A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected Via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Subjects (PREDICTRA)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 149
- 试验地点
- 140
- 主要终点
- Association Between Baseline Bone Marrow Edema RAMRIS Score and Flare up to Week 40 in the Tapering Arm
研究概览
简要总结
The primary objective of the study was to investigate the association between residual disease activity at Baseline as detected by Magnetic Resonance Imaging (MRI) and the occurrence of flares in participants with rheumatoid arthritis (RA) randomized to an adalimumab dose tapering regimen controlled by adalimumab withdrawal.
详细描述
This was a Phase 4, multicenter, randomized, double-blind, parallel-group study. The study included a Screening period of up to 28 days (unless extended with justification approved by study-designated physician), a 4-week Lead-In Period with open label (OL) 40 mg adalimumab administered subcutaneously (sc) every other week (eow), and a randomized 36-week double-blind period with 40 mg adalimumab sc every 3 weeks (q3wks; tapering arm) or placebo sc q3wks (withdrawal arm). Participants were randomized in a 5:1 ratio (tapering arm: withdrawal arm) after confirmation of meeting the disease activity score (DAS) criteria. Participants who experienced a protocol-defined flare at any time were to enter a rescue arm with OL 40 mg adalimumab administered sc eow for 16 weeks.
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
- •Participant had a diagnosis of rheumatoid arthritis (RA) as defined by the 1987 revised American College of Rheumatology (ACR) classification criteria and/or the ACR /European League Against Rheumatism (EULAR) 2010 classification criteria (any duration since diagnosis).
- •Participant must have met the following criteria:
- •Must have been treated with adalimumab 40 mg subcutaneously every other week (sc eow) for at least 12 months prior to Week 0 Visit
- •Must have been treated with concomitant methotrexate (MTX) at a stable dose (oral, sc or intramuscular (im) at any dose) for at least 12 weeks prior to Week 0 Visit or if not on MTX, must have been treated with other allowed conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) at a stable dose for at least 12 weeks prior to Week 0 Visit or if not treated with csDMARDs must maintain this regimen for at least 12 weeks prior to Week 0 Visit.
- •Participant must be in sustained clinical remission based on the following:
- •At least one documented 4 or 3 (if Patient's Global Assessment ; PGA is not available) variables Disease Activity Score 28 Erythrocyte sedimentation rate (DAS28 ESR) or DAS28 C-reactive protein (CRP) < 2.6 (or calculated based on documented components of the DAS28) in the participant's chart 6 months or longer prior to the Screening Visit;
- •4 variables DAS28 (ESR) assessed at Screening < 2.6, with all components including ESR assessed at Screening.
- •If participant was receiving concomitant allowed csDMARDs (in addition or not to MTX) the dose must have been stable for at least 12 weeks prior to the Week 0 Visit (e.g., chloroquine, hydroxychloroquine, sulfasalazine, gold formulations [including auranofin, gold sodium thiomalate, and aurothioglucose] and/or leflunomide).
- •If participant was receiving concomitant oral corticosteroids, prednisone or equivalent must have been < 10 mg/day and the dose must have been stable for at least 4 weeks prior to the Week 0 Visit.
- •If participant was receiving concomitant non-steroidal anti-inflammatory drugs (NSAIDs), tramadol or other equivalent opioids and/or non-opioid analgesics, the dose and/or therapeutic scheme must have been stable for at least 4 weeks prior to the Week 0 Visit.
- •Participant must have been able and willing to provide written informed consent and comply with the requirements of this study protocol.
排除标准
- •Any 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 (CRP) (or calculated based on documented components of the DAS28) assessed within 6 months prior to the Screening Visit ≥ 2.
- •Participant was on an additional concomitant biological disease-modifying anti-rheumatic drug (bDMARD) (including but not limited to abatacept, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab or tocilizumab).
- •Participant had been treated with intra-articular or parenteral corticosteroids within the last four weeks before Screening.
- •Participant had undergone joint surgery within 12 weeks of Screening (at joints to be assessed by magnetic resonance imaging (MRI) and/or ultrasound).
- •Participant had a medical condition precluding an MRI (e.g. magnetic activated implanted devices - cardiac pace-maker, insulin pump, neuro stimulators, etc. and metallic devices or fragments or clips in the eye, brain or spinal canal and in the hand/wrist undergoing MRI)
- •Participant had a medical condition precluding a contrast MRI with gadolinium [e.g. nephrogenic systemic fibrosis, previous anaphylactic/anaphylactoid reaction to gadolinium containing contrast agent, pregnancy or breast feeding, severe renal insufficiency with an estimated Glomerular Filtration Rate (eGFR) below 30 mL/min/1.73m^2 at Screening, hepato-renal syndrome, severe chronic liver function impairment]
- •Participant had been treated with any investigational drug of chemical or biologic nature within a minimum of 30 days or five half-lives (whichever is longer) of the drug prior to the Screening Visit.
研究组 & 干预措施
Adalimumab 40 mg eow Rescue Arm
40 mg adalimumab administered subcutaneously every other week from Flare Week 0 to Flare Week 16 (Open-label Rescue Period)
干预措施: Adalimumab (Biological)
Adalimumab Tapering
40 mg adalimumab administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)
干预措施: Adalimumab (Biological)
Adalimumab Withdrawal Arm
Placebo administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)
干预措施: Placebo (Other)
Adalimumab 40 mg eow
40 mg adalimumab administered subcutaneously every other week (eow) from Week 0 to Week 4 (Lead-in Period)
干预措施: Adalimumab (Biological)
结局指标
主要结局
Association Between Baseline Bone Marrow Edema RAMRIS Score and Flare up to Week 40 in the Tapering Arm
时间窗: From Week 4 to Week 40
Bone marrow edema in each bone was scored separately. The scale is 0-3 based on the proportion of bone with edema, as follows-0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of \> 0.6 AND DAS28 \[ESR\] \> 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 \[ESR\]. The association between baseline bone marrow edema rheumatoid arthritis MRI scoring system (RAMRIS) score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.
Association Between Baseline Hand and Wrist Synovitis Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score and Flare up to Week 40 in the Tapering Arm
时间窗: From Week 4 to Week 40
Synovitis was assessed in three wrist regions (the distal radioulnar joint; the radiocarpal joint; the intercarpal and carpometacarpal joints) and in each Metacarpophalangeal joint (MCP) joint. The first carpometacarpal joint and the first MCP joint are not scored. The scale is 0-3. Score 0 is normal, and 1-3 (mild, moderate, severe) are by thirds of the presumed maximum volume of enhancing tissue in the synovial compartment. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of \> 0.6 AND DAS28 \[ESR\] \> 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 \[ESR\]. The association between baseline hand and wrist synovitis RAMRIS score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.
Association Between a Composite of Baseline Hand and Wrist Synovitis and Bone Marrow Edema RAMRIS Scores and Flare up to Week 40 in the Tapering Arm
时间窗: From Week 4 to Week 40
The composite score is the sum of the baseline hand and wrist synovitis and bone marrow edema RAMRIS scores. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of \> 0.6 AND DAS28 \[ESR\] \> 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 \[ESR\]. The association between the composite baseline hand and wrist synovitis score and baseline bone marrow edema rheumatoid arthritis MRI scoring system (RAMRIS) score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.
次要结局
- Number of Participants Maintaining Clinical Remission Defined By DAS28 (ESR) < 2.6, SDAI ≤ 3.3, and CDAI ≤ 2.8 at Each Visit By Treatment Arm(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Participants' Assessment of Flare Severity(At the Flare Week 0 Visit)
- Mean Change From Double-blind Baseline in Disease Activity Score 28 (DAS28)(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed During In-office Visits(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Physician's Global Assessment of Disease Activity(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Morning Stiffness Duration(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Morning Stiffness Severity(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Number of Participants Who Regained Clinical Remission in the Open-Label Rescue Arm Over Time(From Flare Week 0 to Flare Week 16)
- Median Time to Clinical Remission From the Occurrence of Flare(From Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Clinical Disease Activity Index (CDAI) Score(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline to Week 40 or Final Visit in Magnetic Resonance Imaging (MRI) Synovitis Score(From Week 4 to Week 40 or Final visit)
- Mean Change From Flare Week 0 in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed at Home(Flare Week 0 and Flare Weeks 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15)
- Mean Change From Double-blind Baseline in Participant's Global Assessment of Rheumatoid Arthritis Pain(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Median Time to Flare(From Week 4 to Week 40)
- Physicians' Assessment of Flare Severity(At the Flare Week 0 Visit)
- Percentage of Participants With a Flare(From Week 4 to Week 40)
- Mean Change From Double-blind Baseline in Swollen Joint Count 66(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Tender Joint Count 28(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Tender Joint Count 68(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Participant's Global Assessment of Disease Activity(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Effectiveness Score(At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Simplified Disease Activity Index (SDAI) Score(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Marrow Edema (BME) Score(From Week 4 to Week 40 or Final visit)
- Mean Change From Double-blind Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) Score Over Time(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Swollen Joint Count 28(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Erosions Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score(From Week 4 to Week 40 or Final Visit)
- Number of Participants With Health Assessment Questionnaire- Disability Index (HAQ-DI) Score ≤ 0.5 at Double-blind Baseline and at Week 40(Week 4 and Week 40)
- Mean Change From Double-blind Baseline in Participant's Assessment of Sleep Disturbance(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Convenience Score(At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Physical Component Summary (PCS) Score(At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale(At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Serum Levels of Erythrocyte Sedimentation Rate (ESR)(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Score(At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Serum Levels of C-reactive Protein (CRP)(From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Side Effects Score(At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16)
- Mean Change From Double-blind Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment and Activity Impairment Scores(At Weeks 4, 28, and 40 and Flare Weeks 0, 10, and 16)
- Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Mental Component Summary (MCS) Score(At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16)