TOFA-SSc: Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc)

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT03274076
• Collaborator: Pfizer (Industry)
• Enrollment: 15
• Locations: 2
• Arms: 2
• Actual Duration (Months): 25.7
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This Phase I/II placebo controlled trial will evaluate tofacitinib in subjects with diffuse cutaneous systemic scleroderma (dcSSc). This trial is intended to provide safety, and tolerability data in participants with dcSSc when dosed to target exposures similar to that used in adult participants with rheumatoid arthritis.

Condition or Disease	Intervention/Treatment	Phase
Systemic Sclerosis; Scleroderma	Drug: Tofacitinib; Drug: Placebo Oral Tablet	Phase 1/Phase 2

Detailed Description

The purpose of this clinical research study is to evaluate the safety, tolerability and efficacy of treatment with tofacitinib (study drug) versus placebo (a substance with no active ingredients and therefore may have no treatment benefit) in people with diffuse cutaneous systemic scleroderma. Subjects will be randomized to tofacitinib vs. placebo in a 2:1 ratio at 5 mg twice a day for 24 weeks. Subjects will then be offered to participate in an open label phase during which they will receive tofacitinib 5 mg twice a day for 24 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Eligible subjects will be randomized to tofacitinib or placebo in a 2:1 manner.Eligible subjects will be randomized to tofacitinib or placebo in a 2:1 manner.
• Masking: Double (Participant, Investigator)
• Masking Description: The study staff (with the exception of the study pharmacist) and the patient are blinded to the treatment assignment.
• Primary Purpose: Treatment
• Official Title: Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc): A Phase I/II Two Center Safety and Tolerability Study
• Actual Study Start Date: Sep 25, 2017
• Actual Primary Completion Date: Apr 8, 2019
• Actual Study Completion Date: Nov 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tofacitinib 5mg Tofacitinib twice a day	Drug: Tofacitinib; Oral medication tofacitinib 5 mg twice a day for 24 weeks.; Other Names: Xeljanz
Placebo Comparator: Placebo 5mg Placebo twice a day	Drug: Placebo Oral Tablet; Oral Placebo 5 mg twice a day for 24 weeks

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24 [24 weeks]

   Primary outcome is met if any participants experience a grade 3 or higher event prior to Week 24. A grade 3 AE would constitute as "severe". Grading was following using CTCAE v 4.03. Note that the planned statistical analysis (Fisher's exact test) could not be performed because there were no events.

Secondary Outcome Measures

1. Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study [Week 12, 24, 36, and 48]

   Grade 3 or higher adverse events (AEs) assessed throughout the study ( 48 weeks). A grade 3 AE would constitute as "severe". Grading was following using CTCAE v 4.03. Note that the planned statistical analysis (calculation of rate ratio and 90% CI) could not be performed at Weeks 12 and 24 due to no events, and could not be performed at Week 36 because there were no events in the placebo group (denominator).

2. Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study [Week: 12, 24, 36, and 48]

   Grade 2 or higher assessed 12 weeks apart. Grade 2 AEs are determined as " moderate". Grading was performed following CTCAE v 4.03 guidance.

3. Number of Adverse Events of Special Interest (AESI) Throughout the Study [Weeks 12, 24, 36 and 48]

   AESI are pre-defined adverse events as indicated in the protocol. They include: infections, stomach perforations, malignancy, herpes zoster and lab abnormalities. Note that the planned statistical analysis (calculation of rate ratio and 90% CI) could not be performed at Weeks 12 and 24 because there were no events in placebo group (denominator).

4. Change in Modified Rodnan Skin Score (mRSS) [Change from Baseline at weeks: 12, 24, 36, and 48]

   The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. Skin thickness in 17 anatomic areas was rated on a 0-3 scale and scores are summed to obtain the mRSS (range from 0 - 51), with higher mRSS scores indicating worse disease activity

5. Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis [Week:12, 24, and 48]

   CRISS components included the following domains: modified Rodnan skin score, forced vital capacity percent predicted, Physician Global Assessment, Patient Global Assessment, and Health Assessment Questionnaire Disability-Index. An algorithm determines the predicted probability of improvement from baseline by incorporating change in the mRSS, FVC percent predicted, Physician and Patient Global Assessments, and HAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A cut-off at 0.6 in the predicted probability of being improved has yielded the smallest misclassification error. Subjects are not considered improved if, between Visit 1 and 6, they develop new: 1) renal crisis; 2) decline in FVC% predicted by 15% (relative) from baseline and confirmed after 1 month; or 3) left ventricular failure (systolic ejection fraction < 45%) or pulmonary artery hypertension. Higher CRISS scores indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of systemic sclerosis (SSc), as classified using the 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc.

2. Diffuse Cutaneous Systemic Sclerosis (dcSSc) as defined by 2001 LeRoy and Medsger

3. Disease duration ≤ 60 months (defined as time from the first non-Raynaud phenomenon manifestation)

4. Modified Rodnan Skin Score (mRSS) units ≥ 10 and ≤ 45 at screening.

5. Agreement to receive varicella-zoster vaccination (Zostavax®) 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. Ability to provide informed consent.

Exclusion Criteria:

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. 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. 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 1 month prior to baseline visit.

8. Prior history of treatment in the 3 months prior to baseline with biological disease modifying anti-rheumatic drugs (DMARDs)potent immunosuppressants such as cyclosporine and azathioprine

9. Treatment with etanercept within ≤ 2 weeks of baseline: infliximab, certolizumab, golimumab, abatacept, tocilizumab, or adalimumab within ≤ 8 weeks of baseline; and anakinra within ≤ 1 week prior to the baseline visit.

10. Intravenous corticosteroids within 2 weeks prior to baseline visit.

11. Treatment with any investigational agent ≤ 4 weeks prior to baseline (or 5 half-lives of the investigational drug, whichever is longer)

12. Other investigational or marketed biologics with immunomodulatory properties within 3 months prior to baseline.

13. Treatment with anti-CD20 6 months prior to baseline and B cell counts <LLN

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®) ≤ 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® prior to entering the study)

17. Pulmonary disease with Forced Vital Capacity (FVC) ≤ 50% of predicted, or Diffusing capacity of the lungs for carbon monoxide (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):

1. Specifically excluded from this study will be participants with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; (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.

1. Positive for hepatitis B surface antigen at or within 30 days of screening

2. Positive for hepatitis C antigen at or within 30 days of screening

3. Current or recent history of uncontrolled clinically significant renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease.

4. History of human immunodeficiency virus (HIV), (as determined by medical records or patient reported).

5. History of diverticulitis or chronic, ulcerative lower gastrointestinal (GI) disease such as Crohns disease, ulcerative colitis, or other symptomatic, lower GI conditions that might predispose a patient to perforations.

6. Pregnant or breastfeeding female subjects; and 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.

7. 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.

8. History of systemic sclerosis (SSc) Renal Crisis within the 6 months prior to baseline.

9. Any of the following lab results at screening:

• 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 > upper limit of normal (ULN) at Screening.

• Estimated glomerular filtration rate [GFR] <40mL/min/1.73 m2

1. Prior rituximab use without documentation of normalized b cell counts.

2. 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

3. 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.

4. 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.

5. Significant trauma or surgery procedure within 1 month prior to first dose of study drug.

6. History of alcohol or substance abuse, unless in full remission for greater than 6 months prior to first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48104
2	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15261

Sponsors and Collaborators

• University of Michigan
• Pfizer

Investigators

• Principal Investigator: Dinesh Khanna, MD, University of Michigan

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 25, 2019
• Study Protocol - Sep 17, 2018

More Information

Publications

None provided.

• Responsible Party: Dinesh Khanna, MD, MS, Frederick G L Huetwell Professor of Rheumatology and Professor of Internal Medicine, Medical School, University of Michigan
• ClinicalTrials.gov Identifier: NCT03274076
• Other Study ID Numbers: HUM00131837
• First Posted: Sep 6, 2017
• Last Update Posted: May 8, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Dinesh Khanna, MD, MS, Frederick G L Huetwell Professor of Rheumatology and Professor of Internal Medicine, Medical School, University of Michigan: diffuse; scleroderma; systemic sclerosis
• Additional relevant MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis; Tofacitinib

Study Results

Participant Flow

Recruitment Details	Participants were recruited from University of Michigan and University of Pittsburgh Scleroderma clinics. The recruitment period began in September 2017 and ended with the last participant randomization in October 2018.

Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks	Placebo Double Blind 0-24 Weeks	Tofacitinib to Tofacitinib Open Label 24-48 Weeks	Placebo to Tofacitinib Open Label 24-48 Weeks
Arm/Group Description	Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with an oral placebo 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Period Title: 24 Weeks Double Blind
STARTED	10	5	0	0
COMPLETED	10	4	0	0
NOT COMPLETED	0	1	0	0
Period Title: 24 Weeks Double Blind
STARTED	0	0	10	4
COMPLETED	0	0	8	3
NOT COMPLETED	0	0	2	1

Baseline Characteristics

Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks	Placebo Double Blind 0-24 Weeks	Total
Arm/Group Description	Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with oral placebo tablet 5 mg twice a daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Total of all reporting groups
Overall Participants	10	5	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.2 (13.9)	60.0 (9.7)	50.8 (14.0)
Sex: Female, Male (Count of Participants)
Female	7 70%	3 60%	10 66.7%
Male	3 30%	2 40%	5 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	10 100%	5 100%	15 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 20%	1 6.7%
White	10 100%	4 80%	14 93.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	10 100%	5 100%	15 100%
Disease Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.0 (1.3)	2.4 (1.2)	2.1 (1.2)
Baseline Modified Rodnan Skin Score (mRSS (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	22.7 (9.3)	24.4 (6.9)	23.3 (8.4)
Forced Vital Capacity (FVC) % Predicted (percent predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent predicted]	90.7 (16.5)	83.8 (17.5)	88.4 (16.6)
Diffusion in liters of carbon monoxide (DLCO) % Predict (percent predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent predicted]	82.4 (19.7)	92.0 (20.5)	85.6 (19.8)
Health Assessment Questionnaire - Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.01 (0.6)	0.80 (0.5)	0.98 (.59)
Proportion of Participants with Tender Friction Rubs (Count of Participants)
Count of Participants [Participants]	1 10%	1 20%	2 13.3%
Proportion of Participants with Large Joint Contractures (Count of Participants)
Count of Participants [Participants]	5 50%	0 0%	5 33.3%
Proportion of Participants with Background Immunosuppressive (Count of Participants)
Count of Participants [Participants]	9 90%	4 80%	13 86.7%
Proportion of Participants Using Prednisone (Count of Participants)
Count of Participants [Participants]	2 20%	2 40%	4 26.7%
Proportion of Participants with Interstitial Lung Disease on High-resolution computed tomography (Count of Participants)
Count of Participants [Participants]	4 40%	2 40%	6 40%
Proportion of Participants with Small Joint Contractures (Count of Participants)
Count of Participants [Participants]	9 90%	5 100%	14 93.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24
Description	Primary outcome is met if any participants experience a grade 3 or higher event prior to Week 24. A grade 3 AE would constitute as "severe". Grading was following using CTCAE v 4.03. Note that the planned statistical analysis (Fisher's exact test) could not be performed because there were no events.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All participants were included in this analysis although 1 placebo participant withdrew prior to week 24. They remained in the intent to treat population.

Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks	Placebo Double Blind 0-24 Weeks
Arm/Group Description	Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with oral placebo tablet 5 mg twice a day for 24 weeks with option to enter 24 weeks of open label tofacitinib.
Measure Participants	10	5
Count of Participants [Participants]	0 0%	0 0%

2. Secondary Outcome

Title	Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study
Description	Grade 3 or higher adverse events (AEs) assessed throughout the study ( 48 weeks). A grade 3 AE would constitute as "severe". Grading was following using CTCAE v 4.03. Note that the planned statistical analysis (calculation of rate ratio and 90% CI) could not be performed at Weeks 12 and 24 due to no events, and could not be performed at Week 36 because there were no events in the placebo group (denominator).
Time Frame	Week 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

One placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48 but after completing week 24 and entering the open label portion.

Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks	Placebo Double Blind 0-24 Weeks	Tofacitinib to Tofacitinib Open Label 24-48 Weeks	Placebo to Tofacitinib Open Label 24-48 Weeks
Arm/Group Description	Participants treated with an oral medication tofacitinib 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with an oral placebo tablet 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Measure Participants	10	5	10	4
Week 12	0	0
Week 24	0	0
Week 36	2	0
Week 48	1	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: Rate of grade 3 (severe) or higher adverse events that occur throughout week 48 in Placebo = Rate of grade 3 (severe) or higher adverse events that occur throughout week 48 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 90%; 0.19 to 8.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tofacitinib represents the numerator, and placebo represents the denominator.

3. Secondary Outcome

Title	Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study
Description	Grade 2 or higher assessed 12 weeks apart. Grade 2 AEs are determined as " moderate". Grading was performed following CTCAE v 4.03 guidance.
Time Frame	Week: 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

One placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48 but after completing week 24.

Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks	Placebo Double Blind 0-24 Weeks	Tofacitinib to Tofacitinib Open Label 24-48 Weeks	Placebo to Tofacitinib Open Label 24-48 Weeks
Arm/Group Description	Participants treated with an oral medication tofacitinib 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with an oral placebo tablet 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Post double blind completion, participants receive 5 mg tofacitinib twice daily for 24 weeks.	Post double blind completion, participants receive 5 mg tofacitinib twice daily for 24 weeks.
Measure Participants	10	5	10	4
Week 12	7	5
Week 24	5	5
Week 36	14	3
Week 48	4	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib Double Blind 0-24 Weeks, Placebo Double Blind 0-24 Weeks
	Comments	H0: Rate of grade 2 (moderate) or higher adverse events that occur throughout week 12 in Placebo = Rate of grade 2 (moderate) or higher adverse events that occur throughout week 12 in Tofacitinib
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 90%; 0.25 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tofacitinib represents the numerator, and Placebo represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib Double Blind 0-24 Weeks, Placebo Double Blind 0-24 Weeks
	Comments	H0: Rate of grade 2 (moderate) or higher adverse events that occur throughout week 24 in Placebo = Rate of grade 2 (moderate) or higher adverse events that occur throughout week 24 in Tofacitinib
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 90%; 0.26 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tofacitinib represents the numerator, and Placebo represents the denominator.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: Rate of grade 2 (moderate) or higher adverse events that occur throughout week 36 in Placebo = Rate of grade 2 (moderate) or higher adverse events that occur throughout week 36 in Tofacitinib
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 90%; 0.49 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tofacitinib represents the numerator, and Placebo represents the denominator.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: Rate of grade 2 (moderate) or higher adverse events that occur throughout week 48 in Placebo = Rate of grade 2 (moderate) or higher adverse events that occur throughout week 48 in Tofacitinib
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 90%; 0.52 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tofacitinib represents the numerator, and Placebo represents the denominator.

4. Secondary Outcome

Title	Number of Adverse Events of Special Interest (AESI) Throughout the Study
Description	AESI are pre-defined adverse events as indicated in the protocol. They include: infections, stomach perforations, malignancy, herpes zoster and lab abnormalities. Note that the planned statistical analysis (calculation of rate ratio and 90% CI) could not be performed at Weeks 12 and 24 because there were no events in placebo group (denominator).
Time Frame	Weeks 12, 24, 36 and 48

Outcome Measure Data

Analysis Population Description

Placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48.

Arm/Group Title	Tofacitinib Double Blind 0 - 24 Weeks	Placebo Double Blind 0 - 24 Weeks	Tofacitinib to Tofacitinib Open Label 24-48 Weeks	Placebo to Tofacitinib Open Label 24-48 Weeks
Arm/Group Description	Participants treated with an oral medication tofacitinib 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with an oral placebo tablet 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Measure Participants	10	5	10	4
Week 12	4	0
Week 24	1	0
Week 36	4	1
Week 48	0	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: Rate of adverse events of special interest throughout week 36 in Placebo = Rate of adverse events of special interest throughout week 36 in Tofacitinib
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	3.85
	Confidence Interval	(2-Sided) 90%; 0.68 to 21.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tofacitinib represents the numerator, and Placebo represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: Rate of adverse events of special interest throughout week 48 in Placebo = Rate of adverse events of special interest throughout week 48 in Tofacitinib
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.87
	Confidence Interval	(2-Sided) 90%; 0.5169 to 6.7652
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tofacitinib represents the numerator, and Placebo represents the denominator.

5. Secondary Outcome

Title	Change in Modified Rodnan Skin Score (mRSS)
Description	The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. Skin thickness in 17 anatomic areas was rated on a 0-3 scale and scores are summed to obtain the mRSS (range from 0 - 51), with higher mRSS scores indicating worse disease activity
Time Frame	Change from Baseline at weeks: 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48.

Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks	Placebo Double Blind 0-24 Weeks	Tofacitinib (DB Tofacitinib) Open Label 24 - 48 Weeks	Tofacitinib (DB Placebo) Open Label 24-48 Weeks
Arm/Group Description	.Participants treated with an oral medication tofacitinib 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with an oral placebo tablet 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Measure Participants	10	5	8	3
Week 12	-2	0.5
Week 24	-5.5	-2.5
Week 36	-10	-6
Week 48	-12.5	-9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib Double Blind 0-24 Weeks, Placebo Double Blind 0-24 Weeks
	Comments	H0: The absolute change in mRSS from week 0 to week 12 in placebo = The absolute change in mRSS from week 0 to week 12 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1978
	Comments
	Method	Exact Wilcoxon
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib Double Blind 0-24 Weeks, Placebo Double Blind 0-24 Weeks
	Comments	H0: The absolute change in mRSS from week 0 to week 24 in placebo = The absolute change in mRSS from week 0 to week 24 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4665
	Comments
	Method	Exact Wilcoxon
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: The absolute change in mRSS from week 0 to week 36 in placebo = The absolute change in mRSS from week 0 to week 36 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3063
	Comments
	Method	Exact Wilcoxon
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: The absolute change in mRSS from week 0 to week 48 in placebo = The absolute change in mRSS from week 0 to week 48 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6000
	Comments
	Method	Exact Wilcoxon
	Comments

6. Secondary Outcome

Title	Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis
Description	CRISS components included the following domains: modified Rodnan skin score, forced vital capacity percent predicted, Physician Global Assessment, Patient Global Assessment, and Health Assessment Questionnaire Disability-Index. An algorithm determines the predicted probability of improvement from baseline by incorporating change in the mRSS, FVC percent predicted, Physician and Patient Global Assessments, and HAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A cut-off at 0.6 in the predicted probability of being improved has yielded the smallest misclassification error. Subjects are not considered improved if, between Visit 1 and 6, they develop new: 1) renal crisis; 2) decline in FVC% predicted by 15% (relative) from baseline and confirmed after 1 month; or 3) left ventricular failure (systolic ejection fraction < 45%) or pulmonary artery hypertension. Higher CRISS scores indicates improvement.
Time Frame	Week:12, 24, and 48

Outcome Measure Data

Analysis Population Description

Placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48.

Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks	Placebo Double Blind 0-24 Weeks	Tofacitinib to Tofacitinib Open Label 24-48 Weeks	Placebo to Tofacitinib Open Label 24-48 Weeks
Arm/Group Description	Participants treated with an oral medication tofacitinib 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Participants treated with an oral placebo tablet 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Measure Participants	10	5	10	4
Week 12	0.07	0.02
Week 24	0.28	0.09
Week 48	0.99	0.83

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib Double Blind 0-24 Weeks, Placebo Double Blind 0-24 Weeks
	Comments	H0: The CRISS score at week 12 in placebo = The CRISS score at week 12 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4535
	Comments
	Method	Exact Wilcoxon
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib Double Blind 0-24 Weeks, Placebo Double Blind 0-24 Weeks
	Comments	H0: The CRISS score at week 24 in placebo = The CRISS score at week 24 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8392
	Comments
	Method	Exact Wilcoxon
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tofacitinib to Tofacitinib Open Label 24-48 Weeks, Placebo to Tofacitinib Open Label 24-48 Weeks
	Comments	H0: The CRISS score at week 48 in placebo = The CRISS score at week 48 in Tofacitinib.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9212
	Comments
	Method	Exact Wilcoxon
	Comments

Adverse Events

Time Frame	This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks.
Adverse Event Reporting Description	Coding of adverse events into body system was performed by the study chair for adverse events and by the medical monitors for serious adverse events.
Arm/Group Title	Tofacitinib Double Blind 0-24 Weeks		Placebo Double Blind 0-24 Weeks		Tofacitinib to Tofacitinib Open Label 24-48 Weeks		Placebo to Tofacitinib Open Label 24-48 Weeks
Arm/Group Description	.Participants treated with an oral medication tofacitinib 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.		Participants treated with an oral placebo tablet 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.		Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.		Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
All Cause Mortality
	Tofacitinib Double Blind 0-24 Weeks		Placebo Double Blind 0-24 Weeks		Tofacitinib to Tofacitinib Open Label 24-48 Weeks		Placebo to Tofacitinib Open Label 24-48 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/5 (0%)		0/10 (0%)		0/4 (0%)
Serious Adverse Events
	Tofacitinib Double Blind 0-24 Weeks		Placebo Double Blind 0-24 Weeks		Tofacitinib to Tofacitinib Open Label 24-48 Weeks		Placebo to Tofacitinib Open Label 24-48 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/5 (0%)		3/10 (30%)		1/4 (25%)
General disorders
Worsening SSc-Inpatient	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Infections and infestations
Cytomegalovirus-induced Hepatitis, Drug-Induced Hepatitis	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Nervous system disorders
Bells's Palsy	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Diabetic foot ulcer (non-infection), complicated by thermal injury.	0/10 (0%)	0	0/5 (0%)	0	0/10 (0%)	0	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Tofacitinib Double Blind 0-24 Weeks		Placebo Double Blind 0-24 Weeks		Tofacitinib to Tofacitinib Open Label 24-48 Weeks		Placebo to Tofacitinib Open Label 24-48 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/10 (90%)		5/5 (100%)		9/10 (90%)		3/4 (75%)
Cardiac disorders
Hypertension	0/10 (0%)	0	1/5 (20%)	1	1/10 (10%)	1	0/4 (0%)	0
Tachycardia	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Palpatations	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Premature Ventricular Contractions	0/10 (0%)	0	0/5 (0%)	0	0/10 (0%)	0	1/4 (25%)	1
Ear and labyrinth disorders
Sinusitis	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Increased GERD	3/10 (30%)	3	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Diarrhea	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Colititis	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Gastric Bloating	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Constipation	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
General disorders
Weight Gain	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Fatigue	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Flu-like Symptoms	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Intentional Weight Loss	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Infections and infestations
Otis Externa	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Ulcer Infection	1/10 (10%)	1	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Sinus Infection	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	1/4 (25%)	1
Drug-induced hepatitis	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Herpes Zoster	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Drug Induced Hepatitis	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Upper Respiratory Infection	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Investigations
Hypercholesterolemia	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Hyperkalemia	0/10 (0%)	0	0/5 (0%)	0	0/10 (0%)	0	1/4 (25%)	1
Hypertensive Urgency	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
> 50% LDL/HDL	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	1/4 (25%)	1
Elevated Creatine Phosphokinase	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Hypertriglyceridemia	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Bilateral Wrist Synovitis	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Joint Pain	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Low Back Pain	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Left Hip Pain	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Left Knee Pain	0/10 (0%)	0	0/5 (0%)	0	0/10 (0%)	0	1/4 (25%)	1
Right trochanteric bursitis	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Cervical Myositis	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Nervous system disorders
Headache	2/10 (20%)	2	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Migraine	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Diziness	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Renal and urinary disorders
Urinary Tract Infection	2/10 (20%)	2	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Chronic Kidney Disease	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Non-obstructive Renal Calculi	0/10 (0%)	0	0/5 (0%)	0	0/10 (0%)	0	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Sinus Congestion	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Pulmonary Fibrosis	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Muscle Weakness	0/10 (0%)	0	1/5 (20%)	1	0/10 (0%)	0	0/4 (0%)	0
Worsening ILD	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Digital Ulcer	0/10 (0%)	0	0/5 (0%)	0	2/10 (20%)	5	0/4 (0%)	0
Pruritis	1/10 (10%)	1	0/5 (0%)	0	0/10 (0%)	0	0/4 (0%)	0
Rash	0/10 (0%)	0	0/5 (0%)	0	1/10 (10%)	1	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.