Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage

伴有症状性出血的海绵状血管瘤的试验准备情况

• 批准号: 10312762
• 负责人: ISSAM A AWAD
• 金额: $ 71.82万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312762
• 关键词: Academia; Address; Advisory Committees; Assessment tool; Biological; Biological Markers; Blood Vessels; Brain; Brain Stem; Cavernous Hemangioma; Characteristics; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Communities; Data; Data Coordinating Center; Data Element; Databases; Development; Diagnostic; Disease; Drug Industry; Enrollment; Epidemiology; Equipoise; Evaluation; Event; Excision; Gender; Genotype; Goals; Hemangioma; Hemorrhage; Imaging Techniques; Industry; Inflammatory Response; Iron; Knowledge; Length; Lesion; Link; Location; Magnetic Resonance Imaging; Measurement; Measures; Modeling; Monitor; Morbidity - disease rate; Multi-Institutional Clinical Trial; National Institute of Neurological Disorders and Stroke; Natural History; Neurologic; North America; Operative Surgical Procedures; Outcome; Outcome Assessment; Outcome Measure; Patient advocacy; Patients; Perfusion; Pharmaceutical Preparations; Predisposition; Protocols documentation; Quality of life; Recurrence; Reproducibility; Research; Research Personnel; Resected; Risk; Sample Size; Severity of illness; Signal Transduction; Site; Stratification; Subgroup; Suggestion; Support Groups; Testing; Time; Vascular Permeabilities; adjudicate; base; clinical center; cohort; contrast enhanced; cost; data harmonization; disability; drug candidate; drug development; evidence based guidelines; experience; experimental study; feasibility testing; follow-up; functional status; gene function; imaging biomarker; instrument; interest; magnetic resonance imaging biomarker; meetings; multi-site trial; novel; novel marker; novel therapeutics; pre-clinical; prevent; prospective; recruit; research clinical testing; response; risk stratification; safety testing; screening; therapeutic candidate; therapeutic target; trial readiness

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.

今天在北美有不到200，000例脑海绵状血管瘤患者患有症状性出血。海绵状血管瘤伴症状性出血（CASH）可能会再出血，导致进一步的神经系统后遗症，因此是药物开发的主要焦点。CASH患者包括不同的基因型和病变部位，可能预示着可变的疾病严重程度或预期风险。近年来，从机制研究中出现了候选治疗药物，其中一些已经在临床前实验中显示出预防病变发展或出血，符合最严格的NINDS客观性和翻译严谨性标准。制药业正在研究几种专门用于这种疾病的药物，目前正处于不同的开发阶段。目前正在探索临床使用的其他药物，以证明概念效应，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中心临床试验中进行安全性和有效性测试。在了解CASH的流行病学和自然史方面取得了很大进展，并提出了几种结局评估工具，包括与病变生物学机制和临床活动相关的新型生物标志物。然而，筛选、招募和风险分层CASH病例的能力从未在多个研究中心进行过前瞻性评估。生物标志物和其他结局工具的相对敏感性和可靠性尚未得到评价，也没有在多个研究中心进行协调。该项目汇集了领先的海绵状血管瘤研究人员，卓越的临床中心和经验丰富的试验者，他们提出解决这些知识差距。他们旨在评估（1）使用常见临床数据元素进行CASH筛选、入组率、基线疾病分类和随访的可行性，（2）多个研究中心高级成像生物标志物的可靠性，以及（3）在合格病例的前瞻性随访期间复发性出血的相对发生率和功能状态、生活质量和生物标志物测量值的变化。已聘请高级统计学家根据新出现的结果为多中心试验构建可行的模型。该项目确保了最严格的试验假设，定义了现实的入组率，并验证了合格受试者的基线特征。它承诺支持或拒绝基于经验观察的结果工具和/或生物标志物，假设假定治疗的临床意义的影响。它还将决定样本量、随访时间和检验试验假设所需的研究中心数量。一个咨询委员会将为工业界或学术界可行的试验提供指导和优先次序。必然的目标是准备试点网站在这些方面的疾病评估和随访的专业知识，部署和模仿前瞻性临床试验。其他目标是完成启动CASH实际试验所需的准备和监管里程碑，并组建研究核心团队，监督和管理这些前瞻性试验。

项目成果

Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project.

• DOI: 10.1161/strokeaha.120.033487
• 发表时间: 2021-12
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Kim H;Flemming KD;Nelson JA;Lui A;Majersik JJ;Cruz MD;Zabramski J;Trevizo O;Lanzino G;Zafar A;Torbey M;Mabray MC;Robinson M;Narvid J;Lupo J;Thompson RE;Hanley DF Jr;McBee N;Treine K;Ostapkovich N;Stadnik A;Piedad K;Hobson N;Carroll T;Shkoukani A;Carrión-Penagos J;Mendoza-Puccini C;Koenig JI;Awad I
• 通讯作者: Awad I

Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains.

• DOI: 10.1007/s00401-022-02533-1
• 发表时间: 2023-03
• 期刊: Acta neuropathologica
• 影响因子: 12.7