Rivastigmine Patch in Veterans with Cognitive Impairment Following TBI

利斯的明贴剂用于治疗 TBI 后出现认知障碍的退伍军人

• 批准号: 8793723
• 负责人: OLGA BRAWMAN-MINTZER
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793723
• 关键词: Acetylcholine; Activities of Daily Living; Acute; Affect; Afghanistan; Attention; Auditory; Beck depression inventory; Brain; California; Caring; Cause of Death; Chemicals; Cholinesterase Inhibitors; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Communication; Complex; Conflict (Psychology); Craniocerebral Trauma; Critical Care; Data; Digit structure; Discrimination; Distress; Double-Blind Method; Enrollment; Episodic memory; Equipment and supply inventories; Experimental Designs; Family; Frequencies; Functional disorder; Future; Health; Hour; Image; Impaired cognition; Impairment; Individual; Injury; Intelligence; Iraq; Laboratories; Learning; Length; Letters; Light; Measures; Medical; Memory; Memory impairment; Military Personnel; Moods; Neurobehavioral Manifestations; Oral; Patients; Performance; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Placebo Control; Placebos; Population; Population Research; Prevalence; Process; Quality of life; Questionnaires; Randomized; Rehabilitation therapy; Research; Risk; Running; Safety; Severities; Short-Term Memory; Single-Blind Study; Site; Source; System; Testing; Titrations; Trail Making Test; Trauma; Traumatic Brain Injury; United States; Universities; Verbal Learning; Veterans; Visuospatial; Vocabulary; Word Association Tests; base; biological research; cholinergic; cognitive function; comparative efficacy; design; disability; evidence base; evidence based guidelines; executive function; experience; health administration; impression; improved; indexing; meetings; mild traumatic brain injury; mortality; neurobehavioral; patient population; placebo controlled study; rivastigmine; satisfaction; screening; skills; treatment center; treatment duration; treatment effect; treatment response; young adult

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.

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“标志性伤害”。 TBI 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。记忆和注意力障碍尤其成问题，因为这些相对基本的认知功能的破坏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，会显着影响日常功能，并且是受影响个体长期残疾和痛苦的根源。然而，尽管 TBI 护理取得了进步，但 TBI 认知缺陷的治疗仍然滞后，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。该提案旨在开始为临床医生提供循证指南，用于对受伤后患有持续性认知缺陷的 TBI 退伍军人进行药物治疗。这一目标将通过对遭受 TBI 后患有中度至重度创伤后记忆障碍的退伍军人进行临床试验来实现。具体来说，该提案将评估卡巴拉汀透皮贴剂（一种中效胆碱酯酶抑制剂）在该人群中的功效和安全性。 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 周终点进行测试时，卡巴拉汀透皮贴剂在治疗患有 TBI 的退伍军人中度至重度创伤后记忆障碍方面比安慰剂更有效，并且同样安全。探索性假设指出，与安慰剂相比，卡巴拉汀贴剂在治疗将继续进行总共 26 周的随机、安慰剂对照阶段的患者时将更有效且同样安全。为了检验这些假设，我们将评估卡巴拉汀 9.5 毫克/24 小时 (10cm2) 透皮贴剂在 256 名退伍军人中的效果和安全性，这些退伍军人符合或超过闭合性、非穿透性、轻度 TBI 的标准，并且在基线时存在中度至重度记忆障碍。记忆障碍将被定义为霍普金斯语言学习测试修订版 (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分数至少低 25%。该研究由筛选期、为期一周的单盲安慰剂磨合期和为期12周的双盲急性治疗期（第一期）组成。受试者将按 1:1 的比例随机分配至卡巴拉汀透皮贴剂 9.5 毫克/24 小时 (10cm2) 或匹配的安慰剂。在第一阶段，将有一个初始的 4 周滴定期，随后是 8 周的持续阶段。在 12 周的急性治疗阶段之后，随机分组的患者将继续进入双盲阶段（第二阶段）另外 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比例来确定，应答者的定义是 HVLT 较基线提高 5 点。将检查功能能力的次要测量，评估记忆改善对现实世界功能的影响，TBI 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。研究结果将为建立患有创伤后记忆障碍和其他认知缺陷的退伍军人的护理标准提供所需的证据。