Rivastigmine Patch in Veterans with Cognitive Impairment Following TBI

描述(由申请人提供)： 创伤性脑损伤(TBI)是与军事任务有关的最重大的健康风险之一；迅速成为伊拉克和阿富汗冲突的“标志性损伤”。脑外伤患者经常经历多种认知问题，其中最常见的是记忆、注意力和执行功能障碍。记忆和注意力的障碍尤其有问题，因为这些相对基本的认知功能的中断可能会加剧或导致执行功能、沟通和其他更复杂的认知领域的额外障碍。这些认知缺陷，特别是当记忆受到影响时，会显著影响日常功能，是受影响个人挥之不去的残疾和痛苦的来源。然而，尽管在脑外伤治疗方面取得了进展，但脑外伤认知障碍的治疗仍然滞后，迫使临床医生在没有循证科学数据指导的情况下提供治疗。这项建议旨在开始为临床医生提供基于证据的指南，用于对患有创伤后持续认知缺陷的退伍军人进行药物治疗。这一目标将通过对患有脑外伤后中度至严重创伤后记忆障碍的退伍军人进行临床试验来实现。具体地说，这项建议将评估利瓦斯明透皮贴剂的有效性和安全性，利瓦斯明是一种中间作用的胆碱酯酶抑制剂，在该人群中。我们假设，在为期12周的随机、多点、平行设计、安慰剂对照试验中，利瓦斯明透皮贴片在治疗患有脑外伤的退伍军人的中到重度创伤后记忆障碍方面将比安慰剂更有效，也与安慰剂同样安全。这一探索性假说指出，与安慰剂相比，利瓦斯明贴片在治疗将在随机、安慰剂对照阶段持续总共26周的患者时将更有效，同样安全。为了验证这些假设，我们将评估利凡斯明9.5 mg/24小时(10cm2)透皮贴片在256名退伍军人中的疗效和安全性，这些退伍军人符合或超过闭合性、非穿透性、轻度脑外伤的标准，且基线时存在中度至严重的记忆障碍。记忆障碍将被定义为霍普金斯语言学习测验修订版(HVLT-R)的总回忆指数(试验1-3)，该指数至少比WAIS-IV信息和词汇分测验评估的智力调整后的预期分数低25%。该研究包括筛查期、为期一周的单盲、安慰剂磨合阶段和为期12周的双盲急性治疗阶段(第一阶段)。受试者将以1：1的比例随机接受利凡斯明透皮贴片9.5 mg/24小时(10cm2)或与之匹配的安慰剂。在第一阶段，最初将有4周的滴定期，然后是8周的持续阶段。在为期12周的急性治疗阶段之后，随机患者将继续进入双盲阶段(第二阶段)，再持续14周或直到研究治疗期结束。疗效将通过比较每个治疗组中在第12周被归类为应答者的患者的比例来确定，根据HVLT较基线改善5点来定义。评估记忆改善对现实世界功能的影响的功能能力的次要测量，将检查受脑损伤影响的认知域的其他测量，即注意力、工作和情景记忆和执行功能，以及情绪和生活质量的测量。研究结果将有助于为患有创伤后记忆障碍和其他认知缺陷的退伍军人建立护理标准所需的大量证据。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) represents one of the most significant health risks related to military duty; rapidly becoming the "signature injury" of the Iraq and Afghanistan conflicts. TBI patients often experience multiple cognitive problems, with disturbances in memory, attention, and executive functions among the most common. Disturbances in memory as well as attention are particularly problematic, as disruption of these relatively basic cognitive functions may exacerbate or cause additional disturbances in executive function, communication and other more complex cognitive domains. These cognitive deficits, especially when memory is affected, significantly impact day-to-day functioning and are the source of lingering disability and distress to the affected individuals. However, despite advances made in TBI care, treatment of cognitive deficits in TBI lag behind, forcing clinicians to provide treatment without the guidance of evidence-based scientific data. This proposal aims to begin the process of providing clinicians with evidence-based guidelines for pharmacological management of Veterans with TBI suffering from persistent cognitive deficits following their injuries. This aim will be accomplished by conducting a clinical trial in Veterans suffering from moderate to severe posttraumatic memory impairment following TBI. Specifically, this proposal will evaluate the efficacy and safety of rivastigmine transdermal patch, an intermediate-acting cholinesterase inhibitor, in this population. We hypothesize that rivastigmine transdermal patch will be more effective than, and equally safe as, placebo in the treatment of moderate to severe posttraumatic memory impairment in Veterans with TBI when tested in a randomized, multi-site, parallel design, placebo-controlled trial, at a 12-week endpoint. The exploratory hypothesis states that compared to placebo, rivastigmine patch will be more effective and equally safe in the treatment of patients who will continue in a randomized, placebo-controlled phase for a total of 26 weeks. To test these hypotheses we will evaluate the effect and the safety of rivastigmine 9.5 mg/24 hours (10cm2) transdermal patch in 256 Veterans who meet or exceed the criteria for closed, non-penetrating, mild TBI and who present at baseline with moderate to severe memory impairment. Memory impairment will be defined as a Total Recall index (Trials 1-3) of the Hopkins Verbal Learning Test-Revised (HVLT-R) that is at least 25% lower than the intelligence-adjusted expected score, as assessed by the WAIS-IV Information and Vocabulary subtests. The study consists of a screening period, one-week single-blind, placebo run-in phase, and a 12-week double-blind acute treatment phase (Phase I). Subjects will be randomized 1:1 to rivastigmine transdermal patch 9.5mg/24 hours (10cm2) or matching placebo. During Phase I, there will be an initial 4- week titration period followed by an 8-week continuation phase. Following the 12-week acute treatment phase, randomized patients will continue in the double-blind phase (Phase II) for additional 14 weeks or until study treatment period ends. Efficacy will be determined by comparing the proportion of patients in each treatment group who are classified as responders at week 12 as defined by a 5-point improvement on the HVLT from baseline. Secondary measure of functional capacity assessing the impact of memory improvement on real- world functioning, other measures of cognitive domains affected in TBI, namely attention, working and episodic memory and executive functions, as well as measures of mood and quality of life will be examined. Study findings will contribute to the body of evidence needed to establish standards of care for Veterans with posttraumatic memory impairment and other cognitive deficits.