den Broeder Alfons A, Verhoef Lise M, Fransen Jaap, Thurlings Rogier, van den Bemt Bart J F, Teerenstra Steven, Boers Nadine, den Broeder Nathan, van den Hoogen Frank H J
Department of Rheumatology, Sint Maartenskliniek, PO Box 9011, 6500 GM, Nijmegen, The Netherlands.
Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
Trials. 2017 Aug 30;18(1):403. doi: 10.1186/s13063-017-2134-x.
A standard low-dosing schedule of rituximab (RTX; 2 × 500 mg or 1 × 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 × 1000 mg). Moreover, several small uncontrolled studies suggest that even lower-dosed treatment with RTX also leads to good treatment response in patients with RA. Retreatment with such an 'ultra-low' dose RTX in patients who responded well to RTX induction treatment is of special interest, as long-term use of lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. However, the effect of ultra-low dose of RTX has not been investigated using a controlled trial of proper design and dimensions.
METHODS/DESIGN: REDO is an investigator driven six-month pragmatic, double-blind, randomised controlled non-inferiority trial on the effects of ultra-low-dose RTX (1 × 500 or 1 × 200 mg) compared to standard low dose (1 × 1000 mg) in RA patients who are being retreated with RTX. A total of 140 RA patients, having reached low disease activity (DAS28CRP < 2.9) after the previous RTX infusion and DAS28CRP < 3.5 at moment of retreatment, are randomised in a ratio of 1:2:2 to 1 × 1000 mg, 1 × 500 mg or 1 × 200 mg. The primary objective is testing non-inferiority of the ultra-low-dose vs. standard low-dose RTX, by comparing mean change in DAS28CRP from baseline to six months to the non-inferiority margin of 0.6. Secondary outcomes over the same period are: function; quality of life; safety; costs; and pharmacokinetics and dynamics as process measures.
This study protocol shares characteristics of both early dose finding trials as well as late pragmatic clinical studies. Several choices in the design of this trial are described and possible consequences for RA treatment and expected biosimilar introduction are discussed.
Dutch Trial Register, NTR6117 . Registered on 15 November 2016 (CMO NL57520.091.16 , 8 November 2016).
利妥昔单抗（RTX）的标准低剂量给药方案（2×500mg或1×1000mg）对活动性类风湿关节炎（RA）的疗效与注册剂量（2×1000mg）相同。此外，几项小型非对照研究表明，RTX更低剂量的治疗在RA患者中也能带来良好的治疗反应。对于RTX诱导治疗反应良好的患者，使用这种“超低”剂量RTX进行再治疗具有特殊意义，因为长期使用较低剂量的RTX可能会缩短输注时间、降低不良事件风险并降低成本。然而，超低剂量RTX的效果尚未通过设计合理、规模适当的对照试验进行研究。
方法/设计：REDO是一项由研究者发起的为期六个月的实用、双盲、随机对照非劣效性试验，旨在比较超低剂量RTX（1×500mg或1×200mg）与标准低剂量（1×1000mg）对接受RTX再治疗的RA患者的影响。共有140名RA患者，在上次RTX输注后达到低疾病活动度（DAS28CRP＜2.9）且再治疗时DAS28CRP＜3.5，按1:2:2的比例随机分为1×1000mg、1×500mg或1×200mg组。主要目标是通过比较从基线到六个月时DAS28CRP的平均变化与非劣效界值0.6，来检验超低剂量RTX相对于标准低剂量RTX的非劣效性。同期的次要结局包括：功能；生活质量；安全性；成本；以及作为过程指标的药代动力学和药效学。
本研究方案兼具早期剂量探索试验和后期实用临床研究的特点。描述了本试验设计中的几个选择，并讨论了对RA治疗和预期生物类似药引入的可能影响。
荷兰试验注册库，NTR6117。于2016年11月15日注册（CMO NL57520.091.16，2016年11月8日）。
