BEACH: Biomarker and Edema Attenuation in IntraCerebral Hemorrhage Phase 2a Trial

BEACH：脑出血 2a 期试验中的生物标志物和水肿减弱

• 批准号: 10349432
• 负责人: DANIEL F HANLEY
• 金额: $ 196.67万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349432
• 关键词: Acute; Acute Brain Injuries; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; American; Animal Model; Anti-Inflammatory Agents; Attenuated; Biochemical; Biological; Biological Markers; Brain; Brain Injuries; Central Nervous System Diseases; Cerebral Amyloid Angiopathy; Cerebral Edema; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Chronic; Clinical; Clinical Research; Clinical Trials; Cognitive deficits; Dementia; Development; Disease; Dose; Double-Blind Method; Drug Kinetics; Edema; Enrollment; Event; Exhibits; Exposure to; Formulation; Functional disorder; Gender; Hour; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intravenous; Investigation; Kinetics; Laboratories; Lead; Link; Measurement; Medical; Molecular; Monitor; Morbidity - disease rate; Nervous System Trauma; Neuraxis; Neuroglia; Neurologic; Neurological outcome; Neuronal Dysfunction; Neuronal Injury; Neurons; Outcome; Participant; Pathologic Processes; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Plasma; Preclinical Drug Development; Process; Property; Randomized; Risk; Safety; Serious Adverse Event; Symptoms; Synapses; Testing; Therapeutic; Time; Toxicology; Trauma; Traumatic Brain Injury; Vascular Diseases; acute care; age related; attenuation; base; central nervous system injury; cerebrovascular; clinical candidate; cognitive performance; cytokine; drug candidate; improved; mortality; neuroinflammation; neurological recovery; neurotoxic; new therapeutic target; novel; novel therapeutics; pre-clinical; preclinical efficacy; prospective; radiological imaging; recruit; response; response to injury; small molecule; success; therapeutic candidate; therapeutic target; therapeutically effective; volunteer

PROJECT SUMMARY Acute brain injuries resulting from cerebrovascular injury or trauma, such as intracerebral hemorrhage (ICH) or traumatic brain injury, are major medical problems that cause considerable mortality and morbidity in older Americans. Secondary neuroinflammatory events after ICH can further damage the brain and lead to increased risk of neurologic complications including Alzheimer’s disease (AD) and related dementias. Despite significant advances in the medical management of these patients, there is a clear and urgent need for interventions that improve neurologic recovery and outcomes. To address this unmet need, the clinical candidate, MW189, is a CNS-penetrant, small molecule that selectively attenuates injury- and disease-induced proinflammatory cytokine overproduction. Proinflammatory cytokine overproduction from abnormally activated glia contributes to cerebral edema, long-term neurological damage, and cognitive deficits following acute brain injuries. This mechanistic linkage of the acute cytokine surge to progression of injury, plus the attractive therapeutic time window of hours to days post-insult, provide a rational therapeutic target for intervention in the acute care setting. The Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) trial is a first-in-patient phase 2a, proof-of-concept study of MW189 in patients with ICH. The study aims are to: (1) Prepare, recruit, and conduct the phase 2a clinical study of MW189, and (2) Evaluate safety, pharmacokinetics (PK), inflammatory biomarkers, and clinical outcomes. This multicenter, prospective, randomized, double-blind controlled trial will enroll 120 non-traumatic ICH participants, with an anticipated average age in their mid-60s and substantial numbers of individuals with cerebral small vessel disease and cerebral amyloid angiopathy. Patients will be randomized to MW189 or placebo in a 1:1 ratio, with the first dose initiated within 24 hours of symptoms, then dosing every 12 hours for 5 days (or until discharge, whichever is first). Safety and tolerability of MW189 compared to placebo, and PK profiles of MW189 will be determined. Exploratory outcomes will include radiographic and clinical endpoints and measurement of plasma levels of brain-derived inflammatory and neuronal injury biomarkers to demonstrate engagement of pharmacological mechanism. Success with MW189 in ICH patients will further de-risk the compound for subsequent larger trials of acute CNS injury and/or to develop the drug for AD and other age-related dementias. The study will also generate important information about the utility of targeting the acute proinflammatory cytokine aspects of neuroinflammation in older Americans with vascular disease.

项目摘要 脑血管损伤或创伤导致的急性脑损伤，如脑出血（ICH）或 创伤性脑损伤是导致老年人相当大的死亡率和发病率的主要医学问题。 美国人脑出血后继发性神经炎症事件可进一步损害大脑， 神经系统并发症的风险，包括阿尔茨海默病（AD）和相关痴呆症。尽管取得了重大 随着对这些患者的医疗管理的进步，显然迫切需要采取干预措施， 改善神经恢复和结果。为了解决这一未满足的需求，临床候选药物MW 189是一种 CNS渗透剂，选择性减弱损伤和疾病诱导的促炎性的小分子 细胞因子过度产生。异常激活的神经胶质细胞产生的促炎细胞因子过量有助于 脑水肿、长期神经损伤和急性脑损伤后的认知缺陷。这 急性细胞因子激增与损伤进展的机制联系，加上有吸引力的治疗时间 损伤后数小时至数天的时间窗，为急性护理中的干预提供合理的治疗目标 设置.脑内出血的生物标志物和水肿减轻（海滩）试验是首次住院患者 在ICH患者中进行的MW 189的IIa期概念验证研究。本研究的目的是：（1）准备，招募， 并进行MW 189的2a期临床研究，以及（2）评价安全性、药代动力学（PK）， 炎症生物标志物和临床结果。这项多中心、前瞻性、随机、双盲 一项对照试验将招募120名非创伤性ICH参与者，预期平均年龄在60多岁 以及大量患有脑小血管病和脑淀粉样血管病的个体。 患者将以1：1的比例随机分配至MW 189或安慰剂组，首次给药在给药后24小时内开始。 症状，然后每12小时给药一次，持续5天（或直至出院，以先发生者为准）。安全性和耐受性 将测定MW 189与安慰剂相比的PK特征。探索性成果将 包括放射学和临床终点以及脑源性炎症血浆水平测量 和神经元损伤生物标志物来证明药理学机制的参与。成功与 在ICH患者中使用MW 189将进一步降低该化合物的风险，用于后续更大规模的急性CNS损伤试验 和/或开发用于AD和其他年龄相关性痴呆的药物。这项研究还将产生重要的 关于靶向神经炎症的急性促炎细胞因子方面的效用的信息 患有血管疾病的美国老年人