Efficacy of a Sequential Treatment Strategy in Rheumatoid Arthritis. A Randomized Controlled Trial With an Independent Efficacy Assessor.
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 220
- 试验地点
- 17
- 主要终点
- Percentage of patients in remission
研究概览
简要总结
In rheumatoid arthritis (RA), the consensual 1st line conventional synthetic disease modifying antirheumatic drugs (csDMARD) of RA is methotrexate (MTX). In case of contra-indication or intolerance to MTX, leflunomide is an alternative. If the treatment target is not achieved with csDMARD strategy, addition of a biological DMARD (TNF inhibitors, anti-Interleukin 6 (anti-IL6)), abatacept, or rituximab) or a targeted synthetic (ts) DMARD (JAK inhibitors) is considered.
Current practice is to start a bDMARD (biologic Disease Modifying Antirheumatic Drugs) and especially TNF inhibitors (etanercept or monoclonal anti-TNF antibodies) with the benefit of hindsight. However, abatacept and TNF inhibitors have demonstrated similar efficacy in patients with insufficient response to csDMARD (AMPLE trial).
Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors. Indeed, in real world study, compared to TNF inhibitors it seems that discontinuation of abatacept is more related to lack of effectiveness than safety issues.
Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors followed by abatacept to induce an immunological remission would optimize response and tolerance of ACPA positive patients with RA. To demonstrate our hypothesis, the investigaors propose a randomized controlled trial with one arm receiving an induction therapy for 12 weeks with a TNF inhibitor followed by a cell-targeted bDMARD (abatacept) and the other arm, receiving TNF inhibitors.
详细描述
In rheumatoid arthritis (RA), the consensual 1st line conventional synthetic disease modifying antirheumatic drugs (csDMARD) of RA is methotrexate (MTX) (1). In case of contra-indication or intolerance to MTX, leflunomide is an alternative. If the treatment target is not achieved with csDMARD strategy, addition of a biological (b) DMARD (TNF inhibitors, anti-IL6, abatacept, or rituximab) or a targeted synthetic (ts) DMARD (JAK inhibitors) is considered.
Current practice is to start a bDMARD and especially TNF inhibitors (etanercept or monoclonal anti-TNF antibodies) with the benefit of hindsight. However, abatacept and TNF inhibitors have demonstrated similar efficacy in patients with insufficient response to csDMARD (AMPLE trial).
Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors. Indeed, in real world study, compared to TNF inhibitors it seems that discontinuation of abatacept is more related to lack of effectiveness than safety issues.
This is the first study to propose a therapeutic sequential strategy with an induction therapy using a TNF inhibitor for 12 weeks to control inflammation followed by a cell-targeted biological DMARD targeting T cells (abatacept) in order to decrease auto-antibodies (rheumatoid factor and/or ACPA).
Presence of auto-antibodies (ACPA/RF) are predictive of better response to cell- targeted DMARDs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
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
- •Aged between 18 or above
- •Rheumatoid arthritis according to ACR-EULAR 2010 (American College of Rheumatology-European League Against Rheumatism)
- •ACPA positive
- •Under methotrexate or leflunomide treatment for at least 3 months
- •DAS28-CRP>3.2 under methotrexate or leflunomide calculated with CRP dated less than 7 days from baseline
- •Escape under synthetic background treatment defined by an elevation of C-reactive protein (CRP) (CRP> 5mg/L ) or Erythrocyte sedimentation rate (ESR) (for men: > age in years/2 ; for women: > age (+10) /2)) within the last 6 months before baseline
- •Targeted DMARDs (biological and targeted synthetic DMARDs) naïve
- •Indication for a TNF inhibitor
排除标准
- •Subject unable to read or/and write
- •Planned longer stay outside the region that prevents compliance with the visit plan
- •Subject unable to sign informed consent form
- •Subject not covered by public health insurance
- •Fibromyalgia
- •Contra-indications to TNF inhibitor and/or Abatacept
- •Absence of tuberculosis screening in the previous 3 months before baseline
- •Patient with untreated active tuberculosis
- •Patient who cannot be followed during 48 weeks
- •Drug addiction, addiction to alcohol
- •Protected populations according to the French Public Health Code Articles L1121-5,6,8 (For example, pregnant, parturient or lactating women, prisoners, adults under guardianship or otherwise unable to consent).
- •Women of child bearing potential, unless they are using an effective method of birth control
- •Patient under law protection
- •Prisoners
- •Subject who are in a dependency or employment with the sponsor or the investigator
- •Participation in another interventional clinical trial or administration of an investigational product within the last 4 weeks before the screening date
- •Subject with moderate to severe heart failure (class 3 or class 4 cardiac disease as defined by the New York Heart Association Functional Classification)
- •Patients had a history of chronic obstructive pulmonary disease (COPD) and heavy smoking
- •Patients had a planned surgical procedure at least 30 days before the screening day
- •Known allergy or intolerance to an anti-TNF therapy
- •Hypersensitivity to the Abatacept or to any of its excipients
- •Patient with untreated active hepatitis B
- •Patient vaccinated with a live vaccine within 30 days prior to screening
- •Patients with an Inflammatory Bowel Disease (IBD) (loss of chance if switching from an anti-TNF to abatacept)
研究组 & 干预措施
Experimental
All included patients will receive TNF inhibitors subcutaneous for 12 weeks. In the experimental arm, a therapeutic sequential strategy will be proposed from W12 visit.
At 12 weeks (W12), patients who have at least a moderate EULAR response (delta DAS28-CRP between W0 and W12>0.6 and DAS28-CRP≤5.1 at W12) will be randomized with a 1:1 ratio in the sequential strategy arm or the control arm.
In the sequential strategy (experimental) arm, the 88 randomized RA patients will be switched to abatacept subcutaneous for 36 weeks.
干预措施: Abatacept (W12-W48) (Drug)
Experimental
All included patients will receive TNF inhibitors subcutaneous for 12 weeks. In the experimental arm, a therapeutic sequential strategy will be proposed from W12 visit.
At 12 weeks (W12), patients who have at least a moderate EULAR response (delta DAS28-CRP between W0 and W12>0.6 and DAS28-CRP≤5.1 at W12) will be randomized with a 1:1 ratio in the sequential strategy arm or the control arm.
In the sequential strategy (experimental) arm, the 88 randomized RA patients will be switched to abatacept subcutaneous for 36 weeks.
干预措施: TNF Inhibitor (W0-W12) (Drug)
Control
All included patients will receive TNF inhibitors subcutaneous for 12 weeks. In the control group, the 88 randomized RA patients will be treated with TNF inhibitor subcutaneous for another 36 weeks (from W12 visit).
In case of insufficient response to a first TNF inhibitor at 24 or 36 weeks, a second TNF inhibitor will be proposed.
干预措施: TNF Inhibitor (W12-W48) (Drug)
Control
All included patients will receive TNF inhibitors subcutaneous for 12 weeks. In the control group, the 88 randomized RA patients will be treated with TNF inhibitor subcutaneous for another 36 weeks (from W12 visit).
In case of insufficient response to a first TNF inhibitor at 24 or 36 weeks, a second TNF inhibitor will be proposed.
干预措施: TNF Inhibitor (W0-W12) (Drug)
结局指标
主要结局
Percentage of patients in remission
时间窗: 36 weeks following randomization
Percentage of patients in remission defined by DAS28-CRP\<2.6 score during the 36 weeks following randomization. Disease Activity Score-28 with C-Reactive Protein (DAS28-CRP) describes severity of rheumatoid arthritis using clinical and laboratory data, specifically CRP. It includes 4 variables (number of painful joints out of 28 joints, number of swollen joints out of 28 joints, global assessment of the disease by the patient on a Visual Analogue Scale (VAS), markers of inflammation : CRP) A DAS28-CRP score \> 5.1 means high disease activity, DAS28-CRP \< or = 3.2 indicates low disease activity, a DAS28-CRP \< 2.6 indicates disease remission.
次要结局
- Percentage of patients in remission at 24 weeks after randomization (Boolean)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- percentage of patients in remission at 12 weeks after randomization (DAS28-ESR)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- percentage of patients in remission at 12 weeks after randomization (Boolean)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Percentage of patients in remission at 36 weeks after randomization (CDAI)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Percentage of patients in remission at 36 weeks after randomization (Boolean)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Percentage of patients with low disease activity at 12 weeks after randomization (CDAI)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Percentage of patients with low disease activity at 24 weeks after randomization (SDAI)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Percentage of patients with low disease activity at 36 weeks after randomization (DAS28-ESR)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Variation in autoantibody titers (RF)(between baseline and 48 weeks)
- percentage of patients in remission at 12 weeks after randomization (SDAI)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Percentage of patients with low disease activity at 12 weeks after randomization (DAS28-ESR)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Variations in the results of health assessment questionnaires administered to patients - SF-36(Between baseline and 48 weeks)
- Frequency of flares(between baseline and 48 weeks)
- Variation of medical costs on Quality Adjusted Life Year(between baseline and 48 weeks)
- percentage of patients in remission at 12 weeks after randomization (CDAI)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Percentage of patients in remission at 24 weeks after randomization (DAS28-ESR)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Percentage of patients in remission at24 weeks after randomization (CDAI)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Percentage of patients with low disease activity at 12 weeks after randomization (SDAI)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Percentage of patients with low disease activity at 24 weeks after randomization (DAS28-ESR)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Percentage of patients with low disease activity at 36 weeks after randomization (DAS28-CRP)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Percentage of patients with low disease activity at 36 weeks after randomization (SDAI)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Proportion of responder patients at 24 weeks after randomization(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Proportion of responder patients at 36 weeks after randomization(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Variations in the results of health assessment questionnaires administered to patients - HAQ-DI(Between baseline and 48 weeks)
- Variations in the results of health assessment questionnaires administered to patients - EQ5D(Between baseline and 48 weeks)
- Percentage of patients in remission at 24 weeks after randomization (SDAI)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Percentage of patients in remission at 36 weeks after randomization (SDAI)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Percentage of patients with low disease activity at 12 weeks after randomization (DAS28-CRP)(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Percentage of patients with low disease activity at 24 weeks after randomization (CDAI)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Proportion of responder patients at 12 weeks after randomization(At 24 weeks visit (corresponding to 12 weeks after randomization))
- Variation in autoantibody titers (ACPA)(between baseline and 48 weeks)
- Percentage of Serious Adverse Events Occurring(between baseline and 48 weeks)
- Percentage of patients in remission at 36 weeks after randomization (DAS28-ESR)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Percentage of patients with low disease activity at 24 weeks after randomization (DAS28-CRP)(At 36 weeks visit (corresponding to 24 weeks after randomization))
- Percentage of patients with low disease activity at 36 weeks after randomization (CDAI)(At 48 weeks visit (corresponding to 36 weeks after randomization))
- Cumulative doses of steroids consumed(between baseline and 48 weeks)
- Variation of Sharp's score(between baseline and 48 weeks)
- Percentage of patients remaining on abatacept(At 48 weeks visit (corresponding to 36 weeks after randomization))