A Study of Ocrelizumab in Combination With Methotrexate in Patients With Rheumatoid Arthritis Who Are Naive to Methotrexate (FILM)

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of ocrelizumab, compared with placebo, in combination with methotrexate in patients with active rheumatoid arthritis who are naive to methotrexate. Patients will be randomized to receive placebo, ocrelizumab 200mg i.v. or ocrelizumab 500mg i.v. on Days 1 and 15. Repeat courses of i.v. treatment will be administered at weeks 24, 52 and 76. All patients will receive concomitant methotrexate (7.5 mg escalating to 20mg p.o. weekly). The anticipated time on study treatment is 2+ years, and the target sample size is 500+ individuals.

Official Title
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A Randomized, Double-Blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Ocrelizumab in Combination With Methotrexate (MTX) Compared to MTX Alone in Methotrexate- Naive Patients With Active Rheumatoid Arthritis

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: Age ≥ 18 Rheumatoid arthritis for 3 months-5 years Naive to methotrexate If receiving steroids or NSAIDs, must be on a stable dose for 4 weeks prior to baseline Exclusion criteria: Rheumatic autoimmune disease or inflammatory joint disease other than RA Prior receipt of any biologic therapy for RA Concurrent treatment with any DMARD

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 placebo intravenously on Days 1 and 15 and Weeks 24, 26, 52, 54, 76, and 78. Participants also received methotrexate 7.5 mg orally weekly starting on Day 1. The dose of methodrexate was increased to a dose of 20 mg per week by Week 8, administered in 1 dose or divided into 3 equal doses administered at 12-hour intervals. Participants also received folate ≥ 5 mg/week either as a single dose or as a divided weekly dose. Participants were also allowed to continue receiving background corticosteroid therapy, at a dose of ≤ 10 mg/day of prednisolone or prednisolone. | Drug: Placebo<br>* Intravenous repeating dose<br>|
| Experimental: Ocrelizumab 200 mg<br>Participants received ocrelizumab 200 mg intravenously on Days 1 and 15 and Weeks 24, 26, 52, 54 and 76. Participants also received methotrexate 7.5 mg orally weekly starting on Day 1. The dose of methodrexate was increased to a dose of 20 mg per week by Week 8, administered in 1 dose or divided into 3 equal doses administered at 12-hour intervals. Participants also received folate ≥ 5 mg/week either as a single dose or as a divided weekly dose. Participants were also allowed to continue receiving background corticosteroid therapy, at a dose of ≤ 10 mg/day of prednisolone or prednisolone. | Drug: Methotrexate<br>* Oral repeating dose<br>Drug: Ocrelizumab<br>* Intravenous repeating dose<br>|
| Experimental: Ocrelizumab 500 mg<br>Participants received ocrelizumab 500 mg intravenously on Days 1 and 15 and Weeks 24, 26, 52, 54, and 76. Participants also received methotrexate 7.5 mg orally weekly starting on Day 1. The dose of methodrexate was increased to a dose of 20 mg per week by Week 8, administered in 1 dose or divided into 3 equal doses administered at 12-hour intervals. Participants also received folate ≥ 5 mg/week either as a single dose or as a divided weekly dose. Participants were also allowed to continue receiving background corticosteroid therapy, at a dose of ≤ 10 mg/day of prednisolone or prednisolone. | Drug: Methotrexate<br>* Oral repeating dose<br>Drug: Ocrelizumab<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Modified Total Sharp Score (mTSS) at Week 52 | The mTSS is a measure of joint damage and includes measures of joint erosion (JE) and joint space narrowing (JSN). The JE score, using the van der Heijde modification, measures erosion severity in 32 hand joints and 12 foot joints. Each hand joint is scored from 0 to 5 and each foot joint is scored from 0 to 10; the total score ranges from 0 to 280. Each joint is scored according to the surface area involved. A score of 10 indicates extensive loss of bone from more than one-half of the articulating bone; a score of 0 indicates no erosion. The JSN score measures the severity of JSN in 30 hand joints (15 per hand) and 12 foot joints (6 per foot). Each joint is scored from 0 to 4; the total score ranges from 0 to 168. A higher score indicates more joint space narrowing. The mTSS ranges from 0 to 448 (280+168). A higher mTSS score indicates greater damage. A negative change score indicates improvement. | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Without Radiographic Progression (RP) at Week 52 | RP was defined as a change from Baseline in the modified Total Sharp Score (mTSS) ≤ 0. The mTSS is a measure of joint damage and includes measures of joint erosion (JE) and joint space narrowing (JSN). The JE score, using the van der Heijde modification, measures erosion severity in 32 hand joints and 12 foot joints. Each hand joint is scored from 0 to 5 and each foot joint is scored from 0 to 10; the total score ranges from 0 to 280. Each joint is scored according to the surface area involved. A score of 10 indicates extensive loss of bone from more than one-half of the articulating bone; a score of 0 indicates no erosion. The JSN score measures the severity of JSN in 30 hand joints (15 per hand) and 12 foot joints (6 per foot). Each joint is scored from 0 to 4; the total score ranges from 0 to 168. A higher score indicates more joint space narrowing. The mTSS ranges from 0 to 448 (280+168). A higher mTSS score indicates greater damage. A negative change score indicates improvement. | Week 52 | 
| Percentage of Participants With an Improvement ≥ 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline to Week 52 | Improvement must be seen in tender (68) and swollen (66) joint counts. Joints were assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation. Improvement must also be seen in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, the extreme left end of the line none [symptom-free and no arthritis symptoms] and the extreme right end maximum [maximum arthritis disease activity]; patient assessment of pain in the previous 24 hours on a VAS (extreme left end of the line none and the extreme right end unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C-reactive protein (CRP), or erythrocyte sedimentation rate if CRP was missing. | Baseline to Week 52 | 
| Percentage of Participants in Disease Activity Score 28 (DAS28) Remission at Weeks 24 and 52 | A participant was in DAS28 remission if their DAS28 score < 2.6). The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where a higher score indicates more disease activity. | Week 24 and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FILM, RA, anti-CD20, CD20