SmART-TBI: a fully remote protocol for a placebo-controlled double-masked randomized clinical trial for a dietary...

Traumatic brain injury (TBI) is associated with 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 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 b.i.d. ("high" 30 g; "medium" 20 g; and "low" 10 g) and one placebo-control (rice protein, 10 g b.i.d.). Outcomes 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. The primary outcomes are overall feasibility/acceptability metrics, and secondarily, preliminary efficacy for BCAAs to improve subjective sleep as assessed by the Insomnia Severity Index. Additional sleep measures were obtained for future analyses using a combination of actigraphy, mattress-sensors, sleep diaries, as well as pre-/post-BCAA overnight polysomnography. Additional exploratory outcomes included sweat-based biomarkers. Analyses of primary outcome measures indicated high feasibility and acceptability for this fully protocol.