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: 10547796
• 负责人: DANIEL F HANLEY
• 金额: $ 194.1万
• 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/10547796
• 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; 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; Inpatients; Intervention; Intravenous; Investigation; Kinetics; Laboratories; Link; Measurement; Medical; Molecular; Monitor; Morbidity - disease rate; Nervous System Trauma; Neuroglia; Neurologic; Neurological outcome; Neuronal Dysfunction; Neuronal Injury; Neurons; Outcome; Participant; Pathologic Processes; Patients; Pharmaceutical Preparations; Phase; Placebos; Plasma; Preclinical Drug Development; Process; Production; Property; Randomized; Risk; Safety; Serious Adverse Event; Symptoms; Synapses; Testing; Therapeutic; Time; Toxicology; Trauma; Traumatic Brain Injury; Traumatic CNS injury; Vascular Diseases; acute care; age related; attenuation; central nervous system injury; cerebrovascular; clinical candidate; cognitive performance; cytokine; drug candidate; improved; mortality; neuroinflammation; neurological recovery; neurotoxic; new therapeutic target; novel; novel therapeutics; pharmacologic; pre-clinical; preclinical efficacy; prospective; radiological imaging; recruit; response; response to injury; safety assessment; small molecule; success; therapeutic candidate; therapeutic target; therapeutically effective; trial readiness; 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 脑血管损伤或创伤引起的急性脑损伤，例如脑内出血（ICH）或 创伤性脑损伤是主要的医疗问题，导致年龄较大的死亡率和发病率很大 美国人。 ICH之后的继发性神经炎症事件会进一步损害大脑并导致增加 神经系统并发症的风险，包括阿尔茨海默氏病（AD）和相关痴呆症。尽管很重要 这些患者的医疗管理进展，明确而迫切需要干预措施 改善神经系统恢复和结果。为了满足这种未满足的需求，临床候选人MW189是一个 中枢神经系统渗透剂，小分子，有选择地减弱损伤和疾病诱导的促炎性 细胞因子过量生产。绝对活化神经胶质的促炎细胞因子过量产生有助于 急性脑损伤后的脑水肿，长期神经损害和认知缺陷。这 急性细胞因子激增与损伤进展的机械连锁，加上有吸引力的治疗时间 灭亡后数小时到几天，为干预急性护理提供了合理的治疗目标 环境。脑出血（海滩）试验中的生物标志物和水肿衰减是一个患者 2A阶段，MW189在ICH患者中的概念验证研究。该研究的目的是：（1）准备，招募， 并进行MW189的2A期临床研究，（2）评估安全性，药代动力学（PK）， 炎症生物标志物和临床结果。这个多中心，前瞻性，随机，双盲 对照试验将招募120名非创伤ICH参与者，预计60年代中期的平均年龄 以及大量患有脑小血管疾病和脑淀粉样血管病的人。 患者将以1：1的比例随机分为MW189或安慰剂，首次剂量在24小时内开始 症状，然后每12小时服用5天（或直到排出，以先到者为准）。安全性和耐受性 与安慰剂相比，MW189的MW189和MW189的PK轮廓将被确定。探索结果将 包括射线照相和临床终点以及血浆脑源性炎症水平的测量 和神经元损伤生物标志物以证明药物机制的参与度。成功 ICH患者中的MW189将进一步降低危险的急性中枢神经系统损伤试验 和/或开发用于AD和其他与年龄相关的痴呆症的药物。该研究也将产生重要 有关靶向神经炎症急性促炎细胞因子方面的效用的信息 患有血管疾病的年长美国人。