Siebert Stefan, Pratt Arthur G, Stocken Deborah D, Morton Miranda, Cranston Amy, Cole Michael, Frame Sheelagh, Buckley Christopher D, Ng Wan-Fai, Filer Andrew, McInnes Iain B, Isaacs John D
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow.
Translational and Experimental Medicine Institute, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne.
Medicine (Baltimore). 2020 Jun 26;99(26):e20458. doi: 10.1097/MD.0000000000020458.
Targeted biologic therapies demonstrate similar efficacies in rheumatoid arthritis despite distinct mechanisms of action. They also exhibit a ceiling effect, with 10% to 20% of patients achieving remission in clinical trials. None of these therapies target synovial fibroblasts, which drive and maintain synovitis. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase inhibitor that suppresses fibroblast proliferation, and is efficacious in preclinical arthritis models. We aim to determine the toxicity and preliminary efficacy of seliciclib in combination with biologic therapies, to inform its potential as an adjunctive therapy in rheumatoid arthritis.
TRAFIC is a non-commercial, multi-center, rolling phase Ib/IIa trial investigating the safety, tolerability, and efficacy of seliciclib in patients with moderate to severe rheumatoid arthritis receiving biologic therapies. All participants receive seliciclib with no control arm. The primary objective of part 1 (phase Ib) is to determine the maximum tolerated dose and safety of seliciclib over 4 weeks of dosing. Part 1 uses a restricted 1-stage Bayesian continual reassessment method based on a target dose-limiting toxicity probability of 35%. Part 2 (phase IIa) assesses the potential efficacy of seliciclib, and is designed as a single arm, single stage early phase trial based on a Fleming-A'Hern design using the maximum tolerated dose recommended from part 1. The primary response outcome after 12 weeks of therapy is a composite of clinical, histological and magnetic resonance imaging scores. Secondary outcomes include adverse events, pharmacodynamic and pharmacokinetic parameters, autoantibodies, and fatigue.
The study has been reviewed and approved by the North East - Tyne & Wear South Research Ethics Committee (reference 14/NE/1075) and the Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom. Results will be disseminated through publication in relevant peer-reviewed journals and presentation at national and international conferences.
ISRCTN, ISRCTN36667085. Registered on September 26, 2014; http://www.isrctn.com/ISRCTN36667085Current protocol version: Protocol version 11.0 (March 21, 2019).
尽管作用机制不同，但靶向生物疗法在类风湿性关节炎中显示出相似的疗效。它们还表现出一种天花板效应，在临床试验中，10%至20%的患者实现缓解。这些疗法均未针对驱动和维持滑膜炎的滑膜成纤维细胞。塞利西利布（R-罗哌卡因）是一种口服可用的细胞周期蛋白依赖性激酶抑制剂，可抑制成纤维细胞增殖，在临床前关节炎模型中有效。我们旨在确定塞利西利布与生物疗法联合使用的毒性和初步疗效，以评估其作为类风湿性关节炎辅助疗法的潜力。
TRAFIC是一项非商业性、多中心、滚动的Ib/IIa期试验，研究塞利西利布在接受生物疗法的中度至重度类风湿性关节炎患者中的安全性、耐受性和疗效。所有参与者均接受塞利西利布治疗，无对照组。第1部分（Ib期）的主要目标是确定塞利西利布在4周给药期内的最大耐受剂量和安全性。第1部分使用基于35%的目标剂量限制毒性概率的受限1阶段贝叶斯连续重新评估方法。第2部分（IIa期）评估塞利西利布的潜在疗效，设计为基于Fleming-A'Hern设计的单臂、单阶段早期试验，使用第1部分推荐的最大耐受剂量。治疗12周后的主要反应结果是临床、组织学和磁共振成像评分的综合结果。次要结果包括不良事件、药效学和药代动力学参数、自身抗体和疲劳。
该研究已获得东北-泰恩和威尔南部研究伦理委员会（参考编号14/NE/1075）和英国药品和医疗产品监管局（MHRA）的审查和批准。结果将通过在相关同行评审期刊上发表以及在国内和国际会议上展示进行传播。
ISRCTN，ISRCTN36667085。于2014年9月26日注册；http://www.isrctn.com/ISRCTN36667085当前方案版本：方案版本11.0（2019年3月21日）。
