PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
METHODS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
摘要：
背景：脑白质萎缩症“白质消失”（VWM）是一种孤儿疾病，具有神经系统衰退和高死亡率。目前,VWM没有批准的治疗方法，但是在理解病理生理学方面的进展导致了有希望的治疗方法的确定。几种研究性药物正在或即将进入临床试验阶段。VWM的临床试验提出了严峻的挑战，由于VWM具有发作性病程；疾病表型高度异质性，仅在早期发作时才可预测；并且研究能力受到患者人数少的限制。为了应对这些挑战并加速治疗，VWM联盟,一群具有VWM专业知识的学术临床医生，决定开发一个核心协议作为试验的模板，为了改进试验设计并促进控制数据的共享，同时允许对其他试验细节的灵活性。核心协议的总体目标是收集安全性，耐受性,以及用于治疗评估和上市许可的疗效数据。
方法：要开发核心协议，VWM财团指定了一个委员会，包括VWM联盟的临床医生成员，家庭和病人团体倡导者，和统计专家，临床试验设计和与工业联盟。我们起草了三个针对特定年龄的协议，分层为更同质的患者组，年龄≥18岁，≥6至<18年和<6年。我们选择双盲,随机化，≥6岁患者的安慰剂对照设计;<6岁患者的开放标签非随机自然史对照设计。协议描述了研究人群，年龄特定的终点，纳入和排除标准，学习时间表,样本量测定，和统计方面的考虑。
结论：核心方案提供了跨试验的共享一致性，启用共享控件池，并减少每次试验所需的患者总数，限制服用安慰剂的患者数量。所有VWM临床试验都建议遵守核心方案。其他试验组成部分，如主要结果的选择，药代动力学，药效学,和生物标志物是灵活的，不受核心协议的约束。每个赞助商都负责他们的审判执行，而控制数据由共享的研究组织处理。该核心协议有利于VWM中并行和连续试验的效率，我们希望加快VWM治疗的时间。
背景：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介入试验在临床试验登记册中进行登记.
方法：要开发核心协议，VWM财团指定了一个委员会，包括VWM联盟的临床医生成员，家庭和病人团体倡导者，和统计专家，临床试验设计和与工业联盟。我们起草了三个针对特定年龄的协议，分层为更同质的患者组，年龄≥18岁，≥6至<18年和<6年。我们选择双盲,随机化，≥6岁患者的安慰剂对照设计;<6岁患者的开放标签非随机自然史对照设计。协议描述了研究人群，年龄特定的终点，纳入和排除标准，学习时间表,样本量测定，和统计方面的考虑。
结论：核心方案提供了跨试验的共享一致性，启用共享控件池，并减少每次试验所需的患者总数，限制服用安慰剂的患者数量。所有VWM临床试验都建议遵守核心方案。其他试验组成部分，如主要结果的选择，药代动力学，药效学,和生物标志物是灵活的，不受核心协议的约束。每个赞助商都负责他们的审判执行，而控制数据由共享的研究组织处理。该核心协议有利于VWM中并行和连续试验的效率，我们希望加快VWM治疗的时间。
背景：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介入试验在临床试验登记册中进行登记.
