Rivastigmine Patch in Veterans with Cognitive Impairment Following TBI

描述（由申请人提供）： 创伤性脑损伤（TBI）是与军事任务相关的最重要的健康风险之一;迅速成为伊拉克和阿富汗冲突的“标志性损伤”。TBI患者通常会遇到多种认知问题，其中最常见的是记忆，注意力和执行功能的障碍。记忆和注意力的干扰尤其成问题，因为这些相对基本的认知功能的干扰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干扰。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，并且是受影响个体的挥之不去的残疾和痛苦的来源。然而，尽管在TBI护理方面取得了进展，但TBI中认知缺陷的治疗仍然落后，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。该提案旨在开始为临床医生提供基于证据的指南，用于创伤后患有持续认知缺陷的退伍军人TBI的药理学管理。这一目标将通过在TBI后患有中度至重度创伤后记忆障碍的退伍军人中进行临床试验来实现。具体而言，本提案将评价卡巴拉汀透皮贴剂（一种中效胆碱酯酶抑制剂）在该人群中的疗效和安全性。 我们假设，在一项随机、多中心、平行设计、安慰剂对照试验中，在12周终点时，rivastigmine透皮贴剂在治疗TBI退伍军人中中度至重度创伤后记忆障碍方面比安慰剂更有效，且安全性与安慰剂相同。探索性假设指出，与安慰剂相比，rivastigmine贴剂在治疗将继续随机化、安慰剂对照阶段共26周的患者时更有效且同样安全。为了检验这些假设，我们将在256名符合或超过闭合性、非穿透性、轻度TBI标准且基线时存在中度至重度记忆障碍的退伍军人中评价rivastigmine 9.5 mg/24小时（10 cm 2）透皮贴剂的疗效和安全性。记忆障碍将定义为霍普金斯言语学习测试修订版（HVLT-R）的总回忆指数（试验1-3）比WAIS-IV信息和词汇子测试评估的智力调整预期评分低至少25%。本研究包括筛选期、1周单盲安慰剂导入期和12周双盲急性治疗期（I期）。受试者将以1：1的比例随机接受利斯的明透皮贴剂9.5 mg/24小时（10 cm 2）或匹配安慰剂治疗。在I期，将有一个最初的4周滴定期，随后是一个8周的继续期。12周急性治疗期后，随机化患者将继续进入双盲期（II期）额外14周或直至研究治疗期结束。将通过比较每个治疗组中在第12周被分类为应答者（定义为HVLT较基线改善5分）的患者比例来确定疗效。将检查评估记忆改善对真实的世界功能的影响的功能能力的次要测量，TBI中受影响的认知领域的其他测量，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.