Clinical trial NCT04603443: SmART-TBI: Supplementation With Amino Acid Rehabilitative Therapy in TBI
Official title: Supplementation With Amino Acid Rehabilitative Therapy in TBI (SmART-TBI): A Randomized Placebo-Controlled Trial to Improve Sleep
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Traumatic Brain Injury
Keywords: TBI
sleep
cognition
bcaa
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Children's Hospital of Philadelphia
name: Oregon Health and Science University
First posted: 2020-10-26
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blinded, placebo-controlled feasibility study
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Actiwatch Adherence
timeFrame: Year 1
measure: Study Drug Adherence by drug accounting
timeFrame: Year 1
measure: Study drug adherence by sleep diary
timeFrame: Year 1
measure: Change in Monitoring of Side Effects Scale (MOSES)
timeFrame: 12 weeks
measure: Study Drug Adherence by serum or sweat assay
timeFrame: Year 1
measure: Patient satisfaction with overall study process
timeFrame: 12 weeks
measure: Monitoring of Side Effects Scale (MOSES)
timeFrame: 4 weeks
measure: Change in Monitoring of Side Effects Scale (MOSES)
timeFrame: 8 weeks
measure: Reasons for non-adherence
timeFrame: 4 weeks
measure: Change in Reasons for non-adherence
timeFrame: 8 weeks
measure: Change in Reasons for non-adherence
timeFrame: 12 weeks
measure: Recruitment
timeFrame: Year 1
measure: Recruitment source
timeFrame: Year 1
measure: Retention
timeFrame: Year 1
measure: Retention by arm
timeFrame: Year 1
measure: Incidence of non-participation
timeFrame: Year 1
measure: Screen Failures
timeFrame: Year 1
measure: Screen Failures
timeFrame: Year 2
measure: Screen Failures
timeFrame: Year 3
measure: Screen Failures
timeFrame: Year 4
measure: Incidence of non-participation
timeFrame: Year 2
measure: Incidence of non-participation
timeFrame: Year 3
measure: Incidence of non-participation
timeFrame: Year 4
measure: Retention by arm
timeFrame: Year 2
measure: Retention by arm
timeFrame: Year 3
measure: Retention by arm
timeFrame: Year 4
measure: Retention
timeFrame: Year 2
measure: Retention
timeFrame: Year 3
measure: Retention
timeFrame: Year 4
measure: Recruitment source
timeFrame: Year 2
measure: Recruitment source
timeFrame: Year 3
measure: Recruitment source
timeFrame: Year 4
measure: Recruitment
timeFrame: Year 2
measure: Recruitment
timeFrame: Year 3
measure: Recruitment
timeFrame: Year 4
measure: Study Drug Adherence by serum or sweat assay
timeFrame: Year 2
measure: Study drug adherence by serum or sweat assay
timeFrame: Year 3
measure: Study drug adherence by serum or sweat assay
timeFrame: Year 4
measure: Study Drug Adherence by sleep diary
timeFrame: Year 2
measure: Study Drug Adherence by sleep diary
timeFrame: Year 3
measure: Study Drug Adherence by sleep diary
timeFrame: Year 4
measure: Study drug adherence by drug accounting
timeFrame: Year 2
measure: Study drug adherence by drug accounting
timeFrame: Year 3
measure: Study drug adherence by drug accounting
timeFrame: Year 4
measure: Actiwatch Adherence
timeFrame: Year 2
measure: Actiwatch Adherence
timeFrame: Year 3
measure: Actiwatch Adherence
timeFrame: Year 4
Secondary outcomes:
Other outcomes:
Locations:
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
Study officials:
affiliation: VA Portland Health Care System, Portland, OR
name: Miranda M Lim, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: