Belimumab for the Treatment of Diffuse Cutaneous Systemic Sclerosis

Study Overview
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Brief Summary
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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.

Detailed Description
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The specific objectives of this study are to: Determine whether belimumab used in combination with MMF is safe and tolerable in the treatment of patients with early diffuse cutaneous systemic sclerosis (Disease duration < 3 years). Determine whether belimumab used in combination with MMF is more effective in the treatment of diffuse cutaneous systemic sclerosis than MMF alone, as measured by change in 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. 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.

Official Title
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Belimumab for the Treatment of Diffuse Cutaneous Systemic Sclerosis: A Phase 2a, Single-centered, Randomized, Placebo-controlled, Double-blind, Proof-of-concept Pilot Study.

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: Belimumab
* Drug: Mycophenolate Mofetil
* Other: Placebo Infusion


Participation Criteria
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Eligibility Criteria
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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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate mofetil + Belimumab<br>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<br>* 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.<br>* Other names: Benlysta;Drug: Mycophenolate Mofetil<br>* 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.<br>* Other names: MMF, Cellcept;|
| Placebo Comparator: Mycophenolate Mofetil + Saline (placebo)<br>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<br>* 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.<br>* Other names: MMF, Cellcept;Other: Placebo Infusion<br>* Infusion of normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Scleroderma Health Assessment Questionnaire Disability Index (SHAQ DI) | The Scleroderma Health Assessment Questionnaire (SHAQ) consist of the Health Assessment Questionnaire (HAQ) and 8 other domains addressing scleroderma related manifestations that contribute to disability. It is a quality of life measure. Each question is scored from 0 (without difficulty) to 3 (unable to do). Some domains in the SHAQ are visual analog scales that are measured first and then changed to a 0-3 scale. The maximum from each category is added together and divided by the number of categories completed. The total scale range is 0-3. A higher score indicates worse functionality. Change in Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI) is measured as median change (and interquartile range) from Baseline median to week 52 median. The reported median change can range from -3 to 3. A negative median change indicates a better outcome. | Baseline and Week 52 | 
| Change in in Short Form-36 (SF-36) Questionnaire:Mental Component Summary | The Short Form 36 (SF-36) is a validated 36 item questionnaire which measures quality of life across eight domains: physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, general health. The mental component score (MCS) is composed of a subset of the 8 health domains. Each component is directly transformed into a 0 to 100 scale on the assumption that each question carries equal weight. A score of 0 is equal to maximum disability, and a score of 100 is equivalent to no disability. The SF-36 mental component can be obtained by looking at the mean average of all the emotionally relevant items. Change in Short Form 36 mental (SF-36 MC) is measured by median change (and interquartile range) from Baseline to week 52. The median change can range from -100 to 100. A positive median change indicates indicates an improved outcome. | Baseline and at 52 weeks | 
| Change in Short Form-36 (SF-36) Questionnaire: Physical Component Summary | The Short Form 36 (SF-36) is a 36 item questionnaire which measures quality of life across eight domains: physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, general health. The physical component score is composed of a subset of the 8 health domains.The SF-36 physical component can be obtained by looking at the mean average of all the physically relevant items. Each component is directly transformed into a 0 to 100 scale on the assumption that each question carries equal weight. A score of 0 is equal to maximum disability, and a score of 100 is equivalent to no disability. Change in Short Form 36 physical component (SF-36 PC) is measured by median change (and interquartile range) from Baseline to week 52. The median change can range from -100 to 100. A positive median change indicates indicates an improved outcome. | Baseline and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse cutaneous systemic sclerosis, Early Diffuse cutaneous systemic sclerosis