SmART-TBI: A fully remote protocol for a randomized placebo-controlled double-blinded clinical trial for a dietary supplement to improve sleep in Veterans

Traumatic brain injury (TBI) is associated with chronic sleep disturbances and cognitive impairment, with limited effective therapeutic strategies. Our previous work showed dietary supplementation with branched chain amino acids (BCAAs; isoleucine, leucine, valine), the primary substrate for de novo glutamate/GABA synthesis in the CNS, restored normal sleep-wake patterns and improved cognitive function in rodents. Our recent pilot work in humans showed preliminary feasibility/acceptability and limited efficacy for BCAAs to improve sleep in Veterans with TBI. However, these pilot data were limited in sample size, treatment dosages/duration, and therefore unable to establish efficacy or provide insight into dosing/duration parameters. The present study, SmART-TBI (supplementation with amino acid rehabilitative therapy in TBI: NCT04603443), represents a fully powered, placebo-controlled, double-masked randomized clinical trial (target n=120). Covariate adaptive randomization controlling for age, sex, TBI recency, pain, depression, and PTSD, allocated participants 1:1:1:1 to four groups comprising 3 BCAA doses ( high 30g b.i.d.; medium 20g b.i.d.; and low 10g b.i.d.) and one placebo-control (rice protein, 10g b.i.d.). Outcome measures were assessed following a 2-week baseline period; after 4 weeks, 8 weeks, and 12 weeks of intervention; and after 4 weeks and 12 weeks post-intervention. Primary outcomes were feasibility and acceptability of the protocol. Exploratory outcomes included preliminary efficacy in improving sleep, assessed via a combination of actigraphy, mattress-sensors, sleep diaries (all analyzed daily), as well as pre- and post-BCAA overnight polysomnography for sleep staging, cognition, and quality of life measures. Results indicated high feasibility and acceptability of this fully remote protocol among Veterans with TBI.