Belimumab for the Treatment of Diffuse Cutaneous Systemic Sclerosis

NCT01670565 | Completed Phase 2 Results DMC

• 1 other identifier: 2014-279
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Systemic Sclerosis

Keywords

Diffuse cutaneous systemic sclerosis; Early Diffuse cutaneous systemic sclerosis

Outcome Measures

Primary Outcomes (4)

• Change in Modified Rodnan Skin Score (MRSS)

  Change in MRSS is measured by median change (and interquartile range) from Baseline median to week 52 median. The efficacy of the drug will be measured as the change in the Modified Rodnan Skin Score (MRSS) at 52 weeks. The Modified Rodnan Skin Score (MRSS) measures dermal skin thickness through the examination of 17 body areas: fingers, hands, forearms, arms, feet, legs, and thighs (in pairs), and face, chest, and abdomen. The skin score is 0 for uninvolved skin through 3 for severe thickening (hidebound skin). The total skin score is the sum of the skin scores of the individual areas. The minimum score is 0 and the maximum score is 51. A higher score indicates greater severity of disease

  Baseline and at 52 weeks

• Number of Adverse Events and Serious Adverse Events

  The safety and tolerability of belimumab in patients with systemic sclerosis will be as assessed by comparing the rates of adverse events (AEs) and serious adverse events (SAEs) between treatment and placebo groups.

  At 52 weeks

• Change in Forced Vital Capacity (FVC)

  Forced vital capacity (FVC) is the amount of air that can be forcibly exhaled from the lungs after taking a deep breath. It is used to determine the severity of lung disease. FVC for a given individual is compared to reference or predicted values. The reference values are based on healthy individuals with normal lung function and indicates values that would be expected for someone of the same sex, age and height. FVC % predicted compares the patients FVC values with the reference values. Results are considered normal if FVC is 80 percent or more of the predicted value. Change in FVC % predicted is measured by median change (and interquartile range) from Baseline median to week 52 median.

  Baseline and Week 52

• Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)

  Diffusing capacity of the lungs for carbon monoxide (DLCO) measures how much oxygen travels from the alveoli of the lungs to the blood stream. It is used to determine the severity of lung disease. DLCO for a given individual is compared to reference or predicted values. The reference values are based on healthy individuals with normal lung function and indicates values that would be expected for someone of the same sex, age and height. DLCO % predicted compares the patients DLCO values with the reference values. An individuals DLCO result that is at least 80% of the predicted value is considered normal. Change in DLCO % predicted is measured by median change (and interquartile range) from Baseline median to week 52 median.

  Baseline and Week 52

Secondary Outcomes (3)

• Change in Scleroderma Health Assessment Questionnaire Disability Index (SHAQ DI)

  Baseline and Week 52

• Change in in Short Form-36 (SF-36) Questionnaire:Mental Component Summary

  Baseline and at 52 weeks

• Change in Short Form-36 (SF-36) Questionnaire: Physical Component Summary

  Baseline and Week 52

Study Arms (2)

Mycophenolate mofetil + Belimumab

EXPERIMENTAL

All patients who enroll in this trial will FIRST receive mycophenolate mofetil (MMF, Cellcept), which is a drug commonly given to patients with scleroderma in clinical practice. This drug will be given at no cost to the patient. After the patient has been titrated to 2 grams of MMF per day, the patient will receive EITHER a 10 mg/kg belimumab (Benlysta) intravenous infusion OR a placebo (saline) infusion. This medication and infusion will of course be covered by the study.

Drug: Belimumab; Drug: Mycophenolate Mofetil

Mycophenolate Mofetil + Saline (placebo)

PLACEBO COMPARATOR

In order to observe the difference between belimumab/MMF compared to MMF alone, half of the patients will receive a normal saline infusion that appears identical to the belimumab infusion.

Drug: Mycophenolate Mofetil; Other: Placebo Infusion

Interventions

Belimumab DRUG

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.

Also known as: Benlysta

Mycophenolate mofetil + Belimumab

Mycophenolate Mofetil DRUG

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.

Also known as: MMF, Cellcept

Mycophenolate Mofetil + Saline (placebo); Mycophenolate mofetil + Belimumab

Placebo Infusion OTHER

Infusion of normal saline

Mycophenolate Mofetil + Saline (placebo)

Eligibility Criteria

• Age: 18 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.
• 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.
• Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-Raynaud's symptom.

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" (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.
• 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.
• 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.

Sponsors & Collaborators

• Hospital for Special Surgery, New York: lead
• Human Genome Sciences Inc.: collaborator

Study Sites (1)

Hospital for Special Surgery

New York, New York, 10021, United States

Location

Related Publications (1)

• Gordon JK, Martyanov V, Franks JM, Bernstein EJ, Szymonifka J, Magro C, Wildman HF, Wood TA, Whitfield ML, Spiera RF. Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. Arthritis Rheumatol. 2018 Feb;70(2):308-316. doi: 10.1002/art.40358. Epub 2017 Dec 29.

  PMID: 29073351 DERIVED

Related Links

• Scleroderma, Vasculitis, \& Myositis Center Website

MeSH Terms

Conditions

Scleroderma, Systemic; Scleroderma, Diffuse

Interventions

belimumab; Mycophenolic Acid

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Results Point of Contact

• Title: Annel Fernandez
• Organization: Hospital For Special Surgery

fernandeza@hss.edu

212 774 2123

Study Officials

• Robert Spiera, MD

  Hospital for Special Surgery, New York

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: August 15, 2012
• First Posted: August 22, 2012
• Study Start: August 1, 2012
• Primary Completion: November 1, 2015
• Study Completion: February 1, 2016
• Last Updated: May 24, 2022
• Results First Posted: May 24, 2022

Record last verified: 2022-05

Locations

US (1)