October 04, 2012
Institutional Review Board, Hospital for Special Surgery
The safety of our participants is our top priority. The trial/study is approved and periodically reviewed by the Institutional Review Board (IRB), which includes doctors, administrators, ethicists, and members of the general public. The safety of clinical trials is reviewed by the U.S. Food and Drug Administration.
Before enrolling in a clinical trial or research study, the investigator will explain the purpose of the trial/study, its expected benefits, any possible risks or side effects, and what your role will be. If you want to join the trial/study, you must sign informed consent documents. You can leave a trial/study at any time without penalty.
For further information, see Understanding Clinical Trials/Research Studies.
Jessica K. Gordon, MD
Horatio Wildman, MD, Ph.D
Lindsay Lally, MD
Cynthia Margo, MD
Stephen Lyman, Ph.D
Jason Zheng, Pharm.D
Uzunma Udeh, BA
Nina Paddu, BA
This is a 48 week, phase IIa, single center, randomized, double-blind, placebo-controlled, proof-of-concept pilot study, which investigates the safety, tolerability, and efficacy of belimumab (Benlysta ®) in combination with mycophenalate mofetil (MMF, Cellcept ®) for the treatment of early diffuse cutaneous systemic sclerosis. Systemic sclerosis (SSc) is a multi-system inflammatory disease where dysregulated fibrosis, autoimmunity, and vasculopathy lead to disability, organ failure, and accelerated mortality. B-Cell abnormalities are part of the immune dysregulation seen in systemic sclerosis (SSc) and other related autoimmune conditions. Belimumab has been FDA approved for the treatment of systemic lupus erythematosus (SLE) and has been shown to decrease B-Cell survival in patients. Due to the similarities between SSc and SLE, belimumab has a high potential to treat early diffuse cutaneous SSc.
The purpose of this project is to determine the safety, efficacy, and tolerability of belimumab (Benlysta) in combination with mycophenalate mofetil (MMF, Cellcept ®) in the treatment of early diffuse cutaneous systemic sclerosis (diagnosis <3 years). Safety and tolerability will be assessed by a comparison of adverse and serious adverse effects. Efficacy of the drug will be measured by a change in the patients’ modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), hemoglobin corrected diffusion capacity (DLCO), Medsger Severity Scale (MSS), and by other physician and patient derived outcome measures. This project also aims to determine the biological activity of Belimumab/MMF as assessed by effect on histology of skin, change in B-Cell profiles, effect on BLyS levels, and effect on serological and cutaneous biomarkers of disease activity.
INCLUSION CRITERIA
• Age greater than or equal to eighteen years.
• 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. The modified Rodnan skin score must be greater than or equal to sixteen at screening and initiation of therapy.
• A stable MRSS > 16 at screening and stable MRSS between screening and baseline visits is defined by:
MRSS at screen Allowable MRSS at baseline
16 up to 20
17-20 16-24
21-25 + 4
26-30 +5
> 31 +7
• 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
• Inability to render informed consent in accordance with institutional guidelines.
• Disease duration of greater than 3 years.
• Patients with mixed connective tissue disease or “overlap” (i.e. those who satisfy more than one set of ACR criteria for a rheumatic disease.)
• Limited scleroderma.
• Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic rapeseed oil, vinyl chloride, or bleomycin.
• Ongoing treatment with immunosuppressive therapies including cyclophosphamide, azathioprine, methotrexate, or cyclosporine, or use of those medications within 1 month of trial entry.
• 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.
• 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.
• Treatment with MMF at a dose of ≥ 2 grams daily for > 3 months.
• 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.
• A positive pregnancy test at entry into this study.
o Men and women with reproductive potential will be required to use effective means of contraception through the course of the study, such as (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, or (3) 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.
• Woman not willing to use effective birth control for the duration of the study
• Breastfeeding. Breastfeeding is contraindicated with the use of MMF.
• Participation in another clinical research study involving the evaluation of another investigational drug within ninety days of entry into this study.
• The presence of severe lung disease as defined by a diffusion capacity of less than 30% of predicted or requiring supplemental oxygen.
• History of HIV infection
• 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
• 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
• Prior use of Belimumab, Rituximab, or other B-Cell depleting therapies ever
• The use of other biologics including TNF inhibitors, abatacept, or tocilizumab within 1 month of enrollment [this is a safety issue]
• Patients with a history of severe depression, psychosis, or suicidal ideation will be excluded.
Nina Paddu, BA
paddun@hss.edu
212-774-7194