This is a 52 week, single center, randomized, double-blind, placebo-controlled study.
After patients maintain a stable dose of Mycophenolate Mofetil (MMF) for at least 1 month, they will be randomized to treatment with either Belimumab \& Rituximab or placebo.Patients in both groups will be on background MMF for the entirety of the study. Belimumab will be administered subcutaneously and Rituximab intravenously. Placebo injections and infusions will be of normal saline. Randomization will be done in a 2:1 manner to favor the treatment group. It is hypothesized that that Rituximab and Belimumab combination therapy with Mycophenolate Mofetil background therapy will improve fibrosis in SSc skin when compared to treatment with placebo and Mycophenolate Mofetil in a group of patients with early dcSSc.
Age greater than or equal to eighteen years and less than or equal to 80.
Classification of systemic sclerosis (SSc), as defined using the 2013 American College of Rheumatology/European Union League Against Rheumatism classification of SSc.
Diagnosis of dcSSc, as defined by LeRoy and Medsger.
Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-Raynaud's symptom.
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" unless the dominant features of the illness are diffuse systemic sclerosis.
Limited scleroderma.
Parallel
Belimumab
DrugBelimumab 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. The background above provides a robust rationale for the investigation of belimumab in the treatment of dcSSc.
Rituximab
DrugRituxan® (rituximab) is a genetically engineered IgG1 kappa chimeric murine/human monoclonal antibody containing murine light- and heavy-chain variable region sequences and human constant region sequences. The antibody reacts specifically with the CD20 antigen found on the surface of malignant and normal B cells, and established B cell lines. Studies have shown that rituximab binds via its Fc domain to human complement and lyses lymphoid B cell lines by complement dependent cytotoxicity through the induction of apoptosis and via antibody-dependent cell mediated cytotoxicity. Rituximab is approved by the U.S. Food and Drug Administration (FDA) to treat some types of cancer, rheumatoid arthritis and vasculitis.
Placebo Subcutaneous Injection
Other interventionNormal Saline
Placebo Infusion
Other interventionNormal Saline
MMF
DrugMMF belongs to a group of medicines known as immunosuppressive agents. It is used with other medicines to lower the body's natural immunity.
Primary Efficacy Outcome: Change in the ACR Revised CRISS at 12 months
The revised CRISS (rCRISS) is a proposed new composite endpoint developed in response to recent queries of the ACR CRISS (Composite Response Index in Systemic Sclerosis), showing concerns of high ceiling and floor effects and difficult interpretation. The exponential algorithm determines the predicted probability of change from baseline, incorporating change in 5 core items: the mRSS, FVC percent predicted, physician and patient global assessments, and HAQ-DI. The possible scores range from 0.00 to 1.00, where a higher score indicates a better outcome.
Primary Safety Outcome: The proportion of participants who experience at least one Grade 3 or higher adverse event at or before 12 months
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.Grade 3 = Severe and undesirable adverse event
Proportion of patients who experience at least one grade 2 or higher adverse event
Grade 2 = Moderate adverse event
Number Infectious Adverse Events Across all Participants
infectious adverse events
Number Adverse Infusion Reactions Across all Participants
infusion reactions
Number Injection Site Reactions Across all Participants
injection site reactions
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Hospital for Special Surgery, New York
Lead sponsor
GlaxoSmithKline
Collaborator
