Supplementation With Amino Acid Rehabilitative Therapy in TBI (SmART-TBI): A Randomized Placebo-Controlled Trial to Improve Sleep
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 160
- 试验地点
- 1
- 主要终点
- Patient satisfaction with overall study process
研究概览
简要总结
The most persistent and disabling postconcussive symptoms following mild traumatic brain injury (mTBI) are sleep disturbances and cognitive dysfunction, with few tractable interventions currently available. Here, a novel therapy will be tested consisting of dietary supplementation with branched chain amino acids (BCAA), based on the study team's previous preclinical work showing restoration of glutamate neurotransmitter balance in sleep and memory circuits. Supplementation with Amino acid Rehabilitative Therapy in TBI (SmART-TBI) is a randomized, placebo-controlled, double-blinded, exploratory clinical trial of BCAA intended to establish the feasibility, acceptability, and limited efficacy of long-term BCAA to improve sleep and cognition in Veterans with mTBI. These results will inform the optimal study design of 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 benefit the most.
详细描述
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.
The study team's 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 the 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. Preliminary 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. With these data, the study team has also meticulously mapped the optimal dosing, duration, and route of administration in mice. Further, the study team now has 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.
The central hypothesis is that BCAA dietary supplementation will improve sleep quality in Veterans with mTBI. As a first step towards testing this hypothesis, herein is proposed 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.
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. This work will aos be used to generate hypotheses on the effect of BCAA on cognition and overall quality of life measures to inform future research.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Both participants and study team members will be double blinded to intervention. The biostatistician and Research Pharmacist dispensing drug will be the only ones with the key to unblinding.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be Veterans (male and female; any race; 18-65 years of age)
- •Be English speaking
- •Be accessible via phone
- •Be non-decisionally impaired
- •Attest to there being no chance of being or becoming pregnant during the study (if female)
- •Attest to no history of maple syrup urine disease or known family history of maple urine syrup disease
- •Have either a history of self-reported sleep disturbances, either as determined via the Insomnia Severity Index, Functional Outcomes of Sleep Questionnaire or Epworth Sleepiness Scale, clinical assessment, and/or a history of self-reported cognitive disturbance (e.g., poor memory, concentration, attention)
- •Not have an allergy to sucralose
- •Not be a shift worker (e.g. have worked night or rotating shifts more than twice in the past month)
- •Not have a diagnosis of amyotrophic lateral sclerosis
- •Not be currently supplementing their diet with branched chain amino acids
- •Not be starting another sleep intervention (e.g., positive airway pressure therapy for sleep apnea, sedative-hypnotic medication, or cognitive behavioral therapy for insomnia) during the study
- •if already engaged in another sleep intervention, this must be stable and not undergo further changes during the study
- •Meet diagnostic criteria for TBI using a validated clinical interview
排除标准
- •Pregnancy or female trying to conceive
- •Under 18 years old
- •Known history of maple syrup urine disease
研究组 & 干预措施
BCAA 20g/daily
Branched Chain Amino Acids, 10g BID x 12 weeks
干预措施: Branched Chain Amino Acids (Dietary Supplement)
BCAA 40g/daily
Branched Chain Amino Acids, 20g BID x 12 weeks
干预措施: Branched Chain Amino Acids (Dietary Supplement)
BCAA 60g/daily
Branched Chain Amino Acids, 30g BID x 12 weeks
干预措施: Branched Chain Amino Acids (Dietary Supplement)
Placebo 20g/daily
Protein without BCAA, 10g BID x 12 weeks
干预措施: Protein Control (Dietary Supplement)
结局指标
主要结局
Patient satisfaction with overall study process
时间窗: 12 weeks
Likert scale (1-5, higher= more satisfied) assessing satisfaction with consent process, staff, medication dispensing and regimen, devices/equipment, sleep study, questionnaires, cognitive testing, and overall experience of the study.
Actiwatch Adherence
时间窗: Year 4
Proportion of days with actiwatch worn (goal \>70% days)
Study Drug Adherence by drug accounting
时间窗: Year 1
Proportion of study drug consumed within each timepoint assessed by drug accounting.
Retention
时间窗: Year 4
Number of completers out of the total number consented as descriptive statistic
Retention by arm
时间窗: Year 4
Proportion of drop out within each arm
Study drug adherence by drug accounting
时间窗: Year 4
Proportion of study drug consumed within each timepoint assessed by drug accounting.
Change in Reasons for non-adherence
时间窗: 12 weeks
Change in Likert scale questions assessing response to statements including: "It upset my stomach", "I didn't have time", "it was too much to drink", "I didn't like the taste", "I didn't feel a benefit". Scale= 0-25, higher=agree more with statement.
Recruitment
时间窗: Year 4
Number of subjects consented of those eligible as descriptive percent
Incidence of non-participation
时间窗: Year 4
Reasons for not participating after initial contact and before consent as descriptive percent.
Study drug adherence by sleep diary
时间窗: Year 1
Proportion of study drug consumed assessed by sleep diary.
Reasons for non-adherence
时间窗: 4 weeks
Likert scale questions assessing response to statements including: "It upset my stomach", "I didn't have time", "it was too much to drink", "I didn't like the taste", "I didn't feel a benefit". Scale= 0-25, higher=agree more with statement.
Change in Monitoring of Side Effects Scale (MOSES)
时间窗: 8 weeks
Change in Monitoring of side effects scale with emphasis on GI, neurological, psychiatric side effects. Range= 0-124, higher= more side effects.
Study Drug Adherence by serum or sweat assay
时间窗: Year 2
Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal \>70% and \>20% increase in levels.
Monitoring of Side Effects Scale (MOSES)
时间窗: 4 weeks
Monitoring of side effects scale with emphasis on GI, neurological, psychiatric side effects. Range= 0-124, higher= more side effects.
Recruitment source
时间窗: Year 4
Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)
Screen Failures
时间窗: Year 4
Number of subjects enrolled who were later found ineligible as a descriptive percent
Study drug adherence by serum or sweat assay
时间窗: Year 4
Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal \>70% and \>20% increase in levels.
Study Drug Adherence by sleep diary
时间窗: Year 4
Proportion of study drug consumed assessed by sleep diary.
Actiwatch Adherence
时间窗: Year 1
Proportion of days with actiwatch worn (goal \>70% days)
Change in Monitoring of Side Effects Scale (MOSES)
时间窗: 12 weeks
Change in Monitoring of side effects scale with emphasis on GI, neurological, psychiatric side effects. Range= 0-124, higher= more side effects.
Study Drug Adherence by serum or sweat assay
时间窗: Year 1
Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal \>70% and \>20% increase in levels.
Change in Reasons for non-adherence
时间窗: 8 weeks
Change in Likert scale questions assessing response to statements including: "It upset my stomach", "I didn't have time", "it was too much to drink", "I didn't like the taste", "I didn't feel a benefit". Scale= 0-25, higher=agree more with statement.
Recruitment
时间窗: Year 1
Number of subjects consented of those eligible as descriptive percent
Recruitment source
时间窗: Year 1
Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)
Retention
时间窗: Year 1
Number of completers out of the total number consented as descriptive statistic
Retention by arm
时间窗: Year 1
Proportion of drop out within each arm
Incidence of non-participation
时间窗: Year 1
Reasons for not participating after initial contact and before consent as descriptive percent.
Screen Failures
时间窗: Year 1
Number of subjects enrolled who were later found ineligible as a descriptive percent
Screen Failures
时间窗: Year 2
Number of subjects enrolled who were later found ineligible as a descriptive percent
Screen Failures
时间窗: Year 3
Number of subjects enrolled who were later found ineligible as a descriptive percent
Incidence of non-participation
时间窗: Year 2
Reasons for not participating after initial contact and before consent as descriptive percent.
Incidence of non-participation
时间窗: Year 3
Reasons for not participating after initial contact and before consent as descriptive percent.
Retention by arm
时间窗: Year 2
Proportion of drop out within each arm
Retention by arm
时间窗: Year 3
Proportion of drop out within each arm
Retention
时间窗: Year 2
Number of completers out of the total number consented as descriptive statistic
Retention
时间窗: Year 3
Number of completers out of the total number consented as descriptive statistic
Recruitment source
时间窗: Year 2
Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)
Recruitment source
时间窗: Year 3
Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)
Recruitment
时间窗: Year 2
Number of subjects consented of those eligible as descriptive percent
Recruitment
时间窗: Year 3
Number of subjects consented of those eligible as descriptive percent
Study drug adherence by serum or sweat assay
时间窗: Year 3
Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal \>70% and \>20% increase in levels.
Study Drug Adherence by sleep diary
时间窗: Year 2
Proportion of study drug consumed assessed by sleep diary.
Study Drug Adherence by sleep diary
时间窗: Year 3
Proportion of study drug consumed assessed by sleep diary.
Study drug adherence by drug accounting
时间窗: Year 2
Proportion of study drug consumed within each timepoint assessed by drug accounting.
Study drug adherence by drug accounting
时间窗: Year 3
Proportion of study drug consumed within each timepoint assessed by drug accounting.
Actiwatch Adherence
时间窗: Year 2
Proportion of days with actiwatch worn (goal \>70% days)
Actiwatch Adherence
时间窗: Year 3
Proportion of days with actiwatch worn (goal \>70% days)
次要结局
未报告次要终点