SmART-TBI: Supplementation With Amino Acid Rehabilitative Therapy in TBI

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Dietary Supplement: Branched Chain Amino Acids
* Dietary Supplement: Branched Chain Amino Acids
* Dietary Supplement: Branched Chain Amino Acids
* Dietary Supplement: Protein Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: Pregnancy or female trying to conceive Under 18 years old Known history of maple syrup urine disease Dementia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blinded, placebo-controlled feasibility study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCAA 20g/daily<br>Branched Chain Amino Acids, 10g BID x 12 weeks | Dietary Supplement: Branched Chain Amino Acids<br>* Isoleucine, Leucine, and Valine<br>* Other names: BCAA;|
| Experimental: BCAA 40g/daily<br>Branched Chain Amino Acids, 20g BID x 12 weeks | Dietary Supplement: Branched Chain Amino Acids<br>* Isoleucine, Leucine, and Valine, 20 g BID x 12 weeks<br>* Other names: BCAA-40;|
| Experimental: BCAA 60 g/daily<br>Branched Chain Amino Acids, 30g BID x 12 weeks | Dietary Supplement: Branched Chain Amino Acids<br>* Isoleucine, Leucine, and Valine, 30 g BID x 12 weeks<br>* Other names: BCAA-60;|
| Placebo Comparator: Placebo 20 g/daily<br>Protein without BCAA, 10g BID x 12 weeks | Dietary Supplement: Protein Control<br>* Protein placebo control - all amino acids except for BCAA, 30 g BID x 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Actiwatch Adherence | Proportion of days with actiwatch worn (goal >70% days) | Year 1 | 
| Study Drug Adherence by drug accounting | Proportion of study drug consumed within each timepoint assessed by drug accounting. | Year 1 | 
| Study drug adherence by sleep diary | Proportion of study drug consumed assessed by sleep diary. | Year 1 | 
| Change in Monitoring of Side Effects Scale (MOSES) | Change in Monitoring of side effects scale with emphasis on GI, neurological, psychiatric side effects. Range= 0-124, higher= more side effects. | 12 weeks | 
| Study Drug Adherence by serum or sweat assay | Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal >70% and >20% increase in levels. | Year 1 | 
| Patient satisfaction with overall study process | 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. | 12 weeks | 
| Monitoring of Side Effects Scale (MOSES) | Monitoring of side effects scale with emphasis on GI, neurological, psychiatric side effects. Range= 0-124, higher= more side effects. | 4 weeks | 
| Change in Monitoring of Side Effects Scale (MOSES) | Change in Monitoring of side effects scale with emphasis on GI, neurological, psychiatric side effects. Range= 0-124, higher= more side effects. | 8 weeks | 
| Reasons for non-adherence | 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. | 4 weeks | 
| Change in Reasons for non-adherence | 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. | 8 weeks | 
| Change in Reasons for non-adherence | 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. | 12 weeks | 
| Recruitment | Number of subjects consented of those eligible as descriptive percent | Year 1 | 
| Recruitment source | Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc) | Year 1 | 
| Retention | Number of completers out of the total number consented as descriptive statistic | Year 1 | 
| Retention by arm | Proportion of drop out within each arm | Year 1 | 
| Incidence of non-participation | Reasons for not participating after initial contact and before consent as descriptive percent. | Year 1 | 
| Screen Failures | Number of subjects enrolled who were later found ineligible as a descriptive percent | Year 1 | 
| Screen Failures | Number of subjects enrolled who were later found ineligible as a descriptive percent | Year 2 | 
| Screen Failures | Number of subjects enrolled who were later found ineligible as a descriptive percent | Year 3 | 
| Screen Failures | Number of subjects enrolled who were later found ineligible as a descriptive percent | Year 4 | 
| Incidence of non-participation | Reasons for not participating after initial contact and before consent as descriptive percent. | Year 2 | 
| Incidence of non-participation | Reasons for not participating after initial contact and before consent as descriptive percent. | Year 3 | 
| Incidence of non-participation | Reasons for not participating after initial contact and before consent as descriptive percent. | Year 4 | 
| Retention by arm | Proportion of drop out within each arm | Year 2 | 
| Retention by arm | Proportion of drop out within each arm | Year 3 | 
| Retention by arm | Proportion of drop out within each arm | Year 4 | 
| Retention | Number of completers out of the total number consented as descriptive statistic | Year 2 | 
| Retention | Number of completers out of the total number consented as descriptive statistic | Year 3 | 
| Retention | Number of completers out of the total number consented as descriptive statistic | Year 4 | 
| Recruitment source | Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc) | Year 2 | 
| Recruitment source | Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc) | Year 3 | 
| Recruitment source | Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc) | Year 4 | 
| Recruitment | Number of subjects consented of those eligible as descriptive percent | Year 2 | 
| Recruitment | Number of subjects consented of those eligible as descriptive percent | Year 3 | 
| Recruitment | Number of subjects consented of those eligible as descriptive percent | Year 4 | 
| Study Drug Adherence by serum or sweat assay | Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal >70% and >20% increase in levels. | Year 2 | 
| Study drug adherence by serum or sweat assay | Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal >70% and >20% increase in levels. | Year 3 | 
| Study drug adherence by serum or sweat assay | Proportion of study drug consumed assessed by serum or sweat assays of BCAA (goal >70% and >20% increase in levels. | Year 4 | 
| Study Drug Adherence by sleep diary | Proportion of study drug consumed assessed by sleep diary. | Year 2 | 
| Study Drug Adherence by sleep diary | Proportion of study drug consumed assessed by sleep diary. | Year 3 | 
| Study Drug Adherence by sleep diary | Proportion of study drug consumed assessed by sleep diary. | Year 4 | 
| Study drug adherence by drug accounting | Proportion of study drug consumed within each timepoint assessed by drug accounting. | Year 2 | 
| Study drug adherence by drug accounting | Proportion of study drug consumed within each timepoint assessed by drug accounting. | Year 3 | 
| Study drug adherence by drug accounting | Proportion of study drug consumed within each timepoint assessed by drug accounting. | Year 4 | 
| Actiwatch Adherence | Proportion of days with actiwatch worn (goal >70% days) | Year 2 | 
| Actiwatch Adherence | Proportion of days with actiwatch worn (goal >70% days) | Year 3 | 
| Actiwatch Adherence | Proportion of days with actiwatch worn (goal >70% days) | Year 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TBI, sleep, cognition, bcaa