A Canadian Study to Evaluate Early Use of Adalimumab After Methotrexate Failure in Early Rheumatoid Arthritis

Study Overview
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Brief Summary
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A Canadian study to evaluate early use of adalimumab after methotrexate failure in early rheumatoid arthritis. The study hypothesis will verify if adalimumab effectively reduces joint damage in more participants when introduced earlier than in current practice.

Official Title
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Radiographic, Clinical and Patient Outcomes in a Multicenter, Open Label Phase IV Randomized Trial of Earlier Adalimumab Introduction Therapy Versus Later Introduction as Per Standard of Care After Initial Methotrexate Failure in Early Rheumatoid Arthritis Patients

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: adalimumab
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a diagnosis of Rheumatoid Arthritis as defined by the 1987-revised American College of Rheumatology-classification criteria and has disease duration of less than 2 years from diagnosis. Subject must have been on a dose of methotrexate therapy either subcutaneously or orally administered (15-25 mg/week) for at least 3 months prior to baseline visit and has had an inadequate response to treatment defined as having a Disease Activity Score DAS28 > 3.2 (at Screening visit). Subject must also meet the following three criteria (at screening visit): at least 4 swollen joints out of 66 assessed; at least 4 tender joints out of 68 assessed; subject must have an elevated erythrocyte sedimentation rate >/= 20 mm/1h or C-reactive protein > upper limit of normal. Subject must fulfill at least one of the following three criteria: history of rheumatoid factor positive; history of at least one erosion on X-ray or magnetic resonance imaging; history of anti-cyclic-citrullinated protein antibody positive. Exclusion Criteria: Subject has previous exposure to any biologic therapy including adalimumab. Prior disease-modifying antirheumatic drugs triple therapy with methotrexate. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the preceding 4 weeks prior to baseline visit. Inhaled corticosteroids for stable medical conditions are allowed. Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study) of Baseline. Subject has a poorly controlled medical condition, such as uncontrolled diabetes, unstable heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the Investigator, would put the subject at risk by participating in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early Adalimumab<br>Participants in the Early Adalimumab arm will receive adalimumab and methotrexate at Baseline and every other week for study duration. | Biological: adalimumab<br>* Study drug will be provided to participants in Early Adalimumab arm as a sterile, preservative-free solution for subcutaneous injection, contained in a pre-filled syringe housed in a pen device (pre-filled pen). 40 mg of adalimumab will be administered subcutaneously at Baseline and then every other week for 24 months. Adalimumab may be initiated in participants in standard of care (SOC) arm after a minimum of 6 months of treatment recommended by their study doctor.<br>* Other names: Humira;Drug: Methotrexate<br>* Participants in both arms will receive a methotrexate regimen based on local guidelines and their study doctor's judgment.<br>* Other names: Rheumatrex;|
| Active Comparator: Standard of Care<br>Participants in the Standard of Care arm will receive methotrexate and other disease modifying antirheumatic drugs as per local treatment guidelines and study doctor's judgement. Adalimumab may be initiated after a minimum of 6 months. | Biological: adalimumab<br>* Study drug will be provided to participants in Early Adalimumab arm as a sterile, preservative-free solution for subcutaneous injection, contained in a pre-filled syringe housed in a pen device (pre-filled pen). 40 mg of adalimumab will be administered subcutaneously at Baseline and then every other week for 24 months. Adalimumab may be initiated in participants in standard of care (SOC) arm after a minimum of 6 months of treatment recommended by their study doctor.<br>* Other names: Humira;Drug: Methotrexate<br>* Participants in both arms will receive a methotrexate regimen based on local guidelines and their study doctor's judgment.<br>* Other names: Rheumatrex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With No Radiographic Progression at Month 12 | Radiographic progression was defined as change from Baseline in the modified Total Sharp Score (mTSS) of ≤ 0.5 units). The mTSS is a measure of change in joint health: digitized images of radiographs of hands and feet obtained at Screening and Month 12 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, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With No Radiographic Progression at Month 6 and Month 24 | Radiographic progression was defined as change from Baseline in the modified Total Sharp Score (mTSS) of ≤ 0.5 units). The mTSS is a measure of change in joint health: digitized images of radiographs of hands and feet obtained at Screening and Month 12 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, Month 6, Month 24 | 
| Change From Baseline in mTSS at Months 6, 12 and 24 | The mTSS is a measure of change in joint health: digitized images of radiographs of hands and feet obtained at Screening and Month 12 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, Month 6, Month 12, Month 24 | 
| Percentage of Participants With Rapid Radiographic Progression at Month 12 | Radiographic progression was defined as a change from Baseline in mTSS that is ≥ 5 units. The mTSS is a measure of change in joint health: digitized images of radiographs of hands and feet obtained at Screening and Month 12 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. | Month 12 | 
| Percentage of Participants With American College of Rheumatology 20% (ACR20) Response at Months 3, 6, 9, 12, 18 and 24 | A participant is an ACR20 responder if the following 3 criteria for improvement from Baseline are 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: - Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Disability Index of the Health Assessment Questionnaire Acute phase reactant (erythrocyte sedimentation rate/C-reactive protein [CRP]). | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants With American College of Rheumatology 50% (ACR50) Response at Months 3, 6, 9, 12, 18 and 24 | A participant is an ACR50 responder if the following 3 criteria for improvement from Baseline are 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: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Disability Index of the Health Assessment Questionnaire Acute phase reactant (erythrocyte sedimentation rate/CRP). | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants With American College of Rheumatology 70% (ACR70) Response at Months 3, 6, 9, 12, 18 and 24 | A participant is an ACR70 responder if the following 3 criteria for improvement from Baseline are 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: - Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Disability Index of the Health Assessment Questionnaire Acute phase reactant (erythrocyte sedimentation rate/CRP). | Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Swollen Joint Count 66 at Months 3, 6, 9, 12, 18 and 24 | Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The presence of swelling is scored 1 and no swelling is 0; range of score is 0-66, with higher scores indicating more swollen joints. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Swollen Joint Count 28 at Months 3, 6, 9, 12, 18 and 24 | Twenty-eight joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The presence of swelling is scored 1 and no swelling is 0; range of score is 0-28, with higher scores indicating more swollen joints. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Tender Joint Count 68 at Months 3, 6, 9, 12, 18 and 24 | Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The presence of tenderness is scored 1 and no tenderness is 0; range of score is 0-68, with higher scores indicating more tender joints. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Tender Joint Count 28 at Months 3, 6, 9, 12, 18 and 24 | Twenty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The presence of tenderness is scored 1 and no tenderness is 0; range of score is 0-28, with higher scores indicating more tender joints. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Physician's Global Assessment of Disease Activity at Months 3, 6, 9, 12, 18 and 24 | Physicians were asked to indicate the participant's disease activity (independent of the participant's self assessment) on a visual analogue scale (VAS) from 0 (very good) to 100 (very bad). A negative change from Baseline indicates improvement. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Patient's Global Assessment of Disease Activity at Months 3, 6, 9, 12, 18 and 24 | Participants were asked to indicate how they were doing with their RA on a VAS from 0 (very well) to 100 (very poorly). A negative change from Baseline indicates improvement. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Patient's Global Assessment of Pain at Months 3, 6, 9, 12, 18 and 24 | Participants were asked to indicate how severe their pain had been in the previous week on a VAS from 0 (no pain) to 100 (pain as bad as it could be). A negative change from Baseline indicates improvement. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in CRP at Months 3, 6, 9, 12, 18 and 24 |  | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Disease Activity Score DAS28(CRP) at Months 3, 6, 9, 12, 18 and 24 | The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants With DAS28(CRP) Remission at Months 3, 6, 9, 12, 18 and 24 | DAS28(CRP) remission was defined as DAS28(CRP) < 2.6. The DAS28(CRP) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity. | Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants With DAS28(CRP) Low Disease Activity at Months 3, 6, 9, 12, 18 and 24 | DAS28(CRP) low disease activity was defined as DAS28(CRP) < 3.2. The DAS28(CRP) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity. | Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Months 3, 6, 9, 12, 18 and 24 | A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. The DAS28 score ranges from 0-10, with higher scores indicating more disease activity. A Good EULAR Response is defined as an improvement (decrease) in the DAS28 of ≥ 1.2 compared with Baseline and attainment of a DAS28 score of ≤ 3.2. | Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants With EULAR Moderate Response at Months 3, 6, 9, 12, 18 and 24 | A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. The DAS28 score ranges from 0-10, with higher scores indicating more disease activity. A Moderate EULAR Response is defined as either: an improvement (decrease) in the DAS28 of > 0.6 and < 1.2 from Baseline and attainment of a DAS28 score of ≤ 5.1; or an improvement (decrease) in the DAS28 of ≥ 1.2 from Baseline and attainment of a DAS28 score of > 3.2. | Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants With Flare-Up After Remission by Month 24 | Percentage of participants with a flare-up after remission by Month 24, defined as participants who reached remission (DAS28 < 2.6) but later had two consecutive visits with DAS28 ≥ 2.6 (based on observed cases only). The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity. | Month 24 | 
| Change From Baseline in Disability Index of the Health Assessment Questionnaire (HAQ-DI) at Months 3, 6, 9, 12, 18 and 24 | HAQ is a participant-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 lower HAQ-DI score is better. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants Achieving Minimal Clinical Important Difference (MCID) in HAQ at Months 3, 6, 9, 12, 18 and 24 | The percentage of participants achieving MCID in HAQ, defined as a 0.22 unit decrease in HAQ. HAQ is a participant-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 lower HAQ-DI score is better. | Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants Achieving HAQ < 0.5 at Months 3, 6, 9, 12, 18 and 24 | The percentage of participants achieving HAQ < 0.5. HAQ is a participant-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. HAQ remission indicating normal physical function is defined by HAQ-DI < 0.5. A lower HAQ-DI score is better. | Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale at Months 3, 6, 9, 12, 18 and 24 | The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions on a scale from 'not at all' (0) to 'very much' (4). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Percentage of Participants Achieving MCID in FACIT-Fatigue Scale at Months 3, 6, 9, 12, 18 and 24 | The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions on a scale from 'not at all' (0) to 'very much' (4). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue. The MCID was defined as a 3.56-unit decrease in FACIT-Fatigue Scale. | Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Work Limitations Questionnaire (WLQ) at Months 3, 6, 9, 12, 18 and 24 | The WLQ was used to measure the impairment in work-related productivity, with reference to the previous two weeks. Each work-related question is scored from 0 to 4 and the total score ranges from 0-100, with lower scores signifying fewer limitations at work. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in EuroQOL Questionnaire (EQ-5D) Index Score at Months 3, 6, 9, 12, 18 and 24 | The EQ-5D is a participant answered questionnaire scoring 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by applying a formula that essentially attaches values (also called QOL weights or QOL utilities) to each of the levels in each dimension. EQ-5D Summary Index values range from -0.594 to 1 (with higher scores indicating better health state). | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in EQ-5D VAS at Months 3, 6, 9, 12, 18 and 24 | The EQ-5D VAS records the participant's self-rated health on a scale from 0-100 where 100 is the 'best imaginable health state' and 0 is the 'worst imaginable health state.' | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Change From Baseline in Beck Depression Inventory (BDI-II) Scores at Months 3, 6, 9, 12, 18 and 24 | BDI is a 21-item questionnaire, participant self-report rating inventory that measures characteristic attitudes and symptoms of depression. The range of scores is 0 to 63, with a higher value representing a worse outcome. | Baseline, Months 3, 6, 9, 12, 18, 24 | 
| Likert Scale for Participant's Satisfaction With Care at Months 3, 6, 9, 12, 18 and 24 | Participants measured their satisfaction with care by specifying their in response to the question How satisfied are you with the results of your RA treatment? on a 5-point Likert scale, from the following 5 answers: not satisfied, a little satisfied, moderately satisfied, well satisfied, very well satisfied. Scores range from 1 to 5, with higher scores indicating more satisfaction with their care. | Months 3, 6, 9, 12, 18, 24 | 
| Health Care Resources Questionnaire (HCR): Medical Insurance at Baseline | The HCR consists of four aspects: medical insurance, health care for RA in the past 4 weeks, hospitalization in the past 4 weeks, and out of pocket expenses incurred for the current study condition. Participants were asked whether and what type of health insurance they had. Types of Canadian insurance included: Régie de l'assurance maladie du Québec (RAMQ); Société de l'assurance automobile du Québec (SAAQ); Commission de la santé et de la sécurité du travail (CSST); Canadian Health Insurance Program (CHIP); and L'indemnisation des victimes d'actes criminals (IVAC). | Baseline | 
| HCR: Medical Insurance at Final Visit | The HCR consists of four aspects: medical insurance, health care for RA in the past 4 weeks, hospitalization in the past 4 weeks, and out of pocket expenses incurred for the current study condition. Participants were asked whether and what type of health insurance they had. Types of Canadian insurance included: Régie de l'assurance maladie du Québec (RAMQ); Société de l'assurance automobile du Québec (SAAQ); Commission de la santé et de la sécurité du travail (CSST); Canadian Health Insurance Program (CHIP); and L'indemnisation des victimes d'actes criminals (IVAC). | Final Visit (up to Month 24) | 
| HCR: Health Care for RA in the Past 4 Weeks at Baseline | The HCR consists of four aspects: medical insurance, health care for RA in the past 4 weeks, hospitalization in the past 4 weeks, and out of pocket expenses incurred for the current study condition. Participants were asked about their use of health care for RA in the past 4 weeks. | Baseline | 
| HCR: Health Care for RA in the Past 4 Weeks at Final Visit | The HCR consists of four aspects: medical insurance, health care for RA in the past 4 weeks, hospitalization in the past 4 weeks, and out of pocket expenses incurred for the current study condition. Participants were asked about their use of health care for RA in the past 4 weeks. | Final Visit (up to Month 24) | 
| HCR: Out of Pocket Expenses Incurred for the Current Study Condition in the Past 4 Weeks at Baseline | The HCR consists of four aspects: medical insurance, health care for RA in the past 4 weeks, hospitalization in the past 4 weeks, and out of pocket expenses incurred for the current study condition. Participants were asked what type of out-of-pocket expenses they had incurred for their RA in the past 4 weeks. Based on Canadian dollars. | Baseline | 
| HCR: Out of Pocket Expenses Incurred for the Current Study Condition in the Past 4 Weeks at Final Visit | The HCR consists of four aspects: medical insurance, health care for RA in the past 4 weeks, hospitalization in the past 4 weeks, and out of pocket expenses incurred for the current study condition. Participants were asked what type of out-of-pocket expenses they had incurred for their RA in the past 4 weeks. Based on Canadian dollars. | Final Visit (up to Month 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Anti-Inflammatory, Biological Therapy, adalimumab, Disease-Modifying Antirheumatic Drugs, Antirheumatic Agents, Agents