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.

如今，北美的脑海绵体血管瘤只有不到200,000例症状性出血。具有症状性出血（现金）的海绵状血管瘤可能会重新出血，从而导致进一步的神经系统后遗症，因此是药物发育的主要重点。现金患者包括不同的基因型和病变位置，潜在地适应可变疾病的严重程度或前瞻性风险。近年来，候选疗法已经出现在机械研究中，并且已经证明有些人在临床前实验中可以防止病变的发展或出血，符合客观性和转化严格的最严格的NINDS标准。制药行业专门针对该疾病追求几个特工，目前处于各种发展阶段。正在探索当前临床用途的其他药物以证明概念效应，以重新利用该疾病。所有这些候选药物最终将需要在多站点临床试验中测试安全性和功效。在了解现金的流行病学和自然历史方面已经取得了很多进展，并提出了几种结果评估工具，包括与病变中生物学机制和临床活动相关的新型生物标志物。但是，从未在多个站点进行筛查，注册和风险分解现金案例的能力。生物标志物和其他结果工具尚未被评估为其相对敏感性和可靠性，也没有在多个地点进行协调。该项目聚集了领先的海绵状血管瘤研究人员，卓越的临床中心以及经验丰富的试验者，他们建议解决这些知识差距。 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.已经招募了高级统计学家，以根据新兴结果构建可行的多站点试验模型。该项目确保了试验假设中最严格的严格性，定义了现实的入学率和验证合格受试者的基线特征。它有望根据经验观察认可或拒绝结果工具和/或生物标志物，从而假设假定疗法对临床意义上有意义的影响。它将确定样本量，随访时间和测试试验假设所需的地点数量。咨询委员会将提供行业或学术界可行试验的指导和优先级。必然的目标是准备在这些疾病评估和随访方面具有专业知识的试点站点，并将在前瞻性临床试验中进行部署和模仿。其他目标是完成以现金启动实际试验所需的准备和监管里程碑，并组装将监督和管理这些前瞻性试验的研究核心团队。

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