A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Subjects With Moderately to Severely Active Rheumatoid Arthritis Who Are on a Stable Background of Methotrexate (MTX) and Who Have an Inadequate Response to MTX (MTX-IR)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 1,629
- 试验地点
- 370
- 主要终点
- Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
研究概览
简要总结
The purpose of this study was to assess efficacy, including inhibition of radiographic progression, and safety with upadacitinib versus placebo and versus an active comparator, adalimumab, in adults with with moderately to severely active rheumatoid arthritis (RA) who are on a stable background of methotrexate (MTX and who have an inadequate response to MTX.
详细描述
This study consists of a 48-week double-blind treatment period (Period 1) and a long-term extension period (Period 2).
Period 1 is a 48-week randomized, double-blind, parallel-group, placebo-controlled and active comparator-controlled period designed to compare the safety and efficacy of upadacitinib versus placebo, and versus adalimumab. Participants will be randomized in a 2:2:1 ratio to one of three treatment groups:
- Placebo (up to Week 26)
- Upadacitinib 15 mg once daily (QD)
- Adalimumab 40 mg every other week (eow)
Participants randomized to placebo who do not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded upadacitinib treatment. At Week 26, all participants still receiving placebo will be switched to blinded upadacitinib treatment regardless of clinical response.
Participants randomized to adalimumab who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded upadacitinib. Participants still receiving adalimumab at Week 26 who do not achieve low disease activity (LDA) according to Clinical Disease Activity Index (CDAI; LDA is defined as CDAI ≤ 10) will be switched to blinded upadacitinib treatment to Week 48.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Adult male or female, at least 18 years old.
- •Diagnosis of RA for greater than or equal to 3 months.
- •Subjects must have been on oral or parenteral methotrexate (MTX) therapy greater than or equal to 3 months and on a stable prescription of greater than or equal to 15 to 25 mg/week (or greater than or equal to 10 mg/week in subjects intolerant of MTX at doses greater than or equal to 12.5 mg/week) for at least 4 weeks prior to the first dose of study drug. In addition all subjects should take a dietary supplement of folic acid or folinic acid throughout the study participation.
- •Meets the following minimum disease activity criteria: greater than or equal to 6 swollen joints (based on 66 joint counts) and greater than or equal to 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits.
- •At least one of the following at Screening: greater than or equal to 3 bone erosions on x-ray OR greater than or equal to 1 bone erosion and a positive rheumatoid factor OR greater than or equal to 1 bone erosion and a positive anti-cyclic citrullinated peptide autoantibodies.
- •Subjects with prior exposure to only one biological disease-modifying anti-rheumatic drugs (bDMARD) (except adalimumab) may be enrolled (up to 20% of total study population) if they have documented evidence of intolerance to the bDMARD or limited exposure (less than 3 months), but required washout periods need to be satisfied.
- •Except for MTX, subject must have discontinued all conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).
排除标准
- •Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib).
- •Subjects who have been exposed to adalimumab or who are considered inadequate responders to bDMARD therapy as determined by the Investigator.
- •History of inflammatory joint disease other than RA. History of secondary Sjogren's Syndrome is permitted.
研究组 & 干预措施
Placebo followed by ABT-494
Participants were to receive placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26, all remaining participants were to be switched to 15 mg upadacitinib QD until Week 48 (end of Period 1).
Participants who complete Period 1 will continue to receive 15 mg upadacitinib orally QD for up to 5 years in Period 2.
干预措施: Placebo for Adalimumab (Drug)
Placebo followed by ABT-494
Participants were to receive placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26, all remaining participants were to be switched to 15 mg upadacitinib QD until Week 48 (end of Period 1).
Participants who complete Period 1 will continue to receive 15 mg upadacitinib orally QD for up to 5 years in Period 2.
干预措施: Placebo for Upadacitinib (Drug)
Placebo followed by ABT-494
Participants were to receive placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26, all remaining participants were to be switched to 15 mg upadacitinib QD until Week 48 (end of Period 1).
Participants who complete Period 1 will continue to receive 15 mg upadacitinib orally QD for up to 5 years in Period 2.
干预措施: Upadacitinib (Drug)
Adalimumab
Participants were to receive placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26 remaining participants who did not achieve low disease activity (defined as Clinical Disease Activity Index [CDAI] ≤ 10) were to be switched to 15 mg upadacitinib orally QD until Week 48.
Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.
干预措施: Adalimumab (Drug)
Adalimumab
Participants were to receive placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26 remaining participants who did not achieve low disease activity (defined as Clinical Disease Activity Index [CDAI] ≤ 10) were to be switched to 15 mg upadacitinib orally QD until Week 48.
Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.
干预措施: Placebo for Upadacitinib (Drug)
Adalimumab
Participants were to receive placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26 remaining participants who did not achieve low disease activity (defined as Clinical Disease Activity Index [CDAI] ≤ 10) were to be switched to 15 mg upadacitinib orally QD until Week 48.
Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.
干预措施: Upadacitinib (Drug)
Upadacitinib
Participants were to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 40 mg adalimumab eow. At Week 26 remaining participants who did not achieve low disease activity (defined as CDAI ≤ 10) were to be switched to 40 mg adalimumab eow until Week 48.
Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.
干预措施: Placebo for Adalimumab (Drug)
Upadacitinib
Participants were to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 40 mg adalimumab eow. At Week 26 remaining participants who did not achieve low disease activity (defined as CDAI ≤ 10) were to be switched to 40 mg adalimumab eow until Week 48.
Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.
干预措施: Adalimumab (Drug)
Upadacitinib
Participants were to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 40 mg adalimumab eow. At Week 26 remaining participants who did not achieve low disease activity (defined as CDAI ≤ 10) were to be switched to 40 mg adalimumab eow until Week 48.
Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.
干预措施: Upadacitinib (Drug)
结局指标
主要结局
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
时间窗: Baseline and Week 12
The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 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 * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 12
时间窗: Week 12
The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission, based on a Disease Activity Score 28 (DAS28)-CRP score of \< 2.6 at Week 12. The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28 score less than 2.6 indicates clinical remission.
次要结局
- Change From Baseline in DAS28 (CRP) at Week 12(Baseline and Week 12)
- Change From Baseline in Modified Total Sharp Score (mTSS) at Week 26(Baseline and Week 26)
- Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12(Baseline and Week 12)
- Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12(Baseline and Week 12)
- Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12(Baseline and Week 12)
- Change From Baseline in in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)(Baseline and Week 12)
- Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12(Week 12)
- Percentage of Participants Achieving Low Disease Activity Based on CDAI at Week 12(Week 12)
- Change From Baseline in Duration of Morning Stiffness at Week 12(Baseline and Week 12)
- Change From Baseline in Patient's Assessment of Pain at Week 12(Baseline and Week 12)
- Percentage of Participants With No Radiographic Progression at Week 26(Baseline and Week 26)
- Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12(Baseline and Week 12)