Study to Determine the Effects of Different Doses of Methotrexate (MTX) When Taken With Adalimumab in Subjects With Early Rheumatoid Arthritis (RA)

Study Overview
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Brief Summary
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The purpose of this study is to determine the effects of different doses of methotrexate (MTX) when taken with adalimumab in subjects with early rheumatoid arthritis (RA).

Official Title
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A Double-Blind, Randomized, Parallel-Arm, Multicenter Study to Determine the Dose Response of Methotrexate (MTX) in Combination Therapy With Adalimumab in Subjects With Early Rheumatoid Arthritis (CONCERTO)

Conditions
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Early 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: Male and female subjects at least 18 years of age Subject has a diagnosis of Rheumatoid Arthritis (RA) as defined by either the 1987-revised American College of Rheumatology (ACR) classification criteria or the new ACR/ European League Against Rheumatism (EULAR) diagnostic criteria for RA 2010 and has a disease duration of less than 1 year from diagnosis by a licensed health care provider Subject must meet the following criteria: Disease Activity Score of C-reactive Protein (DAS28[CRP]) ≥ 3.2 (at the Baseline visit only) At least 6 swollen joints out of 66 assessed (at the Screening and Baseline visits) At least 8 tender joints out of 68 assessed (at the Screening and Baseline visits) C-reactive protein (CRP) ≥ 1.5 mg/dL (at the Screening visit only), or erythrocyte sedimentation rate (ESR) ≥ 28 mm/1h (at the Screening and Baseline visits) Fulfill at least one of the following three criteria: Rheumatoid Factor (RF) positive, have at least 1 bony erosion, anti-cyclic citrullinated peptide (anti-CCP) antibody positive Subject is judged to be in good health as determined by the Principal Investigator based upon the results of medical history, laboratory profile, physical examination, chest x-ray (CXR), and a 12-lead electrocardiogram (ECG) performed during Screening Exclusion Criteria: Subject has previous exposure to any systemic biologic therapy including adalimumab Subject has been previously treated with greater than 1 disease modifying antirheumatic drugs (DMARDs) or with methotrexate (MTX) Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study) Subject has chronic arthritis diagnosed before age 17 years History of invasive infection (e.g., listeriosis and histoplasmosis), chronic or active Hepatitis C infection, human immunodeficiency virus (HIV) infection, immunodeficiency syndrome, chronic recurring infections or active tuberculosis (TB) Hepatitis B virus: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the hepatitis B virus DNA (HBV DNA) polymerase chain reaction (PCR) qualitative test Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the Baseline visit 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 |
| --- | --- |
| Active Comparator: ADA + 2.5 mg MTX<br>2.5 mg methotrexate (MTX) oral capsule weekly with 40 mg adalimumab (ADA) subcutaneous (SC) injection every other week (EOW) for 26 weeks | Biological: adalimumab<br>* Pre-filled syringe every other week<br>* Other names: Humira;Drug: methotrexate<br>* weekly oral capsule dosing<br>|
| Active Comparator: ADA + 5 mg MTX<br>5 mg MTX oral capsule weekly with 40 mg ADA SC injection EOW for 26 weeks | Biological: adalimumab<br>* Pre-filled syringe every other week<br>* Other names: Humira;Drug: methotrexate<br>* weekly oral capsule dosing<br>|
| Active Comparator: ADA + 10 mg MTX<br>10 mg MTX oral capsule weekly with 40 mg ADA SC injection EOW for 26 weeks | Biological: adalimumab<br>* Pre-filled syringe every other week<br>* Other names: Humira;Drug: methotrexate<br>* weekly oral capsule dosing<br>|
| Active Comparator: ADA + 20 mg MTX<br>MTX oral capsule dose escalation from 10 mg to 20 mg in 2.5 mg increments every other week (10 mg x 2 weeks, 12.5 mg x 2 weeks, 15 mg x 2 weeks, 17.5 mg x 2 weeks), then 20 mg for 18 weeks with 40 mg ADA SC injection EOW for 26 weeks | Biological: adalimumab<br>* Pre-filled syringe every other week<br>* Other names: Humira;Drug: methotrexate<br>* weekly oral capsule dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With 28-Joint Disease Activity Score of C-reactive Protein (DAS28[CRP]) Low Disease Activity at Week 26 | Percentage of participants achieving low disease activity as defined by a clinical response (DAS28[CRP] < 3.2). 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 are 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 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With DAS28(CRP) Remission at Week 26 | Disease remission was defined as a disease activity score, based on CRP, for 28 joints that was < 2.6 (DAS28[CRP] < 2.6). 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 are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. | Week 26 | 
| Percentage of Participants With American College of Rheumatology (ACR) 20 Criteria Response at Week 26 | Response, as defined by ACR 20 criteria at Week 26. A participant is a 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 value (C-reactive protein). | Baseline, Week 26 | 
| Percentage of Participants With American College of Rheumatology (ACR) 50 Criteria Response at Week 26 | Response, as defined by ACR 50 criteria at Week 26. A participant is a 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 value (C-reactive protein). | Baseline, Week 26 | 
| Percentage of Participants With American College of Rheumatology (ACR) 70 Criteria Response at Week 26 | Response, as defined by ACR 70 criteria at Week 26. A participant is a 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 value (C-reactive protein). | Baseline, Week 26 | 
| Percentage of Participants With American College of Rheumatology (ACR) 90 Criteria Response at Week 26 | Response, as defined by ACR 90 criteria at Week 26. A participant is a responder if the following 3 criteria for improvement from Baseline are met: ≥ 90% improvement in tender joint count; ≥ 90% improvement in swollen joint count; and ≥ 90% 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 value (C-reactive protein). | Baseline, Week 26 | 
| Percentage of Participants With American College of Rheumatology (ACR) 100 Criteria Response at Week 26 | Response, as defined by ACR 100 criteria at Week 26. A participant is a responder if the following 3 criteria for improvement from Baseline are met: ≥ 100% improvement in tender joint count; ≥ 100% improvement in swollen joint count; and ≥ 100% 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 value (C-reactive protein). | Baseline, Week 26 | 
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 26 | The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 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 0 represents no disability and 3 very severe, high-dependency disability. HAQ remission indicating normal physical function is defined by HAQ-DI score of < 0.5. Negative change from Baseline in the overall score indicates improvement. | Baseline, Week 26 | 
| Percentage of Participants With a Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ -0.22 at Week 26 | 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. The minimal clinically important difference (MCID) defined for the HAQ-DI is a change from Baseline of ≥ 0.22. HAQ remission indicating normal physical function is defined by HAQ-DI score of < 0.5. Negative change from Baseline in the overall score indicates improvement. | Baseline, Week 26 | 
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 26 | The modified Total Sharp Score (mTSS) is a measure of change in joint health from digitized images of radiographs of hands and feet. 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, Week 26 | 
| Percentage of Participants With No Radiographic Progression at Week 26 | No radiographic progression was defined as a change from Baseline in modified Total Sharp Score (mTSS) at Week 26 of ≤ 0.5. mTSS is a measure of change in joint health from digitized images of radiographs of hands and feet. 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, Week 26 | 
| Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission at Week 26 | SDAI is a measure of disease activity derived as follows: SDAI = SJC28 + TJC28 + GH (cm) + PhGA (cm) + CRP (mg/dL), where TJC28 and SJC28 represent total tender joint count and total swollen joint count, respectively, based on 28 joints (including the left and right side of the body), GH = Patient's Global Assessment of Disease Activity, and PhGA = Physician's Global Assessment of Disease Activity (both measured on a visual analogue scale with a range of 0 [none] to 10 [severe]), and CRP is C-reactive protein measured in mg/dL. SDAI total score = 0 to 86. SDAI ≤ 3.3 indicates disease remission, > 3.4 to 11 = low disease activity, > 11 to 26 = moderate disease activity, and > 26 = high disease activity. | Week 26 | 
| Percentage of Participants With Clinical Disease Activity Index (CDAI) Remission at Week 26 | CDAI is a measure of disease activity derived as follows: CDAI = SJC28 + TJC28 + GH (cm) + PhGA (cm) where TJC28 and SJC28 represent total tender joint count and total swollen joint count, respectively, based on 28 joints (including the left and right side of the body), GH = Patient's Global Assessment of Disease Activity, and PhGA = Physician's Global Assessment of Disease Activity (both measured on a visual analogue scale with a range of 0 [none] to 10 [severe]). CDAI total score = 0 to 76. CDAI ≤ 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. | Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arthritis, Erosion, Humira, Adalimumab, Injection, Rheumatoid, Methotrexate