A Study of the Safety and Efficacy of Rituximab in Patients With Moderate to Severe Rheumatoid Arthritis Receiving Methotrexate

Study Overview
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Brief Summary
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This was a Phase II, randomized, double-blind, multicenter study designed to evaluate the safety and efficacy of rituximab, administered at two different regimens for 2 years, in patients with moderate to severe active rheumatoid arthritis (RA) receiving stable doses of methotrexate (MTX).

Official Title
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A Double-Blind, Randomized, Multicenter, Phase II Study of the Safety and Efficacy of Two Rituximab Regimens in Subjects With Moderate to Severe Active Rheumatoid Arthritis Receiving Stable Doses of Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: folate
* Drug: methotrexate
* Drug: methylprednisolone
* Drug: Placebo
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of RA for at least 6 months. Inadequate response to MTX Use of folate If female and of childbearing potential, have a negative serum pregnancy test within 8 weeks prior to first rituximab infusion Exclusion Criteria: Diagnosis of juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis) and/or RA before age 16 Any surgical procedure, including bone/joint surgery or planned surgery within 8 weeks prior to screening or within 16 weeks of Week 1 (Day 1) visit Inflammatory arthritis other than RA (e.g., inflammatory bowel disease, systemic lupus erythematosus (SLE), or psoriatic arthritis) Functional Class IV as defined by the American College of Rheumatology (ACR) classification of functional status in RA Use of disease-modifying anti-rheumatic drugs (DMARDs) other than MTX within 4 weeks prior to randomization (8 weeks prior for infliximab, adalimumab, or leflunomide) Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer) Previous treatment with Tysabri<TM> (natalizumab) Previous treatment with rituximab Previous treatment with any cell-depleting therapies, including investigational agents Treatment with IV &-globulin or Prosorba(R) Column within the previous 6 months Use of intra-articular or parenteral corticosteroids within 4 weeks prior to screening visit Receipt of a vaccine within 4 weeks prior to Day 1 infusion History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies Primary or secondary immunodeficiency (history of or active) Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, renal, hepatic, endocrine, gastrointestinal, or pulmonary disease, including any pulmonary or other condition that would preclude subject participation over the ensuing 2 years Known active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) History of recurrent significant infection or any significant episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening History of significant cytopenias or other bone marrow disorders History of cancer, including solid tumors and hematologic malignancies (except basal cell and squamous cell carcinoma of the skin that have been excised and cured) Pregnant or nursing (breast feeding) women Lack of peripheral venous access Chronic daily use of narcotic analgesics History of alcohol, drug, or chemical abuse within 6 months prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: 500 mg Rituximab<br>Rituximab: 1000 mg intravenous (IV) on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk). | Drug: folate<br>* Minimum of 1 mg/day oral (or folinic acid 5 mg/week)<br>Drug: methotrexate<br>* 15-25 mg/week oral or parenteral (10-14 mg/week if intolerant)<br>Drug: methylprednisolone<br>* 100 mg intravenous (IV) prior to each rituximab infusion (For Arm B, for the Months 6 and 18 cycles, IV saline was administered prior to each placebo infusion)<br>Drug: Rituximab<br>* 500 mg or 1000 mg IV*2.<br>|
| Experimental: Arm B: 1000 mg Rituximab<br>Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12.) For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk). | Drug: folate<br>* Minimum of 1 mg/day oral (or folinic acid 5 mg/week)<br>Drug: methotrexate<br>* 15-25 mg/week oral or parenteral (10-14 mg/week if intolerant)<br>Drug: methylprednisolone<br>* 100 mg intravenous (IV) prior to each rituximab infusion (For Arm B, for the Months 6 and 18 cycles, IV saline was administered prior to each placebo infusion)<br>Drug: Placebo<br>* To maintain the blind, patients in Arm B (Rituximab 1000 mg) received placebo infusions at Months 6 and 18.<br>Drug: Rituximab<br>* 500 mg or 1000 mg IV*2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Either an Infection or a Grade III or IV Adverse Event (National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI CTCAE], Version 3.0) | A Grade III Adverse Event (AE) is severe; defined as considerable interference with the subject's daily activities, medical intervention/therapy required and hospitalization possible. A Grade IV AE is life-threatening; defined as extreme limitation in activity, significant medical intervention/therapy required, hospitalization probable. Because of the small sample size and the small number of subjects who completed Week 104, the analysis were limited to descriptive statistics only. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score 28-4 C-reactive Protein (DAS28-4(CRP)) | The DAS28-4(CRP) score is a measure of the subject's disease activity. DAS28-4(CRP) is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and CRP. DAS28 provides a number on a scale (0 to 10) indicating current disease activity. A score above 5.1 means high disease activity and a score below 3.2 indicates low disease activity. Change from baseline at 24 months was analyzed for DAS28-4 (CRP). | Baseline, 24 months | 
| Number of Participants With American College of Rheumatology Responses (ACR20, ACR50, and ACR70) | ACR20 response was defined as satisfying the following 3 criteria improvement from baseline: ≥ 20% in tender joint count; ≥ 20% in swollen joint count; ≥ 20% improvement from baseline in 3 of the following 5 criteria: Subject's Global Assessment of Pain Subject's Global Assessment of Disease Activity Physician's Global Assessment Subject's Self-Assessment Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) Note: The definitions of ACR50 and ACR70 are the same as ACR20, except that the 20% value in the above definition is replaced by 50% and 70% values, respectively. | Baseline, 24 months | 
| Number of Participants With American College of Rheumatology (ACR) Major Clinical Response and/or Remission | Major clinical response is an ACR70 response defined as improvement from baseline: ≥70% in tender joint count; ≥70% in swollen joint count; ≥70% in 3 of the following: Patient Pain Assessment, Patient Global Assessment, Physician Global Assessment, Patient Self-Assessed Disability, ESR or CRP for ≥169 consecutive days. Remission: ≥5 requirements fulfilled for ≥2 consecutive months: Duration of morning stiffness <15 minutes, No fatigue, No joint pain, No joint tenderness or pain on motion, No soft tissue swelling in joints or tendon sheaths, ESR <30 mm/hour for women and <20 mm/hour for men. | 24 months | 
| Number of Participants With European League Against Rheumatism (EULAR) Response and Remission Using Disease Activity Score 28-4 (DAS28-4)C-reactive Protein (CRP) | EULAR remission = DAS28-4(CRP) < 2.6 (Fransen et al. 2004. EULAR response categories (van Gestel et al. 1999): Good response = final DAS28-4(CRP) < 3.2 and decreased > 1.2 points from baseline Moderate response = final DAS28-4(CRP) ≥ 3.2 but ≤ 5.1 and decreased > 0.6 points from baseline or final DAS28-4(CRP) > 5.1 and decreased > 1.2 from baseline. | Baseline, 24 months | 
| Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores | The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning (PF), Role Physical (RP), Bodily Pain(BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE),Mental Health (MH). Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. | Baseline, 24 Months | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) | The Stanford HAQ-DI is a patient-reported questionnaire specific for RA. It consists of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The questionnaire was provided in a certified translation of the local languages at the participating sites and was scored based on the instructions from the Stanford University Medical Center.The questions are evaluated on a 4-point scale: 0=without any difficulty, 1= with some difficulty, 2= with much difficulty, and 3= unable to do. Higher scores= greater dysfunction. | Baseline, 24 Months | 
| Change From Baseline in Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F) | FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the patient's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the patient's health status. | Baseline, 24 Months | 
| DAS28-4 Erythrocyte Sedimentation Rate(ESR) | The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10, where a score of less than or equal to 3.2 implies well controlled disease and greater than or equal to 5.1 implies active disease In this trial, CRP rather than ESR was used, unless the CRP value was missing at both Day 1 and screening, in which case ESR value was used. | 24 Months | 
| Change From Baseline in Rheumatoid Factor (RF) | Serum levels of rheumatoid factor at baseline, month 24 and change from baseline to month 24. | Baseline, 24 Months | 
| Change From Baseline in Cyclic Citrullinated Peptide (CCP) Antibodies/Cytokines | Because of the different laboratory methods that were used to measure anti-CCP antibody levels, no summary statistics were calculated. | Baseline, 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituxan, RA