons) that will be stored in a 
repository for use in several different types of research tests designed to provide 
information about the causes of scleroderma and the mechanisms by which it involves the 
skin and the lungs. This will be taken at the same time as your other blood sample and will 
not require an extra needle-stick. 
• 
You will have a more extensive history and physical examination with the study physician 


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that will include an overall assessment of your health in addition to issues specifically 
related to Scleroderma and Scleroderma-related lung disease 
Visit 21 (Month 18 = 504 days, +/- 14 days) 
In addition to testing completed at the Regular Follow-up Visits described above, the following will 
take place: 
• 
You will give a blood sample (approximately 2-3 tablespoons) that will be stored in a 
repository for use in several different types of research tests designed to provide 
information about the causes of scleroderma and the mechanisms by which it involves the 
skin and the lungs. This will be taken at the same time as your other blood sample and will 
not require an extra needle-stick. 
• 
You will undergo a high resolution CT (HRCT) scan of the chest. 
 
Final Follow-up Telephone Visit (Visit 22 or within 30 days of permanently stopping treatment if that 
should happen) 
At a pre-arranged date and time, the study team will contact you to carry out the final study contact. 
This might occur one month after completing the entire 18 months of active drug treatment or it 
might occur within 30 days of permanently stopping treatment and prematurely withdrawing from 
the study, if that should occur. As part of this final telephone visit, the following will take place. 
• 
You will review any changes in your health or use of medications and answer 
questions about your symptoms. 
• 
You will be asked to report any side effects or adverse health events 
 
Additional Visit for those who prematurely discontinue taking the study treatment: 
If you prematurely and permanently stop taking study drugs for any reason (i.e. stop both 
pirfenidone/placebo and mycophenolate), you will be asked to return to the clinic for the Month 12  and 
Month 18  visits as described above. The additional visits and the data obtained from them will help 
achieve our research goals even if you are no longer taking study drug. While we ask that you return for 
the visits if at all possible, you have the right to refuse to complete the visits. 
However, If only the pirfenidone/placebo study drug is permanently stopped, and you are approved to 
continue taking mycophenolate according to the protocol, then you may continue participation in all 
study visits according to the normal study protocol. 
 
Management of Treatment Failures: 
If, after the first 3 months of being on study drug, your lung function markedly decreases, you will be 
asked to stop taking the study drugs (both the pirfenidone/placebo capsules and the mycophenolate 
capsules.) If that situation occurs, the study team will work with you and your treating physician to 
review your medical condition and develop an alternative treatment plan that is independent from this 
research study. The exact type of treatment that you might receive, including the responsibility for all 
the medications and testing involved, would be up to you and your treating physician to determine. 
However, regardless of the type of treatment that you receive after stopping the study drug, we would 
ask that you return to and complete the Month 12 and Monh 18 visits as detailed above. The additional 
visits and the data obtained from them will help achieve our research goals even if you are no longer 
taking study drug. While we ask that you return for the visits if at all possible, you have the right to 
refuse to complete the visits. 
 


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HOW LONG WILL I BE IN THIS STUDY?  
This study will last approximately 19 months from the time you are assigned to a specific treatment 
group, which includes the 18 months of active drug therapy and the final telephone follow-up 
approximately 30 days after stopping drug therapy. Your participation is voluntary and if you should 
decide to do so, you may withdraw at any time in which case your participation would be shorter than 
described. 
In addition to your participation in the study visits described above, you will be asked at the end of this 
consent form (section on “Signature of the Participant”) to indicate whether you are willing (or not) to 
be contacted on an annual basis for up to 5 years after you complete this study. During this contact you 
will be asked to provide an update regarding your health, symptoms related to your scleroderma and to 
describe any other treatments that you might have received for your condition.  
 
WHAT KINDS OF RISKS OR DISCOMFORTS COULD I EXPECT?  
For your safety, you must tell the study staff about all medications you are taking before you start the 
study, and any changes in your medications while on the study. There may be unknown or 
unforeseeable risks to participation in the study. It is important that you report any and all symptoms or 
possible reactions to your study doctor, even if you think it isn’t related to your study participation. 
All drugs and testing have the potential for side effects. Although the experimental drug treatments that 
will be used in this study have been well- tested in laboratory and animal studies, and in patients taking 
them for other reasons, the potential side effects in patients with scleroderma are not completely 
known at this time. You will be followed closely by the study team for the entire time you are a part of 
this study. If you experience any side effects from the study, the researchers will provide you with the 
treatment that has the best chance of taking care of the side effects. If you experience any side effects 
related to the study drugs that continue at the end of study, we will continue to follow-up with you until 
these effects stabilize or resolve. 
 
Known risks and discomforts associated with the study drugs: 
Risk of pregnancy and breast feeding during study treatment: 
Mycophenolate can harm the fetus when administered to a pregnant woman and use of 
mycophenolate during pregnancy is associated with an increased risk of first 
trimester pregnancy loss and an increased risk of congenital malformations, especially 
external ear and other facial abnormalities including cleft lip and palate, and anomalies of 
the distal limbs, heart, esophagus, kidney and nervous. There are no adequate and well-controlled 
studies of pirfenidone in pregnant women but it was not found to be harmful in animal studies. It is 
not known whether or not these drugs are excreted in human breast milk, but many drug are. In 
addition, there may also be other unknown risks of the study drugs and procedures to pregnant 
women, fetuses, and nursing children. As all study participants will receive mycophenolate, those 
who are able to become pregnant (those less than age 55, who have not been postmenopausal for 
at least 5 years and who have not had surgery to remove the fallopian tubes, uterus and/or ovaries) 
and wish to participate will be required to use approved contraception methods and to be 
monitored with frequent urine pregnancy tests throughout the study. Women who are 
breastfeeding will not be eligible to participate in this study.  
For this reason, women who are able to become pregnant must agree to either abstinence (to avoid 
heterosexual intercourse completely) or use two acceptable methods of birth control throughout 
the study and must have negative urine pregnancy tests in order to continue their participation in 


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the study. Acceptable methods of birth control include hormonal contraceptives (oral contraceptive 
pills, patch, vaginal ring), implantable contraceptives (such as Norplant, levonorgestal IUS), 
injectable contraceptive (such as Depo-Provera), barrier methods (such as male/female condoms, 
diaphragm, cervical cap), spermicides (such as vaginal sponge, spermicidal cream, foam or jelly), 
intrauterine contraceptive devices (IUD), or surgical sterilization (tubal ligation, vasectomy). The 
study staff will discuss this with you further. If you think you are pregnant or become pregnant, you 
must tell the study doctor immediately. Follow-up information on the outcome of your pregnancy 
will be requested, such as if there is anything unusual in the progress of your pregnancy or if it ends 
early. The study doctor may share this information with the sponsor, the funding source 
(Genentech, Inc.) and with the IRB (Institutional Review Board). 
Risks of Mycophenolate: 
For the risks of the study drug noted below, the number in parentheses indicates the percentage of 
patients in whom the side effects have been seen. 
Common risks experienced by patients taking mycophenolate to prevent organ transplant rejection 
include: 
• Urinary tract infection (37%) 
• Diarrhea (31%), constipation (23%), and nausea (20%) 
• Hypertension (28%)  
• Peripheral edema (swelling of tissues, usually in the lower limbs, 29%) 
• Anemia* (low red blood cells, 26%), leucopenia (low white blood cells, 23%), and 
thrombocytopenia (low blood platelets, 10%) 
*Anemia may cause easy fatigue or loss of energy; rapid heartbeat, shortness of breath, and 
headache especially during exercise; difficulty concentrating; dizziness; and pale skin.  The 
effects of anemia may be reduced with treatment like certain dietary supplements. 
• Abdominal (belly) pain (25%), fever (21%), headache (21%) and infection (19%) 
• Respiratory infection (22%), dyspnea (shortness of breath, 16%), and increased cough (16%) 
• Tremor (shakiness, 11%), insomnia (inability to sleep, 9%), and dizziness (6%) 
• Skin rashes (8%) and acne (10%) 
• Hypokalemia (low potassium in the blood, usually with no symptoms, 9%) 
• Gastrointestinal hemorrhage (heavy bleeding from the lining of your stomach or intestine, 
5%)  
Like all drug treatments that suppresses the immune system, the use of mycophenolate can increase 
the risk of infections and it is important to use good hygiene, avoid obvious exposures to those with 
active infections, and to report any concerns about infection as early as possible to your primary 
doctor and the study team. Other side effects may be dose-dependent and this study will slowly 
increase the dose of mycophenolate over several months, monitor for any problems, and adjust the 
dosing if necessary to help avoid serious problems. 
 
Rare (infrequent) but serious risks experienced by patients taking mycophenolate to prevent organ 
transplant rejection include:  
• Progressive multifocal leukoencephalopathy (PML) is a neurologic disorder that can be fatal 
and has been reported in patients that were taking mycophenolate. However, all of the 
patients receiving mycophenolate for prevention of transplant rejection in whom PML has 
been reported were receiving other drugs that cause severe immunosuppression at the 
same time and PML has not previously been reported in patients treated with 
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• BK Virus has been rarely reported when mycophenolate is used in combination with other 
drugs that cause immunosuppression. A large portion of the general population already 
carries BK Virus with no symptoms, but taking mycophenolate may cause you to develop 
symptoms, like kidney problems. In general, reactivation of latent (resting) viruses is a 
theoretical risk whenever the immune system has been severely depressed by drugs. 
• Pure red cell aplasia (PRCA) is a type of anemia in which the bone marrow stops producing 
red blood cells, and may cause symptoms like paleness, weakness, and tiredness. Cases of 
PRCA have been reported in patients treated with mycophenolate when used in 
combination with other drugs that suppress the immune system. PRCA has not previously 
been reported in patients treated with mycophenolate as the sole immunosuppressive drug 
for scleroderma-related lung disease.  
• Patients receiving immunosuppression that involves a combinations of drugs, including 
mycophenolate as part of the treatment, are at increased risk of developing lymphomas and 
other malignancies, particularly of the skin. The risk appears to be related to the intensity 
and duration of immunosuppression rather than to the specific use of mycophenolate. As 
usual for patients with increased risk for skin cancer, exposure to sunlight and UV light 
should be limited by wearing protective clothing and using a sunscreen with a high 
protection factor. Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of 
patients when they were receiving mycophenolate (2 g or 3 g daily) along with other 
immunosuppression as part of the treatment for kidney, heart, and liver transplantation. 
Lymphoma has not previously been reported in patients treated with mycophenolate as the 
sole immunosuppressive drug for scleroderma-related lung disease, although there have 
been reports of benign skin cancer. 
Most of the patients in whom the rare but serious side effects noted above were seen were also 
receiving other drugs known to cause immune suppression and to be associated with these 
complications. Few serious side effects have been reported in patients receiving mycophenolate for 
scleroderma-related lung disease and this study has been specifically designed to avoid the use of 
other potent immune suppressive drugs. 
Risks of Pirfenidone: 
For the risks of the study drug noted below, the number in parentheses indicates the percentage of 
patients in whom the side effects have been seen. 
Common risks experienced by patients taking pirfenidone to treat idiopathic pulmonary fibrosis 
include: 
• Skin rashes (30%), photosensitivity skin reactions (those occurring in sun-exposed skin; 9%), 
and itching (8%) 
• Nausea (36%), Diarrhea (26%), Abdominal discomfort (which can include stomach, upper 
abdomen or lower abdomen; 22%), Indigestion (19%), Vomiting (13%), and gastroesophageal 
reflux (the feeling that acid is backing up into the esophagus; 11 %), 
• Fatigue (26%)  
• Dizziness (18%), altered taste (6%), Insomnia (10%) 
• Decreased appetite (13%), Weight loss (10%) 
• Achy joints (10%) 
• Elevation of liver enzymes (ALT, AST, GGT, 0.3% - 4% each) 
In most cases (>80%), the common side effects associated with taking pirfenidone are only mild to 
moderate in severity, occur more frequently when first starting the drug treatment and often 


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resolve with time, and are dose-dependent. Skin rashes that occur in sun-exposed skin can be 
avoided by wearing hats, long sleeves, and using sunscreen whenever you are going to be out in the 
sun. If skin rashes do develop, the most often respond to a simple over the counter topical 1% 
cortisol cream. Pirfenidone should be taken with some food to reduce the impact on the stomach 
and abdominal symptoms. This study was also specifically designed to slowly increase the dose of 
pirfenidone, monitor for any problems, and adjust the dosing if necessary to help avoid serious 
problems. 
Rare (infrequent) but serious risks experienced by patients taking pirfenidone to treat idiopathic 
pulmonary fibrosis include:  
• Angioedema (swelling of the face, lips, tongue and throat) has rarely been reported in 
patients (in the range of 1 in 100 to 1 in 1,000 patients) who recently started pirfenidone, 
usually occurring in the first 90 days of treatment. This condition has not been observed in 
any patients involved in clinical trials with pirfenidone but should symptoms occur, they 
require immediate medical attention as swelling of the tongue and throat can be serious 
and potentially life-threatening. 
• Usually, the changes in liver function tests that occur with pirfenidone do not impair liver 
function, but rarely altered liver function is also observed (an elevated bilirubin test). In all 
cases that were observed during prior clinical trials, this has been reversible with holding or 
stopping the medication and it is important to have regular blood test monitoring and to 
adjust the dose of study drug if asked by your study team to do so. However, in 
postmarketing reports, very rare cases of atypical drug-induced liver injury have occurred, 
including severe liver injury with fatal outcome. 
 
Known risks and discomforts associated with the study tests and assessments: 
Risks associated with randomization:  
You will be assigned to a study group at random (by chance). Your assignment is based on chance 
(like a coin flip) rather than a medical decision made by the researchers. The study group you are 
assigned to might not be the group you would prefer to be in. It might also prove to be less effective 
or have more side effects than the other study group even though information about such an 
outcome is not currently known. 
Loss of confidentiality:  
As this study involves the use of your identifiable, personal information, there is a chance that a loss 
of confidentiality will occur. The researchers have procedures in place to lessen the possibility of this 
happening (see “How will my information be kept confidential?” section below).  
Risks associated with questionnaires: 
Questionnaires require that you provide information about your health, how you feel, and how 
different situations impact on your activity and well-being. Sometimes questions of this type can 
cause a person to feel anxious or vulnerable. You have the right to refuse to answer any question 
you do not wish to answer. 
Blood draw risks:  
Drawing blood may cause temporary pain from the needle stick, bruising or swelling at the site, and 
rarely, infection or fainting. 
Risks of Breathing Tests: 
Discomfort is unusual during these breathing tests. However, some people experience temporary 
shortness of breath, cough, chest discomfort, lightheadedness or fainting, or headache while 


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undergoing these tests. These feelings are usually temporary and resolve on their own. You will be 
closely monitored during these tests, and treatment will be available in case you experience any 
symptoms.  If you start to feel any unusual symptoms, please tell the study staff immediately. 
HRCT scan risks: 
HRCT scans involve exposure to radiation, a form of energy that is known for its potential to cause 
tissue injury. You are exposed to radiation on a daily basis, both from natural (sun and earth) and 
manmade sources. The estimated radiation dose that you will receive as a participant for this type 
of research is compared below to the limits allowed for a radiation worker. This limit for radiation 
workers is low and is set at a level that is not expected to be harmful. The estimated radiation dose 
that you will receive as a result of each additional CT scan in this study has been calculated to be 
about 2.4% of the annual limit allowed radiation workers. One HRCT scan is proposed during the 
screening phase of the study and a second will occur at completion of the study, 18 months later. 
The person obtaining your consent can answer any questions you have, and provide more detailed 
information about the amount of radiation resulting from this study. 
Having an HRCT scan may mean some added discomfort for you. In particular, you may be bothered 
by feelings of claustrophobia or anxiety when placed inside the CT scanner, or by lying in one 
position for a long time. However, the HRCT protocol included in this study is relatively brief and the 
time inside the enclosed portion of the scanner is usually no more than a few minutes.  
 
Unknown risks and discomforts: 
The experimental treatments may have side effects that no one knows about yet.  The researchers will 
let you know if they learn anything that might make you change your mind about participating in the 
study.  
 
ARE THERE ANY BENEFITS IF I PARTICIPATE? 
Possible benefits to me: 
You may not receive any specific benefits from participation in this study. However, if mycophenolate or 
pirfenidone is effective in the treatment of scleroderma-related lung disease, then it could be possible 
that you may receive the benefits of improvement in lung function and possibly even improvement in 
other organ involvement (that is, other organs that have been affected by your scleroderma such as the 
skin or heart).  
Possible benefits to others or society: 
This study will also help the researchers learn more about these drug treatments. Hopefully this 
information will help in the treatment of future patients with conditions like yours.  
 
WHAT OTHER CHOICES DO I HAVE IF I DON’T WANT TO PARTICIPATE? 
If you decide not to take part in this study, or if you withdraw from this study before it is completed, you 
can still discuss potential alternative treatments with your personal physicians. There is one medication 
approved by the FDA (nintedanib, brand name Ofev®) that may slow the rate of decline in some aspects 
of lung function in patients with scleroderma-related interstitial lung disease. Your physicians may be 
able to prescribe this medication or a course of treatment based on what they decide is in the best 
interest of your care even if it is not FDA approved. Alternatively, there may be other research studies 
that offer other forms of experimental therapy that you could consider. Before you decide to take part 
in this study, you may discuss the benefits and risks of potential alternatives with the study doctor. 
 


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CAN THE RESEARCHERS REMOVE ME FROM THIS STUDY?  
The researchers may end your participation in this study for a number of reasons, such as if your safety 
and welfare are at risk, if you do not follow instructions or if you miss scheduled visits. The researchers 
or the study sponsor might also decide to stop the study at any time. 
If you are asked to permanently discontinue both study drugs for any reason,  the researcher will ask 
you to partake in a close-out telephone interview and return unused study medication. The data 
collected about you up to the point of withdrawal will remain part of the study and may not be removed 
from the study database. In addition, you will be asked to return to the clinic for the Month 12 and 
Month 18 visits that are described above (see section on, “What will happen if I take part in this study”). 
These additional visits and the data obtained from them will help achieve our research goals even if you 
are no longer taking study drug. While we ask that you return for these visits if at all possible, you have 
the right to refuse to complete either one or both of the requested visits. 
 
HOW WILL INFORMATION ABOUT ME AND MY PARTICIPATION BE KEPT CONFIDENTIAL? 
The researchers will do their best to make sure that your private information is kept confidential. 
Information about you will be handled as confidentially as possible, but participating in research may 
involve a loss of privacy and the potential for a breach in confidentiality. Study data will be physically 
and electronically secured.  As with any use of electronic means to store data, there is a risk of breach of 
data security.   
Storage and use of personal information that can identify you: 
When you receive hospital services, testing and medical evaluations that are intended for your personal 
medical care, such information will be stored and handled as would any other confidential medical 
records for hospital and physician services. Information and blood samples that are stored for the 
purposes of the research study will be coded with a unique study identification number to protect your 
identity. Personal identify information, such as name and date of birth, will not be attached to such 
samples or information. However, the UCLA Principal Investigator and the Data Coordinating Center for 
the study, which is separately located at the University of Michigan School of Public Health, will maintain 
a link between the code and your personal identifying information. This code will be maintained in a 
secured and password-protected manner so that only the Principal Director and the Data Coordinating 
Center Director will have access. Other researchers who may use your samples or information obtained 
about you during the study will not be provided with the link or any personal identifying information.  
People and agencies that will have access to your information: 
The research team, authorized UCLA personnel, the Data Coordinating Center, and regulatory agencies 
such as the Food and Drug Administration (FDA), may have access to study data and records to monitor 
the study.  Genentech, Inc., the manufacturer of pirfenidone (Esbriet®), may also have access to study 
data and records in the event of a required audit or in the course of preparing filings to regulatory 
agencies such as the FDA. Research records provided to authorized, non-UCLA personnel will not contain 
identifiable information about you. Publications and/or presentations that result from this study will not 
identify you by name. 
How long information from the study will be kept: 
Research data, records and specimens will be maintained for a period of at least 7 years after the 
initiation of this research study and may be retained for longer periods if required to achieve the study 
goals or by regulatory agencies such as the FDA.  


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ARE THERE ANY COSTS FOR TAKING PART IN THIS STUDY? 
The study will supply and pay for the cost of supplying and administering the study drugs and extra 
laboratory tests that are carried out specifically for the research which include the HRCT scan of the 
chest performed during the screening and at the 18-month visit, and the breathing tests that are 
performed every 3 months during the course of your participation in the study.  
However, you and your insurer may be billed for the costs of all other study procedures and for the costs 
of any standard medical care that you receive during your participation in the study and you will be 
responsible for any associated co-payments and deductibles. There is a possibility that your medical 
insurance company may not cover these costs because you are in a research study. If this happens you 
might have unexpected expenses from being in this study, such as the costs associated with treating side 
effects. Financial counseling and itemized cost estimates are available upon request.  
 
WILL I BE PAID FOR MY PARTICIPATION?  
You will not be paid for your participation in this research study. 
 
WHAT OTHER THINGS SHOULD I CONSIDER BEFORE PARTICIPATION? 
Use of My Specimens: 
Any specimens (e.g., tissue, blood, urine) obtained for the purposes of this study will become the 
property of the University of California. Once you provide the specimens you will not have access to 
them. The University may share your specimens in the future with other researchers or outside 
institutions. Information that identifies you will not be shared with anyone outside of UCLA. The 
specimens will be used for research and such use may result in inventions or discoveries that could 
become the basis for new products or diagnostic or therapeutic agents. In some instances, these 
inventions and discoveries may be of potential commercial value and may be patented and licensed by 
the University. You will not receive any money or other benefits derived from any commercial or other 
products that may be developed from use of the specimens. 
Researcher Financial Interests in this Study: 
[To be updated by UCLA site investigators as part of their separate IRB application] 
  
WHO CAN I CONTACT IF I HAVE QUESTIONS ABOUT THIS STUDY? 
The Research Team: 
You may contact [name(s) to be updated by UCLA site investigators as part of their separate IRB 
application] at [phone number(s) to be updated by UCLA site investigators as part of their separate IRB 
application] with any questions or concerns about the research or your participation in this study. You 
can also call the UCLA Page Operator at (310) 825-6301 to reach [insert name(s)] 24 hours a day, 7 days 
week. 
UCLA Office of the Human Research Protection Program (OHRPP): 
If you have questions about your rights while taking part in this study, or you have concerns or 
suggestions and you want to talk to someone other than the researchers about the study, you may 
contact the UCLA OHRPP by phone: (310) 825-5344; by email: mirb@research.ucla.edu or U.S. mail: 
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Public Information about this Study: 
ClinicalTrials.gov is a website that provides information about federally and privately supported clinical 
trials. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.  
 
WHAT HAPPENS IF I BELIEVE I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?  
It is important that you promptly tell the researchers if you believe that you have been injured because 
of taking part in this study. You can tell the researcher in person or call him/her at the number(s) listed 
above. 
 
If you are injured as a result of being in this study, UCLA will provide necessary medical treatment. The 
costs of the treatment may be covered by the University of California or billed to you or your insurer just 
like other medical costs, depending on a number of factors. The University does not normally provide 
any other form of compensation for injury.  For more information about this, you may call the UCLA 
Office of the Human Research Protection Program at 310-825-5344 or send an email to 
mirb@research.ucla.edu. 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY?  
Taking part in this study is your choice. You can choose whether or not you want to participate. 
Whatever decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. 
• You have a right to have all of your questions answered before deciding whether to take part. 
• Your decision will not affect the medical care you receive from UCLA. 
• If you decide to take part, you can leave the study at anytime.  
• 
If you decide to stop being in this study you should notify the research team right away. The 
researchers may ask you to complete some procedures in order to protect your safety.  
• If you decide not to take part, you can still get medical care from UCLA. 
 
HOW DO I INDICATE MY AGREEMENT TO PARTICIPATE?  
If you agree to participate in this study you should sign and date below. You have been given a copy of 
this consent form and the Research Participant’s Bill of Rights to keep. You will be asked to sign a 
separate form authorizing access, use, creation, or disclosure of health information about you. 
 
SIGNATURE OF THE PARTICIPANT  
 
______________________________________ 
Name of Participant 
 
______________________________________ ______________________ 
Signature of Participant  
 
 
 
 
 
      Date 
 
 
Please initial one of the spaces below to indicate whether we may contact you annually for up to 5 years 
after the study: 
 


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 I agree to be contacted annually for up to 5 years after the study. 
 
  
 I decline to be contacted annually for up to 5 years after the study 
 
SIGNATURE OF PERSON OBTAINING CONSENT 
 
______________________________________ ______________________ 
Name of Person Obtaining Consent  
 
 
      Contact Number 
 
______________________________________ ______________________ 
Signature of Person Obtaining Consent 
 
 
Date 
 


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SCHEDULE OF STUDY VISITS AND ASSESSMENTS 
 
 
SCREENING AND INITIAL 6 MONTHS 
Type of Visit: 
Screen 
Baseline 
Phone 
Regular 
Phone 
Regular Regular Regular Regular Regular 
Visit #: 
S1-2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study Month: 
 
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
 
 
Assessments 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Review Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Describe Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Lung function testing 
X 
X 
 
 
X 
X 
Blood sample  
X 
X 
 
X 
X 
X 
X 
X 
Questionnaires 
X 
X 
 
 
X 
X 
HRCT scan of chest 
X 
 
Pregnancy test* 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Blood for storage 
X 
 
 
 
* For women who are able to become pregnant; require a blood test at screening then urine testing. 
 
 
MONTHS 7-19 AND (OPTIONAL) EXTRA FOLLOW-UP FOR 5 YEARS 
Type of Visit: 
Phone 
Regular 
Phone 
One 
Year 
Phone 
Regular 
Phone 
18 
Month 
Final 
Phone 
Extra 
Visit #: 
10-11 
12 
13-14 
15 
16-17 
18 
19-20 
21 
22 
 
Study Month: 
7, 8 
9 
10, 11 
12 
13, 14 
15 
16, 17 
18 
19 
Yrs 2-5 
 
 
Assessments 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
 
X 
 
X 
 
X 
 
X 
 
 
Medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lung function testing 
 
X 
 
X 
 
X 
 
X 
 
 
Blood sample  
 
X 
 
X 
 
X 
 
X 
 
 
Questionnaires 
 
X 
 
X 
 
X 
 
X 
 
 
HRCT scan of chest 
 
 
 
 
 
 
 
X 
 
 
Pregnancy test* 
 
X 
 
X 
 
X 
 
X 
 
 
Blood for storage 
 
 
 
X 
 
 
 
X 
 
 
* For women who are able to become pregnant; require a blood test at screening then urine testing. 
 
 
 


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13.5 PARTICIPANT AND DATA CONFIDENTIALITY  
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records.  
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations.  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the University of Michigan Data Coordinating Center. This will not 
include direct links to the participant’s contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study data entry 
and study management systems used by clinical sites and by the University of Michigan Data 
Coordinating Center research staff will be secured and password protected. At the end of the study 
when all subject follow-up and analysis is complete, verified and secured, all study databases will be de-
identified and archived.  
 
13.6 FUTURE USE OF STORED DATA AND SPECIMENS  
Data and biological samples collected for this study will be prepared, analyzed and/or stored at the 
University of Michigan Data Coordinating Center and the UCLA Administrative and Contracting Core, 
respectively, under the direction of their Directors. After specific phases of the study are completed, as 
appropriate, the de-identified, archived data and specimens will be available for use by other 
researchers including those outside of the study. Permission to use data and specimens for such 
purposes will be provided by consenting participants and included in the informed consent, with such 
use approved by the appropriate institutional IRBs.  
Such data and samples are intended for research into the causes of Scleroderma-associated ILD and its 
associated conditions, the natural history and biology of the disease, its progression and its treatment.  
 
14 DATA HANDLING AND RECORD KEEPING  
 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Comprehensive data coordinating center (DCC) functions for this clinical trial, including clinical 
monitoring, database development, web-based data entry and management, as well as the creation and 
export of study reports for the DSMB will be provided by the University of Michigan Statistical Analysis 
of Biomedical and Education Research (SABER) group.  Housed in the top nationally ranked Department 


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of Biostatistics, SABER, in its 17-year existence, has served as the DCC for over 50 studies, including 
multiple NIH-sponsored networks.   
The DCC will use OpenClinica® (OpenClinica Clinical Trial Software; OpenClinica, LLC, Waltham, MA), a 
clinical trial software platform for electronic remote (i.e., site-based entry) data capture and clinical data 
management, as the basis for our custom-designed data entry and management system. The majority of 
data will be collected via electronic Case Report Forms (CRFs); however, other data sources, such as 
laboratory data from the central laboratory, may be used. In these circumstances, the DCC will also 
utilize electronic data transfer. Protocols for the transfer of data, with careful attention to data integrity, 
will be written by experienced programmers and stored in the OpenClinica database or data mart.   
The DCC has established a set of standard operating procedures (SOPs) governing the processes used to 
ensure patient privacy and data confidentiality, including the use of anonymous participant IDs on CRFs 
and in reports. OpenClinica® enables compliance with Good Clinical Practice (GCP) and regulatory 
requirements by providing differentiated user roles and privileges, password and user authentication 
security, electronic signatures, SSL encryption, and comprehensive auditing to record and monitor 
access and data changes. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported.  In addition to the protocol, the DCC will prepare a Manual of Operations will 
provides additional detail on data collection procedures, including source documentation, eCRF 
completion guidelines, data handling procedures and procedures for data monitoring and quality control 
that ensure these data are accurate, consistent, complete and reliable and in accordance with ICH 36.   
 
14.2 STUDY RECORDS RETENTION  
Study documents are to be retained for a minimum of 2 years after the last approval of a marketing 
application and until there are no pending or contemplated marketing applications or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational 
product for the studied purpose. These documents should be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained. 
 
14.3 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. 
The noncompliance may be either on the part of the participant, the investigator, or the study site staff.   
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation or scheduled protocol-required activity.  The 
DCC will also assess compliance with the protocol during its monitoring visits.  The DCC will summarize 
protocol deviations in site performance reports.  As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
 
14.4 PUBLICATION AND DATA SHARING POLICY 
The Faculty of the University of California are committed to disseminating its research and scholarship 
as widely as possible. In particular, as part of a public university system, the Faculty is dedicated to 
making its scholarship available to the people of California and the world. Each Faculty member grants 


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to the University of California a nonexclusive, irrevocable, worldwide license to exercise any and all 
rights under copyright relating to each of his or her scholarly articles, in any medium, and to authorize 
others to do the same, for the purpose of making their articles widely and freely available in an open 
access repository. This policy does not transfer copyright ownership, which remains with Faculty authors 
under existing University of California policy.  
The study will comply with Section 801 of the Food and Drug Administration Amendments Act of 2007, 
and this clinical trial will be registered in ClinicalTrials.gov, a freely available public registry sponsored by 
the National Library of Medicine.  
In addition, an explicit goal of this study is to present the primary and related outcomes of this study at 
Scientific Meetings and to publish, as possible, in peer-reviewed Scholarly Journals to assure 
dissemination of the findings. The authority to do so resides with the participant investigators and not 
with any sponsor. 
A bio-specimen repository will be created in which de-identified blood speciments and linked clinical 
and research data will be made available to qualified researchers who submit meritorious applications 
for the access and use of such samples. Oversight for the review of requests and the dissemination of 
study materials will be through the Study Executive and Steering Committees and/or any sub-
committees that they may appoint for this process. 
 
15 STUDY ADMINISTRATION AND OVERSIGHT 
 
15.1 STUDY LEADERSHIP 
The overall management and day-to-day operational structure proposed for the SLS-III study is outlined 
in the two organizational charts below (Figures 15.1A-B).  
 
Figure 15.1A: Organizational Chart depicting Study Administrative Oversight and Management 
 


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Note that the Executive Committee (indicated in Yellow) will serve as the central body responsible for 
oversight and management and will meet every 1 to 2 weeks throughout the 5-year course of the study. 
It is directly supported in this function by the presence of two Coordinating Units, The UCLA 
Administrative and Contracting Core and the University of Michigan Data Coordinating Center 
(highlighted in blue). These three units [Executive Committee; Administrative Core and Data 
Coordinating Center] are responsible for interacting with the full Steering Committee, which includes 
representation from every participating clinical site, and with the independent Data, Safety and 
Monitoring Committee. The UCLA Administrative Core will hold the study IND and the overall study IRB 
approval and represent the study in those respects. 
 
Figure 15.1B: Day-to-Day Operational Flow Chart 
 
Note that in the day-to-day operational flow, the Participating Clinical Sites (indicated in Yellow) serve as 
the central body responsible for the interaction with study patients and the day-to-day clinical oversight 
of both patient care and testing. The Clinical Sites are directly supported in their task by the Data 
Coordinating Center (highlighted in blue), which is responsible for the data collection and monitoring. 
The UCLA Administrative Core (highlighted in green) only has an indirect role in the day-to-day 
operations in that it is in constant contact with the Data Coordinating Center and oversees the 6 UCLA 
Core Services (appear in white) which directly support the day-to-day operations of the Clinical Sites. 
Should the Data Coordinating Centers or Cores identify day-to-day issues that require input, they are 
empowered to immediately interact with the UCLA Administrative Core or to address those issues in the 
regularly scheduled Executive Committee meetings.  
 
15.1.1 UCLA Administrative & Contracting Core 
The designated Principal Investigator for SLS III will direct the UCLA Administrative and Contracting 
Core, which will be operationally responsible for all aspects of the clinical trial and contracting with 
participating clinical sites. The Principal Investigator will be assisted by a National Study Coordinator 


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with experience in the conduct of scleroderma-associated clinical research and operational 
familiarity with all administrative and clinical aspects of the clinical trial and the participating sites, 
investigators and coordinators at participating sites.  The Administrative and Contracting Core will 
be responsible for finalizing the SLS III protocol, IND and ClinicalTrial.gov filings, and overseeing the 
contracting and reimbursements for all of the sub-contracted clinical sites. In addition to the 
Contracting Core, the UCLA Administrative and Contracting Core will also oversee essential Core 
services in support of the study including the provision of a National Study Coordinator and the 
HRCT QIA Imaging Core, Pulmonary Function QA Core, Pharmacy Core, and a Bio-repository Core, all 
of which will develop operational guidelines and oversee the services defined by their titles. 
 
15.1.2 
Data Coordinating Center (DCC) 
The Director of the DCC, housed at the University of Michigan within the Statistical Analysis of 
Biomedical & Educational Research (SABER) Unit of the School of Public Health, will also serve as 
thes Senior Statistician. The DCC staff will include a Database programmer, Data manager, Statistical 
Analyst, Project Manager, Clinical Monitor, Web Programmer/Designer, and a Research 
Administrator. In addition, the Co-PI for the overall studywill be located at the University of 
Michigan and will act as the on-site Clinical Advisor for the DCC in addition to  other responsibilities. 
The DCC plays a pivotal role in the design, implementation, execution and administration of the 
study. The DCC will be responsible for randomization, data forms and online reporting systems, 
preparation of the manual of operations, addressing questions regarding protocol issues, data 
screening, entry and analysis, monitoring recruitment, follow-up and adherence to protocol, and 
scheduling and arranging meetings of the Executive Committee, Steering Committee, and DSMB. 
The Clinical Monitor will interact regularly with the National Study Coordinator at UCLA and in the 
initial year, will visit all of the clinical sites for on-site monitoring. Subsequent routine monitoring 
will be done remotely, using regularly scheduled web-based meetings for document and protocol 
review. The DCC will also evaluate sites for meeting performance goals, completing documentation, 
and producing reimbursement documents for the Administrative Core at UCLA. The DCC will prepare 
all of the routine study reports for the Executive Committee, Steering Committee, DSMB, and in 
support of annual filings with for the IND, etc. The DCC will interact with all of the Cores and send 
out study notices, including those related to lab alerts, adverse events and SAEs using automated 
notification networking.  
 
15.1.3 
Executive Committee 
The Executive Committee, chaired by the Principal Investigator for the study, will meet every one-to-
two weeks and interact closely with the DCC and the Cores to administratively direct and monitor 
the progress of the clinical trial and to respond to any design, implementation or administrative 
issues that arise during the study. The Executive Committee will set the agenda for the Steering 
Committee meetings as a mechanism to disseminate and collect essential information, and to 
implement modifications related to the clinical trial. Other members of the Executive Committee 
include an Executive Consultant, Study co-PI, and the Director of the DCC, the National Coordinator 
and ad hoc representation from the Directors of the named Cores as needed. Each Executive 
Committee meeting will include a review of enrollment, randomization, retention, drop-outs, AEs, 
SAEs, medication control issues, site performance and problems, Core reports, study compliance 
issues, and any interval protocol issues. 
 


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15.1.4 
Steering Committee 
A Steering Committee chaired by the study Principal Investigator will provide overall scientific 
direction for the trial with input from the key personnel at each participating study site. Voting 
members will include the Chairman, one Pulmonary and one Rheumatology investigator from each 
Clinical Center, the DCC Director, and the Director of each Core. The Steering Committee will be 
responsible for developing a final protocol and Manual of Operations; approving any changes in 
these; monitoring recruitment and follow-up at each center; and presenting/publishing results from 
the trial. The Committee will meet face-to-face at least once prior to the initiation of the trial and at 
least annually for the duration of the trial. Steering Committee members will also participate in 
monthly teleconference/web calls for the duration of the trial. The Steering Committee will also 
have the authority to organize and empower working subcommittees (as needed for the study) 
including:  
• 
Recruitment and Patient Issues Committee 
• 
Quality Control Committee 
• 
Drug Distribution and Safety Monitoring Committee 
• 
Ancillary Studies Committee 
• 
Manuscript Preparation Committee 
 
15.1.5 
Data & Safety Monitoring Board (DSMB) 
A 3-member external Data and Safety Monitoring Board (DSMB) will be appointed and composed of 
individuals who have no direct conflicting involvement with the study or an active salaried 
appointment with any of the participating institutions. The recommended composition of the DSMB 
will be to include a pulmonologist, a rheumatologist, and a biostatistician with an expectation that 
each member will have experience in one or more of the following areas:  
• 
interstitial lung disease  
• 
idiopathic pulmonary fibrosis  
• 
systemic sclerosis  
• 
collagen-vascular disease associated ILD  
• 
clinical trial design and management  
• 
data management and statistical analysis  
• 
patient safety monitoring 
• 
the ethical conduct of clinical research  
• 
clinical use of Pirfenidone and/or Mycophenolate  
The DSMB Chair will be appointed by the Study Executive Committee from among experts in the 
field and then recommend the remainder of the Committee Members for consideration by the study 
Executive Committee using the defined expertise and affiliation criteria.  
The DSMB will review the protocol and suggest any changes that might be required prior to its 
implementation.  Once the trial is initiated, the DSMB will review cumulative trial results to evaluate 
the treatment for beneficial and adverse effects, including the review of all Serious Adverse Events.  
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 every 6 
months by teleconference and/or web videoconferencing for the duration of the trial and will 
interact directly with the Data Coordinating Center for access to study data and interim reports.  
 


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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 and produce written reports that will advise the 
sponsor and Executive Committee as to whether the DSMB recommends that the study continue as 
is, consider specific safety and/or data management changes, or consider early termination due to 
specific safety or ethical management concerns. 
 
15.1.6 
Study Cores 
The Study Cores are provided as a centralized resource that will a) develop and disseminate 
operational guidelines for their areas of expertise; b) provide site training in their areas of expertise; 
c) deliver key services, d) and provide standardization and quality assurance. The Core Directors will 
be members of the Executive Committee in order to completely integrate these aspects of study 
services and oversight into the overall flow and oversight of the Clinical Trial. The Study Cores are: 
• 
Contracting Core: Uniform contracting guidelines and assurances will be developed and 
executed with each of the participating clinical sites to carry out the described clinical trial. 
With data input from the Data Coordinating Center, the Contracting Core will also approve 
site expenditures and reimbursements for the performance of study services. 
• 
National Study Coordinator: The National Study Coordinator acts as a core resource to 
liason between the Investigators and Administration of the study and the actual 
performance of the clinical trial by the site personnel. The National Study Coordinator will 
help to standardize and distribute regulatory documents, including IRB consents and drug 
safety notifications, and lead regular meetings of the study coordinators from all 
participating sites so that lessons and experiences at each site can be shared with the other 
sites, which is key in the study of an orphan disease where patient numbers and individual 
experience are limiting features. The National Study Coordinator also acts as a readily 
available resource to field and trouble-shoot day-to-day operational issues that arise in the 
conduct of the study. 
• 
HRCT QIA Imaging Core: The Imaging Core will include a Director, research physicist, 
coordinators and staff that are responsible for establishing and overseeing the CT imaging 
protocol including the development of the manual of operations, interacting with 
radiologists and technicians at each site to categorize, standardize and program their 
equipment for participation in the imaging protocol, and will assure that HIPAA compliant 
protocols are in place for data transfer and storage. In addition to these aspects of raw data 
acquisition, the imaging core will be responsible for carrying out the quantitative image 
analysis required for all CT data sets and for assessing and reporting quality assurance and 
compliance with operational guidelines. If imaging problems should arise, they will work 
with an individual site to identify and resolve these issues.  
• 
Pulmonary Function QA Core: In addition to preparing a PFT manual of operations and 
helping to establish satisfactory standardization and quality of PFT tests performed at all 
clinical centers, the PFT Core will review all patient test results for completeness, 
compliance with protocol requirements, and accuracy. If deficiencies should arise, the Core 
Director will work one-on-one with a site to establish the reason and resolution of such 
deficiencies. If repeat testing is required, the PFT Core Director will communicate this 
information to the Data Coordinating Center and to the site. 
• 
Pharmacy Core:  The Investigational Drug Unit of the Department of Pharmaceutical 
Services, University of California Los Angeles, at the Ronald Reagan Medical Center will 


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serve as the central drug packaging and distribution site for all participating institutions. 
Responsibilities include drug procurement, storage and inventory, drug accountability and 
drug distribution to all participating sites. They will establish the operational procedures by 
which all sites will receive, label and distribute drug supply for the study, but each site will 
be responsible for drug inventory control, distribution and disposal at their individual sites 
after receipt of study drug from the Core.  
• 
Bio-repository Core: The UCLA Bio-repository Core will establish standard procedures and 
train sites for the collection, processing, storage and shipping of blood samples from study 
patients. They will provide centralized kits and instructions and also house the returned 
sample in a secure storage system at UCLA for later use. They will track performance and 
provide inventory control and also, when applicable, at the direction of the Executive 
Committee, distribute samples to individual investigators for analysis. 
 
15.2 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 
 
16.1 COMPLIANCE WITH 21 CFR PART 54 
The investigators and sponsors will comply with the FDA regulations governing financial disclosure by 
clinical investigators, 21 CFR part 54, in case a new drug application should be filed in conjunction with 
the work supported by this clinical trial. As per the regulations, applicants will certify the absence of 
certain financial interests and arrangements of clinical investigators that could affect the reliability of 
data submitted to FDA, or alternatively disclose those financial interests and arrangements to the 
agency and identify steps taken to minimize the potential for bias (21 CFR § 54.4(a)).  
 
16.1.1 
Disclosable Financial Interests & Arrangements under 21 CFR part 54 
The financial interests, arrangements, and payments that must be disclosed (see 21 CFR § 
54.4(a)(3), referred to herein as “disclosable financial interests and arrangements”) are 
described below.  


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16.1.1.1 
Any compensation made to the investigator by any sponsor of the covered 
clinical study in which the value of compensation could be affected by study outcome. 
16.1.1.2 
A proprietary interest in the tested product including, but not limited to, a 
patent, trademark, copyright or licensing agreement.  
16.1.1.3 
Any equity interest in any sponsor of the covered clinical study, i.e., any 
ownership interest, stock options, or other financial interest whose value cannot be 
readily determined through reference to public prices. The requirement applies to 
interests held during the time the clinical investigator is carrying out the study and for 
one year following completion of the study. 
16.1.1.4 
Any equity interest in any sponsor of the covered study if the sponsor is a publicly 
held company and the interest exceeds $50,000 in value. The requirement applies to 
interests held during the time the clinical investigator is carrying out the study and for 
one year following completion of the study. 
16.1.1.5 
Significant payments of other sorts (SPOOS) are payments that have a cumulative 
monetary value of $25,000 or more and are made by any sponsor of a covered study to 
the investigator or the investigator’s institution during the time the clinical investigator 
is carrying out the study and for one year following completion of the study. This would 
include payments that support activities of the investigator (e.g., a grant to the 
investigator or to the institution to fund the investigator’s ongoing research or 
compensation in the form of equipment), exclusive of the costs of conducting the 
clinical study or other clinical studies, or to provide other reimbursements such as 
retainers for ongoing consultation or honoraria. See Section IV, Questions C.4, C.5, and 
C.6 for additional information on SPOOS. 
 
16.1.2 
Completion of Forms FDA 3455 & 3454 under 21 CFR part 54 
For each clinical investigator [a “listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects,” including the spouse and 
each dependent child of the investigator or subinvestigator] who is not identified as an 
employee of the sponsor, one of the following must be submitted (21 CFR § 54.4(a)): 
16.1.2.1 
FORM FDA 3455 Disclosure Statement. Form 3455 shall be completed for each 
clinical investigator who, or whose spouse or dependent child, had disclosable financial 
interests in and/or arrangements with any sponsor of the covered clinical study. The 
form should include an attachment with detailed information about those financial 
interests and arrangements and a description of the steps taken to minimize the 
potential for bias resulting from the disclosed financial interests and arrangements (21 
CFR § 54.4(a)(3)). 
16.1.2.2 
FORM FDA 3454 Certification Form 3454 shall be completed for any clinical 
investigator who has no disclosable financial interests in or arrangements with any 
sponsor of the covered clinical study (21 CFR § 54.4(a)(1)); the applicant may append a 
list of investigator names to a single FORM FDA 3454 for those investigators with no 
disclosable financial interests or arrangements. 
 


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16.2 
COMPLIANCE WITH LOCAL STATE AND UNIVERSITY REGULATIONS & POLICY  
In addition to FDA regulations, Investigators at the University of California Los Angeles will follow UCLA 
Procedure  925.2:  Disclosing Financial Interests in Non-Governmental Sponsors of Contracts, Grants, 
and Material Transfer Agreements for Research. In addition, Investigators at the Data Coordinating 
Center and all participating clinical sites will be held to their applicable local State and University Conflict 
of Interest Regulations and Policies. Compliance will be certified as a condition of sub-contract awards. 
 
17   EMERGENCY DISASTER/PANDEMIC MANAGEMENT PLAN 
Emergency disasters, including infectious outbreaks such as the Coronavirus Disease 2019 (COVID-19) 
pandemic, may disrupt patient access or the capacity for institutions to provide usual study care.  
Modifications to normal study operations including inclusion and exclusion criteria, screening and 
randomization, handling of study drugs, study visits, testing and site monitoring may be required in 
order to protect patients and maintain the integrity of the clinical trial.  
The emergency procedures described herein may be activated by the Executive Committee and 
implemented as needed, in whole or in part and for an appropriate duration, in order to respond to the 
specific circumstances imposed by the emergency.  
The declaration of an emergency situation and details regarding the exact components of the protocol 
that will be modified in response to the situation, will be codified in the Manual of Operations and 
distributed as Emergency Updates to all participating clinical sites, study investigators and staff, and 
study cores.  
Provisions that may be required to immediately protect patient well-being, as determined by study 
investigators, may be immediately implemented. However, activation of an Emergency 
Disaster/Pandemic Management Plan and the exact details of that plan are to be reported in a timely 
manner to the local IRB, the SLS III DSMB and to the FDA if required by the nature of the changes.  
Once activated, the specific provisions of the Emergency Disaster/Pandemic Management Plan will 
supercede normal study operations until the emergency is declared over by the Executive Committee. 
While the Emergency Disaster/Pandemic Management Plan is active, following the provisions of that 
management plan will be considered consistent with the official Study Protocol and not designated as 
protocol deviations. The Data Coordinating Center will track related compliance and any missing study 
data due to the emergency. 
 
17.1 MODIFICATIONS TO INCLUSION AND EXCLUSION CRITERIA 
During an emergency, protocol-defined inclusion and exclusion criteria (detailed in the Protocol Sections 
5.1 and 5.2) will be reviewed to determine whether modifications are required. Such determinations will 
be based on the nature of the emergency and a resulting need to assure the safety of study participants 
and/or the integrity of the study.  
Potential modifications may include the following examples (not intended to be an exclusive list):  
a) The age of study participants if required to protect the safety of an identified population at risk 
during the emergency. 
b) Testing for exposure to, or the presence of, an infection as may be required in a pandemic 
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c) Additional screening blood tests or modification of existing allowable test thresholds (for 
example, allowable liver function or blood counts) as may be required to reduce or eliminate a 
disaster-specific risk. 
 
17.2 DETERMINATION OF RISK AND OPTIONS FOR MANAGEMENT OF STUDY DRUGS 
In an emergency situation, the Executive Committee will review the safety profile for the study drugs 
and discuss the impact of any emergency guidelines issued by the FDA, Center for Disease Control (CDC) 
or related health advisory organization and determine whether the indications or contraindications for 
study drugs have changed and whether the nature of the emergency will impact on patient participation 
in the study.  Patient safety during an emergency will be considered the first priority.  All active study 
participants will be notified of potential risk to them posed by the emergency and the options for 
management of study drugs and/or their continued participation in the study. If necessary, study drugs 
may be shipped to patients during an emergency when on-site visits are not possible or not advised due 
to the nature of the emergency. 
 
17.2.1 
Risk assignment during COVID-19 pandemic 
a) According to the CDC, adults age 65 or older, those with underlying lung disease, heart 
disease or diabetes, and individuals with an identified immune deficit are considered "at high 
risk" for complications from COVID-19 infection.   
b) Due to the presence of underlying lung disease in all study participants and their treatment 
with a study drug with immunosupressive properties, all active study participants will be 
notified that their underlying condition and its treatment according to the study define them 
as being "at high risk" for infectious complications from COVID-19 according to CDC criteria. 
 
17.2.2 
Options for management of study drugs during COVID-19 pandemic 
a) Participants will be encouraged to follow all Center for Disease Control (CDC) and local public 
health guidelines to reduce exposure risk.  
c) In the absence of evidence that withdrawing treatment for their lung disease is advisable, 
participants who are asymptomatic (from infectious perspective) are not recommended to 
stop study medication.  
d) However, subjects will be advised to communicate any fever or cold symptoms such as 
cough, chills or new shortness of breath with the local study team and their treating 
physicians as soon as possible.  
e) Section 6.1.5.2 of the SLSIII protocol will be followed for dose management 
recommendations in the event of any signs of active infection. Per protocol and local 
investigator discretion, MMF may be held during an infection and doing so in this case should 
be considered in a timely manner.  
f) Study participants will be advised, as already noted in their signed study consent, that 
participation in the study is voluntary and participants may decide to withdraw from drug 
treatment or the entire study at any time.  
g) While we are not advising the prophylactic suspension of MMF at this time, study 
participants are allowed to be off MMF for up to 60 days related to potential tolerability or 
toxicity issues and remain in the study (Section 6.1.5.1.i ). Any study participant that holds or 
suspends study drugs in this setting will be notified of their options and invited to remain in 
the study regardless of their decision about continuing with study drugs (see Protocol Section 
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17.2.3 
Dispensing of study drugs during COVID-19 pandemic 
Due to the impact of COVID-19 on the operation of participating clinical sites and the perceived risk 
for study participants in attending Medical Center visits during the pandemic, study drugs will be 
shipped as needed to the participant’s home after completion of required "remote visit".  
a) Remote visits are required (as detailed in Section 17.4 below) to assess drug compliance and 
assure the safety of continued drug administration before prescribing.  
b) Shipping of study drugs will require inventory control measures and verification that study 
drugs were received by the participant. 
 
17.3 IMPACT OF THE EMERGENCY ON SCREENING AND RANDOMIZATION 
During an emergency, the ability to screen or randomize patients may be impaired due a disruption of 
services offered at a participating clinical site, issues with patient access, or concerns regarding the 
safety associatd with initiation of therapy during the emergency. Options to be considered include: 
a) Proceed with screening and/or randomization if, after notification and consultation with the 
patient, it is determined to be in the patient's best interest to do so and if the participating 
clinical site can safely proceed and complete all of the study requirements. 
• 
A remote visit (as detailed in Section 17.4 below) may be utilized for aspects of the 
screening and randomization visits, but completion of the informed consent, screening vitals 
and physical examination must be completed in person. 
• 
Completion of required pulmonary function testing, mRSS test, and thoracic HRCT must be 
completed in person in order to meet eligibility criteria. 
b) Delay the completion of scheduled screening visits or planned randomizations to a later time if 
the patient will be able to complete randomization within the allowed 90 days from the 
initiation of screening visit #1. 
c) Cancel further screening or randomization visits until such time as resources are available or it is 
deemed safe to proceed. Any participant who has their screening or randomization cancelled 
should be considered for re-screening when the emergency ends, but would be required to 
meet study inclusion and exclusion criteria at that time. 
 
17.4 ALLOWABLE MODIFICATIONS TO STUDY VISITS AND PROCEDURES 
Study operations may be placed on complete hold or suspended during an emergency when 
institutional closures and/or perceived risk to the study population prohibit the safe conduct of the 
study. This determination will be made by the Executive Committee and carried out in conjunction with 
review by institutional IRBs and the SLS III DSMB, who will be provided with a study closure mitigation 
plan to address participant notification and referral to alternative care providers if possible under the 
circumstances. An early termination visit will be carried out as per Protocol Section 7.2.4 when possible.  
Alternatively, the study may convert in person (on-site) study visits to “remote study visits” in order to 
compensate for emergency issues that limit either institutional or patient access.  
 
17.4.1 
Conversion from in person to remote study visits 
a) Screening, baseline and follow-up visits, regardless of whether in  person or remote, are to 
be carried out within established visit windows.   


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b) When an in person visit is converted to a remote visit, this may be carried out using a formal 
telemed or video conference system or by simple phone contact between the study staff and 
the study patient. 
• 
Regardless of the mechanism employed, the remote visit encounter must be 
accompanied by appropriate source documentation. 
• 
Study records should indicate when an in person visit is converted to a remote visit. 
• 
Study records should indicate whenever specific components of a study visit cannot 
be completed remotely due to the activation of the emergency protocol. 
c) Pre-specified phone follow-up visits are to continue as indicated in Section 7.2.3.3. 
 
17.4.2 
Components of study visits that can be carried out remotely 
a) Patient history or interim history. 
• 
Proceed using telemed, video or phone visits 
b) Review of concomitant medications 
• 
Proceed using telemed, video or phone visits 
c) Assessment of adverse events 
• 
Proceed using telemed, video or phone visits 
d) Modified study drug reconciliation 
• 
Proceed using telemed, video or phone visits 
• 
Review patient drug diary in detail and have patient provide copy for record if 
possible 
• 
Have participant describe available medication supply  
• 
Direct pill counts will not be possible 
e) Toxicity monitoring and pregnancy testing utilizing available commercial laboratories 
• 
Arrange for particpant to have complete blood count with differential and platelet 
count, comprehensive metabolic panel and pregnancy testing completed at any 
available clinical laboratory 
• 
Pregnancy test may be carried out by qualitative urine or blood test as available 
• 
All clinical lab results must be collected and retained as source documents 
f) Study drug dispensing 
• 
Once a remote visit has been carried out and toxicity monitoring reviewed and 
approved, study drug may be shipped to the participant as detailed in Section 17.2.3 
g) Patient reported outcomes (PROs) 
• 
Email or mail (with return envelope and postage) visit-specific questionnaires to 
participants to complete and follow-up with them within 7 days to assure that 
participants have completed and returned them. 
• 
If preferred by participant or coordinator, questionnaires may be administered over the 
phone with the coordinator asking questions verbatim and stating all potential choices 
before recording participant responses.  
• 
Note that the SHAQ VAS page cannot be completed by phone; either mail the DCC 
provided form to the participant or skip its administration. 
h) Modified Mahler Transitional Dyspnea Index 
• 
Complete the Mahler TDI, if required for the visit, by phone 
i) 
Physician and Patient Global Assessments 
• 
Proceed using telemed, video or phone visits 


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17.4.3 
Components of study visits that cannot be carried out remotely 
Components of study visits that require direct examination or on-site completion may not be 
available during an emergency due to limitations in institutional or patient access. These components 
cannot be carried out remotely (by telephone or video visits) and the inability to complete will 
require deviation from that described in Protocol Section 7.2, Study Schedule. Absence of the 
following test results for a remote visit should be so noted in the study record as due to “COVID-19 
Restrictions”  or other emergency situation to address this deviation. Missing assessments may be 
collect out of window or at next on-site study visit, if appropriate. 
a) Physical examination 
b) mRSS 
c) Pulmonary function tests (spirometry and DLCO). 
d) Thoracic HRCT 
e) Blood collection for Biological Specimen Repository  
 
17.4.4 
Completion of pulmonary function tests at a remote facility  
Pulmonary function tests are an established standard of care test for patients with SSc-ILD and 
required at routine intervals to monitor patients for the state of their lung disease, inter-current 
illnesses and treatment failures that might warrant additional evaluation and/or management.  
In the setting of prolonged restrictions on travel or institutional access, or when ongoing safety 
concerns limit the ability for participating study patients to complete these outcome assessments at 
their assigned clinical site, the Executive Committee may allow such testing to be completed at a 
remote facility. Testing at remote facilities should be carried out in accord with ATS standards and 
by Certified Pulmonary Function Technologists. All requests for remote PFTs must be reviewed and 
approved in advance by the Executive Committee. Testing will be carried out as a recommended 
standard-of-care clinical assessment and therefore completed at the discretion of the study 
participant after being informed of the indications and potential financial implications. Data 
generated from such assessments may be included as official study outcome measures if reviewed 
by the Pulmonary Function QA Core and determined to meet minimum quality and reproducibility 
requirements.  
 
17.5 REVISED SITE MONITORING 
On-site monitoring visits may not be possible during an emergency. The Data Coordinating Center will 
utilizing remote monitoring with remote source data verification, as required, to maintain oversight of 
clinical sites as outlined in Protocol Section 9, CLINICAL MONITORING. 
Given the potential impact of an emergency situation on institutional resources, study personnel and 
the capacity to schedule and travel to visits, the time windows for the completion of study visits (as 
detailed in Protocol Section 7) may be extended by up to 30 days at the discretion of the Executive 
Committee. Decisions regarding the length of extended visit windows will take into account issues such 
as availability/access for visits, patient safety monitoring, standard-of-care and the presence of 
adequate study drug reserves. 
 
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56. Varga J. Systemic sclerosis: an update. Bull NYU Hosp Jt Dis. 2008;66(3):198-202. 
57. White B. Pulmonary fibrosis and pulmonary vascular involvement in systemic sclerosis. 9a. Pulmonary 
fibrosis in systemic sclerosis. In Systemic Sclerosis, 2nd edition (PJ Clements, DE Furst, edit). Lippincott, 
Williams, & Wilkins, New York, NY. 2004:163-183. 
58. Winstone TA, Assayag D, Wilcox PG, Dunne JV, Hague CJ, Leipsic J, Collard HR, Ryerson CJ. Predictors 
of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. 
Chest. 2014;146(2):422-36.  
 
 
 


Scleroderma Lung Study III                                           [Confidential] 
Version 2.5 
Protocol #UCLA-SLS3 
11/17/21 
FDA IND #: 135848 
 
131 
APPENDIX LIST 
 
Version 
Date 
Description 
Significant Revisions 
1.0 
04/25/17 
App #A: Study Questionnaires 
 
     1.1 
07/2019 
App #B: Drug Packaging Inserts 
Pirfenidone (Esbriet) drug packaging 
insert updated 
 
 

SAP_001.pdf: 
SLS III SAP 
 
Page 1 of 46 
 
SLS III Statistical Analysis Plan 
 
TRIAL FULL TITLE 
Scleroderma Lung Study III 
SAP VERSION 
1.0 
SAP VERSION DATE 
24May2022 
TRIAL STATISTICIAN 
 
Protocol Version (SAP associated with) 
Protocol Version 2.5 
17NOV2021 
TRIAL PRINCIPAL INVESTIGATOR 
Michael D. Roth, MD 
Dinesh Khanna, MD, MSc 
SAP AUTHOR(s) 
Yihsuan Tu, PhD 
 
 


SLS III SAP 
 
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1 SAP Signatures 
 
Statistician (Author) 
Name: 
Yihsuan Tu, PhD 
Signature:  
Date: 
24 May 2022 
 
Statistician Reviewer (As applicable) 
Name: 
Cathie Spino, ScD  
Signature:  
Date: 
24 May 2022 
 
Principal Investigator 
Name: 
Michael D. Roth, MD  
Signature:  
Date: 
24 May 2022 
 
 
Co-Principal Investigator 
Name: 
Dinesh Khanna, MD, MSc  
Signature: Dinesh Khanna 
Date: 
24 May 2022 
 
 


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2 Table of Contents 
 
1 
SAP Signatures .................................................................................................................................. 2 
2 
Table of Contents .............................................................................................................................. 3 
3 
Abbreviations and Definitions........................................................................................................... 6 
4 
Introduction ...................................................................................................................................... 9 
4.1 
Preface .......................................................................................................................................... 9 
4.2 
Scope of the Analyses ................................................................................................................... 9 
5 
Study Objectives and Endpoints ....................................................................................................... 9 
5.1 
Study Objectives ........................................................................................................................... 9 
5.1.1 
Primary Objective .................................................................................................................. 9 
5.1.2 
Secondary Objective ............................................................................................................. 9 
5.1.3 
Exploratory Objectives ........................................................................................................ 10 
5.2 
Endpoints .................................................................................................................................... 10 
5.2.1 
Primary Endpoint ................................................................................................................ 10 
5.2.2 
Secondary Endpoints .......................................................................................................... 10 
5.2.3 
Other Endpoints .................................................................................................................. 11 
6 
Study Methods ................................................................................................................................ 12 
6.1 
General Study Design and Plan ................................................................................................... 12 
6.2 
Inclusion-Exclusion Criteria and General Study Population ........................................................ 12 
6.2.1 
Inclusion Criteria ................................................................................................................. 12 
6.2.2 
Exclusion Criteria ................................................................................................................. 13 
6.3 
Randomization and Blinding ....................................................................................................... 14 
6.4 
Study Assessments ...................................................................................................................... 15 
6.4.1 
Primary Efficacy Assessment ............................................................................................... 17 
6.4.2 
Secondary Efficacy Assessments ......................................................................................... 17 
6.4.3 
Other Assessments ............................................................................................................. 20 
7 
Sample Size ..................................................................................................................................... 21 
8 
General Analysis Considerations ..................................................................................................... 28 
8.1 
Timing of Analyses ...................................................................................................................... 28 
8.2 
Analysis Populations ................................................................................................................... 28 
8.2.1 
Modified Intention to Treat Population .............................................................................. 28 
8.2.2 
Per Protocol Population ...................................................................................................... 28 
8.2.3 
Completers Population ....................................................................................................... 28 


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8.2.4 
Safety Population ................................................................................................................ 28 
8.3 
Covariates and Subgroups .......................................................................................................... 28 
8.4 
Missing Data ................................................................................................................................ 29 
8.5 
Interim Analyses and Data Monitoring ....................................................................................... 29 
8.6 
Multiple Testing .......................................................................................................................... 29 
9 
Summary of Study Conduct Data .................................................................................................... 29 
9.1 
Subject Disposition ...................................................................................................................... 29 
9.2 
Protocol Deviation ...................................................................................................................... 29 
9.3 
Demographic and Baseline Variables.......................................................................................... 30 
9.4 
Treatment Compliance ............................................................................................................... 30 
10 
Efficacy Analyses ............................................................................................................................. 30 
10.1 
Primary Efficacy Analysis ............................................................................................................. 31 
10.2 
Secondary Efficacy Analyses ....................................................................................................... 32 
10.2.1 
Secondary Analyses of Primary Efficacy Endpoint .............................................................. 32 
10.2.2 
Secondary Efficacy Analyses ............................................................................................... 32 
11 
Safety Analyses ............................................................................................................................... 35 
11.1 
Extent of Exposure ...................................................................................................................... 35 
11.2 
Definition of Adverse Events ....................................................................................................... 35 
11.2.1 
Treatment-emergent AEs (TEAEs) ....................................................................................... 36 
11.2.2 
AEs of Special Interest ......................................................................................................... 36 
11.3 
Definition of Serious Adverse Events (SAEs) ............................................................................... 36 
11.4 
Definition of Unanticipated Problems (UP – unexpected AEs & Problems) ............................... 37 
11.5 
Classification of an Adverse Event .............................................................................................. 37 
11.5.1 
Severity of Event ................................................................................................................. 37 
11.5.2 
Relationship to Study Intervention ..................................................................................... 38 
11.5.3 
Expectedness ...................................................................................................................... 38 
11.5.4 
Treatment Failures .............................................................................................................. 38 
11.6 
Pregnancies ................................................................................................................................. 38 
11.7 
Clinical Laboratory Evaluations ................................................................................................... 39 
11.8 
Prior and Concurrent Medications.............................................................................................. 39 
11.9 
Other Safety Measures ............................................................................................................... 39 
12 
Other Analyses ................................................................................................................................ 40 
13 
Reporting Conventions ................................................................................................................... 40 
14 
Summary of Changes to the Protocol and/or SAP .......................................................................... 40 
15 
References ...................................................................................................................................... 46 


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16 
Planned Tables, Listings and Figures ............................................................................................... 46 
 
 
 


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3 
Abbreviations and Definitions 
AE  
Adverse Event 
ACR 
American College of Rheumatology 
ADL 
Activities of daily living 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance  
AST 
Aspartate Aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
BID 
Twice daily 
BDI 
Baseline Mahler Modified Dyspnea Index 
BAL 
Bronchoalveolar lavage 
BUN 
Blood Urea Nitrogen 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum concentration 
CMP 
Clinical monitoring plan 
CMV 
Cytolomegalovirus 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF  
Case Report Form 
CRISS 
Combined Response index in Systemic Sclerosis 
CTCAE 
Common Terminology Criteria for Adverse Events V4.03-2010 
CYC 
Cyclophosphamide 
CYP 
Cytochrome P450 
DCC  
Data Coordinating Center 
DLCO 
Single-Breath Diffusing Capacity of the Lung for Carbon Monoxide 
DLCO-Hb-% 
DLCO, adjusted for age, height, gender and hemoglobin 
DMARD 
Disease-modifying antirheumatic drug 
DSMB  
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
ERS 
European Respiratory Society 
EULAR 
European League Against Rheumatism 
FEV1 
Forced Expiratory Volume in the first second 
FDA 
Food and Drug Administration 
FVC 
Forced vital capacity 
FVC-% 
Forced vital capacity as a percentage of the age-, height-, gender- and race-adjusted 
predicted value 
GERD 
Gastroesophageal reflux disease 
GCP 
Good Clinical Practice 
GGO 
Ground glass opacification 
GLP  
Good Laboratory Practices 


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GMP  
Good Manufacturing Practices 
H&P 
History and physical 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIPAA  
Health Insurance Portability and Accountability Act 
HRCT 
High resolution computerized tomography 
HRCT-TLC 
HRCT-measured total lung capacity at maximum inspiration 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
IFN-γ 
Interferon-gamma 
ILD 
Interstitial lung disease 
IND  
Investigational New Drug Application 
IPF 
Idiopathic pulmonary fibrosis 
IRB  
Investigational Review Board 
JC 
Polyomavirus JC 
LCQ 
Leicester Cough Questionnaire 
LFTs 
Liver function test 
MCP-1 
Macrophage chemotactic protein-1 
MCTM 
Markov Chain Transition Matrix 
mITT 
Modified intention to treat 
MPA 
Mycophenolic acid 
MPAG 
phenolic glucuronide metabolite of MPA 
MMF 
Mycophenolate mofetil; same as CellCept 
MMP 
Matrix metalloproteinase 
MOP 
Manual of Procedures 
mRSS 
Modified Rodnan Skin Score 
NIH  
National Institutes of Health 
NSIP 
Non-specific interstitial pneumonia 
OHRP  
Office for Human Research Protections 
PAH 
Pulmonary arterial hypertension 
PDGF 
Platelet derived growth factor 
PFD 
Pirfenidone; same as Esbriet 
PFT 
Pulmonary function test 
PI  
Principal Investigator 
Plac 
Placebo 
PML 
Progressive multifocal leukoencephalopathy associated with JC virus 
PP 
Per protocol 
PPI 
Proton pump inhibitors 
PRCA 
Pure Red Cell Aplasia 
PRO 
Patient Reported Outcome 
PROMIS-29 
Patient-reported outcomes measurement information system 29-item health profile 
PVAN 
Polyomavirus associated nephropathy 
QA 
Quality Assurance 
QC 
Quality Control 
QGG 
Quantitative ground glass 


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QHC 
Quantitative honeycomb change 
QIA 
Quantitative image analysis 
QILD-LM 
Quantitative interstitial lung disease score in the lobe of maximal involvement 
QILD-WL 
Quantitative interstitial lung disease score in the whole lung 
QLF-LM 
Quantitative lung fibrosis score in the lobe of maximal involvement 
QLF-WL 
Quantitative lung fibrosis score in the whole lung 
SABER 
Statistical Analysis of Biomedical and Educational Research Unit 
SAE  
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SGRQ 
St. George's Respiratory Questionnaire 
SHAQ 
Scleroderma Health Assessment Questionnaire 
SLS 
Scleroderma Lung Study 
SMC  
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP  
Standard Operating Procedure 
SSc 
Scleroderma (same as Systemic Sclerosis) 
SSc-lc 
Scleroderma with limited cutaneous features 
SSc-dc 
Scleroderma with diffuse cutaneous features 
SSc-ILD 
Scleroderma-related interstitial lung disease 
TDI 
Transitional Mahler Modified Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
TGF-β1 
Transforming growth factor beta-1 
TID 
Three times daily 
UCLA SCTC 
GIT 2.0 
University of California, Los Angeles, Scleroderma Clinical Trials Consortium 
Gastrointestinal Scale 
UIP 
Usual interstitial pneumonia 
ULN 
Upper limit of normal 
UP  
Unanticipated Problem 
US  
United States 
WBC 
White blood cell 
 
 


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4 Introduction 
4.1 
Preface 
This Statistical Analysis Plan (SAP) describes statistical methods and analyses for the SLS III (Scleroderma 
Lung Study III) trial. This document should be read in tandem with the SLS III Study Protocol version 2.5, 
dated November 17, 2021. 
Scleroderma Lung Study III proposes to investigate a new combination therapy for patients with SSc-ILD 
that will combine the established effects of immunosuppression, as mediated by MMF, with the anti-
fibrotic effects of PFD. The primary hypothesis is that the rapid onset and anti-fibrotic activity of PFD, 
which have been observed in the treatment of IPF, will complement the delayed anti-inflammatory and 
immunosuppressive effects of MMF, to produce a significantly more rapid and/or greater improvement 
in lung function over time than occurs in patients receiving control therapy with MMF (and Plac) alone. A 
secondary objective is to demonstrate that combination therapy with PFD and MMF is well tolerated, in 
comparison to MMF alone, and not associated with limiting toxicity that impacts on the overall treatment 
effect. 
The SLS III study is designed as a Phase II multi-center, double-blind, parallel group, randomized and 
placebo-controlled clinical trial addressing the treatment of patients with active and symptomatic SSc-ILD. 
Participants were randomized in a 1:1 assignment to receive either oral MMF and Plac (acting as a control 
arm) or a combination of oral MMF and oral PFD (acting as an experimental arm), with both regimens 
administered for 18 months. The length of therapy, 18 months, was established based on prior studies 
with immunosuppressive therapy alone, which demonstrated that 18 months represents the time 
required to achieve a peak treatment response. The primary outcome will include physiologic measures 
of lung function, HRCT imaging measures of lung inflammatory and fibrotic changes, dyspnea, 
assessments of skin inflammation and thickening, and patient reported measures of symptoms and quality 
of life.  Tolerability and toxicity of the two treatments will also be assessed. 
4.2 
Scope of the Analyses 
The purpose of this document is to describe primary, secondary and exploratory statistical analyses to 
be conducted with regard to the SLS III clinical trial. Ancillary analyses are not covered in this document. 
5 Study Objectives and Endpoints 
5.1 
Study Objectives 
5.1.1 
Primary Objective 
To assess the impact of combined PFD and MMF, as compared to treatment with MMF alone (i.e., 
combined with placebo), on the overall course of lung function over an 18-month course of therapy. 
 
5.1.2 
Secondary Objective 
To demonstrate that combination therapy with PFD and MMF is well tolerated, in comparison to MMF 
alone, and not associated with limiting toxicity that impacts on the overall treatment effect. 
 


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5.1.3 
Exploratory Objectives 
To explore the relationships among participant characteristics, study medication, and clinical outcomes, 
we define the following pre-specified exploratory objectives: 
1. To identify baseline features that predict treatment responsiveness, disease progression and the 
course of lung and skin disease over time.  
2. To identify biomarkers that predict disease features, treatment responsiveness, disease progression 
and the course of lung and skin disease over time. 
 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
The primary endpoint is the change from baseline, measured at 3-month intervals, in the mean forced 
vital capacity (represented as the percentage of the age-, height-, gender- and race-adjusted predicted 
value, i.e. FVC-%) over the course of the 18-month double-blind treatment period. 
 
5.2.2 
Secondary Endpoints 
1. The change from baseline to 18 months, measured at 3-month intervals, over the course of the 18-
month treatment period in:  
a. Single-breath diffusing capacity for carbon monoxide (DLCO), calculated as a percent of 
the age-, height-, gender-, race- and hemoglobin-adjusted predicted value (DLCOHb-%).  
b. Modified Rodnan Skin Score (mRSS). 
c. Forced vital capacity volume (FVC, in ml) 
d. St. George Respiratory Questionnaire (SGRQ) 
 
2. Transition Dyspnea Index at 18 months, measured at 3-month intervals, over the course of the 18-
month treatment period. 
 
3. The change from baseline to 18 months, measured at 6-month intervals, over the course of the 18-
month treatment period in Health assessment questionnaire modified for scleroderma (SHAQ) 
includes: 
a. HAQ-DI calculated without aids/devices  
b. Scleroderma-HAQ-DI visual analogue scales (VAS) assessing burden of pain, burden of 
digital ulcers, Raynaud’s, GI involvement , breathing, and overall disease 
 
4. The change from screening to month 18 in quantitative HRCT measures of SSc-ILD which specifically 
include: 
a. Quantitative lung fibrosis score in the whole lung (QLF-WL). 
b. Quantitative lung fibrosis score in the lobe of maximal involvement (QLF-LM). 
c. Quantitative interstitial lung disease score in the whole lung (QILD-WL). 
d. Quantitative interstitial lung disease score in the lobe of maximal involvement (QILD-
LM). 
e. Total lung capacity at maximum inspiration (HRCT-TLC) 
 
5. The time (in months) required for each treatment arm to achieve a 3.0% (absolute) or greater 
improvement from baseline in the FVC-% over the 18-month treatment period. 


SLS III SAP 
 
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6. The proportion of participants in each treatment arm achieving greater than a 5% (absolute) 
improvement from baseline in FVC-% over the 18-month treatment period.  
 
7. The proportion of participants in each treatment arm achieving absolute change of FVC-% from 
baseline to month 18 as: 
a. Improvements by up to 5%, from 5% to <10% and from 10% to <15% or worsening by up 
to 5%, from 5% to <10% and from 10% to <15%. 
b. Positive responders (improved at least 3% or more), negative responders (worsened at 
least 3% or more), and stable (> -3% to < 3%) 
c. Responder (> 0) and non-responders (≤ 0). 
 
8. The proportion of participants in each treatment arm achieving absolute change of mRSS from 
baseline to month 18 as: 
a. Using 4 points increments: worsen (1 to 4, ≥ 5), no change (=0), improved (≤ -13, -12 to 
-9, -8 to -5, -4 to -1). 
b. Improved (< -5), no change (-5 to 5), and decreased (> 5). 
 
9. The proportion of participants in each treatment arm achieving the TDI focal score at month 18 as : 
a. Improved by 1-3, 4-6 and 7-9 points, no change (0) and worsened by 1-3, 4-6 and 7-9 
points. 
b. Improved (>0), no change, deterioration (<0). 
 
10. Tolerability and toxicity of combined MMF and Plac vs MMF and PFD over the course of the 18-
month treatment period. 
a. The time from start of treatment to withdrawal or removal from active drug therapy for 
any reason. 
b. Number of participants with treatment-emergent adverse events related to study 
medication as assessed by system organ classification using preferred Medical 
Dictionary for Regulatory Activities (MedDRA) terms. 
 
5.2.3 
Other Endpoints 
1. The change from baseline to month 18, measured at 6-month intervals, in PROMIS-29 version 2.0 
with the following domains: Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Pain 
Interference, Impact on Social Roles, and a single item on pain intensity.   
2. The proportion of participants in each treatment from screening to month 18 with a 2% increment 
in QILD-WL. It is also categorized as better (<-2%), stable (≥-2%, ≤2%) and worsen (>2%).  
3. The proportion of participants in each treatment arm with a 3% or greater decline from baseline in 
FVC-% over the 18-month treatment period.  
4. The proportion of participants in each treatment arm with a 5% or greater decline from baseline in 
FVC-% over the 18-month treatment period.   
5. The change from baseline to month 6, 12, and 18 in patient global assessment of “overall health” in 
the past week.  
6. Patient transition questions of global assessment at month 6, 12, and 18 comparing their i) overall 


SLS III SAP 
 
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health and ii) lung involvement to that at the baseline visit.  
7. The change from baseline to month 6, 12, and 18 in supplemental questions in Leicester Cough 
Questionnaire (LCQ) regarding the cough severity, cough frequency and phlegm production.  
 
6 Study Methods 
6.1 
General Study Design and Plan 
This study is designed as a phase II multi-center, double-blind, parallel group, randomized and placebo-
controlled clinical trial addressing the treatment of patients with active and symptomatic SSc-ILD. 
Eligibility for the study was assessed during a 3-month screening period. Eligible participants were 
randomized in a 1:1 assignment to receive either oral MMF and Plac (acting as a control arm) or a 
combination of oral MMF and oral PFD (acting as an experimental arm), with both regimens administered 
for 18 months.  
 
MMF was administered orally twice daily with a 4-step titration at monthly intervals to a target dose of 
1500 mg twice daily as tolerated. PFD/PBO was administered orally three times daily with a 3-step titration 
at 2 week intervals to a target dose of 801 mg three times daily as tolerated. Patients could receive 
ongoing treatment with a maximum tolerated dose for either drug that was less than the target dose 
according to rules defined by the protocol. MMF is approved for use as an immunosuppressant in solid 
organ transplantation (cardiac, hepatic and renal) at doses up to 1.5 g twice daily and for the treatment 
of Lupus nephritis, an autoimmune manifestation of systemic lupus erythematosus, in the dose range of 
1 to 3 g daily. PFD is currently approved for the treatment of IPF at a recommended dose of 801 mg (3 
capsules of 267 mg each) 3 times daily. They were administered in this study at doses that fall within these 
FDA-defined dosing ranges but as experimental therapy for SSc-ILD. 
 
A participant was considered to have completed the study if he or she completed all phases of the study 
including the last visit, or the last scheduled procedure, regardless of the dose of either study drug.  
Participants were followed in the study even if study drug was prematurely discontinued unless they had 
withdrawn their consent to do so. End of study was constituted by completion of the entire potential 18 
months in all randomized participants.  
 
6.2 
Inclusion-Exclusion Criteria and General Study Population 
6.2.1 
Inclusion Criteria 
In order to be eligible for randomization as a study participant, an individual must have met all of the 
following inclusion criteria. Patients were provided consent prior to the screening and screening was 
included as part of the consent process.  
 
Screening criteria that met prior to moving forward to HRCT imaging 
1. Age >18 years 
2. Scleroderma as determined by the 2013 ACR/EULAR classification criteria. 
3. Grade ≥2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index (Becomes short 
of breath with moderate or average tasks such as walking up a gradual hill, climbing less than three 
flights of stairs, or carrying a light load on the level.  


SLS III SAP 
 
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4. FVC-% of ≤85% at screening. (The original cutpoint was <80%; the cutpoint was changed in protocol 
amendment version 1.2 [December 1, 2021] to ≤85%.) 
5. Onset of the first non-Raynaud manifestation of SSc within the prior 84 months. 
 
Screening HRCT imaging   
6. Presence of any ground glass opacification (any GGO) on thoracic HRCT  
 
Final screening criteria fulfilled at Baseline Visit, but prior to randomization 
7. Repeat FVC-% at the baseline visit within 10% of the FVC-% value measured at screening. If these 
criteria are not met, a repeat FVC-% may be obtained within 7 days and the subject may qualify for 
randomization if the repeat FVC-% agrees within 10% of the FVC-% obtained at screening. 
 
6.2.2 
Exclusion Criteria 
An individual who met any of the following criteria was excluded from participation in this study.  The 
majority of exclusion criteria were assessed at screening, unless explicitly stated.    
1. Disease features supporting the primary diagnosis of another connective tissue disease such as 
rheumatoid arthritis, systemic lupus erythematosus or mixed connective tissue disease (Features 
consistent with a secondary Sjogren syndrome or scleroderma-associated myopathy were allowed).  
2. FVC-% <45% at either screening or baseline. 
3. FEV1/FVC ratio <0.65 at either screening or baseline. 
4. DLCOHb-% of <30% at screening or <25% at baseline. 
5. Diagnosis of clinically significant resting pulmonary hypertension or mild pulmonary hypertension 
requiring treatment with more than one oral medication as ascertained prior to study evaluation or 
as part of a standard of care clinical assessment performed outside of the study protocol. 
6. Evidence of uncontrolled congestive heart failure, unstable ischemic heart disease, history of 
complicated pulmonary embolism impacting on heart or lung function, or unstable cardiac arrhythmia 
requiring chronic anticoagulation. 
7. Clinically significant abnormalities on HRCT not attributable to SSc.   
8. Hematologic abnormality at screening including:  
a. Leukopenia (white blood cells [WBC] <4.0x103/µl),  
b. Thrombocytopenia (platelet count <120.0x103/µl), 
c. Clinically significant anemia [Hemoglobin (Hgb) <10.0 g/dl].  
Participants with an identified and correctable etiology may have been eligible if repeat testing within 
the maximal 90-day screening period met all criteria. 
9. A diagnosis of chronic liver disease or abnormal baseline liver function test (LFTs) or total bilirubin 
that were >2.0 x upper normal limit. 
10. Serum creatinine >2.0mg/dl. 
11. History of recurrent aspiration, uncontrolled heartburn, or gastroesophageal reflux disease with a 
reflux scale score of >1.00 as determined by a UCLA Scleroderma Clinical Trial Consortium 
Gastrointestinal Scale (UCLA SCTC GIT), Version 2.0. 
Participants with uncontrolled heartburn or GERD that was amenable to medical management may 
have been eligible if repeat testing within the maximal 90-day screening period met this criteria. 
12. Known achalasia, esophageal stricture or esophageal dysfunction sufficient to limit the ability to 
swallow medication.  
13. Pregnancy (documented by serum pregnancy test) and/or breast feeding. 
14. If of child bearing potential (a female participant < 55 years of age who had not been postmenopausal 
for ≥ 5 years or who had not had a bilataeral salpingectomy, hysterectomy and/or oophorectomy), 


SLS III SAP 
 
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failure to employ two reliable means of contraception which may include  surgical sterilization, barrier 
methods, spermicidals, intrauterine devices, and/or hormonal contraception, unless the participant 
chooses abstinence (to avoid heterosexual intercourse completely).  If a subject chose abstinence, 
then a second reliable means of contraception was not needed. 
15. Prior use of potential disease modifying antirheumatic drugs (DMARDs) according to the following 
exposure rules: 
a. Use of oral cyclophosphamide (CYC), MMF, azathioprine or other oral or short half-life 
DMARDs for more than 6 months in the past year, as determined at the time of the initial 
screening visit. 
b. Treatment with more than three intravenous doses of CYC, more than one course of 
Rituximab or other intravenous or injectable DMARDs in the past year. 
c. More distant history of treatment with a DMARD was allowed as long as the patient had a 
new diagnosis/new episode of active SSc-ILD since stopping that treatment and mets the 
criteria noted in 15a or 15b. 
16. Use of CYC, MMF, azathioprine, Rituximab or other DMARD in the 30 days prior to the baseline visit 
unless the patient is on MMF and the responsible physician indicated that continued use was in the 
best clinical interest of the patient.  
17. Active infection (lung, ulcers or elsewhere) whose management would be compromised by 
immunosuppression. 
18. Other serious concomitant medical illness (e.g., active malignancy within the past 5 years other than 
surgically-removed local skin cancer such as a basal cell carcinoma), chronic debilitating illness (other 
than SSc), unreliability or drug abuse that might compromise the patient’s participation in the trial. 
19. Current use, or use within the 30 days prior to their baseline visit, of prednisone (or equivalent) in 
doses >10 mg/day. 
20. Smoking of cigars, pipes, or cigarettes during the past 6 months.  
21. Use of contraindicated medications, including medications with putative disease-modifying 
properties that do not meet the exposure limits described in Exclusion Criteria #15 and #16, moderate 
or strong inhibitors of cytochrome P450 (CYP) isozyme 1A2 (CYP1A2) (note ciprofloxacin allowed up 
to a dose of 500 mg twice daily), and moderate inducers of CYP1A2 (such as tobacco smoke or 
phenytoin). 
 
6.3 
Randomization and Blinding 
This study used randomization and masking as two of the cardinal principles of clinical trials to minimize 
bias. 
 
Randomization.  Participants were randomized after all screening assessments were completed and the 
investigator verified that eligibility criteria were met.  Eligible participants were randomized to MMF+PFD 
or MMF+Plac in a 1:1 manner, stratified by clinical site (pooled into 4 groups) and prior MMF exposure 
(naïve, >0 to <3 months, and >3 months to <6 months).  Randomization to the different strata were to be 
capped if necessary to maintain at least 50% of randomized subjects within the treatment naïve strata (no 
prior therapy with MMF or DMARD) in order to maintain adequate power. The DCC prepared the 
randomization schedule, using computer-generated block randomization with the block size(s) known 
only by the DCC.  A secure web-based application was built for use by the coordinators to enter participant 
information (e.g., participant ID, stratification factor) and to obtain the randomization number.  The 
information was printed and sent and/or emailed directly to the site pharmacists.  Participants who 
withdrew from the study prior to completion of the treatment period were not replaced.   
 


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Blinding.   This is a double-blind study.  The study staff (except for select staff at the DCC and Research 
Pharmacists) and the participant were blinded to the treatment assignment. 
 
6.4 
Study Assessments 
The Schedule of Activities details the study procedures: 
 


SLS III SAP 
 
Page 16 of 46 
 
 
 
Screen 
 
Randomized Double-blind Phase 
 
Exit 
visit* 
Visit # 
 
S1 
S2 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
 
V22 
Month on Study 
(Month = 28 days) 
 
Sc-1 
Sc-2 
 
0 
 
0.5 (14 
days) 
±7d 
1 (28 
days) 
±7d 
1.5 (42 
days) 
±7d 
2 (56 
days) 
±10d 
3 (84 
days) 
±10d 
4 (112 
days) 
±10d 
5 (140 
days) 
±10d 
6 (168 
days) 
±10d 
7 (196 
days) 
±10d 
8 (224 
days) 
±10d 
9 (252 
days) 
±10d 
10 (280 
days) 
±10d 
11 (308 
days) 
±10d 
12 (336 
days) 
±14d 
13 (364 
days) 
±10d 
14 (392 
days) 
±10d 
15 (420 
days) 
±14d 
16 (448 
days) 
±10d 
17 (476 
days) 
±10d 
18 (504 
days) 
±14d 
 
Month 19 (532 
days)  
±10d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone contact 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
On-Site Visit 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Complete H&P 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
F/u SSc-H&P  
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Vital signs 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
mRSS 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Study Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
Medications 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense meds 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Drug reconciliation 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Mahler BDI/TDI  
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
SGRQ 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
SHAQ, PROMIS-29, 
UCLA SCTC GIT, 
CRISS, LCQ, Global 
Assessments 
 
UCLA 
SCTC 
GIT 
 
 
X 
(except 
CRISS) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
LABS: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - CBC, diff, plat  
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
  - Metabolic/liver 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
  - Serum Preg+ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - Urine Preg+ 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HRCT 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Spiro/DLCO 
 
X 
 
 
X‡ 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biorepository  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
‡Screen and Baseline FVC value must be within an absolute difference in percent-predicted of 10% - may repeat within 7 days if not and proceed to enroll if criteria met 
+For women of childbearing potential, initial serum pregnancy testing will be carried out with subsequent urine testing at each visit using test kits provided by the study. 
*Exit visit will also be carried out within 30 days (±10d) of early termination/withdrawal from the protocol. All subjects who terminate/withdraw early will be encouraged to return for the outcome assessments as detailed above for the 12 month (V15) 
and 18 month (V21) visits. 
**Refer to Protocol Section 17.0 (EMERGENCY DISASTER/ PANDEMIC MANAGEMENT PLAN) for allowed adjustments in the event of a disaster/pandemic that disrupts patient or institutional access. 


SLS III SAP 
 
Page 17 of 46 
 
6.4.1 
Primary Efficacy Assessment 
The primary endpoint is change from baseline in the mean forced vital capacity, measured as the 
percentage of the age-, height-, gender- and race-adjusted predicted value (FVC-%) over the course of the 
18-month treatment period, as reported quarterly (i.e., months 3, 6, 9, 12, 15 and 18.) The change from 
baseline at each time point is calculated as FVC-% at x months minus FVC-% at baseline. The calculation 
of percent predicted FVC is based on equations from Hankinson4 (see table below). 
 
Result name 
Formula 
     Age 
(Date of PFT – Date of birth)/365.25 
1. For screening, rescreening, baseline, and repeat baseline visits, round down to 
the nearest integer. This is used for eligibility determination.  
2. For all efficacy analyses, use the fractional age (i.e., do not round) for all values 
including baseline. 
FVC 
Predicted 
(Reference) 
Where H = height in centimeters and Age = Age defines as above 
 Caucasian 
Males≥20:           FVC(L) = 0.00018642*H2 + 0.00064*Age – 0.000269*Age2 – 0.1933  
Males<20:           FVC(L) = 0.00018642*H2 – 0.20415*Age + 0.010133*Age2 – 0.2584 
Females≥18:      FVC(L) = 0.00014815*H2 + 0.01870*Age – 0.000382*Age2 – 0.3560  
  
African-American  
Males≥20:           FVC(L) = 0.00016643*H2 – 0.01821*Age – 0.1517 
Males<20:           FVC(L) = 0.00016643*H2 – 0.15497*Age + 0.007701*Age2 – 0.4971 
Females≥18:      FVC(L) = 0.00013606*H2 + 0.00536*Age – 0.000265*Age2 – 0.3039  
   
NOTE 1:  Those subjects who indicate that they are both African American and Mexican-American or 
Hispanic will use the African American reference equations; those subjects who indicate that they are both 
Caucasian and Mexican-American or Hispanic will use the Caucasian reference equations. 
NOTE 2:  Those subjects who indicate that they are Asian will use 0.88x the Caucasian values. 
NOTE 3:  If Race is “Unknown or Not Reported”, then use Caucasian values. 
FVC Percent 
Predicted 
(FVC Observed / FVC Predicted) * 100 
 
6.4.2 
Secondary Efficacy Assessments  
6.4.2.1 FVC 
FVC is measured in milliliters at baseline and months 3, 6, 9, 12, 15 and 18. 
 
6.4.2.2 DLCOHb-%  
Single-breath diffusing capacity for carbon monoxide (DLCO), calculated as a percent of the age-, 
height-, gender-, and hemoglobin-adjusted predicted value (DLCOHb-%). It is assessed at baseline, and 
months 3, 6, 9, 12, 15, and 18. The calculation of predicted DLCO is based on equations from Neas and 
Schwartz6 and the calculation of hemoglobin-adjusted predicted DLCO is based on equations from 
Cotes1 (see table below). 
 
 
 
 


SLS III SAP 
 
Page 18 of 46 
 
 
 
 
 
Result name 
Formula 
Age 
(Date of PFT – Date of birth)/365.25 
1. For screening, rescreening, baseline, and repeat baseline visits, round down to the 
nearest integer. This is used for eligibility determination.  
2. For all efficacy analyses, use the fractional age (i.e., do not round) for all values 
including baseline. 
DLCO Predicted 
(Reference) 
Where H = height in centimeters and Age = Age defined as above. 
 
Caucasians 
Males:  
DLCO (mL/min/mmHg) = 0.291*H – 0.208*Age – 7.86 
Females: 
DLCO (mL/min/mmHg) = 0.255*H – 0.097*Age – 12.40 
 
African-Americans 
Males:  
DLCO (mL/min/mmHg) = 0.323*H – 0.198*Age – 16.46 
Females: 
DLCO (mL/min/mmHg) = 0.136*H – 0.108*Age + 4.77 
 
NOTE 1: For minorities other than African-Americans, the prediction equations for Caucasians will be used. 
NOTE 2: If “Unknown or Not Reported”, then use Caucasian values. 
DLCO, Adjustment for 
hemoglobin 
Men: 
 
DLCO_Hgb_adjusted_reference = DLCOreference x (1.7 x Hgb)/ (10.22+ Hgb) 
Women: 
DLCO_Hgb_adjusted_reference = DLCOreference x (1.7 x Hgb)/ (9.38+ Hgb) 
 
NOTE 1: The hemoglobin will be reported from the study blood draw closest to the DLCO measurement. Ideally this 
will be within 4 weeks. 
DLCO Percent Predicted 
(Adjusted for Hgb) 
(DLCO Observed / DLCO_Hgb_adjusted reference) * 100 
 
6.4.2.3 Modified Rodnan Skin Score (mRSS) 
The modified Rodnan skin score (mRSS) calculated by summation of skin thickness in 17 different body 
sites using a 0–3 scale, where 0 = normal, 1 = mild thickness, 2 = moderate thickness and 3 = severe 
thickness. Total skin score can range from 0 (no thickening) to 51 (severe thickening in all 17 areas). Each 
body site needs to be scored otherwise total score should not be calculated. 
 
6.4.2.4 Baseline and Transition Dyspnea Index (BDI and TDI, respectively) 
The baseline (BDI) and transition (TDI) dyspnea indices assess breathlessness in domains related to 
functional impairment, magnitude of task and magnitude of effort. The BDI score ranges from 0 (very 
severe impairment) to 4 (no impairment) for each domain and are summed to determine the BDI total 
score (0–12). The TDI score ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain. The sum of all domains yields the TDI total score (-9 to +9). For both BDI and TDI, each domain 
needs to be answered otherwise total score should not be calculated. 
 
6.4.2.5 St. George Respiratory Questionnaire (SGRQ) 
SGRQ includes three component scores: Symptoms, Activity, and Impacts and are summed to calculate 
the total score. Each questionnaire response has a unique empirically derived ‘weight’. Symptoms 
component is the summed weights for the positive responses to questions 1-8 and will tolerate a 


SLS III SAP 
 
Page 19 of 46 
 
maximum of 2 missed items. Activity component is the summed weights for the positive responses to 
questions 11 and 15 and will tolerate a maximum of 4 missed items. Impacts component is the summed 
weight for the positive responses to questions 9-10, 12-14 and 16-17 and will tolerate a maximum of 6 
missed items. The weight for the missed item of symptoms, activity or impacts is subtracted from the total 
possible weight for the corresponding component and from the total weight. The total score is calculated 
by summing all positive responses in the questionnaire and expressing the result as a percentage of the 
total weight for the questionnaire. Each component and total score range from 0 (no impairment) to 100 
(maximum impairment). 
 
6.4.2.6 Scleroderma Health assessment questionnaire (SHAQ) 
The SHAQ consists of the HAQ-disability index (HAQ-DI, 8 domains and an overall score) and 6 visual 
analogue scales assessing the burden of pain, burden of digital ulcers, Raynaud’s, GI involvement, 
breathing, and overall disease. There are 41 total questions in HAQ-DI: 20 are 4-point Likert-scale 
questions, 13 questions assessing use of aids or devices, and 8 questions assessing help received from 
another.  Twenty specific activities are assessed on a 4-point Likert-scale where 0 = without difficulty, 1 = 
with some difficulty, 2 = with much difficulty and 3 = unable to do. There are 3 steps to scoring the HAQ-
DI:  
(1) The 20 activities are grouped into 8 functional categories with each category given a single score to 
the maximum value of their component activities. The score is adjusted for use of aids/help by increasing 
the category score from 0 or 1 to a 2 if aids/help are used for that category. If the category score is already 
a 2 or 3, no adjustment is made;  
(2) Sum the category scores; and  
(3) Divide the final sum by the number of categories answered to obtain the final HAQ-DI score rounded 
to the nearest value evenly divisible by 0.125.  
A complementary scoring method ignores scores for aids and devices when computing the category scores 
and represents residual disability after compensatory efforts; this measure (without adjustment) will be 
used in our analyses. HAQ-DI requires a minimum of six categories answered; if less, the score is not 
calculated. The final HAQ-DI score ranges from 0 to 3. Higher HAQ-DI score indicates more disability.  
 
Category 
Variable name 
Dressing and Grooming 
SHAQ1DRS 
SHAQ2SHM 
Arising 
SHAQ3SND 
SHAQ4BED 
Eating 
SHAQ5MEA 
SHAQ6CUP 
SHAQ7MLK 
Walking 
SHAQ8WLK 
SHAQ9CLB 
Hygiene 
SHAQ10WAS 
SHAQ11TUB 
SHAQ12TOI 
Reach 
SHAQ13REA 
SHAQ14BND 
Gripping and opening 
things 
SHAQ15DOR 
SHAQ16JAR 
SHAQ17FAU 


SLS III SAP 
 
Page 20 of 46 
 
Errands and chores 
SHAQ18SHP 
SHAQ19CAR 
SHAQ20VAC 
 
The VAS scale line from the far left indicates “no pain” to the far right indicate “the most intense pain 
imaginable”. The measurement is between 0 to 10 cm.  
 
6.4.2.7 HRCT measures 
Volumetric thoracic HRCT was done at screening and 18 months. We measured the extent of lung 
involvement by fibrosis (reticulations), ground glass opacity, and honeycombing on thoracic HRCT with a 
validated, computer-aided scoring method.12   High resolution CT scores are provided for quantitative 
extent of lung fibrosis on high resolution for the whole lung and lobe of maximum involvement and 
quantitative extent of total interstitial lung disease for whole lung and lobe of maximal involvement. 
 
6.4.3 
Other Assessments 
6.4.3.1 Patient-reported outcomes measurement information system 29-item (PROMIS-29 version 
2.0) 
The PROMIS-29 assesses each of the seven domains with four questions with an additional pain intensity 
numeric rating scale (NRS) that is question 29 of the score. The seven domains include Physical Function, 
Anxiety, Depression, Fatigue, Sleep Disturbance, Pain Interference, and Impact on Social Roles. Each 
question is scored from 1-5 (with the exception of the NRS which is from 0 = no pain to 10=worst pain 
imaginable). The sum of each domain results in the raw score, which lies between 4 and 20. There is no 
total score, but each axis forms its own score. PROMIS assessments use an Item Response Theory (IRT) 
based score called “Expected A Posteriori” or EAP scores, which are then transformed onto a final T-score 
metric. This means that the scores are mapped so that the values follow a normal distribution with a 
population mean T-score of 50 and a standard deviation of 10. It is done by uploading the data to website: 
HealthMeasures Scoring Service (assessmentcenter.net). Lower scores on Physical Function and Impact 
on Social Roles indicate better quality of life, while higher scores on other domains indicate better quality 
of life. 
 
6.4.3.2 Physician and Patient global assessment for overall disease 
The Physician Global Assessment employs a 0-10 Likert scale to assess the patient’s “overall health” in the 
past 1 week. The single-item question is anchored from 0 (excellent health) to 10 (extremely poor). Using 
a similar approach, the Patient Global Assessment employs a 0-10 Likert scale for the patient to assess 
their overall health in the past 1 week. The single-item question is anchored from 0 (excellent health) to 
10 (extremely poor). 
 
6.4.3.3 Physician and Patient global assessment for overall disease follow up 
In addition to 6.4.3.2, physician assesses changes in the patient’s overall health and lung involvement by 
transition questions: Compared to the baseline visit, how would you rate your patient’s i) overall health 
and ii) overall lung involvement. The scale ranges from 1=much better to 5=much worse. Using a similar 
approach, patient assesses changes in their overall health and lung involvement by transition questions: 
Compared to your baseline visit, how would you rate your i) overall health and ii) overall lung involvement. 
The scale ranges from 1=much better to 5=much worse. 
 
6.4.3.4 Leicester Cough Questionnaire (LCQ) 


SLS III SAP 
 
Page 21 of 46 
 
Each question has a score from 1 (severe impact of cough) to 7 (no impact of cough). The total score is 
the average of three domains: physical, psychological, and social. Total score ranges from 3 to 21. Physical 
domain will tolerate a maximum of 4 missed items; psychological domain will tolerate maximum of 3 
missed items; and social domain will tolerate a maximum of 2 missed items. Higher LCQ score indicates 
less impact of cough. Three supplement questions after the LCQ questionnaire assess cough severity 
(0=No cough to 3=Severe), cough frequency (1=Infrequent to 3=Persistent), and phlegm production 
(1=None to 3=Frequent) in past two weeks. 
 
6.4.3.5 Dosing and Adherence 
The proportion of participants reaching and sustaining the maximum dose, and the time to reach the 
maximum dose and the time remaining at the maximum dose in each treatment group. The time to reach 
the maximum dose is defined as from date of first dose to the date of 12 pills/day for MMF (1500 
mg) and 9 pills/day for PFD (801 mg) and placebo.  If a participant did not achieve the maximum dose, 
they were not included in the calculation of the time to reach maximum dose. 
 
Adherence per protocol is defined as the number of pills taken divided by the number prescribed per the 
protocol for the duration of time the participant received study medication. Adherence prescribed by PI 
is defined as the number of pills taken divided by the number prescribed per site PI (e.g., temporarily 
holding study medication administration for tolerability) for the duration of time the participant received 
study medication.   
 
7 Sample Size 
An initial sample size target of 150 participants (up to 190 consented and screened subjects to achieve 75 
randomized per treatment group) was identified based on recent clinical trial experience and logistical 
considerations including the number of clinical centers with appropriate leadership and infrastructure to 
be considered as state of the art for treating SSc-ILD.  Statistical analysis, using a clinical trials simulation 
approach, was then employed to estimate the power to detect various treatment effects on the primary 
endpoint with a two-sided Type I error of 5% and an 18-month attrition estimate of 24%.   
Data from the SLS I and II clinical trials7, 9-10 were used to estimate the baseline characteristics of the 
proposed study population and their response over time to treatment with MMF, including the impact of 
prior treatment with MMF (occurring prior to study randomization), on the predicted course of lung 
function changes over time. Note that SLS III will employ essentially the same patient recruiting centers 
and investigators as those that participated in the prior studies (with some new additions) and that the 
enrollment criteria have been relatively conserved over time to assure reproducibility. Furthermore, both 
the control arm and experimental arm of the proposed study will be treated with a course of cytotoxic 
therapy that is essentially identical to that reported from the SLS I and II studies.  For the impact of PFD, 
safety and tolerability data from the LOTUSS trial5 and outcome data from studies in which PFD was used 
to treat IPF2,3 were considered informative. 
Two outcome scenarios were considered based on the two potential mechanisms of action by which 
the addition of PFD might improve the response to treatment with MMF alone. Both scenarios assume 
that the average response pattern to MMF alone (the control arm) would approximate the average 
response pattern to cytotoxic therapy observed from SLS II. In that study, the overall improvement 
from baseline in the FVC-% was approximately 3.0% at the 12 month time point and 4.25% at 18 


SLS III SAP 
 
Page 22 of 46 
 
months. Two different response scenarios were then proposed to represent the range of possible 
responses in patients treated with combined MMF+PFD (the experimental arm).  
• 
In Scenario 1, it is assumed that treatment with PFD is associated with an early slowing of the 
decline in lung function normally observed during the first 3-6 months of cytotoxic therapy and 
that there is only a small additive effect of PFD to the later improvement in lung function. The 
collective result is a 2.5% greater response to treatment at 12 months in the experimental versus 
control arms and this difference between the groups remains the same for the duration of the 18-
month study. 
• 
In Scenario 2, it is assumed that treatment with PFD is associated with both an early slowing of 
the decline in lung function and a definite additive effect on the overall improvement in FVC-% 
that continues throughout the entire treatment period.  The collective result is a 3.125% greater 
response to treatment at 12 months in the experimental versus control arms which continues to 
slowly increase to a final 3.25% difference between the two groups at 18 months. 
Figure 7.1. Hypothesized Response Trajectories over the 18-Month Double-Blind Treatment Period 
by Treatment Group with two scenarios considered, all participants naïve to therapy.  
 
The power to detect a response based on each Scenario was then calculated by carrying out 1,000 
clinical trials simulations for each scenario in SAS 9.4, using a linear mixed model with participant-
month in the study (3, 6, 9, 12, 15 and 18) as the unit of analysis and the change from baseline in FVC-% 
as the outcome, with terms for treatment group, baseline FVC-%, month and the interaction of 
treatment group with month as a fixed covariate and participant as a random effect to account for 
the correlation of outcomes over time within a participant.  (This is a simplification of the model used 
for the primary analysis of the primary endpoint described above.)  We used a compound symmetry 
variance-covariance structure.  The average power is calculated as the number of simulations where 
the F-test used to test the hypothesis that the mean change from baseline during the double-blind 
treatment period differs between the two treatment groups is rejected (p<0.05) divided by the 
number of simulations.  95% Cis for power are calculated based on the exact binomial proportion. 
Table 7.1.  Power to detect differences in the response pattern from baseline to 18 months for the 
primary outcome (change in FVC-%) when comparing the course of change in lung function over time 
for the MMF+PFD arm and the MMF+Plac arm according to the two proposed outcome scenarios. 
Results assume a 5% two-sided type I error and are provided for three different sample sizes (N = 
75/arm; 70/arm and 65/arm) 


SLS III SAP 
 
Page 23 of 46 
 
Assumptions: 
-  Drop-out rates, variances and data inter-correlations presented below are derived from SLS I and 
II data and assumed to be identical for the two defined scenarios 
-  A 5% two-sided type I error is assumed 
-  The difference in the outcome measure between treatment arms (relative difference in the 
change from baseline in absolute FVC %-predicted) for each scenario was estimated based on the 
hypothetical response to PFD proposed for each scenario as detailed in Figure 7.5.4. 
Scenario 1 
Difference between 
treatment arms 
(FVC-%) 
Scenario 2 
Difference 
between treatment 
arms (FVC-%) 
Dropout 
(Cumulative 
%) 
SD Estimate 
 
Assumed Correlations 
(AR1): 
Mo   3:     0.5 
Mo   6:     1.375 
Mo   9:     2.25 
Mo 12:     2.5 
Mo 15:     2.5 
Mo 18:     2.5 
Mo   3:     0.75 
Mo   6:     1.75 
Mo   9:     3.0 
Mo 12:     3.125 
Mo 15:     3.25 
Mo 18:     3.25 
Mo   3:  6.5% 
Mo   6:   13% 
Mo   9:   17% 
Mo 12:   20% 
Mo 15:   23% 
Mo 18:   24% 
Mo   3:   4.1 
Mo   6:   5.1 
Mo   9:   6.2 
Mo 12:   6.9 
Mo 15:   6.2 
Mo 18:   6.2 
3-mo intervals:    
0.866 
6-mo intervals:    
0.834 
9-mo intervals:    
0.802 
12-mo intervals:  
0.790 
15-mo intervals:  
0.780 
Power Calculations Scenario 1: 
Evaluation of Statistical Power by sample size, adjusting for drop outs over time, based on 1000 
clinical trial outcome simulations: 
N per arm at 
baseline 
N per arm 
at 18 mo 
Estimated 
Statistical Power 
95% Lower Bound of 
Statistical Power 
95% Upper Bound of 
Statistical Power 
75 
57 
82.3% 
79.8% 
84.6% 
70 
53 
78.6% 
75.9% 
81.1% 
65 
49 
76.3% 
73.5% 
78.9% 
Power Calculations Scenario 2: 
Evaluation of Statistical Power by sample size, adjusting for drop outs over time, based on 1000 
clinical trial outcome simulations: 
N per arm at 
baseline 
N per arm 
at 18 mo 
Estimated 
Statistical Power 
95% Lower Bound of 
Statistical Power 
95% Upper Bound of 
Statistical Power 
75 
57 
95.6% 
94.1% 
96.8% 
70 
53 
92.6% 
90.8% 
94.2% 
65 
49 
91.8% 
89.9% 
93.4% 
Note that with the given m-ITT design, the linear mixed effects model will actually include data from 
all subjects who have at least a baseline and one follow-up measure of FVC-%. In this setting, even 
with an overall 24% attrition by the end of 18 months, it is estimated that 83% of the maximal possible 
study outcome data points (assuming no attrition) would be included in the analysis.   
 


SLS III SAP 
 
Page 24 of 46 
 
According to Scenario 1, which is strictly based on the documented capacity for PFD to slow the rate of 
decline of lung function in patients with IPF who are not receiving any other treatment, a sample size of 
75 patients per treatment arm is required to obtain a minimum power of 80% (i.e., 80% is within the 95% 
CI for this prediction).  If PFD has novel effects when combined with MMF so that it both reduces the rate 
of lung decline and works in concert with MMF to improve overall lung function (i.e., Scenario 2), then the 
predicted outcome will be much more reliably detected and a smaller sample size would be sufficient. 
Having established adequate estimates of study power in a population of treatment naïve patients, 
the clinical trial Scenarios were then adjusted to assess the impact of a mixed starting population of 
patients in which some of the participants are treatment naïve and others have been on prior 
treatment with MMF (or DMARD with similar activity) for a period of 3, 6 or 9 months. Additional 
assumptions associated with these modified Scenarios include: 
1) The mean change in FVC-% over a given 3-month interval and the corresponding impact on the 
standard deviation of the FVC-% measurement will always reflect the total time that a patient 
has been on therapy, including therapy that was administered before randomization and 
therapy that was administered following randomization.  
2) The treatment effect is measured as the change from baseline, in which baseline is determined 
at the time of randomization (baseline visit). The baseline FVC-% measurement therefore 
establishes the zero reference value for evaluating change over time in response to the time 
that a patient is on the protocol.  In this setting, patients who have been on 3 months or more 
of MMF will not be expected to experience the initial decline in lung function that occurs when 
enrolling treatment naïve patients. 
3) As one of the hypothesized benefits of starting PFD and MMF at the same time in treatment 
naïve patients is the prevention of an early decline in lung function, there is a relative treatment 
penalty in the predicted PFD+MMF arm when patients have been on prior therapy with MMF. 
This results in less and less separation between the course of the two treatment arms as the 
length of time on prior MMF increases. This impact must be accounted for when modeling 
treatment outcomes and predicting study power. 
 
Figure 7.2.  Hypothesized Response Trajectories over the 18-Month Double-Blind Treatment Period 
by Treatment Group for Scenario 2 based on length of time on MMF therapy prior to randomization. 


SLS III SAP 
 
Page 25 of 46 
 
 
The power to detect a response according to Scenario 2, when taking into account the length of prior 
treatment with MMF (naïve, 3 mo, 6 mo and 9 mo strata) and the percentage of subjects within each 
of these strata, was then calculated by carrying out 1,000 clinical trials simulations for each situation 
in SAS 9.4 as already described. We varied the proportion of patients from 100% naïve down to 50% 
naïve, with the distribution across the prior treatment with MMF strata varied as described below. 
Estimates of the differences between treatment arms and the standard deviation for the 
measurements at a given time were adjusted according to the scenario curves shown in Figure 7.2. 
 
Table 7.2. Power to detect differences in the response pattern from baseline to 18 months for the 
primary outcome (change in FVC-%) when comparing the course of change in lung function over time 
for the MMF+PFD arm and the MMF+Plac arm according to Scenario 2 with different mixtures of 
treatment naïve patients and those who were on prior MMF therapy for 3, 6 or 9 months as indicated. 
Results assume a 5% two-sided type I error and are provided for three different sample sizes (N = 
75/arm; 70/arm and 65/arm) 
 
a. Scenario 2: N = 75 per arm 
% per stratum  
(length of prior MMF) 
Estimated statistical power based on 
1000 clinical trial outcome simulations  
Naive 
3 mo 
6 mo 
9 mo 
Power 
95% Lower 
Bound  
95% Upper 
Bound  
1.00 
0.00 
 
 
95.6% 
94.1% 
96.8%


SLS III SAP 
 
Page 26 of 46 
 
0.80 
0.20 
 
 
93.8% 
92.1% 
95.2% 
0.75 
0.25 
 
 
92.2% 
90.4% 
93.8% 
0.70 
0.30 
 
 
90.8% 
88.8% 
92.5% 
0.60 
0.40 
 
 
90.5% 
88.5% 
92.2% 
0.50 
0.50 
 
 
86.1% 
83.8% 
88.2% 
0.80 
0.10 
0.10 
 
91.4% 
89.5% 
93.1% 
0.70 
0.20 
0.10 
 
89.5% 
87.4% 
91.3% 
0.70 
0.10 
0.20 
 
90.2% 
88.2% 
92.0% 
0.60 
0.30 
0.10 
 
89.0% 
86.9% 
90.9% 
0.60 
0.20 
0.20 
 
88.2% 
86.0% 
90.1% 
0.60 
0.10 
0.30 
 
85.2% 
82.8% 
87.3% 
0.50 
0.40 
0.10 
 
84.7% 
82.3% 
86.9% 
0.50 
0.30 
0.20 
 
82.7% 
80.2% 
85.0% 
0.50 
0.20 
0.30 
 
82.7% 
80.2% 
85.0% 
0.50 
0.10 
0.40 
 
79.7% 
77.1% 
82.2% 
0.70 
0.10 
0.10 
0.10 
86.4% 
84.1% 
88.5% 
0.60 
0.20 
0.10 
0.10 
86.2% 
83.9% 
88.3% 
0.60 
0.10 
0.20 
0.10 
83.7% 
81.3% 
85.9% 
0.50 
0.30 
0.10 
0.10 
79.9% 
77.3% 
82.3% 
0.50 
0.20 
0.20 
0.10 
79.3% 
76.7% 
81.8% 
 
b. Scenario 2: N = 70 per arm 
% per stratum  
(length of prior MMF) 
Estimated statistical power based on 
1000 clinical trial outcome simulations  
Naive 
3 mo 
6 mo 
9 mo 
Power 
95% Lower 
Bound  
95% Upper 
Bound  
1.00 
0.00 
 
 
91.8% 
89.9% 
93.4% 
0.80 
0.20 
 
 
91.3% 
89.4% 
93.0% 
0.70 
0.30 
 
 
88.1% 
85.9% 
90.0% 
0.60 
0.40 
 
 
86.0% 
83.7% 
88.1% 
0.50 
0.50 
 
 
84.6% 
82.2% 
86.8% 
0.80 
0.10 
0.10 
 
89.4% 
87.3% 
91.2% 
0.70 
0.20 
0.10 
 
88.7% 
86.6% 
90.6% 
0.70 
0.10 
0.20 
 
85.6% 
83.3% 
87.7% 
0.60 
0.30 
0.10 
 
85.7% 
83.4% 
87.8% 
0.60 
0.20 
0.20 
 
82.9% 
80.4% 
85.2% 
0.60 
0.10 
0.30 
 
81.5% 
79.0% 
83.9% 
0.50 
0.40 
0.10 
 
83.0% 
80.5% 
85.3% 
0.50 
0.30 
0.20 
 
81.5% 
79.0% 
83.9% 


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0.50 
0.20 
0.30 
 
79.9% 
77.3% 
82.3% 
0.50 
0.10 
0.40 
 
79.9% 
77.3% 
82.3% 
 
c. Scenario 2: N = 65 per arm 
% per stratum  
(length of prior MMF) 
Estimated statistical power based on 
1000 clinical trial outcome simulations  
Naive 
3 mo 
6 mo 
9 mo 
Power 
95% Lower 
Bound  
95% Upper 
Bound  
1.00 
0.00 
 
 
91.8% 
89.9% 
93.4% 
0.80 
0.20 
 
 
88.2% 
86.0% 
90.1% 
0.70 
0.30 
 
 
85.5% 
83.2% 
87.6% 
0.60 
0.40 
 
 
81.4% 
78.9% 
83.8% 
0.50 
0.50 
 
 
79.7% 
77.1% 
82.2% 
0.80 
0.10 
0.10 
 
87.1% 
84.9% 
89.1% 
0.70 
0.20 
0.10 
 
85.5% 
83.2% 
87.6% 
0.70 
0.10 
0.20 
 
83.2% 
80.7% 
85.5% 
0.60 
0.30 
0.10 
 
78.4% 
75.7% 
80.9% 
0.60 
0.20 
0.20 
 
77.5% 
74.8% 
80.0% 
 
According to these predictions for Clinical Trial Scenario 2, representing the primary outcome to be 
investigated, the study is adequately powered (80% power or greater) to detect a difference between 
the two treatment arms when the sample size is 150 and the patient population contains at least 50% 
treatment naïve patients. If the remaining 50% of enrolled patients are limited to no more than 6 
months of prior therapy with MMF, then adequate power is maintained across the entire range of 
anticipated distributions between subjects with up to 3 mo of prior therapy and those with between 3 
to 6 mo of prior therapy.  
 
As a result, the target study population will consist of at least 50% of patients who are treatment naïve 
and up to 50% of patients who recently started on therapy within 6 months of entering the study (as 
detailed in Table 7.2 above). With this mixture of patients, the power remains adequate even if only 
70 patients are enrolled in each arm (total randomization 140 patients), providing optimal flexibility 
for the enrollment phase of the study. 
 
When a similar statistical approach is applied to Clinical Trial Scenario 1, in which only a small additive 
effect of PFD is modeled in addition the underlying treatment response to MMF, the power to detect 
a difference between the two treatment arms is adequate (80% power or greater) when the sample 
size is 150 and the patient population contains at least 75% treatment naïve patients.  When the 
percentage of treatment naïve patients is reduced to 50%, the predicted power is at best 75% 
(assumes % per stratum of 50% naïve, 40% 3 mo, 10% 6 mo). 
 


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8 General Analysis Considerations 
8.1 
Timing of Analyses 
The final analyses of the clinical trial will be performed after 
1) All enrolled participants either (a) completed 18 months of follow-up from enrollment or (b) 
discontinued early from the study. 
2) Any chart reviews or investigations needed to confirm dates of elements of the primary 
composite endpoint were identified and completed. 
3) All study data were entered, locked and unblinded as per SABER SOPs. 
This SAP document was finalized and approved prior to the double-blind database lock and unblinding. 
 
8.2 
Analysis Populations 
8.2.1 
Modified Intention to Treat Population 
The main population for efficacy is the modified intention-to-treat population (m-ITT), defined as all 
participants randomized, receiving at least one dose of study medication, and having at least one post-
baseline efficacy assessment. Subjects were analyzed by assigned treatment. 
 
8.2.2 
Per Protocol Population 
The Per Protocol (PP) analysis set consists of all participants in the m-ITT population who completed 18 
months of study medication (i.e., both MMF and PFD/Plac) and do not have a major protocol violation, 
defined as violation of entry criteria or taking prohibited medications. The study window for month 18 
visit is ± 6 weeks. Membership in the PP analysis population was determined before study unblinding.  
 
8.2.3 
Completers Population 
The Completers analysis set consists of all subjects in the m-ITT population who had an 18-month efficacy 
outcome (regardless of completion of study medication).  It can be different depending on the outcome 
that is analyzed. 
 
8.2.4 
Safety Population 
The Safety Population is defined as all participants who were randomized and received at least one dose 
of the study medication.  The Safety Population was used for all safety analyses.  Subjects were analyzed 
by assigned treatment. 
 
8.3 
Covariates and Subgroups  
Prior MMF therapy (stratification factor: naïve, >0 to <3 months, and >3 months to 6 months) and FVC-% 
at baseline were included as covariates in the analysis of the primary efficacy endpoint. Several other 
covariates are incorporated in specific analyses that are denoted in the analysis specifications described 
below (e.g., secondary analysis of primary endpoint including baseline mRSS as a covariate).  No subgroup 
analyses were planned.  
 


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8.4 
Missing Data 
 Our primary analytic approach assumes a missing-at-random mechanism8.  Sensitivity analyses are 
performed to assess how subjects who withdrew might affect conclusions of the analysis for the primary 
endpoint.  
 
8.5 
Interim Analyses and Data Monitoring 
No formal interim analyses were planned nor carried out for this study.  The study was overseen by a Data 
and Safety Monitoring Board (DSMB) that reviewed the pooled and by-treatment subject disposition, 
study conduct and safety data approximately every 6 months.   
 
8.6 
Multiple Testing 
Statistical testing is conducted at the 0.05 significance level using two-tailed tests; two-sided p-values are 
reported. No adjustments for multiplicity were planned since there is one primary analysis of the primary 
endpoint at the end of the study.  Secondary analyses of the primary endpoint and analyses of the 
secondary endpoints serve to assess the robustness of the results and consistency of treatment effect on 
clinical outcomes important in this disease. 
 
9 Summary of Study Conduct Data 
Descriptive summary statistics are tabulated for baseline patient demographics and clinical characteristics, 
separately by treatment group and overall. Intervention groups are characterized as “MMF+PFD” and 
“MMF+Plac”. For pooled summaries, “Overall” is used as the column heading. All tables are annotated 
with the total population size relevant to that table, including any missing observations. 
 
Continuous variables are summarized using descriptive statistics including n, mean, median, standard 
deviation, range (e.g., minimum and maximum) and using boxplots to examine the distributions of 
baseline characteristics by treatment group.  Qualitative variables are summarized using counts and 
percentages. Unless otherwise specified, statistical analyses are performed using SAS Version 9 or higher. 
 
9.1 
Subject Disposition 
Participant disposition is summarized descriptively. The number and percentage of participants 
randomized, completed, and withdrawing, along with reasons for withdrawal, are tabulated and 
summarized in a CONSORT diagram overall, and by treatment group. The number of participants in each 
analysis population are reported. Other disposition and study conduct information, including major 
protocol violations are summarized. Duration of the study follow-up is summarized overall and by 
treatment group. 
 
9.2 
Protocol Deviation 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. 
Protocol deviations were classified as major or not major by the study team; major protocol deviations 
are incorporated into the definition of the Per Protocol Analysis Set.  Protocol deviations are summarized 
overall and by treatment group.  Major protocol deviations are provided in a listing by treatment group.   


SLS III SAP 
 
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9.3 
Demographic and Baseline Variables 
Demographic and baseline variables for participants include: age in years at consent, dichotomized age 
(18-35 years, >35-55 years, >55-75 years, >75 years), sex (Male/Female), ethnicity (Hispanic or Latino/not 
Hispanic or Latino), race (White/Black or African American/Asian/American Indian or Alaskan 
native/native Hawaiian or other Pacific islander), % predicted FVC, FVC (ml), % predicted DLCO (corrected 
for hemoglobin), time from first non-Raynaud manifestation of SSc in months at screening, modified 
Rodnan Skin Score (mRSS), Scleroderma classification, Mahler Baseline Dyspnea Index (BDI), St. George’s 
Respiratory Questionnaire (SGRQ) – total and each domain score, Scleroderma Scleroderma Health 
Assessment Questionnaire (SHAQ), including HAD-DI without Aids/Devices and SHAQ-DI VAS domains, 
Leicester Cough Questionnaire (LCQ) – total and three supplemental questions, PROMIS-29 domains, 
UCLA SCTC GIT, physician global assessment, patient global assessment, height, weight, HRCT at screening 
– quantitative lung fibrosis score in the whole lung (QLF-LM), quantitative lung fibrosis score in the lobe 
of maximal involvement (QLF-WL), quantitative interstitial lung disease score in the whole lung  (QILD-
LM), quantitative interstitial lung disease score in the lobe of maximal involvement (QILD-WL), and total 
lung capacity at maximum inspiration (HRCT-TLC), and laboratory data at screening – sodium, potassium, 
chloride, CO2, BUN, creatinine, glucose, protein, albumin, bilirubin, alkaline phosphate, AST, ALT, 
cholesterol, WBC, hemoglobin, hematocrit, platelets, neutrophil percent, absolute neutrophil count, 
lymphocyte percent, absolute lymphocyte count. 
 
9.4 
Treatment Compliance 
Compliance with study medication (MMF and PFD/Plac) is assessed and summarized, including 
• 
the proportion of participants who adhered to study treatment, overall and at each study visit,  
• 
the median duration of adherence to study treatment (defined in section 11.1),  
• 
the proportion of participants reaching maximum dose, 
• 
the proportion of participants who sustain their maximum dose,  
• 
the time to reach the maximum dose, and 
• 
the time remaining at the maximum dose. 
These are calculated and summarized overall and by treatment group. The maximum dose is 
12 pills/day for MMF (1500 mg) and 9 pills/day for PFD (801 mg)/Plac. The proportion of the maximum 
dose that the participants reached during study period is summarized overall and by treatment group. 
Participants were expected to take study medication unless it was permanently discontinued due to an 
AE. The study medication log (Form 027), adverse event form (Form 044), serious adverse event form 
(Form 045) and final status form (Form 035) are used to derive the compliance measure. 
 
The proportion of participants who permanently discontinued study medication will be summarized with 
descriptive statistics, overall and by treatment group.  A Kaplan-Meier curve will present the time to 
permanent discontinuation of study medication by treatment group. A listing of these participants with 
their reason for permanent discontinuation of study medication will be provided. 
 
10 Efficacy Analyses 
Continuous variables will be summarized using descriptive statistics including n, mean, median, standard 
deviation, and range (e.g., minimum and maximum). Qualitative variables will be summarized using 
counts and percentages. Summaries will be provided by treatment groups and overall.  
 


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10.1 Primary Efficacy Analysis 
The primary endpoint is change from baseline in the mean forced vital capacity, measured as the 
percentage of the age-, height-, gender- and race-adjusted predicted value (FVC-%) over the course of the 
18-month treatment period, as reported quarterly (i.e., months 3, 6, 9, 12, 15 and 18). The primary efficacy 
analysis tests the null hypothesis that the differences between the MMF+PFD and MMF+Plac is zero. The 
primary analysis of the primary efficacy endpoint uses the m-ITT analysis set. The endpoint is analyzed 
using a linear mixed model with participant-month in the study (3, 6, 9, 12, 15, 18) as the unit of analysis 
and the change from baseline in FVC-% as the outcome, with terms for baseline FVC-%, treatment group, 
month, the interaction of month and treatment group, and prior MMF therapy (stratification factor: 
naïve, >0 to <3 months, and >3 months to 6 months), as fixed covariates.  Study participant is treated as 
a random effect to account for the correlation of outcomes over time within a participant.   
 
The model is summarized below. 
 
FVC-%𝑖𝑖𝑖𝑖 = 𝜇𝜇0 + 𝜇𝜇1TRT𝑖𝑖+ 𝜇𝜇2 MONTH𝑖𝑖𝑖𝑖+ 𝜇𝜇3TRT𝑖𝑖× MONTH𝑖𝑖𝑖𝑖+ 𝐱𝐱𝐢𝐢
′ 𝛃𝛃+ 𝜖𝜖𝑖𝑖𝑖𝑖,  
 
where FVC-%𝑖𝑖𝑖𝑖 is the change of FVC-% from baseline at time 𝑡𝑡 for patient 𝑖𝑖 (that is, FVC-% at time t - FVC-% 
at baseline), 𝑖𝑖= 1, … , 51; 𝑡𝑡= 1, … ,6 (corresponding to 3, 6, 9, 12, 15 and 18 months). TRT𝑖𝑖 is treatment 
group (equal to 1 for the PFD and MMF and 0 for Plac and MMF) for patient 𝑖𝑖. MONTH𝑖𝑖𝑖𝑖 is the study month 
at time t for patient i. Two dummy variables for prior MMF therapy (stratification factor: naïve, >0 to <3 
months, and >3 months to 6 months), and baseline FVC-% for subject 𝑖𝑖 are included in a vector 𝐱𝐱i of 3 
covariates (𝑥𝑥1, 𝑥𝑥2, x3) and associated fixed effects are stored in vector 𝛃𝛃= (β1, β2, β3). We assume that 
residual errors 𝜖𝜖it   ( t = 1, … , 6) for subject 𝑖𝑖 are normally distributed with zero mean and 6x6 
general/unstructured variance-covariance matrix.  
 
In the context of the primary analysis of the primary endpoint, we are interested in parameter 𝜇𝜇3, 
representing the trajectories of the primary endpoint adjusted for stratifying variables and baseline 
covariates.  
 
The model generates adjusted estimates of change from baseline in the FVC-% for each treatment group 
and month, and an F-test is used to test the hypothesis that the mean change from baseline during the 
treatment period differs between the two treatment groups.  
 
The model-based adjusted mean change from baseline in FVC-% will be presented graphically by 
treatment group by study month, with 95% confidence intervals (CIs) provided at each month.   
 
Analysis 
Primary Analysis of the Primary Endpoint: mean FVC-% change from 
baseline during the treatment period differs between the two treatment 
groups 
Analysis Set 
mITT Population 
Methods 
Linear mixed model for repeated measures with correlated errors 
Dependent 
Variable 
Change of FVC-% measured at 3, 6, 9, 12, 15 and 18 months 
(FVC-% at x months – FVC-% at baseline, where x=3, 6, 9, 12, 15 and 18) 
Model 
Fixed effects: 
• 
Treatment 
• 
Study month 
• 
Interaction of treatment and study month 


SLS III SAP 
 
Page 32 of 46 
 
• 
Stratifying variable: prior MMF therapy with 3 categories 
• 
Baseline FVC-% 
Results 
• 
Estimates of mean change from baseline in FVC-% during the 
treatment period (slope) by treatment group and treatment 
difference  
• 
95% confidence interval for treatment estimates and treatment 
difference 
• 
P-value for treatment difference 
 
 
10.2 Secondary Efficacy Analyses 
10.2.1 
Secondary Analyses of Primary Efficacy Endpoint 
Several sensitivity analyses are performed to assess how alternative approaches to missing data and 
model assumptions affect the conclusions of the analysis of the primary outcome: 
 
1. Analysis of the primary efficacy variable as described in section 10.1 is performed using the PP 
population.  
 
2. Analysis of the primary efficacy variable described in section 10.1 with the m-ITT analysis set 
except that HRCT fibrosis scores in the lobe of maximal involvement (QLF-LM) at screening is 
added as a covariate.  
 
3. Analysis of the primary efficacy variable described in section 10.1 with the m-ITT analysis set 
except that baseline mRSS is added as a covariate.  
 
4. Analysis of covariance (ANCOVA) is used to analyze the change of FVC-% from baseline to month 
18 (that is, FVC-% at month 18 - FVC-% at baseline). The model includes the treatment group, 
baseline FVC-% and prior MMF therapy.  
 
5. In addition to the assessment of the overall trajectory of pulmonary response which integrates 
the timing of the onset of response and the overall magnitude of effect at 18 months, we evaluate 
the individual components of this response.  This is accomplished by using the linear mixed effects 
model with same covariates described for the analysis of primary efficacy variable and provide 
adjusted estimates of change from baseline in FVC-% for each treatment group and treatment 
difference for each time point (e.g., 3, 6, 9, 12, 15 and 18 months).   
 
6. Descriptive statistics are provided to assess more granular changes in FVC-% by treatment 
adherence (e.g., premature discontinuation of study treatment prior to 3, 6, 9, 12, 15 and 18 
months) in the completers population. 
 
10.2.2 
Secondary Efficacy Analyses 
The m-ITT analysis set will be used in the analyses of secondary endpoints if not otherwise indicated. 
1. The linear mixed model as described for the primary analysis of the primary endpoint is performed 
to compare the two treatment groups for the change from baseline to 18 months, measured by 


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3-month intervals, in the following outcomes. The model is adjusted by treatment, study month, 
interaction of treatment and study month, prior MMF therapy and baseline outcome. For FVC 
(measured in ml), the model also includes age (measured as a real number and not an integer), 
height, sex and race (i.e., the same variables used in the percent predicted equations). The model 
generates adjusted estimates of the change from baseline for each treatment group and month, 
and an F-test is used to test the hypothesis that the mean change from baseline during the 
treatment period differs between the two treatment groups. The model-based adjusted mean 
change from baseline will be presented graphically by treatment group and study month, with 95% 
confidence intervals (CIs) provided at each month. 
a. Hemoglobin-adjusted DLCOHb-% 
b. mRSS 
c. FVC (in ml)  
d. SGRQ: Total score, Symptoms, Activity, Impacts  
 
2. The linear mixed model as described for the primary analysis of the primary endpoint is performed 
to compare the two treatment groups for the change from baseline to 18 months, measured at 
3-month intervals, in dyspnea. The model is adjusted by treatment, study month, interaction of 
treatment and study month, prior MMF therapy, and BDI. The model generates adjusted 
estimates of TDI for each treatment group and month, and an F-test is used to test the hypothesis 
that the mean change from baseline during the treatment period differs between the two 
treatment groups. The model-based adjusted mean TDI will be presented graphically by 
treatment group and study month, with 95% confidence intervals (CIs) provided at each month.  
 
3. The linear mixed model as described for the primary analysis of the primary endpoint is performed 
to compare the two treatment groups for the change from baseline to 18 months, measured at 
6-month interval, in SHAQ. The model is adjusted by treatment, study month, interaction of 
treatment and study month, prior MMF therapy and baseline SHAQ. The model generates 
adjusted estimates of the change from baseline in SHAQ for each treatment group and month, 
and an F-test is used to test the hypothesis that the mean change from baseline during the 
treatment period differs between the two treatment groups. The model-based adjusted mean 
change from baseline in SHAQ will be presented graphically by treatment group and study month, 
with 95% confidence intervals (CIs) provided at each month. SHAQ includes: 
a. HAQ-DI without Aids/Devices: Total score  
b. SHAQ-DI VAS assessing burden of pain, burden of digital ulcers, Raynaud’s, GI 
involvement, breathing, and overall disease 
 
4. For each HRCT outcomes – QLF-LM, QLF-WL, QILD-LM, QILD-WL, and HRCT-TLC, analysis of 
covariance (ANCOVA) is used to analyze the change of the HRCT outcome from screening to 
month 18. The model includes the treatment group, HRCT outcome at screening, and prior MMF 
therapy. 
 
5. For time (in months) required to achieve a 3.0% (absolute) or greater improvement from baseline 
in the FVC-% over the 18-month treatment period, Kaplan-Meier methods are used to graphically 
present treatment group differences.  The median time to event, with 95% CIs, will be presented 
by treatment group, and a stratified (by prior MMF therapy) log-rank test p-value are presented. 
The time (in months) is defined as the time from baseline until the time of the first change of FVC-% 


SLS III SAP 
 
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from baseline is greater or equal to 3%. Participants are censored at date of FVC-% collected at 
month 18 visit or at the last date of FVC-% collected if the participants permanently discontinued 
study. 
 
6. Logistic regression is performed to evaluate the proportion of participants who achieve greater 
than a 5% improvement from baseline in the FVC-% over the 18-month treatment period. The 
model includes treatment group, baseline FVC-%, and prior MMF therapy as covariates. A 
participant with FVC-% at 18 months minus FVC-% at baseline that is greater than 5% defines a 5% 
improvement or greater.  . The odds ratio with corresponding 95% CI is presented; the p-value for 
the test of treatment group differences is also presented.  
 
7. Box plots are used to summarize the frequency distributions of changes from baseline to 18 
months by treatment group for key secondary endpoints: Hemoglobin-adjusted DLCOHb-%, mRSS 
(for all patients and for diffuse cutaneous scleroderma [dcSSc] patients), SGRQ (total score, 
Symptoms, Activity and Impacts subscores), HAQ-DI without aids/devices score, and Scleroderma-
HAQ-DI visual analogue scales (VAS) scores. A box plot is also used to summarize the frequency 
distribution of TDI during the study period. 
 
8. A frequency table and bar chart are used to show the frequency distribution of the change of FVC-% 
from baseline to month 18 with a 5% increment (e.g., improved by up to 5%, from 5% to <10% 
and from 10% to <15% or worsened by up to 5%, from 5% to <10%, and from 10% to <15%), overall 
and in each treatment group in the completers population, and separately for those who 
completed the treatment period and those who prematurely discontinued treatment but 
returned for the 18-month FVC-%. 
 
9. A frequency table is used to show the frequency distribution of the change of FVC-% from baseline 
to month 18 in negative responders (≤ -3%) and stable (> -3% to < 3%) overall and in each 
treatment group in the completers population, and separately for those who completed the 
treatment period and those who prematurely discontinued treatment but returned for the 18-
month FVC-%.  
 
10. A frequency table is used to show the frequency distribution of the change of FVC-% from baseline 
to month 18 in responder (>0) and non-responder (≤ 0) overall and in each treatment group in 
the completers population, and separately for those who completed the treatment period and 
those who prematurely discontinued treatment but returned for the 18-month FVC-%.  
 
11. A frequency table and bar chart are used to show the frequency distribution of the change of 
mRSS from baseline to month 18 categorized in 4 points increments: worsen (1 to 4, ≥ 5), no 
change (=0), and improved (≤ -13, -12 to -9, -8 to -5, -4 to -1) overall and in each treatment group 
in the completers population, and separately for those who completed the treatment period and 
those who prematurely discontinued treatment but returned for the 18-month mRSS. A 
frequency distribution of the change of mRSS is also shown in patients with dcSSc in the 
completers population. The proportions of participants with improved (< -5), no change (-5 to 5), 
and decreased (> 5) in the change from baseline in mRSS, overall and in each treatment group, 
are also presented. 
 


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12. A frequency table and bar chart are used to show the frequency distribution of the TDI at month 
18 categorized as improved by 1-3, 4-6 and 7-9 points, no change (0), and worsened by 1-3, 4-6 
and 7-9 points, overall and in each treatment group in the completers population, and separately 
for those who completed the entire treatment period and those who prematurely discontinued 
treatment but returned for the 18-month TDI. The proportions of participants with improved (>0), 
no change, and deterioration (<0), overall and in each treatment group, are also presented.   
 
11 Safety Analyses 
Safety data, including AEs, clinical laboratory tests, vital signs, physical examinations, and concomitant 
medication usage will be summarized descriptively overall and by treatment group for the Safety 
Population. AEs include frequency of events and/or incidence of study subjects experiencing events, by 
study arm for the following: 
a) Study-defined treatment failures 
b) Study-defined treatment emergent AEs of special Interest 
c) All treatment-emergent AEs, total and by organ system classification  
d) All treatment-emergent AEs related to study medication, total and by organ system 
classification  
e) All treatment-emergent SAEs, total and by organ system classification  
f) All treatment-emergent SAEs related to study medication, total and by organ system 
classification  
g) All treatment-emergent AEs and SAEs that result in discontinuation of study medication 
h) Time to treatment failure 
i) 
Time to treatment-emergent AEs and SAEs resulting in premature discontinuation of study 
medication 
 
For categorical safety outcomes, numbers and percentages will be used.  For continuous safety outcomes, 
number, mean, standard deviation, median, interquartile range, minimum and maximum are used to 
summarize changes from baseline to each study visit in laboratory tests and vital signs.  Percent change 
from baseline for laboratory values are summarized. The primary organ system associated with each 
adverse event was coded by the medical monitor. Kaplan-Meier methods are used to summarize 
graphically the time to treatment failure, and treatment-emergent AEs and SAEs that result in premature 
discontinuation of study medication. 
 
11.1 Extent of Exposure 
Total participant months of exposure to study medication is defined as the number of days from date of 
last dose of study medication minus the date of the first dose of study medication plus one.  It is converted 
to months by divided the total number of days by 28.  It is summarized descriptively by treatment group. 
Both full and partial amount of drug received is counted in the assessment of exposure. 
 
11.2 Definition of Adverse Events 
Adverse event means any untoward medical occurrence, such as an abnormal laboratory finding, 
physical sign, symptom, or diagnosis of a disease state, that is temporally associated with the use of 
an interventional treatment or procedure in a human subject regardless of whether or not it is 
considered intervention-related [consistent with 21 CFR 312.32 (a)]. 


SLS III SAP 
 
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11.2.1 
Treatment-emergent AEs (TEAEs) 
TEAEs are those that start or worsen after the start of study treatment and up to 7 days (for AEs) 
and 30 days (for serious AEs) after the last dose of study treatment. This AE definition would 
include the following: 
• 
Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of the study treatment administration 
• 
Complications resulting from protocol-mandated procedures 
• 
AEs occurring as a result of product withdrawal, abuse or overdose 
• 
A change in a laboratory variable if considered by the investigator to be clinically significant 
or if it is caused (or should have caused) the investigator to reduce or discontinue the use of 
the product or initiate a non-protocol therapy or procedure 
 
11.2.2 
AEs of Special Interest  
AEs of Special Interest represent a specific subset of all AEs and are defined by the study protocol based 
on two distinct features: 1) their likely association with the investigational drug(s), and 2) the presence 
of pre-specified study drug management guidelines that are to be followed when the AE occurs.  
 
AEs meeting the following criteria will be classified and reported as AEs of Special Interest in addition to 
their inclusion in the overall frequency and incidence of AEs.   
• 
Leukopenia, defined as WBC <2.5x103/µl of blood 
• 
Neutropenia, defined as an absolute neutrophil count < 1.0x103/µl of blood  
• 
Clinically significant anemia, defined as blood hemoglobin < 10.0 gm/dl or a drop in 
hemoglobin to < 9.0 gm/dl if the baseline hemoglobin was < 11.0 gm/dl 
• 
Liver enzyme elevations that exceed 3× the upper limit of normal (ULN) ALT and/or AST. 
• 
New onset or worsening of existing gastrointestinal symptoms that do not respond to 
medical management and are of sufficient clinical importance to warrant drug dose 
adjustment (including nausea, diarrhea, vomiting, and dyspepsia). 
• 
Documentation of gastrointestinal ulcer, gastrointestinal bleeding or abdominal emergency 
• 
Infection requiring hospitalization, intravenous antibiotics, or judged as requiring the 
withdrawal of immune suppression for effective treatment. 
• 
New or reactivated viral infections including PVAN, JC virus associated PML, CMV infections, 
reactivation of HBV or HCV. 
• 
Photosensitivity skin reactions that do not respond to sunscreen, avoidance, and as-needed 
use of over the counter topical creams, and are of sufficient clinical importance to warrant 
drug dose adjustment. 
• 
Development of a proven malignancy other than basal cell cancer of the skin or cervical 
carcinoma in situ removed entirely by biopsy. 
• 
Angioedema 
 
11.3 Definition of Serious Adverse Events (SAEs) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator 
or sponsor, it results in any of the following outcomes:  
• 
Death,  


SLS III SAP 
 
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• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• 
A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. [Consistent with 21 CFR 312.32 (a)] 
 
11.4 Definition of Unanticipated Problems (UP – unexpected AEs & Problems) 
An AE or suspected adverse reaction is considered "unanticipated" if it is not listed or characterized 
in the Package Insert or in the current Investigator Brochure or is not listed at the specificity or 
severity that has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or elsewhere in the 
current application, as amended. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. [Consistent with 21 CFR 312.32 (a)] 
 
11.5 Classification of an Adverse Event  
11.5.1 
Severity of Event 
The intensity of all AEs will be graded using a five-point grading scale in which the following descriptions 
of severity will apply. Note that for some AEs, Grades 4 and/or 5 may not be applicable. In those cases 
only 3 different grades (Grade 1-3) are to be considered: 
 
8.2.1.1 
Grade 1: 
“Mild”; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
8.2.1.2 
Grade 2: 
“Moderate”; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
8.2.1.3 
Grade 3: 
“Severe”; medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL**. 
8.2.1.4 
Grade 4: 
 “Life-threatening consequences”; urgent intervention indicated. 
8.2.1.5 
Grade 5: 
“Death related to AE”. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 


SLS III SAP 
 
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**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.5.2 
Relationship to Study Intervention 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. A binary assessment (related/not 
related) will be made and take into consideration the natural history of the underlying disease, 
concurrent illness, concomitant therapy, study-related procedures, accidents, and other external 
factors. While the relationship to the study drug (related/not related) is part of the documentation 
process, it is not a factor in determining what is or is not reported in the study. All AEs are recorded 
regardless of relatedness. 
 
Related 
The AE is known to occur with the study agent, there is a 
reasonable possibility that the study agent caused the AE, or there 
is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study agent and the AE. An AE can 
be deemed related even if other factors may have contributed to 
the event. 
Not Related 
There is not a reasonable possibility that the administration of the 
study agent caused the event, there is no temporal relationship 
between the study agent and event onset, or an alternate etiology 
has been established or appears to provide a plausible explanation 
(e.g. the participant’s clinical condition, underlying disease or 
concomitant treatments). 
 
11.5.3 
Expectedness 
For all SAEs, the Clinical Site Principal Investigator, in consultation with a designated Medical Monitor 
whenever possible, will be responsible for determining whether the SAE is expected or unexpected 
using the definition from section 11.4 above. 
 
11.5.4 Treatment Failures 
Treatment failures are participants who, after >3 months of study, demonstrate  
• 
an absolute fall in FVC-% of ≥ 15% from their baseline determination, or 
• 
an FVC-% ≤ 35%, regardless of the absolute change from baseline. 
To meet these definitions, participants must have two FVC-% measurements greater than 15 days apart, 
both showing an absolute decrement of ≥ 15% from baseline and/or a FVC-% of ≤ 35%. Participants with 
treatment failures will be withdrawn from active drug treatment (both PFD/Plac and MMF). Participants 
who fail treatment will be encouraged to return for key outcome determinations at 12 and 18 months. 
 
11.6 Pregnancies 
A listing of all pregnancies occurring after the start of study medication is provided.  
 


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11.7 Clinical Laboratory Evaluations 
Clinical laboratory evaluations are summarized using number, mean, standard deviation, median, 
interquartile range, minimum and maximum. Absolute and relative changes from baseline to each study 
visit are similarly summarized. These summaries are reported overall and by treatment group. 
 
Laboratory values collected during the study are: 
 
Type 
Name 
Units 
Values 
Abnormal 
(checked 
yes/no) 
applicable 
upper or 
lower limit of 
normal 
Metabolic 
panel 
Sodium 
Mmol/L 
X 
X 
X 
Potassium 
Mmol/L 
X 
X 
X 
Chloride 
Mmol/L 
X 
X 
X 
CO2 
Mmol/L 
X 
X 
X 
BUN 
Mg/dL 
X 
X 
X 
Creatinine 
Mg/dL 
X 
X 
X 
Glucose 
Mg/dL 
X 
X 
X 
Protein – total 
g/dL 
X 
X 
X 
Albumin 
g/dL 
X 
X 
X 
Bilirubin – total 
Mg/dL 
X 
X 
X 
Alkaline phosphatase 
IU/L 
X 
X 
X 
AST 
IU/L 
X 
X 
X 
ALT 
IU/L 
X 
X 
X 
Cholesterol 
Mg/dL 
X 
X 
X 
CBC with 
differential 
WBC 
K/uL 
X 
X 
X 
Hemoglobin 
g/dL 
X 
X 
X 
Hematocrit 
% 
X 
X 
X 
Platelets 
K/uL 
X 
X 
X 
Neutrophil percent 
% 
X 
X 
X 
Absolute neutrophil count 
K/uL 
X 
X 
X 
Lymphocyte percent 
% 
X 
X 
X 
Absolute lymphocyte count 
K/uL 
X 
X 
X 
 
 
11.8 Prior and Concurrent Medications 
Prior and concurrent medications are summarized descriptively by time point, overall, and by treatment 
group. 
 
11.9 Other Safety Measures 
Vital signs including weight, heart rate, blood pressure, and oxygen saturation are summarized using 
similar methods to those given in Section 11.7. 
 


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12 Other Analyses 
 Analyses of the following outcomes will be summarized and allow for further interpretation of the study 
results. The m-ITT analysis set is used in the analyses.  
 
1. The linear mixed model as described for the primary analysis of the primary endpoint is performed 
to compare two treatment groups on the change of the PROMIS-29 version 2.0 (in Physical 
Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Pain Interference, Impact on Social 
Roles, and a single item on pain intensity) from baseline to month 18, measured by 6-month 
intervals. The model is adjusted by treatment, study month, interaction of treatment and study 
month, prior MMF therapy and baseline PROMIS-29. The model generates adjusted estimates of 
change from baseline in PROMIS-29 for each treatment group and month, and an F-test is used 
to test the hypothesis that the mean change from baseline during the treatment period differs 
between the two treatment groups. The model-based adjusted mean change from baseline in 
PROMIS-29 will be presented graphically by treatment group by study month, with 95% 
confidence intervals (CIs) provided at each month.  
2. A frequency table and bar chart are used to show the frequency distribution of the change of 
QILD-WL from screening to month 18 categorized in 2% increments. The proportions of 
participants with better (<-2%), stable (≥ -2% to ≤ 2%) and worsening (>2%) QILD-WL in each 
treatment group are also presented.  
3. A frequency table is used to evaluate the proportion of participants with a 3% or greater decline 
from baseline in FVC-% over the 18-month treatment period between the two treatment 
groups.  
4. A frequency table is used to evaluate the proportion of participants with a 5% or greater decline 
from baseline in FVC-% over the 18-month treatment period between the two treatment 
groups.   
5. Descriptive statistics are used to show the change from baseline to month 6, 12, and 18 in 
patient global assessment of “overall health” in the past week, overall and in each treatment 
group.  
6. Descriptive statistics are used to show the patient transition questions of global assessment at 
month 6, 12, and 18 comparing patient’s (i) overall health and (ii) lung involvement to that at 
the baseline visit, overall and in each treatment group. 
7. Descriptive statistics are used to show the change from baseline to month 6, 12, and 18 in cough 
severity, cough frequency, and phlegm production, overall and in each treatment group.  
 
13 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 figures. 
14 Summary of Changes to the Protocol and/or SAP 
a. Additional Secondary Endpoint 


SLS III SAP 
 
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FVC in ml is added to the analysis as one of the secondary endpoints. It will help us to compare SLSIII 
results with other studies, including SENCIS and TRAIL-1. 
PROTOCOL: 
N/A 
 
SAP: 
Section 5.2.2 Secondary Endpoints 
1. The change from baseline to 18 months, measured at 3-month intervals, over the course of the 18-
month treatment period in: 
    c. Forced vital capacity volume (FVC, in ml). 
 
b. Remove Other Endpoints. 
Physician global assessments and UCLA Scleroderma Clinical Trial Consortium GIT 2.0 will not be 
analyzed due to small sample size. 
 
PROTOCOL: 
Section 4.2.3 Other Important Endpoints 
 
4.2.3.1 Physician and Patient Global Assessments 
a) Physician global assessment of patient’s “overall health” in the past week on a Likert scale; 6 
month intervals  
b) Physician transition questions comparing patient’s i) overall health and ii) lung involvement to 
that at the baseline visit; 6 month intervals 
4.2.3.2 UCLA Scleroderma Clinical Trial Consortium GIT 2.0 (UCLA SCTC GIT 2.0); 6 month intervals 
 
SAP: 
Not included. 
 
c. Additional Other Endpoints 
Because we had to stop enrollment before the planned sample size was achieved, we changed the 
classification of “other important endpoints” to “other endpoints”; modified the classification of PROMIS-
19 endpoints to “other”; and added or clarified the additional other endpoints:  categorized QILD-WL and 
two FVC-% endpoints based on the meaningful clinical importance difference; remove frequency 
distribution of DLCOHb-% because it is the most variable of the PFTs, and changed LCQ to the 
supplemental questions in LCQ.  These changes clarify the importance of interpreting endpoints in the 
context of the reduced sample size. 
 
PROTOCOL: 
Section 4.2.2 Secondary Endpoints 
 


SLS III SAP 
 
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4.2.2.4 The change from baseline to 18 months, measured at 3-month or 6-month intervals, in Patient 
Reported Outcomes (PROs), which provide subjective measures of dyspnea and quality of life based on 
patient responses to standardized patient questionnaires which include: 
c) Patient-reported outcomes measurement information system 29-item health profile (PROMIS-
29 version 2.0); 6 month intervals 
 
4.2.2.6 Differences in the frequency distribution of individual patient responses when grouped into 
defined intervals of improvement or worsening (defined by the change in an outcome measure from 
baseline to 18 months) for the following outcome measures:  
b) Single-breath diffusing capacity for carbon monoxide (DLCO), calculated as a percent of the 
age, height, gender-, race- and hemoglobin-adjusted predicted value (DLCOHb-%).  
 
Section 4.2.3 Other Important Endpoints 
 
4.2.3.3 Leicester Cough Questionnaire (LCQ); 6 month intervals 
 
SAP: 
Section 5.2.3 Other Endpoints 
1. The change from baseline to month 6, 12, and 18 in PROMIS-29 version 2.0 with the following 
domains: physical function, anxiety, depression, fatigue, sleep disturbance, pain interference, ability 
to participate in social roles and activities, and a single item on pain intensity.   
2. The proportion of participants in each treatment from screening to month 18 with a 2% increment 
in QILD-WL. It is also categorized as better (<-2%), stable (≥-2%, ≤2%) and worsen (>2%).  
3. The proportion of participants in each treatment arm with a 3% or greater decline from baseline in 
FVC-% over the 18-month treatment period.   
4. The proportion of participants in each treatment arm with a 5% or greater decline from baseline in 
FVC-% over the 18-month treatment period.    
7. The change from baseline to month 6, 12, and 18 in supplemental questions in Leicester Cough 
Questionnaire (LCQ) regarding the cough severity, cough frequency and phlegm production.   
 
 
d. Remove Exploratory Endpoints and Analyses of Exploratory Outcomes. 
The pre-specified exploratory endpoints and implicit associated analyses in the protocol will not be 
conducted owing to the small sample size and ensuing limitations on multivariable analyses.   
 
PROTOCOL: 
4.2.4  Exploratory Endpoints 
Exploratory endpoints will include the following: 
4.2.4.1 
Identification of baseline features that predict treatment responsiveness, disease 
progression and the course of lung and skin disease over time.  
4.2.4.2 
Identification of biomarkers that predict disease features, treatment responsiveness, 
disease progression and the course of lung and skin disease over time. 
4.2.4.3 
Composite outcome measures that distinguish early and late treatment responses 


SLS III SAP 
 
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4.2.4.4  
Performance of CRISS index at 6, 12 and 18-months 
 
10.4.3.2  Analyses of Exploratory Outcomes.   
Comparable methods as described above for primary and secondary outcomes will be used for the 
exploratory aims described in Section 4.2.3.  For example, identification of baseline features that 
predicted treatment responsiveness, disease progression and course of lung and skin disease over time 
will employ the appropriate models with the baseline covariate and potentially the interaction of 
treatment and baseline as covariates.  Separate models would be assessed for each outcome and 
baseline.  Biomarker identification would be handled similarly.  The identification of composite outcome 
measures that distinguish early and late treatment responses will be detailed in the SAP.  These analyses 
will be considered exploratory and hypothesis-generating. 
 
SAP:   
Not included 
 
e. Add Completers Population  
Add Completers analysis set that wasn’t in the protocol to provide an analysis population for descriptive 
statistics of select efficacy endpoints. 
 
PROTOCOL: 
N/A 
 
SAP: 
8.2.3 Completers Population 
The Completers analysis set consists of all subjects in the m-ITT population who had an 18-month efficacy 
outcome (regardless of completion of study medication).  It can be different depending on the outcome 
that is analyzed. 
 
f. Change Analyses of Secondary Endpoints 
Due to small sample size, instead of considering binary secondary endpoints and using logistic 
regression, we consider clinically meaningful cutpoints and using the frequency table and bar chart to 
demonstrate the frequency distribution of the secondary endpoints. 
 
PROTOCOL: 
Section 10.4.3.1 Analyses of Secondary Endpoints 
There are three categories of secondary outcomes: 
2. Dichotomous outcomes such as the proportion of subjects who report improvement 
on the TDI at 18 months during the treatment period.   
For dichotomous secondary outcomes, logistic or Poisson regression will be used with treatment group, 
site, and prior MMF therapy (stratification factor: naïve, >0 to <3 months and >3 months to 6 months) 
included as covariates.   
 


SLS III SAP 
 
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SAP: 
Section 10.2.2 
8. A frequency table and bar chart is used to show the frequency distribution of the change of FVC-% 
from baseline to month 18 with a 5% increment (e.g., improved by up to 5%, from 5% to <10% 
and from 10% to <15% or worsened by up to 5%, from 5% to <10%, and from 10% to <15%) overall 
and in each treatment group in the completers population, and separately for those who 
completed the treatment period and those who prematurely discontinued treatment but 
returned for the 18-month FVC-%.  
9. A frequency table is used to show the frequency distribution of the change of FVC-% from baseline 
to month 18 in negative responders (≤ -3%) and stable (> -3% to < 3%) overall and in each 
treatment group in the completers population, and separately for those who completed the 
treatment period and those who prematurely discontinued treatment but returned for the 18-
month FVC-%.   
10. A frequency table is used to show the frequency distribution of the change of FVC-% from baseline 
to month 18 in responder (>0) and non-responder (≤ 0) overall and in each treatment group in 
the completers population, and separately for those who completed the treatment period and 
those who prematurely discontinued treatment but returned for the 18-month FVC-%.  
11. A frequency table and bar chart are used to show the frequency distribution of the change of 
mRSS from baseline to month 18 categorized in 4 points increments: worsen (1 to 4, ≥ 5), no 
change (=0), and improved (≤ -13, -12 to -9, -8 to -5, -4 to -1) overall and in each treatment group 
in the completers population, and separately for those who completed the treatment period and 
those who prematurely discontinued treatment but returned for the 18-month mRSS. A 
frequency distribution of the change of mRSS is also shown in patients with dcSSc in the 
completers population. The proportions of participants with improved (< -5), no change (-5 to 5), 
and decreased (> 5) in the change from baseline in mRSS, overall and in each treatment group, 
are also presented.  
12. A frequency table and bar chart are used to show the frequency distribution of the TDI at month 
18 categorized as improved by 1-3, 4-6 and 7-9 points, no change (0), and worsened by 1-3, 4-6 
and 7-9 points, overall and in each treatment group in the completers population, and separately 
for those who completed the entire treatment period and those who prematurely discontinued 
treatment but returned for the 18-month TDI. The proportions of participants with improved (>0), 
no change, and deterioration (<0), overall and in each treatment group, are also presented. 
 
g. Remove One of Analysis of the Primary Efficacy Endpoint 
Because we had to stop enrollment before the planned sample size was achieved, we don’t have 
sufficient data to perform the analysis to access the change point for response.  
 
PROTOCOL: 
10.4.2 Analysis of the Primary Efficacy Endpoint 
Using the same model as for the primary endpoint, we will assess the change point for response to 
evaluate the onset of response for the two treatment groups, and the change from baseline to month 
18 to evaluate the overall magnitude of effect at the end of the treatment period. 
 
SAP: 
Not included. 


SLS III SAP 
 
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h. Elimination of reports regarding death 
There were no deaths in the study and so the planned descriptive statistics and Kaplan-Meier plot are 
not presented. 
 
PROTOCOL: 
8.1 Specification of Safety Parameters 
g) All treatment-emergent deaths 
i) Time to Time to treatment failure, treatment-emergent AEs and SAEs resulting in premature 
discontinuation of study medication, and death 
10.4.4   Safety Analyses 
Kaplan-Meier methods will be used to summarize graphically the time to treatment failure, treatment 
emergent AEs and SAEs that result in discontinuation of treatment, and death. 
 
SAP: 
Not included. 
 
i. 
Biomarkers will not be analyzed 
Because we had to stop enrollment before the planned sample size was achieved, we will not assess 
biomarkers in this primary analysis. 
 
PROTOCOL: 
4.2.4 Exploratory Endpoints  
Exploratory endpoints will include the following: 
4.2.4.2 
Identification of biomarkers that predict disease features, treatment responsiveness, 
disease progression and the course of lung and skin disease over time. 
 
10.4.3.2  Analyses of Exploratory Outcomes.   
Biomarker identification would be handled similarly.  The identification of composite outcome measures 
that distinguish early and late treatment responses will be detailed in the SAP. These analyses will be 
considered exploratory and hypothesis-generating.  
 
SAP: 
Not included. 
 
 


SLS III SAP 
 
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15 References 
1. Cotes JE, Dabbs JM, Elwood PC, Hall AM, McDonald A, Saunders MJ. Iron-deficiency anaemia: its 
effect on transfer factor for the lung (diffusing capacity) and ventilation and cardiac frequency 
during sub-maximal exercise. Clinical Science. 1972; 42: 325–335. 
2. Esbriet Package Insert, NDA-022535, Genentech Inc., Approved Oct 15, 2014. 
3. Fan MH, Feghali-Bostwick CA, Silver RM. Update on scleroderma-associated interstitial lung disease. 
Curr Opin Rheumatol. 2014;26(6):630-6.  
4. Hankinson JL OJ, Fedan KB. Spirometric reference values from a sample of the general U.S. 
population. Am J Respir Crit Care Med. 1999;159(1):179–87. 
5. Khanna D, Albera C, Fischer A, N. Khalidi, G. Raghu, L. Chung, D. Chen, E. Schiopu, 8, E. Gorina, M. 
Tagliaferri, J. R. Seibold. Safety And Tolerability Of Pirfenidone In Patients With Systemic Sclerosis-
Associated Interstitial Lung Disease - The Lotuss Study. Am J Respir Crit Care Med. 2015; 191: A1175 
6. Neas LM, and Schwartz J. The determinants of pulmonary diffusing capacity in a national sample of 
U.S. adults. Am J Respir Crit Care Med. 1996; 153 (2): 656-664. 
7. Roth MD, Tseng CH, Clements PJ, Furst DE, Tashkin DP, Goldin JG, Khanna D, Kleerup EC, Li N, 
Elashoff D, Elashoff RM; Scleroderma Lung Study Research Group. Predicting treatment outcomes 
and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum. 2011; 
63(9):2797-808.  
8. Rubin D. (1976). Inference and missing data (with discussion). Biometrika 63:581-592.  
9. Tashkin DP, Elashoff R, Clements PJ, et al. for the Scleroderma Lung Study (SLS) Research Group. 
Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung 
disease. Am J Respir Crit Care Med 2007 177(10): 1026.  
10. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, 
Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Wigley F, White B, Steen V, Read C, Mayes M, 
Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M for the 
Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung 
disease. N Engl J Med 2006; 354:2655-66.  
11. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, MD, Kleerup EC, Goldin J, Arriola E, 
Volkmann ER, Kafaja S, Silver R, Steen V, Strange C, Wise R, Wigley F, Mayes M, Riley DJ, Hussain S, 
Assassi S, Hsu VM, Patel B, Phillips K, Martinez F, Golden J, Connolly MK, Varga, MD J, Dematte J, 
Hinchcliff ME, Fischer A, Swigris J, Meehan R, Theodore A, Simms R, Volkov S, Schraufnagel DE, 
Scholand MB, Frech T, Molitor JA, Highland K, Read CA, Fritzler MJ, Kim GHJ, Tseng C-H, Elashoff RM, 
for the Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral 
cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, 
double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708-19.  
12. Kim HJ, Tashkin DP, Clements PJ, et al. A computer-aided diagnosis system for quantitative scoring 
of extent of lung fibrosis in scleroderma patients. Clin Exp Rheumatol 2010; 5: S26–35. 
 
16 Planned Tables, Listings and Figures 
See separate document.