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).
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 799
- 试验地点
- 123
- 主要终点
- Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 52
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Adalimumab
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.
干预措施: Adalimumab (Biological)
Adalimumab
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.
干预措施: Methotrexate placebo (Drug)
Adalimumab + methotrexate
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.
干预措施: Adalimumab (Biological)
Adalimumab + methotrexate
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.
干预措施: Methotrexate (Drug)
Methotrexate
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.
干预措施: Methotrexate (Drug)
Methotrexate
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.
干预措施: Adalimumab placebo (Biological)
结局指标
主要结局
Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 52
时间窗: Baseline and 52 Weeks
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.
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52
时间窗: Baseline and 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.
次要结局
- Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52(Baseline and Week 52)
- Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 104(Baseline and Week 104)
- Change From Baseline in Modified Total Sharp Score (mTSS) at Week 104(Baseline and Week 104)
- Number of Participants Who Achieved Clinical Remission, Defined as a Disease Activity 28 (DAS28) Score < 2.6 at Week 52(Week 52)
- Change From Baseline in the Physical Component of the Short Form-36 Health Status Survey (SF-36) at Week 52(Baseline and Week 52)
- Number of Participants With Major Clinical Response After 104 Weeks of Treatment(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(Baseline and Week 52)
- Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Weeks 26 and 76(Baseline and Weeks 26 and 76)
- Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria During the Double-blind Phase(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(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(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(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(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(Baseline and Weeks 26 and 104)
- Numeric American College of Rheumatology (ACR-N) During the Double-blind Treatment Phase(Baseline and Weeks 26, 52, 76, and 104)
- Change From Baseline in Disease Activity Score (DAS28) During the Double-blind Treatment Phase(Baseline and Weeks 26, 52, 76, and 104)
- Change From Baseline in Joint Erosion Score During the Double-blind Treatment Period(Baseline and Weeks 52 and 104)
- Change From Baseline in Joint Space Narrowing Score During the Double-blind Treatment Period(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(Baseline and Weeks 52 and 104)
- Number of Participants With No Erosions at Baseline and No New Erosions at Weeks 52 and 104(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(Baseline and Weeks 52 and 104)
- Number of Participants Meeting ACR20 Response Criteria Over 10 Years by Adalimumab Exposure(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(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(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(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(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(After 1, 2, 5, and 10 years of adalimumab exposure)
- Change From Baseline in Modified Total Sharp Score (mTSS) Over 10 Years(Baseline (prior to first study drug treatment) and Years 2 and 10)
- Number of Participants With No Radiographic Progression Over 10 Years(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(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(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.)