Efficacy and Safety of Adalimumab and Methotrexate (MTX) Versus MTX Monotherapy in Subjects With Early Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of the study is to assess the safety and efficacy of adalimumab in combination with methotrexate in patients with recent onset rheumatoid arthritis (RA), and to assess the long-term safety and maintenance of efficacy after treatment with adalimumab for up to 10 years.

Detailed Description
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This study had an initial 2-year double-blind treatment period followed by an 8-year open-label extension period, for a total of up to 10 years study duration. The study was designed to assess the potential of adalimumab + methotrexate to improve signs and symptoms of disease and to inhibit radiographic progression in patients with recent onset (disease duration less than 3 years) rheumatoid arthritis not previously treated with methotrexate. Adalimumab is a human anti-tumor necrosis factor (TNF) monoclonal antibody.

Official Title
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A Prospective Multi-Centre Randomised, Double-Blind, Active Comparator-Controlled, Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNFα Antibody Adalimumab Given Every Second Week With Methotrexate Given Weekly and the Combination of Adalimumab and Methotrexate Administered Over 2 Years in Patients With Early Rheumatoid Arthritis (PREMIER).

Conditions
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Early Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Adalimumab
* Drug: Methotrexate
* Biological: Adalimumab placebo
* Drug: Methotrexate placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject was age 18 or older and in good health (Investigator discretion) with a recent stable medical history. Diagnosis of rheumatoid arthritis (RA) as defined by the 1987-revised American College of Rheumatology (ACR) criteria, with a disease duration less than 3 years, at least 8 swollen joints out of the 66 joints assessed, at least 10 tender joints out of the 68 joints assessed, at least 1 joint erosion or rheumatoid factor (RF) positivity, erythrocyte sedimentation rate (ESR) >= 28 mm/1h or C-reactive protein (CRP) >= 1.5 mg/dl Exclusion Criteria: Chronic arthritis diagnosed before the age of 16 Preceding treatment with MTX, cyclophosphamide, cyclosporin, azathioprine or more than 2 other disease-modifying anti-rheumatic drugs (DMARDs) Subject previously received anti-tumor necrosis factor (TNF) therapy Permanently wheelchair-bound or bedridden patients Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study Female subject who is pregnant or breast-feeding or considering becoming pregnant

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: Adalimumab<br>Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase and then adalimumab 40 mg every other week for up to 8 years in the open-label extension. | Biological: Adalimumab<br> <br> * Other names: Humira;Drug: Methotrexate placebo<br> <br> |
| Experimental: Adalimumab + methotrexate<br>Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase. | Biological: Adalimumab<br> <br> * Other names: Humira;Drug: Methotrexate<br> <br> |
| Experimental: Methotrexate<br>Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase. | Drug: Methotrexate<br> <br> Biological: Adalimumab placebo<br> <br> |

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 50% (ACR50) Response Criteria at Week 52 | American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); Acute phase reactant value (C-Reactive Protein). Participants who withdrew early were considered non-responders. | Baseline and 52 Weeks | 
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 | The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 52 were scored in a blinded manner. Joints were scored for erosions on a scale from 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale from 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52 | The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement. | Baseline and Week 52 | 
| Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 104 | American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders. | Baseline and Week 104 | 
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 104 | The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 104 were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 and Week 104 | 
| Number of Participants Who Achieved Clinical Remission, Defined as a Disease Activity 28 (DAS28) Score < 2.6 at Week 52 | The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C reactive protein, and general health were included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission. | Week 52 | 
| Change From Baseline in the Physical Component of the Short Form-36 Health Status Survey (SF-36) at Week 52 | The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement. | Baseline and Week 52 | 
| Number of Participants With Major Clinical Response After 104 Weeks of Treatment | Major clinical response was defined as an American College of Rheumatology 70% (ACR70) response for any six continuous months, over 104 weeks of treatment. A participant was a responder if the following criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were non-responders. | Any 6 continuous months from Baseline to Week 104 | 
| Change From Baseline in the Mental Component of the Short Form-36 Health Status Survey (SF-36) at Week 52 | The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement. | Baseline and Week 52 | 
| Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Weeks 26 and 76 | American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders. | Baseline and Weeks 26 and 76 | 
| Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria During the Double-blind Phase | American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 20% improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders. | Baseline and Weeks 26, 52, 76, and 104 | 
| Number of Participants Meeting American College of Rheumatology 70% (ACR70) Response Criteria During the Double-blind Phase | American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders. | Baseline and Weeks 26, 52, 76, and 104 | 
| Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) During the Double-blind Treatment Phase | The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement. | Baseline and Weeks 12, 26, 76, and 104 | 
| Number of Participants With Improvement in the HAQ-DI Score ≥ 0.3 During the Double-blind Treatment Phase | The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. | Baseline and Weeks 26, 52, 76, and 104 | 
| Change From Baseline in Health Utilities Index Mark 2 and Mark 3 (HUI 2/3) During the Double-blind Treatment Phase | The HUI 2/3 is an assessment of various aspects of participants' health and ability to perform various tasks on a day-to-day basis, including reading, seeing, hearing, speaking, general outlook on life, pain/discomfort, ability to walk, use of hands, memory, ability to think/solve, and ability to perform basic activities such as eating, bathing, and dressing. The HUI 2/3 is a combined 15-item questionnaire based on a recall period of the previous 4 weeks. HUI-2 and HUI-3 scores are calculated independently. The HUI-2 score includes 6 attributes: Sensation, Mobility, Emotion, Cognition, Self-Care, and Pain. The HUI-3 score is comprised of 8 attributes: Vision, Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition, and Pain. The range of each score is from 0 (dead) to 1 (perfect health). An increase from Baseline indicates improvement. | Baseline and Weeks 26, 52, and 104 | 
| Change From Baseline in the Short Form-36 Health Status Survey (SF-36) During the Double-blind Treatment Phase | The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component and items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement. | Baseline and Weeks 26 and 104 | 
| Numeric American College of Rheumatology (ACR-N) During the Double-blind Treatment Phase | ACR-N is a composite, continuous variable which measures the percentage of improvement from Baseline in individual participants based on the 7 core set variables of the ACR. ACR-N is defined as the smallest percent change from Baseline of 3 measures: tender joint counts (TJC), swollen joint counts (SJC), and the median percent improvement in the 5 remaining measures (Patient's Assessment of Pain, Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Health Assessment Questionnaire - Disability Index [HAQ-DI], and C-Reactive Protein). A positive ACR-N value indicates improvement; a negative ACR-N value indicates worsening; ACR-N of 0 indicates no change. | Baseline and Weeks 26, 52, 76, and 104 | 
| Change From Baseline in Disease Activity Score (DAS28) During the Double-blind Treatment Phase | The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables: 28 tender joint counts, 28 swollen joint counts, C-reactive protein, and Patient's global assessment of disease activity. Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. | Baseline and Weeks 26, 52, 76, and 104 | 
| Change From Baseline in Joint Erosion Score During the Double-blind Treatment Period | Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion)to 230 (worst). A large increase in erosion score is indicative of worsening, whereas a small change or no change is indicative of inhibition of joint erosion. | Baseline and Weeks 52 and 104 | 
| Change From Baseline in Joint Space Narrowing Score During the Double-blind Treatment Period | Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joint space narrowing (JSN) scores were recorded for each hand/wrist (16 joints) and each forefoot (5 joints) on a 5-point scale (0 = no narrowing; 1 = up to 25% narrowing; 2 = 26-65% narrowing; 3 = 66-99% narrowing; and 4 = complete narrowing). Scores were summed to calculate the total score ranging from 0 (no narrowing) to 168 (maximum narrowing). A large increase in joint narrowing score is indicative of worsening, whereas a small change or no change is indicative of inhibition of JSN. | Baseline and Weeks 52 and 104 | 
| Number of Participants With No Worsening in Modified Total Sharp Score or Components During the Double-blind Treatment Phase | The number of participants with no worsening in the modified Total Sharp Score (mTSS) and in erosion and joint space narrowing (JSN) scores, where no worsening is defined as a change from Baseline of ≤ 0 in mTSS, erosion score and JSN score, at Weeks 52 and 104. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 and Weeks 52 and 104 | 
| Number of Participants With No Erosions at Baseline and No New Erosions at Weeks 52 and 104 | The number of participants with no erosions at Baseline and no erosions at Weeks 52 and 104, where no erosions and no new erosions are defined as an erosion score = 0. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion) to 230 (worst). | Baseline and Weeks 52 and 104 | 
| Number of Participants With Non-Involved Joints at Baseline and No Newly Involved Joints at Weeks 52 and 104 | Number of participants with non-involved joints at Baseline and no newly involved joints at Weeks 52 and 104, where involved joints or no newly involved joints are defined as modified Total Sharp Score (mTSS) = 0. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). | Baseline and Weeks 52 and 104 | 
| Number of Participants Meeting ACR20 Response Criteria Over 10 Years by Adalimumab Exposure | American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 20% improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Baseline is the last value prior to the first dose of adalimumab. For participants randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase. | Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab. | 
| Number of Participants Meeting ACR50 Response Criteria Over 10 Years by Adalimumab Exposure | American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase. | Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab. | 
| Number of Participants Meeting ACR70 Response Criteria Over 10 Years by Adalimumab Exposure | American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase. | Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab. | 
| Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) Over 10 Years by Adalimumab Exposure | The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement. | Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106. | 
| Change From Baseline in DAS28 Over 10 Years by Adalimumab Exposure | The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables: 28 tender joint counts, 28 swollen joint counts, C-reactive protein, and Patient's global assessment of disease activity. Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. | Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106. | 
| Number of Participants With DAS28 < 2.6 and < 3.2 Over 10 Years by Adalimumab Exposure | The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables: 28 tender joint counts, 28 swollen joint counts, C-reactive protein, and Patient's global assessment of disease activity. Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. | After 1, 2, 5, and 10 years of adalimumab exposure | 
| Change From Baseline in Modified Total Sharp Score (mTSS) Over 10 Years | The modified TSS (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 (prior to first study drug treatment) and Years 2 and 10 | 
| Number of Participants With No Radiographic Progression Over 10 Years | The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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. The number of participants with change from Baseline ≤ 0.5 and ≤ 0 is reported as a measure of no disease progression. | Baseline (prior to first study drug treatment) and Years 2 and 10. | 
| Composite Score of ACR50 Plus No Change in Modified Total Sharp Score |  | Year 10 | 
| Number of Participants With a Major Clinical Response Over 10 Years by Adalimumab Exposure | A major clinical response was defined as maintenance of an ACR70 response for at least a 6-month continuous period at any time during the study following the first dose of adalimumab. A participant was a responder if the following criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); Acute phase reactant value (C-Reactive Protein). | From the first dose of adalimumab (at Week 1 or Week 106 for patients initially randomized to methotrexate in the DB phase) to Year 10 | 
| Number of Participants With Improvement in HAQ-DI by 0.22 and 0.5 Units Over 10 Years by Adalimumab Exposure | The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A decrease in the HAQ-DI score represents an improvement in physical function; a clinically significant improvement is defined as a decrease of least 0.22 from Baseline in the HAQ-DI score. The number of participants with improvement in HAQ-DI of at least 0.22 and 0.5 units from Baseline is reported. | Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106. | 

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