Efficacy and Safety of Adalimumab in Patients With Active Rheumatoid Arthritis Treated Concomitantly With Methotrexate.

Study Overview
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Brief Summary
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The purpose of the study was to assess the safety, immunogenicity, and clinical efficacy of adalimumab compared with placebo (during double-blind phase) and to to evaluate the long-term safety and maintenance of efficacy following repeated administration of adalimumab (during open-label extension phase) in patients with persistently active rheumatoid arthritis who were receiving concurrent methotrexate therapy.

Detailed Description
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This was a 10-year study which had an initial 52-week, double-blind, placebo-controlled phase followed by an open-label extension phase up to 9 years in duration. Data were analyzed for the double-blind phase using all patients who were randomized and received at least one dose of study drug through Week 52 and for all patients who received at least one dose of adalimumab during the 10-year study (the Intent-to-Treat [ITT] population).

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Rheumatoid Arthritis Patients Currently Receiving Treatment With Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Adalimumab
* Biological: Adalimumab
* Drug: Placebo
* Biological: Adalimumab
* Biological: Adalimumab
* Biological: Adalimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or older and in good health (Investigator discretion) with a recent stable medical history Met American College of Rheumatology (ACR) criteria for diagnosis of active rheumatoid arthritis (RA) and had at both screening and baseline visits >=6 swollen joints and >=9 tender joints, despite a minimum of 3-months treatment with methotrexate (MTX). (Distal interphalangeal joints [DIPs] were not to be included in joint count for inclusion. The screening and baseline visits could be 3 to 28 days apart for patients not previously receiving disease-modifying anti-rheumatic drugs [DMARDs] other than MTX or 4 to 6 weeks for patients requiring a DMARD washout period.) Insufficient efficacy with MTX 12.5 to 25 mg per week (10 mg per week if MTX intolerant). If patient on a second-line treatment (DMARD) other than MTX, he/she had to discontinue it for at least 28 days before the baseline visit (the washout period). Treatment with oral folic acid 1-3 mg/day or, if appropriate, up to 10 mg leucovorin per week. Both rheumatoid factor positivity and a C-reactive protein value >=1 mg/dL, or at least one joint erosion on X-ray. Exclusion Criteria: Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study. Female subject who was pregnant or breast-feeding or considering becoming pregnant. Preceding treatment with any tumor necrosis factor (TNF) antagonist, including adalimumab. Prior exposure to alkylating agents, such as chlorambucil or cyclophosphamide. Intra-articular, intramuscular, or intravenous administration of corticosteroids within 4 weeks prior to the screening visit. Subject was wheelchair bound or bedridden.

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: DB adalimumab 20 mg ew<br>Subjects received 20 mg adalimumab subcutaneously (SC) once weekly (ew) and concomitant methotrexate (MTX) during the double-blind (DB) phase. | Biological: Adalimumab<br>* Self-administered, subcutaneous injection of 20 mg adalimumab (1.6 mL/injection) once weekly (ew) for up to 52 weeks.<br>* Other names: Humira;|
| Experimental: DB adalimumab 40 mg eow<br>Subjects received 40 mg adalimumab subcutaneously (SC) every other week (eow) and concomitant methotrexate (MTX) during the double-blind (DB) phase. Subjects received placebo injections SC and concomitant MTX on the alternate weeks during the DB phase. | Biological: Adalimumab<br>* Self-administered, subcutaneous injection of 40 mg adalimumab (1.6 mL/injection) every other week (eow) for up to 52 weeks.<br>* Other names: Humira;|
| Placebo Comparator: DB placebo ew<br>Subjects received placebo subcutaneously (SC) once weekly (ew) and concomitant methotrexate (MTX) during the double-blind (DB) phase. | Drug: Placebo<br>* Self-administered, subcutaneous injection of placebo (1.6 mL/injection) once weekly (ew) for up to 52 weeks.<br>|
| Experimental: DB adalimumab 20 mg ew/OL adalimumab 40 mg eow<br>Subjects received adalimumab 20 mg subcutaneously (SC) once weekly (ew) during the double-blind (DB) phase, then adalimumab 40 mg SC every other week (eow) during the open-label (OL) extension phase, along with concomitant methotrexate (MTX). | Biological: Adalimumab<br>* Self-administration, subcutaneous (SC) injection of adalimumab 20 mg (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.<br>* Other names: Humira;|
| Experimental: DB adalimumab 40 mg eow/OL adalimumab 40 mg eow<br>Subjects received adalimumab 40 mg subcutaneously (SC) every other week (eow) with placebo on alternate weeks during the double-blind (DB) phase, then adalimumab 40 mg SC eow during the open-label (OL) extension phase, along with concomitant methotrexate (MTX). | Biological: Adalimumab<br>* Self-administration, subcutaneous (SC) injection of adalimumab 40 mg (1.6 mL/injection) every other week (eow) (with a placebo 1.6 mL/injection on alternate weeks) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL injection) eow for up to Week 520.<br>* Other names: Humira;|
| Experimental: DB placebo ew/OL adalimumab 40 mg eow<br>Subjects received placebo subcutaneously (SC) once weekly (ew) during the double-blind phase, then adalimumab 40 mg SC every other week (eow) during the open-label (OL) extension phase, along with concomitant methotrexate (MTX). | Biological: Adalimumab<br>* Self-administration, subcutaneous (SC) injection of placebo solution (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.<br>* Other names: Humira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 24 | Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders. | Week 24 | 
| Change From Baseline in Modified Total Sharp X-ray Score at Week 52 | Modified total Sharp x-ray score (mTSS) is a measure of change in joint health. Radiographs of hands/wrists and feet were obtained at screening and Week 52. Digitized images of these were scored in a blinded manner. Joints were scored for erosions from 0 (no damage) to 5 and for joint space narrowing from 0 (no damage) to 4; scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). Large positive change indicates disease progression; small positive/no change indicates slowing/halting of disease progression; and negative change may indicate improvement of disease. | Baseline and Week 52 | 
| Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 52 | Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Negative mean changes from baseline in the disability index of the HAQ indicated improvement. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Meeting ACR20 Response Criteria at Week 52 | Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders. | Week 52 | 
| Change From Baseline in Modified Total Sharp X-ray Score at Week 24 | Modified total Sharp x-ray score (mTSS) is a measure of change in joint health. Radiographs of hands/wrists and feet were obtained at screening and Week 24. Digitized images of these were scored in a blinded manner. Joints were scored for erosions from 0 (no damage) to 5 and for joint space narrowing from 0 (no damage) to 4; scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). Large positive change indicates disease progression; small positive/no change indicates slowing/halting of disease progression; and negative change may indicate improvement of disease. | Baseline and Week 24 | 
| Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 24 | Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Negative mean changes from baseline in the disability index of the HAQ indicated improvement. | Baseline and Week 24 | 
| Maintenance of the Disability Index of the HAQ at Week 52 for Participants Who Were Responders at Week 12 or Week 24 | Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Responders had a >= 0.22-unit decrease (improvement) in HAQ scores from baseline to Week 12 or 24. | Week 52 | 
| Maintenance of ACR20 Response at Week 52 for Participants Who Were ACR20 Responders at Week 24 | Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders. | Week 52 | 
| Number of Participants With a Continuous ACR70 Response for 6 Months During 52 Weeks of Treatment | Patients were responders if they had: >= 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: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders. | Baseline through Week 52 | 
| Time to First Response According to ACR20 Criteria - Number of Participants Meeting ACR20 Criteria for the First Time at Each Time Point | Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders. | Baseline through Week 52 | 
| Time to First Response According to ACR50 Criteria - Number of Participants Meeting ACR50 Criteria for the First Time at Each Time Point | Patients were responders if they had: >= 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: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders. | Baseline through Week 52 | 
| Time to First Response According to ACR70 Criteria - Number of Participants Meeting ACR70 Criteria for the First Time at Each Time Point | Patients were responders if they had: >= 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: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders. | Baseline through Week 52 | 
| Estimated Yearly Progression of Rheumatoid Arthritis | Estimated yearly progression was defined as modified total Sharp x-ray score at baseline divided by duration of rheumatoid arthritis disease at baseline. Actual progression during the study was defined as modified total Sharp x-ray score at Week 52 minus modified total Sharp x-ray score at baseline divided by the duration of the study. The range of scores for the modified total Sharp x-ray score was 0 (normal) to 398 (maximal disease). | Baseline and Week 52 | 

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