Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage

今天，北美只有不到20万例脑海绵状血管瘤患者出现了症状性出血。有症状出血的海绵状血管瘤可能会再次出血，导致进一步的神经后遗症，因此是药物开发的主要焦点。现金患者包括不同的基因类型和病变位置，可能预示着不同的疾病严重程度或潜在风险。近年来，从机制研究中出现了候选疗法，其中一些已经在满足最严格的NINDS客观性和翻译严谨性标准的临床前实验中被证明可以防止病变发展或出血。制药行业正在寻找几种专门治疗这种疾病的药物，目前正处于不同的开发阶段。目前临床使用的其他药物正在探索概念效应的证据，目的是重新用于这种疾病。所有这些候选药物最终都需要在多个地点的临床试验中进行安全性和有效性测试。在了解现金的流行病学和自然历史方面取得了很大进展，并提出了几种结果评估工具，包括与病变中的生物机制和临床活动有关的新生物标记物。然而，对现金案例进行筛选、登记和风险分层的能力从未在多个地点进行过前瞻性评估。生物标记物和其他结果工具尚未就其相对敏感性和可靠性进行评估，也未在多个地点进行协调。该项目汇集了领先的海绵状血管瘤研究人员、临床卓越中心和经验丰富的试验者，他们建议解决这些知识差距。他们的目标是评估(1)使用公共临床数据元素进行筛查、参保率、基线疾病分类和现金随访的可行性，(2)先进成像生物标记物在多个地点的可靠性，以及(3)在符合条件的病例的预期随访期间，复发出血的相对比率以及功能状态、生活质量和生物标记物测量的变化。已聘请高级统计师，根据新出现的结果，为多地点试验建立可行的模型。该项目确保了试验假设的最严格的严谨性，定义了现实的入学率，并验证了符合条件的受试者的基线特征。它承诺支持或拒绝基于经验性观察的结果工具和/或生物标记物，假设推定治疗的临床意义影响。它将确定样本大小、跟踪调查的长度以及检验试验假设所需的地点数量。咨询委员会将为工业界或学术界的可行试验提供指导和确定优先次序。其必然的目标是准备好在疾病评估和后续治疗的这些方面具有专业知识的试点站点，以便在未来的临床试验中部署和模拟。其他目标是完成以现金形式启动实际试验所需的准备和监管里程碑，并组建负责监督和管理这些预期试验的研究核心团队。

There are fewer than 200,000 cases of brain cavernous angiomas in North America today who have suffered a symptomatic hemorrhage. Cavernous angiomas with symptomatic hemorrhage (CASH) are likely to re-bleed, causing further neurologic sequelae, and are thus the primary focus of drug development. CASH patients include different genotypes and lesion locations, potentially portending variable disease severity or prospective risk. Candidate therapeutics have emerged in recent years from mechanistic studies, and some were already shown to prevent lesion development or hemorrhage in preclinical experiments meeting the most stringent NINDS criteria of objectivity and translational rigor. Several agents are being pursued by the pharmaceutical industry specifically for this disease, and are currently at various stages of development. Other drugs in current clinical use are being explored for proof of concept effect, with the aim of repurposing for this disease. All these candidate agents will ultimately require testing of safety and efficacy in multi-site clinical trials. Much progress has been made in understanding the epidemiology and natural history of CASH, and several outcome assessment tools have been proposed, including novel biomarkers linked to the biologic mechanisms and clinical activity in the lesions. Yet, the ability to screen, enroll and risk-stratify CASH cases has never been assessed prospectively at multiple sites. Biomarkers and other outcomes instruments have not been evaluated for their relative sensitivity and reliability, nor have they been harmonized at multiple sites. This project assembles leading cavernous angioma researchers, clinical centers of excellence, and experienced trialists who propose to address these knowledge gaps. They aim to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization and follow-up of CASH using common clinical data elements, (2) the reliability of advanced imaging biomarkers at multiple sites, and (3) the relative rates of recurrent hemorrhage and change in functional status, quality of life and biomarker measurements during prospective follow-up of eligible cases. Senior statisticians have been recruited to construct workable models for multi-site trials based on emerging results. The project insures the most stringent rigor in trial assumptions, defining realistic enrollment rates and validating baseline features of eligible subjects. It promises to endorse or reject outcome instruments and/or biomarkers based on empiric observations, hypothesizing a clinically meaningful impact of putative therapies. And it will determine the sample size, length of follow-up, and number of sites needed to test trial hypotheses. An Advisory Committee will provide guidance and prioritization of workable trials by industry or academia. Corollary goals are to ready pilot sites with expertise in these facets of disease evaluation and follow-up, to be deployed and emulated in prospective clinical trials. Other goals are to complete preparatory and regulatory milestones needed for launching actual trials in CASH, and to assemble research core teams who would oversee and manage these prospective trials.