A Study to Evaluate the Efficacy and Safety of Mabthera Alone and in Combination With Either Cyclophosphamide or Methotrexate in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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WA16291 is a Phase IIa proof-of-concept study. The primary objective of this study is to determine the safety and efficacy of rituximab (a B cell depleting chimeric monoclonal antibody) used either as monotherapy or in combination with methotrexate or cyclophosphamide in participants with rheumatoid arthritis who have failed prior Disease Modifying Anti-Rheumatic Drug (DMARD) therapy and currently have an inadequate clinical response to methotrexate.

Official Title
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A Randomised, Double Dummy Controlled, Parallel Group Study of the Efficacy and Safety of MabThera (Rituximab) Alone or in Combination With Either Cyclophosphamide or Methotrexate, in Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Methotrexate
* Other: Placebo Cyclophosphamide
* Other: Placebo Methotrexate
* Other: Placebo Rituximab
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with moderate to severe rheumatoid arthritis (RA) who have previously failed 1-5 DMARDS who currently have partial clinical response to treatment with methotrexate Using methotrexate as a single DMARD for at least 16 weeks, of which the last 4 weeks prior to baseline on a stable oral dose greater than or equal to (>=) 10 milligrams per week (mg/week) >=21 years of age Swollen Joint Count (SJC) and Tender Joint Count (TJC) >= 8 (out of 66 and 68 joints respectively) At least 2 of the following parameters at Baseline: C- Reactive Protein >= 15 mg/dL; Erythrocyte Sedimentation Rate >= 30 millimeters per hour (mm/hr); Morning stiffness >45 minutes Rheumatoid factor titer >=20 International units per milliliter (IU/mL) Corticosteroid (less than or equal to [=<] 12.5 milligrams per deciliter [mg/d] prednisone or equivalent) or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are permitted if stable for at least 4 weeks prior to baseline Exclusion Criteria: American Rheumatism Association (ARA) Class IV RA disease Concurrent treatment with any DMARD (apart from randomized treatment) or anti-TNF-alpha therapy Active infection or history of recurrent significant infection Prior history of cancer including solid tumors and hematologic malignancies (except basal carcinoma of the skin that have been excised and cured) Evidence of serious uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders Bone/joint surgery within 6 weeks prior to screening Rheumatic Autoimmune disease other than RA Active rheumatoid vasculitis Prior history of gout Chronic fatigue syndrome

Ages Eligible for Study
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Minimum Age: 21 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A: Methotrexate<br>Participants will receive methotrexate at dosage >=10 milligrams per week (mg/week) orally as determined by the investigator. They also receive placebo infusion on days 1 and 15 in place of rituximab and on Days 3 and 17 in place of cyclophosphamide. | Drug: Methotrexate<br>* Participants will receive >= 10 mg/week methotrexate orally up to 24 weeks<br>Other: Placebo Cyclophosphamide<br>* Participants will receive placebo in place of cyclophosphamide on Days 3 and 17<br>Other: Placebo Rituximab<br>* Participants will receive placebo in place of rituximab on days 1 and 15<br>|
| Experimental: Group B: Rituximab Monotherapy<br>Participants will receive 1 g intravenous infusions of rituximab on Days 1 and 15. They also receive Weekly placebo orally instead of methotrexate and placebo infusion in place of cyclophosphamide on Days 3 and 17. | Other: Placebo Cyclophosphamide<br>* Participants will receive placebo in place of cyclophosphamide on Days 3 and 17<br>Other: Placebo Methotrexate<br>* Participants will receive weekly oral placebo in place of Methotrexate<br>Drug: Rituximab<br>* Participants will receive 1g infusions of rituximab on Days 1 and 15<br>|
| Experimental: Group C: Rituximab and Cyclophosphamide<br>Participants will receive 1g IV infusion of rituximab on Days 1 and 15 and 750 mg infusion of Cyclophosphamide on Days 3 and 17. They also receive weekly oral placebo in place of methotrexate. | Drug: Cyclophosphamide<br>* Participants will receive 750 mg infusions of cyclophosphamide on Days 3 and 17<br>Other: Placebo Methotrexate<br>* Participants will receive weekly oral placebo in place of Methotrexate<br>Drug: Rituximab<br>* Participants will receive 1g infusions of rituximab on Days 1 and 15<br>|
| Experimental: Group D: Methotrexate and Rituximab<br>Participants will receive >=10 mg/week methotrexate orally along with 2 times 1 gram (g) rituximab IV infusions on Days 1 and 15. Participants will also receive placebo infusions on Days 3 and 17 in place of cyclophosphamide. | Drug: Methotrexate<br>* Participants will receive >= 10 mg/week methotrexate orally up to 24 weeks<br>Other: Placebo Cyclophosphamide<br>* Participants will receive placebo in place of cyclophosphamide on Days 3 and 17<br>Drug: Rituximab<br>* Participants will receive 1g infusions of rituximab on Days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants achieving American College of Rheumatology (ACR) 50 response at Week 24 |  | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants achieving ACR 20 and ACR 70 responses at Week 24 |  | Week 24 | 
| Area Under the Curve (AUC) of American College of Rheumatology Response (ACRn) |  | Baseline up to Week 24 | 
| AUC of the mean Disease Activity Scores (DAS) |  | Baseline up to Week 24 | 
| Change from Baseline in the Swollen Joint Count |  | Baseline, Weeks 12, 16, 20 and 24 | 
| Change from Baseline in the Tender Joint Count |  | Baseline, Weeks 12, 16, 20 and 24 | 
| Change from Baseline in participant's global assessment of disease activity using a Visual Analog Scale (VAS) |  | Baseline, Weeks 8, 12, 16, 20 and 24 | 
| Change from Baseline in physician's global assessment of disease activity using VAS |  | Baseline, Weeks 8, 12, 16, 20 and 24 | 
| Change from Baseline in the Health Assessment Questionnaire - Disease Index (HAQ-DI) scores |  | Baseline, Weeks 12, 16, 20 and 24 | 
| Change from Baseline in participant's pain measured by VAS |  | Baseline, Weeks 12, 16, 20 and 24 | 
| Change from Baseline in C-Reactive Protein (CRP) Levels |  | Baseline, Weeks 12, 16, 20 and 24 | 
| Change from Baseline in Erythrocyte Sedimentation Rate (ESR) |  | Baseline, Weeks 12, 16, 20 and 24 | 
| Mean change in Rheumatoid factor levels at 24 weeks |  | Baseline and Week 24 | 
| Percentage of participants who withdrew due to insufficient therapeutic response |  | Up to 24 Weeks |