A Study of Combination Treatment With MabThera (Rituximab) and RoActemra (Tocilizumab) Versus RoActemra in Patients With Rheumatoid Arthritis With an Incomplete Response to Methotrexate

Study Overview
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Brief Summary
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This 2 part study will investigate the safety, tolerability and efficacy of MabT hera in combination with RoActemra in patients with active rheumatoid arthritis despite a stable dose of methotrexate. In Part 1 of the study, patients will be randomized to receive either MabThera 0.5g iv or placebo on days 1 and 15, follo wed by RoActemra at one of the ascending doses between 2mg/kg and 8mg/kg at week s 4, 8 and 12 (MabThera arm) or 8mg/kg (placebo arm). In Part 2, additional pati ents will be randomized to one of 2 groups to receive MabThera 0.5g on days 1 an d 15 followed by the selected dose (from Part 1)of RoActemra at weeks 4, 8 and 1 2, or placebo on days 1 and 15 followed by RoActemra 8mg/kg at weeks 4,8 and 12. All patients will then be eligible to receive extension treatment withRoActemra every 4 weeks. The anticipated time on study treatment is 12 months, and the tar get sample size is <100 individuals.

Official Title
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A Randomized, Active Controlled, Double-blind, Study to Compare the Safety and Reduction in Disease Activity With the Combination of Rituximab (MabThera®)and Tocilizumab (RoActemra®) Versus Tocilizumab in Patients With Active Rheumatoid Arthritis With an Incomplete Response to Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Placebo
* Drug: rituximab [MabThera/Rituxan]
* Drug: tocilizumab [RoActemra/Actemra]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, 18-65 years of age; rheumatoid arthritis, functional status I-III; SJC>=4 (28 joint count) and TJC>=4 (28 joint count) at screening and baseline; RF and/or anti-CCP positive; may have failed up to 1 approved anti-TNF agent (infliximab, etanercept or adalimumab); inadequate response to methotrexate, at a dose of 7.5-25mg weekly for at least 12 weeks, at a stable dose for past 4 weeks. Exclusion Criteria: rheumatic autoimmune disease other than rheumatoid arthritis, or significant systemic involvement secondary to rheumatoid arthritis; history of, or current, inflammatory joint disease other than rheumatoid arthritis; diagnosis of juvenile idiopathic arthritis and/or rheumatoid arthritis before age 16; significant cardiac or pulmonary disease; previous treatment with any biologic agent for rheumatoid arthritis (other than infliximab, etanercept or adalimumab).

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: 1<br> | Drug: rituximab [MabThera/Rituxan]<br>* 0.5g iv on days 1 and 15 (Parts 1 and 2)<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 2mg/kg-8mg/kg iv in Part 1 and selected dose in Part 2, on weeks 4, 8 and 12---Arm 1\n8mg/kg iv on weeks 4,8 and 12 (Parts 1 and 2)--- Arm 2<br>|
| Active Comparator: 2<br> | Drug: Placebo<br>* iv on days 1 and 15 (Parts 1 and 2)<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 2mg/kg-8mg/kg iv in Part 1 and selected dose in Part 2, on weeks 4, 8 and 12---Arm 1\n8mg/kg iv on weeks 4,8 and 12 (Parts 1 and 2)--- Arm 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Low Disease Activity (LDA) at Week 16 Assessed Using Disease Activity Score Based on 28 Joint Count and Erythrocyte Sedimentation Rate (DAS28-ESR) | The Disease Activity Score based on 28 joint count (DAS28) and Erythrocyte Sedimentation Rate (ESR), is a measure of the participant's disease activity. It is based on the Tender Joint Count (TJC [28 joints]), Swollen Joint Count (SJC [28 joints]), participant's global assessment of disease activity (PtGA) Visual Analog Scale (VAS) in millimeters (mm), and ESR in millimeters per hour (mm/hour). DAS28-ESR scores range from 0 - 10. Definition of LDA was based on DAS28-ESR scores. To achieve LDA the DAS28-ESR had to be (less than or equal to) ≤ 3.2. DAS28-ESR equals (=) (0.56 times (*) (square root)√ TJC plus (+) (0.28 * √ SJC + (0.70 * ln(ESR))+(0.014 * (Global Health) GH) Where: TJC = based on 28 joints SJC = based on 28 joints ESR = erythrocyte sedimentation rate in mm/hour GH = participant's global assessment of disease activity ln = natural log | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Remission at Week 16 Assessed Using DAS28-ESR | The DAS28-ESR score is a measure of the participant's disease activity. It is based on the TJC (28 joints), SJC (28 joints), participant's global assessment of disease activity (mm), and ESR (mm/hour). DAS28-ESR is expressed on a unit on a scale with the minimum score=0 (best) to maximum score=10 (worst). Remission was defined as DAS28-ESR less than (<) 2.6 | Week 16 | 
| Percentage of Participants by European League Against Rheumatism (EULAR) Response Category at Week 16 | DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline (greater than) >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or DAS28-ESR >5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; nonresponders: change from baseline ≤0.6 or change from baseline >0.6 and ≤1.2 with DAS28 >5.1. | Week 16 | 
| Change From Baseline in DAS28-ESR | The DAS28-ESR score is a measure of the participant's disease activity. It is based on the TJC (28 joints), SJC (28 joints), participant's global assessment of disease activity (mm), and ESR (mm/hour). DAS28-ESR is expressed as a score on a scale with the minimum score=0 (best) to maximum score=10 (worst). DAS28-ESR scores were calculated as follows: DAS28-ESR = (0.56 * √TJC)+(0.28 * √SJC)+(0.70 * ln(ESR))+(0.014 * GH). No imputation used for tender and swollen joint counts, ESR, and patient's global assessment of disease activity VAS. | Weeks 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Clinical Disease Activity Index Scores | The Clinical Disease Activity Index (CDAI) score was calculated according to the following formula: CDAI = SJC + TJC + GH/10 + EGA/10 Where: SJC = swollen joint count based on 28 joints; TJC = tender joint count based on 28 joints; GH = Participant's global assessment of disease activity; EGA = evaluator's (physician's) global assessment of disease activity. CDAI scores range from 0-76 and the following cut-off points for different disease activity states have been used: high disease activity >22; moderate disease activity >10 and ≤22; LDA >2.8 and ≤10; and remission ≤ 2.8. No imputation used for TJC, SJC, Patient's Global Assessment of Disease Activity VAS and Physicians global assessment of disease activity VAS. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40 and 48 | 
| Simplified Disease Activity Index (SDAI) Scores | The SDAI is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), Participant and Physician assessed global disease activity (assessed on 0-100 mm VAS; higher scores = greater affection due to disease activity), and ESR (mm/hour). SDAI total score ranged from 0 to 86. Higher scores indicated greater disease activity. | Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40, and 48 | 
| Change From Baseline to Week 48 in SJC and TJC | An assessment of 28 joints for swelling and tenderness will be made. Joints will be assessed and classified as swollen (1)/not swollen (0) and tender(1)/not tender (0) by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints were not taken into consideration for swelling or tenderness. The 28 joints assessed comprise shoulders (2 joints), elbows (2 joints), wrists (2 joints), metacarpophalangeal joints on digits 1-5 (10 joints), interphalangeal on digit 1 (2 joints), proximal interphalangeal joints on digits 2-5 (8 joints), and knees (2 joints). | Baseline and Week 48 | 
| Change From Baseline to Week 48 in Health Assessment Questionnaire (HAQ) | The Stanford Health Assessment Questionnaire disability index specific for rheumatoid arthritis was completed by the participants for efficacy assessments. | Baseline and Week 48 | 
| Change From Baseline to Week 48 in C-Reactive Protein (CRP) | CRP is an acute phase reactant and is a measure of inflammation. | Baseline and Week 48 | 
| Change From Baseline to Week 48 in ESR | ESR is an acute phase reactant and is a measure of inflammation. | Baseline and Week 48 | 
| Change From Baseline to Week 48 in Physician's Global Assessment of Disease Activity | Physician Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no disease activity and 100 mm= maximum disease activity. The physician marked the line according to their assessment and the distance from the left edge was measured. | Baseline and Week 48 | 
| Change From Baseline to Week 48 in Participant's Global Assessment of Disease Activity | Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no disease activity and 100 mm = maximum disease activity. The participant marked the line according to their assessment and the distance from the left edge was measured. | Baseline and Week 48 | 
| Change From Baseline to Week 48 in Participant's Assessment of Pain | Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no pain and 100 mm = maximum pain. The participant marked the line according to their assessment and the distance from the left edge was measured. | Baseline and Week 48 |