Scleroderma, Systemic Sclerosis
Conditions
Keywords
diffuse, scleroderma, systemic sclerosis
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.
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.
Interventions
DRUGTofacitinib
Oral medication tofacitinib 5 mg twice a day for 24 weeks.
DRUGPlacebo Oral Tablet
Oral Placebo 5 mg twice a day for 24 weeks
Sponsors
Pfizer
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The study staff (with the exception of the study pharmacist) and the patient are blinded to the treatment assignment.
Intervention model description
Eligible subjects will be randomized to tofacitinib or placebo in a 2:1 manner.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
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): 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 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 human immunodeficiency virus (HIV), (as determined by medical records or patient reported). 24. 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. 25. 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. 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 systemic sclerosis (SSc) Renal Crisis within the 6 months prior to baseline. 28. 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 29. Prior rituximab use without documentation of normalized b cell counts. 30. 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 31. 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. 32. 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. 33. Significant trauma or surgery procedure within 1 month prior to first dose of study drug. 34. History of alcohol or substance abuse, unless in full remission for greater than 6 months prior to first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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). |
| 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 |
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Tofacitinib Double Blind 0-24 Weeks Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib. | 10 |
| Placebo Double Blind 0-24 Weeks Participants treated with oral placebo tablet 5 mg twice a daily for 24 weeks with option to enter 24 weeks of open label tofacitinib. | 5 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 24 Weeks Double Blind | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| 24 Weeks Open Label | Adverse Event | 0 | 0 | 2 | 0 |
| 24 Weeks Open Label | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Tofacitinib Double Blind 0-24 Weeks | Placebo Double Blind 0-24 Weeks | Total |
|---|---|---|---|
| Age, Continuous | 46.2 years STANDARD_DEVIATION 13.9 | 60.0 years STANDARD_DEVIATION 9.7 | 50.8 years STANDARD_DEVIATION 14 |
| Baseline Modified Rodnan Skin Score (mRSS | 22.7 units on a scale STANDARD_DEVIATION 9.3 | 24.4 units on a scale STANDARD_DEVIATION 6.9 | 23.3 units on a scale STANDARD_DEVIATION 8.4 |
| Diffusion in liters of carbon monoxide (DLCO) % Predict | 82.4 percent predicted STANDARD_DEVIATION 19.7 | 92.0 percent predicted STANDARD_DEVIATION 20.5 | 85.6 percent predicted STANDARD_DEVIATION 19.8 |
| Disease Duration | 2.0 years STANDARD_DEVIATION 1.3 | 2.4 years STANDARD_DEVIATION 1.2 | 2.1 years STANDARD_DEVIATION 1.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 5 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Forced Vital Capacity (FVC) % Predicted | 90.7 percent predicted STANDARD_DEVIATION 16.5 | 83.8 percent predicted STANDARD_DEVIATION 17.5 | 88.4 percent predicted STANDARD_DEVIATION 16.6 |
| Health Assessment Questionnaire - Disability Index (HAQ-DI) | 1.01 units on a scale STANDARD_DEVIATION 0.6 | 0.80 units on a scale STANDARD_DEVIATION 0.5 | 0.98 units on a scale STANDARD_DEVIATION 0.59 |
| Proportion of Participants Using Prednisone | 2 Participants | 2 Participants | 4 Participants |
| Proportion of Participants with Background Immunosuppressive | 9 Participants | 4 Participants | 13 Participants |
| Proportion of Participants with Interstitial Lung Disease on High-resolution computed tomography | 4 Participants | 2 Participants | 6 Participants |
| Proportion of Participants with Large Joint Contractures | 5 Participants | 0 Participants | 5 Participants |
| Proportion of Participants with Small Joint Contractures | 9 Participants | 5 Participants | 14 Participants |
| Proportion of Participants with Tender Friction Rubs | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 4 Participants | 14 Participants |
| Region of Enrollment United States | 10 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 5 | 0 / 10 | 0 / 4 |
| other Total, other adverse events | 9 / 10 | 5 / 5 | 9 / 10 | 3 / 4 |
| serious Total, serious adverse events | 0 / 10 | 0 / 5 | 3 / 10 | 1 / 4 |
Outcome results
Primary
Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tofacitinib Double Blind 0-24 Weeks | Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24 | 0 Participants |
| Placebo Double Blind 0-24 Weeks | Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24 | 0 Participants |
Secondary
Change in Modified Rodnan Skin Score (mRSS)
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
Population: Placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tofacitinib Double Blind 0-24 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 12 | -2 score on a scale |
| Tofacitinib Double Blind 0-24 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 24 | -5.5 score on a scale |
| Placebo Double Blind 0-24 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 12 | 0.5 score on a scale |
| Placebo Double Blind 0-24 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 24 | -2.5 score on a scale |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 36 | -10 score on a scale |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 48 | -12.5 score on a scale |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 48 | -9 score on a scale |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Change in Modified Rodnan Skin Score (mRSS) | Week 36 | -6 score on a scale |
Comparison: 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.p-value: 0.1978Exact Wilcoxon
Comparison: 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.p-value: 0.4665Exact Wilcoxon
Comparison: 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.p-value: 0.3063Exact Wilcoxon
Comparison: 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.p-value: 0.6Exact Wilcoxon
Secondary
Number of Adverse Events of Special Interest (AESI) Throughout the Study
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
Population: Placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tofacitinib Double Blind 0-24 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 12 | 4 Adverse Events |
| Tofacitinib Double Blind 0-24 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 24 | 1 Adverse Events |
| Placebo Double Blind 0-24 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 12 | 0 Adverse Events |
| Placebo Double Blind 0-24 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 24 | 0 Adverse Events |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 36 | 4 Adverse Events |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 48 | 0 Adverse Events |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 48 | 1 Adverse Events |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Number of Adverse Events of Special Interest (AESI) Throughout the Study | Week 36 | 1 Adverse Events |
Comparison: H0: Rate of adverse events of special interest throughout week 36 in Placebo = Rate of adverse events of special interest throughout week 36 in Tofacitinib90% CI: [0.68, 21.77]
Comparison: H0: Rate of adverse events of special interest throughout week 48 in Placebo = Rate of adverse events of special interest throughout week 48 in Tofacitinib90% CI: [0.5169, 6.7652]
Secondary
Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tofacitinib Double Blind 0-24 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 12 | 7 Adverse Events |
| Tofacitinib Double Blind 0-24 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 24 | 5 Adverse Events |
| Placebo Double Blind 0-24 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 12 | 5 Adverse Events |
| Placebo Double Blind 0-24 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 24 | 5 Adverse Events |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 36 | 14 Adverse Events |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 48 | 4 Adverse Events |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 48 | 1 Adverse Events |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study | Week 36 | 3 Adverse Events |
Comparison: 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 Tofacitinib90% CI: [0.25, 1.71]
Comparison: 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 Tofacitinib90% CI: [0.26, 1.07]
Comparison: 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 Tofacitinib90% CI: [0.49, 1.49]
Comparison: 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 Tofacitinib90% CI: [0.52, 1.52]
Secondary
Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tofacitinib Double Blind 0-24 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 12 | 0 Adverse Events |
| Tofacitinib Double Blind 0-24 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 24 | 0 Adverse Events |
| Placebo Double Blind 0-24 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 12 | 0 Adverse Events |
| Placebo Double Blind 0-24 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 24 | 0 Adverse Events |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 36 | 2 Adverse Events |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 48 | 1 Adverse Events |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 48 | 1 Adverse Events |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study | Week 36 | 0 Adverse Events |
Comparison: 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.90% CI: [0.19, 8.33]
Secondary
Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis
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
Population: Placebo participant withdrew prior to week 24. 1 additional placebo participant and 2 tofacitinib participants withdrew prior to week 48.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tofacitinib Double Blind 0-24 Weeks | Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis | Week 12 | 0.07 score on a scale |
| Tofacitinib Double Blind 0-24 Weeks | Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis | Week 24 | 0.28 score on a scale |
| Placebo Double Blind 0-24 Weeks | Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis | Week 12 | 0.02 score on a scale |
| Placebo Double Blind 0-24 Weeks | Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis | Week 24 | 0.09 score on a scale |
| Tofacitinib to Tofacitinib Open Label 24-48 Weeks | Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis | Week 48 | 0.99 score on a scale |
| Placebo to Tofacitinib Open Label 24-48 Weeks | Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis | Week 48 | 0.83 score on a scale |
Comparison: H0: The CRISS score at week 12 in placebo = The CRISS score at week 12 in Tofacitinib.p-value: 0.4535Exact Wilcoxon
Comparison: H0: The CRISS score at week 24 in placebo = The CRISS score at week 24 in Tofacitinib.p-value: 0.8392Exact Wilcoxon
Comparison: H0: The CRISS score at week 48 in placebo = The CRISS score at week 48 in Tofacitinib.p-value: 0.9212Exact Wilcoxon