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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: MabThera/Rituxan
* Drug: Methotrexate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

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 |
| --- | --- |
| Placebo Comparator: Placebo Plus Methotrexate<br>Participants will be administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg per os (p.o.) or parenterally once a week up to 24 weeks and will be followed up to Week 104. | Drug: Methotrexate<br>* 2<br>Other: Placebo<br>* 3<br>|
| Experimental: Rituximab plus Methotrexate<br>Participants will be administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and will be followed up to Week 104. | Drug: MabThera/Rituxan<br>* 1<br>Drug: Methotrexate<br>* 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With American College of Rheumatology 20 Response at Week 24 | American College of Rheumatology (ACR) 20 response is defined as >= 20% improvement (reduction) in score compared with baseline for both tender joint count (TJC)-68 joints and swollen joint count (SJC)-66 joints, as well as for 3 of the additional 5 ACR core set variables: Patient's Assessment of Pain over the previous 24 hours using a Visual Analog Scale (VAS) ranging from score 0 (no pain) to 100 (unbearable pain); Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS ranging score 0 (no disease activity) to 100 (maximum disease activity); Health Assessment Questionnaire (HAQ):8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do) for a total possible score of 0 (best) to 3 (worst); and acute-phase reactant, either C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score | The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score for erosions of 0-3.5 (8 gradations) is assigned for 14 joints in each hand and wrist, and 6 joints in each foot. Joint space narrowing scores of 0-4 (9 gradations) are assigned to 13 joints in each hand and 6 joints in each foot. The maximum erosion score is 40 x 3.5 = 140. The maximum joint space narrowing score is 38 x 4.0 = 152. Both the erosion and joint space narrowing scores are normalized to 145 and are added together for a maximum total Genant-modified Sharp score of 290. For all the three radiograph assessment, the minimum score is 0. A higher score indicates more damage and a negative change score indicates improvement. The change in score is to be calculated as: Change from Baseline = difference between the score at Weeks 24, 56, or 104 and the score at Baseline. | From Baseline (Day 1) to Weeks (W) 24, 56, and 104 | 
| Percentage of Participants Without Erosive Progression | The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score for erosions of 0-3.5 (8 gradations) is assigned for 14 joints in each hand and wrist, and 6 joints in each foot. The maximum erosion score is 40 x 3.5 = 140 which is normalized to 145. The minimum score is 0 and the maximum score is 145. A higher score indicates more damage and negative change score indicates improvement. | Up to Week 104 | 
| Number of Participants With an ACR 50 Response at Week 24 | ACR 50 response is defined as a >= 50% improvement (reduction) in score compared with baseline for both TJC -68 joints and SJC -66 joints, as well as for 3 of the additional 5 ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a VAS ranging from score '0'=no pain to score '100'=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS ranging from score '0'=no disease activity to score '100'=maximum disease activity; HAQ : Health Assessment Questionnaire (HAQ):which included 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do), where the sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst); and acute-phase reactant, either CRP or ESR. | Week 24 | 
| Number of Participants With ACR 70 Response at Week 24 | ACR 70 response is defined as a >= 70% improvement (reduction) in score compared with baseline for both TJC -68 joints and SJC -66 joints, as well as for 3 of the additional 5 ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a VAS ranging from score '0'=no pain to score '100'=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS ranging from score '0'=no disease activity to score '100'=maximum disease activity; HAQ : Health Assessment Questionnaire (HAQ):which included 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do), where the sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst); and acute-phase reactant, either CRP or ESR. | Week 24 | 
| Mean Change From Baseline in Disease Activity Score of 28 Joints at Week 24 | The disease activity score (DAS28) is an evaluation index of rheumatoid arthritis. The DAS28 applies a mathematical formula based on the following parameters: 1. TJC-28 joints, 2. SJC -28 joints, 3. ESR or CRP measurement, 4. Participant's judgement on his own overall health (global health [GH]) status expressed by a VAS (0 [no disease activity] to 100 [maximum disease activity]). The mathematical formula is 0.56 × √28TJC + 0.28 × √28SJC + 0.7 x loge ESR + 0.014 × GH. The DAS28 scale ranges from score of 0 to 10, where lower scores indicate best disease control and higher scores indicate worsening of disease. Change from Baseline = difference between the score at Week 24 and the score at Baseline. | From Baseline (Day 1) to Week 24 | 
| Percentage of Participants With DAS28 Low Disease Activity and DAS28 Remission at Week 24 | The DAS28 is an evaluation index of RA. The DAS28 applies a mathematical formula based on the following parameters: 1. TJC- 28 joints, 2. SJC- 28 joints, 3. ESR or CRP measurement, 4. Participant's judgement on his own overall health status (GH) expressed by a visual analogue scale VAS (0 [no disease activity] to 100 [maximum disease activity]). The mathematical formula is 0.56 × √28TJC + 0.28 × √28SJC + 0.7 x loge ESR + 0.014 × GH. The DAS28 scale ranges from score of 0 to 10. A participant was categorized as having low disease activity, if participant's DAS28 score was <= 3.2, and was categorized as having clinical remission if participant's DAS28 score was < 2.6. | Week 24 | 
| Number of Participants With Good, Moderate, or no European League Against Rheumatism Responses at Week 24 | European League Against Rheumatism (EULAR) response is defined based on the DAS28 score and the EULAR response criteria (Van Gestel et al, 1996 and 1999). The DAS28 scale ranges from score of 0 to 10, where lower scores indicate best disease control and higher scores indicate worsening of disease. At a given visit, participants with a DAS28 score of < 3.2 are considered good responders if the change from baseline in their DAS28 score is >1.2. Participants with a DAS28 score >= 3.2 to 5.1 are considered moderate responders if the change from baseline in their DAS28 score is <=1.2 to >=0.6. Participants with DAS28 score >5.1 are considered non-responders if the change from baseline in their DAS28 score is <=1.2 to >=0.6. | Week 24 | 
| 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 | Percentage change in the scores of the following parameters of ACR core set relative to respective baseline scores in both study arms was analyzed : SJC (28 and 66 joints) and TJC (28 and 66 joints), patient's global assessment and physician's global assessment based on disease activity (both are expressed by VAS [0 = no disease activity to 100 = maximum disease activity]), HAQ (based on HAQ disability index [HAQDI]) which included 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do), where the sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst), pain assessment using a VAS ranging from score 0 (no pain) to 100 (unbearable pain), CRP concentration, and ESR. | From Baseline (Day 1) to Week 24 | 
| Mean Change From Baseline of Short Form 36 Total Scores at Week 24 | The Short Form (SF)-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual daily activities because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems since last month; 7) limitations in usual work (house hold and outside) due to emotional problems 8) current and 1 year past status of health 9) general mental health. Transforming and standardizing these domains leads to the calculation of the physical component summary and mental component summary measures. Scores on each item were summed and averaged (range 0 [worst] to 100 [best]); increase in score from baseline indicated improvement. Change from Baseline = difference between the score at Week 24 and the score at Baseline. | From Baseline (Day 1) to Week 24 | 
| Number of Participants With Categorical Change From Baseline in the Physical Component Scores of SF-36 | The SF-36 determined participants' overall quality of life by assessing :1) limitations in physical functioning due to health problems; 2) limitations in usual daily activities because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems since last month; 7) limitations in usual work (house hold and outside) due to emotional problems 8) current and 1 year past status of health 9) general mental health. Scores on physical component were summed and averaged (range 0 [worst] to 100 [best]); If participants' had shown change from baseline in physical health component score >5.42, it was considered as improved; score between -5.42 to 5.42 was considered as unchanged, and score < -5.42 was considered as worsened. Change from Baseline = difference between the score of physical component at Week 24 and the score at Baseline. | From Baseline (Day 1) to Week 24 | 
| Number of Participants With Change From Baseline in the Mental Component Scores of SF-36 | The SF-36 determined participants' overall quality of life by assessing :1) limitations in physical functioning due to health problems; 2) limitations in usual daily activities because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems since last month; 7) limitations in usual work (house hold and outside) due to emotional problems 8) current and 1 year past status of health 9) general mental health. Scores on mental component were summed and averaged (range = 0 [worst]-100 [best]); increase from baseline indicated improvement. If participants' had shown change from baseline in mental health score >6.33, it was considered as improved; scores between -6.33 to 6.33 was considered unchanged, and score <-6.33 was considered as worsened. Change from Baseline = difference between the mental component score at Week 24 and the score at Baseline. | From Baseline (Day 1) to Week 24 |