BCAA Supplementation for Concussion

Annually, between 100,000 to 140,000 children present to the emergency department for concussion in the United States.1 The Centers for Disease Control now estimates that 1.6 - 3.8 million sports related concussions occur each year in the United States. A large proportion of these patients have enduring cognitive and neurobehavioral problems. Concussion is a heterogeneous insult to the brain that precipitates a complex pathophysiological process that can result in a cascade of deleterious side effects. At present, there are no proven therapies to mitigate or prevent the neurocognitive and neurobehavioral consequences of concussions. The limbic hippocampus, a brain structure crucial for learning and memory, is often damaged in concussion. In preclinical studies in our laboratory, analysis of ipsilateral hippocampi isolated from mice after traumatic brain injury (TBI) demonstrated that only the concentrations of the three BCAA's (valine, isoleucine, and leucine) were significantly altered (reduced) after injury. When these brain-injured animals received dietary supplementation with BCAA's, the concentrations of these amino acids were restored in the injured hippocampus and the injured animals demonstrated significant cognitive improvement to levels comparable to those obtained in non-injured control animals. In light of these results and the increasing awareness and morbidity associated with concussion, we are proposing a pilot therapeutic exploratory clinical trial to determine the effects of BCAA's in reducing the neurocognitive side effects of concussion injury.

• Branched Chain Amino Acids (Drug): The three BCAA's will be combined together and dissolved in a flavored solution.
• Placebo solution (Drug): The placebo solution will have similar taste, texture, consistency and appearance as the BCAA solution.

Primary outcomes

• Reaction Time Difference Between Drug and Placebo Groups [Day 21]: Processing speed subtest of the Axon Sports Computerized Cognitive Assessment Tool. The values provided are the median of log reaction time to the processing speed subtest, where a lower score indicates a faster time and thus improved processing speed.

Secondary outcomes

• Clinical Symptoms [Day 21]: Evaluate whether BCAA supplementation reduces total symptom burden on a total symptom scale of 9 concussion symptoms rated each from 0-6, minimal value 0, maximum value 54, a higher score indicates a higher symptom burden and therefore a worse outcome
• Return to Physical Activity Baseline [Day 21]: Determine whether BCAA supplementation more rapidly facilitates a return to physical baseline. The physical activity score is scaled on a 6 point Likert scale (0-5), where 0 represents no activity and 5 represents full activity, therefore a higher score represents a closer return to baseline activity by the end of the study period
• Neurocognitive Recovery-- Attention [Day 21]: Determine whether administration of BCAAs improves the median log reaction time of the attention subtest of the neurocognitive testing battery. A lower median log reaction time represents improved attention
• Compliance and Adherence to Treatment [Day 21]: Adherence to treatment among dosage groups, reported as the median percent drink consumed among the group across the study period, where 100% = all drink (2 doses per day x 21 days) consumed, and 0% represents no drink consumed
• Tolerability of BCAA's Based on Adverse Events [Day 21]: Assess the tolerability of BCAA doses based on subject reported adverse events, measured as the percent of participants in each study arm reporting adverse events
• Safety and BCAA Supplementation [Day 21]: Asses the safety of BCAA doses in concussed athletes through subject reported serious adverse events (SAEs). Reported as the number of participants in each arm experiencing an SAE.
• Neurocognitive Recovery-- Working Memory [Day 21]: Determine whether administration of BCAAs improves the the median of log reaction time of the working memory subtest of the neurocognitive testing battery. A lower median log reaction time represents improved working memory.
• Neurocognitive Recovery-- Visual Memory [Day 21]: Determine whether administration of BCAAs improves the accuracy score of the visual memory subtest of the neurocognitive testing battery. A higher accuracy score (scaled 0-1.5) represents improved visual memory
• Return to Baseline Cognitive Activity [Day 21]: Determine whether BCAA supplementation more rapidly facilitates a return to cognitive activity baseline. The cognitive activity score is scaled on a 5 point Likert scale (0-4), where 0 represents no activity and 4 represents full activity, therefore a higher score represents a closer return to baseline cognitive activity by the end of the study period

Sex: All, ages: 11 Years to 34 Years

Inclusion Criteria

1. Males and females, ages 11 - 34 years, of any race.
2. Subjects who had a concussion, as diagnosed by a qualified physician, within 72 hours prior to enrollment.
3. Ability to have daily email and internet access.
4. Females must have a negative urine pregnancy test and must use an acceptable method of contraception.
5. Subjects must, in the opinion of the referring physician, have the capacity to provide informed consent.
6. Informed consent by the subject, or for subjects <18 years old both informed consent by a parent/guardian and child assent.

Exclusion Criteria

1. Witnessed seizure at the time of injury or penetrating head injury.
2. Prior concussion or TBI within 90 days.
3. Concussion or TBI severe enough to require admission to an intensive care unit for observation or intervention.
4. Previous history of TBI or concussion requiring admission to the hospital, disabling stroke, epilepsy, brain tumor, neurodegenerative condition, or psychiatric disease.
5. Subjects taking neurological or psychoactive medications as a regular daily prescription medication.
6. Known history of maple syrup urine disease or known family history of maple syrup urine disease.
7. Any investigational drug use within 30 days prior to enrollment.
8. Allergy to Food, Drug, and Cosmetic (FD\&C) Red #40 (red dye 40) or Sucralose.
9. Lactating females.
10. Parents/guardians or subjects who, in the opinion of the investigators, may be non-compliant with study schedules or procedures.

Participant flow

Outcome results

• Reaction Time Difference Between Drug and Placebo Groups (Primary), Median, log(milliseconds): Placebo 2.44 (2.41 to 2.51); Branched Chain Amino Acids (7.5g BID) 2.49 (2.44 to 2.55); Branched Chain Amino Acids (15g BID) 2.52 (2.48 to 2.56); Branched Chain Amino Acids (22.5g BID) 2.48 (2.46 to 2.57); Branched Chain Amino Acids (27g BID) 2.48 (2.42 to 2.49) (p 0.871)
• Clinical Symptoms (Secondary), Median, units on a scale: Placebo 3 (2 to 5); Branched Chain Amino Acids (7.5g BID) 2 (0.5 to 3); Branched Chain Amino Acids (15g BID) 0 (0 to 1.5); Branched Chain Amino Acids (22.5g BID) 0 (0 to 0); Branched Chain Amino Acids (27g BID) 0 (0 to 0) (p 0.140)
• Return to Physical Activity Baseline (Secondary), Median, score on a scale: Placebo 2 (1 to 2); Branched Chain Amino Acids (7.5g BID) 1.5 (1 to 3); Branched Chain Amino Acids (15g BID) 3 (1 to 5); Branched Chain Amino Acids (22.5g BID) 3 (2 to 4); Branched Chain Amino Acids (27g BID) 5 (3.5 to 5) (p 0.267)
• Neurocognitive Recovery-- Attention (Secondary), Median, log(milliseconds): Placebo 2.65 (2.60 to 2.71); Branched Chain Amino Acids (7.5g BID) 2.60 (2.55 to 2.65); Branched Chain Amino Acids (15g BID) 2.73 (2.67 to 2.80); Branched Chain Amino Acids (22.5g BID) 2.74 (2.62 to 2.86); Branched Chain Amino Acids (27g BID) 2.69 (2.65 to 2.77) (p 0.476)
• Compliance and Adherence to Treatment (Secondary), Median, Percent of total drink consumed: Placebo 81 (14.3 to 87.9); Branched Chain Amino Acids (7.5g BID) 64.3 (28.4 to 91.4); Branched Chain Amino Acids (15g BID) 54.8 (15.0 to 55.6); Branched Chain Amino Acids (22.5g BID) 23.8 (11.9 to 42.5); Branched Chain Amino Acids (27g BID) 49.0 (22.7 to 72.6) (p 0.581)
• Tolerability of BCAA's Based on Adverse Events (Secondary), Count of participants, Participants: Placebo 3; Branched Chain Amino Acids (7.5g BID) 3; Branched Chain Amino Acids (15g BID) 1; Branched Chain Amino Acids (22.5g BID) 0; Branched Chain Amino Acids (27g BID) 1 (p 0.203)
• Safety and BCAA Supplementation (Secondary), Count of participants, Participants: Placebo 0; Branched Chain Amino Acids (7.5g BID) 0; Branched Chain Amino Acids (15g BID) 0; Branched Chain Amino Acids (22.5g BID) 0; Branched Chain Amino Acids (27g BID) 0 (p 1.00)
• Neurocognitive Recovery-- Working Memory (Secondary), Median, log(milliseconds): Placebo 2.69 (2.62 to 2.78); Branched Chain Amino Acids (7.5g BID) 2.70 (2.59 to 2.80); Branched Chain Amino Acids (15g BID) 2.84 (2.82 to 2.87); Branched Chain Amino Acids (22.5g BID) 2.82 (2.68 to 2.97); Branched Chain Amino Acids (27g BID) 2.74 (2.66 to 2.91) (p 0.482)
• Neurocognitive Recovery-- Visual Memory (Secondary), Median, score on a scale: Placebo 1.24 (1.15 to 1.29); Branched Chain Amino Acids (7.5g BID) 1.11 (0.88 to 1.34); Branched Chain Amino Acids (15g BID) 0.99 (0.93 to 1.04); Branched Chain Amino Acids (22.5g BID) 0.75 (0.22 to 1.27); Branched Chain Amino Acids (27g BID) 1.05 (0.99 to 1.08) (p 0.393)
• Return to Baseline Cognitive Activity (Secondary), Median, score on a scale: Placebo 2 (2 to 4); Branched Chain Amino Acids (7.5g BID) 3 (1.5 to 4); Branched Chain Amino Acids (15g BID) 4 (3.5 to 4); Branched Chain Amino Acids (22.5g BID) 4 (4 to 4); Branched Chain Amino Acids (27g BID) 3 (1.5 to 4) (p 0.629)
• Regression Model Processing Speed Change (Post hoc), Least squares mean, log(milliseconds): Entire Study 0.008 +/- 0.016 (p 0.624)
• Regression Model Attention Change (Post hoc), Least squares mean, log(milliseconds): Entire Study 0.014 +/- 0.012 (p 0.2554)
• Regression Model Working Memory Change (Post hoc), Least squares mean, log(milliseconds): Entire Study 0.004 +/- 0.0016 (p 0.7964)
• Regression Mode Visual Learning Change (Post hoc), Least squares mean, score on a scale: Entire Study -0.013 +/- 0.046 (p 0.7749)
• Total Symptom Score Change (Post hoc), Least squares mean, score on a scale: Entire Study, Symptom/Activity Questionnaire -4.4 +/- 1.4 (p 0.0036)
• Physical Activity Score Change (Post hoc), Least squares mean, score on a scale: Entire Study, Symptom/Activity Questionnaire 0.503 +/- 0.164 (p 0.0053)
• Regression Model Cognitive Activity Score Change (Post hoc), Least squares mean, score on a scale: Entire Study, Symptom/Activity Questionnaire 0.051 +/- 0.224 (p 0.8234)

Adverse events

Time frame: 21 days (duration of study period)

Other adverse events by term

Limitations and caveats: There are several key limitations to our study that necessitate a larger, more definitive trial. Due to a combination of initially more strict inclusion criteria, and the impact of the coronavirus pandemic, our sample size was smaller than anticipated. This, combined with poorer than expected follow-up, led us to have to use alternative statistical analytic methods. We were further limited by missing data. This also necessitated the alternative analytic approach / post-hoc analysis.

• Cole JT, Mitala CM, Kundu S, Verma A, Elkind JA, Nissim I, Cohen AS. Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):366-71. doi: 10.1073/pnas.0910280107. Epub 2009 Dec 7. PMID 19995960

• Study Protocol and Statistical Analysis Plan (PDF, 2019-06-17)
• Informed Consent Form (PDF, 2020-12-21)

• Sage Myers, MD, Principal investigator, Children's Hospital of Philadelphia