A Study to Evaluate Ocrelizumab Compared With Placebo in Patients With Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate Therapy

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of ocrelizumab, compared to placebo, in patients with active rheumatoid arthritis who have an inadequate response to methotrexate therapy. Patients will be randomized 2:2:1 to receive 1) infusions of ocrelizumab 200mg iv on Days 1 and 15, 2) infusions of ocrelizumab 400mg iv on Day 1 and placebo iv on Day 15, or 3) infusions of placebo iv on Days 1 and 15. At the end of the placebo-controlled treatment period at 24 weeks, patients in groups 1 and 3 will be re-randomized to receive either a single infusion of 400mg iv ocrelizumab or 2 infusions of 200mg iv ocrelizumab, and group 2 will receive a second single infusion of 400mg iv ocrelizumab. All patients will receive a stable dose of concomitant methotrexate (7.5-25mg/week) throughout the study. The anticipated time on study treatment is 1-2 years. Target number of patients to be enrolled in this trial is 300.

Official Title
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A Randomized, Double-Blind, Parallel-Group, International Study to Evaluate the Safety and Efficacy of Ocrelizumab Given As a Single Infusion or Dual Infusion Compared With Placebo in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate Therapy

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Ocrelizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Adult patients, ≥ 18 years of age Active rheumatoid arthritis Inadequate treatment with any DMARD other than methotrexate Exclusion criteria: Rheumatic autoimmune disease or inflammatory joint disease other than rheumatoid arthritis Concurrent treatment with any DMARD other than methotrexate Previous treatment with any cell-depleting therapies Any surgical procedure in past 12 weeks, or planned within 48 weeks after baseline

Ages Eligible for Study
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Minimum Age: 18 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<br>Participants received matching placebo: on Day 15 of Cycle 1 (Participants who were administered OCR 400 mg on Day 1 of a Cycle 1 in combination with Methotrexate) on both Days 1 and Day 15 of Cycle 1 (Participants who were randomized to the Placebo + Methotrexate group) | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Placebo<br>* Intravenous repeating dose<br>|
| Experimental: Ocrelizumab 400mg<br>Participants received Ocrelizumab 400mg in combination with Methotrexate on Day 1, Cycle 1. | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Ocrelizumab was administered as a slow intravenous (iv) infusion during each course as either 200 mg on Day 1 and Day 15 (OCR 200×2) or as 400 mg given on Day 1 (OCR 400×1). Ocrelizumab was administered in combination with Methotrexate.<br>|
| Experimental: Ocrelizumab 200mg<br>Participants received Ocrelizumab 200 mg in combination with Methotrexate on Day 1 and Day 15, Cycle 1. | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Ocrelizumab was administered as a slow intravenous (iv) infusion during each course as either 200 mg on Day 1 and Day 15 (OCR 200×2) or as 400 mg given on Day 1 (OCR 400×1). Ocrelizumab was administered in combination with Methotrexate.<br>|
| Experimental: Ocrelizumab 200mg/ Ocrelizumab 200mg<br>Participants who received two 200 mg infusions of Ocrelizumab + Methotraxate during Cycle 1 were re-randomized (1:1 randomization ratio) to receive two infusions of 200 mg Ocrelizumab + Methotraxate during Cycle 2 | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Ocrelizumab was administered as a slow intravenous (iv) infusion during each course as either 200 mg on Day 1 and Day 15 (OCR 200×2) or as 400 mg given on Day 1 (OCR 400×1). Ocrelizumab was administered in combination with Methotrexate.<br>|
| Experimental: Ocrelizumab 200mg/ Ocrelizumab 400mg<br>Participants who received two 200 mg infusions of Ocrelizumab + Methotraxate during Cycle 1 were re-randomized (1:1 randomization ratio) to receive a single infusion of 400 mg Ocrelizumab + Methotraxate during Cycle 2 | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Ocrelizumab was administered as a slow intravenous (iv) infusion during each course as either 200 mg on Day 1 and Day 15 (OCR 200×2) or as 400 mg given on Day 1 (OCR 400×1). Ocrelizumab was administered in combination with Methotrexate.<br>|
| Experimental: Ocrelizumab 400mg/ Ocrelizumab 400mg<br>Participants who received single 400mg infusions of Ocrelizumab + Methotraxate during Cycle 1 received a infusion of 400 mg Ocrelizumab + Methotraxate during Cycle 2 | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Ocrelizumab was administered as a slow intravenous (iv) infusion during each course as either 200 mg on Day 1 and Day 15 (OCR 200×2) or as 400 mg given on Day 1 (OCR 400×1). Ocrelizumab was administered in combination with Methotrexate.<br>|
| Experimental: Placebo/ Ocrelizumab 200mg<br>Participants who received placebo during Cycle 1 were re-randomized (1:1 randomization ratio) to receive two infusions of 200 mg Ocrelizumab + Methotraxate during Cycle 2 | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Ocrelizumab was administered as a slow intravenous (iv) infusion during each course as either 200 mg on Day 1 and Day 15 (OCR 200×2) or as 400 mg given on Day 1 (OCR 400×1). Ocrelizumab was administered in combination with Methotrexate.<br>Drug: Placebo<br>* Intravenous repeating dose<br>|
| Experimental: Placebo/ Ocrelizumab 400mg<br>Participants who received placebo during Cycle 1 were re-randomized (1:1 randomization ratio) to receive single infusion of 400 mg Ocrelizumab + Methotraxate during Cycle 2 | Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Ocrelizumab was administered as a slow intravenous (iv) infusion during each course as either 200 mg on Day 1 and Day 15 (OCR 200×2) or as 400 mg given on Day 1 (OCR 400×1). Ocrelizumab was administered in combination with Methotrexate.<br>Drug: Placebo<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With American College of Rheumatology (ACR) 20 Response | ACR20 response: greater than or equal to (≥) 20% improvement in tender or swollen joint counts and 20% improvement in 3 of the following 5 criteria: 1) Physician's global assessment of disease activity, 2) participant assessment of disease activity, 3) Patient Assessment of Pain (visual analog scale [VAS]), 4) participant assessment of functional disability via a Health Assessment Questionnaire (HAQ), and 5) erythrocyte sedimentation rate (ESR) at each visit. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) | The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity. | Week 24 | 
| Change in DAS28 From Baseline | The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity. The change is the difference in adjusted mean change from baseline in DAS28 between ocrelizumab 400 x 1 and ocrelizumab 200 x 2 with placebo. | Week 24 | 
| European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) |  | Week 24 | 
| Percentage of Participants Achieving an ACR50 Response | The ACR50 response at any time was defined as >/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). | Week 24 | 
| Percentage of Participants Achieving an ACR70 Response | The ACR70 response at any time was defined as >/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). | Week 24 | 
| Change From Baseline in the Individual Parameters of the ACR Core Set | Change in the scores of the following parameters of ACR core set relative to respective baseline scores was measured: 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). | Week 24 | 
| Change From Baseline in the Individual Parameters of the ACR Core Set: C-Reactive Protein (CRP) Concentration |  | Week 24 | 
| Change From Baseline in the Individual Parameters of the ACR Core Set: Erythrocyte Sedimentation Rate (ESR) |  | Week 24 | 
| Percentage of Participants With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score |  | Week 24 | 
| Change in SF-36 Subscale and Summary Scores From Baseline | Improved, change > 5.42; Unchanged, -5.42 <= Change <= 5.42; Worsened, change < -5.42 | Week 24 | 
| Change in FACIT-F Fatigue Assessment From Baseline | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participants 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 participant'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). Clinically relevant improvement is defined as a greater than or equal to (≥)5-point change from Baseline. | Baseline, Weeks 4, 12, and 24 | 
| Percentage of Participants Achieving an ACR20 Response | ACR20 response: greater than or equal to (≥) 20% improvement in tender or swollen joint counts and 20% improvement in 3 of the following 5 criteria: 1) Physician's global assessment of disease activity, 2) participant assessment of disease activity, 3) Patient Assessment of Pain (visual analog scale [VAS]), 4) participant assessment of functional disability via a Health Assessment Questionnaire (HAQ), and 5) erythrocyte sedimentation rate (ESR) at each visit. | Week 48 | 
| Percentage of Participants Achieving an ACR50 Response | The ACR50 response at any time was defined as >/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). | Week 48 | 
| Percentage of Participants Achieving an ACR70 Response | The ACR70 response at any time was defined as >/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). | Week 48 | 
| Percentage of Participants Achieving DAS28 Remission (DAS28 < 2.6) |  | Week 48 | 
| Cmax: Maximum Observed Serum Concentration of Ocrelizumab Following First Infusion |  | Week 24, 48 | 
| Csecond: Maximum Observed Serum Concentration of Ocrelizumab Following Second Infusion |  | Day 15 of Cycles 1 and 2 | 

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