A Study of Ocrelizumab Compared to Placebo in Patients With Active Rheumatoid Arthritis Continuing Methotrexate Treatment (STAGE)

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 have had an inadequate response to methotrexate. 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 7.5mg - 25mg/week concomitant methotrexate at a stable dose. The anticipated time on study treatment is 1-2 years. 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 Continuing Methotrexate Treatment

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 Rheumatoid arthritis for ≥ 3 months Inadequate clinical response to methotrexate at a dose of 7.5-25mg/week for ≥ 12 weeks 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 (other than methotrexate)

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 × 2 IV + MTX<br>Participants received two intravenous (IV) infusion matching placebo to ocrelizumab on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 milligram (mg) was administered weekly. | Drug: Methotrexate<br>* Methotrexate tablet was administered orally at a dose 7.5-25 mg<br>Drug: Placebo<br>* Matching placebo to ocrelizumab was administered via IV infusion<br>|
| Experimental: Ocrelizumab 200 mg × 2 IV + MTX<br>Participants received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly. | Drug: Methotrexate<br>* Methotrexate tablet was administered orally at a dose 7.5-25 mg<br>Drug: ocrelizumab<br>* Ocrelizumab was administered via IV infusion at a dose specified in arm description<br>|
| Placebo Comparator: Ocrelizumab 500 mg × 2 IV + MTX<br>Participants received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly. | Drug: Methotrexate<br>* Methotrexate tablet was administered orally at a dose 7.5-25 mg<br>Drug: ocrelizumab<br>* Ocrelizumab was administered via IV infusion at a dose specified in arm description<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 at Week 24 | ACR20 is defined as 20 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). | Week 24 | 
| Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 48 | ACR20 is defined as 20 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). | Week 48 | 
| Percentage of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a subject administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. Pre-existing conditions which worsened during the study were also reported as AEs. | From baseline up to 8.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Major Clinical Response (ACR70 for ≥ 6 Months) at Week 48 | ACR70 is defined as 70 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). | Week 48 | 
| Percentage of Participants Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) at Weeks 24 and 48 | The Disease Activity Score (DAS28) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and Erythrocyte Sedimentation Rate (ESR). DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. | Weeks 24 and 48 | 
| Change From Baseline in DAS28 at Weeks 24 and 48 | The Disease Activity Score (DAS28) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and Erythrocyte Sedimentation Rate (ESR). DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. | Weeks 24 and 48 | 
| European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) at Weeks 24 and 48 | DAS 28 score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and ESR. DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. EULAR Good response: DAS28 ≤ 3.2 and a change from Baseline < -1.2. EULAR Moderate response: DAS28 >3.2 to ≤ 5.1 or a change from Baseline < -0.6 to ≥ -1.2. | Weeks 24 and 48 | 
| Percentage of Participants Achieving an ACR50 Response at Weeks 24 and 48 | ACR50 is defined as 50 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). | Weeks 24 and 48 | 
| Percentage of Participants Achieving an ACR70 Response at Weeks 24 and 48 | ACR70 is defined as 70 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). | Weeks 24 and 48 | 
| Percent Change From Baseline in Swollen Joint Count (SJC) at Weeks 24 and 48 | 66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. | Baseline, Week 24, 48 | 
| Change From Baseline in Tender Joint Count (TJC) at Weeks 24 and 48 | 68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68. | Baseline, Weeks 24, 48 | 
| Change From Baseline in Patient's Pain Visual Analogue Scale (VAS) at Weeks 24 and 48 | The patient assessed their pain on a 0 to 100 millimeters (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as no pain and the right-hand extreme equals 100 mm as unbearable pain. A negative change indicated improvement. | Baseline, Week 24, 48 | 
| Change From Baseline in Physician's Global VAS at Weeks 24 and 48 | The physician's global assessment of disease activity is assessed on a 0 to 100 millimetres (mm) horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as maximum disease activity (maximum arthritis disease activity). | Baseline, Week 24, 48 | 
| Change From Baseline in Patient's Global VAS at Weeks 24 and 48 | The patient's global assessment of disease activity is assessed on a 0 to 100 millimeters (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as maximum disease activity (maximum arthritis disease activity). A negative change from Baseline indicated improvement. | Baseline, Week 24, 48 | 
| Change From Baseline in C-Reactive Protein (CRP) at Weeks 24 and 48 | The serum concentration of C-Reactive Protein (CRP) is measured in milligrams per deciliter (mg/dL). A reduction in the level is considered an improvement. | Baseline, Week 24, 48 | 
| Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 48 | HAQ-DI is a self-completed patient questionnaire specific for Rheumatoid Arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Calculate HAQ-DI the patient must have a domain score for at least 6 of 8 domains. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. | Baseline, Week 24, 48 | 
| Change From Baseline in the Erythrocyte Sedimentation Rate (ESR) at Weeks 24 and 48 | HAQ-DI is a self-completed patient questionnaire specific for Rheumatoid Arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Calculate HAQ-DI the patient must have a domain score for at least 6 of 8 domains. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. | Baseline, Week 24, 48 | 
| Change From Baseline in the Modified Total Sharp Score (mTSS) at Weeks 24 and 48 | mTSS: measure of joint damage that combines scores for bone erosion and joint space narrowing (JNS). Erosion score: total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=normal to 3.5=very severe erosion. JNS score: total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=normal to 4.0=definite ankylosis (stiffness or fixation of a joint). mTSS scores ranged from 0 (normal) to 292 (worst possible total score). Change= mTSS score at Week 24 minus score at baseline. An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement. | Baseline, Week 24, 48 | 
| Change From Baseline in Modified Erosion Score at Weeks 24 and 48 | The erosion score is a summary of erosion severity in 32 joints of the hands (16 joints per hand) and 12 joints in the feet (6 joints per foot). Each joint is scored, according to the surface area involved, from 0 to 5, with 5 indicating extensive loss of bone from more than one-half of the articulating bone (0 indicates no erosion). Because each side of a foot joint is graded separately on this scale, the maximum erosion score for a foot joint is 10. The maximal erosion score is 280. | Baseline, Week 24, 48 | 
| Change From Baseline in Modified Joint Space Narrowing Score at Weeks 24 and 48 | The joint space narrowing score summarizes the severity of joint space narrowing in 30 joints of the hands and 12 joints of the feet. Assessment of joint space narrowing for each hand (15 joints per hand) and foot (6 joints per foot), including subluxation, is scored from 0 to 4, with 0 indicating no/normal joint space narrowing and 4 indicating complete loss of joint space, bony ankylosis, or luxation. The maximum joint space narrowing score is 168. | Baseline, Week 24, 48 | 
| Percentage of Participants Without Radiographic Progression Defined as Change in mTSS ≤ 0 at Weeks 24 and 48 | Radiographic progression was defined as a change of ≤ 0 in the total Genant-modified Sharp 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; the minimum score is 0. A higher score indicates more damage. | Weeks 24, 48 | 
| Percentage of Participants With a Reduction in Modified Total Sharp Score (mTSS) From Baseline at Week 48 | mTSS: measure of joint damage that combines scores for bone erosion and joint space narrowing (JNS). Erosion score: total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=normal to 3.5=very severe erosion. JNS score: total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=normal to 4.0=definite ankylosis (stiffness or fixation of a joint). mTSS scores ranged from 0 (normal) to 292 (worst possible total score). Change= mTSS score at Week 24 minus score at baseline. An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement. | Baseline, Week 48 | 
| Percentage of Participants With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score at Weeks 24 and | HAQ-DI is a self-completed patient questionnaire specific for Rheumatoid Arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Calculate HAQ-DI the patient must have a domain score for at least 6 of 8 domains. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. | Week 24, 48 | 
| Change From Baseline in Short Form Health Survey (SF-36) Subscale and Summary Scores at Weeks 24 and 48 | The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical and Mental Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. | Baseline, Week 24, 48 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Fatigue Assessment at Weeks 24 and 48 | 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, Week 24, 48 | 
| Change From Baseline in Pain Quality and Impact of Pain on Daily Function Measured by the Brief Pain Inventory (BPI) Short Form at Weeks 24 and 48 | The modified BPI (short-form) is a short questionnaire to assess the severity of pain and the impact of pain on daily functions. The first two questions relate to average and current pain respectively and are assessed on a scale from 0 to 10, where 0 represents no pain, and 10 represents pain as bad as one can imagine. The degree to which pain has interfered with 7 different aspects is also rated on a scale from 0 to 10, where 0 represents that pain does not interfere and 10 that pain completely interferes. | Baseline, Week 24, 48 | 

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