方案论文：一项多中心、双盲、随机、6 个月、安慰剂对照研究，随后进行 12 个月的开放标签扩展，以评估 Saracatinib 在纤维发育不良性骨化进展症（STOPFOP）中的安全性和疗效。
Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP).
机构信息
Department of Internal Medicine Section Endocrinology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
Tissue Function and Regeneration, Amsterdam Movement Sciences, Amsterdam, The Netherlands.
出版信息
BMC Musculoskelet Disord. 2022 Jun 1;23(1):519. doi: 10.1186/s12891-022-05471-x.
BACKGROUND
Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP.
METHODS
The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include F NaF PET activity and patient reported outcome measures.
DISCUSSION
Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.
TRIAL REGISTRATION
EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL .
CLINICALTRIALS
gov , NCT04307953 . Registered 13 March 2020.
背景
纤维性骨发育不良（FOP）是一种遗传、进行性和破坏性疾病，其特征为严重异位骨化（HO）、运动能力丧失和早逝。目前尚无美国食品和药物管理局（FDA）批准的药物。STOPFOP 团队发现 AZD0530（saracatinib）是一种有效的 ALK2/ACVR1-激酶抑制剂，ALK2/ACVR1-激酶是这种罕见骨病的致病基因。AZD0530 已被证明可预防 FOP 小鼠模型中的 HO 形成。STOPFOP 试验研究了 AZD0530 的重新定位，AZD0530 最初是为治疗卵巢癌而开发的，现用于治疗 FOP 患者。
方法
STOPFOP 试验是一项 2a 期研究。它是一项欧洲、多中心、6 个月的双盲随机对照试验，比较 AZD0530 与安慰剂，随后进行为期 12 个月的试验，比较开放标签延长 AZD0530 治疗与自然病史数据作为对照。纳入 20 例年龄在 18-65 岁之间、携带经典 FOP 突变（ALK2 R206H）的 FOP 患者。主要终点是 RCT 阶段通过低剂量全身计算机断层扫描（CT）测量的异位骨量的客观变化。次要终点包括 F NaF PET 活性和患者报告的结局测量。
讨论
在研究人群有限的罕见病中进行临床试验带来了独特的挑战。限制早期临床试验风险的理想解决方案是药物再定位——将现有临床药物用于新的疾病适应证。使用现有资产也可能使药物更顺利地过渡到临床实践中。如果研究结果为阳性，AZD0530 可能为 FOP 提供一种治疗方法，由于 AZD0530 已有 28 项涉及 600 多名患者的注册临床试验的现有安全性数据，因此该药物可迅速进入临床实践。
试验注册
EudraCT，2019-003324-20。2019 年 10 月 16 日注册，https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL。
临床试验
gov，NCT04307953。2020 年 3 月 13 日注册。
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