背景:由于缺乏现实世界的转化知识,罕见疾病的临床试验设计常常变得复杂。纤维发育不全骨化性进行性(FOP)是一种极其罕见的遗传性疾病,其特征是骨骼畸形和进行性异位骨化(HO)。帕罗瓦汀是一种选择性视黄酸受体γ激动剂。这里,我们描述了FOP中palovarotene临床开发计划中的三项研究的方法,并讨论了可以为未来研究提供信息的见解,包括终点适用性和试验设计的影响。
方法:PVO-1A-001(NCT02322255)是一种前瞻性,协议指定,纵向FOP自然史研究(NHS)。PVO-1A-201(NCT02190747)是一个随机的,双盲,安慰剂对照II期试验;PVO-1A-202(NCT02279095)是其开放标签扩展.试验设计,包括治疗方案和影像学评估,根据研究进展中出现的数据,在PVO-1A-201和PVO-H1A-202之间以及PVO-1A-202内进行了细化。使用突然治疗方案(高剂量2/4周,随后是较低剂量4/≥8周;从发作开始),有或没有伴随慢性(每日)治疗。评估发作和疾病进展结果,包括发作期间和/或每年新HO的发生率和数量,以及其他临床,患者报告,和探索性结果。在所有研究中监测安全性。
结果:总体而言,114和58名FOP患者参加了NHS和II期试验,分别。NHS和PVO-1A-201的结果于2022年发布;PVO-1A-202的完整结果将在适当的时候公开。这些研究一起产生了关于终点适用性的重要信息,包括低剂量全身计算机断层扫描是每年评估HO进展的最佳成像模式,并且需要较长的研究持续时间来检测功能和患者报告结局的实质性变化.
结论:对于开发不足的罕见疾病,需要灵活的临床开发计划来克服所面临的许多挑战。这里,NHS提供了FOP进展的纵向评估,介入试验基于新出现的数据.描述的研究为III期MOVE试验(NCT03312634)中实施的设计和终点提供了信息,并为未来的临床试验开发奠定了基础。
背景:NCT02322255(注册23/12/2014);NCT02190747(注册15/07/2014);NCT02279095(注册30/10/2014)。
The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design.
PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history
study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II
trial; PVO-1A-202 (NCT02279095) was its open-label extension.
Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies.
Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long
study durations are needed to detect substantial changes in functional and patient-reported outcomes.
A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical
trial development.
NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).