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: 10015814
• 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/10015814
• 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; 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，轻度创伤性脑损伤（MTBI）过去对所有OEF/OIF退伍军人占60％以上 十年，这些退伍军人中有20％以上诊断出脑震荡综合征。可以说最多 残疾后脑中的症状是睡眠效果和认知障碍。睡眠，认知功能和 MTBI之后，相关症状通常> 10 - 15年。这些症状不仅是 自己很难生活，但是睡眠和认知差也会干扰持续的 康复干预措施，并防止重新融入平民生活并恢复有酬工作。最多 MTBI后的现有睡眠效果和认知功能障碍的疗法仅是症状，它们是 也患有低疗效和/或患者的可接受性。因此，迫切需要识别机制 - MTBI之后的基于睡眠和认知问题的干预措施，以促进最佳康复 和功能结果。 我们的长期目标是实施大脑活性药理干预措施，以解决睡眠和 MTBI患者的认知障碍。该应用程序的总体目标，代表我们 朝着这一目标的第一步是测试高度有希望的疗法的可行性和有限的功效 饮食补充剂，分支链氨基酸（BCAA;即亮氨酸，异亮氨酸和瓣膜）的处理 MTBI患者的睡眠障碍。有令人信服的科学先例和安全数据可以支持 MTBI退伍军人的BCAA治疗测试。我们的临床前数据表明 BCAA的作用，充当兴奋性神经递质谷氨酸的前体，恢复了平衡 激发抑制功能失调的脑回路中的睡眠和认知的抑制作用。23-26与 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 MICE.27此外，我们现在有一项双眼，安慰剂对照的研究的试点数据，表明3周 补充饮食BCAA，但不安慰剂，在退伍军人中显着改善了自我报告的睡眠。 其他研究小组在多种条件下在人类中使用饮食BCAA补充 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 我们的核心假设是，BCAA饮食补充剂将改善 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 对BCAA对睡眠影响的有限疗效研究将是随机，安慰剂对照和双重的 盲目。 MTBI的退伍军人将被随机分配为以20、40或60克/天的口服接收BCAA （PO）或安慰剂（每组n = 50）持续12周。可行性，可接受性和有限的功效结果 将评估睡眠（例如自我报告，连续的动作法和隔夜多摄影术）。 我们预计这些结果将为未来的最佳研究方法和设计提供信息 比例随机对照试验，包括鉴定BCAA的适当剂量和持续时间 改善睡眠和MTBI退伍军人的潜在亚群，可能会受到差异的影响 BCAA。我们还打算利用这项工作来产生关于BCAA对认知和整体影响的影响的假设 生活质量措施为未来的研究提供信息。