Study Evaluating the Efficacy and Safety of Etanercept and Methotrexate in Japanese Subjects With Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to examine the effects of etanercept (10 mg and 25 mg) compared with methotrexate (up to 8 mg per week) on the slowing of joint destruction.

Official Title
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A Randomized, Double-Blind, Multicenter, Comparative Study Evaluating the Efficacy and Safety of Etanercept and Methotrexate in Japanese Subjects With Active Rheumatoid Arthritis

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Etanercept
* Drug: Etanercept
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be Japanese and live in Japan Must be age 20 to 75 years Diagnosed less than or equal to 10 years from time of first visit Exclusion Criteria: Anyone who has received etanercept or TNF-inhibitors such as infliximab or adalimumab in the past Patient with other rheumatic diseases or conditions that could predispose the patient to infection Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Etanercept<br>* 10 mg twice weekly, subcutaneous injection for 52 weeks<br>|
| Experimental: 2<br> | Drug: Etanercept<br>* 25 mg, twice weekly, subcutaneous injection for 52 weeks<br>|
| Active Comparator: 3<br> | Drug: Methotrexate<br>* up to 8 mg per week, oral dosing for 52 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 | mTSS = sum of erosion and JSN scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change = scores at observation minus score at Baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represents improvement. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 | mTSS = sum of erosion and JSN scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change = scores at observation minus score at Baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represents improvement. | Week 24 | 
| Change From Baseline in Erosion Score at Weeks 24 and 52 | Joint erosion score: erosion severity in 44 joints (16 per hand, 6 per foot). Each joint scored according to surface area involved, from 0 (no erosion) to 5 (extensive bone loss from more than one half of articulating bone). Because each side of foot joint was graded, maximum erosion score for foot joint was 10. Thus, maximum erosion score was 280. Change = score at observation minus score at Baseline. An increase in score from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline, Week 24, and Week 52 | 
| Change From Baseline in Joint Space Narrowing (JSN) Score at Weeks 24 and 52 | JSN score: severity of JSN in 42 joints (15 per hand and 6 per foot), including subluxation, scored from 0 (no/normal JSN) to 4 (complete loss of joint space, bony ankylosis, or luxation). Maximum JSN score was 168. Change = scores at observation minus score at Baseline. An increase in score from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline, Week 24, and Week 52 | 
| Percentage of Participants With no Progression of Joint Destruction at Week 52 | Absence of joint destruction defined by 3 categories (mTSS change <=0.5, <=3.0, and <smallest detectable difference [SDD] where SDDs were scores >3.0). mTSS = sum of erosion and JSN scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). | Baseline and Week 52 | 
| Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | American College of Rheumatology (ACR) swollen joint count was an assessment of 68 joints. Joints classified as either swollen or not swollen. Change = scores at observation minus score at Baseline, and total possible scores ranged from -68 to 68. An increase in swollen joints from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 71 joints assessed by the investigator using criteria based on pressure and joint manipulation. Change = scores at observation minus score at Baseline, and total possible scores ranged from -71 to 71. An increase in tender joint count from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | Physician Global Assessment of symptoms, assessed using a 11-point rating scale, where 0=asymptomatic and 10=severe symptoms. Change = scores at observation minus score at Baseline. An increase in score from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | Patient's Global Assessment of symptoms, assessed using a 11-point rating scale, where 0=asymptomatic and 10=severe symptoms. Change = scores at observation minus score at Baseline. An increase in score from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | Morning stiffness in and around the joints lasting at least 1 hour before maximal improvement. Change = scores at observation minus score at Baseline. An increase in stiffness duration from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 100 millimeter (mm) line (VAS) marked by participant. Intensity of pain range (over past week): 0mm = no pain to 100mm = worst possible pain. Change = scores at observation minus score at Baseline. An increase in score from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 100mm line (VAS) marked by participant. Participants asked, In general how would you rate your health over the last 2-3 weeks? 0mm=very well to 100mm=extremely bad. Change = scores at observation minus score at Baseline. An increase in score from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | HAQ-DI: participant-reported assessment of ability to perform tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) hygiene; and 8) common activities over past week. Each item scored on 4-point Likert scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Change = scores at observation minus score at Baseline and total possible scores ranged from -3 to 3. An increase in score from baseline represented disease progression and/or joint worsening and a decrease represented improvement. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response | ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Percentage of Participants With an ACR50 Response | ACR50 response: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Percentage of Participants With an ACR70 Response | ACR70 response: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | DAS: weighted calculation of joint tenderness score (Ritchie Articular Index[RAI]), swollen joint count of 44 joints, natural logarithm (ln) of erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and general health (GH) using VAS. RAI defined as sum of 26 possible 0 to 3 tender scores. DAS = 0.53938 square root (√) (RAI) + 0.06465 (swollen joint count) + 0.330 (ln ESR) + 0.00722 (GH). Change from baseline = DAS at Week x minus Baseline DAS. Total DAS scores could range from 10 (worse outcome) to 0 (better outcome). | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | DAS based on 28 painful joint counts, 28 swollen joint counts, ESR, and GH. DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH. Change from baseline = DAS at Week x minus Baseline DAS. Total DAS scores could range from 10 (worse outcome) to 0 (better outcome). | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | CRP: marker of inflammation. Higher level consistent with inflammation. Normal CRP range: 0 to 1.0 milligrams per deciliter (mg/dL). | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | ESR: laboratory test that provided a non-specific measure of inflammation. The test assessed the rate at which red blood cells fell in a test tube and was measured in mm/hour. Normal range: 0-30mm/h. Higher rate consistent with inflammation. | Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Arthritis