Belimumab for the Treatment of Diffuse Cutaneous Systemic Sclerosis
Condition: Systemic Sclerosis
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Intervention: Belimumab; Mycophenolate Mofetil; Placebo Infusion
Intervention description: Belimumab (Benlysta®) decreases B-Cell survival and has been FDA approved for the treatment of systemic lupus erythematosus, another rheumatic autoimmune disease. Belimumab is a recombinant, fully human monoclonal antibody; it binds to the soluble human B lymphocyte stimulator (BLyS) with high affinity and inhibits its biologic activity. Prior research provides a robust rationale for the investigation of belimumab in combination with MMF (Cellcept ®) for the treatment of early diffuse cutaneous systemic sclerosis.; Patients received background MMF therapy, some who were naive to MMF were titrated up to 1,000 mg twice daily and others had been receiving MMF at <2,000 mg/day for <3 months. MMF was chosen so that background therapy would be uniform and not a further source of variability in the small study.; Infusion of normal saline
Intervention MeSH terms: Mycophenolic Acid; Belimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diffuse cutaneous systemic sclerosis; Early Diffuse cutaneous systemic sclerosis

Summary:

      This is a 48 week, phase IIa, single center, randomized, double-blind, placebo-controlled,
      proof-of-concept pilot study. All participants will first be treated with mycophenolate
      mofetil (MMF, Cellcept) and titrated up to a dose of 2 grams/day. Following this period, half
      will be given either a belimumab (Benlysta®) or placebo intravenous infusion to treat early
      diffuse cutaneous systemic sclerosis. Belimumab/MMF is expected to improve disease activity
      measured by an improvement in skin thickening and stability of pulmonary function test
      measurements when compared to patients treated with placebo/MMF.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age greater than or equal to eighteen years.

          2. Clinical diagnosis of diffuse systemic sclerosis by ACR criteria, with a stable
             modified Rodnan skin score in the one month preceding introduction of belimumab
             therapy.

          3. Disease duration of less than or equal to 3 years as defined by the date of onset of
             the first non-Raynaud's symptom.

        Exclusion Criteria:

          1. Inability to render informed consent in accordance with institutional guidelines.

          2. Disease duration of greater than 3 years.

          3. Patients with mixed connective tissue disease or "overlap" (i.e. those who satisfy
             more than one set of ACR criteria for a rheumatic disease.)

          4. Limited scleroderma.

          5. Systemic sclerosis-like illness associated with environmental or ingested agents such
             as toxic rapeseed oil, vinyl chloride, or bleomycin.

          6. Ongoing treatment with immunosuppressive therapies including cyclophosphamide,
             azathioprine, methotrexate, or cyclosporine, or use of those medications within 1
             month of trial entry.

          7. The use of other anti-fibrotic agents including colchicine, D-penicillamine,
             minocycline, tyrosine kinase inhibitors (nilotinib, imatinib, dasatinib), or Type 1
             oral Collagen in the month prior to enrollment.

          8. Use in the prior month of corticosteroids at doses exceeding the equivalent of
             prednisone 10 mg daily. Use of corticosteroid at < 10 mg of prednisone can continue
             during the course of the study.

          9. Treatment with MMF at a dose of ≥ 2 grams daily for > 3 months.

         10. Concurrent serious medical condition which in the opinion of the investigator makes
             the patient inappropriate for this study such as uncontrollable CHF, arrhythmia,
             severe pulmonary or systemic hypertension, severe GI involvement, hepatic impairment,
             serum creatinine of greater than 2.0, active infection, severe diabetes, unstable
             atherosclerotic cardiovascular disease, malignancy, HIV, or severe peripheral vascular
             disease.

         11. A positive pregnancy test at entry into this study.

         12. Men and women with reproductive potential will be required to use effective means of
             contraception through the course of the study, such as a tubal ligation or
             hysterectomy, condom or diaphragm used with a spermicide,or an intrauterine device
             (IUD). Approved hormonal contraceptives (such as birth control pills, patches,
             implants or injections) may interact with and reduce the effectiveness of MMF and
             thus, are not acceptable. Contraceptive measures such as Plan B (TM), sold for
             emergency use after unprotected sex, are not acceptable methods for routine use.

         13. Breastfeeding. Breastfeeding is contraindicated with the use of MMF.

         14. Participation in another clinical research study involving the evaluation of another
             investigational drug within ninety days of entry into this study.

         15. The presence of severe lung disease as defined by a diffusion capacity of less than
             30% of predicted or requiring supplemental oxygen.

         16. History of HIV infection

         17. Known active bacterial, viral, fungal, mycobacterial, or other infection r any major
             episode of infection requiring hospitalization or treatment with IV antibiotics within
             4 weeks of screening, or oral antibiotics within 2 weeks prior to screening

         18. Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications

         19. Prior use of Belimumab, Rituximab, or other B-Cell depleting therapies ever

         20. The use of other biologics including TNF inhibitors, abatacept, or tocilizumab within
             1 month of enrollment [this is a safety issue]

         21. Patients with a history of severe depression, psychosis, or suicidal ideation will be
             excluded.