CASTBI Trial Planning Grant: Cyclosporine in Traumatic Brain Injury

CASTBI 试验计划资助：环孢素治疗创伤性脑损伤

基本信息

批准号：
7408299
负责人：
Alfred Byron Young
金额：
$ 16.22万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7408299
关键词：
Affect Animal Model Animals Applications Grants Attenuated Bolus Infusion Brain Brain Injuries Case Report Form Certification Cessation of life Clinical Data Clinical Trials Committee Members Complex Continuous Infusion Craniocerebral Trauma Cyclosporine Cyclosporins Data Disease Dose End Point Failure Glasgow Outcome Scale Grant Hospitalization Hour Human Injury Investigation Investigational New Drug Application Laboratories Manuals Molecular Morbidity - disease rate Multi-Institutional Clinical Trial Neuraxis Operative Surgical Procedures Outcome Outcome Assessment Patients Pattern Pharmaceutical Preparations Phase Phase III Clinical Trials Placebos Protocols documentation Recruitment Activity Research Personnel Site Statistical sensitivity System TBI Patients Testing Therapeutic Agents Training Translating Traumatic Brain Injury data management day design double-blind placebo controlled trial functional outcomes improved mitochondrial dysfunction mortality pre-clinical prevent protective effect success trend

项目摘要

DESCRIPTION (provided by applicant): Head injury is a complex disease involving two distinct patterns of injury, primary injury and secondary injury. There is significant morbidity and mortality associated with brain injury with about 50,000 deaths and 235,000 hospitalizations each year. In spite of major advancements in the understanding of the molecular mechanisms associated with secondary injury induced by traumatic brain injury (TBI), failure to discover a therapeutic agent to mitigate these affects in humans has been a persistent disappointment to researchers. Several agents have shown promise in the laboratory but have not translated into success beyond the animal model. When trials were comprehensively reviewed, inadequate statistical sensitivity, inadequate pre-clinical data and lack of drug disposition data documenting access to the brain were identified as important contributing factors. Cyclosporine A (CsA) has been shown in multiple animal models to be neuroprotective by attenuating mitochondrial dysfunction and preventing axonal destruction thus improving outcomes. Animal studies have shown that a continuous infusion preceded by a bolus dose given within 12 hours of injury maximizes CsA protective effects. In addition, our early clinical trial investigations of CsA in severe TBI have shown that the drug is safe, that higher continuous infusion doses are more effective, that CsA is detected in the central nervous system, and that CsA treated patients have a trend toward better outcomes. This planning grant proposal is necessary to complete the steps required for the initiation of a Phase III multi-center clinical trial in severe TBI patients evaluating CsA therapy (CASTBI). A double-blind, placebo controlled trial of 1218 patients investigating CsA will be designed to test the hypothesis that patients suffering from a severe TBI treated with a continuous infusion of CsA for three days will have an improved functional outcome compared to placebo. The primary endpoint assessment of functional outcome will be the Glasgow Outcome Scale at 6 months. This planning grant period will be used to: (1) identify executive committee and sub-committee members; (2) finalize study documents including protocol, manual of operations, case report forms, and investigational new drug application; (3) recruit study sites; (4) prepare and validate the data management systems; (5) develop training and certification materials for outcome assessments; (6) organize investigator's meeting; and (7) prepare Phase III CASTBI grant for submission.

描述（由申请人提供）：头部损伤是一种复杂的疾病，涉及两种不同的损伤模式：原发性损伤和继发性损伤。与脑损伤相关的发病率和死亡率很高，每年约有 50,000 人死亡和 235,000 人住院。尽管在理解与创伤性脑损伤（TBI）引起的继发性损伤相关的分子机制方面取得了重大进展，但未能找到减轻人类这些影响的治疗药物一直令研究人员感到失望。几种药物已在实验室中显示出前景，但尚未在动物模型之外取得成功。当对试验进行全面审查时，统计敏感性不足、临床前数据不足以及缺乏记录大脑通路的药物处置数据被认为是重要的影响因素。环孢素 A (CsA) 已在多种动物模型中被证明具有神经保护作用，可减轻线粒体功能障碍并防止轴突破坏，从而改善预后。动物研究表明，在受伤后 12 小时内连续输注并推注剂量可最大限度地提高 CsA 的保护作用。此外，我们对 CsA 治疗严重 TBI 的早期临床试验研究表明，该药物是安全的，更高的连续输注剂量更有效，在中枢神经系统中检测到 CsA，并且 CsA 治疗的患者有改善的趋势。结果。该规划拨款提案对于完成启动评估 CsA 治疗的严重 TBI 患者 III 期多中心临床试验 (CASTBI) 所需的步骤是必要的。一项针对 1218 名 CsA 患者的双盲、安慰剂对照试验旨在检验这样的假设：患有严重 TBI 的患者接受连续输注 CsA 三天后，与安慰剂相比，功能结果将得到改善。功能结果的主要终点评估将是 6 个月时的格拉斯哥结果量表。该规划拨款期将用于： (1) 确定执行委员会和小组委员会成员；（2）完成研究文件，包括方案、操作手册、病例报告表和新药试验申请；（三）招募学习点； (4) 准备并验证数据管理系统； (5) 制定成果评估的培训和认证材料；（六）组织研究者会议； (7) 准备第三期 CASTBI 拨款以供提交。