Supplementation with Amino Acid Rehabilitative Therapy in TBI (SmART-TBI): A Randomized Placebo-Controlled Trial to Improve Sleep

TBI 中补充氨基酸康复疗法 (SmART-TBI)：一项改善睡眠的随机安慰剂对照试验

• 批准号: 10427255
• 负责人: Miranda M Lim
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427255
• 关键词: Address; Adherence; Affect; Amino Acids; Brain; Branched-Chain Amino Acids; Client satisfaction; Clinical Trials; Cognition; Cognitive; Data; Diagnosis; Dietary Supplementation; Dose; Double-Blind Method; Employment; Equilibrium; Failure; Functional disorder; Future; Glutamates; Goals; Human; Impaired cognition; Impairment; Individual; Intervention; Isoleucine; Leucine; Life; Maps; Measures; Memory; Methodological Studies; Methods; Mus; Neurotransmitters; Oral; Participant; Patient Self-Report; Patients; Pharmacology; Placebo Control; Placebos; Polysomnography; Quality of life; Randomized; Randomized, Controlled Trials; Rehabilitation Outcome; Rehabilitation therapy; Research; Research Design; Route; Safety; Sampling; Serum; Sleep; Sleep Disorders; Sleep disturbances; Structure; Supplementation; Symptoms; Syndrome; Testing; Valine; Veterans; Work; acceptability and feasibility; actigraphy; amino acid therapy; base; brain dysfunction; cognitive function; design; diaries; dietary; dietary supplements; efficacy outcomes; efficacy study; efficacy trial; feasibility testing; functional outcomes; improved; mild traumatic brain injury; novel therapeutics; placebo controlled study; placebo group; poor sleep; pre-clinical; prevent; randomized placebo controlled trial; recruit; response; restoration; side effect; sleep quality; treatment group

Mild traumatic brain injury (mTBI) has impacted over 60% of all OEF/OIF Veterans over the past decade, and over 20% of these Veterans carry a diagnosis of postconcussion syndrome. Arguably the most disabling postconcussion symptoms are sleep-wake and cognitive disturbances. Sleep, cognitive function, and related symptoms often remain impaired >10-15 years following mTBI. Not only are these symptoms themselves exceedingly difficult to live with, but poor sleep and cognition also interfere with ongoing rehabilitation interventions, and prevent reintegration into civilian life and return to gainful employment. Most existing therapies for sleep-wake and cognitive dysfunction following mTBI are merely symptomatic, and they also suffer from low efficacy and/or patient acceptability. Thus, there is an urgent need to identify mechanism- based interventions for sleep and cognitive problems following mTBI, in order to facilitate optimal rehabilitation and functional outcomes. Our long-term goal is to implement a brain-bioactive pharmacological intervention to address sleep and cognitive disturbance in individuals with mTBI. The overall objective of this application, which represents our first step towards this goal, is to test the feasibility and limited efficacy of a highly promising therapy consisting of a dietary supplement, branched chain amino acids (BCAA; i.e., leucine, isoleucine, and valine), to treat sleep disturbances in individuals with mTBI. There is compelling scientific precedent and safety data to support the testing of BCAA therapy in Veterans with mTBI. Our preclinical data has shown that the mechanism of action for BCAA, acting as a precursor to the excitatory neurotransmitter glutamate, restores the balance of excitation to inhibition within the dysfunctional brain circuits for both sleep and cognition in mTBI.23-26 With these data, we have also meticulously mapped the optimal dosing, duration, and route of administration in mice.27 Further, we now have pilot data from a double-blinded, placebo-controlled study showing that 3 weeks of dietary BCAA supplementation, but not placebo, significantly improved self-reported sleep in Veterans. Other research groups have used dietary BCAA supplementation in humans across multiple conditions at doses up to 60 grams/day and durations up to 12 months with few to no side effects.32-49 Our central hypothesis is that BCAA dietary supplementation will improve sleep quality in Veterans with mTBI. As a first step towards testing this hypothesis, we propose a long-term feasibility, acceptability, and limited efficacy study of BCAA's effects on sleep that will be randomized, placebo-controlled, and double- blinded. Veterans with mTBI will be randomly assigned to receive BCAA at 20, 40 or 60 grams/day per oral (PO) or a placebo (n=50 per group) for 12 weeks. Feasibility, acceptability, and limited efficacy outcomes based on sleep (e.g., self-report, continuous actigraphy, and overnight polysomnography) will be assessed. We expect that these results will inform the optimal study methodology and design for a future, full- scale randomized controlled trial, including the identification of the proper dose and duration of BCAA to improve sleep and the potential subpopulations of Veterans with mTBI that may be differentially affected by BCAA. We also intend to use this work to generate hypotheses on the effect of BCAA on cognition and overall quality of life measures to inform future research.

过去，超过 60% 的 OEF/OIF 退伍军人受到轻度创伤性脑损伤 (mTBI) 的影响 十年来，超过 20% 的退伍军人被诊断患有脑震荡后综合症。可以说是最 脑震荡后的致残症状是睡眠觉醒和认知障碍。睡眠、认知功能和 mTBI 后相关症状通常持续受损 >10-15 年。不仅有这些症状 他们自己非常难以忍受，但睡眠和认知不佳也会干扰持续的生活 康复干预措施，并阻止他们重新融入平民生活和重返有酬就业。最多 现有的治疗 mTBI 后睡眠-觉醒和认知功能障碍的疗法仅是对症治疗，而且它们 还遭受低功效和/或患者可接受性的困扰。因此，迫切需要确定机制—— 针对 mTBI 后的睡眠和认知问题进行干预，以促进最佳康复 和功能结果。 我们的长期目标是实施大脑生物活性药物干预措施来解决睡眠和睡眠问题 mTBI 患者的认知障碍。该应用程序的总体目标代表了我们 实现这一目标的第一步是测试一种非常有前途的疗法的可行性和有限功效，该疗法包括 膳食补充剂、支链氨基酸（BCAA；即亮氨酸、异亮氨酸和缬氨酸），以治疗 mTBI 患者的睡眠障碍。有令人信服的科学先例和安全数据支持 对患有 mTBI 的退伍军人进行 BCAA 治疗测试。我们的临床前数据表明，其机制 BCAA 的作用，作为兴奋性神经递质谷氨酸的前体，恢复平衡 mTBI 中睡眠和认知功能失调的大脑回路中的兴奋到抑制。23-26 根据这些数据，我们还精心绘制了最佳剂量、持续时间和给药途径 27 此外，我们现在获得了一项双盲、安慰剂对照研究的初步数据，显示 3 周 膳食支链氨基酸补充剂（而非安慰剂）显着改善了退伍军人自我报告的睡眠质量。 其他研究小组已在多种情况下在人体中使用膳食支链氨基酸补充剂 剂量高达 60 克/天，持续时间长达 12 个月，几乎没有副作用。32-49 我们的中心假设是，BCAA 膳食补充剂将改善患有以下疾病的退伍军人的睡眠质量 mTBI。作为检验这一假设的第一步，我们提出了长期可行性、可接受性和 关于 BCAA 对睡眠影响的有限功效研究将是随机的、安慰剂对照的、双重的 蒙蔽了。患有 mTBI 的退伍军人将被随机分配接受 BCAA，每次口服 20、40 或 60 克/天 (PO) 或安慰剂（每组 n=50）12 周。可行性、可接受性和有限的疗效结果 将根据睡眠（例如自我报告、连续体动记录仪和夜间多导睡眠图）进行评估。 我们期望这些结果将为未来的最佳研究方法和设计提供信息，全面 规模随机对照试验，包括确定 BCAA 的适当剂量和持续时间 改善睡眠以及患有 mTBI 的退伍军人的潜在亚群，这些亚群可能会受到不同程度的影响 支链氨基酸。我们还打算利用这项工作来生成关于 BCAA 对认知和整体影响的假设 生活质量衡量标准为未来的研究提供信息。