Clinical trial NCT00468546: A Study to Evaluate the Safety and Efficacy of MabThera (Rituximab) in Combination With Methotrexate (MTX) in Participants With Active Rheumatoid Arthritis Who Failed on Anti-Tumor Necrosis Factor Alpha Therapy
Official title: A Randomized, Placebo-controlled, Double-blind, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Alpha Therapies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Biogen
First posted: 2007-05-02
Enrollment: 520
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will assess the safety and efficacy of rituximab combined with MTX in participants with active rheumatoid arthritis (RA) who have had an inadequate response to anti-Tumor Necrosis (TNF) alpha therapy. The anticipated time in the study is up to 2 years and the target sample size is 500 participants. Eligible participants may receive re-treatment with rituximab under a separate protocol WA17531.


Eligibility criteria: Inclusion Criteria:

* Adult participants 18-80 years of age with active RA for at least 6 months;
* Received treatment for RA on an outpatient basis and experienced an inadequate response or intolerance to treatment with at least 1 anti-TNF alpha therapy (etanercept, infliximab or adalimumab);
* Must have received MTX for a minimum of 12 weeks, with the last 4 weeks, prior to screening at a stable dose;
* Participants with swollen joint count (SJC) and tender joint count (TJC) of at least 8 joints at screening and at randomization;
* Radiographic evidence of at least 1 joint with a definite erosion due to RA;
* Participants of reproductive potential must be using reliable contraceptive methods.

Exclusion Criteria:

* Bone or joint surgery within 8 weeks prior to screening or joint surgery planned within 24 weeks of randomization;
* Class IV functional status of RA;
* Previous treatment within 6 months with intravenous gamma globulin, or the Prosorba column;
* Intraarticular or parenteral corticosteroids within 4 weeks prior to screening visit;
* With a live vaccine within 4 weeks prior to randomization;
* Previous treatment with rituximab or other cell-depleting therapies;
* Concurrent treatment with any disease-modifying anti-rheumatic drug (except for MTX) or any anti-TNF alfa factor or other biologic therapy;
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies;
* Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders;
* Known contraindications to receiving rituximab;
* Known active bacterial, viral, fungal, mycobacterial or other infection;
* History of recurrent significant infection or history of recurrent bacterial infections;
* Primary or secondary immunodeficiency (history of, or currently active);
* History of cancer, including solid tumors and hematologic malignancies (except basal cell or squamous cell carcinoma of the skin that have been excised and cured);
* Women who are pregnant or breast-feeding;
* History of alcohol, drug or chemical abuse within 6 months prior to screening;
* Neuropathies and neurovasculopathies which might interfere with pain evaluation;
* Participants with poor peripheral venous access;
* Intolerance or contraindications to oral or intravenous corticosteroids.

Primary outcomes:
measure: Number of Participants With American College of Rheumatology 20 Response at Week 24
timeFrame: Week 24
Secondary outcomes:
measure: Number of Participants With an ACR 50 Response at Week 24
timeFrame: Week 24
measure: Number of Participants With ACR 70 Response at Week 24
timeFrame: Week 24
measure: Mean Change From Baseline in Disease Activity Score of 28 Joints at Week 24
timeFrame: From Baseline (Day 1) to Week 24
measure: Percentage of Participants With DAS28 Low Disease Activity and DAS28 Remission at Week 24
timeFrame: Week 24
measure: Number of Participants With Good, Moderate, or no European League Against Rheumatism Responses at Week 24
timeFrame: Week 24
measure: Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score
timeFrame: From Baseline (Day 1) to Week 24
measure: Mean Change From Baseline of Short Form 36 Total Scores at Week 24
timeFrame: From Baseline (Day 1) to Week 24
measure: Number of Participants With Categorical Change From Baseline in the Physical Component Scores of SF-36
timeFrame: From Baseline (Day 1) to Week 24
measure: Number of Participants With Change From Baseline in the Mental Component Scores of SF-36
timeFrame: From Baseline (Day 1) to Week 24
measure: Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score
timeFrame: From Baseline (Day 1) to Weeks (W) 24, 56, and 104
measure: Percentage of Participants Without Erosive Progression
timeFrame: Up to Week 104
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Mesa
country: United States
state: Arizona
city: Paradise Valley
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Little Rock
country: United States
state: Arkansas
city: Fullerton
country: United States
state: California
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Palo Alto
country: United States
state: California
city: Pasadena
country: United States
state: California
city: Rancho Mirage
country: United States
state: California
city: Santa Maria
country: United States
state: California
city: Upland
country: United States
state: California
city: Danbury
country: United States
state: Connecticut
city: Boca Raton
country: United States
state: Florida
city: Delray Beach
country: United States
state: Florida
city: Fort Lauderdale
country: United States
state: Florida
city: Jupiter
country: United States
state: Florida
city: Largo
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Boise
country: United States
state: Idaho
city: Coeur D'alene
country: United States
state: Idaho
city: Meridian
country: United States
state: Idaho
city: Chicago
country: United States
state: Illinois
city: Chicago
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Indianapolis
country: United States
state: Indiana
city: Shreverport
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Kalamazoo
country: United States
state: Michigan
city: Lansing
country: United States
state: Michigan
city: Rochester
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: St Louis
country: United States
state: Missouri
city: Albany
country: United States
state: New York
city: Manhasset
country: United States
state: New York
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Smithtown
country: United States
state: New York
city: Chapel Hill
country: United States
state: North Carolina
city: Durham
country: United States
state: North Carolina
city: Greenville
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Dayton
country: United States
state: Ohio
city: Mayfield
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Oklahoma City
country: United States
state: Oklahoma
city: Tulsa
country: United States
state: Oklahoma
city: Duncansville
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Amarillo
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Waco
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Burlington
country: United States
state: Vermont
city: Seattle
country: United States
state: Washington
city: Seattle
country: United States
state: Washington
city: Spokane
country: United States
state: Washington
city: Madison
country: United States
state: Wisconsin
city: Madison
country: United States
state: Wisconsin
city: Bruxelles
country: Belgium
city: Bruxelles
country: Belgium
city: Gent
country: Belgium
city: Liege
country: Belgium
city: Calgary
country: Canada
state: Alberta
city: Edmonton
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Hamilton
country: Canada
state: Ontario
city: London
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Le Kremlin Bicetre
country: France
city: Montpellier
country: France
city: Paris
country: France
city: Rouen
country: France
city: Strasbourg
country: France
city: Toulouse
country: France
city: Tours
country: France
city: Berlin
country: Germany
city: Dresden
country: Germany
city: Leipzig
country: Germany
city: Ratingen
country: Germany
city: Wuerzburg
country: Germany
city: Cork
country: Ireland
city: Dublin
country: Ireland
city: Haifa
country: Israel
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Petach Tikva
country: Israel
city: Ramat Gan
country: Israel
city: Tel Aviv
country: Israel
city: Udine
country: Italy
state: Friuli-Venezia Giulia
city: Arenzano
country: Italy
state: Liguria
city: Genova
country: Italy
state: Liguria
city: Brescia
country: Italy
state: Lombardia
city: Milano
country: Italy
state: Lombardia
city: Pisa
country: Italy
state: Toscana
city: Amsterdam
country: Netherlands
city: Drammen
country: Norway
city: Lillehammer
country: Norway
city: Oslo
country: Norway
city: Tromsø
country: Norway
city: Cannock
country: United Kingdom
city: Leeds
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Newcastle Upon Tyne
country: United Kingdom
city: Wirral
country: United Kingdom
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_CHAIR
References:
citation: Lal P, Su Z, Holweg CT, Silverman GJ, Schwartzman S, Kelman A, Read S, Spaniolo G, Monroe JG, Behrens TW, Townsend MJ. Inflammation and autoantibody markers identify rheumatoid arthritis patients with enhanced clinical benefit following rituximab treatment. Arthritis Rheum. 2011 Dec;63(12):3681-91. doi: 10.1002/art.30596.
citation: Keystone E, Burmester GR, Furie R, Loveless JE, Emery P, Kremer J, Tak PP, Broder MS, Yu E, Cravets M, Magrini F, Jost F. Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Arthritis Rheum. 2008 Jun 15;59(6):785-93. doi: 10.1002/art.23715.