A Safety and Efficacy Study of LymphoStat-B™ (Monoclonal Anti-BLyS Antibody) in Subjects With Rheumatoid Arthritis (RA)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of 3 different doses of belimumab, administered in addition to standard therapy, in patients with rheumatoid arthritis (RA).

Detailed Description
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The purpose of this study is to evaluate the safety and efficacy of three different doses of belimumab (1 mg/kg, 4 mg/kg, and 10 mg/kg), administered in addition to standard therapy, compared to placebo plus standard therapy in patients with RA. All patients were to be dosed on Days 0, 14, and 28, then every 28 days for the remainder of 24 weeks. Patients completing the 24-week period could enter a 24-week open-label extension; belimumab patients received the same dose or were switched to 10 mg/kg at the investigator's discretion and former placebo patients received belimumab 10 mg/kg.

Official Title
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A Phase 2, Multi-Center, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety, Tolerability, and Efficacy of LymphoStat-B™ Antibody (Monoclonal Anti-BLyS Antibody) in Subjects With Rheumatoid Arthritis (RA)

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Placebo
* Drug: Belimumab 1 mg/kg
* Drug: Belimumab 4 mg/kg
* Drug: Belimumab 10 mg/kg


Participation Criteria
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Eligibility Criteria
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Primary Inclusion Criteria: Diagnosis of RA for at least 1 year Failed at least 1 disease modifying anti-rheumatic drug (DMARD) due to toxicity or lack of efficacy. These drugs must include 1 or more of the following: methotrexate, parenteral gold, sulfasalazine, leflunomide, and tumor necrosis factor-alpha (TNFα) inhibitors (infliximab, etanercept or adalimumab) Active RA disease of at least moderate disease activity Be on a stable RA treatment regimen for at least the past 60 days (for DMARDS); if on non-steroidal anti-inflammatory drugs (NSAIDs) or steroids these must be at a stable dose for the last 30 days Primary Exclusion Criteria: Received a non-FDA approved investigational agent within the last 28 days Currently receiving or received within the last 60 days the following: TNFα-inhibitors (infliximab, etanercept, adalimumab) or interleukin-1 receptor antagonist (anakinra) Currently receiving or received within the last 6 months the following: anti-CD20 antibody (rituximab) or cyclophosphamide Steroid injection into any joint within the last 30 days History of hypogammaglobulinemia or immunoglobulin A (IgA) deficiency History of chronic infection that has been active within last 6 months, or herpes zoster within last 90 days, or any infection requiring hospitalization or intravenous medication within last 60 days Human immunodeficiency virus (HIV), Hepatitis-B, Hepatitis-C

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Placebo Comparator: Placebo plus SOC<br> | Drug: Placebo<br>* Placebo IV plus standard therapy (SOC) for RA; placebo administered on Days 0, 14, 28, and every 28 days thereafter through 24 weeks in the double-blind period. In the open-label extension period, placebo patients who opted to participate received belimumab 10 mg/kg IV plus SOC every 28 days for an additional 24 weeks.<br>|
| Experimental: Belimumab 1 mg/kg plus SOC<br> | Drug: Belimumab 1 mg/kg<br>* Belimumab 1 mg/kg IV plus standard therapy (SOC) for RA; belimumab 1 mg/kg administered on Days 0, 14, 28, and every 28 days thereafter through 24 weeks in the double-blind period. In the open-label extension period, patients who opted to participate either continued on the same dose of belimumab or may have been switched to belimumab 10 mg/kg at the investigator's discretion for an additional 24 weeks.<br>* Other names: BENLYSTA®;|
| Experimental: Belimumab 4 mg/kg plus SOC<br> | Drug: Belimumab 4 mg/kg<br>* Belimumab 4 mg/kg IV plus standard therapy (SOC) for RA; belimumab 4 mg/kg administered on Days 0, 14, 28, and every 28 days thereafter through 24 weeks in the double-blind period. In the open-label extension period, patients who opted to participate either continued on the same dose of belimumab or may have been switched to belimumab 10 mg/kg at the investigator's discretion for an additional 24 weeks.<br>* Other names: BENLYSTA®;|
| Experimental: Belimumab 10 mg/kg plus SOC<br> | Drug: Belimumab 10 mg/kg<br>* Belimumab 10 mg/kg IV plus standard therapy (SOC) for RA; belimumab 10 mg/kg administered on Days 0, 14, 28, and every 28 days thereafter through 24 weeks in the double-blind period. In the open-label extension period, patients who opted to participate continued on the same dose of belimumab (10 mg/kg) for an additional 24 weeks.<br>* Other names: BENLYSTA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With ACR20 (American College of Rheumatology) Response at Week 24, Based on Erythrocyte Sedimentation Rate (ESR) | An ACR20 response is defined as having at least a 20% improvement in tender and swollen joints as well as a 20% improvement in 3 of 5 other criteria (patient assessment, physician assessment, pain scale, disability/functional questionnaire, and acute phase reactant value based on erythrocyte sedimentation rate [ESR]). | Baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With an ACR50 Response at Week 24, Based on ESR | An ACR50 response is defined as having at least a 50% improvement in tender and swollen joints as well as a 50% improvement in 3 of 5 other criteria (patient assessment, physician assessment, pain scale, disability/functional questionnaire, and acute phase reactant value based on erythrocyte sedimentation rate [ESR]). | Baseline, 24 weeks | 
| Percentage of Patients With an ACR70 Response at Week 24, Based on ESR | An ACR70 response is defined as having at least a 70% improvement in tender and swollen joints as well as a 70% improvement in 3 of 5 other criteria (patient assessment, physician assessment, pain scale, disability/functional questionnaire, and acute phase reactant value based on erythrocyte sedimentation rate [ESR]). | Baseline, 24 weeks | 
| Time to First ACR20 Response, Based on ESR | The time to first ACR20 response (based on ESR) is defined as the time from the first dose to the first visit at which a patient first exhibited an ACR20 response, which may or may not have been sustained through Week 24. | 0 to 24 weeks | 
| Time to First ACR50 Response, Based on ESR | Measure not posted because time to ACR50 response was unable to be determined due to the small number of patients achieving an ACR50 response in the study. | 0 to 24 weeks | 
| Time to First ACR70 Response, Based on ESR | Measure not posted because time to ACR70 response was unable to be determined due to the small number of patients achieving an ACR70 response in the study. | 0 to 24 weeks | 
| Mean Change in Disease Activity Score 28 (DAS28) at Week 24 | DAS is a composite index of a patient's level of RA disease activity. DAS28 is an abbreviated version of DAS, using a subset of 28 joints in the assessment, calculated based on 4 variables: 1) number of tender joints out of a total of 28 joints, 2) number of swollen joints out of a total of 28 joints, 3) ESR, 4) patient's global assessment of disease activity based on a 100-mm visual analog scale. The calculation provides a number on a scale from 0 to 10 (>5.1=active disease; <3.2=well controlled disease; <2.6=remission). Change from baseline >1.2 = good response and ≤0.6 = non-response. | Baseline, 24 weeks | 
| Time to First DAS28 Response | DAS28 response is defined as the time from the first dose to the first time at which a patient exhibited a good or a moderate improvement in RA disease activity, based on DAS28 improvements compared to baseline. Good response was defined as >1.2 change from baseline and DAS28 score ≤ 3.2. No response was defined as ≤ 0.6 change from baseline in DAS28 score or change between ≤ 1.2 and > 0.6 with a DAS28 score of > 5.1. | 0 to 24 weeks | 
| Mean Change in Modified Total Sharp Score at Week 24 | The modified total Sharp score method was used to evaluate radiographs of hands/wrists for erosions (ERO) and joint space narrowing (JSN). The total modified Sharp score ranges from 0 (no radiographic damage) to 200 (worst possible radiographic damage) and is the sum of the normalized ERO score (range 0-100) and the normalized JSN score (range 0-100). Higher scores indicated more damage. | Baseline, 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RA