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

Traumatic Brain Injury Clinical Trial

— SmART-TBI  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04603443
• Other study ID #: NURR-003-19F
• Secondary ID: I01CX002022
• Status: Recruiting
• Phase: N/A
• Start date: June 1, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: March 2024
• Source: VA Office of Research and Development
• Contact: Miranda M Lim, MD PhD
• Phone: (503) 220-8262
• Email: miranda.lim[@]va.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury

Intervention

Dietary Supplement:
• Branched Chain Amino Acids
Isoleucine, Leucine, and Valine, 10g BID x 12 weeks
• Branched Chain Amino Acids
Isoleucine, Leucine, and Valine, 20g BID x 12 weeks
• Branched Chain Amino Acids
Isoleucine, Leucine, and Valine, 30g BID x 12 weeks
• Protein Control
Protein placebo control - all amino acids except for BCAA, 10g BID x 12 weeks

Locations

Country	Name	City	State
United States	VA Portland Health Care System, Portland, OR	Portland	Oregon

Sponsors (3)

Lead Sponsor	Collaborator
VA Office of Research and Development	Children's Hospital of Philadelphia, Oregon Health and Science University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Actiwatch Adherence	Proportion of days with actiwatch worn (goal >70% days)	Year 1
Primary	Study Drug Adherence by drug accounting	Proportion of study drug consumed within each timepoint assessed by drug accounting.	Year 1
Primary	Study drug adherence by sleep diary	Proportion of study drug consumed assessed by sleep diary.	Year 1
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Recruitment	Number of subjects consented of those eligible as descriptive percent	Year 1
Primary	Recruitment source	Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)	Year 1
Primary	Retention	Number of completers out of the total number consented as descriptive statistic	Year 1
Primary	Retention by arm	Proportion of drop out within each arm	Year 1
Primary	Incidence of non-participation	Reasons for not participating after initial contact and before consent as descriptive percent.	Year 1
Primary	Screen Failures	Number of subjects enrolled who were later found ineligible as a descriptive percent	Year 1
Primary	Screen Failures	Number of subjects enrolled who were later found ineligible as a descriptive percent	Year 2
Primary	Screen Failures	Number of subjects enrolled who were later found ineligible as a descriptive percent	Year 3
Primary	Screen Failures	Number of subjects enrolled who were later found ineligible as a descriptive percent	Year 4
Primary	Incidence of non-participation	Reasons for not participating after initial contact and before consent as descriptive percent.	Year 2
Primary	Incidence of non-participation	Reasons for not participating after initial contact and before consent as descriptive percent.	Year 3
Primary	Incidence of non-participation	Reasons for not participating after initial contact and before consent as descriptive percent.	Year 4
Primary	Retention by arm	Proportion of drop out within each arm	Year 2
Primary	Retention by arm	Proportion of drop out within each arm	Year 3
Primary	Retention by arm	Proportion of drop out within each arm	Year 4
Primary	Retention	Number of completers out of the total number consented as descriptive statistic	Year 2
Primary	Retention	Number of completers out of the total number consented as descriptive statistic	Year 3
Primary	Retention	Number of completers out of the total number consented as descriptive statistic	Year 4
Primary	Recruitment source	Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)	Year 2
Primary	Recruitment source	Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)	Year 3
Primary	Recruitment source	Proportion of subjects recruited from various sources (clinical referral, flyers, ads, etc)	Year 4
Primary	Recruitment	Number of subjects consented of those eligible as descriptive percent	Year 2
Primary	Recruitment	Number of subjects consented of those eligible as descriptive percent	Year 3
Primary	Recruitment	Number of subjects consented of those eligible as descriptive percent	Year 4
Primary	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
Primary	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
Primary	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
Primary	Study Drug Adherence by sleep diary	Proportion of study drug consumed assessed by sleep diary.	Year 2
Primary	Study Drug Adherence by sleep diary	Proportion of study drug consumed assessed by sleep diary.	Year 3
Primary	Study Drug Adherence by sleep diary	Proportion of study drug consumed assessed by sleep diary.	Year 4
Primary	Study drug adherence by drug accounting	Proportion of study drug consumed within each timepoint assessed by drug accounting.	Year 2
Primary	Study drug adherence by drug accounting	Proportion of study drug consumed within each timepoint assessed by drug accounting.	Year 3
Primary	Study drug adherence by drug accounting	Proportion of study drug consumed within each timepoint assessed by drug accounting.	Year 4
Primary	Actiwatch Adherence	Proportion of days with actiwatch worn (goal >70% days)	Year 2
Primary	Actiwatch Adherence	Proportion of days with actiwatch worn (goal >70% days)	Year 3
Primary	Actiwatch Adherence	Proportion of days with actiwatch worn (goal >70% days)	Year 4