Abatacept Versus Tocilizumab by Subcutaneous Administration for the Treatment of Rheumatoid Arthritis in TNF Alpha Inhibitor Inadequate Responder Patients: A Randomized, Open-labeled, Superiority Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 224
- 试验地点
- 26
- 主要终点
- Change from baseline to 6 months of the Clinical Disease Activity Index (CDAI)
研究概览
简要总结
Rheumatoid arthritis (RA) is the most common inflammatory rheumatoid disease in France, affecting 0.3% of the general population. Without effective treatment, the persistent inflammation causes invalidating pain and joint destruction, leading to major functional disability.
Biological agents have been proposed for patients with RA who have the most severe form of the disease and that are inadequate responder patients to conventional synthetic Disease-modifying antirheumatic drugs (csDMARDs). TNF inhibitors (TNFi) are historically proposed as the first biological DAMRD for inadequate responder patients to csDMARDs. A diverse therapeutic arsenal has become available in recent years with the development of non-anti-TNFα drugs whose mechanisms of action are different from the classical TNFi. This new biotherapy class includes tocilizumab and abatacept, two drugs recently available for subcutaneous administration that enables ambulatory care for patients who would otherwise require repeated in-hospital care.
The role of these new treatments in the therapeutic strategy has been emphasized by studies that demonstrated their efficacy as first-line treatments. However, in clinical practice, TNFi remain the most common first-line treatment for the majority of patients, non-anti-TNFα biological agents being reserved for inadequate responder patients.
In second line, several studies have investigated therapeutic strategies for inadequate responder patients to TNFi. Current data suggest that it could be wise to change the therapeutic target after failure of a first-line treatment with TNFi.
Data about the comparative efficacy of different biologics proposed after failure of a first-line treatment with TNFi are in progress. Meta-analyses from registries and academic trials conducted in France and The Netherlands suggest that non-anti-TNFα agents would have equivalent or superior efficacy compared with a second TNFi. This finding suggests clinicians to switch for an alternate therapeutic target after failure of a first-line TNFi.
Data comparing different non-anti-TNFα biologics in inadequate responder patients to TNFi are scare. Industrial trials have demonstrated sustained biological efficacy of non-anti-TNFα biologics after failure of a TNFi. However, there is very little solid data on the direct comparison between them.
详细描述
Rheumatoid arthritis (RA) is the most common inflammatory rheumatoid disease in France, affecting 0.3% of the general population. Without effective treatment, the persistent inflammation causes invalidating pain and joint destruction, leading to major functional disability as well as progressive structural damage resulting in major joint deformity.
Biologic agents are taking on an increasingly important role in the management of patients with an inadequate response to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs).
Biological DMARD (bDMARD) therapy consists in the use of monoclonal antibodies or fusion proteins, administered intravenously or subcutaneously. The earliest developed biologic agents have been available for more than 15 years. Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, was the first cytokine successfully targeted by a biologic agent for RA treatment. TNF inhibitors (TNFi) are historically proposed as the first bDAMRD for inadequate responder patients to csDMARDs. More recently non-anti-TNFα drugs have emerged, with other biological targets such as interleukin-6 receptor (tocilizumab) or B- (rituximab) and T-lymphocytes (abatacept) that are implicated in the inflammatory response. Initially administered strictly intravenously, these drugs are now available in formulations adapted to subcutaneous administration, which allows ambulatory care for patients who otherwise would require repeated in-hospital care.
National and international guidelines, especially those issued in 2013 by the European League Against Rheumatism (EULAR) and also in 2013 by the French Society of Rheumatology now recommend first-line treatment not only with TNFi but also with non-anti-TNFα biologic agents. However, in routine practice, most clinicians preferably prescribe TNFi for the first-line regimen, reserving non-anti-TNFα drugs to TNFi inadequate responder patients.
There is a growing body of research focusing on first-line biologic agents but there is very little solid data on the direct randomized comparison between them. Actually, all three of the published studies have systematically compared a non-anti-TNFα biomedication versus TNFi (one study with a blinded design and two open studies).
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
- 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
- •age >18 years
- •RA according to the ACR/EULAR 2010 criteria
- •inadequate response to a subcutaneously administered first-line TNFi defined as moderate to high disease activity (DAS28-ESR>3.2 and CDAI>10) after at least 3 months of treatment with a TNFi
- •beneficiary of the French National Health Insurance Fund
- •signed informed consent form
- •for women of childbearing age: effective contraception during treatment period with engagement to continue such contraception for 14 weeks after last administration
排除标准
- •counter-indication for one or other of the two drugs under study
- •prior failure of the TNFi due to intolerance
- •receiving ≥15 mg/day prednisone for more than 4 weeks
- •pregnant or nursing women
研究组 & 干预措施
Tocilizumab Prefilled Syringe
Market approval recommendations will be respected. Treatment should be started within 7 days of randomization.
The treatment protocol has no specific provision for treatment adaptation. Treatment will be managed in compliance with the marketing approval recommendations and drug labeling described below.
干预措施: Tocilizumab Prefilled Syringe (Drug)
Abatacept Prefilled Syringe
Market approval recommendations will be respected. Treatment should be started within 7 days of randomization.
The treatment protocol has no specific provision for treatment adaptation. Treatment will be managed in compliance with the marketing approval recommendations and drug labeling described below.
干预措施: Abatacept Prefilled Syringe (Drug)
结局指标
主要结局
Change from baseline to 6 months of the Clinical Disease Activity Index (CDAI)
时间窗: 6 months
The CDAI is a composite score combining clinical items only: Tender 28-joint count, Swollen 28-joint count, Patient Global Disease Activity (PGA), Evaluator"s Global Disease Activity (EGA). This score provides a numerical assessment reflecting disease activity independently of cute phase reactants. It will be measured at baseline and 6 months after inclusion
次要结局
- Change from baseline of the SDAI(3, 6 and 12 months)
- Proportion of patients having achieved low disease activity(3, 6 and 12 months)
- Rates of severe infection requiring in-hospital care(3, 6 and 12 months)
- Change from baseline in SF-36 quality-of-life scores(3, 6 and 12 months)
- Change from baseline in HAQ quality-of-life scores(3, 6 and 12 months)
- Change from baseline in Patient's Pain Assessment (PPA)(3, 6 and 12 months)
- Change from baseline in PGA visual analogic scale (VAS)(3, 6 and 12 months)
- Proportion of patients achieving ACR50 response(3, 6 and 12 months)
- Changes in Sharp score in hands, wrists and feet X-Ray(12 months)
- Change from baseline of the Clinical Disease Activity Index (CDAI)(3 and 12 months)
- Change from baseline in disease self assessment(3, 6 and 12 months)
- Proportion of patients in good or moderate EULAR therapeutic response(3, 6 and 12 months)
- Proportion of patients achieving ACR70 response(3, 6 and 12 months)
- Rates of patients presenting at least one adverse events(3, 6 and 12 months)
- Rates of treatment withdrawals for intolerance(3, 6 and 12 months)
- Rates of treatment withdrawals for intolerance requiring in-hospital care(3, 6 and 12 months)
- Rates of cardiovascular events(3, 6 and 12 months)
- Changes in joint US-Doppler synovitis and Doppler hyperemia grade of the hands and wrists(6 months)
- Change from baseline of the disease activity score(3, 6 and 12 months)
- Rates of perturbation of the lipid profile(3, 6 and 12 months)
- Rate of rescue medication use authorized by the protocol and treatment dose of patients achieving treatment persistence(3, 6 and 12 months)
- Change in vascular endothelial growth factor (VEGF) levels(At 3 and 6 months)
- Proportion of patients achieving ACR20 response(3, 6 and 12 months)
- Rates of treatment persistence(3, 6 and 12 months)
- Changes in immunoglobulin (quantitative assay)(6 months)
- Changes in interleukin-6 serum levels(6 months)