A Study of Ocrelizumab Compared to Placebo in Patients With Active Rheumatoid Arthritis Who Don't Have a Response to Anti-TNF-α Therapy (SCRIPT)

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 patients with active rheumatoid arthritis who have an inadequate response to at least one anti-TNF-alpha therapy. Patients will be randomized to receive placebo, 200mg of intravenous ocrelizumab, or 500mg of i.v. ocrelizumab on days 1 and 15. A repeat course of i.v. treatment will be administered at weeks 24 and 26. All patients will receive stable doses of either concomitant methotrexate (7.5-25mg/week) or leflunomide (10-20mg po daily) and may receive additional DMARDs. The treatment period is planned for 48 weeks (until primary analysis) and then participants will enter the open label phase until the drug is commercialized. Target sample size is 1000.

Official Title
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A Randomized, Double-Blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Ocrelizumab Compared to Placebo in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to at Least One Anti-TNF-α Therapy

Conditions
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Rheumatoid Arthritis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, ≥ 18 years of age Rheumatoid arthritis for at least 3 months Inadequate response to previous or current treatment with at least one anti-TNF-alpha agent Receiving either leflunomide or methotrexate for ≥ 12 weeks, with a stable dose for the last 4 weeks Swollen joint count (SJC) ≥ 4 (66 joint count) and tender joint count (TJC) ≥ 4 (68 joint count) at screening and baseline. CRP ≥ 0.6 mg/dL using a high-sensitivity assay. Positive rheumatoid factor or positive anti-CCP antibody or both. Exclusion Criteria: Rheumatic autoimmune disease or inflammatory joint disease, other than RA Any surgical procedure in past 12 weeks,or planned within 48 weeks of 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 |
| --- | --- |
| Experimental: Ocrelizumab 200 mg x 2 IV + Non-Biologic DMARD Therapy<br>Participants will receive 2 intravenous (IV) infusions of 200 milligram (mg) of ocrelizumab, separated by 14 days (Day 1 and Day 15) in combination with any non-biologic DMARD | Drug: Leflunomide<br>* Oral repeating dose<br>Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Intravenous repeating dose (200mg)<br>|
| Experimental: Ocrelizumab 500 mg x 2 IV + Non-Biologic DMARD Therapy<br>Participants will receive 2 IV infusions of 500 mg of ocrelizumab, separated by 14 days (Day 1 and Day 15) in combination with any non-biologic DMARD | Drug: Leflunomide<br>* Oral repeating dose<br>Drug: Methotrexate<br>* Oral or parenteral repeating dose<br>Drug: Ocrelizumab<br>* Intravenous repeating dose (500mg)<br>|
| Placebo Comparator: Placebo x 2 IV + Non-Biologic DMARD Therapy<br>Participants will receive ocrelizumab matching placebo IV in two infusions, separated by 14 days (Day 1 and Day 15) in combination with any non-biologic DMARD | Drug: Leflunomide<br>* Oral repeating dose<br>Drug: Methotrexate<br>* Oral or parenteral repeating dose<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 20 (ACR20) Responses | 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. | Weeks 24 and 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Major Clinical Response | Major clinical response was defined as achieving an ACR70 response and maintaining this response for a consecutive period of at least 6 months. | Week 48 | 
| Percentage of Participants Achieving Disease Activity Score (DAS28) Remission | 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 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. | Weeks 24 and 48 | 
| Change in DAS28 From Baseline | 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 0 to approximately 10. | Weeks 24 and 48 | 
| Percentage of Participants With EULAR Response Rates of Good/ Moderate | The EULAR response rate was based on the assessment of disease activity using the DAS28. The EULAR response criteria included not only change in disease activity but current disease activity. To be classified as responders, participants had to have a significant change in DAS28 and a low current disease activity. There were 4 categories of EULAR response rates: good, moderate, good/moderate, and none. | Weeks 24 and 48 | 
| Percentage of Participants Achieving an ACR50 Response | ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: physician's global assessment of disease activity (MDG), patient's global assessment of disease activity (PGA), patient's assessment of pain, Health Assessment Questionnaire with Disability Index (HAQ-DI), and C-Reactive Protein (CRP). | Weeks 24 and 48 | 
| Percentage of Participants Achieving an ACR70 Response | ACR70 response is defined as a ≥ 70% improvement (reduction) compared with Baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: physician's global assessment of disease activity (MDG), patient's global assessment of disease activity (PGA), patient's assessment of pain, HAQ-DI and CRP. | Weeks 24 and 48 | 
| Percentage of Participants With a Reduction in the HAQ-DI Score | Health Assessment Questionnaire - Disability Index (HAQ-DI): The Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA. It consists of 20 questions referring to eight component. Reduction in the HAQ-DI score of 0.25 units from baseline to weeks 24 and 48 represented a minimal clinically relevant improvement. | Weeks 24 and 48 | 

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