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

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Methotrexate; Other: Placebo Cyclophosphamide; Other: Placebo Rituximab; Other: Placebo Methotrexate; Drug: Rituximab; Drug: Cyclophosphamide

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Darlinghurst, Australia, 2010
  • Kogarah, Australia, 2217
  • Woodville, Australia, 5011
• Belgium
  • Diepenbeek, Belgium, 3590
  • Gent, Belgium, 9000
  • Liege, Belgium, 4000
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1M4
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
  • Quebec
    • Montreal, Quebec, Canada, H2L 1S6
• Czech Republic
  • Praha, Czech Republic, 128 50
• Germany
  • Leipzig, Germany, 04107
  • Ratingen, Germany, 40882
  • Wiesbaden, Germany, 65191
• Israel
  • Haifa, Israel, 31048
  • Haifa, Israel, 34354
• Italy
  • Brescia, Italy, 25123
  • Genova, Italy, 16132
  • Modena, Italy, 41100
  • Siena, Italy, 53100
• Netherlands
  • Leiden, Netherlands, 2333 ZA
• Poland
  • Lublin, Poland, 20-022
  • Poznan, Poland, 61-545
  • Warszawa, Poland, 02-637
  • Wroclaw, Poland, 50-556
• Spain
  • Guadalajara, Spain, 19002
  • La Laguna, Spain, 38320
  • Madrid, Spain, 28046
  • Madrid, Spain, 28007
  • Sevilla, Spain, 41014
• United Kingdom
  • Cannock, United Kingdom, WS11 5XY
  • Leeds, United Kingdom, LS1 3EX
  • London, United Kingdom, W1P 9PG
  • Stoke-on-trent, United Kingdom, ST6 7AG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A: 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.	Drug: Methotrexate; Participants will receive >= 10 mg/week methotrexate orally up to 24 weeks; Other: Placebo Cyclophosphamide; Participants will receive placebo in place of cyclophosphamide on Days 3 and 17; Other: Placebo Rituximab; Participants will receive placebo in place of rituximab on days 1 and 15
Experimental: Group B: Rituximab Monotherapy; 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; Participants will receive placebo in place of cyclophosphamide on Days 3 and 17; Other: Placebo Methotrexate; Participants will receive weekly oral placebo in place of Methotrexate; Drug: Rituximab; Participants will receive 1g infusions of rituximab on Days 1 and 15
Experimental: Group C: Rituximab and 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.	Other: Placebo Methotrexate; Participants will receive weekly oral placebo in place of Methotrexate; Drug: Rituximab; Participants will receive 1g infusions of rituximab on Days 1 and 15; Drug: Cyclophosphamide; Participants will receive 750 mg infusions of cyclophosphamide on Days 3 and 17
Experimental: Group D: Methotrexate and 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.	Drug: Methotrexate; Participants will receive >= 10 mg/week methotrexate orally up to 24 weeks; Other: Placebo Cyclophosphamide; Participants will receive placebo in place of cyclophosphamide on Days 3 and 17; Drug: Rituximab; Participants will receive 1g infusions of rituximab on Days 1 and 15

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hofffmann-La Roche

Study record dates

Study Major Dates

• Study Start: February 1, 2001
• Primary Completion (Actual): August 1, 2002
• Study Completion (Actual): August 1, 2004

Study Registration Dates

• First Submitted: February 23, 2016
• First Submitted That Met QC Criteria: February 25, 2016
• First Posted (Estimate): February 26, 2016

Study Record Updates

• Last Update Posted (Estimate): November 1, 2016
• Last Update Submitted That Met QC Criteria: October 29, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Rituximab; Methotrexate
• Other Study ID Numbers: WA16291