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

Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc): A Phase I/II Two Center Safety and Tolerability Study

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.

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.

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.