A Study of Retreatment With Rituximab in Patients With Rheumatoid Arthritis Receiving Background Methotrexate

Study Overview
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Brief Summary
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This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy of retreatment with rituximab in subjects with active rheumatoid arthritis (RA) who are receiving Methotrexate (MTX).

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Retreatment With Rituximab in Subjects With Rheumatoid Arthritis Receiving Background Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: placebo
* Drug: rituximab
* Drug: methotrexate
* Drug: folate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form Ability and willingness to comply with the requirements of the study protocol Age 18-80 years Diagnosis of RA for at least 6 months Receiving treatment for RA on an outpatient basis Documented moderate to severe active RA activity at screening and Day 1 Documented inadequate response to previous or current treatment with one or more of the following: etanercept, infliximab, and/or adalimumab because of toxicity or inadequate efficacy Use of MTX 10-25 mg/wk for ≥ 12 weeks prior to Day 1 at a stable dose for ≥ 4 weeks Willingness to receive oral folic acid If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to Day 1 Use of one NSAID is permitted if the dose is stable for ≥ 2 weeks prior to Day 1 For men and women of reproductive potential, willingness to use a reliable means of contraception for ≥ 30 days prior to Day 1 and for the study duration or the duration that the subject's peripheral CD19 B cells are depleted, whichever is longer Exclusion Criteria: Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA; Secondary Sjogren's syndrome with RA is permitted. History of or current inflammatory joint disease other than RA or other systemic rheumatic disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, or overlap syndrome) History of deep space/tissue infection within 52 weeks prior to Day 1 Diagnosis of juvenile idiopathic arthritis (JIA), juvenile rheumatoid arthritis (JRA), and/or RA before age 16 Functional Class IV, as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement), within 12 weeks prior to Day 1 or planned within 48 weeks after Day 1 Known hypersensitivity to any component of a humanized or murine monoclonal antibody Receipt of any vaccination within 4 weeks prior to Day 1 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 Known active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease but excluding fungal infections of the nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Day 1 or oral antibiotics within 2 weeks of Day 1 History of serious recurrent or chronic infection (a chest X-ray will be performed at screening if one has not been performed within 12 weeks of screening that showed no clinically significant abnormality) History of or currently active primary or secondary immunodeficiency, including HIV infection History of cancer, including solid tumors and hematologic malignancies (except basal cell or squamous cell carcinoma of the skin that has 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 Day 1 Pregnancy or lactation Neuropathies and neurovasculopathies that might interfere with pain evaluation Poor peripheral venous access Intolerance or contraindications to oral or IV corticosteroids Positive hepatitis B surface antigen or hepatitis C antibody serology For women of childbearing potential (including those who have had a tubal ligation), a positive serum pregnancy test at screening Current use of any DMARD other than MTX Concurrent treatment with any biologic agent Treatment with any investigational agent within 4 weeks prior to Day 1 or five half-lives of the investigational drug (whichever is longer) Any previous treatment with rituximab or other cell-depleting therapies, including CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD11a, anti-CD22, anti-BLys/ BAFF, and other anti-CD20 agents Previous treatment with a co-stimulation blocking agent, including abatacept Previous treatment with an anti-<alpha> 4 integrin agent, including natalizumab Previous treatment within 6 months of screening with IV & globulin or the Prosorba(R) Column Intra-articular or parenteral corticosteroids within 4 weeks prior to Day 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Rituximab Retreatment<br>1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by re-treatment during weeks 24 -40 consisting of two additional doses of 1000 mg rituximab 14 days apart plus 10-25 mg/week methotrexate. | Drug: rituximab<br>* Intravenous repeating dose<br>Drug: methotrexate<br>* Oral or parenteral repeating dose<br>Drug: folate<br>* Intravenous repeating dose<br>|
| Placebo Comparator: Arm B: Placebo Retreatment<br>1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by retreatment during weeks 24 -40 consisting of two doses of placebo 14 days apart plus 10-25 mg/week methotrexate. | Drug: placebo<br>* Intravenous repeating dose<br>Drug: methotrexate<br>* Oral or parenteral repeating dose<br>Drug: folate<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retreated Subjects With an American College of Rheumatology 20% (ACR20) Response at Week 48 Relative to Baseline | ACR20 response was defined as a ≥ 20% improvement compared with baseline in both tender joint count (TJC) [68 joints] and swollen joint count (SJC) [66 joints] as well as a ≥ 20% improvement in three of five additional measurements: 1) Physician's Global Assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [visual analog scale: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [visual analog scale: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) erythrocyte sedimentation rate. | 48 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retreated Subjects With American College of Rheumatology 50% (ACR50) Response and American College of Rheumatology 70% (ACR70) Response at Week 48 Relative to Baseline | ACR50 or ACR70 response was defined as a ≥ 50% or 70% improvement compared with baseline in both tender joint count (TJC) [68 joints] and swollen joint count (SJC) [66 joints] as well as a ≥ 50% or 70% improvement in three of five additional measurements: 1) Physician's Global Assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [visual analog scale: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [visual analog scale: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) erythrocyte sedimentation rate. | Baseline, Week 48 | 
| Change From Baseline in the Disease Activity Score Using 28 Joint Counts (DAS28-ESR) at Week 48 | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement. | 48 weeks | 
| Change From Baseline in Disease Activity Score (DAS28-CRP) at Week 48 | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and C-Reactive Protein (CRP) for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement. | Baseline, Week 48 | 
| Percentage of Retreated Subjects With a European League Against Rheumatism (EULAR) Response at Week 48 | Change of the Disease Activity Score 28 score from baseline was used to determine EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Swollen Joint Count at Week 48 | A Rheumatologist or an skilled arthritis assessor evaluated 66 joints at baseline and at Week 48. A negative change from baseline in Swollen Joint Count indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Tender Joint Count at Week 48 | A Rheumatologist or an skilled arthritis assessor evaluated 68 joints at baseline and at Week 48. A negative change from baseline in the Tender Joint Count indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 48 | The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip,and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Subject's Global Assessment of Disease Activity at Week 48 | Participants rated their disease activity at baseline and Week 48 using the Visual Analog Scale (VAS) on a scale of 0 (best) to 100 (worse). A negative change from baseline indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Physician's Global Assessment of Disease Activity at Week 48 | A Rheumatologist or a skilled Arthritis assessor rated the patient's disease activity at baseline and Week 48 using the Visual Analog Scale (VAS) on a scale of 0 (best) to 100 (worse). A negative change from baseline indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Subject's Assessment of Pain at Week 48 | Patients rated their pain at baseline and Week 48 using the Visual Analog Scale (VAS) on a scale of 0 (none) to 100 (unbearable pain). A negative change from baseline indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: C-Reactive Protein at Week 48 | Blood was collected for C-Reactive Protein, an inflammatory marker, at Baseline and Week 48. A negative change from baseline indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Erythrocyte Sedimentation (ESR) at Week 48 | Blood was collected for Erythrocyte Sedimentation Rate, an inflammatory marker, at Baseline and Week 48. A negative change from baseline indicates improvement. | Baseline, Week 48 | 
| Percentage of Retreated Subjects With a Change ≥ 0.22 From Baseline in HAQ-DI at Week 48 | The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do). HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. | Baseline, Week 48 | 
| Percentage of Retreated Subjects With a Change ≥ 0.3 From Baseline in HAQ-DI at Week 48 | The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. | Baseline, Week 48 | 
| ACRn in Retreated Subjects at Week 48 | The ACRn is calculated for each participant by taking the lowest percentage improvement in (1) swollen joint count or (2) tender joint count or (3) the median of the remaining 5 components of the ACR response (participant's assessment of disease activity; participant's global assessment of pain; physician's assessment of disease activity; participant's assessment of physical function; an acute phase reactant value - CRP). A positive ACRn Score indicates an improvement. | Baseline, Week 48 | 
| Change From Baseline in SF-36 Health Summary Scores at Week 48 in Retreated Subjects | The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. 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. A positive change from baseline indicates improvement. | Baseline, Week 48 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) at Week 48 in Retreated Subjects | 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, Week 48 | 
| Percentage of Retreated Subjects Achieving DAS28-ESR Remission at Week 48 | DAS28-ESR remission was defined as a DAS28-ESR < 2.6 | Week 48 | 
| Percentage of Retreated Subjects Achieving DAS28-ESR Low Disease at Week 48 | The DAS28-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-ESR scores range from 0 - 10. Low disease activity is defined as achieving a DAS28-ESR score of less than or equal to 3.2. | Week 48 |