Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.
Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.
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DOI：
10.1186/s12883-023-03354-9
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发表时间：
2023-08-17
期刊：
影响因子：
2.6
通讯作者：
van der Knaap, Marjo S.
中科院分区：
文献类型：
--
作者：
Schoenmakers, Daphne H.;Leferink, Prisca S.;Vanderver, Adeline;Bonkowsky, Joshua L.;Kraegeloh-Mann, Ingeborg;Bernard, Genevieve;Bertini, Enrico;Fatemi, Ali;Fogel, Brent L.;Wolf, Nicole I.;Skwirut, Donna;Buck, Allyson;Holberg, Brett;Saunier-Vivar, Elise F.;Rauner, Robert;Dekker, Hanka;van Bokhoven, Pieter;Stellingwerff, Menno D.;Berkhof, Johannes;van der Knaap, Marjo S.
关键词：
脑白质营养不良“消失的白色物质”（VWM）是一种具有神经功能衰退和高死亡率的孤儿病。目前，VWM还没有批准的治疗方法，但在理解病理生理学方面的进展已经导致了有希望的治疗方法的确定。几种试验用药品正处于或即将进入临床试验阶段。VWM的临床试验带来了严峻的挑战，因为VWM具有发作性病程;疾病表型高度异质性，仅可预测早期发作;研究能力受到患者数量少的限制。为了应对这些挑战并加速治疗交付，VWM联盟（一组具有VWM专业知识的学术临床医生）决定制定一项核心方案，作为试验模板，以改善试验设计并促进对照数据的共享，同时允许其他试验细节的灵活性。核心方案的总体目标是收集安全性、耐受性和疗效数据，用于治疗评估和上市许可。为了制定核心方案，VWM联盟指定了一个委员会，成员包括VWM联盟的临床医生成员、家庭和患者团体倡导者以及统计学、临床试验设计和行业联盟方面的专家。我们起草了三个年龄特异性方案，将患者分为更同质的患者组，年龄≥ 18岁，≥ 6至< 18岁和< 6岁。对于年龄≥ 6岁的患者，我们选择双盲、随机、安慰剂对照设计;对于年龄< 6岁的患者，我们选择开放标签、非随机、自然病史对照设计。该方案描述了研究人群、年龄特异性终点、入选和排除标准、研究时间表、样本量确定和统计学考虑。核心方案提供了试验间的共享一致性，实现了共享对照池，并减少了每项试验所需的患者总数，限制了安慰剂组的患者数量。建议所有VWM临床试验遵循核心方案。其他试验组成部分，如主要结局、药代动力学、药效学和生物标志物的选择是灵活的，不受核心方案的限制。每个申办者负责其试验执行，而对照数据由共享研究组织处理。该核心方案有利于VWM平行和连续试验的效率，我们希望加快VWM治疗的可用性。NA.从科学和伦理的角度来看，强烈建议所有使用该核心方案的干预性试验在临床试验注册中心注册。
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.
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影响因子：
11.2
作者：
Hamilton, Eline M. C.;van der Lei, Hannemieke D. W.;van der Knaap, Marjo S.
通讯作者：
van der Knaap, Marjo S.
影响因子：
3
作者：
Feeny, D;Furlong, W;Boyle, M
通讯作者：
Boyle, M
影响因子：
3.7
作者：
Gaasterland, C. M. W.;Jansen-van der Weide, M. C.;van der Lee, J. H.
通讯作者：
van der Lee, J. H.
影响因子：
3.5
作者：
Herdman, M.;Gudex, C.;Lloyd, A.;Janssen, M. F.;Kind, P.;Parkin, D.;Bonsel, G.;Badia, X.
通讯作者：
Badia, X.
影响因子：
6.7
作者：
Barker, A. D.;Sigman, C. C.;Esserman, L. J.
通讯作者：
Esserman, L. J.