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

Phase 2

Completed

• Conditions: Rheumatoid Arthritis
• Interventions: Drug: Methotrexate; Drug: Cyclophosphamide; Other: Placebo Cyclophosphamide; Other: Placebo Methotrexate; Other: Placebo Rituximab; Drug: Rituximab

• Registration Number: NCT02693210
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study Start: 2001-02
• Primary Completion: 2002-08
• Study Completion: 2004-08
• Study First Submitted: 2016-02-23
• Study First Submitted QC: 2016-02-25
• Study First Posted: 2016-02-26
• Status Verified: 2016-10
• Last Update Submitted: 2016-10-29
• Last Update Posted: 2016-11-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 161

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: Methotrexate	Placebo Cyclophosphamide	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.
Group B: Rituximab Monotherapy	Placebo Cyclophosphamide	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.
Group A: Methotrexate	Methotrexate	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.
Group D: Methotrexate and Rituximab	Methotrexate	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.
Group A: Methotrexate	Placebo Rituximab	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.
Group B: Rituximab Monotherapy	Placebo Methotrexate	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.
Group D: Methotrexate and Rituximab	Rituximab	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.
Group C: Rituximab and Cyclophosphamide	Placebo Methotrexate	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.
Group C: Rituximab and Cyclophosphamide	Rituximab	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.
Group D: Methotrexate and Rituximab	Placebo Cyclophosphamide	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.
Group B: Rituximab Monotherapy	Rituximab	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.
Group C: Rituximab and Cyclophosphamide	Cyclophosphamide	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.

Primary Outcome Measures

Name	Time	Method
Percentage of participants achieving American College of Rheumatology (ACR) 50 response at Week 24	Week 24

Secondary Outcome Measures

Name	Time	Method
Area Under the Curve (AUC) of American College of Rheumatology Response (ACRn)	Baseline up to Week 24
Mean change in Rheumatoid factor levels at 24 weeks	Baseline and Week 24
AUC of the mean Disease Activity Scores (DAS)	Baseline up to Week 24
Change from Baseline in the Health Assessment Questionnaire - Disease Index (HAQ-DI) scores	Baseline, Weeks 12, 16, 20 and 24
Percentage of participants who withdrew due to insufficient therapeutic response	Up to 24 Weeks
Percentage of participants achieving ACR 20 and ACR 70 responses at Week 24	Week 24
Change from Baseline in the Tender Joint Count	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
Change from Baseline in the Swollen 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 participant's pain measured by VAS	Baseline, Weeks 12, 16, 20 and 24