Clinical trial NCT02981082
Conditions: Systemic Sclerosis Pulmonary; Hypertension
Keywords: Systemic Sclerosis, Scleroderma, PAH, Pulmonary Hypertension
Sponsor: Robert Lafyatis
Start date: 2016-12-01; Completion date: 2020-02-10
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study will determine safety and the primary outcome variability for DMF in treating SSc-PAH; the primary outcome of clinical efficacy in this pilot trial will be improvement in 6-minute walk distance (6MWD).

Detailed description:
A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study medication will be added to stable background PAH medication(s). Subjects will be dosed for 24 weeks, will undergo examination every 8 weeks, and will be finally evaluated 12 weeks after completion of treatment. Dosage will begin at once daily oral doses of 120mg for the first 7 days and follow the up-titration schedule to a maintenance dose of 240mg twice a day (or highest tolerated dose of a minimum of 120mg twice a day by the start of Week 8) for the remainder of the study. Participation will be for a total of 40 weeks, including a 4-week screening period, 24 weeks of drug, and a safety follow-up 12 weeks after the last dose. The study will determine the safety and the primary outcome variability for DMF in treating SSc-PAH; the primary outcome of clinical efficacy in this pilot trial will be improvement in 6-minute walk distance (6MWD).

Arms: arm 1: Twice daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days followed by the maintenance dose of Dimethyl Fumarate (DMF) 240mg twice a day. Subjects will be dosed for 24 weeks arm 2: Twice daily oral doses of placebo for 12 weeks
Interventions: intervention 1: Dimethyl Fumarate (DMF) intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis. intervention 2: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Principal Investigator 
Version 7   14-May-2019 
 
Page 1 
 
                                                                                                                                                 
A DOUBLE-BLINDED, PLACEBO-CONTROLLED PILOT STUDY OF DMF IN 
PULMONARY ARTERIAL HYPERTENSION (PAH) ASSOCIATED WITH 
SYSTEMIC SCLEROSIS (SSC-PAH): THE EFFECT OF DMF ON CLINICAL 
DISEASE AND BIOMARKERS OF OXIDATIVE STRESS 
 
Test drug: 
Dimethyl fumarate (Tecfidera, DMF) 
Study purpose: 
Safety and efficacy 
Clinical study phase: 
1b 
Principal Investigator:          Robert Lafyatis, MD 
Professor of Medicine 
Thomas Medsger Endowed Professor of Scleroderma Research 
Division of Rheumatology and Clinical Immunology 
University of Pittsburgh 
7 South BST, 200 Lothrop Street 
Pittsburgh, PA 15261 
Phone:  412-383-8000 
Fax: 412-648-9643 
rlafyatis@gmail.com 
 
Protocol Number:                 US-BGT-16-11075 
DATE: 14-May-2019 
Version 7 
FINAL 
 
 
 


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INVESTIGATORS SIGNED AGREEMENT OF STUDY PROTOCOL 
Version 7.0 
13-May-2019 
 
 
I have read the foregoing protocol, “Dimethyl Fumarate In Systemic Sclerosis- Associated 
Pulmonary Arterial Hypertension,” and agree to conduct the study according to the protocol and 
the applicable ICH guidelines and local regulations, and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations. 
 
 
 
____________________________________________________ 
Principal Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Principal Investigator’s Name (Print) 
 
 
 
 
____________________________________________________ 
Site Investigator (Print) 
 
____________________________________________________ 
Site-Investigator’s Signature  
 
 
Date 
 
 


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Staff Roster, Organization and Responsibilities 
Principal Investigator (PI) Coordinating Center  
Robert Lafyatis, MD 
Professor of Medicine 
Thomas Medsger Endowed Professor of Scleroderma Research 
Division of Rheumatology and Clinical Immunology 
University of Pittsburgh 
7 South BST, 200 Lothrop Street 
Pittsburgh, PA 15261 
Phone:  412-383-8000 
Fax: 412-648-9643 
rlafyatis@gmail.com 
Project Manager Coordinating Center 
Kristi Kong  
S726 BST, 200 Lothrop St  
Pittsburgh, PA  15261  
Phone: 412-648-7040 
Fax: 412-648-9643 
krk99@pitt.edu  
Site- Investigator  
Paul M. Hassoun, M.D. (Director, Pulmonary Hypertension Program) 
Johns Hopkins Asthma and Allergy Center 
5501 Hopkins Bayview Circle 
Baltimore, MD 21224-6801 
Phone: (410) 550-2606/(410) 614-5158 
Fax: (410) 550-2612/ (443) 287-3349 
phassou1@jhmi.edu 
Site Investigator  
Robert W Simms, MD 
Chief, Rheumatology Section 
Professor of Medicine 
Boston University School of Medicine 
72 East Concord Street, Evans 501 
Boston, MA 02118-2526 
Phone: (617) 638-4312  
Fax: (617) 638-5226  
rsimms@bu.edu 
Site Investigator  
M. Patricia George MD 
Associate Professor of Medicine 
National Jewish Health 
Molly Blank Building, RM J231 
Denver, CO 80206 
Phone (303) 398-1096 


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georgem@njhealth.org  
Research Coordinator (Johns Hopkins) 
TBD 
 
Research Coordinator (Boston University) 
Eric A Stratton, MTS, MPH 
Senior Clinical Research Manager 
Arthritis Center, Rheumatology 
Boston University School of Medicine 
72 East Concord St, Evans 501 
Boston, MA. 02118-2526 
Phone: 617.414.2507 
Fax: 617.414.1222 
eas@bu.edu 
Research Coordinator (National Jewish) 
Alexa Ramos 
1400 Jackson St., Room K333 
Denver, CO 80206 
Phone: 303-270-2348 
RamosA@NJHealth.org  
Statistician: Yuquing Zhang, yuqing@bu.edu 
Data Manager: Diane Koontz, dik4@pitt.edu  
Coordinating Center Lab Manager 
Christina Morse, BS 
S750 BST, 200 Lothrop St  
Pittsburgh, PA  15261  
412-648-7049 
ninamorse@pitt.edu  
Biogen Pharmacy Contact 
Heather Volatile, MPH, PMP 
Manager, US Medical Affairs Operations | Biogen 
133 Boston Post Road  
Weston, MA 02493 
781.464.5034  
Heather.Volatile@biogen.com 
DSMB 
• Safety Officer/ Cardiologist: Scott Visovatti, MD, FACC, FCCP  
• Biostatistician: Chi-Hong Tseng, Ph.D. 
Pulmonologist: Sandeep Sahay, MD 
Rheumatologist: Elizabeth Volkmann, MD, MS                                       
KAI information 
301-770-2730 
KAIforNIAMS@kai-research.com 
 
 


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Communication Plan : 
There will be an initial Teleconference before study start up and then monthly teleconferences 
there after. 
 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS .......................................................................................9 
2. 
SYNOPSIS .................................................................................................................12 
3. 
SCHEDULE OF EVENTS .........................................................................................15 
4. 
INTRODUCTION ......................................................................................................17 
4.1. 
Background .................................................................................................................19 
4.2. 
Rationale .....................................................................................................................21 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................22 
5.1. 
Primary Objective and Endpoint ................................................................................22 
5.2. 
Additional Objectives and Endpoints .........................................................................22 
6. 
STUDY DESIGN .......................................................................................................24 
6.1. 
Study Overview ..........................................................................................................24 
6.2. 
Overall Study Duration and Follow-Up .....................................................................24 
6.2.1. 
Study Flow Diagram ...................................................................................................24 
6.3. 
Early Termination of Study ........................................................................................25 
7. 
STUDY POPULATION .............................................................................................26 
7.1. 
Inclusion Criteria ........................................................................................................26 
7.2. 
Exclusion Criteria .......................................................................................................26 
8. 
STUDY PROCEDURES ............................................................................................29 
8.1. 
Screening, Enrollment, Re-screen and Randomization of Subjects ...........................29 
8.2. 
Follow-up ....................................................................................................................29 
8.3. 
Stopping Rules ............................................................................................................29 
9. 
STUDY TREATMENT ..............................................................................................31 
9.1. 
Dosing Regimen and Administration .........................................................................31 
9.2. 
Drug Ordering and Accountability .............................................................................32 
9.3. 
Treatment Compliance ................................................................................................32 
9.4. 
DMF/Placebo Stability and Storage ...........................................................................32 
9.4.1. 
DMF/Placebo Handling and Disposal ........................................................................33 
9.5. 
DMF/Placebo Accountability .....................................................................................33 
10. 
DATA COLLECTION ...............................................................................................35 
10.1. 
Assessments ................................................................................................................35 
10.2. 
Safety Assessments .....................................................................................................35 


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10.3. 
Efficacy Assessments .................................................................................................35 
10.3.1. 
6-Minite Walk Distance ..............................................................................................35 
10.3.2. 
NYHA Classification ..................................................................................................35 
10.3.3. 
Modified Rodnan skin score .......................................................................................36 
10.3.4. 
Skin Biopsies ..............................................................................................................36 
10.3.5. 
Biomarkers of Oxidative stress and PAH. ..................................................................36 
10.3.6. 
Biomarkers of skin mRNA. ........................................................................................36 
10.3.7. 
Digital ulcer assessment .............................................................................................36 
10.3.8. 
Patient-Reported Outcomes (PROs) ...........................................................................37 
10.3.9. 
Scleroderma Health Assessment Questionnaire (SHAQ) ...........................................37 
10.3.10. 
Raynaud’s attacks assessment ....................................................................................37 
10.3.11. 
Systemic Sclerosis Skin Questionnaire (PRO-SRSS) ................................................37 
11. 
PROTOCOL DEVIATION DEFINITIONS ..............................................................39 
11.1.1. 
MINOR DEVIATIONS ..............................................................................................39 
11.1.2. 
MAJOR DEVIATIONS ..............................................................................................39 
11.1.3. 
INSTRUCTIONS FOR DOCUMENTING DEVIATIONS .......................................39 
12. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING..............................40 
12.1. 
Definitions ..................................................................................................................40 
12.1.1. 
Adverse Event .............................................................................................................40 
12.1.2. 
Adverse Reaction and Suspected Adverse Reaction (SAR) .......................................40 
12.1.3. 
Unexpected Adverse Event/Reaction .........................................................................41 
12.1.4. 
Serious Adverse Event ................................................................................................41 
12.1.5. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................41 
12.2. 
Grading and Attribution of Adverse Events ...............................................................42 
12.2.1. 
Grading Criteria ..........................................................................................................42 
12.2.2. 
Attribution Definitions ................................................................................................42 
12.3. 
Monitoring and Recording Events ..............................................................................43 
12.3.1. 
Adverse Event Guidelines ..........................................................................................43 
12.3.2. 
Adverse Event Reporting ............................................................................................44 
12.3.3. 
Unanticipated Problems ..............................................................................................44 
12.3.4. 
Serious Adverse Event Reporting ...............................................................................45 
12.3.5. 
Immediate Reporting of Serious Adverse Events .......................................................45 


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12.3.6. 
Deaths .........................................................................................................................47 
12.3.7. 
Suspected Unexpected Serious Adverse Reactions ....................................................47 
12.4. 
Procedures for Handling Special Situations ...............................................................47 
12.4.1. 
Reporting Pregnancy ..................................................................................................47 
12.4.2. 
Overdose .....................................................................................................................47 
12.4.3. 
Medical Emergency ....................................................................................................48 
12.4.4. 
Unblinding for Medical Emergencies .........................................................................48 
12.5. 
Principal Investigator Responsibilities .......................................................................48 
13. 
STATISTICAL CONSIDERATIONS .......................................................................49 
13.1. 
Sample Size Justification ............................................................................................49 
13.2. 
Interim Analysis ..........................................................................................................49 
13.3. 
Endpoint Analysis .......................................................................................................49 
14. 
ETHICAL REQUIREMENTS ...................................................................................51 
14.1. 
Ethics Committee ........................................................................................................51 
14.2. 
Subject Information and Consent ...............................................................................51 
14.3. 
Subject Data Protection ..............................................................................................52 
14.4. 
Compensation for Injury .............................................................................................52 
14.5. 
Conflict of Interest ......................................................................................................52 
14.6. 
Registration of Study and Disclosure of Study Results ..............................................52 
15. 
ADMINISTRATIVE PROCEDURES .......................................................................53 
15.1. 
Study Site Initiation ....................................................................................................53 
15.2. 
Study Funding .............................................................................................................53 
15.3. 
Study Completion .......................................................................................................53 
15.4. 
Publications .................................................................................................................53 
16. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................54 
16.1.1. 
Electronic Data Capture ..............................................................................................54 
16.1.2. 
Local Laboratories for Laboratory Assessments ........................................................54 
16.2. 
Data Safety Monitoring Board ....................................................................................54 
16.3. 
Changes to Final Study Protocol ................................................................................54 
16.4. 
Ethics Committee Notification of Study Completion or Termination ........................54 
16.5. 
Retention of Study Data ..............................................................................................54 
17. 
REFERENCES ...........................................................................................................55 


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1. 
LIST OF ABBREVIATIONS 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
AE 
Adverse Event 
AHI 
Apnea–Hypopnea Index 
ALT 
Alanine aminotransferase 
ARR 
annualized relapse rate  
AST 
Serum aspartate aminotransferase 
BCG 
Bacille Calmette Guerin 
BDI 
Borg Dyspnea Index 
BNP 
B-type natriuretic peptide  
C 
Celsius 
CC  
Coordinating Center 
CCR1 
C-C chemokine receptor type 1 
cm 
centimeters 
CRF 
Case Report From 
CXR 
Chest x-ray 
dcSSc 
diffuse cutaneous systemic sclerosis 
DMF 
Dimethyl fumarate (Tecfidera, DMF) 
DSMB 
Data and Safety Monitoring Board  
EDSS 
Expanded Disability Status Scale  
EKG 
electrocardiogram 
ES 
Executive Secretary 
Gd 
gadolinium-enhancing  
HAQ-DI 
Health Assessment Questionnaire disability index 
HBV 
Hepatitis B 
HCAR2 
Hydroxycarboxylic Acid Receptor 2 
HCV 
Hepatitis C 
HIF-1 
hypoxia inducing factor  
HIV 
human immunodeficiency virus 
HPH 
Hypoxic pulmonary hypertension 
HRCT 
High resolution CT scan  
HRQoL 
HRQoL 
ICF 
Informed consent form 
ICH 
International conference on harmonization guidelines 
ID 
Infectious diseases 
IL13RA1 
interleukin 13 receptor subunit alpha 1 
ILD 
Interstitial lung disease 


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ITT 
Intention to treat 
IUD 
Intrauterine device 
IV 
Intravenous therapy 
JAK2 
Janus kinase 2 
kg 
kilograms 
lcSSc 
limited cutaneous systemic sclerosis 
LVEDP  
Left ventricular end-diastolic pressure 
MMF 
metabolite, monomethyl fumarate  
mPAP 
Mean pulmonary artery pressure 
MRC1 
Mannose Receptor C-Type 1 
MRI 
Magnetic Resonance Imaging  
mRNA 
Messinger ribonucleic acid 
MRss 
Modified Rodnan Skin Score 
NADPH 
Nicotinamide adenine dinucleotide phosphate 
NFkB  
Nuclear factor  
NIAMS 
National Institute of Arthritis and Musculoskeletal and Skin Diseases  
NIH 
National Institutes of Health  
Nrf2 
Nuclear factor (erythroid-derived 2) 
NYHA 
New York Heart Association 
PAH 
Pulmonary arterial hypertension 
PASP 
Pulmonary arterial systolic pressure 
PBMC 
peripheral blood mononuclear cell 
PCWP 
pulmonary capillary wedge pressure 
PDE-5 
Phosphodiesterase Type 5 (PDE5) Inhibitors 
PH 
Pulmonary Hypertension 
PHI 
Patient health information 
PML 
Progressive multifocal leukoencephalopathy  
PO 
Oral administration  
PPD 
Positive purified protein 
PRO 
Patient Reported outcomes 
PVR  
Pulmonary vascular resistance 
RDMS 
Registered Diagnostic Medical Sonographer 
RNS 
Reactive nitrogen species 
ROS 
Reactive oxygen species 
RRMS 
relapsing- remitting multiple sclerosis  
SABR 
Biogen Safety and Benefit Risk 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 


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SHAQ 
Scleroderma Health Assessment Questionnaire 
SOC 
Standard of Care 
PRO-SRSS 
Systemic Sclerosis Skin Questionnaire 
SSc  
Systemic sclerosis 
SSc-PAH 
Systemic sclerosis Pulmonary arterial hypertension 
SUSARs 
Suspected unexpected serious adverse reaction 
TB 
tuberculosis 
TGFb  
Transforming growth factor beta 
TLC 
total lung capacity  
TNF  
Tumor necrosis factor  
UPMC 
University of Pittsburgh Medical Center 
US 
United States 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 


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2. 
SYNOPSIS 
Tracking Number: 
PRO16070614 
Protocol Title: 
A double-blinded, placebo-controlled pilot study of DMF in 
pulmonary arterial hypertension (PAH) associated with systemic 
sclerosis (SSc-PAH): The effect of DMF on clinical disease and 
biomarkers of oxidative stress. 
Version Number: 
5 
Name of Study 
Treatment: 
Dimethyl fumarate (Tecfidera, DMF/ Placebo) 
Study Indication: 
Systemic Sclerosis with Pulmonary Hypertension (SSc-PAH) 
Phase of Development: 
1b 
Rationale for the Study: 
Given the poor treatment options for patients with SSc-PAH, new 
therapies are urgently needed. Ideally, a medication that could be 
added to and complement the current standard of care, i.e. 
vasodilators, would be optimal. DMF, a newly approved drug for 
multiple sclerosis, is known to reduce oxidative damage and 
down-modulate NFB signaling, and has shown activity in 
preclinical studies of PAH, making it an attractive candidate for 
the treatment of SSc-PAH. Showing clinical efficacy of DMF 
and/or a strong effect on biomarkers of oxidative stress in SSc-
PAH would enable a larger, controlled clinical trial. In theory, 
efficacy could extend to additional organ involvement in patients 
with SSc. Thus, this clinical trial will test the effect of DMF on 
biomarkers of oxidative stress, and also on novel PBMC mRNA 
and serum proteins biomarkers of SSc-PAH. Showing that DMF 
inhibits biomarkers of oxidative stress and affects biomarkers and 
clinical measure of disease severity could facilitate a registration 
enabling trial. 
Study Objectives and 
Endpoints: 
Primary Objective:  
• To assess the safety of the treatment with DMF in patients with 
SSc-PAH.  
• To assess the efficacy in this pilot trial will be improvement in 
6-minute walk distance (6MWD).  
 
 


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Primary Endpoint:  
• Safety will be assessed by the incidence of serious adverse 
events (SAEs) and all adverse events in DMF compared to 
placebo treated patients. 
• The efficacy will be assessed by the change in 6MWD at 24 
weeks from baseline in DMF compared to placebo treated 
patients (the study is powered to detect an improvement of 30-
40 M in the 6MWD). 
 
The additional objectives and endpoints of this study in this study 
population are as follows: 
 
Secondary Objectives:  
• Study the effect of DMF on time to clinical worsening: 
determined by: Change in SOC therapy for PAH; 
Hospitalization for PAH; Death; Need for transplantation; Need 
for atrial septostomy; Decline in 6MWD by 15% from the 
baseline 6MWD; Decline in WHO/NYHA functional class. 
• Study the effect of DMF on isoprostane and other serum 
markers of oxidative stress, including lipid, DNA, and 
prostaglandin targets. 
• Study the effect of DMF on PAH associated biomarker gene 
expression by peripheral blood mononuclear cells, including 
IL13RA1, CCR1, JAK2 and MRC1. 
• Study the effect of DMF on serum B‐type natriuretic peptide 
(BNP), Endostatin, Endothelin-1, Endoglin, Vascular 
Endothelial Growth Factor, von Willebrand Factor, and 
Vascular Cellular Adhesion Molecule 1. 
• Study whether DMF affects skin mRNA biomarkers. 
• Study the effect of DMF on Digital Ulcer Net Burden 
Secondary Endpoints: 
• The change in time to clinical worsening in DMF compared to 
placebo treated patients. 
• The change from baseline of serum markers of oxidative stress 
at 24 weeks, comparing DMF to placebo treated patients. 
• The change from baseline of PAH associated biomarkers at 24 
weeks, comparing DMF to placebo treated patients 


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• The change from baseline in proteomic biomarkers, including 
BNP, at 24 weeks, comparing DMF to placebo treated patients. 
• The change in skin nMRA biomarkers at 24 weeks, comparing 
DMF to placebo treated patients compared to baseline. 
• The change in Digital Ulcer Net Burden at 24 weeks, comparing 
DMF to placebo treated patients compared to baseline. 
 
Study Design: 
Randomized, double-blind, placebo-controlled study 
Study Location and 
Number of Sites: 
Approximately five sites in the US. 
Number of Planned 
Subjects: 
34 subjects will be enrolled in the study. 
Study Population: 
This study will be conducted in subjects with SSc‐PAH 
Treatment Groups 
Two cohorts 17 subjects in each cohort, randomized 1:1 to 
receive DMF 240mg bid or placebo 
Duration of Treatment 
and Follow-up: 
Study duration for each subject will be 40 weeks including a 4- 
week screening period, 24 weeks of drug and 12-week safety 
follow-up after the last dose. 
 


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3. 
SCHEDULE OF EVENTS 
  
Schedule of Events 
Study Period 
Screening 
Visit 1 
Phone 
Call 
Phone 
Call 
Visit 2 
Visit 3 
Visit 4/ ET  
Visit 5 
Safety f/u 
Study Week 
< 4 weeks  
Week 
0 
Week 1 
Week 4  
Week 8 
Week 
16 
Week 24 
Week 36 
Window (in Days) 
  
0 
± 1 day 
± 3 days 
± 10 
days 
± 10 
days 
± 10 days 
± 10 days 
Informed Consent 
X 
  
  
  
  
  
  
  
Eligibility (i/exclusion) 
X 
X 
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
SAFETY ASSESSMENTS 
Physical Examination 
X 
X 
  
  
X 
X 
X 
X 
Height 
X 
  
  
  
  
  
  
  
Vital Signs (blood pressure, heart rate, 
weight) 
X 
X 
  
  
X 
X 
X 
X 
Laboratory Tests (CBC Diff w/ Platelets, 
CMP, BNP, Urinalysis)a 
X 
X 
  
  
X 
X 
X 
X 
HIV serologies, HCV/HBV serologies 
X 
  
  
  
  
  
  
  
Urine Dipstick Pregnancy Testb 
X 
X 
  
  
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X  
X 
X 
X 
X 
X 
Adverse Events  
  
X 
X 
X 
X 
X 
X 
X 
EFFICACY ASSESSMENTS 
mRSS 
X 
X 
  
  
X 
X 
X 
X 
Blood Collection for Biomarkers 
 
X 
  
  
X 
X 
X 
X 
NYHA Assessment 
X 
X 
 
 
X 
X 
X 
X 
Digital Ulcer Assessment 
X 
X 
  
  
X 
X 
X 
  
Six minute Walk Testc 
X 
X 
  
  
X 
X 
X 
X 
Study Period 
Screening 
Visit 1 
Phone 
Call 
Phone 
Call 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Study Week 
< 4 weeks  
Week 
0 
Week 1 
Week 4  
Week 8 
Week 
16 
Week 24 
Week 36 
Skin Biopsy d 
 
X 
 
 
 
 
X 
 
Patient Reported Outcomes (SHAQ, 
Raynauds VAS PRO SRSS)
 
X 
 
 
X 
X 
X 
X 


Protocol PRO16070614 
 
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    a All laboratory samples will be analyzed at local lab 
b For women of child-bearing potential 
c 6MWT: Subject should complete assessment with same amount of supplemental oxygen used to complete the Screening 6MWT unless safety will be impacted 
d One 3mm skin biopsy will be obtained from the mid dorsal surface of the forearm., removing a small cylinder of skin.


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4. 
INTRODUCTION 
Pulmonary arterial hypertension (PAH) is a particularly lethal complication of systemic sclerosis 
(SSc). Although vasodilators have emerged as efficacious therapies, many patients do not 
respond or respond only partially to currently available therapeutics, and so there remains a very 
high medical need for new treatments and new approaches to therapy for this disease. In 
particular, it is important to understand the role of inflammation and immunity in promoting 
SSc-PAH and the potential for drugs that do not rely on vasodilation to treat this disease. We will 
investigate the anti-oxidant, DMF, in a double-blind placebo controlled trial of 34 SSc‐PAH 
patients. The study medication will be added to stable background PAH medication(s). Subjects 
will be dosed for 24 weeks, will undergo examination every 8 weeks, and will be finally 
evaluated 12 weeks after completion of treatment.  
DMF/Tecfidera. DMF is marketed under the trade name Tecfidera, a registered trademark of 
Biogen. DMF is approved by the Food and Drug Administration and by the European 
Commission for the treatment of patients with relapsing and relapsing-remitting forms, 
respectively, of multiple sclerosis.  
 
Mechanism of Action. The mechanism of action of DMF in multiple sclerosis is unknown, but 
DMF and the metabolite, monomethyl fumarate (MMF), activate the Nuclear factor (erythroid-
derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway 
is involved in the cellular response to oxidative stress, and activation of this pathway may 
represent the major therapeutic mechanism. However, DMF it has several other activities that 
may be as important for its therapeutic effect. First, DMF can dramatically inhibit NFB 
mediated triggering of the production of inflammatory mediators such as TNF and IL-6 1. While 
NFB translocation to the nucleus is inhibited, the actual molecular mechanism of this effect is 
incompletely understood. Second, DMF can indirectly affect hypoxia inducing factor (HIF-1), a 
transcription factor that orchestrates the response to hypoxia and increases cell survival in 
response to a hypoxic environment, possibly by stabilizing HIF-1 via inhibition of prolyl-
hydrolases that tag HIF-1 for removal 2. Third, DMF increases the activity of a cystine-glutamate 
membrane exchange protein called System Xc 2. System Xc governs the import of cystine into 
the cytoplasm, which is crucial for synthesis of glutathione, the primary redox regulator in the 
cell. Like Nrf2, increased System Xc function is considered to be an accommodation to increased 
oxidative stress 3. Fourth, DMF is a potent agonist of the nicotinic acid receptor, HCAR2 (or 
Gpr109a) 4.  HCAR2 is essential for the protective effects of DMF in an experimental multiple 
sclerosis model 5. Furthermore, HCAR2 is induced upon macrophage activation and has a major 
role in sensing microbiome-derived butyrate in the gut 6.  HCAR2 activation by DMF in 
macrophages leads to a “dampening or suppressive” program in macrophages 5. Thus, in addition 
to ameliorating oxidative stress, DMF has important effects on macrophage activity. All of these 
effects could be beneficial in the setting of SSc-PAH. 
 
Clinical Studies of DMF in Multiple Sclerosis. The efficacy and safety of DMF in patients 
with relapsing- remitting multiple sclerosis (RRMS) have been demonstrated in two studies. 
Both studies included patients who had experienced at least 1 relapse over the year preceding the 
trial or had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at least one 


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gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization. The Expanded Disability 
Status Scale (EDSS) was also assessed and patients could have scores ranging from 0 to 5. 
Neurological evaluations were performed at baseline, every 3 months, and at the time of 
suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2 in a 
subset of patients (44% in Study 1 and 48% in Study 2).  
 
Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 
patients with RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. 
Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense 
lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate 
(ARR), and time to confirmed disability progression. Patients were randomized to receive DMF 
240 mg twice a day, DMF 240 mg three times a day, or placebo for up to 2 years. DMF had a 
statistically significant effect on all of the endpoints. Study 2 was a 2-year multicenter, 
randomized, double-blind, placebo-controlled study that also included an open-label comparator 
arm in patients with RRMS. The primary endpoint was the annualized relapse rate at 2 years. 
Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense 
lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients 
relapsed, and time to confirmed disability progression. Patients were randomized to receive DMF 
240 mg twice a day, DMF 240 mg three times a day, an open-label comparator, or placebo for up 
to 2 years. DMF had a statistically significant effect on the relapse and MRI endpoints. There 
was no statistically significant effect on disability progression. In both of these studies DMF 240 
mg three times daily resulted in no additional benefit over the DMF 240 mg twice daily.  
 
Risks of DMF: Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most 
common reactions, especially at the initiation of therapy, and may decrease over time.  
DMF can decrease lymphocyte counts and can cause liver injury. DMF can cause anaphylaxis 
and angioedema after the first dose or at any time during treatment. Progressive multifocal 
leukoencephalopathy (PML) has occurred rarely in patients taking DMF.  
 
Flushing. In clinical trials, 40% of DMF treated patients experienced flushing. Flushing 
symptoms generally began soon after initiating DMF and usually improved or resolved over 
time. In the majority of patients who experienced flushing, it was mild or moderate in severity. 
The incidence of flushing may be reduced by administration of DMF with food. Alternatively, 
administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to DMF 
dosing may reduce the incidence or severity of flushing. 
 
Lymphopenia. DMF may decrease lymphocyte counts. In the multiple sclerosis placebo 
controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year 
of treatment with DMF and then remained stable. Four weeks after stopping DMF, mean 
lymphocyte counts increased but did not return to baseline. 6% of DMF versus <1% of placebo 
treated patients developed lymphocyte counts lymphocyte counts <0.5 x 109/L. There was no 
increased incidence of serious infections observed in patients treated with DMF in the placebo 
controlled trials, although one patient in an extension study developed PML in the setting of 
prolonged lymphopenia with lymphocyte counts generally <0.5 x 109/L for 3.5 years.  
 
Liver Injury. Clinically significant cases of liver injury have been reported in patients 
treated with DMF in the postmarketing setting. The onset has ranged from a few days to several 
months after initiation of treatment with DMF. These abnormalities resolved upon treatment 
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Progressive Multifocal Leukoencephalopathy. Progressive multifocal 
leukoencephalopathy (PML) has occurred in patients with multiple sclerosis treated with DMF. 
PML is an opportunistic viral infection caused by the JC virus. A fatal case of PML occurred in a 
patient who received DMF for 4 years, associated with prolonged lymphopenia in a clinical trial. 
PML has also occurred in the postmarketing setting in the presence of lymphopenia. The 
majority of cases occurred in patients with lymphocyte counts <0.5 x 109/L.  
 
There are no adequate and well-controlled studies in of use of DMF in pregnant women, 
and it is not known whether DMF is excreted in human milk. In a placebo controlled thorough 
QT study performed in healthy subjects, there was no evidence that DMF causes QT interval 
prolongation of clinical significance.  
 
DMF Pharmacokinetics. After oral administration in humans, DMF is extensively metabolized 
by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it 
reaches the systemic circulation. As DMF is not quantifiable in plasma following oral 
administration, all pharmacokinetic analyses have tested plasma MMF concentrations. Human 
plasma protein binding of MMF is 27-45% and independent of concentration. Metabolism of 
MMF occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 
system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma. Renal 
and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose 
respectively. The terminal half-life of MMF is approximately 1 hour and no circulating MMF is 
present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with 
multiple doses of DMF.  
 
Potential Benefits: The study subjects may receive a benefit from the study drug. Finding a new 
therapy for SSc-PAH could clearly benefit patients with SSc-PAH. Better understanding 
biomarkers could lead to better study designs and facilitate development of other treatments in 
the future. This benefit outweighs the small risk of this trial. 
 
4.1. 
Background 
Systemic Sclerosis. Scleroderma, also known as systemic sclerosis (SSc), is a multisystem 
disease affecting skin and, more variably, other tissues, commonly including joints, muscles, 
lungs, the gastrointestinal tract and kidneys. SSc is an autoimmune disease characterized by 
fibrosis and vasculopathy of various internal organs. It is a complex, multifactorial disease with 
very limited treatment.  
 
Although SSc can affect almost any part of the body, skin disease is the most consistent 
clinical manifestation. Skin disease typically starts in the hands with an edematous phase of hand 
swelling lasting one to several months. The skin then progressively thickens and tethers to 
underlying tissues. In diffuse cutaneous SSc (dcSSc), skin thickening, induration and tethering 
typically extend proximally up the arm and can involve the torso, abdomen, face and legs. 
Patients with limited cutaneous SSc (lcSSc) have skin disease limited to below the elbow and 
face and neck as well as other characteristic clinical features. SSc skin pathology (diffuse and 
limited cutaneous SSc) shows fibrosis and variable perivascular lymphocyte infiltration in the 
deep reticular dermis.                                                                                                                                                  
 
SSc affects multiple other body systems. Most severe complications are seen more 
frequently in dcSSc with considerable morbidity and mortality 7. Lung disease manifests as 


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interstitial fibrosis or pulmonary arterial hypertension (PAH, more common in lcSSc). Lung 
disease remains the leading cause of death among SSc patients. Gastrointestinal disease 
primarily results from dysmotility. In the esophagus and stomach this most commonly leads to 
esophagitis. In the small and large bowel this most commonly leads to constipation, bowel 
obstruction and/or malnutrition. Renal disease is primarily manifest as accelerated hypertension 
and renal insufficiency. Angiotension converting enzyme inhibitors are generally though not 
uniformly effective for treating this manifestation, which previously led to significant mortality.  
 
Other important clinical manifestations include cold-induced vasospastic disease in 
extremities (Raynaud’s phenomenon) and digital ulcers. SSc can also have cardiac 
manifestations. Pericarditis is the most frequent cardiac manifestation. Subclinical pericarditis is 
common with large effusions developing occasionally. Myocardial involvement with low-grade 
myocardial fibrosis is relatively common, but not frequently of clinical importance 8. Fibrosis 
most commonly manifests as the appearance of a septal infarction pattern on EKG in patients 
with normal coronary arteries, or as ventricular conduction delays. Occasionally myocardial 
fibrosis leads to heart failure. Cardiac arrhythmias are seen in ~5% of patients with SSc. Most 
common are atrial or ventricular ectopy, generally not associated with more serious rhythm 
disturbances. However, thallium perfusion defects are associated with sudden cardiac death 9. 
 
Current treatment for SSc is limited 10. For most disease manifestations treatment is 
primarily symptomatic and generally inadequate. The exception is renal disease, scleroderma 
renal crisis, once a major cause of mortality in SSc patients, can often be treated successfully 
with angiotensin converting enzyme inhibitors. Pulmonary complications now represent the 
major cause of mortality. Cyclophosphamide provides some benefit in patients with interstitial 
lung disease (ILD), the most lethal complication of SSc. However, the effect of this agent on 
SSc-associated ILD is modest and transient 11,12. More recently, autologous stem cell transplant 
has emerged as an effective therapy for this disease complication.  
 
Bowel hypomotility also leads to considerable morbidity and sometimes mortality. 
Esophageal hypomotility is treated, frequently without success, with pro-motility and acid-
blocking agents. Dysmotility of the lower bowel and its complications are even more difficult to 
treat with pro-motility agents providing modest relief in some patients and antibiotics helping in 
cases of small bowel overgrowth. Thus there are limited therapeutic alternatives for SSc patients 
faced with progressive lung or bowel disease.  
 
Pulmonary arterial hypertension (PAH) also leads to considerable mortality in SSc 
patients. PAH may respond to vasodilators such as epoprostanol and bosentan, but frequently 
responses are incomplete and mortality still high 13. SSc-PAH is particularly difficult to manage, 
with a 3-year mortality rate of ~60% following diagnosis 14. When compared to other subgroups 
of PAH patients, SSc-PAH patients respond sub-optimally to approved PAH therapies 15.  
 
While the etiology of SSc is unknown several observations suggest that oxidative stress 
plays a key role. Notably, increased levels of markers of DNA and lipid oxidation are present in 
the blood and urine of SSc patients 16-19. Oxidative processes can enhance TGF and Wnt 
pathways promoting fibrosis 20-24. Indeed, the bleomycin model of pulmonary fibrosis relies on 
oxidative DNA damage 25-27, and agents inducing oxidative stress can induce skin fibrosis and 
lung fibrosis 28. Oxidative stress has also been implicated in several animal model of PAH 29. In 
SSc-PAH, multiple lines of evidence implicate oxidative damage including increased production 
of reactive oxygen species (ROS) and nitrogen species (RNS), as well as decreased NO 
bioavailability and reduced downstream responsiveness to NO stimulation 30,31. Dysregulation of 
ROS/NO redox homeostasis impairs vascular function leading to abnormal cell proliferation and 


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obliteration of the vasculature.  Thus inhibition of oxidative stress might be efficacious as a 
therapy for SSc-PAH. 
4.2. 
Rationale 
 
All currently approved medications for PAH are vasodilators despite increasing evidence 
that the immune system is an important and possibly essential contributor to PAH and SSc. Not 
surprisingly, although vasodilators prolong survival, mortality is still very high. Adventitial 
macrophages appear particularly important in PAH pathogenesis 32. Activated macrophages 
through myeloperoxidase and NADPH oxidase produce mediators of oxidative stress, such as 
superoxide, hydrogen peroxide and hypochlorous acid 33. Oxidative stress can lead to endothelial 
cell dysfunction 34. This will be the first study in PAH or SSc-PAH to examine whether blocking 
the observed changes in oxidative stress improves markers of oxidative stress and clinical disease. 
The combination of potential pathways targeted by DMF is highly unique and appropriate for SSc-
PAH. We are not aware of any reports testing the effect of DMF or other inhibitors of oxidative 
stress in SSc or PAH. Although bardoxolone, an unapproved drug with similar activity as DMF 
on Nrf2, is under study for PAH, it has been associated with heart failure and may not have an 
adequate safety profile 35, particularly for SSc-PAH patients, already at high risk for cardiac 
complications. In addition, DMF has distinctive activities compared to bardoxolone. These drugs 
show numerous differences in both Nrf2-dependent and Nrf2-independent gene expression 36.  
 
This study will explore how biomarkers might be effectively utilized in clinical trials of 
SSc-PAH as pharmacodynamic and predictive biomarkers. The effect of DMF on novel mRNA 
and protein biomarkers previously described in SSc-PAH patients, as well as a panel of 
conventional oxidative stress and PAH biomarkers, will be assessed. Peripheral blood 
mononuclear cells (PBMCs) from patients with SSc-PAH express a cluster of macrophage related 
genes that are tightly linked to the presence of PAH 37-39. Novel protein biomarkers of SSc-PAH 
have been identified in previous studies 39. Additionally, upregulated markers of oxidative stress 
are found in the serum in SSc patients 19 and in PBMCs from SSc-PAH patients 38. Although DMF 
is known to block oxidative stress and affect NFB activation, markers of these pathways were 
not examined in the trials leading to approval of DMF for multiple sclerosis. Thus, both testing 
biomarkers of disease as well as testing biomarker targets of DMF are both important aspects of 
the planned study.  
 
Given the poor treatment options for these patients, new therapies are urgently needed. 
Ideally, a medication that could be added to and complement the current standard of care, i.e. 
vasodilators, would be optimal. Since DMF is known to reduce oxidative damage and down-
modulate NFB signaling, it is an attractive candidate for the treatment of SSc-PAH. In theory, 
efficacy could extend to additional organ involvement in SSc, such as the skin and interstitial lung 
disease. Showing clinical efficacy and/or a strong effect on biomarkers of oxidative stress on SSc-
PAH in patients treated with DMF would enable a larger, controlled clinical trial. 


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective and Endpoint 
Primary Objective:  
• To assess the safety of the treatment with DMF in patients with SSc-PAH.  
• To assess the efficacy in this pilot trial will be improvement in 6-minute walk distance 
(6MWD).  
Primary Endpoint:  
• Safety will be assessed by the incidence of serious adverse events (SAEs) and all adverse 
events in DMF compared to placebo treated patients. 
• The efficacy will be assessed by the change in 6MWD at 24 weeks from baseline in DMF 
compared to placebo treated patients (the study is powered to detect an improvement of 30-40 
M in the 6MWD). 
5.2. 
Additional Objectives and Endpoints  
Secondary Objectives:  
• Study the effect of DMF on time to clinical worsening: determined by: Change in SOC therapy 
for PAH; Hospitalization for PAH; Death; Need for transplantation; Need for atrial septostomy; 
Decline in 6MWD by 15% from the baseline 6MWD; Decline in WHO/NYHA functional 
class. 
• Study the effect of DMF on isoprostane and other serum markers of oxidative stress, including 
lipid, DNA, and prostaglandin targets. 
• Study the effect of DMF on PAH associated biomarker gene expression by peripheral blood 
mononuclear cells, including IL13RA1, CCR1, JAK2 and MRC1. 
• Study the effect of DMF on serum B‐type natriuretic peptide (BNP), Endostatin, Endothelin-1, 
Endoglin, Vascular Endothelial Growth Factor, von Willebrand Factor, and Vascular Cellular 
Adhesion Molecule 1. 
• Study whether DMF affects skin mRNA biomarkers. 
• Study the effect of DMF on Digital Ulcer Net Burden 
 
Secondary Endpoints: 
• The change in time to clinical worsening in DMF compared to placebo treated patients. 
• The change from baseline of serum markers of oxidative stress at 24 weeks, comparing DMF to 
placebo treated patients. 
• The change from baseline of PAH associated biomarkers at 24 weeks, comparing DMF to 
placebo treated patients 


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• The change from baseline in proteomic biomarkers, including BNP, at 24 weeks, comparing 
DMF to placebo treated patients. 
• The change in skin nMRA biomarkers at 24 weeks, comparing DMF to placebo treated patients 
compared to baseline. 
• The change in Digital Ulcer Net Burden at 24 weeks, comparing DMF to placebo treated 
patients compared to baseline. 


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6. 
STUDY DESIGN 
6.1. 
Study Overview 
This is a double-blinded, placebo-controlled study of DMF in 34 SSc‐PAH patients, anticipating 
10% dropout to achieve 28 patients completing the study. The study medication will be added to 
stable background PAH medication(s). Subjects will be dosed for 24 weeks, will undergo 
examination every 8 weeks, and will be finally evaluated 12 weeks after completion of treatment. 
Subjects will be recruited from approximately 5 sites in the US and will have two cohorts, 
randomized 1:1 to receive a starting dose of 120 DMF qpm or placebo for 7 days then follow the 
up-titration schedule to a maintenance dose of 240mg bid or placebo (or the highest tolerated 
dose of ≥ 120mg bid by the start of Week 8) for the remainder of the study. Subjects who 
withdraw from the study will not be replaced. 
6.2. 
Overall Study Duration and Follow-Up 
Study duration for each subject will be 40 weeks including a 4- week screening period, 24 weeks 
of drug and 12-week safety follow-up after the last dose. 
6.2.1. 
Study Flow Diagram 
 
 


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6.3. 
Early Termination of Study 
The Principal Investigator, after consultation with NIAMS and Biogen (who supplies the study 
drug), may terminate this study at any time. Study termination would be considered in the event 
of unanticipated serious adverse events in consultation with the data safety monitoring board, or 
in the event of a major new therapeutic advance outside of the study.  
All adverse events will be reviewed by the DSMB as part of their semiannual review. Any 
recurrent unanticipated serious adverse event will trigger ad hoc DSMB review within 14 days of 
submission. The PI will be responsible for informing the DSMB of such events within 48 hours, 
so that a timely meeting can be arranged by teleconference. The PI at his/her discretion may 
temporarily halt the study pending this review. The DSMB will then decide whether to terminate 
the study. In this case study medication dosing would be suspended and final study safety visits 
would be continued.  


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7. 
STUDY POPULATION 
7.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of randomization: 
1. Signed inform consent prior to any study-mandated procedures 
2. Adult patients 18-80 years of age 
3. Clinical diagnosis of systemic sclerosis (either limited or diffuse cutaneous disease).  
4. World Health Organization Group 1 PAH associated with scleroderma (SSc-PAH) 
5. WHO functional Class II-III 
6. Subject must be able to maintain O2 saturation ≥ 90% at rest (with or without oxygen). 
Oxygen use is permitted.  
7. Screening 6MWD of at least 150 meters but not greater than 450 meters 
8. Subjects must have been treated with background medical therapy for PAH (prostanoid, 
endothelin receptor antagonist, PDE-5 inhibitor, and/or guanylate cyclase stimulators) 
and have been on stable dose(s) of those medical therapy(ies) for a minimum of 8 weeks 
prior to randomization with no expectation of change for 24 weeks after randomization. 
9. Lymphocyte count must be >500/microliter 
 
10. Subjects must have either: 
A: Right heart catheterization showing mPAP≥ 25 mmHg and PCWP or left 
ventricular end diastolic pressure ≤15mm Hg a pulmonary vascular resistance of ≥400 
dynes/cm-5 (5 Wood units) within 12 months of study entry. 
 
OR 
 
B: Right heart catheterization showing PAH (mPAP≥ 25 mmHg and PCWP or left 
ventricular end diastolic pressure ≤15mm Hg and pulmonary vascular resistance ≥240 
dynes/cm-5 (3 Wood units)) within 3 months of study entry and no change in therapy 
since that catheterization. 
7.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of randomization: 
1. Pulmonary hypertension associated with 
a. PAH of any etiology other than scleroderma 
b. PH of any etiology other than WHO Group I PAH 
c. Pulmonary venous hypertension defined as PCWP or LVEDP >15 mHg 


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d. Untreated Sleep Apnea with AHI >20 or SaO2 Nadir <87% 
e. Chronic Thromboembolic Disease 
f. Sarcoidosis 
2. Moderate or severe interstitial lung disease as characterized by a forced vital capacity 
(FVC) of < 70% predicted and/or moderate or severe ILD by HPH, except if FVC is 
between 60-70% predicted and the most recent standard of care HRCT shows only mild 
ILD, or the FVC is between 50%-60% predicted and the most recent standard of care 
HRCT shows no ILD. Patients with FVC < 70% predicted should be excluded if there is 
clinical evidence of weakness or other factor the site investigator feels might adversely 
affect the 6MWD.  
3. Participation in a clinical investigational study within the previous 30 days 
4. Moderate to severe hepatic impairment (e.g., Child-Pugh Class B or C) 
5. Renal failure defined as: 
a. estimated creatinine clearance <30 m/min 
b. serum creatinine>2.5 mg/dl 
6. Serum aspartate aminotransferase (AST) and or alanine aminotransferase (ALT) 2 times 
the upper limit of normal  
7. Bilirubin > 2x ULN.  
8. Absolute neutrophil count (ANC) < 1,500/mm3 (or < 1.5 x 109/L).  
9. Platelet count < 100,000/mm3 (or < 100 x 109/L).  
10. Hemoglobin < 9 g/dL.  
11. Persistent hypotension with systolic blood pressure (SBP) < 90 mmHg.  
12. Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary 
rehabilitation program based on exercise 
13. Pregnant or lactating women 
11. Chronic infections including, but not limited to, HIV, tuberculosis (TB), hepatitis B 
(HBV) or hepatitis C (HCV), or chest X-ray (CXR) findings consistent with TB or latent 
fungal infection.  
12. Positive serology for hepatitis B defined by positive HBV surface antigen and/or positive 
HBV core antibody, total.  
 
13. Positive serology for HCV antibody, unless treated and cured of HCV.  
 
14. Evidence of active infection requiring IV or PO antibiotics within 2 weeks of 
randomization. 
15. Evidence of active or latent tuberculosis (TB) within 30 days of screening, including any 
of the following: 


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a. active TB: a history of active TB unless completion of treatment for active TB has 
been documented. 
b. latent TB (a positive PPD and/or QuantiFERON® test, a negative chest x-ray, and 
no symptoms or risk factors), unless one month of prophylaxis has been completed 
prior to inclusion.   
c. an indeterminate QuantiFERON® unless followed by a negative QuantiFERON®, 
or by a subsequent negative PPD and consultation with and clearance by local 
infectious disease (ID) department. 
16. Recent administration of a live vaccine (< 8 weeks) or any other immunization within 4 
weeks of treatment. 
17. A woman of childbearing potential (not post-menopausal or surgically sterile) who is 
unwilling to use a medically acceptable form of birth control (including, but not limited 
to, a diaphragm, an intrauterine device (IUD), progesterone implants or injections, oral 
contraceptives, the double-barrier method, or a condom) throughout the duration of the 
study. 
18. History of non-compliance with other medical therapies. 
19. A history of alcohol or drug abuse within 1 year of randomization.  
20. Planned treatment or treatment with another investigational drug within 1 month prior to 
start. 


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8. 
STUDY PROCEDURES 
Once the investigational site has been activated for study participation, subjects may be enrolled 
if they have met the inclusion criteria in Section 7.1 and have not been excluded based on the 
exclusion criteria in Section 7.2. Biogen will be supplying sites with study drug directly. 
8.1. 
Screening, Enrollment, Re-screen and Randomization of Subjects 
Subjects must be consented before any screening tests or assessments are performed.  At the time 
of consent, the subject will be enrolled into the study.   
Subjects will be randomized after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 7.1 and 7.2.  No subject 
may begin treatment prior to randomization and assignment of a unique subject identification 
number.  Any subject identification numbers that are assigned will not be reused even if the 
subject does not receive treatment. 
Subjects will be randomized to receive DMF 120mg qpm or placebo for 7 days then up-titrate to 
DMF 240mg bid (or highest tolerated dose of ≥ 120mg bid) or placebo in a 1:1 ratio for the 
remainder of the treatment period.  Subjects who withdraw from the study will not be replaced. 
The maximum allowable time between screening and the first administration of study treatment 
is 28 days. If visit 1 does not occur in this time frame, the subject would be required to be re-
screened. All study procedures outlined in the study schema would need to be repeated with the 
exception of the HIV, HCV and HBV serologies. 
The study blind will be maintained using the following procedures:  Almac, a third party 
contracted by Biogen will be supplying clinical sites with pre-labeled study drug and placebo. 
The unblinded staff at the Coordinating Center will provide the site pharmacist with an 
unblinded manifest once shipment is received from Almac. Blinding of study results will be 
maintained until data lock. Patient treatment assignment will be unblinded only if required for 
safety after discussion with Dr. Lafyatis. Data lock will occur after all patients have completed 
the final study visit and all translational studies have been completed. Thus, study investigators 
will remain blinded to treatment assignment until all clinical and translational data have been 
collected.  
8.2. 
Follow-up 
Safety follow-up will be conducted for all subjects at 3 months after the last dose of study 
treatment has been administered.  This period of follow-up is supported by pharmacokinetic 
modeling, which demonstrated that serum drug levels will be completely cleared within several 
days.  If a subject is withdrawn from study drug treatment, a safety follow-up visit will be 
conducted at 3 months from the date of withdrawal from the study medication. 
8.3. 
Stopping Rules 
Subjects must be withdrawn from the study for any one of the following reasons: 
• The subject becomes pregnant. 


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• The subject desires to discontinue study treatment under this protocol. 
• The subject experiences a medical emergency that necessitates permanent discontinuation 
of study treatment and/or unblinding of the subject’s treatment assignment. 
• Stopping rules per patient are is lymphocyte counts are <500 mcL at any two visits. 
• At the First Sign or Symptom Suggestive of Progressive Multifocal 
Leukoencephalopathy, Dmf Will Be Withheld, And Appropriate Diagnostic Evaluation 
Performed.  
• Patients Showing Persistent Elevation in Transaminases > 3x The Upper Limit Of 
Normal Will Be Discontinued From Treatment. 
• Subject is unable to tolerate study drug at 120 mg bid at the start of Week 8 
 
Subjects may also be discontinued from treatment at the discretion of the Principal Investigator. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s case 
report form (CRF). 


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9. 
STUDY TREATMENT 
Biogen will be supplying sites directly with Tacfidera/Placebo unblinded and the site pharmacist 
will be responsible for labeling the study drug with a unique identifier that corresponds with a 
predetermined randomization assignment.  The study treatment will be dispensed to the subject 
by the (pharmacist or study coordinator) or designee per the sites institution for study drug 
dispensing policies. 
9.1. 
Dosing Regimen and Administration 
DMF or placebo will be given as a pill to be taken twice a day. The first week of the study the 
subject will receive 120mg DMF tablets or similar appearing placebo tablets to be taken one 
tablet per day, and after the first week the subject will take one 120mg DMF tablets twice per 
day for two weeks. For the next month, weeks four through eight, the subject will take 120mg 
DMF tablet every morning and 240mg DMF tablet every evening. At weeks 8 – 24 the subject 
will enter the maintenance phase and will take 240 DMF tablet twice a day. By the start of week 
8, the subject must be at a minimum of 120 mg DMF tablets twice a day.  If a subject is unable to 
tolerate the maximum dose of 240mg twice a day, the subject may continue 120mg twice daily 
or highest tolerated dose for the remainder of the maintenance period. DMF or placebo can be 
taken with or without food. Missed doses should not be made up. The next dose should be taken 
as scheduled.  
Administration of DMF with food may reduce the incidence of flushing. Alternatively, 
administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to DMF 
dosing may reduce the incidence or severity of flushing.  
Gastroenterology adverse events, although reported to be mostly mild to moderate in severity, 
are experienced by a significant proportion of patients receiving DMF. Using a Delphi technique, 
neurologists reached consensus on several strategies to manage nausea, vomiting, abdominal 
pain, and diarrhea when using DMF: namely co-administration with food (particularly a high-fat 
meal such as peanut butter, yogurt, and cheese), dose titration up to 4 weeks when initiating 
DMF therapy, temporary dose reduction to 120 mg twice daily for 2–4 weeks, and use of specific 
symptom-directed therapies.  
Ondansetron (Zofran) is useful for reducing the impact of nausea and vomiting, as well as, 
bismuth subsalicylate, promethazine and antacids. Abdominal pain can be managed with bismuth 
subsalicylate, antacids, and anti-secretory drug treatment (dicyclomine hydrochloride or others), 
while diarrhea can be managed with loperamide and diphenoxylate/atropine.  
For the SSc-PAH DMF study the following approach should be taken if patients develop 
gastrointestinal side effects. First, when the medication is started the patient should be educated 
about the benefit of taking DMF with food, particularly high fat meal, such as peanut butter, 
yogurt or cheese.  This should be reinforced at a one-week follow-up telephone call just before 
they increase their dose. Patients should be instructed to call if gastrointestinal or other side 
effects develop at the initial or with the increased dose. If taking the medication with food does 
not ameliorate nausea/vomiting, or if patient is having continuing nausea at the 120 mg BID dose 
then patients should be instructed to stay at the 120 mg BID dose for up to 8 weeks before 
increasing the dose to 120 mg every morning and 240 mg every evening. During the time of dose 


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reduction, the study physician should try the above methods and medications to increase the dose 
to 240 mg BID. If the patient still cannot tolerate a minimum of 120mg BID then the patient 
should be discontinued from the study.     
Patients showing gastrointestinal adverse events such as nausea, vomiting, diarrhea, abdominal 
pain, or dyspepsia will be treated symptomatically or discontinued from treatment depending on 
the severity and patient tolerability at the discretion of the investigator. 
 
9.2. 
Drug Ordering and Accountability 
Initial Orders 
After site activation occurs, the initial drug supply will need to be ordered from Almac. Almac is 
a third party contracted by Biogen for the distribution of study drug and placebo. Detailed 
instructions and forms for the pharmacists will be in the pharmacy manual that will be provided 
by the Coordinating Center. 
Re-Supply 
Subsequent drug supply will need to be ordered from Almac. Detailed instructions and forms for 
the pharmacists will be in the pharmacy binder that will be provided by the Coordinating Center. 
Method of Assigning Subjects to Treatment 
Patients will be randomized after all screening assessments have been completed, entered into 
the EDC database and the investigator has verified that eligibility criteria have been met. The 
Coordinating Center will verify eligibility prior to any subject being randomized. A written letter 
of approval will be sent to the clinical site once review and approval has occurred.The site 
pharmacist will be responsible for randomizing the subject in the EDC database; no participant 
may begin treatment prior to randomization. Eligible participants will be randomized to DMF or 
placebo in a 1:1 manner. The Coordinating Center Data Manager in consultation with the Study 
Statistician will prepare the randomization schedule, using computer-generated block 
randomization with the block size(s) known only by the Coordinating Center Data Manager and 
Study Statistician. A secure web-based application will be used by the site pharmacist to enter 
participant information (e.g., participant ID, stratification factor(s)) and to obtain the treatment 
assignment.  
 
9.3. 
Treatment Compliance 
Compliance with treatment dosing will be monitored and recorded by site staff at each study visit 
by counting all returned study medication. 
9.4. 
DMF/Placebo Stability and Storage 
DMF/ placebo will be supplied in 120 mg capsules in a blister pack/wallet directly to each site 
pharmacy from Biogen. The drug will be shipped unlabeled and will be labeled by each site 


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pharmacy. Each site pharmacist will be responsible for labeling the drug with a unique identifier 
that corresponds with a predetermined randomization assignment. 
120mg DMF/ placebo for initiation, dispensed in blister packs/wallets 
The investigator is responsible for ensuring that the investigational product is stored 
under the appropriate environmental conditions (temperature, light, and humidity), as 
described below: 
• The investigational agent should be stored between 15°C and 30°C (59°F and 85°F) and 
protected from light. Opened wallets should be discarded at the expiration date and 
patients instructed in the proper storage of the drug when it is taken home. 
The study site personnel or their designee (pharmacist or coordinator) at each site will be 
responsible for correct storage and handling of the study drug. 
Study drug will not be used beyond the initial expiration date on the drug packaging. The label 
will include conditions for storage, lot number, and other pertinent information such as Sponsor 
and caution statement. 
The investigational product should be stored in a secure area according to local 
regulations. The investigator is responsible for ensuring that it is dispensed only to 
study participants and only from official study sites by authorized personnel, as dictated 
by local regulations. 
Study site staff should refer to the MOOP for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment. 
9.4.1. 
DMF/Placebo Handling and Disposal 
Study treatment must only be dispensed by a Pharmacist or appropriate trained staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can only be administered to that subject.   
The study site must maintain accurate records demonstrating dates and amount of study drug 
received, to whom they are dispensed (subject-by-subject accounting), and accounts of any study 
drug accidentally or deliberately destroyed.  Unless otherwise notified, the study sites must save 
all unused DMF /Placebo supplies for drug accountability.  Subjects will be expected to return all 
unused drug to the site at either study termination or withdrawal. 
The study sites will destroy the study drug per their institutions destruction policy at the end of 
the trial. The sites must send the documentation of the study drug destruction at the end of the 
trial to the Coordinating Center. Sites will be required to send the Coordinating Center a copy of 
their institutions drug destruction policy.  
9.5. 
DMF/Placebo Accountability 
The clinical site will maintain an Investigational Drug Accountability Log.  The following 
information will be recorded:  
• Total amount of drug received, date of drug receipt, initials of person receiving 


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• Identification of study subject to whom study product was dispensed, date of dispensing, 
quantity dispensed, and initials of person responsible for dispensing 
• Amount of study product returned to the site from the study subject, date of return and 
initials of person receiving/recording the return 
• Record any study drug accidentally or deliberately destroyed 
• Balance of study drug on site 


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10. 
DATA COLLECTION 
10.1. 
Assessments 
Study-related procedures and outcome measures that will be performed as part of this protocol 
are listed below. Specific times at which each test will be performed are summarized in the time 
and events table (section 3). 
10.2. 
Safety Assessments  
• 
Complete medical history. Medical history will be performed as per standard medical 
care. 
• 
Physical examination. A standard complete physical examination will be performed, 
with the addition of the assessment of modified Rodnan Skin Score, digital ulcers. 
• 
Vital signs. Vital signs will include: pulse, blood pressure, respiratory rate, temperature 
(C º), height (cm), and weight (kg). 
• 
Safety Labs. Safety labs (Complete Blood Count (CBC), Complete Metabolic Panel 
(CMP), B-Type Natriuretic Peptide (BNP) and Urinalysis will be done at every visit and 
sent to the local lab for processing. A Urine Dipstick pregnancy test will be done on all 
WOCBP at every visit before any study treatment is dispensed. 
 
10.3. 
Efficacy Assessments  
10.3.1. 
6-Minute Walk Distance 
The 6MWT40 measures the distance an individual is able to walk over a total of six minutes on a 
hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The 
individual is allowed to self-pace and rest as needed as they traverse back and forth along a 
marked walkway. 
10.3.2. 
NYHA Classification 
The New York Heart Association (NYHA) Functional Classification provides a simple way of 
classifying the extent of heart failure. It places patients in one of four categories based on how 
much they are limited during physical activity; the limitations/symptoms are in regard to normal 
breathing and varying degrees in shortness of breath and/or angina. 
 


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10.3.3. 
Modified Rodnan skin score 
The Modified Rodnan skin score (MRss) is a validated physical examination method for 
estimating skin induration. It is correlated with biopsy measures of skin thickness and reflects 
prognosis and visceral involvement, especially in early disease 41,42. It is scored on a 0 (normal) 
to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 and is 
used to categorize severity of SSc. It has been extensively used as primary/ secondary outcome 
in RCTs 43, 44, 45.  This will be collected at every study visit. 
10.3.4. 
Skin Biopsies 
Skin biopsies will be collected from enrolled participants to evaluate transcriptional changes 
following treatment with DMF at Visit 1 and 4. One 3mm skin biopsy will be obtained from the 
mid dorsal surface of the forearm. If affected skin is located in that area, then the affected skin 
should be used. A biopsy will be performed whether affected skin is present or not. Skin biopsies 
from future visits should be conducted on the same arm.  
 
10.3.5. 
Biomarkers of Oxidative stress and PAH.  
• Oxidative stress Biomarkers. Circulating biomarkers of oxidative stress in plasma (8-
isoprostane (total and free) and Total anti-oxidant capacity), and in serum (TBAR and 
8-hydroxydeoxyguanosine) will be measured at baseline 8-, 16-, 24-, and 36-week study 
visits  
• Plasma and serum proteins. Circulating protein biomarker will be measured in plasma 
(NT-ProBNP, IL-6, CCL2/MCP-1) or serum (Endoglin, Endostatin, Endothelin-1, vWF, 
VEGF, VCAM, FSTL3, Spondin-1, Jam-C, CCL28, Midkine) at baseline 8-, 16-, 24-, 
and 36-week study visits.  
• Peripheral Blood Mononuclear Cell (PBMC) RNA. PBMC RNA will be assessed for 
IL13RA1, CCR1, JAK2, MRC1, BIP, ATF6 and DNAJB1 at baseline 8-, 16-, 24-, and 
36-week study visits. 
10.3.6. 
Biomarkers of skin mRNA.  
Biomarkers for the effect of DMF on skin will be assessed by gene expression analyses   
 
10.3.7. 
Digital ulcer assessment 
Digital ulcers are defined as a full thickness skin lesion with loss of epithelium. Ulcers should be 
> 3mm in maximal diameter. Healing is defined by re-epithelialization with loss of pain and 
exudate. Pitting scars and hyperkeratotic lesions are always excluded. Also, eschar is not 
considered as DU. This will be collected at Screening through Week 24 visits. 
Digital ulcer will be assessed by the following methods: 


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• Visual analog score for patient-reported severity of digital ulcers  
• Ulcer count:  
o Total ulcer counts 
o Distal counts: distal (fingertip) – any ulcer including skin area distal to proximal 
interphalangeal (PIP) joint 
1. Non-ischemic ulcers over the PIP and MCP will also be evaluated for healing as 
secondary outcomes 
10.3.8. 
Patient-Reported Outcomes (PROs)  
Three patient-reported outcomes (PROs)—the SHAQ, Raynauds VAS, and Systemic Sclerosis 
Skin Questionnaire—will be completed at every visit by all subjects in the study.  
 
10.3.9. 
Scleroderma Health Assessment Questionnaire (SHAQ) 
The SHAQ consists of 8 domains from the Health Assessment Questionnaire disability index 
(HAQ-DI), a HRQoL instrument that measures self-reported function in 8 domains of activity in 
20 weighted responses and a VAS of pain experienced in the past week. It additionally measures 
5 domains specific to scleroderma using a continuous VAS: Raynaud’s phenomenon, digital tip 
ulcers, lung symptoms, gastrointestinal symptoms, and a global patient assessment46. The VAS 
subscales of the SHAQ were shown to be significantly correlated with objective parameters,46 
and was responsive to change in a cohort and in a Raynaud’s phenomenon trial in SSc.46,47  
 
10.3.10. 
Raynaud’s attacks assessment 
Raynaud’s attacks will be assessed using the following individual outcome measures:  in 
Raynaud’s condition score and patient assessment of Raynaud’s phenomenon using the VAS48 
The Raynaud’s condition score is a daily patient-assessment of Raynaud’s phenomenon activity 
using a 0-10 ordinal scale. It incorporates the cumulative frequency, duration, severity and 
impact of Raynaud’s phenomenon attacks, reflecting the overall degree that Raynaud’s has 
affected use of the patient’s hands48. The Raynaud’s condition score, along with details of the 
frequency and duration of Raynaud’s attacks, will be incorporated into the daily diary that 
subjects will be asked to complete for 1 week (7 days) at the time points shown in the schedule 
of assessments.  
The patient and physician assessment assess the severity of Raynaud’s phenomenon in the past 
week using a 0-100 VAS.  
 
10.3.11. 
Systemic Sclerosis Skin Questionnaire (PRO-SRSS)  
Patient assessment of skin disease activity will be done at specified visits for each enrolled 
subject. The assessment at each specified visit will be performed with a questionnaire of 22 


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questions about how scleroderma affects the skin and how those skin problems affect how the 
person feels and does things. Each question is followed by seven boxes with numbers 0-6, 
spaced equidistance in between. The boxes are anchored by two verbal descriptors, one of “Not 
at all” (box labeled 0) and one of “Very Much” (box labeled 6). The subject will select a box 
labeled by an integer in response to each question.  


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11. 
PROTOCOL DEVIATION DEFINITIONS 
 
Protocol deviations occur when there is non-adherence to the protocol, including failure to 
follow informed consent, safety surveillance and enrollment procedures, or to adhere to Good 
Clinical Practices (GCP). 
 
Deviations may occur when there is non-adherence to study procedures or schedules by either 
the subject or site personnel, as specified by the protocol. 
 
11.1.1. 
MINOR DEVIATIONS 
 
A minor protocol deviation is one that does not have the potential to impact subject safety or 
risk, compromise the integrity of the study data, or affect the subject’s willingness to participate 
in the study.  
 
11.1.2. 
MAJOR DEVIATIONS 
 
Major protocol deviations are variations from protocol-directed conduct of a clinical trial that are 
considered to affect the safety of the subject, the ability of the trial to evaluate the efficacy of the 
study regimens, or failure of the investigator to provide subject protection as required by GCP. 
 
11.1.3. 
INSTRUCTIONS FOR DOCUMENTING DEVIATIONS 
 
All protocol deviations should be recorded, as they are discovered, for your record keeping and 
submission to the CC who will submit to the University of Pittsburgh IRB per their requirements. 
 
All Protocol deviations should be reported to the coordinating center via FAX: (412) 648-
9643 or scan & email: krk99@pitt.edu and entered into the EDC. 
 
A sample of the protocol deviation log is presented as Appendix F with Required Source 
Document.  
 


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12. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING 
OVERVIEW 
This section defines the types of safety data that will be collected under this protocol and outlines 
the procedures for appropriately collecting, grading, recording, and reporting those data. Adverse 
events that are classified as serious according to the definition of health authorities must be 
reported promptly. Reporting of Adverse Events and Serious Adverse Events/Events of Special 
Interest) to the sponsor (NIAMS through KAI) and Biogen. Appropriate notifications will also be 
made to the site investigators, Institutional Review Boards (IRBs), Institutional Ethics 
Committees (IECs), and health authorities. 
 
Information in this section complies with ICH Guideline E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, ICH Guideline E-6: Guideline 
for Good Clinical Practice, 21CFR Parts 312 and 320, and applies the standards set forth in the 
National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03 (June 14, 2010): https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf  
 
Throughout the course of the study, every effort will be made to remain alert to possible adverse 
events (AEs).  If an AE occurs, the first concern should be for the safety of the subject.  If 
necessary, appropriate medical intervention will be provided. At the signing of the ICF, each 
subject must be given the names and telephone numbers of study site staff for reporting AEs and 
medical emergencies. 
 
A sample of the AE, SAE and MEDWATCH form is shown in Appendix E. 
12.1. 
Definitions 
12.1.1. 
Adverse Event 
Any untoward or unfavorable medical occurrence associated with the subject’s participation in 
the research, whether or not considered related to the subject’s participation in the research 
(modified from the definition of adverse events in the 1996 International Conference on 
Harmonization E-6 Guidelines for Good Clinical Practice) (from OHRP "Guidance on 
Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events (1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2)  
 
12.1.2. 
Adverse Reaction and Suspected Adverse Reaction (SAR) 
 
Suspected adverse reaction (SAR) is any adverse event for which there is a reasonable possibility 
that the investigational drug caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug 
and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug (21 CFR 
312.32(a) and ICH E2A). 
 


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An adverse reaction (AR) is any adverse event caused by the study drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. 
 
12.1.3. 
Unexpected Adverse Event/Reaction 
 
A SAR is considered “expected” when it is listed in the investigator brochure, the package insert, 
or the protocol. A SAR is considered “unexpected” when its nature (specificity), severity, or rate 
of occurrence is not consistent with applicable product information as described in the safety 
information provided in the investigator brochure, the package insert, or the protocol (21 CFR 
312.32(a) and ICH E2A). A serious unexpected suspected adverse reaction is referred to as a 
SUSAR. For this study, expectedness will be determined by product information provided in the 
investigator brochure, package insert, and protocol for Dimethyl fumarate (Tecfidera, DMF). 
 
12.1.4. 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or Sponsor (NIAMS) it results in any of the following outcomes (21 CFR 
312.32(a)): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of 
either the investigator or Sponsor (NIAMS) its occurrence places the subject at 
immediate risk of death. It does not include an AE or SAR that, had it occurred in a more 
severe form, might have caused death. 
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5. Congenital anomaly or 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 subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
Elective hospitalizations are not to be reported as an SAE unless hospitalization is prolonged due 
to complications. 
12.1.5. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the study site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 


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• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment. 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.  
12.2. 
Grading and Attribution of Adverse Events 
12.2.1. 
Grading Criteria 
The study site will grade the severity of adverse events experienced by the study subjects 
according to the criteria set forth in the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03 (June 14, 2010). This document (referred to 
herein as the NCI-CTCAE manual) provides a common language to describe levels of severity, 
to analyze and interpret data, and to articulate the clinical significance of all adverse events. 
 
Expectedness of all AEs will be determined by the Principal Investigator according to the 
approved local label. 
 
Adverse events will be graded on a scale from 1 to 5 according to the following standards 
in the NCI-CTCAE manual: 
Grade 1 = mild adverse event. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, 
but not limited to, a radiograph, an ultrasound, an electrocardiogram etc.), a treatment emergent 
adverse event is defined as an increase in grade from baseline or from the last post-baseline value 
that doesn’t meet grading criteria. Changes in grade from screening to baseline will also be 
recorded as adverse events if related to a study-mandated procedure, treatment, or change in 
treatment (but are not treatment-emergent). If a specific event or result from a given clinical or 
laboratory evaluation is not included in the NCI-CTCAE manual, then an abnormal result would 
be considered an adverse event if changes in therapy or monitoring are implemented as a result 
of the event/result. 
 
12.2.2. 
Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study 
procedure(s) will initially be determined by the site investigator and recorded on the appropriate 
AE eCRF. Final determination of attribution for safety events that may be eligible for expedited 
reporting to the FDA will be determined by the sponsor, NIAMS. The relationship of an adverse 
event to study therapy regimen or procedures will be determined using the descriptors and 
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For additional information and a printable version of the NCI-CTCAE manual, consult 
the NCI-CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html. 
 
NCI-CTCAE attribution of adverse events 
Code 
Descriptor 
Relationship (to primary investigational product 
and/or other concurrent mandated study therapy) 
Unrelated Categories 
1 
Unrelated 
The adverse event is clearly not related. 
2 
Unlikely 
The adverse event is unlikely related. 
Related Categories 
3 
Possible 
The adverse event has a reasonable possibility to be 
related; there is evidence to suggest a causal relationship. 
4 
Probable 
The adverse event is likely related. 
5 
Definite 
The adverse event is clearly related. 
 
 
12.3. 
Monitoring and Recording Events 
12.3.1. 
Adverse Event Guidelines 
All adverse events will be collected and will be presented in aggregate in the monitoring body 
periodic reports. 
At a minimum, the following criteria should be used as a guide for recording Adverse Events. 
These guidelines are not all inclusive and the recording of Adverse Events remains at the 
discretion of the investigator. A symptom or condition that is present but does not reach one of 
these levels may still be recorded as an adverse event. 
 
1) A symptom or event that requires discontinuation of study medication. 
2) A worsening of an existing condition. 
3) A newly diagnosed symptom or event that requires a written prescription for treatment. 
4) A newly diagnosed symptom or event that results in a referral to another provider. 
5) Any grade 3 or 4 event according to the NCI Common Toxicity Criteria. 
 
An adverse event is considered a serious adverse event if one or more of the following apply: 
1. results in subject hospitalization or prolongs existing hospitalization 
2. event is life-threatening 
3. results in death 
4. results in significant or permanent disability 
5. requires medical intervention to prevent permanent damage 
6. results in a congenital anomaly or birth defect 


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12.3.2. 
Adverse Event Reporting 
 
If a subject experiences an adverse event (AE) or serious adverse event (SAE), complete the 
Adverse Event Form (AE). 
 
All AEs are collected, analyzed, and monitored by using an Adverse Event Form, a sample of 
which is shown in Appendix E. AEs and/or laboratory abnormalities identified in the protocol as 
critical to participant safety must be reported to NIAMS, and the DSMB through KAI and will 
also be reported to Biogen at the time of each DSMB meeting, typically biannually. All AEs 
experienced by the participant during the time frame specified in the protocol from the time of 
signed consent through the end of the study are to be reported, as outlined in the protocol. 
 
 
12.3.3. 
Unanticipated Problems 
 
Unanticipated Problems are not included in the 45 CFR part 46, but are defined by the OHRP as 
any incident, experience or outcome that meets all of the following requirements:  
 
(1) 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being 
studied; 
(2) 
Related or possibly related to participation in the research. Possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
(3) 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
OHRP recognizes that it may be difficult to determine whether a particular incident, experience, 
or outcome is unexpected and whether it is related or possibly related to participation in the 
research.  OHRP notes that an incident, experience, or outcome that meets the three criteria 
above generally will warrant consideration of substantive changes in the research protocol or 
informed consent process/document, or other corrective actions in order to protect the safety, 
welfare, or rights of participants or others. 
 
Examples of corrective actions or substantive changes that might need to be considered in 
response to an unanticipated problem include:  
 
▪ Changes to the research protocol initiated by the investigator prior to obtaining IRB 
approval to eliminate apparent immediate hazards to subjects; modification of inclusion 


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or exclusion criteria to mitigate the newly identified risks; implementation of additional 
procedures for monitoring subjects; suspension of enrollment of new subjects; suspension 
of research procedures in currently enrolled subjects; modification of informed consent 
documents to include a description of newly recognized risks; and provision of additional 
information about newly recognized risks to previously enrolled subjects. 
 
Only a small subset of adverse events occurring in human subjects participating in research will 
meet these three criteria for an unanticipated problem. Furthermore, there are other types of 
incidents, experiences, and outcomes that occur during the conduct of human subject’s research 
that represent unanticipated problems but are not considered adverse events.  For example, some 
unanticipated problems involve social or economic harm instead of the physical or psychological 
harm associated with adverse events.  In other cases, unanticipated problems place subjects or 
others at increased risk of harm, but no harm occurs. All unanticipated problems that involved 
participant safety should be reported to the NIAMS and the DSMB through KAI and Biogen 
within 48 hours of the Investigator becoming aware for the event. For further information see 
http://www.hhs.gov/ohrp/policy/advevntguid.html.  
 
12.3.4. 
Serious Adverse Event Reporting 
An AE is considered serious if one or more of the following criteria are met: 
 
1) Results in death 
2) Is life-threatening 
3) Requires or prolongs in subject hospitalization (i.e. elective medical/surgical procedures, 
scheduled treatments, or routine check-ups are not SAEs) 
4) Is disabling (i.e. resulted in a substantial disruption of the ability to carry out normal life 
functions) 
5) Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the trial drug prior to conception or during pregnancy) 
6) Does not meet any of the above serious criteria but may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 
Any SAE experienced by a subject after the subject signs the informed consent form (ICF) and 
before End of Study/Premature Withdrawal/Final Follow-up Visit, is to be recorded on an SAE 
Form, regardless of the event relationship to DMF.   
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. 
12.3.5. 
Immediate Reporting of Serious Adverse Events 
It is the Principal Investigator’s responsibility to ensure that the SAE reporting information and 
procedures are used and followed appropriately. 
Site Investigators must report SAEs to Dr. Lafyatis (PI) within 24 hours of becoming aware of 
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If the subject experiences a Serious Adverse Event: 
 
The Clinical Site will: 
 
1. Complete the Serious Adverse Event form. (SAE Form can be found in Appendix E) 
 
2. Fax the completed SAE Form to the Coordinating Center at the University of Pittsburgh 
within 24 hours of knowledge of the event 
 
Fax: (412) 648-9643 
 
3. Call the Coordinating Center (Kristi Kong) during office-hours (including weekends; 
between 9:00 am and 4:00 pm EST M-F; and holidays)  
 
  
 
 
Cell: (267) 371-0521 
The Coordinating Center at the University of Pittsburgh will: 
 
1. The coordinating Center will submit to the Central IRB per the University of Pittsburgh 
IRB submitting guidelines. (These guidelines can be found in Appendix G with the SOP’s) 
2. The Coordinating Center will submit the SAE form to NIAMS and the DSMB through 
KAI within 48 hours of becoming aware of the event. 
3. Dr. Robert Lafyatis will be responsible for reporting to the FDA. 
 
Reporting Information for SAEs 
All SAEs regardless of relatedness must be reported to the NIAMS and the DSMB through 
KAI within 48 hours of the investigator becoming aware of the event 
Any Serious Event that occurs between the time that the subject has signed informed consent 
and Final Follow-up Visit must be reported to Biogen within 24 hours of the study site staff 
becoming aware of the event 
A report must be submitted to Biogen SABR or designee regardless of the relationship to 
DMF/Placebo. 
To report initial or follow-up information on a Serious Event, email a completed SAE report to 
the following:   
Email: KAIforNIAMS@kai-resssearch.com  
Biogen: Jason Mendoza, Email: jason.mendoza@biogen.com, Fax: 888-299-8459 
Email: BiogenPSPVgroup@ppdi.com  
 


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12.3.6. 
Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded and 
reported on the appropriate CRF.  All causes of death must be reported as SAEs.  The 
Investigator should make every effort to obtain and send death certificates and autopsy reports to 
Biogen.  
12.3.7. 
Suspected Unexpected Serious Adverse Reactions 
A Suspected Unexpected Serious Adverse Reaction is known as a SUSAR is when during a 
clinical trial for a certain drug there may be serious adverse reactions in subjects given the drug, 
that may or may not be dose related, but are unexpected, as they are not consistent with current 
information. Reporting a SUSAR is an important aspect of clinical trials involving drugs. 
 
The Principal Investigator will notify Biogen and all participating investigators in an IND safety 
report of potentially serious risks from this clinical trial no later than 15 calendar days after we 
receive the safety information and determine the information qualifies for reporting. Events must 
be reported to Biogen if they meet the definitions for all of the following: (1) Suspected adverse 
reaction (2) Serious and (3) Unexpected. The blind should ordinarily be broken for IND safety 
reports submitted to FDA. Knowledge of the treatment received is necessary for interpreting the 
event, may be essential for the medical management of the subject, and may provide critical 
safety information about a drug that could have implications for the ongoing conduct of the trial 
(e.g., monitoring, informed consent). In general, if the blind is broken and a subject with an 
adverse event that would meet the criteria for reporting as a single event was receiving placebo, 
the event should not be reported in an IND safety report because there is not a reasonable 
possibility that the drug caused the adverse event. Follow-up IND safety report will be used for 
any follow-up information. A “7-day IND safety report” will be used for unexpected fatal or life 
threatening adverse reaction reports. 
 
The Clinical Center is responsible for notifying the Coordinating Center and the Principal 
Investigator is responsible for notifying the University of Pittsburgh Institutional Review Board  
 
12.4. 
Procedures for Handling Special Situations 
12.4.1. 
Reporting Pregnancy 
The Investigator should refer to the approved local label for guidance if female subjects become 
pregnant or are considering becoming pregnant during the study. 
12.4.2. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Overdoses are not considered AEs; however, all overdoses 
should be recorded on an Overdose Form and faxed to <Biogen SABR or designee> within 24 
hours.  An overdose should be reported even if it does not result in an AE.  Overdoses do not 
need to be recorded in the CRF; dosing information is recorded on a CRF. 


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12.4.3. 
Medical Emergency  
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care. 
12.4.4. 
Unblinding for Medical Emergencies 
• 
This is a double-blind study. The study staff (except for select staff at the IDS CC) and 
the patient are blinded to the treatment assignment. 
• 
Blinding is critical to the integrity of this clinical study. However, in the event of a 
medical emergency or pregnancy in a participant, in which knowledge of the investigational 
product is 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. A discussion with the protocol chairs is encouraged prior to proceeding 
with unblinding. 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. NIAMS and the DSMB through KAI should be 
informed in the event of any emergency unblinding. 
12.5. 
Principal Investigator Responsibilities 
The Sponsor- Investigator’s responsibilities include the following (refer to Section 12.3.1for 
details): 
• Review all AEs to determine seriousness and fulfillment of collection criteria  
• Monitor and record all SAEs, regardless of the relationship to DMF/Placebo. 
• Determine the relationship of each SAE to DMF/Placebo. 
• Determine the onset and resolution dates of each SAE 
• Record all pregnancies. 
• Complete the appropriate form for each SAE and fax or email it to Biogen SABR or 
designee within 24 hours of the study site staff becoming aware of the event. 
• Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen SABR or designee within 24 hours of the study site staff 
becoming aware of new information. 
• Ensure all SAE reports are supported by documentation in the subjects’ medical 
records. 
• Report SAEs to local ethics committees, Health Authorities, other Investigators and 
entities as required by local law. 
 


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13. 
STATISTICAL CONSIDERATIONS 
13.1. 
Sample Size Justification 
 
While setting the sample size in a pilot trial via formal power calculations is not necessary, 
providing a sample size justification is useful as we assess aspects of an anticipated phase 3 trial 
of DMF among patients with systemic sclerosis associated pulmonary arterial hypertension, such 
as recruitment rates, adherence to DMF, and the estimates of variance from a pilot trial of DMF. 
We estimated the optimal sample size of 28 for a two armed parallel group randomized controlled 
clinical trial with a two-sided type I error rate of 5% and a power of 80% using approaches 
proposed by Whitehead and colleagues49. We recognize that sample size for a pilot trial can be 
justified based on expected effect size. Published rules of thumb and mathematical modeling also 
factor into sample size justification, but recommendations are variable. Alternative 
recommendations are a pilot randomized controlled trial should have 9, 11 and 14 patients in each 
arm for treatment with expected effect size of 0.5, 0.4, and 0.3 respectively, using the 80% non-
central t-distribution approach49. Our proposal to include 34 patients (allowing for a 20% drop out 
rate) in this study to allow us to estimate the efficacy with a reasonable degree of certainty.   
The pilot study sample size calculation is based on an anticipated future main superiority clinical 
trial, for an anticipated detectable effect size of 0.3. For a main trial powered at 80%, type I error 
rate of 5%, and an effect size of 0.3, 14 patients/arm is the theoretical optimal pilot size trial for a 
main trial of 188 patients/arm using a non-central t-distribution approach [1]. This sample size 
(188) is in line with the sample size for most current phase 3 trials for PAH. The main trial size 
is limited by the size of the available SSc-PAH patient population.    
 
13.2. 
Interim Analysis 
Interim analysis of the study will be conducted due to pre-specified stopping rules as outlined in 
the protocol, or as determined necessary by the DSMB to assess safety concerns. 
 
13.3. 
Endpoint Analysis 
Intention to treat (ITT) analysis will be undertaken to evaluate the effect of DMF.  
 
First, we will compare the baseline characteristics using χ2 test for categorical or nominal variables 
and t-test for continuous variables between treatment and placebo groups.  
 
Second, we will assess whether treatment of DMF will significantly improve the 6MWD, the 
primary outcome variable in this proposal, among patients with SSc-PAH. Specifically, for each 
patient we will calculate the difference in 6MWD assessed at 24 weeks from that assessed at 
baseline. If the change in 6MWD is normally distributed we will calculate the mean of 6MWD 
change for each treatment group and compare the difference in means of 6MWD change between 
two groups using linear regression model. If 6MWD is not normally distributed, we will estimate 
the median value of 6MWD change for each group and test if median value is different using 


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quantile regression model. We will perform multivariable regression model to adjust for potential 
confounder If the baseline characteristics are not evenly distributed between two groups.  
 
Third, since the 6MWD will be assessed repeatedly at baseline, 8-week, 16-week and 24-week 
visits we will examine the effect of DMF on the changes in 6MWD at each follow-up visit (i.e., 8-
, 16-, and 24-week) from that at baseline using mixed-effects regression model. 
We will take the same statistical analysis approach to examine the effect of DMF on each 
biomarker measured for this pilot trial. 
Fourth, since almost all previous studies have examined the cross-sectional association between 
levels of specific biomarkers of SSc-PAH and clinical outcome (i.e., 6MWD) we do not know 
whether changes in levels of these biomarkers will also correspond to changes in clinical 
outcome, such as 6MWD. In this pilot trial, we will collect data on both biomarker and clinical 
outcomes (i.e., 6MWD) simultaneously at four time points (i.e., baseline, 8-, 16-, and 24-week). 
Thus, it will allow us to assess whether change in each biomarker is associated with change in 
6MWD. Specifically, we will assess whether the levels of a specific biomarker assessed at 
baseline (i.e., cross-sectional association) and its change over time (i.e., longitudinal association) 
are associated with a change in 6MWD using mixed-effects linear regression models. In the 
mixed effect model the time will be considered as a categorical variable. We will model both 
treatment assignment and time as the fixed effects, and subjects as a random effect. Missing 
values for covariates and outcome variable will be imputed by a sequential regression method 
based on a set of covariates as predictors 50  
Finally, number of patients with side effects and number of patients of non-adherence will be 
tabulated and compared between the two groups using χ2 test. 
 
The safety outcomes will be reported in summary statistics in DMF and placebo treated patients, 
separately, including frequency or mean of each safety measurement. If necessary we will 
compare the proportions of safety outcome using Chi-square test or difference in means of 
outcome (e.g., lymphocyte counts) using t-test between two groups.   
Secondary outcomes will be analyzed by reporting descriptive statistics in placebo and DMF 
treated groups, including proportions or means. We will compare the difference in proportions as 
well as its 95% confidence intervals using Chi-square test or difference in means as well as its 
confidence intervals between DMF and Placebo groups. 
 


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14. 
ETHICAL REQUIREMENTS 
The Principal Investigator must comply with all instructions, regulations, and agreements in this 
protocol and applicable International Conference on Harmonisation (ICH) guidelines and 
conduct the study according to local regulations. The subject’s privacy; physical, mental, and 
social integrity; and the confidentiality of his or her personal information will be strictly 
respected in accordance with the World Medical Association Declaration of Helsinki. 
14.1. 
Ethics Committee 
The Principal Investigator must obtain ethics committee approval of the protocol, ICF, and other 
required study documents prior to starting the study.   
It is the responsibility of the Investigator(s) to ensure that all aspects of institutional review are 
conducted in accordance with current governmental regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, tracking number, and ICF version, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol. 
Protocol amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. At the completion or termination of the study, the investigational site must submit 
a close-out letter to the ethics committee. 
14.2. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative, as applicable, in accordance with local practice and 
regulations.  Per regulation a physician (PI or CO-I) must obtain informed consent. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
A copy of the signed and dated ICF must be given to the subject or the subject’s legally 
authorized representative.   Confirmation of a subject’s informed consent must also be 
documented in the subject’s research record prior to any testing under this protocol, including 
screening tests and assessments. 
The signed ICF will be retained with the study records.  Local regulations must be complied with 
in respect to the final disposition of the original (wet signature) and copies of the signed and 
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14.3. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., PHI authorization in North 
America). 
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Ethics committees and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the subject’s 
personal medical data confidential. 
14.4. 
Compensation for Injury 
The Principal Investigator must maintain appropriate insurance coverage for clinical trials and 
follow applicable local compensation laws. 
14.5. 
Conflict of Interest 
Throughout the course of the study, any real or perceived COI will be discussed at all monitoring 
meetings.  If applicable, potential COI’s will be reported to the HRPO COI office as soon as they 
are discovered.  Any potential conflicts of interest will be disclosed to the potential participant 
before the subject makes a decision to participate in the study.  If any new COI concerns occur 
during the course of the study, they will be fully disclosed to all participants.  
14.6. 
Registration of Study and Disclosure of Study Results 
The Principal Investigator will register the study and post study results regardless of outcome on 
a publicly accessible website in accordance with the applicable laws and regulations (i.e. 
Clinicaltrials.gov, PubMed) 
 


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15. 
ADMINISTRATIVE PROCEDURES 
15.1. 
Study Site Initiation 
Investigators must not screen or enroll any subjects into the study prior to all prerequisite study 
document completion and agreement by the Principal Investigator and Biogen. 
15.2. 
Study Funding 
This study is funded by NIAMS. Biogen will be supplying the drug/placebo. All financial details 
are provided in the separate contract(s) between NIAMS, the institution, Principal Investigator, 
and Biogen.   
15.3. 
Study Completion 
Participant notification: The Principal Investigator and study staff will send a letter to all 
participants to thank them for their participation and to notify them that the study is over, inform 
them of the treatment group they were in during the first 3 months and we will ask whether they 
would like to be informed of the results. This will be by return postcard and upon publication of 
the findings the participants will be sent a lay summary and the abstract from the publication. 
Close-out activities  
• 
Verification that study procedures have been completed, data have been collected, 
and study intervention(s) and supplies are returned to the pharmacist and discarded as per 
guidance from Biogen. 
• 
Completion of all data queries 
• 
Correspondence and study files will be stored and accessible for external audits 
• 
Study records will all be maintained at each participating site. 
• 
All IRBs will be notified of the study’s completion 
• 
Preparation of a final report for the DSMB and NIAMS 
All records will be maintained at each participating site for 3 years per NIH guidelines for a 
grant-funded study. 
The ethics committee must be notified of completion or termination of the protocol.  Within 3 
months of protocol completion or termination, the investigator must provide a final clinical 
summary report to the ethics committee.  The Principal Investigator will maintain an accurate 
and complete record of all submissions made to the ethics committee, including a list of all 
reports and documents submitted.   
 
15.4. 
Publications 
Details are included in the clinical trial agreement for this study. 


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16. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
16.1.1. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs by RDMS 
developed and supported by University of Pittsburgh, Arthritis and Autoimmunity Center. 
16.1.2. 
Local Laboratories for Laboratory Assessments 
Local laboratories for each site will analyze all hematology, blood chemistry, urine samples 
collected for safety laboratory assessments for this study. 
16.2. 
Data Safety Monitoring Board  
The NIAMS will appoint a 4-5 member Data and Safety Monitoring Board (DSMB). The board 
acts in an advisory capacity to the National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS), National Institutes of Health (NIH) to review participant safety and progress. 
Routine meetings of the DSMB are generally held two times a year (or at other intervals 
determined by the DSMB), in-person or via conference call. To maintain the independent nature 
of the DSMB, the PI and study staff should only communicate DSMB-related requests, questions 
or concerns through the NIAMS or KAI Research the Executive Secretary (ES). The DSMB 
members should only communicate with the PI through the ES and the NIAMS 
16.3. 
Changes to Final Study Protocol 
All protocol amendments must be submitted to the ethics committee and Regulatory Authorities 
as required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
In the event of a protocol modification, the subject consent form may require similar 
modifications (see Sections 14.1 and 14.2). 
It is the responsibility of the Principal Investigator to submit all revisions to the protocol to 
Biogen before submitting to their ethics committee. 
16.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
16.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.   
 


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Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial 
dysfunction in pulmonary arterial hypertension. American journal of respiratory and critical care 
medicine 2013;188:639-46. 
31. 
Tabima DM, Frizzell S, Gladwin MT. Reactive oxygen and nitrogen species in 
pulmonary hypertension. Free radical biology & medicine 2012;52:1970-86. 


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Associated Pulmonary Arterial Hypertension 
 
 
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32. 
El Kasmi KC, Pugliese SC, Riddle SR, et al. Adventitial fibroblasts induce a distinct 
proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. Journal of 
immunology 2014;193:597-609. 
33. 
Hulsmans M, Holvoet P. The vicious circle between oxidative stress and inflammation in 
atherosclerosis. J Cell Mol Med 2010;14:70-8. 
34. 
Pober JS, Min W, Bradley JR. Mechanisms of endothelial dysfunction, injury, and death. 
Annu Rev Pathol 2009;4:71-95. 
35. 
de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and 
stage 4 chronic kidney disease. The New England journal of medicine 2013;369:2492-503. 
36. 
To C, Ringelberg CS, Royce DB, et al. Dimethyl fumarate and the oleanane triterpenoids, 
CDDO-imidazolide and CDDO-methyl ester, both activate the Nrf2 pathway but have opposite 
effects in the A/J model of lung carcinogenesis. Carcinogenesis 2015;36:769-81. 
37. 
Pendergrass SA, Hayes E, Farina G, et al. Limited systemic sclerosis patients with 
pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS 
One 2010;5:e12106. 
38. 
Lenna S, Farina AG, Martyanov V, et al. Increased expression of endoplasmic reticulum 
stress and unfolded protein response genes in peripheral blood mononuclear cells from patients 
with limited cutaneous systemic sclerosis and pulmonary arterial hypertension. Arthritis and 
rheumatism 2013;65:1357-66. 
39. 
Christmann RB, Hayes E, Pendergrass S, et al. Interferon and alternative activation of 
monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension. 
Arthritis and rheumatism 2011;63:1718-28. 
40. 
Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. 
American journal of respiratory and critical care medicine 2002;166:111-7. 
41. 
Amjadi S MP, Furst DE, et al. . Course of the modified Rodnan skin thickness score in 
systemic sclerosis clinical trials: Analysis of three large multicenter, double-blind, randomized 
controlled trials. Arthritis and rheumatism 2009;60:2490-8. 
42. 
Khanna D, Merkel PA. Outcome measures in systemic sclerosis: an update on 
instruments and current research. Curr Rheumatol Rep 2007;9:151-7. 
43. 
Khanna D, Clements PJ, Furst DE, et al. Recombinant human relaxin in the treatment of 
systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-
controlled trial. Arthritis and rheumatism 2009;60:1102-11. 
44. 
Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth 
factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-
controlled phase I/II trial of CAT-192. Arthritis Rheum 2007;56:323-33. 
45. 
Khanna D, Distler O, Avouac J, et al. Measures of response in clinical trials of systemic 
sclerosis: the Combined Response Index for Systemic Sclerosis (CRISS) and Outcome Measures 
in Pulmonary Arterial Hypertension related to Systemic Sclerosis (EPOSS). J Rheumatol 
2009;36:2356-61. 
46. 
Cracowski JL, Minson CT, Salvat-Melis M, Halliwill JR. Methodological issues in the 
assessment of skin microvascular endothelial function in humans. Trends Pharmacol Sci 
2006;27:503-8. 
47. 
Mahe G, Durand S, Humeau-Heurtier A, Leftheriotis G, Abraham P. Impact of 
experimental conditions on noncontact laser recordings in microvascular studies. 
Microcirculation 2012;19:669-75. 


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48. 
Merkel PA, Herlyn K, Martin RW, et al. Measuring disease activity and functional status 
in patients with scleroderma and Raynaud's phenomenon. Arthritis and rheumatism 
2002;46:2410-20. 
49. 
Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a 
pilot randomised trial to minimise the overall trial sample size for the external pilot and main 
trial for a continuous outcome variable. Statistical methods in medical research 2015. 
50. 
Trivellore E. Raghunathan James ML, John Van Hoewyk, Solenberger aP. 
A Multivariate Technique for Multiply Imputing Missing Values  
Using a Sequence of Regression Models Survey Methodology 2001;27:85-95. 
 
 

ICF_001.pdf: 
 
 
                                                                          Page 1 of 14                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
   
CONSENT TO ACT AS A SUBJECT IN A RESEARCH STUDY 
 
TITLE:   DIMETHYL FUMARATE, TECFIDERA, IN PULMONARY ARTERIAL HYPERTENSION 
ASSOCIATED WITH SYSTEMIC SCLEROSIS   
 
 
        
PRINCIPAL INVESTIGATOR: 
Robert Lafyatis, MD 
Professor of Medicine 
Thomas Medsger Professor in Arthritis Research 
Division of Rheumatology and Clinical Immunology 
University of Pittsburgh 
7 South BST, 200 Lothrop Street 
Pittsburgh, PA 15261 
Phone:  412-647-6700 (24 hours) 
 
STUDY COORDINATOR: 
Kristi Kong 
University of Pittsburgh School of Medicine 
Division of Rheumatology and Clinical 
Immunology 
S726 BST, 200 Lothrop Street 
Pittsburgh, PA  15261 
412-648-7040 
 
Maureen Laffoon, BS 
University of Pittsburgh School of Medicine 
Division of Rheumatology and Clinical 
Immunology 
S726 BST, 200 Lothrop Street 
Pittsburgh, PA  15261 
412-648-7871 
 
Source of support:  
National Institutes of Health 
Biogen Idec Corporation will be providing study drug only 
 
Background 
This consent form describes a research study to test whether a drug known as Tecfidera is safe to 
use in systemic sclerosis (also known as scleroderma) patients. Tecfidera is manufactured by Biogen 
Idec Corporation and is currently FDA approved for multiple sclerosis, an inflammatory disease of the 
brain. Its use remains experimental in the treatment of systemic sclerosis. 
You have been asked to participate because you have pulmonary arterial hypertension associated 
with systemic sclerosis. We would like to find out if Tecfidera is safe and helps pulmonary arterial 
hypertension in people who have systemic sclerosis. 
Please read the information carefully. If you have questions please ask the investigator or study staff 
to explain and answer them until you feel completely informed. 
Your doctor may be an investigator of this research study. As an investigator, your doctor is 
interested both in your clinical welfare and in the conduct of this study. Before entering this study or at 
any time during the research, you may want to ask for a second opinion about your care from another 
doctor who is not an investigator in this study. You do not have to participate in any research study 
 
 
University of Pittsburgh 
Department of Medicine 
Division of Rheumatology and Clinical Immunology  
 


 
 
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   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
offered by your doctor. 
Systemic sclerosis is a disease that affects major organs like the skin, lungs, kidneys, and 
gastrointestinal tract. It can also affect your joints, muscles, heart, and blood vessels. Systemic 
sclerosis causes development of excessive connective tissue in the organs. Systemic sclerosis also 
injures blood vessels, leading to pulmonary arterial hypertension. 
Tecfidera is an investigational drug that reduces the activity of chemicals in your body that are 
triggered by inflammation. This process is called oxidative stress. Oxidative stress is increased with 
pulmonary arterial hypertension associated with systemic sclerosis. However, at this time we do not 
know whether Tecfidera will have any effect on pulmonary arterial hypertension associated with 
systemic sclerosis. 
Biomarkers are proteins in your samples that we can look at from one point in time to the next to see 
if there is any change in your disease. Biomarkers are being investigated as part of the study. We will 
measure these from blood samples that you will provide at study visits. 
You are being asked to participate in this study because you have been diagnosed with systemic 
sclerosis and your cardiac catheterization results meet the criteria for pulmonary hypertension. The 
Principal Investigator of this study is Robert Lafyatis, MD. 
 
Purpose 
This is a Phase 1b, double-blinded, placebo-controlled pilot study of Tecfidera in pulmonary arterial 
hypertension (PAH) associated with systemic sclerosis (SSc-PAH): The effect of DMF on clinical 
disease and biomarkers of oxidative stress. The study is designed to see if Tecfidera is safe and 
whether it is associated with any improvement in 6-minute walk test in people with pulmonary arterial 
hypertension associated with systemic sclerosis. It is also designed to see if the drug causes any 
changes in biomarkers in patients with pulmonary arterial hypertension associated with systemic 
sclerosis that reflect the level of disease activity and oxidative stress.  
 
What Happens In This Research Study 
You will be one of approximately 34 subjects recruited from approximately 5 centers in the United 
States.  Subjects recruited from the University of Pittsburgh will have all of the research procedures 
performed for this study at the University of Pittsburgh Medical Center (UPMC) in the Arthritis and 
Autoimmune Center.  
After the Screening Visit, subjects agreeing to participate in this study will be randomly selected to 
receive either Tecfidera or a placebo. There is a 50% chance that you will be randomly assigned (by 
chance, like with the flip of a coin) to receive Tecfidera and a 50% chance that you will receive 
placebo. One half of subjects will receive Tecfidera and one half of subjects the placebo. Tecfidera or 
placebo will be given to you as a pill to be taken twice a day. Tecfidera or placebo comes in pill form 
and will be provided to you by the study.  The first week of the study you will receive 120mg Tecfidera 
tablets or similar appearing placebo tablets to be taken one tablet per night for the first 7 days. After 
the first week you will receive one 120mg tablet in the morning and one tablet at night for the next 2 
weeks. At the start of week 4, you will be asked to increase dosing to one tablet in the morning and 
two at night. The final dosing increase will occur at the start of week 8, with two tablets in the morning 
and two at night. A minimum daily dosing of one tablet in the morning and one tablet at night must be 
tolerated by the start of week 8. Tecfidera or placebo should be taken with high-fat, high-protein food 
to reduce the incidence of side effects. 


 
 
                                                                          Page 3 of 14                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
Screening Visit: You will be asked to sign consent before any screening procedures can be performed. 
Demographic information will be taken. New York Heart Association (NYHA) Functional Classification: 
A table that doctors classify patients' heart failure according to the severity of their symptoms the 
(NYHA) Functional Classification. A complete history and physical examination, including vital signs, a 
skin score and digital ulcer assessment will be performed. You will be asked to perform a Six Minute 
Walk test (6MWT) a test to measure the distance you can walk in 6 minutes. Safety laboratory testing 
will include a complete blood count with differential (CBC), comprehensive metabolic panel (CMP), 
Brain Natriuretic Peptide (BNP), urinalysis, a pregnancy test (for women of child-bearing potential) to 
confirm that you are not pregnant, and HIV and HCV/HBV serology. This is for safety evaluation. Blood 
will be drawn for storage and future analyses. About 4 tablespoons of blood will be drawn at this visit.  
 
After the screening visit test results are known, you will be advised of your eligibility to participate.  You 
may be deemed ineligible for the study for reasons including, but not limited to a positive pregnancy 
test, positive for Hepatitis B or C, or positive for HIV. If you agree to participate in this study your blood 
is tested for Human Immunodeficiency Virus (HIV), the virus which causes AIDS.  If your test results 
are positive, you cannot participate in the study. Your HIV test result is given to you in person, not over 
the phone.  Your medical records are kept confidential to the extent permitted by law. If you have any 
questions regarding the HIV testing or the information provided above, you are encouraged to discuss 
them with your study doctor. Positive HIV tests are to be reported to the Allegheny County Health 
Department  
 
Study Visit 1 (Day 0): After all screening evaluations have been completed (within 4 weeks of 
laboratory tests), you will be scheduled for the first study visit in the UPMC Arthritis and Autoimmune 
Center. On this visit, inclusion and exclusion criteria will be reviewed.  
• Questionnaires will be given including Scleroderma Health Assessment Questionnaire (SHAQ), 
Raynauds VAS, Systemic Sclerosis Skin Questionnaire,  
• Interim history (including safety reporting and medication review) will be taken 
• Physical examination including vital signs, a skin score and digital ulcer assessment will be 
performed.  
• New York Heart Association (NYHA) Functional Classification: A table that doctors classify 
patients' heart failure according to the severity of their symptoms the (NYHA) Functional 
Classification. 
• You will be asked to perform a Six Minute Walk test (6MWT) a test to measure the distance you 
can walk in 6 minutes.  
• Safety laboratory testing will include a complete blood count with differential (CBC), 
comprehensive metabolic panel (CMP), B-Type Natriuretic Peptide (BNP), and urinalysis. 
Research blood will be drawn for storage and future analyses. Women of child-bearing potential 
(WOCBP) will have a urine pregnancy test performed prior to study treatment. About 4 
tablespoons of blood will be drawn.  
• Skin biopsies are taken using a tiny circular blade (punch biopsy) on the skin of your forearm. 
One 3-millimeter (mm) punch biopsy will be collected, removing a small cylinder of skin.  For all 
biopsies, the skin is injected with a local anesthetic (lidocaine) to numb the area to minimize pain 
and discomfort. Each skin punch site will be closed with steri-strips and a pressure dressing. 
The wounds usually heal in 7-10 days and during that time you may feel some mild discomfort.  
If needed, an over the counter pain reliever may be recommended by your study doctor. The 


 
 
                                                                          Page 4 of 14                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
skin biopsy procedure should take approximately 30 minutes to perform.  It is very important for 
you to tell the doctor if you have ever had a reaction to local anesthetics in the past.    
• You will then be given study medication, Tecfidera or placebo tablets. 
 
Day 7 Telephone Call: The study coordinator will call you on the telephone to assess any side effects 
and to confirm that you will increase to the higher study medication dose of two tablets daily (one in the 
morning and one at night).  
 
Day 28 Telephone Call: The study coordinator will call you on the telephone to assess any side 
effects. You will be scheduled for an evaluation in the UPMC Arthritis and Autoimmune Center before 
being given any more study treatment if the study-physician believes any reported side effects are 
unexpected or serious. 
 
 
Study Visit 2 (week 8): You will return to the UPMC Arthritis and Autoimmune Center.  
• Questionnaires will be given including Scleroderma Health Assessment Questionnaire 
(SHAQ), Raynauds VAS, Systemic Sclerosis Skin Questionnaire,  
• Interim history (including safety reporting and medication review) will be taken 
• Physical examination including vital signs, a skin score and digital ulcer assessment will be 
performed. 
• New York Heart Association (NYHA) Functional Classification: A table that doctors classify 
patients' heart failure according to the severity of their symptoms the (NYHA) Functional 
Classification.  
• You will be asked to perform a Six Minute Walk test (6MWT) a test to measure the distance 
you can walk in 6 minutes.  
• Safety laboratory testing will include a complete blood count with differential (CBC), 
comprehensive metabolic panel (CMP), B-Type Natriuretic Peptide (BNP), and urinalysis. 
Women of child-bearing potential (WOCBP) will have a urine pregnancy test performed prior to 
study treatment. About 4 tablespoons of blood will be drawn. 
 
Study Visit 3 (week 16): You will return to the UPMC Arthritis and Autoimmune Center. 
•  Questionnaires will be given including Scleroderma Health Assessment Questionnaire 
(SHAQ), Raynauds VAS, Systemic Sclerosis Skin Questionnaire,  
• Interim history (including safety reporting and medication review) will be taken 
• Physical examination including vital signs, a skin score and digital ulcer assessment will be 
performed.  
• New York Heart Association (NYHA) Functional Classification: A table that doctors classify 
patients' heart failure according to the severity of their symptoms the (NYHA) Functional 
Classification. 
• You will be asked to perform a Six Minute Walk test (6MWT) a test to measure the distance 
you can walk in 6 minutes.  


 
 
                                                                          Page 5 of 14                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
• Safety laboratory testing will include a complete blood count with differential (CBC), 
comprehensive metabolic panel (CMP), B-Type Natriuretic Peptide (BNP), and urinalysis. 
Research blood will be drawn for storage and future analyses. Women of child-bearing 
potential (WOCBP) will have a urine pregnancy test performed prior to study treatment. About 
4 tablespoons of blood will be drawn. 
Study Visit 4 (week 24): You will return to the UPMC Arthritis and Autoimmune Center. 
• Questionnaires will be given including Scleroderma Health Assessment Questionnaire 
(SHAQ), Raynauds VAS, Systemic Sclerosis Skin Questionnaire,  
• Interim history (including safety reporting and medication review) will be taken 
• Physical examination including vital signs, a skin score and digital ulcer assessment will be 
performed.  
• New York Heart Association (NYHA) Functional Classification: A table that doctors classify 
patients' heart failure according to the severity of their symptoms the (NYHA) Functional 
Classification. 
• You will be asked to perform a Six Minute Walk test (6MWT) a test to measure the distance 
you can walk in 6 minutes.  
• Safety laboratory testing will include a complete blood count with differential (CBC), 
comprehensive metabolic panel (CMP), B-Type Natriuretic Peptide (BNP), and urinalysis. 
Research blood will be drawn for storage and future analyses. Women of child-bearing 
potential (WOCBP) will have a urine pregnancy test performed prior to study treatment. About 
4 tablespoons of blood will be drawn. 
• Skin biopsies are taken using a tiny circular blade (punch biopsy) on the skin of your forearm. 
One 3-millimeter (mm) punch biopsy will be collected, removing a small cylinder of skin.  For all 
biopsies the skin is injected with a local anesthetic (lidocaine) to numb the area to minimize pain 
and discomfort. Each skin punch site will be closed with steri-strips and a pressure dressing. 
The wounds usually heal in 7-10 days and during that time you may feel some mild discomfort.  
If needed, an over the counter pain reliever may be recommended by your study doctor. The 
skin biopsy procedure should take approximately 30 minutes to perform.  It is very important for 
you to tell the doctor if you have ever had a reaction to local anesthetics in the past.    
 
Study Visit 5 (week 36): You will return to the UPMC Arthritis and Autoimmune Center.  
Questionnaires will be given including Scleroderma Health Assessment Questionnaire (SHAQ), 
Raynauds VAS, Systemic Sclerosis Skin Questionnaire,  
• Interim history (including safety reporting and medication review) will be taken 
• Physical examination including vital signs, a skin score and digital ulcer assessment will be 
performed.  
• New York Heart Association (NYHA) Functional Classification: A table that doctors classify 
patients' heart failure according to the severity of their symptoms the (NYHA) Functional 
Classification. 
• You will be asked to perform a Six Minute Walk test (6MWT) a test to measure the distance 
you can walk in 6 minutes.  


 
 
                                                                          Page 6 of 14                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
• Safety laboratory testing will include a complete blood count with differential (CBC), 
comprehensive metabolic panel (CMP), B-Type Natriuretic Peptide (BNP), and urinalysis. 
Research blood will be drawn for storage and future analyses. Women of child-bearing 
potential (WOCBP) will have a urine pregnancy test performed prior to study treatment. About 
4 tablespoons of blood will be drawn. 
The study coordinator will collect the leftover medicine vials at your study visits 2 and 3 when new 
study medication is dispensed. Details about how the study treatment will be monitored will be 
explained in detail by the study coordinator. 
 
Risks and Discomforts 
 
Tecfidera: 
Tecfidera can cause allergic reactions after the first dose or at any time during treatment. Symptoms 
of an allergic reaction while taking Tecfidera are: rash, flushing, itching and trouble breathing. When 
you come to the UPMC Arthritis and Autoimmune Center for your first dose of study treatment, you 
will be observed for 30 minutes afterward to make sure you do not develop these symptoms, 
sometimes requiring treatment.  
Tecfidera can cause nausea, vomiting, diarrhea, abdominal pain, and dyspepsia in about 1 in 10 
people. These symptoms usually decrease over time. Serious gastrointestinal events have been seen 
in about 1 in 100 people taking Tecfidera. You should seek immediate medical care if you develop 
any serious gastrointestinal problems.   
Tecfidera frequently causes flushing (in about 4 in 10 patients treated with Tecfidera). This generally 
starts soon after you first start taking Tecfidera and usually improves or resolves over time.  
Tecfidera may affect your white blood cell counts, causing a decrease in one type of your white blood 
cells called lymphocytes (in about 6 in 100 patients). Your white blood cell counts will be monitored 
during the trial.  If your lymphocyte count becomes very low you will be stopped from taking 
Tecfidera. 
In one case a patient who had been taking Tecfidera for 4 years and had very low lymphocyte counts 
died from an infection in the brain called progressive multifocal leukoencephalopathy.  
We do not know the effect of Tecfidera on pregnant women, so if you are a woman of child bearing 
potential, you will be asked to carefully use birth control during the trial and you will have 
a pregnancy test on each study visit.  
 
Other Pulmonary Hypertension Therapy: While the study drug is Tecfidera, you will continue taking 
any other PAH medications at the doses on which you entered the study. These medications may 
include prostacyclins (epoprostenol, Flolan®), endothelin receptor antagonists (bosentan, Tracleer®), 
and/or phosphodiesterase inhibitors (sildenafil, Revatio®, Viagra®). There are no known drug 
interactions with Tecfidera and other PAH medications and none are anticipated. While the physician 
should have reviewed the side effects of these drugs with you prior to starting them, it is important to 
emphasize a few points here.  
Epoprostenol (prostacyclin) may result in significant hypotension (low blood pressure), and combining 
it with other drugs that could lower the blood pressure (diuretics, anti-hypertensives) may enhance 


 
 
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     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
this effect. It should never be stopped abruptly as this could result in rebound hypertension (high 
blood pressure). There is the potential for epoprostanol to increase bleeding in individuals on anti-
platelet drugs or anticoagulants (blood thinners). Other side effects reported with this drug include 
nausea, vomiting, headache, hypotension, and flushing.  
Endothelin receptor antagonists have the potential to cause liver injury. They may also result in 
anemia. It is recommended that liver function tests be checked monthly and blood counts 
(hemoglobin) be checked every 3 months, which can be done with a simple blood test.  
Bosentan or ambrisentan can also cause damage to a fetus, and use of a hormonal contraceptive to 
prevent pregnancy with these drugs may be ineffective. There are also potential drug interactions with 
drugs including ketoconazole, rifampicin, statins to treat high cholesterol, and blood thinners.  
The phosphodiesterase inhibitors (sildenafil) may have side effects including nose bleed, headache, 
stomach upset, flushing, insomnia, and muscle aches. There have been rare reports of visual and 
hearing disturbances or loss at higher doses. If you notice any sudden decrease or loss in hearing or 
vision it is important that you seek immediate medical treatment. There is a serious drug interaction 
with a class of drugs called nitrates. Taking both sildenafil and nitrates at the same time should be 
avoided due to the risk of serious hypotension (low blood pressure). If you are prescribed a new 
medication for any reason, including an antibiotic for an infection, it is critical that you first contact the 
physician treating the SSc-PAH to discuss any potential drug effects before starting the new 
medicine. 
 
Six Minute Walk Test: 
 
During this study you will be asked to perform a six minute walk test.  There is a chance of falling 
during your walk test; a trained member of the research team will also closely supervise the subject 
when the test is performed 
 
Blood Draw:    
 
During this study you will have samples of your blood taken. Blood samples are obtained by inserting 
a needle into a vein and can cause discomfort and may result in bruising, clotting, or, rarely, infection. 
Both discomfort and bruising should disappear in a few days. Common side effects of blood draw 
(occurring in less than 25% or less than 25 out of 100 people) include:  temporary discomfort from the 
needle stick, bruising, inflammation, bleeding, and lightheadedness.  Rare side effects (occurring in 
less than 1%, or 1 out of 100 people) include: fainting, infection at the site of the blood draw, and 
spasm with loss of blood flow.  Blood will be drawn by trained persons and sterile technique will be 
used to minimize the risk of infection. 
 
HIV Serology 
 
During this study you will have samples of your blood taken to confirm your HIV status.  Blood 
samples are obtained by inserting a needle into a vein and can cause discomfort and may result in 
bruising, clotting, or, rarely, infection. Both discomfort and bruising should disappear in a few days. 
Common side effects of blood draw (occurring in less than 25% or less than 25 out of 100 people) 
include:  temporary discomfort from the needle stick, bruising, inflammation, bleeding, and 
lightheadedness.  Rare side effects (occurring in less than 1%, or 1 out of 100 people) include: 


 
 
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     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
fainting, infection at the site of the blood draw, and spasm with loss of blood flow.  Blood will be drawn 
by trained persons and sterile technique will be used to minimize the risk of infection. 
 
Learning that you tested positive for HIV can be overwhelming and stressful. You may become 
depressed and anxious. In the event that you test positive, you will be referred to receive HIV 
counseling services. 
 
Risk of Confidentiality Breach: 
There is a risk that your confidentiality may be breached. The investigator and the study staff will take 
measures to minimize this risk. Your data will be given a unique study number. The investigator will 
keep a logbook that matches the study number to you. This logbook and your data will be kept in a 
secure, locked area where access is limited to the investigator and the study staff. 
With your consent, the blood you provide for storage will be kept in a freezer that is located in an area 
where access is limited to the investigator and the study staff. These samples may be analyzed in 
future studies that may be related to systemic sclerosis. You will not be consented for future use of 
these samples or data collected for the study. In an effort to minimize breach of your confidential 
information, these samples will be given a unique study number and will not contain any direct 
identifiers like your name. The investigator will keep a log that matches the study number to you. This 
log will be kept in a secure, locked area where access is limited to the investigator and the study staff.  
 
Physical Examination: 
During the study the PI will be performing a physical exam at each visit including a skin score and 
digital ulcer assessment.  There are no physical risks in the examination. 
 
Questionnaires: 
During the study you will be asked to complete questionnaires.  There could be a risk of breaching 
confidentiality. Subjects may experience embarrassment or increased depression from questions that 
are asked.  
 
Skin Biopsy: 
The most serious possible risk involved with having a skin biopsy would be an allergic reaction to the 
local anesthetic, lidocaine.  Allergic reactions to lidocaine are rare (less than 1% of cases or less than 
1 out of 100 people).  A severe allergic reaction can be life-threatening.  A less severe allergic 
reaction may cause a rash, hives, or swelling at the injection site.   Please inform the researchers if 
you know that you are allergic to any medication, especially local anesthetics such as lidocaine. 
Side effects of a local injection of lidocaine into the skin are also rare (less than 1% of people or 1 of 
every 100).  It is possible that a small amount of the medication may seep into the blood causing mild 
side effects in some people.  Side effects of lidocaine are related to the amount of the medication in 
the blood.  With high levels of lidocaine in the blood, a person may experience nervousness, 
seizures, sleepiness, irregular or slow heartbeat, high or low blood pressure, blurred vision, ringing in 
the ears, nausea or vomiting. 
The risk of infection from the skin biopsy is also rare.  The signs of infection are increased redness, 


 
 
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     Institutional Review Board    
 
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swelling, pain, or drainage at the biopsy site.  Rarely, a patient will experience a small amount of 
bleeding and may require a pressure dressing. 
It is common (1-25 % of people, or 1 to 25 of 100 people) for patients to experience some discomfort 
at the site of the biopsy, after the local anesthetic wears off.  It is also common for the biopsy to leave 
a small scar.  Scarring is minimized by taking three or four smaller side-by-side samples instead of a 
single larger sample of skin.   
 
Randomization: 
There are no risks involved with randomization. The study drug/placebo is not taking the place of the 
subject's SOC treatments.  
 
Pregnancy: 
If you become pregnant while you are participating in this study, it could be dangerous for the baby. 
Women who are able to become pregnant will be monitored with frequent pregnancy tests throughout 
the study. You must use birth control if you are a woman having sex with men while you are 
participating in this study and for three months afterward. You must agree to use two acceptable 
methods of birth control throughout the study." (i.e. hormonal methods, barrier and mechanical 
methods, bilateral tubal occlusion, vasectomised partner, true abstinence). You should not participate 
in this study if you are a woman who has sex with men and cannot use one of these birth control 
methods. 
 
The effects of Tecfidera on male fertility are unknown.    
 
As with any experimental procedure, there may be adverse events or side effects that are currently 
unknown and certain of these unknown risks could be permanent, severe or life-threatening and 
these particular treatments or procedure may involve risks to you (or to the embryo or fetus, if you are 
or become pregnant), which are currently unforeseeable. Study staff will update you in a timely way 
on any new information that may affect your health, welfare, or decision to stay in this study. 
 
Benefits 
It is not known whether participation in this study will have any beneficial effect on your disease.  The 
symptoms of your disease may improve, stay the same, or worsen during the course of the study.  The 
information collected during this study will help the doctors and researchers to learn more about the 
study drug that may benefit you and other people with SSc.  However, there is no guarantee that this 
will happen. 
 
Alternatives 
The following alternative procedures or treatments are available if you choose not to participate in this 
study: You do not have to participate in this study to receive treatment for your systemic sclerosis. 
Other treatments are available for managing the involvement of organ systems such as the lungs, 
kidneys, and gastrointestinal (gut) symptoms. Your doctor can prescribe medication that is 
appropriate for you. Your study doctor will discuss with you the risks and benefits of alternative 
treatments.  


 
 
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     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
Subject Costs and Payments 
Some of the tests and procedures in this study are standard of care procedures and would be done 
anyway for someone with your illness. These tests and procedures will be billed to you or your 
insurance company. The PAH treatment you are taking are standard of care medications and will 
continue to be billed to your insurance company.  The study will cover the cost of the study drug.  You 
will not be billed for tests and procedures that are performed only because of your participation in this 
research. This will include all study medical evaluations and administration of the study medication.  
At each visit you will be paid $50 on a debit card as payment for your participation.  In addition, if you 
live more than 50 miles away, you will be offered reimbursement for mileage based on IRS regulations. 
There will be no financial charge for the medication. 
 
Subject's Rights 
By consenting to participate in this study you do not waive any of your legal rights. Giving consent 
means that you have heard or read the information about this study and that you agree to participate. 
You will be given a copy of this form to keep. If at any time you withdraw from this study, you will not 
suffer any penalty or lose any benefits to which you are entitled. The investigator or a member of the 
research team will try to answer all of your questions. If you have questions or concerns at any time, 
or if you need to report an injury while participating in this research, contact Dr. Robert Lafyatis at 
412-637-6700 (24-hour contact). 
 
Compensation for Research Related Injury  
If you believe that the research procedures have resulted in an injury to you, immediately contact the 
Principal Investigator who is listed on the first page of this form. Emergency medical treatment for 
injuries solely and directly related to your participation in this research study will be provided to you by 
the hospitals of UPMC. Your insurance provider will be billed for the costs of this emergency treatment, 
but none of those costs will be charged directly to you. If your research-related injury requires medical 
care beyond this emergency treatment, you will be responsible for the costs of this follow-up care. At 
this time, there is no plan for any additional financial compensation. There is no provision for free 
medical care or monetary compensation from the mechanistic study sponsor, the National Institutes of 
Health. 
 
Right to Refuse or Withdraw 
Taking part in this study is voluntary. You have the right to refuse to take part in this study. If you 
decide to be in the study and then change your mind, you can withdraw from the research. Your 
participation is completely up to you. Your decision will not affect your ability to get health care at this 
institution or payment for your health care. It will not affect your enrollment in any health plan or 
benefits you can get. If you choose to take part, you have the right to stop at any time. If you decide to 
withdraw from study participation after you have received the study drug, you should participate in 
additional monitoring follow-up procedures that are being conducted to measure the safety of the 
study drug If there are any new findings during the study that may affect whether you want to 
continue to take part, you will be told about them as soon as possible. The investigator may decide to 
discontinue your participation without your permission because he/she may decide that staying in the 
study will be bad for you There are many reasons why the researchers may need to end your 
participation in the study.  Some examples are: 
✓ The researcher believes that it is not in your best interest to stay in the study. 
✓ You become ineligible to participate (i.e. pregnancy). 


 
 
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     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
✓ Your condition changes and you need treatment that is not allowed while you are taking part in 
the study. 
✓ You do not follow instructions from the researchers. 
✓ The study is suspended or canceled. 
 
STORAGE OF SAMPLES 
 
There is no benefit to you from the storage and sharing of samples and the information learned from 
the research using them.  Your stored blood samples used in this research study may contribute to a 
new discovery or treatment.  In some instances, these discoveries or treatments may be of commercial 
value and may be sold, patented, or licensed by the investigators and the University of Pittsburgh for 
use in other research or the development of new products.  You will not retain any property rights nor 
will you share in any money that the investigators, the University of Pittsburgh, or their agents may 
realize. 
 
Protection of Subject Health Information 
You have certain rights related to your health information. These include the right to know who will get 
your health information and why they will get it. Although every reasonable effort has been taken to 
de-identify your research information, confidentiality cannot be guaranteed and it is possible that re-
identification of research data/samples may occur.  If you choose to be in this research study, we will 
get information about you as explained below.  
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. The researchers can use this Certificate to legally refuse to disclose information 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, for example, if there is a court subpoena. The researchers will use the Certificate to 
resist any demands for information that would identify you, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally‐funded projects or for information that 
must be disclosed in order to meet the requirements of the federal Food and Drug Administration 
(FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, then 
the researchers may not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not be used to prevent disclosure to state or local authorities of 
child abuse and neglect, or harm to self or others 
Health Information About You That Might Be Used or Given Out During This Research: 
• Information from your hospital or office health records at UPMC or elsewhere. This information 
is reasonably related to the conduct and oversight of the research study. If health information 
is needed from your doctors or hospitals outside of UPMC, you will be asked to give 
permission for these records to be sent to the researcher. The information will be coded and 


 
 
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     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
will not contain your name or other traditional identifying information like social security number 
or birthday. It would be very hard for anyone to tell to whom the data belongs. 
• New health information from tests, procedures, visits, interviews, or forms filled out as part of 
this research study. 
• Your HIV status 
• Medication list, date of birth, most recent history, most recent discharge summary, DNA, 
medical specimens, x-rays, imaging records, EKGs, echocardiograms, pulmonary function 
tests, cardiac catheterization, CT scans, and lab results. 
 
Why Your Health Information Might Be Used or Given Out To Others 
The reasons we might use or share your health information are: 
• To do the research described here 
• To make sure we do the research according to certain standard set by ethics, law, and 
quality groups 
• To create the unique code, we assign to your health information to prevent it from being 
linked to you by persons to whom we disclose it. 
• To conduct future research involving scleroderma and other rheumatic disorders. 
• To develop new medical, diagnostic or genetic tests, new drugs or other commercial 
products. 
 
People And Groups That May Use Or Give Out Your Health Information People Or Groups 
Within UPMC: 
• Researchers involved in this research study 
• The University of Pittsburgh Institutional Review Board that oversees this research 
 People or Groups Outside UPMC 
• People or groups that we hire to do certain work for us, such as data storage 
companies, or laboratories. 
• Federal and state agencies if they are required by law or involved in research oversight. 
Such agencies may include the U.S. Department of Health and Human Services, the 
Food and Drug Administration, the National Institutes of Health. 
• Organizations that make sure hospital standards are met 
• The sponsor(s) of the research study, and people or groups it hires to help them do the 
research - Other researchers, including commercial partners such as drug and health 
companies. 
• A group that oversees the research information and safety of this study 
• Government agencies in other countries 
• Other: 
Some people or groups who get your health information might not have to follow the same privacy 
rules that we follow. We share your health information only when we must. We ask anyone who gets 
it from us to protect your privacy. However, once the information leaves the University of Pittsburgh, 
we cannot promise that it will be kept private. In most cases any health data that is being given out to 
others is identified by a unique study number and not with your name.  So, although in some cases it 
is possible to link your name to the study data, this is not usually done. 
 
Time Period for Using or Giving Out Your Health Information 


 
 
                                                                          Page 13 of 14                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
This consent does not expire. Because research is an ongoing process, we cannot give you an exact 
date when we will either destroy or stop using or sharing your health information. University of 
Pittsburgh research record retention policy states that all research records must be maintained for a 
period of at least 7 years following final reporting or publication of a project. 
 
Privacy Rights 
• You have the right not to sign this form that allows us to use and give out your health 
information for research. If you don't sign this form, you can't be in the research. This is 
because we need to use the health information to do the research. 
• You have the right to withdraw your permission to use or share your health information in this 
research study. You have the right to revoke your authorization to participate in the study at 
any time by providing a written and dated notice of this decision to the principal investigator 
listed on the first page of this form. 
• If you withdraw your permission, you will not be able to take back information that has already 
been used or shared with others. This includes information used or shared to do this or other 
research studies or to be sure the research is safe and of high quality. 
• If you withdraw your permission, you cannot continue to be in the study. 
• You have the right to see and get a copy of your health information that is used or shared for 
research. However, you may only get this after the research is finished. To ask for this 
information, please contact the principal investigator listed on the first page of this form. 
 
If Research Results Are Published or Used To Teach Others 
The results of this research study may be published in a medical book or journal, or used to teach 
others. However, your name or other direct identifying information will not be used for these purposes 
without your specific permission. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
Specimen Banking Storage: 
In this study you will have blood drawn for routine labs. In this study you will also have blood samples 
collected to help tell how the study drug affects your disease. If you give permission below, part of 
your blood samples, and data collected may also be used for other studies pertaining to systemic 
sclerosis and other rheumatic disorders. You will not be consented again for future use regarding the 
samples and the data; all future studies will be reviewed by an ethics committee. You will also have 
blood drawn for routine labs. You have the right to withdraw consent at any time by writing to the 
investigators on the study, and we will destroy any unused samples and only keep information 
already analyzed. 
 
You may refuse to have your blood samples stored. If at any time you wish to withdraw your consent 
to store specimens, please inform the investigator or study staff. Your samples will then be destroyed. 
I consent to the storage of my samples and data for use in future research studies 
Yes __________ No _____________ (please initial beside your choice) 
 


 
 
                                                                          Page 14 of 14                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 5/20/2019 
Renewal Date:  9/17/2019 
 
IRB #:   PRO16070614 
 
 
************************************************************************************************************* 
 
 
 
Voluntary Consent: 
 
 
The above information has been explained to me and all of my current questions have been 
answered. I understand that I may always request that my questions, concerns or complaints be 
addressed by Dr. Robert Lafyatis. I understand that I may contact the Human Subjects Protection 
Advocate of the IRB Office, University of Pittsburgh (1-866-212-2668) to discuss problems, concerns, 
and questions; obtain information; offer input; or discuss situations that occurred during my 
participation.  
 
By signing this form, I consent to participate in this research study and provide my authorization to 
share my medical records with the research team. A copy of this consent form will be given to me. 
 
 
_____________________________________  
____________________________ 
Patient/Subject Signature  
 
 
 
Date 
 
 
____________________________________  
____________________________ 
Participant’s name (Printed) 
 
 
 
Time 
 
 
Certification of Informed Consent: 
 
I certify that I have explained the nature and purpose of this research study to the above-named 
individual(s), and I have discussed the potential benefits and possible risks of study participation. Any 
questions the individual(s) have about this study have been answered, and we will always be 
available to address future questions, concerns or complaints as they arise. I further certify that no 
research component of this protocol was begun until after this consent form was signed. 
 
 
_____________________________________  
____________________________ 
Printed Name of Person Obtaining Consent 
 
Role in Research Study 
 
 
____________________________________  
____________________________ 
Signature of Person Obtaining Consent  
 
Date / Time