Clinical trial NCT02161406
Conditions: Diffuse Cutaneous Systemic Sclerosis
Keywords: Scleroderma
Sponsor: Dinesh Khanna, MD, MS
Start date: 2014-09-01; Completion date: 2018-10-17
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study hypothesis is that SC abatacept is safe and shows evidence of efficacy (improvement in modified Rodnan score \[mRSS\]) in patients with diffuse cutaneous systemic sclerosis (dcScc) compared to matching placebo.

Detailed description:
This study is a randomized placebo-controlled double-blind phase 2 trial of patients with dcSSc. Eligible participants will be randomized in a 1:1 ratio to either 125 mg SC abatacept or matching placebo, stratified by duration of dcSSc disease duration (\<18 months vs \>18 to \</=36 months). Study participants will be treated for 12 months on double-blind study medication, followed by an additional 24 weeks of open-label SC abatacept therapy. 86 patients will be randomized in approximately 35 centers in the US, Canada and Europe, with the goal of analyzing 74 participants. The investigators study will test whether abatacept is statistically superior to placebo in reducing the MRSS at month 12 and explore the ability of abatacept to prevent or reverse progression in patients with early disease duration and lower MRSS scores, and reverse established disease in patients with longer disease duration and higher MRSS scores.

Arms: arm 1: 125 mg SC abatacept vs SC placebo administered weekly for 12 months, with a 24-week open-label extension arm 2: 125mg Placebo
Interventions: intervention 1: Abatacept intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will be treated with injections of 125 mg of abatacept or placebo weekly for 52 weeks intervention 2: 125 mg of Placebo

Protocol documents:
Prot_000.pdf: 
 
Abatacept Subcutaneous Formualtion ISR Protocol 
1 
8 December 2015 
 
 
 
 
 
A phase II study to evaluate subcutaneous abatacept vs. placebo in diffuse 
cutaneous systemic sclerosis—a double-blind, placebo-controlled, randomized 
controlled trial 
 
ASSET 
[IM101-344] 
 
Principal Investigator: 
Dinesh Khanna, MD, MS 
Associate Professor of Medicine 
Director, Scleroderma Program 
University of Michigan Rheumatology Division 
300 N. Ingalls building, Suite 7C27 
Ann Arbor, MI 48109-5422 
p.734-763-3182 
f.734-763-5761 
khannad@med.umich.edu 
 
 
Protocol Version 4.0 
December 8, 2015 


 
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8 December 2015 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION .........................................................................................................................................12 
1.1 
Summary of Results of Investigational Program ......................................................................................................... 13 
1.1.1 
Pharmacology of Abatacept .................................................................................................................................... 13 
1.1.2 
Human Pharmacokinetics of Abatacept .................................................................................................................. 13 
1.1.3 
Clinical Safety with Abatacept SC Formulation ..................................................................................................... 16 
1.1.4 
Drug-Related Adverse Events ................................................................................................................................ 19 
1.1.5 
Clinical Efficacy of Abatacept Subcutaneous Formulation .................................................................................... 20 
1.2 
Overall Risk/Benefit Assessment .................................................................................................................................. 21 
1.3 
Research Hypothesis ...................................................................................................................................................... 21 
1.4 
Study Rationale .............................................................................................................................................................. 22 
1.4.1 
Role of T cells in the pathogenesis of SSc .............................................................................................................. 22 
1.4.2 
ABA in SSc ............................................................................................................................................................ 23 
1.4.3 
Pilot study ............................................................................................................................................................... 24 
2 
STUDY OBJECTIVES..................................................................................................................................25 
2.1 
Primary Objectives ........................................................................................................................................................ 25 
2.2 
Secondary Objectives ..................................................................................................................................................... 25 
2.3 
Exploratory Objectives .................................................................................................................................................. 26 
3 
ETHICAL CONSIDERATIONS ..................................................................................................................26 
3.1 
Good Clinical Practice ................................................................................................................................................... 26 
3.2 
Institutional Review Board/Independent Ethics Committee ...................................................................................... 27 
3.3 
Informed Consent ........................................................................................................................................................... 27 
3.4 
Confidentiality ................................................................................................................................................................ 27 
4 
INVESTIGATIONAL PLAN .......................................................................................................................27 
4.1 
Study Design and Duration ........................................................................................................................................... 27 
4.2 
Study Population ............................................................................................................................................................ 29 
4.2.1 
Inclusion Criteria .................................................................................................................................................... 29 
4.2.2 
Exclusion Criteria ................................................................................................................................................... 30 
4.2.3 
Reproductive Status ................................................................................................................................................ 32 
4.2.4 
Discontinuation of Subjects from Treatment .......................................................................................................... 33 
5 
TREATMENTS .............................................................................................................................................34 
5.1 
Study Treatment ............................................................................................................................................................. 34 
5.1.1 
Identification ........................................................................................................................................................... 34 
5.1.2 
Handling and Dispensing ........................................................................................................................................ 35 
5.2 
Drug Ordering and Accountability ............................................................................................................................... 35 
5.2.1 
Initial Orders ........................................................................................................................................................... 35 
5.2.2 
Re-Supply ............................................................................................................................................................... 35 
5.3 
Method of Assigning Subjects to a Treatment ............................................................................................................. 35 
5.4 
Selection and Timing of Dose for Each Subject ........................................................................................................... 36 


 
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5.5 
Blinding/Unblinding ....................................................................................................................................................... 36 
5.6 
Concomitant Treatments ............................................................................................................................................... 36 
5.6.1 
Prohibited and/or Restricted Treatments ................................................................................................................ 36 
5.6.2 
Other Restrictions and Precautions ......................................................................................................................... 37 
5.7 
Treatment Compliance .................................................................................................................................................. 37 
6 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................................37 
6.1 
Study Outcome Assessments ......................................................................................................................................... 37 
6.2 
Schedule of Evaluations ................................................................................................................................................. 40 
6.3 
Safety Assessments ......................................................................................................................................................... 43 
6.4 
Efficacy Assessments ...................................................................................................................................................... 43 
6.4.1 
Primary Efficacy Assessments ................................................................................................................................ 43 
6.4.2 
Secondary Efficacy Assessments ............................................................................................................................ 43 
6.4.3 
Exploratory Efficacy Assessments ......................................................................................................................... 45 
7 
ADVERSE EVENT REPORTING ..............................................................................................................46 
7.1 
Adverse Events ............................................................................................................................................................... 46 
7.1.1 
Serious Adverse Events .......................................................................................................................................... 46 
7.1.2 
Non-serious Adverse Events ................................................................................................................................... 47 
7.1.3 
Assignment of Adverse Event Intensity and Relationship to Abatacept................................................................. 47 
7.2 
Collection and Reporting ............................................................................................................................................... 48 
7.2.1 
Serious Adverse Event Collecting and Reporting ................................................................................................... 48 
7.2.2 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting ......................................................................... 48 
7.3 
Laboratory Test Abnormalities .................................................................................................................................... 49 
7.4 
Overdose ......................................................................................................................................................................... 49 
7.5 
Pregnancy ....................................................................................................................................................................... 49 
7.6 
Potential Drug-Induced Liver Injury (DILI) ............................................................................................................... 50 
7.7 
Other Safety Considerations ......................................................................................................................................... 50 
8 
STATISTICAL CONSIDERATIONS .........................................................................................................50 
8.1 
Sample Size Considerations: ......................................................................................................................................... 50 
8.2 
Analyses ........................................................................................................................................................................... 51 
8.2.1 
Analysis Populations .............................................................................................................................................. 51 
8.2.2 
General Approach ................................................................................................................................................... 51 
8.2.3 
Safety Analyses ...................................................................................................................................................... 52 
8.2.4 
Efficacy Analyses ...................................................................................................................................52 
9 
STUDY MANAGEMENT .............................................................................................................................54 
9.1 
Compliance with the Protocol ....................................................................................................................................... 54 
9.1.1 
Compliance with the Protocol and Protocol Revisions ........................................................................................... 54 
9.2 
Record Retention ............................................................................................................................................................ 54 
9.2.1 
Record Retention .................................................................................................................................................... 54 
9.2.2 
Study Drug Records ................................................................................................................................................ 55 
9.2.3 
Destruction of Investigational Product ................................................................................................................... 55 
9.3 
Study Monitoring ........................................................................................................................................................... 55 


 
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10 
NIH DATA SHARING POLICY .................................................................................................................56 
11 
RESEARCH USE OF STORED SAMPLES ........................................................................................57 
11.1    Use of Stored Samples or Data……………………………………………………………………………………….54 
11.2     Disposition of Stored Samples or Data……………..………………………………………………………….……54 
12 
GLOSSERY OF TERMS ..........................................................................................................................57 
13 
LIST OF ABBREVIATIONS .......................................................................................................................58 
14 
REFERENCES ..............................................................................................................................................61 


 
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PROTOCOL SYNOPSIS 
Protocol Title: 
A phase 2 study to evaluate subcutaneous abatacept vs. placebo in 
diffuse cutaneous systemic sclerosis – a double-blind, placebo-
controlled, randomized controlled trial 
Sponsor 
This is an Investigator-Initiated study and Dinesh Khanna will be the 
Sponsor.  Bristol Myers Squibb will be supplying the drug/placebo 
and study funding. The mechanistic study is supported by DAIT, 
NIAID, and NIH as part of the Clinical ACE grant to UM 
Site Numbers: 
35 sites in the US, Canada and Europe 
Research Hypothesis: 
SC abatacept is safe and shows evidence of efficacy (improvement 
in modified Rodnan score [mRSS]) in patients with diffuse 
cutaneous systemic sclerosis (dcScc) compared to matching placebo. 
Study Schema: 
Drugs / Doses / Length of 
Treatment 
125 mg SC abatacept vs SC placebo administered weekly for 12 
months  with a 6 month open-label extension 
Study Objectives: 
 
 Primary: 
 To assess the safety of treatment with abatacept 125 mg SC 
versus placebo SC given every week 
 To assess the efficacy of treatment with abatacept 125 mg SC 
versus placebo SC given every week on skin fibrosis using the 
mRSS 
 Secondary: 
To assess the efficacy of treatment with abatacept 125 mg SC versus 
placebo SC given every week on: 
 Joint swelling and tenderness as measured by 28 joint count 
 Patient’s and physician’s global assessment on a Likert scale 
 Health-related quality of life (HRQOL) using PROMIS-29 2.0 
 Physical function as assessed by the scleroderma health 
assessment questionnaire-disability index (SHAQ-DI) 
 Fatigue as assessed by PROMIS fatigue scale 
 Sleep as assessed by PROMIS sleep disturbances and 
impairment scales 
 Gastrointestinal symptoms as assessed by UCLA GIT 2.0 


 
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 Combined Response Index in Systemic Sclerosis (CRISS) 
 Percent predicted forced vital capacity (FVC) 
 Exploratory: 
To assess the efficacy of treatment with abatacept 125 mg SC versus 
placebo SC given every week on a core set of items developed for a 
composite index in early dcSSc: 
 Patient interference with the skin involvement in the past 
month on a Likert scale. New or worsened clinically 
significant heart disease, considered secondary to dcSSc, 
including congestive heart failure requiring hospitalization, 
new onset pulmonary hypertension requiring treatment, 
pericardial disease requiring intervention or exhibiting clinical 
decompensation, and arrhythmias and/or conduction defects 
requiring treatment 
 New renal crisis  
  Percent predicted carbon monoxide diffusing capacity 
(DLCO), corrected for hemoglobin 
 Significant ILD defined by a decline in forced vital capacity 
(FVC)% predicted ≥15% (relative), high resolution computer 
tomography (HRCT) to confirm interstitial lung disease (ILD; 
if previous high resolution computer tomography of chest did 
not show ILD) and FVC% predicted below 80% predicted 
 Change from baseline in body mass index 
 Digital ulcer net burden as assessed by the investigator during 
the trial (baseline to 12 months)   
 Pain intensity due to dcSSc over the past week on a 0-150 mm 
VAS 
Ancillary Objective 
To validate a new PRO for Scleroderma-related Skin Symptoms 
(PRO-SRSS) in a subset of patients, identified based on the 
incorporation of this aim in the amended protocol. 
 
Study Design: 
Double-blind randomized placebo-controlled trial.  Subjects will be 
randomized 1:1 to abatacept or placebo within stratum defined by 
dcSSc disease duration (≤ 18 months vs.> 18 to ≤ 36 months).  


 
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Accrual Goal: 
(Total number of 
participants) 
Approximately 121 screened participants to randomize 86 patients  
 
Accrual Rate: 
(Number of 
participants 
expected per month) 
6-8 / month  
Follow-Up: 
 
12 month double-blind follow-up, followed by 6 month open-label 
follow-up, with a 30-day follow-up telephone  after permanent 
discontinuation of study medication. 
Correlative Studies: 
(PK/PD, etc.) 
Skin and blood biomarkers 
Inclusion Criteria: 
1. Signed written informed consent  
2. Diagnosis of SSc, as defined using the 2013 American College of 
Rheumatology/ European Union League Against Rheumatism 
classification of SSc 
3. dcSSc as defined by LeRoy and Medsger 
4. Disease duration of ≤ 36 months (defined as time from the first 
non−Raynaud phenomenon manifestation) 
For disease duration of ≤ 18 months  
 ≥ 10 and ≤ 35 mRSS units at the screening visit 
For disease duration of >18-36 months  
 ≥ 15 and ≤ 45 mRSS units at the screening visit and one of the 
following: 
o Increase ≥ 3 in mRSS units compared with the last visit 
within previous 1–6 months 
o Involvement of one new body area with ≥ 2 mRSS 
units compared with the last visit within the previous 
1–6 months 
o Involvement of two new body areas with ≥ 1 mRSS 
units compared with the last visit within the previous 
1–6 months 
o Presence of 1 or more Tendon Friction Rub 


 
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5.  Age ≥ 18 years at the screening visit 
6.  If female of childbearing potential, the patient must have a negative 
     pregnancy test at screening and baseline visits 
7. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and 
    NSAIDs are permitted if the patient is on a stable dose regimen for  
    ≥ 2 weeks prior to and including the baseline visit. 
8. ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, 
and/or oral vasodilators are permitted if the patient is on a stable 
dose for ≥ 2 weeks prior to and including the baseline visit 
Exclusion Criteria: 
1. Rheumatic disease other than dcSSc; it is acceptable to include 
patients with fibromyalgia and scleroderma-associated myopathy 
2. lcSSc or sine scleroderma at the screening visit 
3. Major surgery (including joint surgery) within 8 weeks prior to 
screening visit 
4. Infected ulcer prior to randomization 
5. Treatment with any investigational agent within ≤ 4 weeks (or 5 
half-lives of the investigational drug, whichever is longer) of the 
baseline visit 
6. Severe (MRSS 3) skin on the inner aspects of thighs, upper arms, 
and abdomen 
7. Previous treatment with cell-depleting therapies, including 
investigational agents, including but not limited to, CAMPATH, 
anti-CD4, anti-CD5, anti-CD3, anti-CD19, and ABA 
8. Anti-CD20, and cyclophosphamide within 12 months prior to 
baseline visit.  
9.  Use of Intravenous Immunoglobulin (IVIG) within 12 weeks prior 
to baseline visit 
10. Previous 
treatment 
with 
chlorambucil, 
bone 
marrow 
transplantation, or total lymphoid irradiation 
11. Immunization with a live/attenuated vaccine within ≤ 4 weeks 
prior to the baseline visit 
12. Treatment with methotrexate, hydroxychloroquine, cyclosporine 
A, azathioprine, mycophenolate mofetil rapamycin, colchicine, or 
D-penicillamine, within≤ 4 weeks prior to the baseline visit  
13. Treatment with etanercept within ≤ 2 weeks, infliximab, 


 
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certolizumab, golimumab, ABA or adalimumab within ≤ 8 weeks, 
anakinra within ≤ 1 week prior to the baseline visit 
14. Pulmonary disease with FVC ≤ 50% of predicted, or DLCO 
(uncorrected for hemoglobin ) ≤ 40% of predicted at the screening 
visit 
15. Pulmonary arterial hypertension (PAH) as determined by right 
heart catheterization or on PAH approved medications for PAH. It 
is acceptable to use PDE-5 inhibitors for Raynaud’s and digital 
ulcers. 
16. Subjects at risk for tuberculosis (TB). Specifically excluded from 
this study will be participants with a history of active TB within 
the last 3 years, even if it was treated; a history of active TB 
greater than 3 years ago, unless there is documentation that the 
prior anti-TB treatment was appropriate in duration and type; 
current clinical, radiographic, or laboratory evidence of active TB; 
and latent TB that was not successfully treated (≥ 4 weeks). 
17. Positive for hepatitis B surface antigen  prior to the baseline visit 
18. Positive for hepatitis C antibody, if the presence of hepatitis C 
virus was also shown with polymerase chain reaction or 
recombinant immunoblot assay prior to baseline visit. 
19. Any of the following prior to the baseline visit:  Hemoglobin <8.5 
g/dL; WBC < 3,000/mm3 (<3 x 109/L); platelets < 100,000/mm3 
(<3 x 109/L); serum creatinine > 2 x ULN; serum ALT or AST > 2 
x ULN 
20. Any other laboratory test results that, in the opinion of the 
investigator, might place a participant at unacceptable risk for 
participation in the study.  
21. The following medical history and concurrent diseases: 
 Subjects who are impaired, incapacitated, or incapable of 
completing study-related assessments 
 Subjects with active vasculitis of a major organ system 
 Subjects with current symptoms of severe, progressive, or 
uncontrolled renal, hepatic, hematologic, gastrointestinal, 
pulmonary, cardiac, neurologic, or cerebral disease, 
whether or not related to SSc and which, in the opinion of 


 
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the investigator, might place a participant at unacceptable 
risk for participation in the study 
 Subjects with a history of cancer in the last 5 years, other 
than non-melanoma skin cell cancers cured by local 
resection or carcinoma in situ. Existing non-melanoma skin 
cell cancers should be removed, the lesion site healed, and 
residual cancer ruled out before administration of the study 
drug 
 Subjects who currently abuse drugs or alcohol 
 Subjects with evidence (as assessed by the investigator) of 
active or latent bacterial or viral infections at the time of 
potential enrollment, including participants with evidence 
of human immunodeficiency virus (HIV) detected during 
screening 
 Subjects with herpes zoster or cytomegalovirus (CMV) that 
resolved less than 2 months prior to screening 
 Subjects with any serious bacterial infection within the last 
3 months, unless treated and resolved with antibiotics, or 
any 
chronic 
bacterial 
infection 
(e.g., 
chronic 
pyelonephritis, osteomyelitis, or bronchiectasis) 
22. Patients with a history of anaphylaxis to abatacept 
Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Evaluation every 3 months 
Statistics: 
Sample Size.  This phase 2 study is primarily sized based on practical 
considerations, rather than a desired power for a pre-specified 
difference.  We anticipate a 15% drop-out rate and thus plan to 
randomize 86 participants to achieve 74 analyzable participants.  With 
the proposed sample size, there is at least 80% power to detect a 24% 
treatment difference in proportions of participants with adverse events 
with a two-sided Type I error of 5% and a placebo rate of 70%. For 
continuous outcomes, the proposed sample size provides at least 80% 
power to detect an effect size of at least 0.66 with a two-sided Type I 


 
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error of 5%.  This effect size (treatment difference / pooled SD) 
translates into a treatment difference in change from baseline to month 
12 in mRSS of 5.3 with a SD of 8.0 points. 
Safety Analysis.  All safety analyses will be performed on the Safety 
Population, defined as all participants who were randomized and 
received at least one dose of the study drug.  Subjects will be analyzed 
by the treatment received.  Safety measures including AEs, clinical 
laboratory tests, vital signs, physical exams, and concomitant 
medication usage will be summarized descriptively.  For quantitative 
variables, descriptive statistics including number of observations, 
mean, median, standard deviation and range will be given for the 
values themselves as well as for change from baseline by treatment 
group at each study visit.  Qualitative variables will be summarized 
using counts and percentages by treatment group at each study visit.   
Efficacy Analysis. The main population for efficacy will be the 
modified intention-to-treat population (MITT), defined as all 
participants randomized and receive at least one dose of study drug.  
Subjects will be analyzed by assigned treatment. No adjustment for 
multiplicity will be made. The change from baseline in mRSS will be 
summarized for each treatment group by study visit. Differences from 
baseline will be calculated and summarized as above, with a 95% 
confidence interval for the mean.   The difference between treatment 
groups in change from baseline to Month 12 in mRSS scores will be 
evaluated using an ANCOVA model with terms for treatment group, 
duration of dcSSc disease (stratification factor) and baseline mRSS 
score.  
Secondary and exploratory efficacy variables that are continuous 
measures will be analyzed similarly to the primary efficacy analyses. 
Exploratory efficacy measures that are categorical will be analyzed 
using the chi-square test. They will be summarized by frequencies and 
percents, overall, and by treatment group. P-values from the secondary 
and exploratory efficacy analyses will be considered nominal.  The 
sensitivity of the results for mRSS to missing data assumptions will be 
explored as outlined in the Statistical Analysis Plan (SAP) for the 
study. Examination of treatment effects over time may be examined 


 
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using methods appropriate for repeated observations depending on 
sample sizes.  Additional exploratory analyses may be performed and 
will be defined and outlined in the SAP for the study. 
 
1 INTRODUCTION 
Systemic sclerosis (Scleroderma, SSc) is one of the most fatal rheumatic diseases, and is associated with 
substantial morbidity1 and many detrimental effects on health-related quality of life. Recent years have 
seen a revolution in the development and validation of outcome measures2-4 and refinement of trial 
methodology in SSc5. This is paralleled by an increased understanding of the pathogenesis of SSc6, 7 and 
development of targeted therapies8, 9. Modified Rodnan Skin Score (mRSS) a measure of skin 
thickness10, 11, has been used as the primary outcome measure in clinical trials of diffuse cutaneous SSc 
(called diffuse SSc or dcSSc from here on). Food and Drug Administration considers improvement in 
mRSS as an approvable end point.  
Several observations support the role of activated T cells in the pathogenesis of SSc.  Skin biopsies 
obtained from SSc patients early in their disease demonstrate a perivascular, mononuclear cell infiltrate 
comprised of T cells and macrophage.  T cell activation is a prominent feature in SSc, as demonstrated 
by the presence of increased numbers of T cells bearing activation markers, such as IL-2 receptor, as 
well as elevated levels of cytokines such as IL-2, IL-4, IL-6, and IL-17 in the peripheral blood of 
patients with SSc.  In addition, oligoclonal T cells have been demonstrated in the skin and 
bronchoalveolar lavage fluid from patients with SSc, implicating specific antigen-driven T cell 
proliferation in the disease process. T and B lymphocyte interactions are important in the pathogenesis 
of SSc, and T cells have been shown to be essential for the production of autoantibodies in this disease.  
Recent data also indicates an imbalance between Th17 and T regulatory cells in patients with SSc.  Th17 
cell concentrations are elevated in the peripheral blood of patients with SSc, while T regulatory cells are 
reduced in skin lesions from SSc patients  Finally, treatments directed against activated T cells, such as 
cyclosporine A, or depletion of T cells have resulted in skin softening in patients with SSc. 
A recent pilot study evaluated the effect of blockade of T cell co-stimulation with intravenous abatacept 
in patients with dSSc showed efficacy and not serious or unanticipated adverse events. Therefore, we 
aim to perform a phase II, multi-center double-blind randomized controlled trial of subcutaneous 
abatacept vs. placebo in patients with early dcSSc. 


 
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1.1 
Summary of Results of Investigational Program 
1.1.1 
Pharmacology of Abatacept 
Abatacept is a recombinant fusion protein consisting of the extracellular domain of human CTLA4 and a 
fragment (hinge- CH2-CH3 domains) of the Fc domain of human IgG1 that has been modified to 
prevent complement fixation and antibody-dependent cellular cytotoxicity. 
Abatacept is the first drug in a new class of agents termed “selective costimulation modulators.” 
Abatacept binds specifically to the CD80 and CD86 molecules, proteins prominently displayed on the 
surface of antigen-presenting cells (APCs). Activation of naive T cells during an immune response 
requires two stimuli from APCs. The first signal is antigen-specific; antigens are presented by APCs, 
with the signal transmitted to the T cell through the T cell’s antigen receptor. The second, or 
costimulatory, signal is not antigen-specific and is delivered following the engagement of a 
costimulatory ligand on the APC with a cognate receptor on the T cell. 
A key costimulatory receptor on T cells is CD28. CD28 is constitutively expressed on resting T cells and 
binds to both CD80 (B7-1) and CD86 (B7-2) on the APC12-15. A costimulatory signal is required not 
only for the full activation of naive T cells, but also may be required for the survival of memory and 
autoimmune effector cells16, 17. At 24 to 48 hours following T cell activation, the T cell expresses 
CTLA4 on its surface, which engages the CD80 and CD86 molecules on the APC surface interfering 
with CD28’s ability to bind to its ligands on the APC; CD80 and CD86 preferentially bind to CTLA4 
with a much higher avidity than with CD28. Although the precise mechanisms are as yet unclear, 
CTLA4 expression is associated with a decrease in T cell activation. 
After the T cell activity has been dampened, the CTLA4 recycles into the T cell’s cytoplasm. The 
CTLA4 section of abatacept binds specifically to CD80 and CD86 (B7-1 and B7-2, respectively) and 
down-modulates the CD28-mediated costimulation of T cells. Thus, abatacept uses a segment of a 
molecule that is part of the normal immune homeostatic mechanism to suppress T cell activity involved 
in the immunopathogenesis of autoimmune diseases. The FC region of abatacept was engineered with 
several point mutations designed to inactivate it. Because of these changes, abatacept does not mediate 
pathways such as antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity18. 
1.1.2 
Human Pharmacokinetics of Abatacept 
Single subcutaneous (SC) doses of abatacept (50 to 150 mg) demonstrated approximately dose 
proportional PK in healthy adult participants19. Following administration of single doses of 50 to 150 mg 
of abatacept, the mean Cmax increased from 3.5 to 10.7 μg/mL and the geometric mean AUC (INF) 
increased from 1490 to 4270 μghour/mL. The median time to occurrence of Cmax (Tmax) following 
SC administration ranged between 48 and 168 hours. Mean T1/2 values in healthy participants ranged 


 
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from 11.2 to 14.7 days. T1/2 values from this study were comparable with the T1/2 values obtained with 
abatacept administered IV to participants with RA (13 to 14 days)20. The fact that T1/2 values following 
SC dosing were comparable to T1/2 values obtained after IV dosing suggests that the elimination 
characteristics of abatacept were not altered following SC administration. 
A double-blind, randomized, placebo-controlled, parallel-group, multiple-dose study (IM101063) 
assessed the steady-state trough serum concentrations of abatacept following SC administration in 
participants with RA21. Subjects were randomized to receive either abatacept or placebo in 1 of 5 
parallel groups based on body weight obtained at the screening visit (Table 1.3.2A). The SC dose 
regimens were selected to target trough levels between 10-30 ug/mL, which was associated with 
efficacy with the IV formulation. 
Table 1.3.2A.  IM101063 Treatment Groups Based on Body Weight 
Treatment 
Group 
Subject weight 
(kg) 
IV dose on  
Day 1 (mg) 
SC dose weekly for 
12 weeks (mg) 
SC injection volume 
(mL) 
1 
< 60 
500 
75 
0.6 
2 
< 60 
500 
125 
1 
3 
60 - 100 
750 
125 
1 
4 
> 100 
1000 
125 
1 
5 
> 100 
1000 
200 
0.6 + 1.0 
Source: Clinical Study report for IM101063: A Study To Assess The Steady-State Trough Serum Concentrations, Safety, 
And Immunogenicity Of Abatacept (BMS-188667) Administered Subcutaneously In Subjects With Active Rheumatoid 
Arthritis Who Are Receiving Disease Modifying Anti-Rheumatic Drugs (DMARDs). Bristol-Myers Squibb; 2008. 
Document Control No. 930025069. 
 
On Day 1, participants received a single IV infusion (loading dose) of abatacept or placebo, based on 
their weight range. Approximately 1 hour after the completion of the IV infusion, participants received 
their assigned SC dose of abatacept or placebo. Abatacept or placebo was administered weekly by the 
SC route, at the same dose as the SC dose on Day 1, for a total of 12 SC injections. Blood samples for 
PK analysis were collected on Day 1 prior to and at the end of the IV infusion. In addition, blood 
samples were collected prior to each weekly SC dose of abatacept. 
Steady-state trough serum concentrations were achieved after ~ 4 to 5 weeks following the combined 
regimen of a single IV loading dose and weekly SC injections. With the exception of treatment group 4 
(abatacept 125 mg SC weekly dose for participants weighing > 100 kg), the mean steady-state trough 
concentrations across all other treatment groups appeared to be comparable.  


 
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15 
However, to truly represent the steady-state serum levels from SC administration without the 
contribution of the IV loading dose, Cmin values on Days 71-85 were selected, since contribution from 
IV was expected to be negligible. Comparison of mean steady-state trough concentrations on Day 71, 78 
and 85 indicated that abatacept did not appear to accumulate following weekly dosing (Table 1.3.2B). 
 
Table 1.3.2B.  Summary Statistics for Abatacept Steady-State Cmin Values on Days 
71, 78, and 85 - IM101063 
Treatment Group 
Study 
Day 
n 
Cmin (g/mL) 
Geometric Mean 
(CV%) 
Cmin (g/mL) 
Median (Min, Max) 
1 (500 mg IV / 75 mg SC) 
71 
7 
22.64 (20.13) 
20.92 (17.06, 29.84) 
 
78 
7 
21.66 (19.99) 
22.40 (16.01, 28.93) 
 
85 
7 
23.62 (31.63) 
21.91 (18.24, 39.60) 
2 (500 mg IV / 125 mg SC) 
71 
4 
28.03 (42.13) 
32.57 (13.73, 43.30) 
 
78 
3 
34.17 (29.49) 
33.10 (25.97, 46.40) 
 
85 
3 
36.73 (31.64) 
37.50 (26.26, 50.30) 
3 (750 mg IV / 125 mg SC) 
71 
26 
24.05 (40.65) 
26.53 (7.97, 54.11) 
 
78 
23 
24.41 (52.35) 
27.54 (5.40, 68.90) 
 
85 
25 
24.93 (38.42) 
26.01 (9.57, 53.80) 
4 (1000 mg IV / 125 mg SC) 
71 
3 
16.22 (24.39) 
15.15 (13.37, 21.07) 
 
78 
5 
11.57 (32.25)  
13.20 (6.89, 16.33) 
 
85 
5 
13.01 (41.35) 
13.30 (6.66, 22.73) 
5 (1000 mg IV / 200 mg SC) 
71 
5 
26.52 (56.53) 
26.20 (8.68, 55.20) 
 
78 
5 
29.21 (52.96) 
40.40 (8.04, 57.10) 
 
85 
5 
27.53 (58.87) 
29.01 (8.74, 62.00) 
Source:  Clinical Study report for IM101063: A Study To Assess The Steady-State Trough Serum Concentrations, 
Safety, And Immunogenicity Of Abatacept (BMS-188667) Administered Subcutaneously In Subjects With Active 
Rheumatoid Arthritis Who Are Receiving Disease Modifying Anti-Rheumatic Drugs (DMARDs). Bristol-Myers Squibb; 
2008. Document Control No. 930025069. Supplemental Table S.8.2.2. 
n=number of observations 
 
Steady-state pharmacokinetic parameters of abatacept after weekly SC administration were determined 
between the SC dosing interval from Day 71 to 78. Cmax and AUC (TAU) appear to be comparable in 
Treatment Groups 1, 3 and 5 (Table 1.3.2C). 


 
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Table 1.3.2C.  Summary Statistics for Abatacept Steady-State Pharmacokinetic 
Parameters - IM101063 
Treatment Group 
Pharmacokinetic Parameter 
Cmax (µg/mL)  
Geometric Mean (CV%) 
AUC(TAU) (µg*h/mL) 
Geometric Mean (CV%) 
1 (500mg IV / 75mg SC) 
n = 7  
26.3 (29.5) 
n = 7 
4066 (22.2) 
2 (500mg IV / 125mg SC) 
n = 4 
34.9 (46.6) 
n = 3 
6699 (20.7) 
3 (750mg IV / 125mg SC) 
n = 26 
31.9 (42.8) 
n = 24 
4607 (38.6) 
4 (1000mg IV / 125mg SC) 
n = 5 
14.7 (44.3) 
n = 4 
2555 (30.1) 
5 (1000mg IV / 200mg SC) 
n = 5 
41.7 (41.2) 
n = 5 
5849 (40.5) 
Source: Clinical Study report for IM101063: A Study To Assess The Steady-State Trough Serum Concentrations, Safety, 
And Immunogenicity Of Abatacept (BMS-188667) Administered Subcutaneously In Subjects With Active Rheumatoid 
Arthritis Who Are Receiving Disease Modifying Anti-Rheumatic Drugs (DMARDs). Bristol-Myers Squibb; 2008. 
Document Control No. 930025069.Supplemental Table S.8.2.3. 
n = number of participants, TAU = 7 days 
Cmax and AUC(TAU) were calculated between a SC dosing intervals from Day 71 to Day 78 profile. 
 
1.1.3 
Clinical Safety with Abatacept SC Formulation 
The safety experience with SC abatacept was characterized in 2 ways: events during cumulative SC 
period and events during the comparative SC/IV period. The key safety findings based on these analyses 
are listed below22.   
The cumulative SC period, during which 1879 participants received SC abatacept for a total exposure 
of 1945.60 person-years (p-y), was based on cumulative (short term/ long term) pooled data of the Phase 
2 and 3b studies from:  
 All participants in the SC abatacept treatment group in the ST period of IM101174  
 All participants in the IV abatacept treatment group in the ST period of IM101174  (including the 
anti-TNF failure substudy) who were treated with SC abatacept in the LT period, from the start of 
SC abatacept in the LT period 
 All participants in ST abatacept treatment groups from IM101063  
 All participants in the ST placebo group from IM101063 who were treated with SC abatacept in 
the LT period, from the start of SC abatacept in the LT period 
 All treated participants in IM101167, IM101173, and IM101185 


 
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No new safety signal was identified for SC abatacept across the parameters of death, SAEs, AEs/SAEs 
leading to discontinuation, treatment-related AE/SAEs, and overall AEs. 
Table 1.1.3A: 
Overall Safety for the Cumulative SC Abatacept Period 
 
Number (%) of 
Subjects 
N = 1879 
Incidence Rate (per 
100 p-y) 
Poisson 95% 
Confidence Interval 
Deaths 
9 (0.5%) 
0.46 
(0.24, 0.89) 
SAEs 
161 (8.6%) 
8.63 
(7.39, 10.07) 
AEs 
1267 (67.4%) 
144.36 
(136.63, 152.53) 
AEs leading to 
discontinuation 
46 (2.4%) 
2.37 
(1.78, 3.16) 
Source: Subcutaneous abatacept summary of clinical safety. Bristol-Myers Squibb, 2010. Document Control No. 
930043734.  
The subgroup analyses by body weight did not identify a differential safety profile for any of the weight 
groups, including the 24% of participants weighing less than 60 kg. No new safety signal was identified 
for AEs of special interest: 
 Infection and infestation AEs were reported in 756 (40.2%) participants with an incidence rate 
(per 100 p-y of exposure) of 54.94. The majority of infections were of mild to moderate intensity. 
The cumulative SC period incidence rate of infections and infestation AEs was consistent with 
previous IV abatacept experience.  
 Malignancies were reported in 20 (1.1%) participants with an incidence rate (per 100 p-y of 
exposure) of 1.04. Malignancies excluding non-melanoma skin cancer  (NMSC) were reported in 
9 (0.5%) participants with an incidence rate (per 100 p-y of exposure) of 0.46. The cumulative SC 
period incidence rate of malignancies was consistent with previous IV abatacept experience. 
 Pre-specified autoimmune events were reported in 17 (0.9%) participants with an incidence rate 
(per 100 p-y of exposure) of 0.88; most were of mild to moderate intensity with the exception of 
1 severe event (vasculitis). One pre-specified autoimmune event was reported as serious 
(sarcoidosis of moderate intensity), which led to premature discontinuation. The cumulative SC 
period incidence rate of autoimmune events was consistent with underlying disease and previous 
IV abatacept experience.  
 Pre-specified local injection site reactions were reported in 58 (3.1%) participants with an 
incidence rate (per 100 p-y of exposure) of 3.09. Most local injection site reactions were of mild 
to moderate intensity; 1 event (severe injection site reaction) was serious and led to premature 
discontinuation. 
 Systemic injection reaction AEs were reported in 131 (7.0%) participants with an incidence rate 
(per 100 p-y of exposure) of 7.21. Most events were of mild to moderate intensity; none were 
serious; 1 event (moderate angioedema) led to premature discontinuation.  


 
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 Pre-specified acute- and peri-infusional AEs were reported in 15 (1.6%) and 35 (3.6%) 
participants, respectively; all events were of mild to moderate intensity with the exception of 1 
severe event (headache).  
 The safety profile of SC abatacept was also assessed under clinical scenarios that might increase 
the development of immunogenicity and determined the consequences of treating with SC 
abatacept (e.g., no IV load, monotherapy without MTX, prolonged withdrawal of therapy, switch 
from IV to SC abatacept).  
 
The comparative SC/IV period (ST period of IM101174), which provided a direct comparison of the 
safety data between the SC and IV abatacept formulations. The cumulative SC period did not have a 
comparator group to provide context for safety assessment; an evaluation was made of the cumulative 
SC period to the safety events reported in the Summary of Clinical Safety submitted to the FDA (June 
2010)23. Overall, consistent safety profiles were observed for the SC abatacept and IV abatacept groups 
across the parameters of death, SAEs, AEs/SAEs leading to discontinuation, treatment-related 
AE/SAEs, and overall AEs (Table 1.1.3B).  
Table 1.1.3B.  Overall Safety for the Comparative SC/IV Abatacept Population - 
IM101174 (short-term Period) 
 
Number (%) of Subjects 
 
SC Abatacept  
N = 736 
IV Abatacept 
N = 721 
Deaths 
2 (0.3%) 
5 (0.7%) 
SAEs 
31 (4.2%) 
35 (4.9%) 
AEs 
493 (67.0%) 
470 (65.2%) 
AEs leading to discontinuation 
15 (2.0%) 
25 (3.5%) 
Source: Subcutaneous Abatacept Summary of Clinical Safety. Bristol-Myers Squibb, 2010. Document Control No. 
930043734. 
 
The subgroup analyses by body weight did not identify a differential safety profile for any of the weight 
groups, including the 24% of participants weighing less than 60 kg indicating that the higher exposures 
(Cmin) due to the fixed dosing regimen did not result in any additional safety risks.  
The safety profiles observed for SC abatacept and IV abatacept were consistent for AEs of special 
interest: 
 Infection and infestation AEs were reported in 234 (31.8%) and 221 (30.7%) participants in the 
SC abatacept and IV abatacept groups, respectively. The majority of infections were of mild to 
moderate intensity.  


 
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 Malignancies were reported in 3 (0.4%) and 5 (0.7%) participants in the SC abatacept and IV 
abatacept groups, respectively. Of these, 2 malignancies from each group were non-melanoma 
skin cancers (NMSC).  
 Pre-specified autoimmune events were reported in 7 (1.0%) and 6 (0.8%) participants in the SC 
abatacept and IV abatacept groups, respectively; all events were of mild to moderate intensity.  
 Pre-specified local injection site reactions were reported in 19 (2.6%) and 18 (2.5%) participants 
in the SC abatacept and IV abatacept (i.e., SC placebo) groups, respectively. All pre-specified 
local injection site reactions were of mild to moderate intensity; none led to premature 
discontinuation.  
 Systemic injection reaction AEs were reported in 56 (7.6%) and 56 (7.8%) participants in the SC 
abatacept and IV abatacept groups; respectively. No serious systemic injection reactions were 
reported in the SC abatacept group; 1 participant in the IV abatacept group had serious systemic 
injection reactions (nausea and headache). In both treatment groups, most pre-specified systemic 
injection reaction AEs were of mild or moderate intensity; none led to premature discontinuation.  
 Pre-specified acute infusional AEs were reported in 20 (2.7%) and 16 (2.2%) participants in the 
SC abatacept and IV abatacept groups, respectively. In both treatment groups, most of the pre-
specified acute infusional events were of mild to moderate intensity; only 1 event in each 
treatment group, both reported on Day 1, led to premature discontinuation. 
Data from the SC abatacept clinical development program indicates that the SC abatacept formulation 
did not lead to increased immunogenicity and when present did not affect safety. 
1.1.4 
Drug-Related Adverse Events 
Injection Site Reactions in Adult RA Patients Treated with Subcutaneous Abatacept 
IM101-174 compared the safety of abatacept including injection site reactions following subcutaneous 
or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 
2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous 
placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) 
were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. 
Immunogenicity in Adult RA Patients Treated with Subcutaneous Abatacept 
IM101-174 compared the immunogenicity to abatacept following subcutaneous or intravenous 
administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% 
(16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous 
experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or 
efficacy. 


 
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Immunogenicity and Safety of Subcutaneous Abatacept Administration as Monotherapy without an 
Intravenous Loading Dose 
IM101-173 was conducted to determine the effect of monotherapy use of abatacept on immunogenicity 
following subcutaneous administration without an intravenous load in 100 RA patients, who had not 
previously received abatacept or other CTLA4 Ig, who received either subcutaneous abatacept plus 
methotrexate (n=51) or subcutaneous abatacept monotherapy (n=49). No patients in either group 
developed anti-product antibodies after 4 months of treatment. The safety observed in this study was 
consistent with that observed in the other subcutaneous studies. 
Immunogenicity and Safety of Subcutaneous Abatacept upon Withdrawal (Three Months) and 
Restart of Treatment 
IM101-167 in the subcutaneous program was conducted to investigate the effect of withdrawal (three 
months) and restart of abatacept subcutaneous treatment on immunogenicity in RA patients treated 
concomitantly with methotrexate. One hundred sixty-seven patients were enrolled in the first 3-month 
treatment period and responders (n=120) were randomized to either subcutaneous abatacept or placebo 
for the second 3-month period (withdrawal period). Patients from this period then received open-label 
abatacept treatment in the final 3-month period of the study (period 3). At the end of the withdrawal 
period, 0/38 patients who continued to receive subcutaneous abatacept developed anti-product 
antibodies compared to 7/73 (9.6%) of patients who had subcutaneous abatacept withdrawn during this 
period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a 
single intravenous infusion of abatacept at the start of period 3 and half received intravenous placebo. At 
the end of period 3, when all patients again received subcutaneous abatacept, the immunogenicity rates 
were 1/38 (2.6%) in the group receiving subcutaneous abatacept throughout, and 2/73 (2.7%) in the 
group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no 
injection reactions, and no differences in response to therapy in patients who were withdrawn from 
subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, 
whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in 
this study was consistent with that observed in the other studies. 
1.1.5 
Clinical Efficacy of Abatacept Subcutaneous Formulation 
The clinical development program for SC abatacept for rheumatoid arthritis included 4 Phase 3b 
efficacy, safety, and immunogenicity studies (IM101167, IM101173, IM101174 and IM101185) plus 2 
clinical pharmacology studies (IM101013 and IM101063). Overall, the efficacy data from the SC 
abatacept development program demonstrated that the efficacy profile of SC abatacept is comparable to 
IV abatacept24. 
The key efficacy results were: 


 
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 The clinical efficacy of a fixed-dose of SC abatacept 125 mg weekly (following a single weight-
tiered IV loading dose on Day 1) was non-inferior to weight-tiered IV abatacept, as assessed by 
the primary endpoint of ACR 20 at Day 169 (point estimates of 76.1% vs 75.7%, respectively). 
The non-inferiority margin ensured that SC abatacept maintained at least 70% of effectiveness of 
IV abatacept. The results from this study established that SC abatacept preserves at least 83% of 
the effect of IV abatacept (Study IM101174). 
 The magnitude of clinical response starting at Day 15 and up to 6-months, across all pre-specified 
efficacy endpoints (ACR 20, ACR 50, ACR 70, DAS28 remission, LDAS) and physical function 
endpoint (HAQ) was comparable between SC abatacept and IV abatacept (Study IM101174). 
 Clinical efficacy as measured by ACR 20 and HAQ response was similar between SC abatacept 
and IV abatacept within all weight subgroups, as well as all other subgroups assessed (Study 
IM101174). 
 Clinical efficacy was maintained with LT administration of SC abatacept for up to 18 months 
(Studies IM101174, IM101173, IM101167, and IM101185).  
 Clinical efficacy achieved after either ST or LT IV abatacept therapy was maintained upon switch 
to SC abatacept (Studies IM101174 LT and IM101185, respectively).  
 Based on reduction in DAS28-CRP score over time and at Day 85 (relative to baseline) in 2 
studies conducted in an open-label setting, the clinical efficacy of SC abatacept with or without 
IV loading dose appeared to be similar; indicating that the IV loading dose at Day 1 may not be 
essential for obtaining early onset of action (Studies IM101167 and IM101173, respectively).  
 The clinical efficacy of SC abatacept also appears to be similar upon re-initiation of SC abatacept 
with or without IV loading dose, based on reduction in DAS28-CRP score over time (Study 
IM101167).   
1.2 
Overall Risk/Benefit Assessment 
This is a proof-of-concept phase 2 study to assess safety and efficacy of abatacept in patients with dSSc. 
Systemic sclerosis (Scleroderma, SSc) is one of the most fatal rheumatic diseases, and is associated with 
substantial morbidity and many detrimental effects on health-related quality of life. There are no Food 
and Drug Administration (FDA) approved drugs for SSc. Please see Section 1.6 for more details.  
1.3 
Research Hypothesis 
SC abatacept is safe and shows evidence of efficacy in patients with dSSc compared to matching 
placebo. 


 
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1.4 
Study Rationale 
1.4.1 
Role of T cells in the pathogenesis of SSc 
CD4+ T cells are central to the pathogenesis of a range of autoimmune diseases, both through their role 
in activating B cell differentiation and autoantibody production, and through secretion of cytokines.  T 
cell subsets can also protect against or attenuate autoimmunity through a variety of regulatory 
mechanisms. The CD4+ T cell population contains distinct subsets classified according to their program 
of cytokine secretion, such as the Th1, Th2 and Th17 cells, regulatory T cells (Tregs), follicular-helper T 
cells, and additional subsets including bi-functional subsets that overlap between more than one Th 
population.  Activation of all subsets of CD4+ T cells requires delivery of at least 2 signals to the T cell, 
one through recognition of antigen-MHC and the second through co-stimulation, primarily by binding of 
the CD28 ligands B7.1 and B7.2 (CD80 and CD86) to CD28 on the T cell membrane. 
Substantial evidence supports the concept that T cells play a key role in the pathogenesis of SSc, 
including cutaneous disease and at least some of the visceral complications. Skin biopsies obtained from 
SSc patients early in their disease demonstrate a perivascular, mononuclear cell infiltrate comprised of T 
cells and macrophages25-27. T cells are the dominant population of lymphocytes in the skin, and are 
activated26.  T cell infiltration correlate with the skin thickening, suggesting a relation between 
inflammation and fibrosis28. The expression of inducible costimulator (ICOS), expressed on activated T 
cells, is elevated in patients with early dcSSc29. T cells transferred from bleomycin-treated mice (a 
mouse model of SSc) to healthy animals induces skin thickening30. Also, the T lymphocytes in SSc 
tissue overexpress TNF receptor II and that these cells, when costimulated with TNF-α, trigger collagen 
production by releasing profibrotic cytokines31. 
Controversy and ambiguity exists, however, regarding which Th subset may be pathogenic in SSc, with 
the focus largely on the Th2 and Th17 cells32, 33. Th2 cells, defined by their production of IL-4, have 
been implicated in SSc because some of their cytokine products, such as IL-13, are pro-fibrotic34-36. 
Moreover, Th2 cells are found in excess in the blood of patients with SSc, and in both cutaneous and 
pulmonary disease.  We showed that Th2 cells in bronchoalveolar lavage fluid in SSc associated 
interstitial lung disease declined during treatment with imatinib37, 38.  Th1 mechanisms appear to be anti-
fibrotic32, 39. 
The more recently described Th17 subset is also expanded in SSc blood and skin, and has been 
suspected to be pathogenic40-44, although Th17 cytokines are not viewed as pro-fibrotic. One report 
suggests that Th22 cells, as well as Th2 and Th17, are expanded in patients with interstitial lung disease 
and SSc 45. Important new evidence suggests that although prevalent in SSc skin, the Th17 cells might 
actually be protective against skin fibrosis46.  Unlike IL-4+ cells, the IL-17A+ cells are in proximity to 
myofibroblasts in SSc skin, but in vitro IL-17A does not induce but rather inhibits myofibroblast 


 
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23 
differentiation, and instead increases collagenase expression. An inverse correlation was found between 
the density of IL-17A+ cells and the extent of skin thickness.  
The genome-wide association studies in SSc47 have led to the discovery of over 30 genes and gene 
regions, including both human leukocyte antigen (HLA) and non-HLA genes, identifying as SSc 
susceptibility loci. Most of these genes are associated with lymphocyte activation and signaling (e.g. 
TNIP148), innate immunity (e.g. IRF849), transcription factors (e.g. STAT450) and cytokine receptors 
(e.g. IL2RA47). T cells from peripheral blood of women with SSc are activated, as judged by over-
expression of CD40-ligand due to DNA demethylation51 and that the level of DNA methyltransferase 1 
is significantly decreased in patients with SSc52. Recently cytosine-phosphate-guanosine demethylation 
within the CD40L gene on the inactive X chromosome has been documented to contribute to CD40L 
overexpression in CD4+ T lymphocytes from female SSc patients51 and could explain the female 
dominance in this condition. 
In summary, available data suggests that Th2 cells are pathogenic and Th17 cells protective in SSc32, 39. 
However, there are large knowledge gaps related in part to small sample sizes of most prior studies, lack 
of longitudinal data (other than serial measurements of bronchoalveolar lavage T cells and IL-4-
producing cells in a small cohort of patients who received imatinib in an open label fashion for 
scleroderma lung disease38), limited data concurrently obtained from skin and blood, and lack of data 
prospectively acquired during a clinical trial of an agent that is expected to affect T cells.  The study 
proposed is designed to address these gaps, and to shed light on the immunopathogenesis of SSc as well 
as on predictors of response to an immunomodulatory treatment. 
1.4.2 
ABA in SSc 
The co-stimulatory molecules expressed by activated T cells represent a unique target for biologic 
activity in SSc. ABA is a recombinant fusion protein consisting of the extracellular domain of human 
CTLA4 and a fragment (hinge- CH2-CH3 domains) of the Fc domain of human IgG1 that has been 
modified to prevent complement fixation and antibody-dependent cellular cytotoxicity. ABA is the first 
drug in a new class of agents termed “selective costimulation modulators.” ABA is approved by the 
Food and Drug Administration for the treatment of rheumatoid arthritis (RA) and juvenile idiopathic 
arthritis. ABA binds specifically to the CD80 and CD86 molecules, proteins prominently displayed on 
the surface of antigen-presenting cells (APCs). Activation of naive T cells during an immune response 
requires two stimuli from APCs. The first signal is antigen-specific; antigens are presented by APCs, 
with the signal transmitted to the T cell through the T cell’s antigen receptor. The second, or 
costimulatory, signal is not antigen-specific and is delivered following the engagement of a 
costimulatory ligand on the APC with a cognate receptor on the T cell. 
A pilot study of ABA in SSc supports undertaking a larger placebo-controlled trial with an emphasis on 
skin and blood biomarker53 (detailed in next section). Although ABA is well established in the treatment 


 
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of RA, there is a striking dearth of data from human clinical trials regarding its mechanisms of action. 
There is evidence that pro-inflammatory cytokines are reduced by ABA treatment of RA54  One study 
examined synovial tissue from 10 patients with RA who had responded to ABA + methotrexate, 
compared to 5 patients treated with only methotrexate55.  The ABA-treated patients had fewer T cells in 
synovial tissue, and also fewer B cells and monocytes.  Pre-ABA biopsies were not examined. The idea 
that ABA might affect not only T cell function, but also various functions of B7.1/2(CD80/86)+ cells is 
supported by a study of monocytes from RA blood before and after treatment with ABA: after treatment 
monocytes accumulated in the blood and had reduced adhesive and migratory capacity56.  Similar effects 
were seen with in vitro exposure of normal human monocytes to CTLA4-Ig.  Although synovial tissue 
was not evaluated in this study the findings imply that decreased ingress of monocytes into inflamed 
synovium is one of the therapeutic mechanisms of ABA, and raise the possibility that in SSc ABA could 
reduce monocyte ingress into lesional skin. In addition, ABA reduces the antigen-induced expression of 
ICOS in a murine model of arthritis57_ENREF_9 and inhibits antigen specific T cell proliferation and 
activation. ABA also strikingly inhibits antigen stimulated T cell secretion of IFNg, IL-17 and IL-13, the 
latter known to be upregulated in the circulation of SSc patients, and possibly contributing to fibrosis. 
Some studies have suggested that ABA can also affect APCs through its binding to CD80/86, 
upregulating indoleamine 2,3-dioxygenase (IDO). Although a role for ABA in dendritic cells 
(DC)/macrophage phenotype was not supported by in vitro microarray studies comparing gene 
expression in ABA-stimulated APC subsets27, only purified APCs were tested in these studies. More 
recent studies have suggested that the effect of ABA on DCs might be indirect, mediated by CTLA-4 on 
regulatory T cells, with CTLA4Ig stimulating FoxP3 expression in murine allografts associated with 
upregulated IDO in DCs25. Thus, ABA can affect multiple T cell types, stimulating Treg cells while 
inhibiting other effector cell types and associated cytokine levels. Based on the immune abnormalities 
observed in SSc, others have suggested that ABA could be an effective agent in SSc58, 59. 
1.4.3 
Pilot study 
A recent single center pilot study evaluated the effect of blockade of T cell co-stimulation with 
intravenous abatacept in patients with dSSc.  Ten patients were randomized in a 2:1 double-blinded 
fashion to receive IV abatacept or placebo at weeks 0, 2, 4, and every 4 weeks for a total of 24 weeks.  8 
women and 2 men, mean age 42.2 years, enrolled in the study. The mean disease duration from the time 
of the first non-Raynaud’s manifestation was 4.4 (SD 3.8) years. 7 patients were randomized to receive 
abatacept and 3 received placebo.  At baseline, there were no significant differences in mRSS, Health 
Assessment Questionnaire-Disability Index (HAQ-DI), patient and physician global assessments by 
visual analogue scale (VAS) and pulmonary function tests (PFTs) between the two groups, although 
participants randomized to abatacept had shorter disease duration (2.4 vs. 8.8 years, p=0.004).  
Compared with those receiving placebo, participants treated with abatacept reported greater 
improvement in patient global assessment by VAS (-8 vs. -2.7, p=0.023).  Subjects receiving abatacept 


 
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had a mean improvement of 8.6 (SD 7.5) in mRSS at week 24, which exceeds the minimal clinical 
important  difference of 5.360. Patients receiving abatacept had a greater improvement in absolute mRSS 
compared with those receiving placebo, but this did not reach statistical significance given the small 
sample size (-8.6 vs -2.3, p=0.059).   No deaths or serious adverse events related to abatacept occurred 
and overall the study drug was well-tolerated. This study was limited by small sample size and skewing 
of disease duration between those randomized to placebo vs abatacept, the latter fact implying that any 
differences between the two groups might be explained by natural history of improvement of cutaneous 
sclerosis early in disease.   
Despite these limitations, our preliminary data support a potential role for abatacept in the treatment of 
cutaneous sclerosis in SSc.  Therefore, we aim to perform a phase 2, multi-center double-blind 
randomized controlled trial of subcutaneous abatacept vs. placebo in patients with early diffuse 
cutaneous SSc. 
2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
 To assess the safety of treatment with abatacept 125 mg SC versus placebo SC given every week 
 To assess the efficacy of treatment with abatacept 125 mg SC versus placebo SC given every 
week on skin fibrosis using the modified Rodnan Skin Score (mRSS) 
2.2 
Secondary Objectives 
To assess the efficacy of treatment with abatacept 125 mg SC versus placebo SC given every week on: 
 Joint tenderness as measured by 28-tender joint count 
 Joint swelling as measured by 28-swollen joint count 
 Patient’s and physician’s global assessment on a Likert scale  
 Health-related quality of life (HRQOL) using PROMIS-29 2.0 
 Physical function as assessed by the scleroderma health assessment questionnaire-disability 
index (SHAQ-DI) 
 Fatigue as assessed by the PROMIS Fatigue scale 
 Sleep as assessed by the PROMIS sleep disturbance and impairment scale 
 Gastrointestinal symptoms as assessed by UCLA SCTC GIT 2.0 
 Combined Response Index in Systemic Sclerosis (CRISS) 
 Percent Predicted forced vital capacity  (FVC) 


 
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2.3 
Exploratory Objectives 
To assess the efficacy of treatment with abatacept 125 mg SC versus placebo SC given every week on a 
core set of items developed for a composite index in early dcSSc: 
 Patient interference with the skin involvement in the past month on a Likert scale 
 New or worsened clinically significant heart disease, considered secondary to dcSSc, including 
congestive heart failure requiring hospitalization, new onset pulmonary hypertension requiring 
treatment, pericardial disease requiring intervention or exhibiting clinical decompensation, and 
arrhythmias and/or conduction defects requiring treatment 
 New renal crisis  
  Percent predicted carbon monoxide diffusing capacity (DLCO), corrected for hemoglobin 
 Change from baseline in body mass index 
 Digital ulcer net burden as assessed by the investigator during the trial (baseline to 12 months)  
Pain intensity due to dcSSc over the past week on a 0-150 mm VAS 
2.4 
Ancillary Objective 
To validate a new PRO for Scleroderma-related Skin Symptoms (PRO-SRSS) in a subset of patients, 
identified based on the incorporation of this aim in the amended protocol. 
 
3 ETHICAL CONSIDERATIONS 
3.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, 
Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any amendments, and the 
participant informed consent will receive Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approval/favorable opinion before initiation of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure; debarment).  


 
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3.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion from the 
IRB/IEC for the protocol, consent form, participant recruitment materials/process (e.g., advertisements), 
and any other written information to be provided to participants. The investigator or sponsor should also 
provide the IRB/IEC with a copy of the Package Insert or product labeling information to be provided to 
participants, and any updates.  
The investigator should provide the IRB/IEC with reports, updates, and other information (e.g., 
expedited safety reports, amendments, and administrative letters) according to regulatory requirements 
or institution procedures. 
3.3 
Informed Consent 
Details regarding the informed consent process are provided in the Manual of Operations.  The rights, 
safety, and well-being of the study participants are the most important considerations and should prevail 
over interests of science and society. 
3.4 
Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report forms 
or other documents submitted to the Sponsor or designee, subjects should be identified by unique initials 
and a subject study number only.  Documents that are not for submission to the Sponsor or designee 
(e.g., signed informed consent/assent forms) should be kept in strict confidence by the Investigator. 
 
4 INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
This study is a randomized placebo-controlled double-blind phase 2 trial of patients with dcSSc.  
Eligible participants will be randomized in a 1:1 ratio to either 125 mg SC abatacept or matching 
placebo, stratified by duration of dcSSc disease duration (<18 months vs >18 to <36 months).  Study 
participants will be treated for 12 months on double-blind study medication, followed by an additional  6 
months of open-label SC abatacept therapy and a 30 day follow-up phone call  upon completion of the 
study. 86 patients will be randomized from approximately 35 centers in the US, Canada and Europe, 
with the goal of analyzing 74 participants. Our study will test whether abatacept is statistically superior 
to placebo in reducing the mRSS at month 12 and explore the ability of abatacept to prevent or reverse 
progression in patients with early disease duration and lower mRSS scores, and reverse established 
disease in patients with longer disease duration and higher MRSS scores. 
The schema below describes the main elements of the study design: 


 
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Escape Therapy 
Starting at Month 6, patients with worsening of skin disease (defined as > 5 units worsening of mRSS) 
have the opportunity to add escape therapy to their randomized study medication (weekly abatacept or 
placebo SC). In addition, worsening of ILD as defined by absolute decline in FVC% predicted by ≥ 10% 
or absolute decline in DLCO% predicted by ≥ 15 (confirmed by repeat pulmonary function testing 
within 1 month) have the opportunity to add escape therapy.  Other indications include: active 
inflammatory polyarthritis or inflammatory myositis. The decision to initiate escape therapy is based on 
investigator discretion in eligible participants. This may include methotrexate, mycophenolate mofetil, 
cyclophosphamide, hydroxychloroquine, azathioprine or intravenous immunoglobulin (IVIG).  This may 
not include other biologic therapies. 
Should a subject worsen at 3 months, the PI may decide that escape therapy should be initiated 
immediately. If this occurs, the subject must be withdrawn from study medication. If the subject agrees 


 
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to continue study follow up (through month 12), participating in visits and procedures, and complying 
with blood/tissue collection, the subject may participate in the open label phase.  
4.2 
Study Population 
Before any study procedures are performed, participants will have the details of the study described to 
them, and they will be given a written informed consent document to read. Then, if participants consent 
to participate in the study, they will indicate that consent by signing and dating the informed consent 
document in the presence of study personnel. 
For entry into the study, the following criteria MUST be met: 
4.2.1 
Inclusion Criteria 
1. Signed Written Informed Consent 
2. Diagnosis of SSc, as defined using the 2013 American College of Rheumatology/ European 
Union League Against Rheumatism classification of SSc 
3. dcSSc as defined by LeRoy and Medsger 
4. Disease duration of ≤ 36 months (defined as time from the first non−Raynaud phenomenon 
manifestation) 
For disease duration of ≤ 18 months  
 ≥ 10 and ≤ 35 mRSS units at the screening visit 
For disease duration of >18-36 months  
 ≥ 15 and ≤ 45 mRSS units at the screening visit and one of the following: 
1. Increase ≥ 3 in mRSS units compared with the last visit within previous 1–6 
months 
2. Involvement of one new body area with ≥ 2 mRSS units compared with the last 
visit within the previous 1–6 months 
3. Involvement of two new body areas with ≥ 1 mRSS units compared with the last 
visit within the previous 1–6 months 
4. Presence of 1 or more Tendon Friction Rub 
5. Age ≥ 18 years at the screening visit 
6. If female of childbearing potential (see 4.2.3), the patient must have a negative pregnancy test at 
screening and baseline visits 


 
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7. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and NSAIDs are permitted if the 
patient is on a stable dose regimen for ≥ 2 weeks prior to and including the baseline visit 
8. ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or oral vasodilators are 
permitted if the patient is on a stable dose for ≥ 2 weeks prior to and including the baseline visit 
For entry into the study, the NONE of the following criteria can be met: 
4.2.2 
Exclusion Criteria 
1. Rheumatic disease other than dcSSc; it is acceptable to include patients with fibromyalgia and 
scleroderma-associated myopathy 
2. Limited cutaneous SSc or sine scleroderma at the screening visit 
3. Major surgery (including joint surgery) within 8 weeks prior to screening visit 
4. Any infected ulcer  prior to randomization 
5. Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational 
drug, whichever is longer) of the baseline visit 
6. Severe (MRSS 3+) skin on the inner aspects of thighs, upper arms, and abdomen  
7. Previous treatment with cell-depleting therapies, including investigational agents, including but 
not limited to, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and ABA 
8. Anti-CD20, and cyclophosphamide within 12 months prior to baseline visit  
 
9.  Use of Intravenous Immunoglobulin (IVIG) within12 weeks prior to baseline visit 
10. Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation 
11. Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to the baseline visit 
12. Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, mycophenolate 
mofetil rapamycin, colchicine, D-penicillamine, within ≤ 4 weeks prior to the baseline visit  
13. Treatment with etanercept within ≤ 2 weeks, infliximab, certolizumab, golimumab, ABA or 
adalimumab within ≤ 8 weeks, anakinra within ≤ 1 week prior to the baseline visit 
14. Pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for hemoglobin) ≤ 40% 
of predicted at the screening visit 
15. Pulmonary arterial hypertension (PAH) as determined by right heart catheterization or on PAH 
approved medications for PAH. It is acceptable to use PDE-5 inhibitors for Raynaud’s and 
digital ulcers. 


 
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16. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will be participants 
with a history of active TB within the last 3 years, even if it was treated; a history of active TB 
greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was 
appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active 
TB; and latent TB that was not successfully treated (≥ 4 weeks). 
17. Positive for hepatitis B surface antigen  prior to the baseline visit 
 
18. Positive for hepatitis C antibody, if the presence of hepatitis C virus was also shown with 
polymerase chain reaction or recombinant immunoblot assay prior to baseline visit 
 
19.  Any of the following prior to the baseline visit: 
 Hemoglobin <8.5 g/dL;  
 WBC < 3,000/mm3 (<3 x 109/L);  
 platelets < 100,000/mm3 (<3 x 109/L);  
 serum creatinine > 2 x ULN; or 
 serum ALT or AST > 2 x ULN 
20. Any other laboratory test results that, in the opinion of the investigator, might place a participant 
at unacceptable risk for participation in the study. 
21. The following medical history and concurrent diseases: 
 Subjects who are impaired, incapacitated, or incapable of completing study-related 
assessments. 
 Subjects with active vasculitis of a major organ system. 
 Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, 
hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, whether or 
not related to SSc and which, in the opinion of the investigator, might place a participant at 
unacceptable risk for participation in the study. 
 Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell 
cancers cured by local resection or carcinoma in situ. Existing non-melanoma skin cell 
cancers should be removed, the lesion site healed, and residual cancer ruled out before 
administration of the study drug. 
 Subjects who currently abuse drugs or alcohol. 


 
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 Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral 
infections at the time of potential enrollment, including participants with evidence of human 
immunodeficiency virus (HIV) detected during screening. 
 Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months prior 
to screening. 
 Subjects with any serious bacterial infection within the last 3 months, unless treated and 
resolved with antibiotics, or any chronic bacterial infection (e.g., chronic pyelonephritis, 
osteomyelitis, or bronchiectasis). 
22. Patients with a history of anaphylaxis to abatacept 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and to ensure that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. 
4.2.3 
Reproductive Status 
Definition of Women of Child-Bearing Potential (WOCBP). WOCBP comprises women who have 
experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal. WOCBP therefore 
includes women using the following methods to prevent pregnancy: Oral contraceptives, other hormonal 
contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical 
products such as intrauterine devices or barrier methods (diaphragm, condoms, spermicides); women 
who are practicing abstinence; and women who have a partner who is sterile (e.g., due to vasectomy). 
The following women are defined as post-menopausal: 
• 
Women who have had amenorrhea for  12 consecutive months (without another cause)  
• 
Women who have irregular menstrual periods and a documented serum FSH level 
> 35 mIU/mL as part of her medical history. 
• 
Women who are taking hormone replacement therapy (HRT). 
WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study 
and for 14 weeks after the last dose of study drug in such a manner that the risk of pregnancy is 
minimized.  
Acceptable methods of contraception are listed below. 
 
 Hormonal methods: combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable) 
 


 
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 Barrier and mechanical methods: intrauterine device (IUD); intrauterine hormone-releasing 
system (IUS), male or female condom with or without spermicide; cap, diaphragm or sponge 
with spermicide 
 
 Bilateral tubal occlusion 
 
 Vasectomised partner (provided that partner is the sole sexual partner of the WOCBP trial 
participant and that the vasectomised partner has received medical assessment of the surgical 
success of the vasectomy) 
 
 True abstinence (where abstinence is a lifestyle choice made by the subject and not only for the 
duration of the trial) 
 
Periodic abstinence (for example, calendar, ovulation, symptom-thermal and post ovulation methods), 
abstinence for the duration of the trial and the withdrawal method are not considered acceptable forms of 
contraception.  
WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 0 to 48 hours before the first dose of study drug.  
Women must not be breast-feeding. 
4.2.4 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and non-investigational product at the discretion of 
the investigator) for any of the following reasons: 
 Withdrawal of informed consent (participant’s decision to withdraw for any reason). 
 Any clinical adverse event, laboratory abnormality, or intercurrent illness which, in the opinion of 
the investigator, indicates that continued participation in the study is not in the best interest of the 
participant. 
 Pregnancy 
 Instruct WOCBP to contact the investigator or study staff immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. Institutional policy and local regulations should determine the frequency of 
on-study pregnancy tests for WOCBP enrolled in the study. 
 Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (e.g., infectious disease) illness. 
 Anaphlaxis or serious allergic reaction 
 


 
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All participants who discontinue should comply with returning to the clinic for an Early Termination 
visit 30 days post last dose of study drug as outlined in Section 6. For subjects whom cannot comply 
with returning to the clinic, then a follow up phone call should occur 30 days post last dose.  The only 
exception to this requirement is when a participant withdraws consent for all study procedures or loses 
the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness). If a participant withdraws before completing the study, the reason for 
withdrawal must be documented appropriately. 
5 TREATMENTS 
5.1 
Study Treatment 
Definition of Investigational Product: A pharmaceutical form of an active substance or placebo being 
tested or used as a reference in a clinical study, including products already with a marketing 
authorization but used or assembled (formulated or packaged) in a way different from the authorized 
form, or used for an unauthorized indication, or when used to gain further information about the 
authorized form. In this protocol, the investigational product is abatacept. 
Definition of Non-Investigational Product: Other medications used in the study as support or escape 
medication for preventative, diagnostic, or therapeutic reasons as components of a given standard of 
care. In this protocol, the non-investigational products are medications used for the management of their 
comorbidities. 
5.1.1 
Identification 
Table 4.1-1: 
Product Description:  
Product Description 
and Dosage Form 
Route of 
Administration 
Potency 
Appearance 
Storage Conditions 
(per label) 
Abatacept Injection 
Subcutaneous 
125mg/syringe 
(125mg/mL) 
Clear to slightly 
opalescent, colorless to 
pale yellow solution, 
essentially free of 
particulate matter on 
visual inspection 
Store refrigerated, 2-8 
deg C (36 – 46 Deg F); 
protect from light; 
protect from freezing) 
Placebo for Abatacept 
Injection 
Subcutaneous 
125mg/syringe 
(125mg/mL) 
Clear to slightly 
opalescent, colorless to 
pale yellow solution, 
essentially free of 
particulate matter on 
Store refrigerated, 2-8 
deg C (36 – 46 Deg F); 
protect from light; 
protect from freezing) 


 
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Table 4.1-1: 
Product Description:  
visual inspection 
5.1.2 
Handling and Dispensing 
 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. 
 The investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity), as described below: 
 Abatacept SC formulations (prefilled syringes) and corresponding placebo should be stored 
under refrigeration (approximately 2 to 8°C) and protected from long-term (more than 24 hours) 
exposure to light. Do not freeze. 
 Abatacept injection, 125 mg/syringe (125 mg/mL) and placebo for SC administration are ready 
to use solutions provided in pre-filled siliconized syringes with a 29 gauge needle.  
 Care should be taken when handling the injectable drug products that are used in this protocol. 
Proper aseptic techniques must be used when preparing and administering sterile parenteral 
products such as abatacept. Parenteral drug products should be inspected visually for particulate 
matter prior to administration. Refer to the Package Insert for additional information regarding 
handling, preparation, and storage of abatacept.  
 If concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product, and contact the DCC immediately. 
5.2 
Drug Ordering and Accountability 
5.2.1 
Initial Orders 
After site activation occurs, the initial drug supply will be sent to the site.  
5.2.2 
Re-Supply 
Subsequent drug supply will be shipped to the site based on site activity. 
5.3 
Method of Assigning Subjects to Treatment 
Patients will be randomized after all screening assessments have been completed and the 
investigator has verified that eligibility criteria have been met.  At the time of randomization, 
patients will be assigned a unique randomization number; no participant may begin treatment 
prior to randomization.  Eligible participants will be randomized to abatacept or placebo in a 1:1 
manner, stratified by dcScc disease duration (<18 months vs >18 to <36 months).  The DCC will 


 
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prepare the randomization schedule, using computer-generated block randomization with the 
block size(s) known only by the DCC.  A secure web-based application will be built that will be 
used by the coordinators to enter participant information (e.g., participant ID, stratification 
factor(s)) and to obtain the randomization number.  The information can be printed and sent 
and/or emailed directly to the site pharmacists. 
5.4 
Selection and Timing of Dose for Each Subject 
The recommended dosage is 125 mg/mL single-dose prefilled glass syringe for subcutaneous injection. 
The injection can be given in front of the thighs, abdomen (except for the 2 inch area around the navel), 
or the outer area of the upper arms. Arms should be performed by caregiver for risk of injection the 
deltoid muscle. The medication will be given on weekly basis for a period of 12 months.  
For a SAE, the dose may be interrupted until the SAE is resolved. The decision to restart the 
investigational drug after an SAE will be local investigator responsibility. For other AEs, the 
investigator will decide on the appropriate action.  
5.5 
Blinding/Unblinding 
 This is a double-blind study.  The study staff (except for select staff at the Data Coordinating 
Center) 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. 
5.6 
Concomitant Treatments  
Patients are allowed to take their medications for underlying comorbidities. Though patients must have a 
stable dose of prednisone or equivalent (<=10 mg/day) and non-steroidal anti-inflammatory agents to 
enter the study the dosage may change after the baseline visit as the local investigator determines. 
Prohibited and/or Restricted Treatments 
Concurrent administration of a TNF antagonist with abatacept has been associated with an increased risk 
of serious infections and no significant additional efficacy over use of the TNF antagonists alone. 
Concurrent therapy with abatacept and TNF antagonists is not recommended. 


 
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The use of live vaccination during the trial and for three months after the last dosage administration is 
not permitted. 
 
5.6.1 
Other Restrictions and Precautions 
Serious infections, including sepsis and pneumonia, have been reported in patients receiving abatacept. 
Some of these infections have been fatal. Many of the serious infections have occurred in patients on 
concomitant immunosuppressive therapy which in addition to their underlying disease could further 
predispose them to infection. Physicians should exercise caution when considering the use of abatacept 
in patients with a history of recurrent infections, underlying conditions which may predispose them to 
infections, or chronic, latent, or localized infections. Patients who develop a new infection while 
undergoing treatment with abatacept should be monitored closely. Administration of abatacept should be 
discontinued if a patient develops a serious infection. For additional information, see Warnings and 
Precautions section 5.1 of the package insert (Appendix I).  
From Abatacept Package Insert (section 5.1): 
Concomitant Use with TNF Antagonists 
In controlled clinical trials in patients with adult RA, patients receiving concomitant ORENCIA and 
TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to 
patients treated with only TNF antagonists (43% and 0.8%, respectively) [see Adverse Reactions (6.1) 
from package insert].  These trials failed to demonstrate an important enhancement of efficacy with 
concomitant administration of ORENCIA with TNF antagonist; therefore, concurrent therapy with 
ORENCIA and a TNF antagonist is not recommended.  While transitioning from TNF antagonist 
therapy to ORENCIA therapy, patients should be monitored for signs of infection. 
5.7 
Treatment Compliance 
Patients will be asked to maintain diaries to record medication taken at home.  These diaries will be 
reviewed by the coordinators at each visit to assess compliance. 
6 STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Study Outcome 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 6.2). 
 Complete medical history. Medical history will be performed as per standard medical care. 


 
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 Physical examination. A standard complete physical examination will be performed, with the 
addition of the assessment of modified Rodnan Skin Score, 28-tender joint count, 28-swollen 
joint count, tendon friction rubs, joint contractures,digital ulcers and skin examination for cancer.  
(See section 6.4). 
 Vital signs. Vital signs will include: pulse, blood pressure, respiratory rate, temperature (C º), 
height (cm), and weight (kg). 
 Pulmonary function tests (PFTs) 
1. Spirometry: Carried out by either certified pulmonary function technologists (National Board 
of Respiratory Care) or experienced staff that meets American Thoracic Society (ATS) 
recommendations61-64. All spirometry equipment and procedures will conform to the most 
recently published standards of the ATS/ERS Task Force. Forced expiratory maneuvers will 
be performed at least in triplicate with the minimal requirement that three maneuvers are 
“acceptable” and that two of these maneuvers meet end-of-test and repeatability criteria for 
FVC and FEV1.  
2. Single-breath diffusing capacity for carbon monoxide (DLCO): performed in accordance 
with recently published ATS/ERS guidelines using equipment and testing techniques that 
meet ATS/ERS requirements61.  At least 2 acceptable tests that meet repeatability criteria will 
be performed and the mean DLCO value (uncorrected for hemoglobin) from acceptable 
measurements will be reported. 
 Scleroderma Autoantibodies: The antibody detection experiments will be performed in the 
divisional laboratories of the University of Texas Health Science Center at Houston, which is also 
the lead site for the NIH funded Scleroderma Family Registry and DNA Repository using plasma.  
Anti-nuclear antibodies and anti-centromere antibodies will be detected by indirect 
immunofluorescence using HEp-2 cell substrates (Antibodies Inc., Davis, CA, USA). Anti–
topoisomerase I, anti-Ro, anti-La, and anti-ribonucleoprotein antibody testing will be performed 
by passive immunodiffusion against calf thymus extract (Inova Diagnostics, San Diego, CA). 
Anti–RNA polymerase III antibodies will be determined by enzyme-linked immunosorbent assay 
(MBL, Nagoya, Japan). Furthermore, less common SSc-related antibodies, anti-fibrillarin, Th/To, 
PM/Scl-75, and PM/Scl-100 antibodies will be detected by a line immunoassay (LIA: 
EUROLINE, Euroimmun, Lubeck, Germany). 
 Skin Biopsy: We will perform two 3-mm skin biopsies at baseline, 3, and 6 months. The skin 
biopsies are required for participation. They will be shipped to Boston University, where one of 
the biopsies from each visit will be shipped in batches to Dartmouth University. 


 
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 Blood samples: 50 ml of blood will be obtained from all study participants at baseline, 1, 3 and 6 
months, and shipped from participating centers to the University of Michigan by an overnight 
express shipping service in insulated shipping containers.  


 
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6.2 
Schedule of Evaluations  
Study Period 
Screening 
Double-Blind Treatment 
Open-Label Treatment 
 
Baseline 
 
Month 
1 
Month 
3 
Month 
6 
Month 
9 
Month 
12j 
Month 
14 
Month 
16 
Month 
18 
End of 
Studyl 
(Phone call) 
Study Week 
≤ -4 
0 
4 
12 
24 
36 
48 
56 
64 
72 
76 
Study Day 
-28 to -1 
0 
28 
84 
168 
252 
336 
392 
448 
504 
534 
Window (in days) 
 
0 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
  Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility (Inclusion/Exclusion) 
Assessment  
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Skin examination for cancer k 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testsa 
 
 
 
 
 
 
 
 
 
 
 
     CBC, Differential, Comp Panel 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
     ESR 
X 
 
 
X 
 
 
X 
 
 
X 
 
     PPD/QuantiFERON/TSpot 
X 
 
 
 
 
 
 
 
 
 
 
     Pregnancy Testb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
    Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
Blood Collection for biomarkers 
(50 mL)c 
 
X 
X 
X 
X 
 
 
 
 
 
 
Skin Biopsyd 
 
X 
 
X 
X 
 
 
 
 
 
 
Echocardiogram and Chest HRCTe 
X 
*if available 
 
 
 
 
 
X 
*if 
available 
 
 
 
 
Pulmonary Function Testsf 
X 
 
 
 
X 
 
X 
 
 
X 
 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
Abatacept Subcutaneous Formulation ISR Protocol 
 
8 December 2015 
41 
Study Period 
Screening 
Double-Blind Treatment 
Open-Label Treatment 
 
Baseline 
 
Month 
1 
Month 
3 
Month 
6 
Month 
9 
Month 
12j 
Month 
14 
Month 
16 
Month 
18 
End of 
Studyl 
(Phone call) 
Study Week 
≤ -4 
0 
4 
12 
24 
36 
48 
56 
64 
72 
76 
Study Day 
-28 to -1 
0 
28 
84 
168 
252 
336 
392 
448 
504 
534 
Window (in days) 
 
0 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
EFFICACY ASSESSMENTS 
mRSS  
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Joint Count, digital ulcer 
assessment, joint contractures, 
tendon friction rubs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Reported Outcomesg 
 
X 
 
X 
X 
 
X 
 
 
X 
 
Exploratory outcomesi 
 
X 
 
X 
X 
 
X 
 
 
X 
 
CLINICAL DRUG SUPPLIES 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Study Drug Supplied 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug Adherence  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a All laboratory samples will be analyzed at local lab 
b For women of child-bearing potential 
c Out of the 45 mL, 10 mL will be used for proteomics analysis, 5 mL will be collected in PAXgene tubes for RNA analysis, 29.5 mL will be used for flow cytometry, and 
0.5 mL for autoantibody measurement 
d Two 3-mm skin biopsies will be collected.  
e Echocardiogram HRCT of Chest is part of standard of care assessments to be performed at the discretion of the PI. The data should be abstracted from the patient records 
at Screening and month 12. Test results from 6 months prior are acceptable.  
f Spirometry with DLCO 
g All Patient-reported outcomes include patient’s and physician’s global assessment, PROMIS-29 2.0, SHAQ-DI, PROMIS fatigue scale, PROMIS sleep disturbance and 
impairment scales, UCLA GIT 2.0 and the PRO-SRSS 
h mRSS will be assessed as one of the inclusion criteria 
i Patient interference with the skin involvement and pain intensity 
j Should a subject terminate early the subject will be brought in to complete all assessments included at the Month 12 visit. Study drug however would not be provided but 


 
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42 
returned at that time. 
k  This skin evaluation will be an assessment of a need for referral to dermatology for formal cancer evaluation and will be assessed alongside every physical exam. 
j  End of Study: A Follow up Phone Call should occur 30 days post completion of OLE (18 month visit) or 30 days post End of double blind (12 month study) should 
participant decides not to enter OLE. Additionally, when a participant discontinues drug, a 30-day post last dose Early Term visit is scheduled; if the participant is unable 
or unwilling to return, a 30 day follow up phone call will suffice.   
 
 
 
 
 


 
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43 
6.3 
Safety Assessments 
All participants who receive a dose of abatacept will be evaluated for safety. Safety outcomes include 
adverse events, clinically significant changes in vital signs, laboratory test abnormalities, and clinical 
tolerability of the drug. The investigator will determine the severity of each adverse event as mild, 
moderate, severe, or very severe. Laboratory findings that the investigator feels are clinically relevant 
should be recorded as adverse events. In addition, the investigator will determine the relationship of the 
adverse event to the administration of the study drug. Any occurrence of an AE/SAE from time of 
consent forward, up to and including follow-up visits will be reported. See Section 7 for the SAE 
Efficacy Assessments 
6.4 
Efficacy Assessments 
6.4.1 
Primary Efficacy Assessments 
The Modified Rodnan skin score 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 disease2, 4. 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 RCTs65-67.  This will be collected at every study 
visit. 
6.4.2 
 Secondary Efficacy Assessments 
 28-Tender joint count: Investigator will assess tenderness of the joints and score them as 
positive or negative. The joints include: proximal interphalangeal joints, metacarpophalangeal 
joints, wrists, elbows, shoulders, and knees. Performed at every visit. 
 28-Swollen joint count: Investigator will assess swelling of the joints and score them as positive 
or negative. The joints include: proximal interphalangeal joints, metacarpophalangeal joints, 
wrists, elbows, shoulders, and knees. Performed at every visit.  
 Patient global assessment for overall disease: This assessment represents the patient’s 
assessment of the patient’s global scleroderma on a 0-10 Likert scale. “On a scale of 0-10, how 
was your overall health in the last week? 0=Excellent; 10=Extremely Poor. Assessed at baseline 
and months 3, 6, 12 and 18. 
 Physician global assessment for overall disease:  This assessment represents the physician’s 
assessment of the patient’s current disease activity on a 0-10 Likert scale. “On a scale of 0-10, 
how was your patient’s overall health in the last week? 0=Excellent; 10=Extremely Poor” . 
Assessed at baseline and months 3, 6, 12 and 18.PROMIS-29 Profile v2.0 measure:  The 
National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information 
System (PROMIS®) Roadmap initiative (www.nihpromise.org) is a cooperative research 


 
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44 
program designed to develop, evaluate, and standardize item banks to measure patient-reported 
outcomes (PROs) across different medical conditions as well as the US population. PROMIS-29 
Profile v2.0 measure contains 29 items, which includes four items each from physical function, 
anxiety, depression, fatigue, sleep disturbance, pain interference, and satisfaction with social 
roles domains, and a single item on pain intensity. With the exception of physical function which 
does not include a time frame, all item banks reference the past 7 days. It is part of the NHLBI-
funded RCT of cyclophosphamide vs. mycophenolate mofetil in SSc-associated interstitial lung 
disease (SSc-ILD).  Assessed at baseline and months 3, 6, 12 and 18. 
 SHAQ-DI: The SHAQ-DI is a disease-targeted, musculoskeletal-targeted measure intended for 
assessing functional ability in arthritis. It is a self-administered 20-question instrument that 
assesses a patient’s level of functional ability and includes questions that involve both upper and 
lower extremities. The SHAQ-DI score ranges from 0 (no disability) to 3 (severe disability). It 
has a 7 day recall period and has been extensively used in SSc65, 67. 5 visual analog scales are 
included  in the scleroderma-HAQ assessing burden of digital ulcers, Raynaud’s, gastrointestinal 
involvement, breathing, and overall disease 68. Assessed at baseline and months 3, 6, 12 and 18. 
 PROMIS Fatigue measure: Apart from assessing the PROMIS-29 measure that assesses 
overall HRQOL, we will assess fatigue as it is one of the common symptoms of patients with 
SSc. We will administer 8-item short form with 1-week recall (available at www.nihpromis.org).  
Assessed at baseline and months 3, 6, 12 and 18. 
 PROMIS sleep disturbance and sleep impairment measures: Sleep disturbances are rated as 
the one of the top complaints from the patients with SSc and will be assessed using 8-items each 
with 1 week recall. (available at www.nihpromis.org).  Assessed at baseline and months 3, 6, 12 
and 18. 
 UCLA SCTC GIT 2.0: This validated instrument assesses scleroderma-related gastrointestinal 
symptoms.  It has 7 scales and a final composite score http://uclascleroderma.researchcore.org.  
Assessed at baseline and months 3, 6, 12 and 18.  
 Combined Response Index in Systemic Sclerosis (CRISS): CRISS is a composite measure for 
early dcSSc. It is determined in a 2-step process that assesses the probability of deterioration 
(step 1) and of improvement (step 2), where each probability ranges from 0.0 to 1.0.  The first 
step assesses whether the patient has had a significant decline in renal or cardiopulmonary 
involvement. The second step assesses the probability of improvement by incorporating changes 
in the modified Rodnan skin score, percent predicted forced vital capacity (FVC), patient and 
physician global assessments, and SHAQ-DI over 1 year.   Assessed at 6 and 12 months. 
 Percent predicted FVC: Assessed at Screening and months 6, 12 and 18.   


 
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6.4.3 
Exploratory Efficacy Assessments 
 Patient interference with the skin involvement in the past month on a 0-10 Likert scale. On a 
scale of 0-10, in the last month how much has your skin involvement interfered with your daily 
activities? 0=Does not limit activity; 10= Very severe limitation. This will be assessed at 
baseline and month 3, 6, 12 and 18. 
 Cardiac involvement at 12 months: New/worsened clinically significant heart disease 
considered secondary SSc, including any of the following: heart failure requiring hospitalization, 
new onset pulmonary hypertension requiring specific treatment, pericardial disease requiring 
intervention or clinical decompensation, and arrhythmias and/or conduction defects requiring 
treatment). 
 New renal crisis at 12 months. 
 Percent predicted DLCO, corrected for hemoglobin. Assessed at months 6, 12, and 18. 
The equation used for adjusting predicted DLCO from hemoglobin is as follows: 
 
For adult males, the equation (expressing Hb in gm•dL-1) is:   
DL,CO,predicted × (1.7Hb / (10.22+Hb)) 
In adult women, the equation is: 
DL,CO,predicted × (1.7Hb / (9.38+Hb)) 
 
 Change from baseline in body mass index at 12 months. 
 Digital ulcer net burden as assessed by the investigator during the trial (after 
randomization to 12 months):  Digital ulcer net burden is defined as the number of overall 
digital ulcers as assessed by the investigator. A digital ulcer is defined as an ulcer at or distal to 
the metacarpophalangeal joint with loss of surface epithelialization. This does not include 
fissures, cracks or calcium extrusion from calcinosis cutis. 
 Pain intensity due to SSc over the past week on a 0-150 mm VAS assessed at baseline, and 3, 6, 
12 and 18 months. 
6.4.4 
Validation of new PRO for Scleroderma-related Skin Symptoms (PRO-SRSS) 
Based on findings from a literature review, qualitative focus groups, and consultation with clinical experts, the 
PRO for Scleroderma-related Skin Symptoms instrument was developed to assess scleroderma-related skin 
thickening among patients with scleroderma. The instrument focuses on seven skin symptoms: skin tightness, skin 
thickening, skin sensitivity, skin color, itchiness, pain from skin tightness, and skin puffiness; the baseline version 
has an additional symptom, skin ulcers. The instrument also assesses limitation to motion of various body parts 
and has several global items.  In the initial assessment, there is a total of 22 items (8 symptom items; 13 limitation 
in motion items; 1 global severity item), and follow-up version includes 22 items (7 symptom items; 13 limitation 
in motion items; 1 global severity; and 1 global rating of change in skin symptoms).  The PRO-SRSS has a 7-day 
recall.  The PRO-SRSS will be administered at baseline and at the 3, 6, 9 and 12 month visits.   


 
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46 
 
7 ADVERSE EVENT REPORTING 
7.1 
Adverse Events 
An Adverse Event (AE) is defined as  
 Any new untoward medical occurrence or worsening of a pre-existing medical condition in a 
patient or clinical investigation participant administered an investigational (medicinal) product 
and that does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of investigational product, whether or 
not considered related to the investigational product. 
 Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants 
should not be questioned regarding the specific occurrence of one or more AEs.) 
7.1.1 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 Results in death 
 Is life-threatening (defined as an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
 Requires inpatient hospitalization or causes prolongation of existing hospitalization (see note 
below for exceptions) 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event, defined as a medical event that may not be immediately life-
threatening or result in death or hospitalization but, based on appropriate medical and scientific 
judgment, may jeopardize the participant or may require intervention (e.g., medical, surgical) to 
prevent one of the other serious outcomes listed above. Examples of such events include but are 
not limited to intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. Potential 
drug induced liver injury (DILI) is also considered an important medical event (see Section 7.6 
for the definition of potential DILI).  


 
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 Suspected transmission of an infectious agent (e.g., any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. 
If any SAE occurs the investigator will report it to the Sponsor (via DCC) within 24 hours of their being 
made aware of the SAE. Although pregnancy, overdose and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs (See Section 7.5 for reporting pregnancies). 
NOTE: The following hospitalizations are not considered SAEs in this study: 
 A visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) 
 Elective surgery planned before signing consent 
 Admissions as per protocol for a planned medical/surgical procedure 
 Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
 Medical/surgical admission for purpose other than remedying ill health state that was planned 
before study entry. Appropriate documentation is required in these cases. 
 Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative). 
7.1.2 
Non-serious Adverse Events 
Non-serious adverse events are all adverse events that are not classified as SAEs. 
7.1.3 
Assignment of Adverse Event Intensity and Relationship to Abatacept 
All adverse events, including those that are serious, will be graded by the investigator as follows: 
 
 Mild (Grade 1): awareness of event but easily tolerated 
 Moderate (Grade 2): discomfort enough to cause some interference with usual activity 
 Severe (Grade 3): inability to carry out usual activity 
 Very Severe (Grade 4): debilitating; significantly incapacitates participant despite 
symptomatic therapy. 
 Death (Grade 5): Death related to AE  
 


 
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The following categories and definitions of causal relationship to investigational product as determined 
by a physician should be used: 
 Related: There is a reasonable causal relationship to investigational product administration 
and the adverse event. 
 Not Related: There is not a reasonable causal relationship between the investigational 
product administration and the adverse event. 
The expression “reasonable causal relationship” is meant to convey in general that there are facts (e.g., 
evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal relationship. 
7.2 
Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a participant. To prevent reporting bias, participants should not be questioned regarding 
the specific occurrence of one or more adverse events. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment required. If 
treatment for the event was administered, it should be recorded in the medical record.   
7.2.1 
Serious Adverse Event Collecting and Reporting  
Following the participant’s written consent to participate in the study, all AE/SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur within 30 days of discontinuation of dosing. 
If applicable, SAEs must be collected that relate to any later protocol-specified procedure (e.g., a follow-
up skin biopsy).  
The investigator should report any SAE occurring after these time periods that is believed to be related 
to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its status of seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy, or a complication of a study procedure), 
the relationship should be specified in the narrative section of the SAE Report Form. 
 
7.2.2 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
The collection of non-serious adverse event (NSAE) information should begin at initiation of study 
drug. NSAE information should also be collected from the start of a placebo lead-in period or other 


 
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49 
observational period intended to establish a baseline status for the participants. NSAEs should be 
followed to resolution or stabilization, or reported as SAEs if they become serious.  
Follow-up is also required for NSAEs that cause interruption or discontinuation of study drug, or those 
that are present at the end of study treatment as appropriate.  
All identified NSAEs must be documented appropriately. 
7.3 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
 Any laboratory test result that is clinically significant or meets the definition of an SAE 
 any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
 any laboratory abnormality that required the participant to receive specific corrective therapy. 
Because some drugs have the potential for drug-related laboratory abnormalities, consider adding 
language specifying which laboratory parameters require follow up and for how long (eg, until 
stabilization or resolution). 
It is expected that whenever possible, the clinical, rather than the laboratory, term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value).   
7.4 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as an 
SAE. 
7.5 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for participant 
safety). Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.  


 
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7.6 
Potential Drug-Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined 
criteria, must be reported as SAEs (see Section 7.2.1 for reporting details). 
Potential drug induced liver injury is defined as:  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), and 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), and 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
7.7 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-
rays, and any other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly. 
8 STATISTICAL CONSIDERATIONS 
8.1 
Sample Size Considerations:  
Previous randomized controlled studies in early dcSSc provide the basis for us to characterize the 
magnitude of treatment differences we could detect with sample sizes of 74-86 participants with a two-
sided Type I error of 5%, 80% power, and a drop-out rate of 15%.  The phase 2 randomized controlled 
trial of recombinant human relaxin vs. placebo in participants studied moderate-to-severe dcSSc patients 
who are similar to those considered for this study.  Khanna et al.65 found no statistically significant 
differences in the change from baseline to week 24 in mRSS between relaxin and placebo.  The pooled 
standard deviation (SD) of the change in mRSS is approximately 7 points.  We conservatively selected a 
larger estimate of the SD for our sample size calculations.  
This phase 2 study is primarily sized based on practical considerations, rather than a desired power for a 
pre-specified difference.  We plan to screen approximately 121 participants in order to randomize 86 
participants to achieve 74 analyzable participants (assuming a 15% attrition rate).  With the proposed 
sample of 74 participants in the study (37 per treatment group), there is at least 80% power to detect a 
24% treatment difference in proportions of participants with adverse events with a two-sided Type I 
error of 5% and a placebo rate of 70% (two-sample test of binomial proportions, East 5.4).  For 
continuous outcomes, there is at least 80% power to detect an effect size of at least 0.66 with a two-


 
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51 
sided Type I error of 5% with this sample size (two-sample t test, East 5.4).  This effect size (treatment 
difference / pooled SD) translates into a treatment difference in change from baseline to month12 in 
mRSS of 5.3 with a SD of 8 points.   If the pooled SD or drop-out rate is smaller, then the given sample 
size would allow for smaller treatment differences to be detected with the same power. 
8.2 
Analyses 
A statistical analysis plan (SAP) will be written for the study, and finalized prior to unblinding of the 
data, that contains more detailed and complete descriptions of the analyses to be performed.   
8.2.1 
Analysis Populations 
Several analysis sets will be used in the analyses of the data: 
• 
Safety Population.  The Safety Population is defined as all participants who are randomized and 
receive at least one dose of study drug.  The Safety Population will be used for all safety analyses.  
Subjects will be analyzed by the treatment received. 
• 
Efficacy Populations.  The main analysis set for efficacy will be the mITT population, defined as 
all participants randomized, receiving at least one dose of study medication, and having at least one 
post-baseline efficacy assessment.  Subjects will be analyzed by assigned treatment.  Membership in the 
analysis populations will be determined before study unblinding. 
8.2.2 
General Approach 
Descriptive summary statistics will be derived for all data at baseline, overall and by treatment group.  
For continuous variables, mean, standard deviation, median, interquartile range, minimum and 
maximum will be reported.  For categorical variables, number and percentages will be reported.  
Graphical methods will be heavily used in this pilot study to assess the pattern of response over time for 
key variables and to assess the relationships among variables. 
We will summarize the extent of missing data over time for the primary endpoint.  We will investigate 
the missing data mechanism (missing at random, not missing at random), which is important for the 
validity of our analytic approaches, through exploratory analysis. Exploratory analyses will include plots 
of the mean profile of mRSS at months 0, 3, 6, 9 and 12 by treatment group for those who have 
complete data throughout the study and those who don’t, as well as plots of the mean change from 
baseline at months 3, 6, 9, and 12 in mRSS in the two treatments within each group (completers and 
non-completers). If the plots reveal consistent differences between completers and non-completers 
within each of the treatment groups, then there is evidence that data are not missing at random. 
If data are missing at random, in the secondary analysis for the primary endpoint, we may fit a linear 
mixed model within a Bayesian framework.  In a Bayesian framework, missing data is treated as an 
additional model parameter to be estimated during model fitting. Missing values are estimated through 


 
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52 
an iterative procedure by imputing them multiple times based on the data model established using the 
most current estimates of the remaining model parameters. If data are not missing at random, the 
analysis will be expanded to include a model for missing data mechanism using a binary variable 
indicating whether an observation is missing or not.  The complete data model will include the linear 
mixed model and a logistic regression model linking the probability that an observation is missing to 
some variables we believe are important in explaining the likelihood of a missing observation (for 
example, in our case, pain or mRSS at previous time point). 
Sensitivity analyses will be carried out to assess the robustness of our conclusions to approaches to deal 
with missing data. 
Two-sided p-values will be reported, and no adjustments for multiplicity will be made.  Thus, p-values 
for secondary and exploratory outcomes will be interpreted with caution. 
8.2.3 
Safety Analyses 
Descriptive summary statistics for adverse and serious adverse events will be reported.  Adverse events 
will be grouped by body system and grade and will be tabulated as numbers and percentages; serious 
adverse events will be enumerated and described as appropriate. The total number of adverse events of 
each grade occurring in the two treatment groups by month 12 will be compared using a Fisher’s exact 
test. Poisson regression or comparable non-parametric methods will be used to compare the total number 
of serious adverse events during the double-blind 12-month period by treatment group.  For laboratory 
and other safety parameters that are continuous, two-sample t-tests or Wilcoxon rank sum tests will be 
performed to compare the two treatment groups. 
8.2.4 
Efficacy Analyses 
Analysis of the Primary Efficacy Endpoint. 
The primary efficacy endpoint is the change from baseline to month 12 in mRSS scores.  For the 
primary analysis, changes in mRSS scores from baseline to month 12 will be compared in the two 
treatment groups using an ANCOVA model with terms for treatment group, duration of dcSSc disease 
(stratification factor) and baseline mRSS score.  If the assumptions of this parametric model are not met, 
an alternative non-parametric model will be used.  Given that the incorporation of escape therapy after 
month 3 is an indication of treatment failure, we will use a last-observation-carried-forward approach to 
reflect the impact of treatment on mRSS at the time just prior to escape therapy.  Sensitivity analyses 
will be used to assess the impact of this approach. 
Additional analyses of mRSS will be conducted to understand the time course of study treatment, and 
escape therapy, on mRSS.  We will analyze mRSS data at months 0 (baseline), 3, 6, 9 and 12 using a 
linear mixed model that includes the fixed effect of time-in-study (expressed as a fraction of a year), the 
interaction between time-in-study and treatment, duration of dcSSc disease (stratification factor), and 


 
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patient specific random effects to account for both heterogeneity among patients and correlation among 
measurements taken on the same participant. To account for the possibility of escape therapy, we will 
define an additional variable that indicates whether a patient initiated escape therapy and if so, the time 
(after month 3) the escape therapy was added to the patient’s randomized study medication. The model 
will account for escape therapy by including, at the time points following the beginning of the patient’s 
escape therapy, an additional interaction term between treatment, escape therapy and time-in-study 
minus time-since-escape-therapy (both expressed as fraction of a year). To test whether there is a 
significant difference in the way mRSS changes over time between the two groups, we will simply test 
whether the interaction term between treatment and time-in-study is significantly different from zero. 
If mRSS does not change linearly as a function of time-in-study, we will extend the linear mixed model 
to include: a polynomial of time-in-study (expressed a fraction of a year) of an appropriate degree, the 
interaction between treatment and the polynomial of time-in-study, duration of dcSSc disease 
(stratification factor), patient specific random effects, and for time points following the beginning of the 
escape therapy, the interaction between treatment, escape therapy and the polynomial of time-in-study 
minus time-since-escape-therapy (both expressed as fractions of a year). In this case, to test whether 
there is a significant difference between the two groups in the way mRSS changes over time, we will 
simply test whether any of the coefficients in the interaction between treatment and the polynomial of 
time-in-study is significantly different from zero.  Given the limited sample size of this phase 2 study, 
we will carefully assess to the fit of these longitudinal models. 
Analyses of Secondary Outcomes. 
Analysis for secondary outcome measures will be performed using a similar approach at to that for the 
primary endpoint.  In a first analysis, we will compare the change in each secondary outcome measure 
from baseline to month 12 between the two treatment groups using an ANCOVA model or its non-
parametric counterpart if the model assumptions aren’t met.  For critical secondary outcomes, a 
longitudinal model (generalized linear mixed model) comparable to that for the primary endpoint will be 
fit.   
Analyses of Exploratory Outcomes. 
Graphical methods will be used to explore the distributions of exploratory outcomes by treatment group, 
and the inter-relationships among the exploratory outcomes and other efficacy outcomes.  Generalized 
linear models will be fit to more formally assess the impact of treatment on the exploratory outcomes, 
adjusting for the duration of dcScc (the stratification factor) and other important covariates.  Non-
parametric methods will be used if distributional assumptions are not met.   
Analyses of Ancillary Objective. 


 
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Descriptive statistics will be used to summarize the change from baseline in the PRO-SRSS at months 3, 6, 
9 and 12.  Statistical models will be built to assess the relationship between this new PRO with other clinical and 
QOL measures in the study to validate its utility in the clinical trials arena. 
9 STUDY MANAGEMENT 
9.1 
Compliance with the Protocol 
9.1.1 
Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in this approved protocol. The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to: 
 IRB/IEC for review and approval/favorable opinion 
 Bristol-Myers Squibb 
 Regulatory Authority(ies), if required by local regulations 
If an amendment substantially alters the study design or increases the potential risk to the participant: (1) 
the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable 
opinion; (2) the revised form must be used to obtain consent from participants currently enrolled in the 
study if they are affected by the amendment; and (3) the new form must be used to obtain consent from 
new participants prior to enrollment. 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
9.2 
Record Retention  
9.2.1 
Record Retention 
Source documents are original documents, data, and records from which the subject’s case report form 
data are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  All original source documents 
supporting entries in the case report forms must be maintained and be readily available. 
The Investigator and the study center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with Section 8 of 
the ICH Guidelines (E6), suitable for inspection at any time by representatives from the Sponsor or 


 
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designee and/or applicable regulatory authorities.  The clinical site’s regulatory document binder 
essential elements should include: 
• 
Subject files containing completed case report forms (eCRFs), informed consents/assents, and 
supporting copies of source documentation 
• 
Study files containing the protocol with all amendments, Package Insert, copies of pre-study 
documentation and all correspondence to and from the IEC/IRB and the Sponsor or designee. 
• 
If drug supplies are maintained at the study center, documentation for proof of receipt, study 
drug accountability records, return of study drug for destruction, final study drug product reconciliation 
statement, and all drug-related correspondence. 
The investigator must retain all study records and source documents for the maximum period required 
by applicable regulations and guidelines, or institution procedures, whichever is longer.  
9.2.2 
Study Drug Records  
It is the responsibility of the investigator to ensure that a current disposition record of investigational 
product is maintained at each study site where study drug is inventoried and dispensed. Records or logs 
must comply with applicable regulations and guidelines.  
9.2.3 
Destruction of Investigational Product  
Study drugs are to be destroyed on site upon BMS approval, it is the investigator’s responsibility to 
ensure that arrangements have been made for disposal, and that procedures for proper disposal have 
been established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained.  
9.3 
Study Monitoring 
Throughout the course of the study, data will be monitored for accuracy and completeness and study 
procedures will be monitored for adherence to the protocol and Good Clinical Practices (GCP). In 
addition to frequent contacts through e-mail and telephone, on-site monitoring visits will be coordinated 
by the Statistical Analysis of Biomedical and Educational Research (SABER) unit at the University of 
Michigan.  SABER (the Data Coordinating Center for this study) will be responsible for operational 
aspects and monitoring of the trial, including annual monitoring visits and/or regular remote source data 
verification.  During the on-site visits, the CRFs will be reviewed for completeness and adherence to the 
protocol, accuracy, consistency of the data, and adherence to local regulations on the conduct of clinical 
research.  The monitor will need access to subject medical records and other study-related records 
needed to verify the entries on the electronic case report forms.  The study monitor will also perform 
drug accountability checks and review the clinical site’s regulatory document binder to assure 
completeness of documentation in all respects of clinical study conduct.   


 
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The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to the ASSET Steering 
Committee to monitor participant enrollment, data collection and patient safety, and evaluate the 
efficacy of this randomized controlled trial of abatacept for the treatment of diffuse cutaneous systemic 
sclerosis. The Data Safety Monitoring Board will consist of at least 3 members. Members are appointed 
by the Investigator Sponsor. Members of the DSMB shall have no financial, scientific, or other conflict 
of interest with the study. The DSMB will meet face to face a minimum of once a year at the call of the 
Chair. In addition, it likely will meet by conference call at intervals of 6 months following the annual 
meeting. 
 
A Medical Safety Monitor, a physician with clinical trials experience and expertise in scleroderma who 
is independent of the conduct of the study, will review all SAEs.   
10 NIH DATA SHARING POLICY 
The mechanistic study is supported by NIH, NIAID, DAIT. NIH has a data sharing policy and 
implementation guidance and the study will follow this 
guidance: http://grants.nih.gov/grants/policy/data_sharing/ 
The goals of the Immunology database and analysis portal at DAIT, NIAID are to accomplish many of 
the guidelines outlined in the NIH sharing policy.  These include: 
 
• accelerating a more collaborative and coordinated research environment 
• creating an integrated database that broadens the usefulness of scientific data and advances 
hypothesis-driven and generating research 
• advancing the pace and quality of scientific discovery while extending the value of scientific data in 
all areas of immunological research 
• promoting rapid availability of important findings, making new discoveries available to the research 
community for further analysis and interpretation 
• providing analysis tools to advance immunological research 
 
11 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
11.1              Use of Stored Samples and Data 
Samples and data collected under this protocol may be used to study effect of abatacept on skin and 
blood gene expression and effect on T-cell biology. No genetic testing will be performed.   
 
11.2               Disposition of Stored Samples and Data 
 Access to stored samples will be limited using a locked freezer.  Samples and data will be stored 
using codes assigned by the investigators.  Data will be kept in password-protected 


 
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computers.  Only investigators will have access to the samples and data. 
 Samples and data acquired will be kept at University of Michigan. Skin biopsies will be housed at 
Boston University and Dartmouth University.  
 At the completion of the protocol (termination), samples and data will be reserved for future, 
unspecified research if the subject has consented to analysis of their specimens outside of this 
protocol. If the subject doesn’t consent to long term storage, the samples will be destroyed at the 
end of the study.  
 Additionally, subjects may decide at any point during the study not to have their samples stored.  In 
this case, the principal investigator will destroy all known remaining samples and report what was 
done to both the subject and to the IRB.  This decision will not affect the subject’s participation in 
this protocol. 
 In the future, other investigators (both at UM and outside) may wish to study these samples and/or 
de-identified data. 
 
12 GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (i.e., not previously described in the Package 
Insert), or that could be associated with the study 
procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(e.g., Investigator Brochure for an unapproved 
investigational product) 
 
 
 


 
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13LIST OF ABBREVIATIONS 
AB 
Antibody  
ACR 
American College of Rheumatology  
AE 
Adverse event 
ALT 
Alanine Transaminase  
APC 
Antigen-Presenting Cell  
ARA 
American Rheumatology Association  
AST 
Aspartate Transaminase  
BCG 
Bacillus Calmette-Guérin  
BMS 
Bristol-Myers Squibb  
BUN 
Blood Urea Nitrogen  
CBC 
Complete Blood Count  
CDC-ACID  
Centers for Disease Control and Prevention Advisory 
Committee on Immunization Practices  
CFR 
Code of Federal Regulations  
CI 
Confidence Interval  
CMV 
Cytomegalovirus  
CRF 
Case Report Forms  
CRP 
C-Reactive Protein  
CTLA 
Cytotoxic T-Lymphocyte Associated  
CXR 
Chest X-Ray  
DMARD 
Disease-Modifying Antirheumatic Drug  
DNA 
Deoxyribonucleic Acid  
D5W 
Dextrose (5%) in Water  
EC 
European Commission  
ESR 
Expedited Safety Report  
EULAR 
European League Against Rheumatism  
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practice  
GGT 
Gamma-Glutamyltransferase  
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor  
HCG 
Human Chorionic Gonadotropin  
HIV 
Human Immunodeficiency Virus  


 
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HLA 
Histocompatibility Leukocyte Antigen  
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee  
IL 
Interleukin  
ILD 
Interstitial Lung Disease 
IND 
Investigational New Drug (Application) 
IRB 
Independent Review Board  
IST 
Investigator-Sponsored Trial 
IU 
International Unit  
IV 
Intravenous  
JRA 
Juvenile Rheumatoid Arthritis  
MHC 
Major Histocompatibility Complex  
MRI 
Magnetic Resonance Imaging  
MRSS 
Modified Rodnan Skin Score 
NPV 
Negative Predictive Value  
NS 
Normal Saline  
NSAE 
Non-Serious Adverse Event 
NSAID 
Non-Steroidal Anti-inflammatory Drug  
OA 
Osteoarthritis  
PCR 
Polymerase Chain Reaction  
PFE 
Phosphodiesterase 
PPD 
Purified Protein Derivative  
PPV 
Positive Predictive Value  
PVC 
Polyvinylchloride  
RA 
Rheumatoid Arthritis  
RF 
Rheumatoid Factor  
SAE 
Serious Adverse Event  
Se 
Sensitivity  
SLE 
Systemic Lupus Erythematosus  
SmPC 
Summary of Product Characteristics  
Sp 
Specificity  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


 
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SWFI 
Sterile Water For Injection  
TB 
Tuberculosis  
TNF 
Tumor Necrosis Factor  
ULN 
Upper Level of Normal  
VAS 
Visual Analog Scale  
WBC 
White Blood Cell  
WOCBP 
Women of Childbearing Potential  
 
 
 


 
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SAP_001.pdf: 
Statistical Analysis Plan 
 
 
 
 
 
 ASSET 
ASSET SAP version 1.0 
06APR2018 
Page 1 of 29 
 
ASSET Statistical Analysis Plan 
 
TRIAL FULL TITLE 
A phase II study to evaluate subcutaneous abatacept vs. placebo in 
diffuse cutaneous systemic sclerosis—a double-blind, placebo-
controlled, randomized controlled trial 
SAP VERSION 
1.0 
SAP VERSION DATE 
06APR2018 
TRIAL STATISTICIAN 
Cathie Spino, DSc 
Protocol Version (SAP 
associated with) 
Protocol Version 4.0 
December 8, 2015 
TRIAL PRINCIPAL 
INVESTIGATOR 
Dinesh Khanna, MD, MS 
SAP AUTHOR(s) 
Cathie Spino, DSc 
 
1 SAP Signatures 
I give my approval for this SAP entitled “ASSET Statistical Analysis Plan,” dated 06APR2018. 
 
Statistician (Author) 
Name:   Cathie Spino, ScD 
 
 
 
Signature:
 
 
Date: 
 
       06APR2018                      
 
 
Statistician Reviewer (As applicable) 
Name:  Robert Parker, ScD 
 
Signature: 
                              
                  
 
Date: 
 
   07 April 2018                                              
 
 
Principal Investigator 
Name:  Dinesh Khanna, MD, MS 
 
Signature: 
 
 
Date: 
 
       06APR2018                       
 
 
 


Statistical Analysis Plan 
 
 
 
 
 
 ASSET 
ASSET SAP version 1.0 
06APR2018 
Page 2 of 29 
2 Table of Contents 
1 
SAP Signatures 
1 
2 
Table of Contents 
1 
3 
Abbreviations and Definitions 
4 
4 
Introduction 
4 
4.1 
Preface 
4 
4.2 
Scope of the analyses 
5 
5 
Study Objectives and End points 
5 
5.1 
Study Objectives 
5 
5.2 
End points 
6 
6 
Study Methods 
7 
6.1 
General Study Design and Plan 
7 
6.2 
Inclusion-Exclusion Criteria and General Study Population 
7 
6.2.1 
Inclusion Criteria 
8 
6.2.2 
Exclusion Criteria 
8 
6.3 
Randomization and Blinding 
9 
6.4 
Study Assessments 
9 
6.5 
Imputation of Dates 
15 
6.6 
Laboratory Reporting 
16 
7 
Sample Size 
17 
8 
General Analysis Considerations 
17 
8.1 
Timing of Analyses 
17 
8.2 
Blinded Data Review 
17 
8.3 
Analysis Populations 
17 
8.3.1 
Modified Intention to Treat Population 
17 
8.3.2 
Per Protocol Population 
18 
8.3.3 
Safety Population 
18 
8.4 
Covariates and Subgroups 
18 
8.4.1 
Multi-center Studies 
18 
8.5 
Missing Data 
18 
8.6 
Interim Analyses and Data Monitoring 
18 
8.7 
Multiple Testing 
19 
9 
Summary of Study Data 
19 
9.1 
Subject Disposition 
19 
9.2 
Protocol Deviations 
19 
9.3 
Demographic and Baseline Variables 
19 
9.4 
Treatment Compliance 
20 
10 Efficacy Analyses 
20 
10.1 
Primary Efficacy Analysis 
20 


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10.2 
Secondary Efficacy Analyses 
20 
10.2.1 
Secondary Analyses of Primary Efficacy End point 
20 
10.2.2 
Analyses of Secondary End points 
21 
10.3 
Exploratory Efficacy Analyses 
21 
11 Safety Analyses 
21 
11.1 
Extent of Exposure 
21 
11.2 
Adverse Events 
21 
11.3 
Deaths, Serious Adverse Events and other Significant Adverse Events 
22 
11.4 
Pregnancies 
23 
11.5 
Clinical Laboratory Evaluations 
23 
11.6 
Prior and Concurrent Medications 
23 
11.7 
Other Safety Measures 
23 
12 Other Analyses 
24 
13 Reporting Conventions 
24 
14 Summary of Changes to the Protocol and/or SAP 
24 
15 References 
27 
16 Listing of Tables, Listings and Figures 
29 
 
 
 


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3 Abbreviations and Definitions 
AE 
Adverse Event 
ALT 
Alanine Transaminase  
AST 
Aspartate Transaminase  
CRF 
Case Report Form 
CMH 
Cochran-Mantel-Haenszel test 
CRISS 
Combined Response Index in Systemic Sclerosis 
DCC 
Data Coordinating Center 
dcSSc 
Diffuse cutaneous systemic sclerosis 
FDA 
Food and Drug Administration 
FVC 
Percent Predicted forced vital capacity   
GGT 
Gamma-Glutamyltransferase  
HAQ 
Health Assessment Questionnaire  
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HIV 
Human Immunodeficiency Virus  
HRCT 
High resolution computer tomography 
HRQOL 
Health-related quality of life 
ILD 
Interstitial lung disease 
IU 
International Unit 
IVIG 
Intravenous Immunoglobulin 
mITT 
Modified intention to treat analysis population 
mRSS 
Modified Rodnan Skin Score 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PROs 
measure patient-reported outcomes 
PRO-SRSS 
PRO for Scleroderma-related Skin Symptoms 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SHAQ-DI 
Scleroderma health assessment questionnaire-disability index 
 
SSc 
Systemic sclerosis 
UCLA SCTC 
GIT 
UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Instrument  
VAS 
Visual analogue scale 
 
4 Introduction 
 
4.1 Preface 
Systemic sclerosis (Scleroderma, SSc) is one of the most fatal rheumatic diseases, and is associated 
with substantial morbidity1 and many detrimental effects on health-related quality of life. Recent years 
have seen a revolution in the development and validation of outcome measures2-4 and refinement of 
trial methodology in SSc.5 This is paralleled by an increased understanding of the pathogenesis of 
SSc6, 7 and development of targeted therapies.8, 9 Modified Rodnan Skin Score (mRSS), a measure of 
skin thickness,10, 11 has been used as the primary outcome measure in clinical trials of diffuse 
cutaneous SSc (called diffuse SSc or dcSSc). The Food and Drug Administration considers 
improvement in mRSS as an approvable end point.  
 
Several observations support the role of activated T cells in the pathogenesis of SSc.  Skin biopsies 
obtained from SSc patients early in their disease demonstrate a perivascular, mononuclear cell 
infiltrate comprised of T cells and macrophage.  T cell activation is a prominent feature in SSc, as 
demonstrated by the presence of increased numbers of T cells bearing activation markers. T and B 
lymphocyte interactions are important in the pathogenesis of SSc, and T cells have been shown to be 


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essential for the production of autoantibodies in this disease.  Finally, treatments directed against 
activated T cells, such as cyclosporine A, or depletion of T cells have resulted in skin softening in 
patients with SSc. 
 
A recent pilot study which evaluated the effect of blockade of T cell co-stimulation with intravenous 
abatacept in patients with dcSSc showed efficacy and not serious or unanticipated adverse events. 
Therefore, we aim to perform a phase II, multi-center double-blind randomized controlled trial of 
subcutaneous abatacept vs. placebo in patients with early dcSSc. 
 
4.2 Scope of the analyses 
These analyses will assess the efficacy and safety of abatacept in comparison with placebo during the 
12-month double-blind period, addressing the primary, secondary and exploratory objectives of study 
through the double-blind period.  The ancillary objective of validating the new PRO for Scleroderma-
related Skin Symptoms (PRO-SRSS), correlative studies (e.g., skin and blood biomarkers), and 
objectives associated with the open-label extension period are not included in this SAP.   
 
5 Study Objectives and End points 
 
5.1 Study Objectives 
 
Primary Objectives 
 
To assess the safety of treatment with abatacept 125 mg SC versus placebo SC given every 
week 
 
To assess the efficacy of treatment with abatacept 125 mg SC versus placebo SC given every 
week on skin fibrosis using the modified Rodnan Skin Score (mRSS) 
 
Secondary Objectives 
To assess the efficacy of treatment with abatacept 125 mg SC versus placebo SC given every week 
on: 
 
Joint tenderness as measured by 28-tender joint count 
 
Joint swelling as measured by 28-swollen joint count 
 
Patient’s and physician’s global assessment on a Likert scale  
 
Health-related quality of life (HRQOL) using PROMIS-29 2.0 
 
Physical function as assessed by the scleroderma health assessment questionnaire-disability 
index (SHAQ-DI) 
 
Fatigue as assessed by the PROMIS Fatigue scale 
 
Sleep as assessed by the PROMIS sleep disturbance and impairment scale 
 
Gastrointestinal symptoms as assessed by UCLA SCTC GIT 2.0 
 
Combined Response Index in Systemic Sclerosis (CRISS) 
 
Percent predicted forced vital capacity  (FVC) 
 
Exploratory Objectives 
To assess the efficacy of treatment with abatacept 125 mg SC versus placebo SC given every week on 
a core set of items developed for a composite index in early dcSSc: 
 
Patient interference with the skin involvement in the past month on a Likert scale 
 
Proportion of participants with new or worsened clinically significant heart disease, 
considered secondary to dcSSc, including congestive heart failure requiring hospitalization, 
new onset pulmonary hypertension requiring treatment, pericardial disease requiring 
intervention or exhibiting clinical decompensation, and arrhythmias and/or conduction defects 
requiring treatment 
 
Proportion of participants with new renal crisis  
 
Percent predicted carbon monoxide diffusing capacity (DLCO), corrected for hemoglobin 
 
FVC (in ml) 


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 
Proportion of subjects with significant ILD defined by a decline in forced vital capacity 
(FVC)% predicted ≥15% (relative), high resolution computer tomography (HRCT) to confirm 
interstitial lung disease (ILD; if previous high resolution computer tomography of chest did 
not show ILD) and FVC% predicted below 80% predicted 
 
Change from baseline in body mass index 
 
Digital ulcer net burden as assessed by the investigator during the trial (baseline to 12 
months)   
 
Pain intensity due to dcSSc over the past week on a 0-150 mm VAS 
 
5.2 End points 
 
5.2.1 
Primary Efficacy End point 
Change from baseline to month 12 in mRSS is the primary end point.   
 
5.2.2 
Secondary Efficacy End points 
 
Change from baseline to month 1, 3, 6, and 9 in mRSS 
 
Change from baseline to month 1, 3, 6, 9 and 12 in: 
o 28-tender joint count 
o 28-swollen joint count 
 
Change from baseline to month 3, 6 and 12 in: 
o Patient global assessment for overall disease 
o Physician global assessment for overall disease 
o PROMIS-29 Profile v2.0 measures in the following domains:  physical function, 
anxiety, depression, fatigue, sleep disturbance, pain interference, and ability to 
participate in social roles and activities, and a single item on pain intensity  
o HAQ-DI overall (HAQ-DI) and 8 categories: Dressing and Grooming, Hygiene, 
Arising, Reach, Eating, Grip, Walking, Common Daily Activities (IADL) 
o Scleroderma-HAQ-DI visual analogue scales (VAS) assessing burden of digital 
ulcers, Raynaud’s, gastrointestinal involvement, breathing, and overall disease 
o PROMIS fatigue measure 
o PROMIS sleep disturbance measure 
o PROMIS sleep impairment measure 
o UCLA SCTC GIT 2.0 final composite score and 7 scales (Reflux, 
Distension/Bloating, Fecal Soilage, Diarrhea, Social Functioning, Emotional 
Wellbeing, and Constipation)  
 
Change from baseline to 6 and 12 months in: 
o Combined Response Index in Systemic Sclerosis (CRISS) 
o Percent predicted FVC 
 
5.2.3 
Exploratory Efficacy End points 
 
Change from baseline to months 3, 6 and 12 in patient interference with the skin involvement  
 
The proportion of participants with cardiac involvement at 12 months, defined as new or 
worsened clinically significant heart disease considered secondary to SSc 
 
The proportion of participants with new renal crisis at 12 months 
 
Change from baseline to months 6 and 12 in percent predicted DLCO, corrected for 
hemoglobin 
 
Change from baseline to months 6 and 12 in FVC (in ml) 
 
The proportion of participants with development of significant ILD  
 
Change from baseline in body mass index at 12 months 
 
Change from baseline to month 12 in digital ulcer net burden  
 
Change from baseline to months 3, 6 and 12 in pain intensity due to SSc over the past week 
on a 0-150 mm VAS  
 


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6 Study Methods 
 
6.1 General Study Design and Plan 
This study is a randomized placebo-controlled double-blind phase 2 trial of patients with dcSSc.  
Eligibility for the study was assessed during a one-month screening period.  Eligible participants were 
randomized in a 1:1 ratio to either 125 mg SC abatacept or matching placebo, stratified by duration of 
dcSSc disease duration (<18 months vs >18 to <36 months).  Study participants were treated for 12 
months on double-blind study medication, followed by an additional  6 months of open-label SC 
abatacept therapy and a 30 day follow-up phone call  upon completion of the study.  
 
86 patients were to be randomized from approximately 35 centers in the US, Canada and Europe, with 
the goal of analyzing 74 participants. Our study was designed to test whether abatacept is statistically 
superior to placebo in reducing the mRSS at month 12, relative to baseline, and explore the ability of 
abatacept to prevent or reverse progression in patients with early disease duration and lower mRSS 
scores, and reverse established disease in patients with longer disease duration and higher MRSS 
scores. 
 
Escape Therapy 
Starting at Month 6, participants with worsening of skin disease (defined as > 5 units worsening of 
mRSS) had the opportunity to add escape therapy to their randomized study medication (weekly 
abatacept or placebo SC). In addition, worsening of ILD as defined by absolute decline in FVC% 
predicted by ≥ 10% or absolute decline in DLCO% predicted by ≥ 15 (confirmed by repeat pulmonary 
function testing within 1 month) had the opportunity to add escape therapy.  Other indications 
included: active inflammatory polyarthritis or inflammatory myositis. The decision to initiate escape 
therapy was based on investigator discretion in eligible participants. Escape therapy included 
methotrexate, mycophenolate mofetil, cyclophosphamide, hydroxychloroquine, azathioprine or 
intravenous immunoglobulin (IVIG).  Other biologic therapies were not acceptable as escape therapy. 
 
Should a participant worsen at 3 months, the PI could decide that escape therapy should be initiated 
immediately. If this occurred, the participant was to be withdrawn from study medication. If the 
subject agreed to continue study follow up (through month 12), participating in visits and procedures, 
and complying with blood/tissue collection, the subject could participate in the open label phase. 
 
The schema below describes the main elements of the study design: 
 
 
6.2 Inclusion-Exclusion Criteria and General Study Population 


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6.2.1 
Inclusion Criteria 
1. Signed Written Informed Consent 
2. Diagnosis of SSc, as defined using the 2013 American College of Rheumatology/ European 
Union League Against Rheumatism classification of SSc 
3. dcSSc as defined by LeRoy and Medsger 
4. Disease duration of ≤ 36 months (defined as time from the first non−Raynaud phenomenon 
manifestation) 
For disease duration of ≤ 18 months  
 
≥ 10 and ≤ 35 mRSS units at the screening visit 
For disease duration of >18-36 months  
 
≥ 15 and ≤ 45 mRSS units at the screening visit and one of the following: 
1. Increase ≥ 3 in mRSS units compared with the last visit within previous 1–6 
months 
2. Involvement of one new body area with ≥ 2 mRSS units compared with the 
last visit within the previous 1–6 months 
3. Involvement of two new body areas with ≥ 1 mRSS units compared with the 
last visit within the previous 1–6 months 
4. Presence of 1 or more Tendon Friction Rub 
5. Age ≥ 18 years at the screening visit 
6. If female of childbearing potential, the patient must have a negative pregnancy test at screening 
and baseline visits 
7. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and NSAIDs are permitted if 
the patient is on a stable dose regimen for ≥ 2 weeks prior to and including the baseline visit 
8. ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or oral vasodilators are 
permitted if the patient is on a stable dose for ≥ 2 weeks prior to and including the baseline visit 
 
6.2.2 
Exclusion Criteria 
1. Rheumatic disease other than dcSSc; it is acceptable to include patients with fibromyalgia and 
scleroderma-associated myopathy 
2. Limited cutaneous SSc or sine scleroderma at the screening visit 
3. Major surgery (including joint surgery) within 8 weeks prior to screening visit 
4. Any infected ulcer  prior to randomization 
5. Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational 
drug, whichever is longer) of the baseline visit 
6. Severe (MRSS 3+) skin on the inner aspects of thighs, upper arms, and abdomen  
7. Previous treatment with cell-depleting therapies, including investigational agents, including but 
not limited to, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and ABA 
8. Anti-CD20, and cyclophosphamide within 12 months prior to baseline visit  
9. Use of Intravenous Immunoglobulin (IVIG) within12 weeks prior to baseline visit 
10. Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid 
irradiation 
11. Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to the baseline visit 
12. Treatment 
with 
methotrexate, 
hydroxychloroquine, 
cyclosporine 
A, 
azathioprine, 
mycophenolate mofetil rapamycin, colchicine, D-penicillamine, within ≤ 4 weeks prior to the 
baseline visit  
13. Treatment with etanercept within ≤ 2 weeks, infliximab, certolizumab, golimumab, ABA or 
adalimumab within ≤ 8 weeks, anakinra within ≤ 1 week prior to the baseline visit 
14. Pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for hemoglobin) ≤ 
40% of predicted at the screening visit 
15. Pulmonary arterial hypertension (PAH) as determined by right heart catheterization or on PAH 
approved medications for PAH. It is acceptable to use PDE-5 inhibitors for Raynaud’s and 
digital ulcers. 
16. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will be participants 
with a history of active TB within the last 3 years, even if it was treated; a history of active TB 


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greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was 
appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active 
TB; and latent TB that was not successfully treated (≥ 4 weeks). 
17. Positive for hepatitis B surface antigen  prior to the baseline visit 
18. Positive for hepatitis C antibody, if the presence of hepatitis C virus was also shown with 
polymerase chain reaction or recombinant immunoblot assay prior to baseline visit 
19.  Any of the following prior to the baseline visit: 
 
Hemoglobin <8.5 g/dL;  
 
WBC < 3,000/mm3 (<3 x 109/L);  
 
platelets < 100,000/mm3 (<3 x 109/L);  
 
serum creatinine > 2 x ULN; or 
 
serum ALT or AST > 2 x ULN 
20. Any other laboratory test results that, in the opinion of the investigator, might place a participant 
at unacceptable risk for participation in the study. 
21. The following medical history and concurrent diseases: 
 
Subjects who are impaired, incapacitated, or incapable of completing study-related 
assessments. 
 
Subjects with active vasculitis of a major organ system. 
 
Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, 
hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, whether 
or not related to SSc and which, in the opinion of the investigator, might place a participant 
at unacceptable risk for participation in the study. 
 
Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell 
cancers cured by local resection or carcinoma in situ. Existing non-melanoma skin cell 
cancers should be removed, the lesion site healed, and residual cancer ruled out before 
administration of the study drug. 
 
Subjects who currently abuse drugs or alcohol. 
 
Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral 
infections at the time of potential enrollment, including participants with evidence of 
human immunodeficiency virus (HIV) detected during screening. 
 
Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months 
prior to screening. 
 
Subjects with any serious bacterial infection within the last 3 months, unless treated and 
resolved with antibiotics, or any chronic bacterial infection (e.g., chronic pyelonephritis, 
osteomyelitis, or bronchiectasis). 
22. Patients with a history of anaphylaxis to abatacept 
 
6.3 Randomization and Blinding 
Patients were randomized after all screening assessments were completed and the investigator verified 
that eligibility criteria were met.  At the time of randomization, patients were assigned a unique 
randomization number; no participant was to begin treatment prior to randomization.  Eligible 
participants were randomized to abatacept or placebo in a 1:1 manner, stratified by dcScc disease 
duration (<18 months vs >18 to <36 months).  The DCC prepared the randomization schedule, using 
computer-generated block randomization with the block size(s) known only by the DCC.  A secure 
web-based application was built for use by the coordinators to enter participant information (e.g., 
participant ID, stratification factor(s)) and to obtain the randomization number.  The information was 
printed and sent and/or emailed directly to the site pharmacists. 
 
6.4 Study Assessments 
 
The following table provides the Schedule of Evaluations used in the study: 
 


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Study Period 
Screening 
Double-Blind Treatment 
Open-Label Treatment 
 
Baseline 
 
Month 
1 
Month 
3 
Month 
6 
Month 
9 
Month 
12j 
Month 
14 
Month 
16 
Month 
18 
End of 
Studyl 
(Phone call) 
Study Week 
≤ -4 
0 
4 
12 
24 
36 
48 
56 
64 
72 
76 
Study Day 
-28 to -1 
0 
28 
84 
168 
252 
336 
392 
448 
504 
534 
Window (in days) 
 
0 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
  Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility (Inclusion/Exclusion) 
Assessment  
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Skin examination for cancer k 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testsa 
 
 
 
 
 
 
 
 
 
 
 
     CBC, Differential, Comp Panel 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
     ESR 
X 
 
 
X 
 
 
X 
 
 
X 
 
     PPD/QuantiFERON/TSpot 
X 
 
 
 
 
 
 
 
 
 
 
     Pregnancy Testb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
    Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
Blood Collection for biomarkers 
(50 mL)c 
 
X 
X 
X 
X 
 
 
 
 
 
 
Skin Biopsyd 
 
X 
 
X 
X 
 
 
 
 
 
 
Echocardiogram and Chest HRCTe 
X 
*if available 
 
 
 
 
 
X 
*if 
available 
 
 
 
 
Pulmonary Function Testsf 
X 
 
 
 
X 
 
X 
 
 
X 
 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EFFICACY ASSESSMENTS 


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Study Period 
Screening 
Double-Blind Treatment 
Open-Label Treatment 
 
Baseline 
 
Month 
1 
Month 
3 
Month 
6 
Month 
9 
Month 
12j 
Month 
14 
Month 
16 
Month 
18 
End of 
Studyl 
(Phone call) 
Study Week 
≤ -4 
0 
4 
12 
24 
36 
48 
56 
64 
72 
76 
Study Day 
-28 to -1 
0 
28 
84 
168 
252 
336 
392 
448 
504 
534 
Window (in days) 
 
0 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
(±10) 
mRSS  
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Joint Count, digital ulcer 
assessment, joint contractures, 
tendon friction rubs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Reported Outcomesg 
 
X 
 
X 
X 
 
X 
 
 
X 
 
Exploratory outcomesi 
 
X 
 
X 
X 
 
X 
 
 
X 
 
CLINICAL DRUG SUPPLIES 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Study Drug Supplied 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug Adherence  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
a All laboratory samples will be analyzed at local lab 
b For women of child-bearing potential 
c Out of the 45 mL, 10 mL will be used for proteomics analysis, 5 mL will be collected in PAXgene tubes for RNA analysis, 29.5 mL will be used for flow cytometry, and 0.5 mL for autoantibody measurement 
d Two 3-mm skin biopsies will be collected.  
e Echocardiogram HRCT of Chest is part of standard of care assessments to be performed at the discretion of the PI. The data should be abstracted from the patient records at Screening and month 12. Test results from 
6 months prior are acceptable.  
f Spirometry with DLCO 
g All Patient-reported outcomes include patient’s and physician’s global assessment, PROMIS-29 2.0, SHAQ-DI, PROMIS fatigue scale, PROMIS sleep disturbance and impairment scales, UCLA GIT 2.0 and the 
PRO-SRSS 
h mRSS will be assessed as one of the inclusion criteria 
i Patient interference with the skin involvement and pain intensity 
j Should a subject terminate early the subject will be brought in to complete all assessments included at the Month 12 visit. Study drug however would not be provided but returned at that time. 
k  This skin evaluation will be an assessment of a need for referral to dermatology for formal cancer evaluation and will be assessed alongside every physical exam. 
j  End of Study: A Follow up Phone Call should occur 30 days post completion of OLE (18 month visit) or 30 days post End of double blind (12 month study) should participant decides not to enter OLE. Additionally, 
when a participant discontinues drug, a 30-day post last dose Early Term visit is scheduled; if the participant is unable or unwilling to return, a 30 day follow up phone call will suffice.   


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 
Given flexibility around subject and care provider scheduling, visits are not required to have 
occurred on a specific date, but rather within a defined window.    
 
Where analyses reference the timing of outcomes and/or covariates, the nominal visit or time 
point as collected in the database will be used.  For instances when there are scheduled visits 
and unscheduled visits in the same analysis time window, scheduled visits will be selected 
over unscheduled visits.  If there are multiple observations for scheduled visits within a 
window, the one closest to the visit target date will be utilized.  Where two observations are 
equi-distant from the target date the later will be utilized.   
 
For determination of escape therapy prior to 3 months, the month 3 visit date will be used; 
i.e., if escape therapy starts prior to the month 3 visit date (not the lower bound, target date, or 
upper bound of the analysis time windows defined below), then the participant will be 
considered to have started escape therapy prior to 3 months.  
 
Analysis Time Windows 
Visit  
Study Month (Day) 
Lower bound of 
Window (Day) 
Target Date (Day) and 
Per protocol window 
Upper bound of 
Window (Day) 
Screening   
-28 
-28 to -1 
-1 
Baseline (0) 
0 
0 
0 
Month 1 (28) 
1 
28 + 10 
56 
Month 3 (84) 
57 
84 + 10 
126 
Month 6 (168) 
127 
168 + 10 
210 
Month 9 (252) 
211 
252 + 10 
294 
Month 12 (336) 
295 
336 + 10 
372 
Month 14 (392)* 
373 
392 + 10 
420 
Month 16 (448)* 
421 
448 + 10 
476 
Month 18 (504)* 
477 
504  + 10 
532 
*note that these visits are not included in the analyses described in this SAP; they will be used in the 
analyses of the open-label extension period. 
 
6.4.1 
Primary Efficacy Assessment 
The primary efficacy end point is based on the Modified Rodnan skin score, 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. 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.  This will be collected at every study visit. 
 
6.4.2 
Secondary Efficacy Assessments 
 
28-Tender joint count: Investigator will assess tenderness of the joints and score them as 
positive or negative. The joints include: proximal interphalangeal joints, metacarpophalangeal 
joints, wrists, elbows, shoulders, and knees. It is performed at every visit. 
 
28-Swollen joint count: Investigator will assess swelling of the joints and score them as 
positive or negative. The joints include: proximal interphalangeal joints, metacarpophalangeal 
joints, wrists, elbows, shoulders, and knees. It is performed at every visit.  


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 
Patient global assessment for overall disease: This assessment represents the patient’s 
assessment of the patient’s global scleroderma on a 0-10 Likert scale. “On a scale of 0-10, 
how was your overall health in the last week? 0=Excellent; 10=Extremely Poor. It is assessed 
at baseline and months 3, 6, 12 and 18. 
 
Physician global assessment for overall disease:  This assessment represents the physician’s 
assessment of the patient’s current disease activity on a 0-10 Likert scale. “On a scale of 0-10, 
how was your patient’s overall health in the last week? 0=Excellent; 10=Extremely Poor” . 
Assessed at baseline and months 3, 6, 12 and 18. 
 
PROMIS-29 Profile v2.0 measure:  The National Institutes of Health (NIH) Patient-Reported 
Outcomes Measurement Information System (PROMIS®) Roadmap initiative 
(www.nihpromise.org) is a cooperative research program designed to develop, evaluate, and 
standardize item banks to measure patient-reported outcomes (PROs) across different medical 
conditions as well as the US population. PROMIS-29 Profile v2.0 measure contains 29 items, 
which includes four items each from physical function, anxiety, depression, fatigue, sleep 
disturbance, pain interference, and satisfaction with social roles domains, and a single item on 
pain intensity. With the exception of physical function which does not include a time frame, 
all item banks reference the past 7 days.  Three scores are available for each PROMIS 
domain:  cumulative score, instrument score and transformed score; the transformed score 
(Tscore) will be the score analysed in this study.  It is assessed at baseline and months 3, 6, 12 
and 18. 
 
SHAQ-DI: The SHAQ consists of the HAQ-DI (8 domains and an overall score) and 6 visual 
analogue scales assessing the burden of pain, digital ulcers, Raynaud’s, gastrointestinal 
involvement, breathing, and overall disease.12 The HAQ-DI is a disease-targeted, 
musculoskeletal-targeted measure intended for assessing functional ability in arthritis. It is a 
self-administered 20-question instrument that assesses a patient’s level of functional ability 
and includes questions that involve both upper and lower extremities. The score for each 
question ranges from 0 (no disability) to 3 (severe disability). There are 8 categories and an 
overall score (HAQ-DI).  It has a 7-day recall period and has been extensively used in SSc.13 
It is assessed at baseline and months 3, 6, 12 and 18. 
 
PROMIS fatigue measure: Apart from assessing the PROMIS-29 measure that assesses 
overall HRQOL, we will assess fatigue as it is one of the common symptoms of patients with 
SSc. We will administer the 8-item short form with 1-week recall (available at 
www.nihpromis.org).  It is assessed at baseline and months 3, 6, 12 and 18. 
 
PROMIS sleep disturbance and sleep impairment measures: Sleep disturbances are rated as 
the one of the top complaints from the patients with SSc and will be assessed using 4 items 
each with 1 week recall. (available at www.nihpromis.org).  They are assessed at baseline and 
months 3, 6, 12 and 18. 
 
UCLA SCTC GIT 2.0: This validated instrument assesses scleroderma-related gastrointestinal 
symptoms.  It has 7 scales and a final composite score (available at 
http://uclascleroderma.researchcore.org.  It is assessed at baseline and months 3, 6, 12 and 18.  
 
Combined Response Index in Systemic Sclerosis (CRISS): CRISS is a composite measure for 
early dcSSc13.14 It is determined in a 2-step process that assesses the probability of 
deterioration (step 1) and of improvement (step 2), where each probability ranges from 0.0 to 
1.0.  The first step assesses whether the patient has had a significant decline in renal or 
cardiopulmonary involvement. The second step assesses the probability of improvement by 
incorporating changes in the modified Rodnan skin score, percent predicted forced vital 
capacity (FVC), patient and physician global assessments, and SHAQ-DI over 1 year.    It is 
assessed at 6 and 12 months. 
 
Percent predicted FVC and FVC are assessed at Screening and months 6, 12 and 18.  The 
calculation of percent predicted FVC is based on equations from Hankinson15 (see table 
below).   
 


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Result name 
Formula 
Age 
(Date of PFT - Date of birth)/365.25 and then rounded down (always down) to the 
nearest integer. 
FVC 
Predicted 
(Reference) 
Where H = height in centimeters and Age = age at last birthday 
  
Caucasian 
Males≥20:           FVC(L) = 0.00018642*H2 + 0.00064*Age - 0.000269*Age2 - 0.1933  
Males<20:           FVC(L) = 0.00018642*H2 - 0.20415*Age + 0.010133*Age2 - 0.2584 
Females≥18:      FVC(L) = 0.00014815*H2 + 0.01870*Age - 0.000382*Age2 - 0.3560  
  
African-American  
Males≥20:           FVC(L) = 0.00016643*H2 - 0.01821*Age - 0.1517 
Males<20:           FVC(L) = 0.00016643*H2 - 0.15497*Age + 0.007701*Age2 - 0.4971 
Females≥18:      FVC(L) = 0.00013606*H2 + 0.00536*Age - 0.000265*Age2 - 0.3039  
   
NOTE 1:  Those subjects who indicate that they are both African American and Mexican-American or 
Hispanic will use the African American reference equations; those subjects who indicate that they are both 
Caucasian and Mexican-American or Hispanic will use the Caucasian reference equations. 
NOTE 2:  Those subjects who indicate that they are Asian will use 0.88x the Caucasian values. 
NOTE 3:  If Race is “Unknown or Not Reported”, then use Caucasian values. 
FVC Percent 
Predicted 
(FVC Observed / FVC Predicted) * 100 
 
 
6.4.3 
Exploratory Efficacy Assessments 
 
Patient interference with the skin involvement in the past month on a 0-10 Likert scale. On a 
scale of 0-10, in the last month how much has your skin involvement interfered with your 
daily activities? 0=Does not limit activity; 10= Very severe limitation. This will be assessed 
at baseline and month 3, 6, 12 and 18. 
 
Cardiac involvement at 12 months: New/worsened clinically significant heart disease 
considered secondary SSc, including any of the following: heart failure requiring 
hospitalization, new onset pulmonary hypertension requiring specific treatment, pericardial 
disease requiring intervention or clinical decompensation, and arrhythmias and/or conduction 
defects requiring treatment). 
 
New renal crisis at 12 months. 
 
Significant ILD defined by a decline in forced vital capacity (FVC)% predicted ≥15% 
(relative), high resolution computer tomography (HRCT) to confirm interstitial lung disease 
(ILD; if previous high resolution computer tomography of chest did not show ILD) and 
FVC% predicted below 80% predicted 
 
Percent predicted DLCO, corrected for hemoglobin. It is assessed at screening, and months 6, 
12, and 18. 
The equation used for adjusting predicted DLCO for hemoglobin is as follows: 
 
For adult males, the equation (expressing Hb in gm•dL-1) is:   
DL,CO,predicted × (1.7Hb / (10.22+Hb)) 
In adult women, the equation is: 
DL,CO,predicted × (1.7Hb / (9.38+Hb)) 
 
 
Height and weight are assessed at baseline and 12 months.  Body mass index is calculated as 
weight (kg) / height x height (m2). 
 
Digital ulcer net burden as assessed by the investigator during the trial (after randomization to 
12 months):  Digital ulcer net burden is defined as the number of overall digital ulcers as 
assessed by the investigator. A digital ulcer is defined as an ulcer at or distal to the 


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metacarpophalangeal joint with loss of surface epithelialization. This does not include 
fissures, cracks or calcium extrusion from calcinosis cutis. 
 
Pain intensity due to SSc over the past week on a 0-150 mm VAS assessed at baseline, and 3, 
6, 12 and 18 months. 
 
6.5 Imputation of Dates 
If partial dates occur, the convention for replacing missing dates for the purpose of calculating derived 
variables is as follows: 
 
For partial original SSc diagnosis dates: (a) if only the day is missing, and the month 
and year match the first dose date, then the day is assigned the first day of the month (01); otherwise 
the day assigned is 15; and (b) if both the day and month are missing then the day/month assigned is 
the first day of July (01JUL), as long as the date is before the first dose date; otherwise, the day/month 
assigned is the first day of January (01JAN). 
 
If start dates are entirely missing for adverse events or medications, then adverse events will be 
classified as treatment‐emergent and medications will be classified as concomitant. For partial AE or 
concomitant medication start dates or end dates, the table below describes the date imputation. 
 
 


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Missing  
Condition – 
START DATE 
Condition – 
END DATE 
Imputation 
Classification 
Start Day 
Start month & 
year match those 
of the first dose 
date 
End date > first 
dose date or 
ongoing 
Set start date = 
first dose date 
AE = treatment-emergent 
& med = concomitant 
End date < first 
dose date 
Set start date = 
01 
AE = not treatment 
emergent & med = prior 
Start year < first 
dose year 
End date > first 
dose date or 
ongoing 
Set start date = 
15 
AE = not treatment-
emergent & med = 
concomitant 
End date < first 
dose date 
Set start date = 
01 
AE = not treatment 
emergent & med = prior 
Start year = first 
dose year and 
start month < 
first dose month 
End date > first 
dose date or 
ongoing 
Set start date = 
15 
AE = not treatment-
emergent & med = 
concomitant 
End date < first 
dose date 
Set start date = 
01 
AE = not treatment 
emergent & med = prior 
Start year = first 
dose year and 
start month > 
first dose month 
All cases 
Set start date = 
15 
AE = treatment-emergent 
& med = concomitant 
Start Day & 
Start Month 
Start year 
matches first 
dose date 
End date > first 
dose date or 
ongoing 
Set start date = 
first dose date 
AE = treatment-emergent 
& med = concomitant 
End date < first 
dose date 
Set start date = 1 
and start month 
= end date 
month 
AE = not treatment 
emergent & med = prior 
Start year < first 
dose year 
All cases 
Set start date = 1 
and start month 
= JAN 
 
Start year > first 
dose year 
All cases 
Set start day =1 
and start month 
= JAN 
AE = treatment-emergent 
& med = concomitant 
End Day 
NA 
All 
Set end date = 
min(last day of 
month, day of 
visit date) 
NA 
End Day & 
End Month 
NA 
All 
Set end day =31 
and end month = 
DEC, or day and 
month of visit 
date if earlier 
NA 
 
 
6.6 Laboratory Reporting  
In general, for quantitative laboratory values reported as “<” or “≤” the lower limit of quantitation 
(LLOQ) or limit of detection (LOD), one‐half of the reported value (i.e., LLOQ/LOD) will be used 
for analysis.. For quantitative laboratory values reported as “>” or “≥” the upper limit of quantitation 
(ULOQ), the reported value (i.e., ULOQ) will be used for analysis.  The number and percentage of 


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subjects with values < or > limits of quantitation or detection will also be provided. 
 
For analysis purposes, repeat laboratory test results will not be used unless the original laboratory 
value is missing or indicated as invalid, in which case the first non‐missing repeat laboratory value 
will be used for data analysis. 
 
7 Sample Size  
Previous randomized controlled studies in early dcSSc provide the basis for us to characterize the 
magnitude of treatment differences we could detect with sample sizes of 74-86 participants with a 
two-sided Type I error of 5%, 80% power, and a drop-out rate of 15%.  The phase 2 randomized 
controlled trial of recombinant human relaxin vs. placebo in participants studied moderate-to-severe 
dcSSc patients who are similar to those considered for this study.  Khanna et al.13 found no 
statistically significant differences in the change from baseline to week 24 in mRSS between relaxin 
and placebo.  The pooled standard deviation (SD) of the change in mRSS is approximately 7 points.  
We conservatively selected a larger estimate of the SD for our sample size calculations.  
 
This phase 2 study was primarily sized based on practical considerations, rather than a desired power 
for a pre-specified difference.  We planned to screen approximately 121 participants in order to 
randomize 86 participants to achieve 74 analyzable participants (assuming a 15% attrition rate).  With 
the proposed sample of 74 participants in the study (37 per treatment group), there is at least 80% 
power to detect a 24% treatment difference in proportions of participants with adverse events with a 
two-sided Type I error of 5% and a placebo rate of 70% (two-sample test of binomial proportions, 
East 5.4).  For continuous outcomes, there is at least 80% power to detect an effect size of at least 
0.66 with a two-sided Type I error of 5% with this sample size (two-sample t test, East 5.4).  This 
effect size (treatment difference / pooled SD) translates into a treatment difference in change from 
baseline to month12 in mRSS of 5.3 with a SD of 8 points.  If the pooled SD or drop-out rate is 
smaller, then the given sample size would allow for smaller treatment differences to be detected with 
the same power. 
 
8 General Analysis Considerations 
 
8.1 Timing of Analyses 
The final analysis of the double-blind period will be performed after all randomized participants have 
completed their 12-month visit or dropped out prior to their 12-month visit, all corresponding data 
have been entered, cleaned, locked and unblinded as per SABER SOPs. This SAP document was 
finalized and approved prior to the double-blind database lock and unblinding. 
 
8.2 Blinded Data Review 
Prior to database lock and the start of any formal analyses, blinded data reviews will be completed, 
including summary statistics of key variables.  This will allow the data for key variables  to be 
examined to identify unusual values that need to be queried and patterns of missing values.   In 
addition, the data reviews will allow the protocol writing committee to assess the format of the data 
presentations.  Note that blinded data reviews incorporate real data but random treatment assignment 
(i.e., investigators do not receive data summarized by actual treatment group, rather they review data 
on two randomly formed groups).  All decisions will be made and documented in this SAP document 
prior to unblinding and database lock. 
 
8.3 Analysis Populations 
All randomized participants will be used in the analyses of subject disposition. 
 
8.3.1 
Modified Intention to Treat Population 
The main analysis set for efficacy is the modified intention to treat (mITT) population, defined as all 
participants randomized and receiving at least one dose of study medication.  Participants are 
analyzed by assigned treatment.  Membership in the mITT analysis population was determined before 


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study unblinding. 
 
8.3.2 
Per Protocol Population 
A per protocol (PP) population is used for sensitivity analyses of the primary end point.  It is defined 
as the mITT population, excluding all participants who have major protocol deviations.  Major 
protocol deviations are defined as eligibility criteria violations for which no exemption was granted, 
study drug compliance <80% and >120% , and receipt of escape medication prior to month 3.   
Membership in the PP analysis population will be determined before study unblinding. 
 
8.3.3 
Safety Population 
The Safety Population is defined as all participants who are randomized and receive at least one dose 
of study drug.  The Safety Population will be used for all safety analyses, as well as demographic and 
baseline analyses.  Subjects will be analyzed by the treatment received if they received the wrong 
treatment for the entire duration of the double-blind period of the study.  
 
8.4 Covariates and Subgroups 
There are a limited number of covariates that will be incorporated in statistical models in our analyses 
because of the relatively small sample size in each treatment group:  the stratification factor duration 
of dcSSc diseaseand baseline outcome measure.  Baseline values of mRSS are available for all 
subjects. We will not impute missing values for other baseline covariates in secondary and 
exploratory analyses in the mITT analysis set. 
 
The primary end point will be summarized by the following subgroups:  (1) baseline mRSS < 22 vs 
>22, (2) baseline SCL-70 positive vs other autoantibodies; and (3) RNA pol 3 positive vs other 
autoantibodies. 
 
8.4.1 
Multi-center Studies 
Given that dcSSc is a relatively rare disease, many centers were required to obtain the required sample 
size.  Study centers will not be incorporated as stratification into the analyses.   Descriptive statistics 
of the primary end point by treatment group, separately by center (Michigan, Toronto [the two largest 
enrolling sites] and the remainder) will be provided.    
 
8.5 Missing Data 
We will summarize the extent of missing data over time for the primary end point.  We will 
investigate the missing data mechanism (missing at random, not missing at random), which is 
important for the validity of our analytic approaches, through exploratory analysis. Exploratory 
analyses will include plots of the mean profile of mRSS at months 0, 3, 6, 9 and 12 by treatment 
group for those who have complete data throughout the study and those who don’t, as well as plots of 
the mean change from baseline at months 3, 6, 9, and 12 in mRSS in the two treatments within each 
group (completers and non-completers). If the plots reveal consistent differences between completers 
and non-completers within each of the treatment groups, then there is evidence that data are not 
missing at random. 
 
The primary analysis of the primary end point (see section 10.1) assumes a missing at random 
mechanism.  If data are not missing at random, we will use a multiple imputation approach within the 
pattern-mixture model framework.16  The imputation models, applied sequentially for each missing 
data pattern, will include baseline mRSS, treatment group, stratification factor (SSc disease duration), 
and demographic variables (age and gender), allowing for the dependence of later time points on 
earlier time points.  The analysis model will include the same covariates used in the primary analysis 
of the primary end point and will incorporate the uncertainty due to imputation in the calculation of 
the standard error, as described by Rubin.17   
 
8.6 Interim Analyses and Data Monitoring 
No formal interim analyses were planned nor carried out for this study.  The study was overseen by a 


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Data and Safety Monitoring Board (DSMB) that reviewed the pooled and by-treatment subject 
disposition, study conduct and safety data approximately every 6 months.   
 
8.7 Multiple Testing 
Two-sided p-values will be reported, and no adjustments for multiplicity will be made.  Thus, p-
values for secondary and exploratory outcomes will be interpreted with caution.  Confidence intervals 
will be provided to summarize treatment differences for efficacy end points. 
 
9  Summary of Study Data 
Descriptive summary statistics will be derived for all data at baseline, separately by treatment 
group and overall.  For efficacy, exploratory and safety data, data will be presented by treatment 
group.  Treatment group will be characterized as “Abatacept” and “Placebo”; for pooled 
summaries, “Overall” will be used as the column heading.  All tables will be annotated with the 
total population size relevant to that table/treatment, including any missing observations. 
 
For continuous variables, mean, standard deviation, median, interquartile range, minimum and 
maximum will be reported.  For categorical variables, number and percentages will be reported 
(excluding missing values).  Graphical methods will be heavily used in this Phase 2 study to assess 
the pattern of response over time for key variables and to assess the relationships among variables. 
 
9.1 Subject Disposition 
The number of participants approached for study participation, the number consented and the number 
who did not consent (including reasons:  screen failures, refusals) will be summarized in a CONSORT 
diagram.  The number of participants who dropped out prior to randomization, and the reasons for 
dropout, will be summarized.  The number randomized and treated and the number who dropped out 
by months 1, 3, 6, 9 and 12 will be provided, as well as the number in each of the analysis populations 
(i.e., mITT, PP, Safety).  Reasons for post-treatment dropout will be provided.    
 
9.2 Protocol Deviations 
Major protocol deviations that exclude a patient from the Per Protocol Population are described in 
section 8.3.2.  A listing of protocol deviations that exclude participants from the Per Protocol 
population will be provided. A listing of participants who receive exemptions for study eligibility will 
also be provided. 
 
9.3 Demographic and Baseline Variables 
Demographic variables include:  age at consent (defined as a continuous variable, e.g., 52.6 years), 
age by category (18 to 35 years, >35 to 55 years, >55 to 75 years, and >75 years), gender, race and 
ethnicity.  
 
Baseline is defined as pre-treatment measures, either at screening (if a measure was only assessed at 
screening) or at baseline (if a measure was assessed at baseline even if also assessed at screening).  
Baseline variables include:   
 
dcSSc disease duration (< 18 vs >18 to <36 months), dcSSc disease duration (analyzed as a 
continuous variable), disease duration since first non-Raynaud’s sign or symptom (years), 
disease duration since Raynaud’s phenomenon (years) 
 
mRSS, percent predicted FVC, percent predicted DLCO corrected for hemoglobin, HAQ-DI, 
SHAQ VAS measures (pain from illness, intestinal problems interfere with daily activities, 
breathing problems interfere with daily activities, Raynaud’s interfere with daily activities, 
finger ulcers interfere with daily activities), physician global assessment, patient global 
assessment, autoantibodies, use of biologics, use of immunosupressives, use of prednisone, 
dose of prednisone, proportions of participants with tendon friction rubs, proportions of 
participants with large joint contractures, swollen joint count, proportion of participants with 
swollen joint count > 0, tender joint count, and proportion of participants with tender joint 
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 
height (cm), weight (kg), creatinine (mg/dL), and hemoglobin (g/dL). 
 
9.4 Treatment Compliance 
Compliance with study medication (injections) will be calculated, for each participant, as the 
proportion of time (weeks) that a participant took the full or partial contents of the syringe.  
Specifically, the percent compliance is calculated as 100 x the ratio of the number of weeks during the 
double-blind period when the participant took the full or partial amount of the syringe divided by the 
number of weeks during the double-blind period during which the participant was expected to take 
study medication. Participants were expected to take study medication unless it was temporarily 
discontinued due to an AE or permanently discontinued due to escape therapy prior to month 3.  The 
study medication log (Form 027), adverse event form (Form 044), serious adverse event form (Form 
045) and final status form (Form 035) are used to derive the compliance measure. 
 
The summary statistics will be produced in accordance with section 9. 
 
10 Efficacy Analyses 
 
10.1  Primary Efficacy Analysis 
The primary efficacy end point is the change from baseline to month 12 in mRSS scores.  The goal of 
the primary analysis will be to test the null hypothesis that the difference between treatments in the 
primary end point is zero.  The analysis will be performed on the mITT population.  For the primary 
analysis, we will use a linear mixed model18 with month in the study (3, 6, 9 and 12) as the unit of 
analysis and the change from baseline in mRSS as the outcome, with terms for treatment group, 
month, the interaction of treatment group with month, baseline mRSS, and duration of dcSSc disease 
(stratification factor).  Study participant will be treated as a random effect to account for both 
heterogeneity among participants and correlation among measurements taken on the same participant.  
An autoregressive (AR(1)) variance-covariance will be assumed. Given that the incorporation of 
escape therapy after month 3 is an indication of treatment failure, we censor primary end point data 
after initiation of escape therapy.   
 
Predicted mean change from baseline to month 12 for an exemplary participant by treatment group 
will be provided, as well as the estimate of the treatment effect at month 12, adjusted for baseline 
covariates, and corresponding 95% confidence interval and p-value for the treatment effect.  
Parameter estimates will be calculated using restricted maximum likelihood (REML) methods, and 
the Kenward-Rogers method will be used to calculate the degrees of freedom. 
 
10.2  Secondary Efficacy Analyses 
 
10.2.1 Secondary Analyses of Primary Efficacy End point 
Several sensitivity analyses will be performed to assess how alternative approaches to missing data 
and model assumptions affect the conclusions of the analysis of the primary outcome: 
 
 
Analysis of the primary efficacy variable as described above will also be performed on the PP 
Population.   
 
Analysis of the primary efficacy variable as described above in the mITT Population, except 
that all primary endpoint data will be incorporated (i.e., no censoring after escape therapy). 
 
Analysis of the primary efficacy variables using time-in-study as a continuous variable 
(expressed as a fraction of a year) instead of the discrete version used in the primary analysis.  
 
If mRSS does not change linearly as a function of time-in-study, we will extend the linear 
mixed model to include: a polynomial of time-in-study (expressed as a fraction of a year) of 
an appropriate degree, the interaction between treatment and the polynomial of time-in-study, 
duration of dcSSc disease (stratification factor), and patient-specific random effects, Given 
the limited sample size of this phase 2 study, we will carefully assess to the fit of these 
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 
Analysis of the primary efficacy variable as described above in the mITT Population, except 
that we will account for the possibility of escape therapy by adding a variable that indicates 
the time (in months) the escape therapy was added to the participant’s randomized study 
medication. The model will account for escape therapy by including, at the time points 
following the beginning of the participant’s escape therapy, the time escape therapy began 
and the interaction term between treatment and time escape therapy began. The model will 
generate adjusted estimates of change in the mRSS score from baseline for each treatment 
group and month.  To test the impact of treatment on mean changes from baseline to month 
12, a linear contrast of the effect of treatment and the interaction of treatment X month will be 
assessed at month 12.  The model is summarized below. 
 
Change in mRSSit =  
  b0 + b1t x TREATMENTi + b2 x MONTHit + b3 x [TREATMENTi * MONTHit ] +  
  b4 x SSc_DURATIONi + b5 x BL_mRSSi +  
  b6 x ESCAPEit + b7 x [TREATMENTi * ESCAPEit ] +  
 
  boi + b1i x TREATMENTi + eit 
 
for i=1, …, n participants, t= 1, 2, 3, 4 (corresponding to 3, 6, 9, 12 months) and ESCAPEit = the 
number of months after escape therapy started.  We assume that residual errors eit (t = 1, 2, 3, 4) for 
participant i are normally distributed with zero mean and 4x4 AR(1) variance-covariance matrix. 
 
10.2.2 Analyses of Secondary End points 
Analysis for secondary outcome measures will be performed using the same approach to that for the 
primary end point, that is, a linear mixed model with censoring of secondary end point data after 
initiation of escape therapy. 
 
10.3  Exploratory Efficacy Analyses 
Graphical methods will be used to explore the distributions of exploratory outcomes by treatment 
group (using boxplots), and the inter-relationships among the exploratory outcomes and the primary 
efficacy end point and the following secondary end points (using scatterplots):  HAQ-DI, percent 
predicted FVC, patient global assessment, physician global assessment and CRISS scores.  Only 
exploratory outcomes assessed at 12 months will be formally tested for treatment differences.  For 
continuous outcomes, ANCOVA models (or non-parametric alternatives) will be used with covariates 
duration of dcScc (stratification factor) and baseline score.  For binary outcomes, Cochran-Mantel-
Haenszel (CMH) tests will be used, stratified by duration of dcScc.  Analyses for the exploratory 
efficacy variables will be performed on the mITT population.  
 
11 Safety Analyses 
Safety data, including AEs, clinical laboratory tests, vital signs, physical examinations, and 
concomitant medication usage will be summarized descriptively by treatment group for the Safety 
Population; select parameters will also be summarized for the entire population (overall).  
 
11.1  Extent of Exposure 
Total participant weeks of exposure to study medication through the month 12 visit will be 
summarized descriptively by treatment group.  Both full and partial amount of drug received will 
count in the assessment of exposure. 
 
 
11.2  Adverse Events 
Treatment-emergent adverse events are AEs that start on or after the first study day treatment is 
administered. The causal relationship of the AE to the study drug is determined by the site PI 
investigator as “not related” or “related”.  Adverse event severity grades are reported according to the 
CTCAE Version 4.0. If the CTCAE does not have a grading for a particular adverse event, the 
Fixed effects 
Random effects 


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severity of the event is reported by the investigator as mild, moderate, severe, or very severe.  In the 
case of multiple occurrences of the same AE within the same subject, AEs will be summarized 
according to the maximum severity reported for each body system and overall.  
 
Descriptive summary statistics for treatment-emergent adverse events (AEs) will be reported.  The 
number of treatment-emergent AEs and the frequencies (number and percentage) of participants with 
one or more treatment-emergent AE will be summarized by treatment group, overall, by severity, and 
by body system.  Coding of adverse events into body system was performed by the study chair for 
adverse events and by the medical monitors for serious adverse events.  All treatment-emergent AEs 
related to study drug will be summarized, as will the frequencies of participants with one or more 
treatment-emergent AE related to study drug.  Similarly, all treatment-emergent AEs causing study 
discontinuation, and frequencies of participants experience these, will be summarized. 
 
A subject listing of all treatment-emergent AEs and treatment-emergent AEs causing study 
discontinuation will be presented.  A subject listing prednisone and rescue (escape) drug use in 
relation to adverse events will be presented. 
 
In addition, the number of treatment-emergent AEs potentially casually related to abatacept will be 
summarized by treatment group.  These were identified in the Investigator’s Brochure and through 
correspondence with BMS. These include: (1) any infection, local or systemic, that requires oral or 
systemic treatment; (2) any new malignancy or reoccurrence, including skin cancers and cancer in 
situ; (3) injection site reaction; (4) new autoimmune disorders, including psoriasis, cutaneous 
vasculitis, Sjogren’s/sicca, E. nodosum, episcleritis; and (5) COPD exacerbation in participants with 
COPD. 
 
In accordance with clincaltrial.gov reporting requirements, the following table summarizing adverse 
events is required and will be provided: 
● Other (Not Including Serious) Adverse Events: A table of anticipated and unanticipated 
events (not included in the serious adverse event table) that exceed 5% within either treatment 
group, grouped by organ system, with number and frequency of such events in each treatment 
group. 
 
Adverse events that occurred after consent and before treatment will be listed. 
 
The summary statistics will be produced in accordance with section 9. 
 
11.3 Deaths, Serious Adverse Events and other Significant Adverse Events 
Descriptive summary statistics for treatment-emergent serious adverse events (SAEs) will be reported.  
The number of treatment-emergent SAEs and the frequencies (number and percentage) of participants 
with one or more treatment-emergent SAE will be summarized by treatment group, overall and by 
body system.  Coding into body system was performed by the medical monitors for SAEs.  All 
treatment-emergent SAEs related to study drug will be summarized, as will the frequencies of 
participants with one or more treatment-emergent SAE related to study drug.  Similarly, all treatment-
emergent SAEs causing study discontinuation, and frequency of participants experiencing these, will 
be summarized.  
 
The number and proportion of participants with at least with one or more treatment-emergent 
infectious and non-infectious SAEs will be summarized. Similarly, the following body systems and 
corresponding SAEs will be summarized:  infections, cardiovascular disorders, gastrointestinal 
disorders, musculoskeletal and connective tissue disorders, skin and subcutaneous tissue disorders, 
vascular disorders, blood and lymphatic system disorders, general disorders and administrative site 
conditions, nervous system disorders, renal and urinary disorders and psychiatric disorders. 
 
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(including the post-treatment follow-up period through month 12) will be presented. 
 
In accordance with clincaltrial.gov reporting requirements, the tables below summarizing deaths and 
SAEs are required: 
● All-Cause Mortality:   A table of all anticipated and unanticipated deaths due to any cause, 
with number and frequency of such events in each treatment group. 
● Serious Adverse Events: A table of all anticipated and unanticipated serious adverse events, 
grouped by organ system, with number and frequency of such events in each treatment group. 
 
The summary statistics will be produced in accordance with section 9. 
 
11.4  Pregnancies 
A listing of all pregnancies occurring after the start of study medication will be provided.  
 
11.5  Clinical Laboratory Evaluations 
Clinical laboratory (complete blood count (CBC) with differential, platelets and ESR, and chemistry) 
test parameters will be summarized using descriptive statistics by study visit and treatment group, as 
both observed value at the time point of interest, change from baseline, and the percent change from 
baseline values.  The summary statistics will be produced in accordance with section 9. 
 
For laboratory and other safety parameters that are continuous, Wilcoxon rank sum tests will be 
performed to compare the two treatment groups for changes from baseline to month 12 (or last time 
point on study medication). 
 
The number and proportion of participants with potential drug-induced liver injury (DILI) over the 
course of the 12-month double-blind period will be summarized in accordance with section 9.  These 
include:  (1) ALT or AST elevation > 3 times the upper limit of normal (ULN), (2) total bilirubin > 2 
x ULN; (3) alkaline phosphatase > 2 x ULN; (4) hemoglobin < 8 mg/dL; (5) decrease in hemoglobin 
> 2 gm/dL; and (6) Hy’s law.  
 
The incidence of clinically-meaningful shifts from baseline for select laboratory measures will be 
provided by treatment group.  These include ALT, AST, total bilirubin, alkaline phosphatase, 
haemoglobin, using the thresholds defined above to define clinically-meaningful shifts from baseline 
to month 12.  In addition, serum creatinine will be summarized, with a 50% worsening from baseline 
to month 12 indicating a clinically meaningful outcome.   
 
11.6 Prior and Concurrent Medications  
 
The proportion of participants on prednisone medications prior to the start of study medication will be 
summarized in the baseline table by treatment group and overall, using summary statistics in 
accordance with section 9. 
 
The proportion of participants who begin escape therapy (overall and by type) will be summarized by 
treatment group and by time point and overall, using summary statistics in accordance with section 9.  
A listing of participants who begin escape therapy and the reason for its initiation will be provided. 
 
No medication coding dictionary was used in this study.  The investigators characterized concomitant 
medications by name, and classified them as escape therapy or not. 
 
11.7  Other Safety Measures 
Vital signs (temperature, respiratory rate, systolic and diastolic blood pressure, and pulse), weight and 
BMI will be summarized using descriptive statistics by clinical visit (through month 12) and treatment 
group, as both observed value at the time point of interest and the change from baseline values. 
 


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12 Other Analyses 
Analyses of the following outcomes will be summarized (in accordance with section 9) and allow for 
further interpretation of the study results.   
 
 
Responder analysis of the percent change from baseline to month 12 in mRSS, dichotomized 
using several different thresholds to define improvement:  20%, 40% and 60%.  Treatment 
differences will be tested use CMH, stratified by duration of dcSSc. 
 
Incidence of clinically meaningful changes in change from baseline to month 12 in mRSS, where 
improvement is defined as change > 5, worsening as change <-5, and no change as -5 < change < 
5. 
 
Incidence of clinically meaningful changes in change from baseline to month 12 in mRSS, where 
improvement is defined as change > 4, worsening as change <-4, and no change as -4 < change < 
4. 
 
Incidence of clinically meaningful changes in change from baseline to month 12 in mRSS, where 
improvement is defined as change >25%, worsening as change <-25%, and no change as -25% < 
change < 25%. 
 
Changes from screening to months 6 and 12 in FEV1 and FEV1/FVC ratio. 
 
Number and proportion of participants who improved, stayed the same, or worsened at month 12 
in chest HRCT findings.   
 
Number and proportion of participants who improved, stayed the same, or worsened at month 12 
in Doppler Echo results.   
 
The proportion of participants with tendon friction rubs at baseline and months 1, 3, 6, 9 and 12.   
 
The proportion of participants with large joint contractures at baseline and months 1, 3, 6, 9 and 
12.   
 
The proportion of participants with small joint contractures at baseline and months 1, 3, 6, 9 and 
12.   
 
13  Reporting Conventions 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 
Estimated parameters, not on the same scale as raw observations (e.g., regression coefficients) 
will be reported to 3 significant figures.  
 
14 Summary of Changes to the Protocol and/or SAP 
The changes from the protocol-specified definitions of aims, outcomes and statistical analytic 
approaches are outlined below.  These changes reflect advances in our knowledge of scleroderma 
since the design of the study in 2013-2014 that were not incorporated as protocol amendments, but 
were discussed during the formation of the Statistical Analysis Plan.  These changes are documented 
herein and represent changes made prior to the database lock. 
 
1. Additional Secondary Objective 
There is a lack of consensus about the way to summarize FVC – using the original scale (ml) or using 
the percent predicted FVC.  To allow for comparison with the literature that supports both approaches, 
we added a secondary objective to include FVC on the original scale. 
 
PROTOCOL: 
N/A 
 
SAP: 
Section 5.1  Study Objectives / Exploratory Objectives 
To assess the efficacy of treatment with abatacept 125 mg SC versus placebo SC given every week on 
FVC (in ml). 


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Section 5.2.3 Exploratory Efficacy End points 
Change from baseline to month 6 and 12 in FVC (in ml). 
 
2. Approach to Handle Missing Data 
We modify the approach to handle missing data for the primary end point using an alternative model 
that is valid under the missing at random mechanism and for which software are more readily 
available in the SAS system – namely, linear mixed effects model which is valid under MAR. 
 
PROTOCOL: 
Section 8.2.2 General Approach of the protocol states: 
If data are missing at random, in the secondary analysis for the primary end point, we may fit a linear 
mixed model within a Bayesian framework.  In a Bayesian framework, missing data are treated as an 
additional model parameter to be estimated during model fitting. Missing values are estimated 
through an iterative procedure by imputing them multiple times based on the data model established 
using the most current estimates of the remaining model parameters 
 
SAP: 
N/A 
 
3. Primary Analysis of the Primary End point 
We modify the approach originally specified for the primary analysis (analysis of covariance using 
last-observation carried forward) to a more contemporary approach using linear mixed effects models 
for repeated measures, which is valid under the missing at random assumptions.   
 
PROTOCOL: 
Section 8.2.4. Efficacy Analyses.  Analysis of the Primary Efficacy End point states: 
The primary efficacy end point is the change from baseline to month 12 in mRSS scores.  For the 
primary analysis, changes in mRSS scores from baseline to month 12 will be compared in the two 
treatment groups using an ANCOVA model with terms for treatment group, duration of dcSSc disease 
(stratification factor) and baseline mRSS score.  If the assumptions of this parametric model are not 
met, an alternative non-parametric model will be used.  Given that the incorporation of escape therapy 
after month 3 is an indication of treatment failure, we will use a last-observation-carried-forward 
approach to reflect the impact of treatment on mRSS at the time just prior to escape therapy.  
Sensitivity analyses will be used to assess the impact of this approach. 
 
SAP: 
Section 10.1.  Primary Efficacy Analysis states: 
The primary efficacy end point is the change from baseline to month 12 in mRSS scores.  The goal of 
the primary analysis will be to test the null hypothesis that the difference between treatments in the 
primary end point is zero.  The analysis will be performed on the mITT population.  For the primary 
analysis, we will use a linear mixed model18 with month in the study (3, 6, 9 and 12) as the unit of 
analysis and the change from baseline in mRSS as the outcome, with terms for treatment group, 
month, the interaction of treatment group with month, baseline mRSS, and duration of dcSSc disease 
(stratification factor).  Study participant will be treated as a random effect to account for both 
heterogeneity among participants and correlation among measurements taken on the same participant.  
An autoregressive (AR(1)) variance-covariance will be assumed. Given that the incorporation of 
escape therapy after month 3 is an indication of treatment failure, we censor primary end point data 
after initiation of escape therapy.   
 
Predicted mean change from baseline to month 12 for an exemplary participant by treatment group 
will be provided, as well as the estimate of the treatment effect at month 12, adjusted for baseline 
covariates, and corresponding 95% confidence interval and p-value for the treatment effect.  
Parameter estimates will be calculated using restricted maximum likelihood (REML) methods, and 
the Kenward-Rogers method will be used to calculate the degrees of freedom. 
 


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4. Secondary Analysis of the Primary End point 
We simplify the approach for the non-linear secondary analysis of the primary end point, eliminating 
the adjustment for escape therapy.  We also include several other sensitivity analyses of the primary 
end point in the SAP that are not discussed in the protocol. 
 
PROTOCOL: 
Section 8.2.4. Efficacy Analyses.  Analysis of the Primary Efficacy End point states: 
If mRSS does not change linearly as a function of time-in-study, we will extend the linear mixed 
model to include: a polynomial of time-in-study (expressed as a fraction of a year) of an appropriate 
degree, the interaction between treatment and the polynomial of time-in-study, duration of dcSSc 
disease (stratification factor), patient specific random effects, and for time points following the 
beginning of the escape therapy, the interaction between treatment, escape therapy and the polynomial 
of time-in-study minus time-since-escape-therapy (both expressed as fractions of a year). In this case, 
to test whether there is a significant difference between the two groups in the way mRSS changes over 
time, we will simply test whether any of the coefficients in the interaction between treatment and the 
polynomial of time-in-study is significantly different from zero.  Given the limited sample size of this 
phase 2 study, we will carefully assess to the fit of these longitudinal models. 
 
SAP: 
Section 10.2.1 Secondary Analyses of Primary Efficacy End point 
 
 
Analysis of the primary efficacy variable as described above will also be performed on the PP 
Population.   
 
Analysis of the primary efficacy variable as described above in the mITT Population, except 
that all primary endpoint data will be incorporated (i.e., no censoring after escape therapy). 
 
Analysis of the primary efficacy variables using time-in-study as a continuous variable 
(expressed as a fraction of a year) instead of the discrete version used in the primary analysis.  
 
If mRSS does not change linearly as a function of time-in-study, we will extend the linear 
mixed model to include: a polynomial of time-in-study (expressed a fraction of a year) of an 
appropriate degree, the interaction between treatment and the polynomial of time-in-study, 
duration of dcSSc disease (stratification factor), and patient-specific random effects, Given 
the limited sample size of this phase 2 study, we will carefully assess to the fit of these 
longitudinal models. 
 
Analysis of the primary efficacy variable as described above in the mITT Population, except 
that we will account for the possibility of escape therapy by adding a variable that indicates 
the time (in months) the escape therapy was added to the participant’s randomized study 
medication. The model will account for escape therapy by including, at the time points 
following the beginning of the participant’s escape therapy, the time escape therapy began 
and the interaction term between treatment and time escape therapy began. The model will 
generate adjusted estimates of change in the mRSS score from baseline for each treatment 
group and month.  To test the impact of treatment on mean changes from baseline to month 
12, a linear contrast of the effect of treatment and the interaction of treatment X month will be 
assessed at month 12.  The model is summarized below. 
 
Change in mRSSit =  
  b0 + b1t x TREATMENTi + b2 x MONTHit + b3 x [TREATMENTi * MONTHit ] +  
  b4 x SSc_DURATIONi + b5 x BL_mRSSi +  
  b6 x ESCAPEit + b7 x [TREATMENTi * ESCAPEit ] +  
 
  boi + b1i x TREATMENTi + eit 
 
for i=1, …, n participants, t= 1, 2, 3, 4 (corresponding to 3, 6, 9, 12 months) and ESCAPEit = the 
number of months after escape therapy started.  We assume that residual errors eit (t = 1, 2, 3, 4) for 
participant i are normally distributed with zero mean and 4x4 AR(1) variance-covariance matrix. 
Fixed effects 
Random effects 


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5. Testing of Safety Outcomes 
We eliminate inferential statistics (hypothesis testing) and focus on descriptive statistics of safety 
outcomes, given the limited power to detect safety signals other than those of large magnitude. 
 
PROTOCOL:   
Section 8.2.3 Safety Analyses states: 
The total number of adverse events of each grade occurring in the two treatment groups by month 12 
will be compared using a Fisher’s exact test.  Poisson regression or comparable non-parametric 
methods will be used to compare the total number of serious adverse events during the double-blind 
12-month period by treatment group.  For laboratory and other safety parameters that are continuous, 
two-sample t-tests or Wilcoxon rank sum tests will be performed to compare the two treatment 
groups. 
 
SAP: 
N/A 
 
6. Analysis Populations 
There is an inconsistency in the protocol with respect to the definition of modified intention-to-treat 
population.  The SAP uses the definition that is more closely aligned with the pure intention-to-treat 
approach. 
 
PROTOCOL: 
Protocol Synopsis states: 
The main population for efficacy will be the modified intention-to-treat population (MITT), defined 
as all participants randomized and receive at least one dose of study drug.   
 
Section 8.2.1 Analysis Populations states: 
The main analysis set for efficacy will be the mITT population, defined as all participants 
randomized, receiving at least one dose of study medication, and having at least one post-baseline 
efficacy assessment 
 
SAP: 
Section 8.3.1.  Modified Intention to Treat Population states: 
The main analysis set for efficacy is the modified intention to treat (mITT) population, defined as all 
participants randomized and receiving at least one dose of study medication.   
 
7. Other Analyses 
Additional analyses of outcomes that were collected, but not explicitly noted in the protocol are 
included to provide further interpretation of study results. 
 
PROTOCOL:  
N/A 
 
SAP: 
See Section 12.  Other Analyses. 
 
15 
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16 Listing of Tables, Listings and Figures 
See separate document.