Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC Location Vrije Universiteit, Amsterdam, The Netherlands.
Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Amsterdam, The Netherlands.
BMC Neurol. 2023 Aug 17;23(1):305. doi: 10.1186/s12883-023-03354-9.
The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization.
To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM Consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥ 18 years, ≥ 6 to < 18 years and < 6 years. We chose double-blind, randomized, placebo-controlled design for patients aged ≥ 6 years; and open-label non-randomized natural-history-controlled design for patients < 6 years. The protocol describes study populations, age-specific endpoints, inclusion and exclusion criteria, study schedules, sample size determinations, and statistical considerations.
The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM.
NA. From a scientific and ethical perspective, it is strongly recommended that all interventional trials using this core protocol are registered in a clinical trial register.
脑白质消融症（VWM）是一种神经退行性疾病，具有高死亡率。目前，VWM 没有批准的治疗方法，但对病理生理学的认识的进步已经导致了有前途的治疗方法的出现。一些正在研究的药物产品或已经进入临床试验阶段，或即将进入临床试验阶段。VWM 的临床试验面临着严峻的挑战，因为 VWM 具有发作性疾病过程；疾病表型高度异质，仅能预测早发性疾病；而且由于患者人数较少，研究能力有限。为了解决这些挑战并加速治疗的提供，VWM 联盟，一个由 VWM 领域的临床医生组成的学术团体，决定制定一个核心方案作为试验模板，以改善试验设计并促进对照数据的共享，同时允许在其他试验细节方面保持灵活性。核心方案的总体目标是收集安全性、耐受性和疗效数据，以评估治疗效果和获得药物营销许可。
为了制定核心方案，VWM 联盟指定了一个委员会，成员包括 VWM 联盟的临床医生、家庭和患者团体的倡导者以及统计学、临床试验设计和与行业结盟方面的专家。我们起草了三个年龄特异性方案，以将患者分为更同质的群体，分别是年龄≥18 岁、≥6 岁至<18 岁和<6 岁。我们为年龄≥6 岁的患者选择了双盲、随机、安慰剂对照设计；为年龄<6 岁的患者选择了开放标签、非随机、自然史对照设计。该方案描述了研究人群、年龄特异性终点、纳入和排除标准、研究时间表、样本量确定和统计考虑。
核心方案为各试验提供了一致性，使对照组可以共享，从而减少了每个试验所需的患者数量，限制了安慰剂组的患者数量。建议所有 VWM 临床试验都遵守核心方案。其他试验组成部分，如主要结局的选择、药代动力学、药效学和生物标志物，是灵活的，不受核心方案的限制。每个赞助商负责其试验的执行，而对照数据则由一个共享的研究组织处理。该核心方案有利于提高 VWM 平行和连续试验的效率，我们希望能加快 VWM 治疗方法的推出时间。
无。从科学和伦理的角度来看，强烈建议使用该核心方案的所有干预性试验都在临床试验注册库中注册。
