Belimumab for the Treatment of Diffuse Cutaneous Systemic... | NCT01670565

NCT01670565

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Human Genome Sciences Inc.	INDUSTRY

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
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.

Outcomes Module

Primary Outcomes

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.

Secondary Outcomes

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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
Robert Spiera, MD	Hospital for Special Surgery, New York	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Hospital for Special Surgery		New York	New York	10021	United States

PubMed Identifier	Type	Citation	Retractions
29073351	Derived	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.

Label	URL
Scleroderma, Vasculitis, \& Myositis Center Website	View source

Arm/Group Information

ID	Title	Description
FG000	Mycophenolate Mofetil + Belimumab	Patients in this arm will FIRST receive mycophenolate mofetil (MMF, Cellcept), which is a drug commonly given to patients with scleroderma in clinical practice titrated to 2 grams of MMF per day, followed by 10 mg/kg belimumab (Benlysta). Belimumab Infusion will be administered 14 times over a period of 48 weeks. MMF will be administered through 48 weeks. Belimumab: 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.
FG001	Mycophenolate Mofetil + Saline (Placebo)	Patients in this arm will FIRST receive MMF alone followed by normal saline infusion that appears identical to the belimumab infusion. Saline Infusion will be administered 14 times over a period of 48 weeks. MMF will be administered through 48 weeks.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Mycophenolate Mofetil + Belimumab	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 placebo (saline) infusion. This medication and infusion will be covered by the study. Belimumab: 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.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

Posted

Median

Inter-Quartile Range

units on a scale

Baseline and at 52 weeks

ID	Title	Description
OG000	Mycophenolate Mofetil + Belimumab	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 being titrated to 2 grams of MMF per day, patients in this experimental group will receive a 10 mg/kg belimumab (Benlysta) intravenous infusion infusion.This medication and infusion will of course be covered by the study. Belimumab: 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

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Mycophenolate Mofetil + Belimumab	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 being titrated to 2 grams of MMF per day, the patient will receive a 10 mg/kg belimumab (Benlysta) intravenous infusion. This medication and infusion will be covered by the study. Belimumab: 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.

ID	Term
D012595	Scleroderma, Systemic
D045743	Scleroderma, Diffuse

ID	Term
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases
D012871	Skin Diseases

ID	Term
C511911	belimumab
D009173	Mycophenolic Acid

ID	Term
D002208	Caproates
D000144	Acids, Acyclic
D002264	Carboxylic Acids
D009930	Organic Chemicals