Trial Outcomes & Findings for Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc) (NCT NCT03274076)

Last Updated: 2020-05-08

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

15 participants

Primary outcome timeframe

24 weeks

Results posted on

2020-05-08

Participant Flow

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.

Participant milestones

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

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Double Blind 0-24 Weeks Participants treated with an oral placebo 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
24 Weeks Double Blind Withdrawal by Subject	1	0	0
24 Weeks Open Label Adverse Event	0	2	0
24 Weeks Open Label Withdrawal by Subject	0	0	1

Baseline Characteristics

Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc)

Baseline characteristics by cohort

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

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tofacitinib Double Blind 0-24 Weeks n=10 Participants Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Placebo Double Blind 0-24 Weeks n=5 Participants Participants treated with oral placebo tablet 5 mg twice a day for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24	0 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Tofacitinib Double Blind 0-24 Weeks n=10 Participants Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Placebo Double Blind 0-24 Weeks n=5 Participants Participants treated with oral placebo tablet 5 mg twice a day for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks n=10 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks n=4 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study Week 12	0 Adverse Events	0 Adverse Events	—	—
Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study Week 24	0 Adverse Events	0 Adverse Events	—	—
Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study Week 36	—	—	2 Adverse Events	0 Adverse Events
Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study Week 48	—	—	1 Adverse Events	1 Adverse Events

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Tofacitinib Double Blind 0-24 Weeks n=10 Participants Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Placebo Double Blind 0-24 Weeks n=5 Participants Participants treated with oral placebo tablet 5 mg twice a day for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks n=10 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks n=4 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study Week 12	7 Adverse Events	5 Adverse Events	—	—
Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study Week 24	5 Adverse Events	5 Adverse Events	—	—
Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study Week 36	—	—	14 Adverse Events	3 Adverse Events
Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study Week 48	—	—	4 Adverse Events	1 Adverse Events

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Tofacitinib Double Blind 0-24 Weeks n=10 Participants Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Placebo Double Blind 0-24 Weeks n=5 Participants Participants treated with oral placebo tablet 5 mg twice a day for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks n=10 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks n=4 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Number of Adverse Events of Special Interest (AESI) Throughout the Study Week 12	4 Adverse Events	0 Adverse Events	—	—
Number of Adverse Events of Special Interest (AESI) Throughout the Study Week 24	1 Adverse Events	0 Adverse Events	—	—
Number of Adverse Events of Special Interest (AESI) Throughout the Study Week 36	—	—	4 Adverse Events	1 Adverse Events
Number of Adverse Events of Special Interest (AESI) Throughout the Study Week 48	—	—	0 Adverse Events	1 Adverse Events

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Tofacitinib Double Blind 0-24 Weeks n=10 Participants Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Placebo Double Blind 0-24 Weeks n=5 Participants Participants treated with oral placebo tablet 5 mg twice a day for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks n=8 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks n=3 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Change in Modified Rodnan Skin Score (mRSS) Week 12	-2 score on a scale Interval -4.0 to -1.0	0.5 score on a scale Interval -2.0 to 4.5	—	—
Change in Modified Rodnan Skin Score (mRSS) Week 24	-5.5 score on a scale Interval -6.0 to -1.0	-2.5 score on a scale Interval -7.5 to 2.5	—	—
Change in Modified Rodnan Skin Score (mRSS) Week 36	—	—	-10 score on a scale Interval -12.0 to -4.0	-6 score on a scale Interval -9.5 to -2.5
Change in Modified Rodnan Skin Score (mRSS) Week 48	—	—	-12.5 score on a scale Interval -15.5 to -5.5	-9 score on a scale Interval -11.0 to -9.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tofacitinib Double Blind 0-24 Weeks n=10 Participants Participants treated with an oral medication tofacitinib 5 mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Placebo Double Blind 0-24 Weeks n=5 Participants Participants treated with oral placebo tablet 5 mg twice a day for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks n=10 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks n=4 Participants Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis Week 12	0.07 score on a scale Interval 0.005 to 0.35	0.02 score on a scale Interval 0.001 to 0.28	—	—
Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis Week 24	0.28 score on a scale Interval 0.001 to 1.0	0.09 score on a scale Interval 0.02 to 0.56	—	—
Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis Week 48	—	—	0.99 score on a scale Interval 0.33 to 1.0	0.83 score on a scale Interval 0.53 to 1.0

Adverse Events

Tofacitinib Double Blind 0-24 Weeks

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo Double Blind 0-24 Weeks

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Tofacitinib to Tofacitinib Open Label 24-48 Weeks

Serious events: 3 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo to Tofacitinib Open Label 24-48 Weeks

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tofacitinib Double Blind 0-24 Weeks n=10 participants at risk .Participants treated with an oral medication tofacitinib 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Placebo Double Blind 0-24 Weeks n=5 participants at risk Participants treated with an oral placebo tablet 5mg twice daily for 24 weeks with option to enter 24 weeks of open label tofacitinib.	Tofacitinib to Tofacitinib Open Label 24-48 Weeks n=10 participants at risk Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.	Placebo to Tofacitinib Open Label 24-48 Weeks n=4 participants at risk Post double blind completion, participants receive 5mg tofacitinib twice daily for 24 weeks.
Skin and subcutaneous tissue disorders Diabetic foot ulcer (non-infection), complicated by thermal injury.	0.00% 0/10 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/5 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/10 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	25.0% 1/4 • Number of events 1 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.
Nervous system disorders Bells's Palsy	0.00% 0/10 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/5 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	10.0% 1/10 • Number of events 1 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/4 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.
Infections and infestations Cytomegalovirus-induced Hepatitis, Drug-Induced Hepatitis	0.00% 0/10 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/5 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	10.0% 1/10 • Number of events 1 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/4 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.
General disorders Worsening SSc-Inpatient	0.00% 0/10 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/5 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	10.0% 1/10 • Number of events 1 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.	0.00% 0/4 • This report includes the entire time frame of the study with both Double Blind and Open Label = 48 weeks. 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.

Other adverse events

Additional Information

Dinesh Khanna

University of Michigan

Phone: 734-763-7182

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place