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: 8967129
• 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/8967129
• 关键词: Acetylcholine; Activities of Daily Living; Acute; Affect; Afghanistan; Attention; Auditory; Beck depression inventory; 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; brain abnormalities; 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 group; 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）代表了与军事义务有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“签名伤害”。 TBI患者经常遇到多个认知问题，并且最常见的记忆力，注意力和执行功能的障碍。记忆和注意力的干扰尤其有问题，因为这些相对基本的认知功能的破坏可能会加剧或在执行功能，交流和其他更复杂的认知领域引起其他干扰。这些认知缺陷，尤其是在记忆受到影响时，会显着影响日常功能，并且是受影响个体挥之不去的残疾和困扰的根源。然而，尽管在TBI护理方面取得了进步，但治疗TBI滞后的认知缺陷，迫使临床医生在没有基于证据的科学数据的指导的情况下提供治疗。该建议旨在开始为临床医生提供基于证据的退伍军人药理管理指南，其受伤后TBI患有持续的认知缺陷。这一目标将通过在TBI后接受中度到严重的创伤后记忆障碍的退伍军人进行临床试验来实现。具体而言，该提案将评估该人群中Rivastigmine Transdrmal Patch（一种中间作用胆碱酯酶抑制剂）的疗效和安全性。 我们假设Rivastigmine透皮贴片将比安慰剂更有效，并且在接受TBI的退伍军人中中度至重度后，同样安全，并且在治疗中等至重度后的记忆障碍中，当在12周的终点。探索性假设指出，与安慰剂相比，Rivastigmine斑块将在治疗将在随机，安慰剂对照期继续进行26周的患者中更有效，同样安全。为了检验这些假设，我们将评估256名退伍军人的ivastigmine 9.5 mg/24小时（10cm2）透明剂贴片的效果和安全严重的记忆力障碍。记忆力障碍将定义为霍普金斯语言学习测试重新定义（HVLT-R）的总回忆指数（试验1-3），该指数比智能调整后的预期得分低25％，如WAIS-评估。 IV信息和词汇子测验。该研究包括一个筛查期，一周单盲，安慰剂磨合期和12周的双盲急性治疗阶段（I期）。受试者将以1：1的方式随机分配给Rivastigmine Transdermal Patch 9.5mg/24小时（10cm2）或匹配的安慰剂。在第一阶段，将有一个最初的4周滴定期，然后进行为期8周的延续阶段。在12周的急性治疗阶段之后，随机患者将在双盲阶段（II期）继续持续14周，或直到研究治疗期结束。疗效将通过比较每个治疗组的患者比例在第12周被归类为响应者的比例，这是由于基线的HVLT对HVLT的5分改进所定义的。功能能力的次要度量评估记忆改善对现实世界功能的影响，TBI影响的其他认知领域的衡量标准，即注意，工作和情节记忆和行政功能以及情绪和生活质量的衡量标准。研究结果将有助于为具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体系。