A Study of Tocilizumab as Monotherapy and in Combination With Methotrexate Versus Methotrexate in Patients With Early Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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This randomized, double-blind, parallel group study will assess the safety, disease remission, and prevention of structural joint damage in patients with early moderate to severe rheumatoid arthritis treated with tocilizumab as monotherapy or in combination with methotrexate, versus methotrexate alone. Patients will be randomized to receive either (A) tocilizumab (8 mg/kg iv every 4 weeks) plus placebo, (B) tocilizumab (8 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), (C) tocilizumab (4 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), or (D) placebo plus methotrexate (7.5-20 mg po weekly). Patients in groups C and D who have not achieved low disease activity at week 52 can receive tocilizumab 8 mg/kg iv every 4 weeks. Anticipated time on study treatment is 104 weeks.

Official Title
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A Multi-center, Randomized, Double-blind, Parallel Group Study of the Safety, Disease Remission and Prevention of Structural Joint Damage During Treatment With Tocilizumab (TCZ), as a Monotherapy and in Combination With Methotrexate (MTX), Versus Methotrexate in Patients With Early, Moderate to Severe Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Placebo to tocilizumab
* Drug: Methotrexate
* Drug: Placebo to methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients ≥ 18 years of age. Rheumatoid arthritis of ≤ 2 years duration. Disease Activity Score 28 (DAS28) > 3.2. Swollen joint count (SJC) ≥ 4 of 66 joints, tender joint count (TJC) ≥ 6 of 68 joints. Rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) positive (if RF and anti-CCP negative > 1 erosion required at screening). Erythrocyte sedimentation rate (ESR) ≥ 28 mm/h or C-reactive protein (CRP) ≥ 10 mg/L at screening. Exclusion Criteria: Previous treatment with tocilizumab. Previous treatment with methotrexate or biologic agent. Rheumatic autoimmune disease other than rheumatoid arthritis (RA). History of or current inflammatory joint disease other than RA. Functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in RA.

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: (A) Tocilizumab 8 mg/kg + placebo to methotrexate<br>Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks. | Drug: Tocilizumab<br>* Tocilizumab was supplied in vials.<br>* Other names: Actemra;Drug: Placebo to methotrexate<br>* Patients received placebo to methotrexate orally once a week.<br>|
| Experimental: (B) Tocilizumab 8 mg/kg + methotrexate<br>Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. | Drug: Tocilizumab<br>* Tocilizumab was supplied in vials.<br>* Other names: Actemra;Drug: Methotrexate<br>* Initially, patients received methotrexate 7.5 mg (3, 2.5 mg tablets) orally once a week. If a patient had swollen or tender joints, the dose was increased to 15 mg and 20 mg weekly, at the Week 4 and Week 8 visits, respectively.<br>|
| Experimental: (C) Tocilizumab 4 mg/kg + methotrexate<br>Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. | Drug: Tocilizumab<br>* Tocilizumab was supplied in vials.<br>* Other names: Actemra;Drug: Methotrexate<br>* Initially, patients received methotrexate 7.5 mg (3, 2.5 mg tablets) orally once a week. If a patient had swollen or tender joints, the dose was increased to 15 mg and 20 mg weekly, at the Week 4 and Week 8 visits, respectively.<br>|
| Active Comparator: (D) Placebo to tocilizumab + methotrexate<br>Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks. | Drug: Placebo to tocilizumab<br>* Placebo to tocilizumab was supplied in vials.<br>Drug: Methotrexate<br>* Initially, patients received methotrexate 7.5 mg (3, 2.5 mg tablets) orally once a week. If a patient had swollen or tender joints, the dose was increased to 15 mg and 20 mg weekly, at the Week 4 and Week 8 visits, respectively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 24 | A participant has a DAS28 remission response if their DAS28 < 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 higher scores represent higher disease activity. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 52 |  | Week 52 | 
| Percentage of Patients With an Improvement ≥ 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline to Weeks 24 and 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 no disease activity [symptom-free and no arthritis symptoms] and the extreme right end maximum disease activity; patient assessment of pain in previous the 24 hours on a VAS (extreme left end of the line no pain and the extreme right end unbearable pain); 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 Weeks 24 and 52 | 
| Change From Baseline in 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, including subluxation, 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 | 
| Change From Baseline in Modified Sharp Erosion Score at Week 52 |  | Baseline to Week 52 | 
| Change From Baseline in Sharp Joint Space Narrowing Score at Week 52 |  | Baseline to Week 52 | 
| Percentage of Participants With a Major Clinical Response at Week 52 | A major clinical response is defined as an ACR70 response that is maintained for 6 consecutive months (24 weeks) for any 24-week period between Week 2 and Week 52. | Baseline to Week 52 | 
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Weeks 24 and 52 | The Stanford HAQ-DI is a patient completed questionnaire specific for rheumatoid arthritis. The HAQ-DI assesses how well the patient is able to perform 8 activities: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The patient answers 20 questions with 1 of 4 responses with the past week as the time frame: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The highest score for any question in a category determines the category score. The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. | Baseline to Weeks 24 and 52 | 
| Change From Baseline in Short Form 36 (SF-36) Physical Component Summary (PCS) Scores at Weeks 24 and 52 | The SF-36 Health Survey (Version 2) is a standardized questionnaire consisting of 36 questions that measures patient-reported symptoms on 8 dimensions; it is used to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100. A positive change score indicates better HRQoL. | Baseline to Weeks 24 and 52 |