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: 10095268
• 负责人: DANIEL F HANLEY
• 金额: $ 207.82万
• 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/10095268
• 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; Diagnostic radiologic examination; 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; 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.

项目总结 脑血管损伤或创伤引起的急性脑损伤，如脑出血或 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疗问题 美国人。脑出血后继发性神经炎性事件可进一步损害大脑并导致 神经并发症的风险，包括阿尔茨海默病(AD)和相关的痴呆。尽管意义重大 在这些患者的医疗管理方面取得了进展，显然迫切需要采取干预措施 改善神经功能恢复和预后。为了解决这一未得到满足的需求，临床候选药物MW189是一种 中枢神经系统穿透性小分子，选择性减弱损伤和疾病诱导的促炎作用 细胞因子过量生产。异常激活的胶质细胞过度产生促炎细胞因子有助于 急性脑损伤后的脑水肿、长期神经损伤和认知障碍。这 急性细胞因子激增与损伤进展的机械联系，加上诱人的治疗时间 伤后数小时至数天窗口，为急性护理干预提供合理的治疗靶点 布景。脑出血的生物标记物和水肿消退(BASTCH)试验是首例住院患者 阶段2a，MW189在脑出血患者中的概念验证研究。本研究的目的是：(1)准备、招募、 并进行MW189的2a期临床研究，以及(2)评价安全性、药代动力学(PK)、 炎性生物标志物和临床结果。这种多中心、前瞻性、随机性、双盲 对照试验将招募120名非创伤性脑出血参与者，预计平均年龄在60岁左右 以及相当数量的脑部小血管疾病和脑淀粉样血管病患者。 患者将按1：1的比例随机服用MW189或安慰剂，第一剂在24小时内开始注射 症状，然后每12小时给药一次，连续5天(或直到出院，以最先为准)。安全性和耐受性 MW189与安慰剂的比较，以及MW189的PK曲线将被确定。探索性成果将 包括放射和临床终点以及脑源性炎症血浆水平的测量 以及神经元损伤的生物标志物，以论证参与的药理机制。在以下方面成功 用于脑出血患者的MW189将进一步降低该化合物在随后的更大规模急性中枢神经系统损伤试验中的风险 和/或开发治疗阿尔茨海默病和其他与年龄相关的痴呆的药物。这项研究还将产生重要的 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。