A Study of the Safety of Rituximab in Combination With Other Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis

NCT ID: NCT00443651

Last Updated: 2017-04-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 578 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2013-02-28

Brief Summary

This is a Phase III, open-label study of a total of approximately 560 subjects with active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Enrollment in the study was conducted in two stages. In Stage I of the study, approximately 400 subjects receiving non-biological DMARDs (with the exception of methotrexate [MTX] monotherapy or MTX and leflunomide combination therapy) were enrolled. In Stage II of the study, approximately 160 subjects receiving a Federal Drug Administration-approved biological DMARD at the time of screening were enrolled.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rituximab 1000 mg (Stage I patients)

Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: DRUG

Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.

Anti-inflammatory drugs

Intervention Type: DRUG

Each rituximab infusion was preceded by methylprednisolone 100 mg IV. Use of stable doses of oral corticosteroids was permitted (≤ 10 mg of prednisone or equivalent per day) as were stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs).

Rituximab 500 mg (Stage II patients)

Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: DRUG

Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.

Anti-inflammatory drugs

Intervention Type: DRUG

Each rituximab infusion was preceded by methylprednisolone 100 mg IV. Use of stable doses of oral corticosteroids was permitted (≤ 10 mg of prednisone or equivalent per day) as were stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs).

Interventions

Rituximab

Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.

Intervention Type: DRUG

Anti-inflammatory drugs

Each rituximab infusion was preceded by methylprednisolone 100 mg IV. Use of stable doses of oral corticosteroids was permitted (≤ 10 mg of prednisone or equivalent per day) as were stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs).

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active rheumatoid arthritis (RA) for ≥ 6 months
• Receiving treatment for RA on an outpatient basis
• Have had an inadequate response to at least one non-biological disease-modifying anti-rheumatic drug (DMARD) and have been receiving this DMARD(s) for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline
• Demonstrated tolerability to currently prescribed DMARDs
• If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to the first day of treatment with rituximab (Day 1)
• Use of one nonsteroidal anti-inflammatory drug (NSAID) is permitted if the dose is stable for ≥ 2 weeks prior to Day 1

• Male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active RA for ≥ 6 months, diagnosed according to the revised 1987 ACR criteria for the classification of RA
• Receiving treatment for RA on an outpatient basis
• Have had an inadequate response to at least one biologic DMARD and have been receiving this agent at screening and for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline
• Have demonstrated tolerability to currently prescribed DMARDs/biologics
• If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to baseline
• Use of one NSAID is permitted if the dose is stable for ≥ 2 weeks prior to baseline

Exclusion Criteria

• Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis, or Felty's syndrome)
• Functional Class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis
• History of or current inflammatory joint disease other than RA or other systemic autoimmune disorder
• Diagnosis of juvenile idiopathic arthritis, or juvenile RA, and/or RA before age 16 years
• Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of enrollment
• Lack of peripheral venous access
• Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
• Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders that, in the investigator's opinion, would preclude subject participation
• Primary or secondary immunodeficiency (history of or currently active), including known history of human immunodeficiency virus (HIV) infection
• Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline
• History of medically significant opportunistic infection
• History of serious recurrent or chronic infection
• History of deep space/tissue infection within 52 weeks prior to baseline
• History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured)
• History of significant cytopenias or other bone marrow disorders
• History of alcohol, drug, or chemical abuse within 24 weeks prior to baseline
• Pregnancy or lactation
• Neuropathies and neurovasculopathies that might interfere with pain evaluation
• Methotrexate (MTX) monotherapy at the time of screening
• Concurrent treatment with MTX and leflunomide in combination
• Concurrent treatment with any biologic agent
• Prior to Day 1, subjects will be discontinued from all DMARDs/combinations that are prohibited in the protocol
• History of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins
• Previous treatment with an anti-α4 integrin agent
• Previous treatment with any cell-depleting therapies, including investigational agents
• Receipt of any vaccine within 28 days prior to baseline
• Intolerance or contraindications to IV corticosteroids
• Receipt of IV immunoglobulin (IVIG) or Prosorba<TM> column within 6 months prior to baseline
• Any previous treatment with rituximab
• Positive hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody

• Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis, or Felty's syndrome)
• Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
• History of, or current, inflammatory joint disease other than RA or other systemic autoimmune disorder
• Diagnosis of juvenile idiopathic arthritis, or juvenile RA, and/or RA before age 16 years
• Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of randomization
• Lack of peripheral venous access
• Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
• Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine or gastrointestinal disorders that, in the investigator's opinion, would preclude subject participation
• Primary or secondary immunodeficiency (history of or currently active), including known history of HIV infection
• Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline
• History of medically significant opportunistic infection
• History of serious recurrent or chronic infection
• History of deep space/tissue infection within 52 weeks prior to baseline
• History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured)
• History of significant cytopenias or other bone marrow disorders
• History of alcohol, drug, or chemical abuse within 24 weeks prior to baseline
• Pregnancy or lactation
• Neuropathies and neurovasculopathies that might interfere with pain evaluation
• Infliximab monotherapy at the time of screening (infliximab should be in combination with MTX)
• Concurrent treatment with MTX and leflunomide in combination
• Concurrent treatment with more than one biologic agent
• Prior to Day 1, subjects will be discontinued from all DMARDs/combinations that are prohibited in the protocol
• History of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins
• Previous treatment with an anti-α4 integrin agent
• Previous treatment with any cell-depleting therapies
• Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is the longer)
• Receipt of any vaccine within 28 days prior to baseline
• Intolerance or contraindications to IV corticosteroids
• Receipt of IVIG or Prosorba<TM> column within 6 months prior to baseline
• Any previous treatment with rituximab
• Positive hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody
• Positive purified protein derivative (PPD) skin test not adequately treated according to Center for Disease Control (CDC) guidelines

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Biogen

INDUSTRY

Sponsor Role: collaborator

Genentech, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Micki Klearman, M.D.

Role: STUDY_DIRECTOR

Genentech, Inc.

References

Rigby WF, Mease PJ, Olech E, Ashby M, Tole S. Safety of rituximab in combination with other biologic disease-modifying antirheumatic drugs in rheumatoid arthritis: an open-label study. J Rheumatol. 2013 May;40(5):599-604. doi: 10.3899/jrheum.120924. Epub 2013 Apr 1.

Reference Type: DERIVED

PMID: 23547218 (View on PubMed)

Other Identifiers

U3924g

Identifier Type: -

Identifier Source: org_study_id