Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc): A Phase I/II Two Center Safety and Tolerability Study
Phase: PHASE1
Conditions: Systemic Sclerosis, Scleroderma
Sponsor: University of Michigan

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Protocol cover page NCT03274076 
 EVALUATION OF TOFACITINIB IN EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS: A PHASE I/II TWO-
CENTER SAFETY AND TOLERABILITY STUDY  
Version Date: Approved September 17, 2018 
 
 

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EVALUATION OF TOFACITINIB IN  
EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS:  
A PHASE I/II TWO-CENTER SAFETY AND TOLERABILITY STUDY  
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
Dinesh Khanna, MD, MS 
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 
 
 
 
 
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Table of Contents 

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1 
BACKGROUND AND RATIONALE ............................................................................ 6 
1.1   Indication .................................................................................................. 6 
1.2   Background .............................................................................................. 6 
1.2.1 Tofactinib ............................................................................. 6 
1.2.2 Exploratory Mechanistic Endpoints ...................................... 7 
1.2.3 Role of T cells in the Pathogenesis of SSc ........................... 7 
1.2.4 Effects of JAK inhibition on T Cells and Fibroblasts ............. 9 
1.2.5 Clinical Safety of Tofacitinib ............................................... 10 
1.3   Overall Risk/Benefit Assessment ............................................................ 13 
1.4   Study Rationale ...................................................................................... 13 
1.5   Summary of Rationale for Proposed Study ............................................. 13 
1.6   Dose Rationale ....................................................................................... 13 
2 
STUDY OUTCOMES ................................................................................................. 13 
2.1   Primary Outcomes .................................................................................. 13 
2.2   Secondary Outcomes ............................................................................. 13 
2.3   Exploratory Outcomes ............................................................................ 14 
3 
REGULATORY OBLIGATIONS ................................................................................ 14 
3.1   Good Clinical Practice (GCP).................................................................. 14 
3.2   Institutional Review Board (IRB) ............................................................. 15 
3.3   Informed Consent ................................................................................... 15 
3.4   Confidentiality ......................................................................................... 15 
4 
INVESTIGATIONAL PLAN ........................................................................................ 15 
4.1   Study Design and Duration ..................................................................... 15 
4.2   Study Schema ........................................................................................ 16 
4.3   Study Population..................................................................................... 16 
4.4   Inclusion Criteria ..................................................................................... 16 
4.5   Exclusion Criteria .................................................................................... 16 
4.6   Reproductive Status ............................................................................... 19 
4.7   Other considerations for potential subjects ............................................. 20 
4.7.1 Vaccine and Exposure to Infection Guidelines ................... 20 
4.7.2 Elective Surgery ................................................................. 21 
4.8   Discontinuation of subjects from Treatment ............................................ 21 
5 
STUDY TREATMENT ................................................................................................ 22 
5.1  Treatment ................................................................................................ 22 
5.1.1 Identification ...................................................................... 22 
5.2   Method of Assigning Subjects to Treatment ............................................ 23 
5.3   Blinding and Unblinding .......................................................................... 22 
5.4   Concomitant Medications ........................................................................ 23 
5.5   Prohibited Medications............................................................................ 23 
5.5.1 Other Restrictions & Precautions ....................................... 23 
6 
STUDY ASSESSMENTS AND PROCEDURES ........................................................ 24 
6.1   Schedule of Events ................................................................................. 27 
7 
ADVERSE EVENT REPORTING ............................................................................... 30 
7.1   Adverse Events ...................................................................................... 30 

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7.2   Serious Adverse Events .......................................................................... 30 
7.3   Non-Serious Adverse Events .................................................................. 31 
7.4   Assignment of Adverse Events ............................................................... 31 
7.5   Adverse Events – Collection and Reporting ............................................ 31 
7.5.1 Adverse Events of Special Interest .................................... 32 
7.6    Serious Adverse Event-Collection and Reporting ................................... 32 
7.7    Non-Serious Adverse Event Collection and Reporting ........................... 33 
7.8    Laboratory Monitoring ............................................................................ 33 
8 
STATISTICAL CONSIDERATIONS ........................................................................... 33 
8.1   Sample Size Considerations ................................................................... 34 
8.2   Statistical Analyses ................................................................................. 34 
8.2.1 Safety Outcomes ............................................................... 34 
8.2.2 Efficacy (Activity) and Exploratory Outcomes ..................... 34 
9 
STUDY MANAGEMENT ............................................................................................ 35 
9.1   Compliance with protocol ........................................................................ 35 
9.2   Record Retention .................................................................................... 35 
9.3   Study Drug Record ................................................................................. 36 
9.4   Study Drug Destruction ........................................................................... 36 
9.5   Study Monitoring ..................................................................................... 36 
10 RESEARCH OF HUMAN SPECIMENS, SAMPLES OR DATA ................................. 37  
10.1 Use of Stored Samples and Data ........................................................... 37 
10.2 Disposition of Stored Samples and Data ................................................ 37 
11 REFERENCES .......................................................................................................... 37 
 
 
 
 

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Study Synopsis 
Protocol Title:
 
Evaluation of tofacitinib in early diffuse cutaneous systemic sclerosis 
(dcSSc): A phase I/II two center safety and tolerability study  
 
Clinical Phase:
Phase I/II 
 
Sponsor:
This is a Clinical and Research Collaborative study and Dinesh 
Khanna, MD, MS will be the sponsor.  Pfizer will be supplying the 
drug/placebo and study funding (including drug distribution at 2 
sites).   
Accrual Objective:
15 subjects (10 active, 5 placebo) 
 
Accrual Rate:
Enroll over 12 month time period 
Study Duration:
Up to 65-day screening period, 24 weeks of double blind follow up, 
followed by 24 weeks of open label, with a 30 day follow up 
telephone call after permanent discontinuation of medication.  
Research Centers:
2: University of Michigan and University of Pittsburgh 
Research 
Hypothesis: 
Tofacitinib is safe and is well-tolerated in patients with early dcSSc 
Study Schema:
5 mg BID of tofacitinib vs placebo for 24 weeks with an open label 
extension receiving tofacitnib 5mg, BID for 24 weeks.  
 
Primary Outcome:
 
Primary Outcome 
Measure: 
The primary endpoint will be the proportion of participants who 
experience Grade 3 or higher adverse events that occur at or before 
Week 24.  
Secondary Outcomes:  To assess the efficacy of tofacitinib in improving skin thickness in 
early dcSSc 
 To assess the efficacy of tofacitinib in improving skin and 
peripheral whole blood biomarkers in early dcSSc 
 To correlate skin and peripheral whole blood biomarkers with 
clinical efficacy assessments 
Secondary Outcome 
Measures:  
 Number of Grade 3 or higher adverse events that occur at or 
before Week 12 
 Number of Grade 3 (severe) or higher adverse events that occur 
at or before weeks: 12, 36, and 48 
 Number of Grade 2 (moderate) or higher adverse events that 
occur at or before weeks: 12, 24, 36, and 48 
 Number of AE’s of special interest (AESI) at weeks: 12, 24, 36, 
and 48 
 Change in modified Rodnan Skin Score (mRSS) at weeks: 12, 24, 
36, and 48 
 Provisional American College of Rheumatology Combined 
Response Index in Systemic Sclerosis at Weeks 12 , 24, and 48. 
 

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Exploratory 
Outcomes: 
Additionally, to assess the efficacy of treatment using 5mg of 
tofacitinib versus placebo. These endpoints will include any change 
in the following scores at the following time points highlighted below:
 
 Proportion of subjects with mRSS improvement of 20%, 40%, 
and 60% at weeks: 12 and 24 
 Comparison of average, most representative, and maximum skin 
score methodology for mRSS. 
 Physician’s global assessment on a Likert scale at weeks: 12, 24, 
     36 and 48 
 Patient’s global assessment on a Likert scale at weeks: 12, 24, 36 
     and 48 
 Health-related quality of life (HRQOL) using PROMIS-29 2.0 at 
weeks: 12, 24, 36 and 48 
 Physical function as assessed by the scleroderma health  
     assessment questionnaire-disability index (SHAQ-DI) at weeks:  
     12, 24, 36 and 48 
 Gastrointestinal symptoms as assessed by UCLA SCTC GIT 2.0 
at weeks: 12, 24, 36 and 48  
 Scleroderma-related skin symptoms assessed by PRO-SRSS at 
weeks: 12, 24, 36 and 48 
 Percent predicted FVC at weeks: 12, 24, and 48 
 Change in left ventricular ejection fraction at week 24  
Change in tricuspid regurgitation jet at week 24
Correlative Studies:
Skin and biomarkers 
 
Study Design
This is a phase I/II placebo controlled study to evaluate the safety, 
and tolerability of tofacitinib, along with any possible efficacy 
descriptors, as a treatment for dcSSc. The study will enroll 15 
Subjects from 18 to 70 [inclusive] years of age with dcSSc with 
disease duration of < 60 months [from 1st non-Raynaud’s 
phenomenon signs or symptom].  Subjects will be randomized to 
tofacitinib vs placebo in a 2:1 ratio at 5 mg twice a day for 24 weeks. 
Subjects will also be offered to participate in an open label phase 
during which they will receive tofacitinib 5 mg twice a day for 24 
weeks. This study will be conducted over a period of approximately 2 
years. Two sites are expected to participate in this study.  
 
 
 

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1. 
BACKGROUND AND RATIONALE  
The safety and effectiveness of tofacitinib for the treatment of rheumatoid arthritis (RA) has 
been demonstrated in adult subjects.  The Sponsor is conducting an investigational program to 
determine the safety, tolerability, and any possible descriptive indicators of efficacy using 
tofacitinib in subjects >18 and <70 years of age with early diffuse cutaneous systemic sclerosis 
(dcSSc).  
1.1 Indication 
Tofacitinib was approved on 06 November 2012 in the United States at a dose of 5 mg 
twice daily (BID) for the treatment of adults with moderately to severely active RA who 
have had an inadequate response or intolerance to MTX (Methotrexate).  As of 05 
November 2015, tofacitinib 5 mg BID is approved as 2nd line therapy for the treatment 
of adults with moderate to severe RA in 50 countries and marketed in 43 countries 
worldwide including the United States, Canada, Switzerland, Australia and Japan.  
Tofacitinib 10 mg twice daily (BID) is also approved for the treatment of RA in 
3 countries (Switzerland, Russia, and Botswana).  In this protocol, we are using the 
FDA approved dosing of 5 mg BID. It may be used in combination with methotrexate or 
other non-biologic disease modifying anti-rheumatic drugs (DMARDs).  
 
1.2 Background 
1.2.1 Tofactinib 
Tofacitinib is a potent selective inhibitor of the Janus Kinase (JAK) family of kinases with 
a high degree of selectivity against other kinases in the human genome.  In kinase 
assays, tofacitinib inhibits JAK1, JAK2, JAK3 and, to a lesser, extent Tyrosine Kinase 
2 (TyK2).  In cellular settings where JAK kinases signal in pairs, tofacitinib preferentially 
inhibits signaling by heterodimeric receptors associated with JAK3 and/or JAK1 with 
functional selectivity over receptors that signal via pairs of JAK2.  Inhibition of JAK1 and 
JAK3 by tofacitinib blocks signaling through the common gamma chain containing 
receptors for several cytokines, including interleukins (IL) IL-2, -4,-7,-9, -15 and -21.  
These cytokines are integral to lymphocyte activation, proliferation and function, and 
inhibition of their signaling may thus result in modulation of multiple aspects of the 
immune response.  In addition, inhibition of JAK1 will result in attenuation of signaling by 
additional pro-inflammatory cytokines, such as IL-6 and interferon (IFN).  At higher 
exposures inhibition of erythropoietin signaling could occur via inhibition of 
JAK2 signaling. 
 
The safety and effectiveness of tofacitinib for the treatment of RA has been 
demonstrated in adult subjects.  Both 5 mg BID and 10 mg BID dose regimens have 
been studied in adults and demonstrated efficacy.  A greater number of adverse events 
were reported at the 10 mg BID dose level. The sponsor is conducting a safety phase 
1/II trial for subjects aged 18 - 70 for treatment of dcSSc. Tyrosine kinase inhibitors have 
been proposed as logical targets for novel treatment strategies in SSc1, but not much 
attention has yet been given to the possible use of JAK inhibitors in SSc. However, the 
various considerations noted above regarding the pathogenesis of SSc and the target 
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clinical testing of this agent in SSc. The ability of tofacitinib to suppress both Th2 
differentiation and the pro-fibrotic effects of Th2 cytokines, while sparing Treg function is 
a combination of effects that may make this drug especially suitable for SSc 
 
1.2.2 Exploratory Mechanistic Endpoints 
In the human CD4+ T cells, inhibiting JAK1 expression completely suppressed IL-6– 
mediated STAT1 phosphorylation2 and showed that tofacitinib inhibits IL-6 production 
and blocks IL 6 signaling. This is supported by a recent phase 2 randomized controlled 
trial of the interleukin-6 receptor-α inhibitor, tocilizumab patients with SSc.3 This global, 
double-blind, placebo-controlled study enrolled adult patients with progressive SSc of ≤5 
years’ duration from first non-Raynaud sign or symptom. Patients were randomly 
assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo for 48 weeks. 
The primary efficacy endpoint was the difference in mean change from baseline in 
modified Rodnan skin score (mRSS) at week 24. 87 patients received tocilizumab (n=43) 
or placebo (n=44). The primary endpoint showed a treatment difference of –2·70 mRSS 
units (95% CI: –5·85, 0·45) in favor of tocilizumab at week 24 but did not meet statistical 
significance (p=0·0915). At week 48, the treatment difference was –3·55 mRSS units 
(95% CI: −7·23, 0·12), favoring tocilizumab over placebo (p=0·0579). Exploratory 
analysis of lung function showed that fewer patients in the tocilizumab arm had a decline 
in percent predicted forced vital capacity than in the placebo arm by comparison of the 
cumulative distribution (week 48, p=0·0373). Tocilizumab downregulated the expression 
of myeloid-associated genes in the skin and decreased circulating levels of CCL18, a 
chemokine associated with fibrosis and progression of SSc-associated lung disease. 
Rates of adverse events/serious adverse events were not different between tocilizumab 
(42/43 [97·7%]/14/43 [32·6%]) and placebo (40/44 [90·9%]/15/44 [34·1%]). 
 
1.2.3 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. Differentiation into T effector subsets is 
controlled by cytokines secreted by antigen-presenting cells, such as IL-12, IL-23, IL-6 
TGF-beta and others, most of which signal through JAK-STAT pathways4. 
 
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 
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demonstrate a perivascular, mononuclear cell infiltrate comprised of T cells and 
macrophages5-7. T cells are the dominant population of lymphocytes in the skin, and are 
activated6.  T cell infiltration correlate with the skin thickening, suggesting a relation 
between inflammation and fibrosis8. The expression of inducible costimulator (ICOS), 
expressed on activated T cells, is elevated in patients with early dcSSc9. T cells 
transferred from bleomycin-treated mice (a mouse model of SSc) to healthy animals 
induces skin thickening10. 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 cytokines11. 
 
Controversy and ambiguity exists, however, regarding which Th subset may be 
pathogenic in SSc, with the focus largely on the Th2 and Th17 cells12, 13. 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-fibrotic14-16. IL-4 itself also upregulates 
expression type I collagen mRNA17, as well as mRNA for the enzyme lysyl hydroxylase 
2, which contributes to collagen cross-linking18. Moreover, Th2 cells are found in excess 
in the blood of patients with SSc, and in both cutaneous and pulmonary disease. Th2 
cells in bronchoalveolar lavage fluid in SSc associated interstitial lung disease declined 
during treatment with imatinib19, 20.  Th1 mechanisms appear to be anti-fibrotic12, 13.  In 
SSc Treg cells that localize to the skin acquire properties of Th2 cells and produce IL-4 
and IL-1321. 
 
The more recently described Th17 subset is also expanded in SSc blood and skin, and 
has been suspected to be pathogenic22-26, 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 SSc27. Important new evidence suggests that 
although prevalent in SSc skin, the Th17 cells might actually be protective against skin 
fibrosis28.  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 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 SSc29 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. TNIP130), innate immunity (e.g. IRF831), 
transcription factors (e.g. STAT432) and cytokine receptors (e.g. IL2RA33). T cells from 
peripheral blood of women with SSc are activated, as judged by over-expression of 
CD40-ligand due to DNA demethylation34 and that the level of DNA methyltransferase 1 
is significantly decreased in patients with SSc35. 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 patients34 and could explain the female dominance in this condition. 

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In summary, available data suggests that Th2 cells are pathogenic and Th17 cells 
protective in SSc12, 13. 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 
disease20), 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.   
 
1.2.4 Effects of JAK inhibition on T Cells and Fibroblasts 
JAK-STAT signaling is essential for the action of numerous cytokines that are either 
produced by T cells or that act on T cells.  These include cytokines that utilize the so-
called common gamma chain in their receptors (IL-2, -4, -7, -9, -15, -21), those that 
signal through gp130 (e.g. IL-6), cytokines that use dimeric receptors (e.g. IL-12, -23), 
the interferons, IL-10, growth factors and others4.  Inherited deficiencies in JAKs lead to 
significant immune deficiencies with T cell dysfunction, and STAT deficiencies have 
been described that alter immune regulation. 
 
Tofacitinib has effects on both numbers and function of various T and NK cell subsets36-
38. Tofacitinib suppresses production of cytokines following T cell activation by anti-CD3, 
including IL-2, -4, -17 -22 and gamma-interferon, but not IL-239. In this study, IL-4 
production was especially sensitive to low concentrations of tofacitinib. In RA effects on 
Th1 and Th17 cells may be most important40, 41. On the other hand, Th2-driven 
processes are especially sensitive to JAK inhibition42. Interestingly, the function of Tregs 
seems to be relatively resistant to tofacitinib compared to other Teffector subsets43.  
Tofacitinib suppresses the differentiation of Th1, Th2 and Th17 cells through 
heterogeneous and distinct mechanisms.  It also suppresses the in vivo response to 
LPS, lowering levels of TNF and IL-6 while raising the level of IL-102.  Its effect on T cell 
responses may be due in part to suppression of the stimulatory capacity (and of 
CD80/86 expression) of dendritic cells44.  In contrast, the numbers of myeloid-derived 
suppressor cells were increased by tofacitinib in a mouse arthritis model45. 
 
Amelioration of inflammatory arthritis by JAK inhibition may in part reflect effects on 
synovial fibroblasts. JAK-3 is heavily phosphorylated in RA synovium and in synovial 
fibroblasts46. Although TNF does not use a JAK-STAT signaling pathway, TNF induction 
of chemokine secretion was blocked by tofacitinib, a phenomenon that was attributed to 
an autocrine loop involving JAK-STAT dependent type I interferon signaling critical to the 
response to TNF47. Tofacitinib also suppresses production of RANK-ligand (critical for 
osteoclast activation in RA) by both T cells and synovial cells48. 
 
The pro-fibrotic effects of TGF-beta, a critically-important cytokine in SSc, were recently 
reported to occur in part through a JAK-2 dependent pathway, which was inhibited by 
TG10120949. Tofacitinib was not used in these experiments.  However, tofacitinib did 
suppress an animal model of graft-versus-host disease, an immune driven process that 
in some respects resembles SSc50. 

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1.2.5 Clinical Safety of Tofacitinib 
The following data includes two Phase 2 and five Phase 3 double-blind, controlled, 
multicenter trials. In these trials, patients were randomized to doses of tofacitinib 
(XELJANZ)5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) 
monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 
patients) in combination with DMARDs (including methotrexate) and placebo (809 
patients). All seven protocols included provisions for patients taking placebo to receive 
treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on 
uncontrolled disease activity) or by design, so that adverse events cannot always be 
unambiguously attributed to a given treatment 
The long-term safety population includes all patients who participated in a double-blind, 
controlled trial (including earlier development phase studies) and then participated in one 
of two long-term safety studies. The design of the long-term safety studies allowed for 
modification of XELJANZ doses according to clinical judgment. This limits the 
interpretation of the long-term safety data with respect to dose. 
The most common serious adverse reactions were serious infections. 
Overall Infections 
In the seven controlled trials, during the 0 to 3 months’ exposure, the overall frequency 
of infections was 20% in the 5 mg twice daily group, respectively, and 18% in the 
placebo group. 
The most commonly reported infections with XELJANZ were upper respiratory tract 
infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, 
respectively). 
Serious Infections 
In the seven controlled trials, during the 0 to 3 months’ exposure, serious infections were 
reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 
patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice 
daily.  
In the seven controlled trials, during the 0 to 12 months’ exposure, serious infections 
were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice 
daily of XELJANZ. 
The most common serious infections included pneumonia, cellulitis, herpes zoster, and 
urinary tract infection.  
Tuberculosis 
In the seven controlled trials, during the 0 to 3 months’ exposure, tuberculosis was not 
reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice 
daily of XELJANZ. 

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In the seven controlled trials, during the 0 to 12 months’ exposure, tuberculosis was 
reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 
events per 100 patient-years) who received 10 mg twice daily of XELJANZ.  Cases of 
disseminated tuberculosis were also reported. The median XELJANZ exposure prior to 
diagnosis of tuberculosis was 10 months (range from 152 to 960 days)  
Opportunistic Infections (excluding tuberculosis) 
In the seven controlled trials, during the 0 to 3 months’ exposure, opportunistic infections 
were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 
mg twice daily of XELJANZ. 
In the seven controlled trials, during the 0 to 12 months’ exposure, opportunistic 
infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 
mg twice daily of XELJANZ. 
The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 
months (range from 41 to 698 days).  
Malignancy 
In the seven controlled trials, during the 0 to 3 months’ exposure, malignancies 
excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 
events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. 
In the seven controlled trials, during the 0 to 12 months’ exposure, malignancies 
excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who 
received 5 mg twice daily of XELJANZ.  
The most common types of malignancy, including malignancies observed during the 
long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal 
cell, prostate cancer, lymphoma, and malignant melanoma.  
Laboratory Abnormalities 
Lymphopenia:  In the controlled clinical trials, confirmed decreases in absolute 
lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg 
twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of 
exposure. 
Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an 
increased incidence of treated and serious infections. 
Neutropenia: In the controlled clinical trials, confirmed decreases in ANC below 1000 
cells/mm3 occurred in 0.07% of patients for the 5 mg twice XELJANZ groups. There 
were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment 
group. 
There was no clear relationship between neutropenia and the occurrence of serious 
infections. 

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Liver Enzyme Elevations: Confirmed increases in liver enzymes greater than 3 times 
the upper limit of normal (3× ULN) were observed in patients treated with XELJANZ. In 
patients experiencing liver enzyme elevation, modification of treatment regimen, such as 
reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in 
XELJANZ dose, resulted in decrease or normalization of liver enzymes. 
In the controlled monotherapy trials (0–3 months), no differences in the incidence of ALT 
or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg 
twice daily groups. 
In the controlled background DMARD trials (0–3 months), ALT elevations greater than 
3× ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 
10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were 
observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice 
daily, respectively. 
One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 
mg twice daily for approximately 2.5 months. The patient developed symptomatic 
elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× 
ULN, which required hospitalizations and a liver biopsy. 
Lipid Elevations: In the controlled clinical trials, dose-related elevations in lipid 
parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were 
observed at one month of exposure and remained stable thereafter. Changes in lipid 
parameters during the first 3 months of exposure in the controlled clinical trials are 
summarized below: 
 
Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm  
 
Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm  
 
Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients. 
In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to 
pretreatment levels in response to statin therapy. 
In the long-term safety population, elevations in lipid parameters remained consistent 
with what was seen in the controlled clinical trials. 
Serum Creatinine Elevations: In the controlled clinical trials, dose-related elevations in 
serum creatinine were observed with XELJANZ treatment. The mean increase in serum 
creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however, with 
increasing duration of exposure in the long-term extensions, up to 2% of patients were 
discontinued from XELJANZ treatment due to the protocol-specified discontinuation 
criterion of an increase in creatinine by more than 50% of baseline. The clinical 
significance of the observed serum creatinine elevations is unknown. 
Other Adverse Reactions: 
At least 2% or more of patients experiences the following adverse reactions: 
Nasopharyngitis, Diarrhea, Upper Respiratory Infection, Headache, Hypertension 

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1.3 Overall Risk/Benefit Assessment 
This phase I/II study will assess the safety, tolerability and efficacy tofacitinib in patients with 
dcSSc. 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 FDA 
approved drugs for SSc. 
 
1.4  Study Rationale 
This study will evaluate tofacitinib treatment in subjects 18 to 70 years of age with dcSSc in 
placebo controlled trial. This phase I/II study is intended to provide safety, and tolerability 
data sin participants with early dcSSc when dosed to target exposures similar to that used in 
adult participant with RA. 
 
 This study will evaluate safety and tolerability, along with descriptive efficacy and 
pharmacokinetics of tofacitinib as treatment for early dcSSc. After 24 weeks of double blind 
treatment, participants will then be able to continue into the open label phase during which 
they will receive tofacitinib 5 mg twice a day for 24 weeks. The primary objective of this 
study will be to demonstrate acceptable safety and tolerability of tofacitinib in early dcSSc. 
 
1.5 Summary of Rationale for the Proposed Study 
Tyrosine kinase inhibitors have been proposed as logical targets for novel treatment 
strategies in SSc1, but not much attention has yet been given to the possible use of JAK 
inhibitors in SSc. However, the various considerations noted above regarding the 
pathogenesis of SSc and the target effects of tofacitinib provide a compelling case for in 
vitro, animal model and human clinical testing of this agent in SSc. The ability of tofacitinib 
to suppress both Th2 differentiation and the pro-fibrotic effects of Th2 cytokines, while 
sparing Treg function is a combination of effects that may make this drug especially suitable 
for SSc.  
 
1.6 Dose Rationale  
The doses of tofacitinib to be evaluated within this study are selected based on the 
regulatory approval for RA. We plan to administer tofacitinib at 5 mg twice daily (BID), an 
approved dose of tofacitinib in adult RA patients in most countries.  
 
2. 
STUDY OUTCOMES 
2.1 Primary Outcomes 
The primary study endpoint will be the proportion of participants who experience Grade 3 
(severe) or higher adverse events that occur at or before Week 24.  
 
2.2 Secondary Outcomes 
The secondary study endpoints will include: 
 
Number of Grade 3(severe) or higher adverse events that occur at or before 
Weeks 12, 36, and 48 

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 
Number of Grade 2 (moderate) or higher adverse events that occur at or before 
Weeks 12, 24, 36, and 48 
 
Number of AE’s of special interest (AESI) at Weeks 12, 24, 36, and 48 
 
Change in modified Rodnan Skin Score (mRSS) at Weeks 12, 24, 36, and 48 
 
Provisional American College of Rheumatology Combined Response Index in  
Systemic Sclerosis at Weeks 12 , 24, and 48. 
2.3 Exploratory Outcomes 
To assess the efficacy of treatment using 5mg of tofacitinib versus placebo. These 
exploratory study endpoints will include any change in the following scores at the 
following time points highlighted below. 
 
Proportion of subjects with mRSS improvement of 20%, 40%, and 60% at weeks: 
12 and 24 
 
Comparison of average, most representative, and maximum skin score  
methodology for mRSS  
 
Physician’s global assessment on a Likert scale at weeks: 12, 24,36 and 48 
 
Patient’s global assessment on a Likert scale at weeks: 12, 24,36 and 48 
 
Health-related quality of life (HRQOL) using PROMIS-29 2.0 at weeks: 12, 24,36 
and 48 
 
Physical function as assessed by the scleroderma health assessment 
questionnaire-disability index (SHAQ-DI) at weeks: 12, 24,36 and 48 
 
Gastrointestinal symptoms as assessed by UCLA SCTC GIT 2.0 at weeks: 12, 
24,36 and 48  
 
Scleroderma-related skin symptoms assessed by PRO-SRSS at weeks: 12, 24, 
36 and 48 
 
Percent predicted FVC at weeks: 12, 24, and 48 
 
Change in left ventricular ejection fraction at week 24  
 
Change in tricuspid regurgitation jet at week 24  
 
3. REGULATORY OBLIGATIONS 
3.1 Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by 
the International Conference on Harmonization (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 

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study personnel where sanctions have been invoked or where there has been scientific 
misconduct or fraud (e.g., loss of medical licensure; debarment). 
 
3.2 Institutional Review Board 
The investigator must have written and dated approval/favorable opinion from the IRB for 
the protocol, consent form, participant recruitment materials/process (e.g., advertisements), 
along with any other written information that is planned to be provided to participants, prior 
the initiation of the study.  
 
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 local institution procedures. 
 
3.3 Informed Consent 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, before any 
study-specific activity is performed, unless a waiver of informed consent has been granted 
by an IRB/EC.  The investigator will retain the original of each subject's signed consent 
document. 
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 is a phase I/II placebo controlled study to evaluate the efficacy, safety, and tolerability, 
and pharmacokinetics of tofacitinib as a treatment for early dcSSc. The study will enroll 
approximately 15 Subjects from 18 to 70 [inclusive] years of age with active dcSSc. Subjects 
will be randomized to tofacitinib vs. placebo in a 2:1 ratio at 5 mg twice a day for 24 weeks. 
Subjects will be able to continue into the open label phase during which they will receive 
tofacitinib 5 mg twice a day for 24 weeks. There will be also be a follow up phone call which 
will occur 30 days post completing/discontinuing study medication. This study will be 
conducted over a period of approximately 2 years. Two sites are expected to participate in 
this study. 
 
 
 

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4.2   Study Schema 
 
 
 
4.3 Study Population 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken 
into consideration when deciding whether a particular subject is suitable for this protocol. 
Subjects will be able to participate with this study drug in combination with methotrexate or 
other non-biologic immunosuppressive agents.  
 
4.4 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study: 
1. Diagnosis of SSc, as classified using the 2013 American College of Rheumatology/ 
European Union League Against Rheumatism classification of SSc51. 
2. dcSSc as defined by 2001 LeRoy and Medsger52 
3. Disease duration ≤ 60 months (defined as time from the first non−Raynaud 
phenomenon manifestation) 
4. mRSS units ≥ 10 and ≤ 45 at screening. 
5. Agreement to receive varicella-zoster vaccination or have received vaccination 
prior to screening.  
6. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) are permitted if the 
patient is on a stable dose regimen for ≥ 2 weeks prior to and including the 
baseline visit. 
7. PDFE-5 inhibitors for Raynaud’s and digital ulcers are permitted to use as oral 
monotherapy 
8. Age ≥ 18 years and ≤ 70 years 
9. Ability to provide informed consent. 
 
4.5 Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the study: 
 

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1. Rheumatic disease other than dcSSc; it is acceptable to include patients with 
fibromyalgia, Sjogren syndrome, and scleroderma-associated myopathy 
2. Limited cutaneous SSc or sine scleroderma 
3. Significant trauma or major surgery (including joint surgery) within 8 weeks prior to 
baseline. 
4. Any infected ulcer at screening 
5. 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) 
6. Oral corticosteroids >10 mg/day of prednisone or equivalent. 
7. Treatment with anti-CD20 6 months prior to baseline and/or B cell counts less than 
the lower limit of normal 
8. Hydroxychloroquine >400 mg/day, methotrexate >25 mg/week, D-Penicillamine 
>1000mg/day or mycophenolate mofetil > 2 grams/day prior to baseline. **Subjects 
can be on combination therapy of hydroxychloroquine and methotrexate or 
hydroxychloroquine and mycophenolate mofetil and must have been on a stable 
dose for at least 1month prior to baseline visit.  
9. Prior history of treatment in the 3 months prior to baseline with biological DMARDs 
potent immunosuppressants such as cyclosporine and azathioprine 
10. Treatment with etanercept within ≤ 2 weeks of baseline: infliximab, certolizumab, 
golimumab, abatacept, tociluzimab, or adalimumab within ≤ 8 weeks of baseline; 
and anakinra within ≤ 1 week prior to the baseline visit. 
11. Intravenous corticosteroids within 2 weeks prior to baseline visit. 
12. Treatment with any investigational agent ≤ 4 weeks prior to baseline (or 5 half-lives  
      of the investigational drug, whichever is longer)  
13. Other investigational or marketed biologics with immunomodulatory properties  
         within 3 months prior to baseline. 
14. Any prior treatment with cell-depleting therapies other than anti-CD20 such as 
CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 
15. Any prior treatment with chlorambucil, bone marrow transplantation, or total 
lymphoid irradiation 
16. Vaccinated or exposed to a live/attenuated vaccine (other than 
Zostavax/Shingrix®) ≤ 6 weeks prior to baseline; or is expected to be vaccinated or 
to have household exposure to these vaccines during treatment or during the 6 
weeks following discontinuation of study medication. (**See additional inclusion for 
obtaining Zostavax/Shingrix® prior to entering the study) 
17. Pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for  
hemoglobin) ≤ 40% of predicted 
18. History of pulmonary arterial hypertension (PAH) with mean PAP> 30 mmHg on 
right heart catheterization requiring subcutaneous or intravenous prostacyclin or 
dual use of oral PAH therapies  
19. Subjects at risk for tuberculosis (TB).  
A. 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 

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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; (TB results within 30 days of screening will be accepted and 
will not to be repeated.  
B. Latent TB at or within 30 days of screening,  
history of or current positive purified protein derivative tuberculin skin test (PPD) ( > 
5mm induration, regardless of Bacille Calmette Guerin [BCG] vaccine and/or 
QuantiFERON Gold, a negative chest x-ray, and no symptoms or risk factors), 
unless one month of prophylaxis has been completed prior to inclusion 
- An indeterminate QuantiFERON® unless followed by a subsequent negative PPD 
or negative QuantiFERON® or a consultation with and clearance by local infectious 
disease (ID) department is required.  
20. Positive for hepatitis B surface antigen at or within 30 days of screening 
21. Positive for hepatitis C antigen at or within 30 days of screening   
22. Current or recent history of uncontrolled clinically significant renal, hepatic,  
         hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or  
         neurologic disease. 
23. History of HIV (as determined by medical records or patient reported).   
24.  History of diverticulitis or chronic, ulcerative lower GI disease such as Crohns 
disease, ulcerative colitis, or other symptomatic, lower GI conditions that might 
predispose a patient to perforations.  
25. Pregnant or breastfeeding female subjects; land female subjects of childbearing 
potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in the protocol for the duration of the study and for at 
least 28 days after discontinuation of study drug. 
26.  Severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase risk associated with study participation and in the judgment of 
the investigator would make the subject inappropriate for entry into this study. 
27. History of SSc Renal Crisis within the 6 months prior to baseline.  
28.  Any of the following lab results at screening:a 
- Hemoglobin <9 g/dL or Hematocrit <30% 
- White Blood Cell count <3.0 x 109/L; 
- Absolute Neutrophil count <1.2 x 109/L; 
- White Blood Cell count <3.0 x 109/L; 
- Absolute Neutrophil count <1.2 x 109/L; 
- Platelet count <100 x 109/L; 
- Absolute Lymphocyte count <0.75 x 109/L. 
- ALT or AST > 1.5 × the upper limit of normal (ULN) of normal at screening or any 
uncontrolled clinically significant laboratory abnormality that would affect 
interpretation of study data or the patient’s participation in the study 
- Total bilirubin > ULN at Screening. 
- Estimated glomerular filtration rate [GFR] <40mL/min/1.73 m2 

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29. History of recurrent (more than one episode) herpes zoster or disseminated (at 
least one episode) herpes zoster, or disseminated (at least one episode) herpes 
simplex 
30. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV)  
         related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and  
         symptoms suggestive of current lymphatic disease. 
31. History of any malignancy in the last 5 years with the exception of adequately 
treated or excised basal cell or squamous cell or cervical cancer in situ. 
32. History of alcohol or substance abuse, unless in full remission for greater than 6   
         months prior to first dose of study drug. 
a Please note thresholds for lab parameters indicated throughout this protocol can 
differ from the published, current package insert due to a new disease and 
concomitant immunosuppressive therapies.   
4.6  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 mLU/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 at least 28 days 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)  
 
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  

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 
Vasectomized partner (provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomized 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.  
 
4.7  Other Considerations for potential subjects 
4.7.1 Vaccine and Exposure to Infections Guidelines  
Subject Specific Recommendations 
It is recommended that all subjects should be up-to-date with respect to standard of care 
vaccinations or SSc guidelines.  Vaccination of subjects with live components is 
prohibited within the 6 weeks prior to first dose of study drug and throughout the study.   
Guidance Regarding Household Contact Vaccine-Related Exposure 
Current routine household contact with children and others who have been vaccinated 
with live vaccine components may pose a risk during treatment and for 6 weeks 
following completion of the study.  Some of these vaccines include varicella 
(“chickenpox”) vaccine oral polio vaccine, and the inhaled flu vaccine.  Following 
vaccination with live component vaccines, the virus may be shed in bodily fluids, 
including stool, and there is a potential risk that the virus may be transmitted.  General 
guidelines for immunosuppressed subjects suggest that exposure (through routine 
contact) should be avoided following vaccination (of others) with these vaccines for the 
stated time period: 
      Varicella or attenuated typhoid fever vaccination for 4 weeks following 
vaccination. 
 
Oral polio vaccination for 6 weeks following vaccination. 
 
Attenuated rotavirus vaccine for 10 days following vaccination. 
 
FluMist (inhaled flu vaccine) for 1 week following vaccination. 
Subjects should avoid exposure to infected persons and contact the Investigator 
promptly should they develop signs or symptoms of infection. 
Due to the increased risk of re-activating varicella-zoster virus, participants will be 
receiving zoster vaccinations before entering the study. Participants who already have 
documented zoster vaccination prior to screening will be able to continue on with 
randomizing once entry criteria are confirmed.    

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All participants who have not received Zostavax ® prior will follow the timeline indicated 
below considering whether or not they are on background immunosuppressive therapy.  
Participants currently on background therapy (i.e.: methotrexate, mycophenolate, D-
Penicillamine) will be asked to temporarily hold these medications for 14 days, receive  
Zostavax®, wait another 14 to re-start the background medication and then 28 days later 
can continue on to randomization.  If the participant is on mycophenolate mofetil at > 
2grams/day (if on Mycophenolic acid prior, must be re-started <1440 mg/day) at the 
screening visit, the mycophenolate will need to be started at <2 grams/day.   Participants 
on stable, acceptable criteria dosages of hydroxychloroquine as background therapy are 
not required to interrupt their background therapy and can follow the same timeline 
indicated for those not on background immunosuppressive therapy.   Participants not on 
background immunosuppressive therapy will only have to wait for 14 days post 
vaccination to be randomized.  
Possible screening timelines: 
1. Screening  Participant had zostavax continue to randomization after criteria is 
confirmed 
 
2. ScreeningParticipant is not on background therapy (or is on stable 
hydroxychloroquine) but requires zostavax confirm criteria and participant obtains 
zostavaxrandomization may occur 14 days post vaccination 
 
3. ScreeningParticipant is on a background therapy that requires interruption for 
vaccination Confirm eligibility, temporarily hold the medications for 14 days 
Receive the zostavax Re-start at eligible doses (ensuring <  2 grams 
mycophenolate/ methotrexate <25)14 days post vaccination ensure stable dosing 
by waiting an additional 28 days Randomization ( up to 65 day window). 
Participants can also enter the study having received the Shingrix vaccine.  If both doses 
of Shingrix have been received the participant may start screening and may randomize 
as long as 4 weeks have passed since receiving the 2nd dose.  Alternatively, a 
participant can begin screening with only one dose if they will be receiving the 2nd dose 
and can complete the 4 weeks waiting period prior to randomization and still staying 
within the window.  
The screening window will be up to 65 days to ensure these steps are all completed.   
4.7.2 Elective Surgery 
During the course of this trial, no elective surgery should be scheduled without first 
consulting with the site investigator. 
Subjects who do require surgery should temporarily discontinue study medication for 
one week prior to the surgical procedure and remain off study medication after the 
surgical procedure until sutures/staples are removed.  If absorbing sutures or chemical 
closure methods are utilized, study medication can be resumed when the operative site 
is sufficiently healed and risk of infection is minimal. 
4.8 
Discontinuation of Subjects from Treatment  

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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.  
 
Anaphylaxis or serious allergic reaction  
 
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. STUDY TREATMENT  
5.1   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 tofacitinib.  
 
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 

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Product 
Description 
and Dosage 
Route of 
Administration
Potency
Appearance
Storage 
Conditions 
 (per label) 
Tofacitinib 
Oral 
5mg 
tablets 
White, round, 
immediate-
release film-
coated tablets 
Store at 20°C to 
25°C (68°F to 
77°F 
Placebo for 
tofacitinib 
Oral 
5mg 
tablets 
White, round, 
immediate-
release film-
coated tablets 
Store at 20°C to 
25°C (68°F to 
77°F 
 
5.2 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 subject 
may begin treatment prior to randomization.  Eligible subjects will be randomized to 
tofacitinib or placebo in a 2:1 manner.  The statistician will prepare the randomization 
schedule, using computer-generated block randomization with the block size(s) only 
known by the statistician.   
 
5.3 Blinding and Unblinding 
 
This is a double-blind study. The study staff (with the exception of the study 
pharmacist) 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.  
 
5.4 Concomitant Medications 
All concomitant medication taken during the study must be recorded with generic 
name of the medication, indication, daily dose, and start and stop dates of 
administration.  A subject who is receiving an allowed concomitant medication for any 
reason must be on a locally-approved medication and dose that is considered 
standard-of-care for the treated indication.  Medications taken after informed consent 
is obtained but before the first dose of study medication will be documented as prior 
medications.  Medications taken after the first dose of study drug has been 

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administered will be documented as concomitant medications. 
 
5.5    Prohibited Medications 
After enrollment, subjects are allowed to continue on their stable background SSc 
therapy, which can include nonsteroidal anti-inflammatory drugs (NSAIDs), 
cyclooxygenase-2 (COX-2) inhibitors, allowed DMARDs (methotrexate – see 
Eligibility), and Corticosteroids. 
 
Use of tofacitinib in combination with biologic disease-modifying antirheumatic drugs 
(DMARDs) or potent immunosuppressants such as azazathioprine and cyclosporine is 
not allowed.  
5.5.1 Other Restrictions and Precautions 
Serious infections leading to hospitalization or death, including tuberculosis and 
bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in 
patients receiving tofacitinib. 
 
Avoid use of tofacitinib during an active serious infection, including localized 
infections.  
 
Gastrointestinal Perforations – Use with caution in patients that may be at 
increased risk.  
 
Laboratory Monitoring – Recommended due to potential changes in 
lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids.  
 
Immunizations – Live vaccines 
 
6. STUDY ASSESSMENTS AND PROCEDURES 
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 
schedule of evaluations table (section 7.1). 
 
Complete medical history -Medical history will be performed as part of screening  
      activities and standard medical care.** Other medical records such as HRCT reports  
      and images, laboratory work, and other tests done as part of clinical care may be       
      accessed for future research data purposes. 
 
Physical examination - A standard complete physical examination will be performed, 
with the addition of the relevant assessments listed below (See Physician Assessments)  
 
Vital signs - Vital signs will include: pulse, blood pressure, temperature (Cº), height 
(cm), and weight (kg) (height and weight only collected at screening).  
 
Assessment of Signs and Symptoms  
Physician Assessments 
o Modified Rodnan skin score (mRSS): is a validated physical examination 
method for estimating skin induration. It is correlated with biopsy measures of 
skin thickness and reflects prognosis and visceral involvement, especially in early 
disease. 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. mRSS will be assessed 3 different ways including: average, maximum 

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scare and representative area.  It has been extensively used as primary/ 
secondary outcome in RCTs.  
Collection: ALL STUDY VISITS with the exception of SAFETY FU phone call 
o Physician’s 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”. Investigators will be asked 
to review their previous score before answering the physician global 
assessment at each visit. 
Collection: ALL STUDY VISITS with the exception SAFETY FU phone call 
o 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 12, 24, and 48 weeks. 
o European Activity Index 
This index assesses disease activity utilizing 6 assessments: patient perception 
of skin involvement, mRSS, digital ulcers, tendon friction rubs, C-Reactive protein 
values and predicted DLCO over 1 year. Assessed at baseline, 24 and 48 
weeks. 
WEIGHT
Patient skin perception
(any progression felt by the patient in 
the last month) 
1.5
Digital ulcers (ongoing ischemic DU)
1.5
Modified Rodnan skin score:
 any value > 18:  
 
for mRSS score equal or lower to 18: 
1.5    
mRSS score x 0.084 
Tendon friction rubs: yes/no
2.25
C-reactive protein > 1 mg/dl: yes/no
2.25
DLCO < 70% of the predicted value: 
Yes/no 
1.0

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Patient reported Outcomes 
o 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. It is part of the 
NHLBI-funded RCT of cyclophosphamide vs. mycophenolate mofetil in SSc-
associated interstitial lung disease (SSc-ILD).  
Collection: Baseline, Week 12, 24,36,48  
 
o Patient’s 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. Participants will be asked to review 
their previous score before answering the patient global assessment at 
each visit. Collection: Baseline, Week 12, 24,36,48 
 
o SHAQ-DI: The SHAQ-DI is a disease-targeted, musculoskeletal-targeted 
measure intended for assessing functional ability in arthritis. A self-administered 
20-question instrument 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 SSc. 5 visual analog scales are 
included in the scleroderma-HAQ assessing burden of digital ulcers, Raynaud’s, 
gastrointestinal involvement, breathing, and overall disease.  
Collection: Baseline, Week 12, 24,36,48 
 
o 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.  
Collection: Baseline, Week 12, 24,36,48 
 
o PRO for Scleroderma-related Skin Symptoms (PRO-SRSS): This 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 the additional symptom, skin ulcers. The PRO-SRSS has a 7-day 
recall. Collection: Baseline, week 12, 24,36 and 48. 
 

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o Patient-reported worsening of the skin disease 
 
Pulmonary function tests (PFTs)  
o 1. Spirometry: Carried out by either certified pulmonary function technologists 
(National Board of Respiratory Care) or experienced staff that meets American 
Thoracic Society (ATS) recommendations. 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.  
Collection: Screening, week 12, 24 and 48  
o 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 requirements. 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.  
Collection: Screening, 24, and 48. 
 
 
Echocardiogram with Doppler 
 Echocardiograms will be performed to assess ejection fraction and TR jet to determine 
pulmonary arterial hypertension.  This assessment will also be used to determine 
systolic or diastolic dysfunction as well as arterial or ventricular enlargement.   
Collection: Screening/Prior to Randomization: Week 24 
 
 
Skin Biopsy 
We will perform two 3-mm skin biopsies. The skin biopsies are required for participation. 
They will be shipped to University of Pittsburgh. Skin tissue from patients with diffuse 
cutaneous SSc (dcSSc) before and after toficitinib or placebo will be collected. Single- 
cell RNA-sequencing analysis will be performed.   
Collection: Baseline, Week 6 
 
 
Blood samples: 40 ml of blood will be obtained from all study participants at baseline, 
Week 6, and Week 24 and shipped from participating centers to the University of 
Michigan.  The analysis will include proteomics analysis, RNA analysis, flow cytometry 
and auto-antibody measurements.    
Collection: Baseline, Week 6, Week 24 
 
6.1  Schedule of Events 
The schedule of events table provides an overview of the protocol visits and procedures.   
Section 6 of the protocol provides detailed information on each procedure and assessment 
required for compliance with the protocol.  
 

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30 
 
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of events in order to conduct evaluations or assessments required to protect the 
well-being of the subject. 

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31 
 
 
Randomized Treatment Period
     Open-Label Treatment Period
Safety 
FU 
Study Visit Datea 
Screening
Baseline 
Week 6 
Week 12 
Phone 
Call  
Week 
18 
Week 
24m 
 
Week 30 
Week 36 
Phone 
Call 
 Week 
42 
Week 48 
End of 
Study 
Phone 
Call +30d 
Study Drug Dispensed 
Tofacitinib or placebo 
 
X 
X 
X 
 
 
 
 
 
 
 
Open-label tofacitinib 
 
 
 
 
 
X 
 
X 
 
 
 
General 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Review  
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Vaccineb 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
Physical Exam  
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
Vital Signsc 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Assessment of Symptoms 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
mRSSd 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
CRISS 
 
 
 
X 
 
X 
 
 
 
X 
 
European Activity Index 
X 
 
 
 
 
X 
 
 
 
X 
 
Physician Assessmentse 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Patient Reported 
Outcomesf 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary Function 
Testsg  
X 
 
 
X**FVC 
only 
 
X 
 
 
 
X 
 
Echocardiogram w/ 
doppler 
X 
 
 
 
 
X 
 
 
 
 
 
Laboratory Assessmentsh 
PPD/Quantiferoni 
X 
 
 
 
 
 
 
 
 
 
 
ESR 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
CRP 
X 
 
 
 
 
X 
 
 
 
X 
 
Hepatitis B and C j 
X 
 
 
 
 
 
 
 
 
 
 
CBC w/ diff 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Lipid Panel n 
X 
 
X 
 
 
 
X 
X 
 
 
 
Comp Panel 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Pregnancy Test (Urine)k 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Research Assessments  
Biomarkers 
 
X 
X 
 
 
X 
 
 
 
 
 

Version 4.0  
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32 
 
 
a Screening window will be -65 to 0 days / Remaining Visit windows will be ± 10 days 
b Follow zostervax or shingrix dosing scheduleprovided on page 20 of this protocol.   
c Blood pressure, Heart Rate, and Temperature.  Height and Weight will also be collected at Screening visit.  
d mRSS will be assessed as one of the inclusion criterion  
e Physician Assessments include: Physician’s global assessment, Tendon Friction Rub, Swollen and Tender Joint Count, Joint Contractures, and Digital Ulcer assessments. 
f Patient Reported Outcomes include: patient’s global assessment, PROMIS-29 2.0, SHAQ-DI, PRO-SRSS and UCLA GIT 2.0 
g FVC and DCLO (Assessments performed within two 2 weeks prior to the screening date are allowable and do not need to be repeated.) 
h All laboratory assessments will be performed at local laboratory  
i Negative results from two weeks prior to the screening visit will be accepted and will not have to be assessed at screening.  
j  For women of child bearing potential  
k 40 mL for proposed blood studies described in the protocol  
 
l Two 3-mm skin biopsies will be collected 
m Should a subject terminate early the subject will be brought in to complete all assessments included at the Week 24 visit. Study drug however would not be provided but returned at this time. 
n All lipid draws require 4 hour fasting.  
 
 
Skin biopsyl 
 
X 
X 
 
 
 
 
 
 
 
 

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33 
 
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.)  
 
7.2  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.  
 
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 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. 
 
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  

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 
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).  
 
7.3 Non-Serious Adverse Events 
Non-serious adverse events are all adverse events that are not classified as SAEs. 
 
7.4 Assignment of Adverse Events 
All adverse events, including those that are serious, will be graded by the investigator based 
on CTCAE v 4.03 as follows:  
 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental ADL (activities of daily living)  
 
Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization indicated; disabling, limiting self-care ADL  
 
Grade 4: Life threatening consequences; urgent intervention indicated 
 
Grade 5: Death related to AE 
 
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. 
 
7.5 Adverse Events – 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.  
 

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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. 
 
7.5.1  Adverse Events of Special Interest 
Included in the secondary outcome analysis are the adverse events of special interest 
(AESI).  The adverse events of interest include but are not limited to: 
 
Gastrointestinal 
perforations 
Patients presenting with new onset abdominal symptoms should be 
evaluated 
promptly for 
early 
identification of 
gastrointestinal 
perforations and  report SAE if event meets criteria. 
Herpes Zoster
Though infection Herpes is a separate event of interest for this study.
Malignancy
Solid cancers, lymphoma, and non-melanoma skin cancer. 
  
Serious Infections 
Serious infections due to bacterial, mycobacterial, invasive fungal, viral, 
or other opportunistic pathogens. Examples of these would include: 
pneumonia, cellulitis, urinary tract infection, and diverticulitis, 
tuberculosis and other mycobacterial infections, cryptococcosis, 
esophageal 
candidiasis, 
pneumocystosis, 
multidermatomal, 
cytomegalovirus, and BK virus. 
Lab value abnormalities 
compared to screening 
at any time point and 
confirmed by repeat 
testing 
1. Lymphocyte count less than 500 cells/mm3 
2. ANC less than 500 cells/mm3 
3. AST/ALT >3 ULN 
4. Hy’s law= ALT > 3x ULN + bilirubin > 2x ULN  
5. A drop of Hb by >2 gm/dL 
6. Hb < 8 gm/dL 
7. Increase in LDL or HDL >50% 
8. Increase in serum creatinine >50%  
 
7.6 Serious Adverse Event Collection 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.  
 

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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. 
 
7.7   Non-Serious Adverse Event Collection 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 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 and reported per the sites individual local 
guidelines.  
 
7.8  Laboratory Monitoring 
A lab monitor will provide oversight and will review subject labs in a blinded manner.  The 
following lab values would result in dose reduction/discontinuation of study drug: 
 
1.  Lymphocyte count less than 500 cells/mm3 and confirmed by repeat testing: 
discontinue drug. 
2.  Neutropenia. ANC 500–1000 cells/mm3: For persistent decreases in this range, 
interrupt dosing until ANC is greater than 1000 cells/mm3.  When greater than 
1000 cells/mm3, resume dose. 
3.  ANC less than 500 cells/mm3: discontinue drug 
4.  Low Hemoglobin. Greater than 2 g/dL decrease or less than 8.0 g/dL: discontinue 
drug until values have normalized.  
 
8 STATISTICAL CONSIDERATIONS 
 
This study is a two-center, double-blind, randomized, placebo-controlled phase 1/2 clinical trial 
in which the safety and tolerability of tofacitinib will be assessed in patients with early dcSSc, 
preliminary efficacy (activity) will be estimated, and exploratory mechanistic research 
assessments will be performed. Fifteen subjects will be enrolled into the trial, which involves a 
24-week course of 5 mg BID tofacitinib or placebo, followed by a 24-week open-label extension 
period of 5 mg BID tofacitinib.   
This section describes the planned analyses; however, a statistical analysis plan (SAP) will be 
written that provides detailed descriptions of the analyses to be conducted.  The SAP will be 
finalized prior to unblinding of the data.   
Continuous variables will be summarized using descriptive statistics including n, mean, median, 
standard deviation, range (e.g., minimum and maximum).  Qualitative variables will be 

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37 
 
summarized using counts and percentages.  Summaries will be provided by treatment group 
and overall.  Unless otherwise specified, statistical analyses will be performed using SAS 
Version 9 or higher.  Where appropriate, statistical tests will be conducted at the 0.1 significance 
level using two-tailed tests and p-values will be reported. Given the study objectives and size of 
this study, the statistical power of any comparisons is limited and p-values will be interpreted as 
hypothesis generating and not definitive.  No adjustment for multiplicity will be made. 
8.1 Sample Size Considerations 
The planned sample size of 15 evaluable early dcScc subjects is based on practical 
considerations, rather than a desired power to detect for a pre-specified treatment 
difference.  With the proposed sample of 15 subjects for the primary efficacy analyses (10 
tofacitinib and 5 placebo), there would be 80% power to detect large treatment differences.  
For example, with a two-sided Type I error of 10% with the planned sample size, there is at 
least 80% power to detect a treatment difference differences in the proportion of participants 
who experience a Grade 3 or higher adverse event of 20% vs 86%, 10% vs 79%, or 5% vs 
74% (placebo vs tofacitinib, respectively).  For continuous efficacy (activity) outcomes, the 
proposed sample size provides 80% power (with a two-sided 10% Type I error) to detect an 
effect size of 1.37, or greater. 
8.2 Statistical Analyses 
8.2.1 Safety Outcomes 
All safety analyses will be performed on the Safety Population, defined as all subjects 
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, ECG, 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.   
 
The primary endpoint is the proportion of participants who experience a Grade 3 or 
higher adverse event at or before Week 24 and will be compared between the two 
treatment groups using an exact Fisher’s exact test.  Exact 90% confidence intervals will 
be calculated to estimate the incidence of the adverse events (both primary and 
secondary endpoints) for each treatment group. Similar methods will be used for the 
secondary safety endpoints.  Treatment comparisons for quantitative safety outcomes 
will be made using two-sample t-tests or their nonparametric counterparts (e.g., 
Wilcoxon rank sum test).  The number (counts) of adverse events will also be compared 
between treatments for select adverse events (e.g., Grade 3 or higher adverse events at 
or before Week 24, adverse events of special interest). 
 

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8.2.2 Efficacy (Activity) and Exploratory Outcomes 
The main population for efficacy and exploratory will be the modified intention-to-treat 
population (MITT), defined as all subjects randomized, receiving at least one dose of 
treatment, and having at least one post-baseline efficacy assessment. Subjects will be 
analyzed by assigned treatment. No adjustment for multiplicity will be made.  
 
Similar methods (described in Section 8.2.1) to compare treatment differences in 
quantitative and qualitative efficacy and exploratory outcomes will be employed. 
Secondary analyses will be performed to assess the robustness of the conclusions and 
may include the use of a secondary analysis set (e.g., the Per Protocol population (PP) 
consisting of all subjects in the MITT population who did not have a major protocol 
violation), alternative methods to deal with missing data, and alternative methods to deal 
with potential violations of distribution assumptions for the primary analyses.  Such 
sensitivity analyses will be outlined in the SAP for the study.  
 
Additional exploratory analyses may be performed and will be defined and outlined in the 
SAP for the study. 
 
9 
 STUDY MANAGEMENT 
 
9.1  Compliance with protocol 
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 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/ approval/favorable opinion, as soon as possible the deviation or 
change will be submitted to:  
 
IRB for review and approval 
 
Pfizer 
 
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) 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).  
 
9.2 Record Retention 

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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 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.  
 
9.3 Study Drug Record 
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.  
 
9.4 Study Drug Destruction 
Study drugs are to be destroyed on site upon sponsor 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.  
 
9.5 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).  Clinical data monitoring will be conducted utilizing experienced clinical 
monitors.  The monitoring plan includes routine remote monitoring with 1 annual site visit.  

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During the on-site visits, the CRFs will be reviewed for completeness and adherence to the 
protocol, accuracy, consistency of data, and adherence to local regulations on the conduct 
of clinical research.  
 
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  RESEARCH USE OF HUMAN SPECIMENS, SAMPLES, OR DATA 
 
10.1 Use of Stored Samples and Data 
Samples and data collection under this protocol may be used to study effect of tofacitinib on 
skin and blood gene expression and effect on T-cell biology. No genetic testing will be 
performed.   
 
10.2 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 
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 University of Pittsburgh 
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.  
 
11 REFERENCES 
 
1. Distler O, Cozzio A. Systemic sclerosis and localized scleroderma--current concepts and 
novel targets for therapy. Semin Immunopathol. 2016;38(1):87-95. doi: 10.1007/s00281-
015-0551-z. PubMed PMID: 26577237. 
2. Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, Warner JD, Tanaka M, 
Steward-Tharp SM, Gadina M, Thomas CJ, Minnerly JC, Storer CE, LaBranche TP, 
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