Belimumab and Rituximab Combination Therapy for the Treatment of Diffuse Cutaneous Systemic Sclerosis

NCT03844061 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 2018-2011
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Systemic Sclerosis

Keywords

Systemic Sclerosis

Outcome Measures

Primary Outcomes (2)

• 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.

  12 months

• 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

  12 months

Secondary Outcomes (18)

• Proportion of patients who experience at least one grade 2 or higher adverse event

  Baseline 1 through month 15

• Number Infectious Adverse Events Across all Participants

  Baseline 1 through month 15

• Number Adverse Infusion Reactions Across all Participants

  Baseline 1 through month 15

• Number Injection Site Reactions Across all Participants

  Baseline 1 through month 15

• Number Adverse Events Across all Participants

  Baseline 1 through month 15

Study Arms (2)

MMF + Rituximab + Belimumab

EXPERIMENTAL

Two infusions of 1000 mg of Rituximab, two weeks apart, weekly subcutaneous injections of 200 mg of Belimumab, and background MMF, 1000 -1500 mg twice daily for 48 weeks.

Drug: Belimumab; Drug: Rituximab; Drug: MMF

MMF + Placebo + Placebo

PLACEBO COMPARATOR

Two placebo infusions of normal saline, two weeks apart, weekly saline placebo subcutaneous injections, and background MMF, 1000 -1500 mg twice daily for 48 weeks.

Other: Placebo Subcutaneous Injection; Other: Placebo Infusion; Drug: MMF

Interventions

Belimumab DRUG

Belimumab 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.

Also known as: Benlysta

MMF + Rituximab + Belimumab

Rituximab DRUG

Rituxan® (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.

Also known as: Rituxan

MMF + Rituximab + Belimumab

Placebo Subcutaneous Injection OTHER

Normal Saline

MMF + Placebo + Placebo

Placebo Infusion OTHER

Normal Saline

MMF + Placebo + Placebo

MMF DRUG

MMF belongs to a group of medicines known as immunosuppressive agents. It is used with other medicines to lower the body's natural immunity.

Also known as: Cellcept, Mycophenolate Mofetil

MMF + Placebo + Placebo; MMF + Rituximab + Belimumab

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• A modified Rodnan Skin Score (mRSS) of \> 14

You may not qualify if:

• 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.
• Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic rapeseed oil, vinyl chloride, or bleomycin.
• The use of other anti-fibrotic agents including colchicine, D-penicillamine, or tyrosine kinase inhibitors (nilotinib, imatinib, dasatinib) 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.
• 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. 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) double-barrier methods (such as a condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository)(3) an intrauterine device (IUD) or intrauterine system (IUS) (4) estrogenic vaginal ring (5) percutaneous contraceptive patches, or (6) implants of levonorgestrel or etonogestrel. Approved hormonal contraceptives (such as birth control pills, patches, implants or injections) may interact with and reduce the effectiveness of MMF so women receiving MMF who are using oral contraceptives for birth control should employ an additional method (e.g. barrier method). Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use.
• Women not willing to use effective birth control for the duration of the study
• Breastfeeding.
• 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 and forced vital capacity (FVC) of less than 45% of predicted.
• Grade 3 hypogammaglobulinemia
• Have a significant IgG deficiency (IgG level \< 400 mg/dL)

Sponsors & Collaborators

• Hospital for Special Surgery, New York: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Hospital for Special Surgery

New York, New York, 10021, United States

RECRUITING

MeSH Terms

Conditions

Scleroderma, Systemic

Interventions

belimumab; Rituximab; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Study Officials

• Robert Spiera, MD

  Hospital for Special Surgery, New York

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Liza Morales

CONTACT

212-774-2048; moralesli@hss.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2019
• First Posted: February 18, 2019
• Study Start: July 29, 2019
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: March 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)