Journal Article

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

Olivo, Cosette, Dovek, Laura, Cohen, Akiva, Lim, Miranda M, Champaigne, Rachel, Hildebrand, Andrea, Sicard, Savanah J, Elliott, Jonathan E, Cunningham, Hannah A, Brewer, Jessica S, Powers, Katherine L

2026

Overview

Abstract 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. Statement of Significance This is the first large-scale double-masked, placebo-controlled randomized clinical trial for dietary BCAA supplementation in Veterans with TBI. Moreover, this study protocol describes the specific aspects of success in implementing this study in a fully remote capacity, enabling potentially nationwide reach of participants. We demonstrated strong success in achieving the primary outcomes of high feasibility and acceptability, and also demonstrated strong preliminary efficacy for the intervention to improve self-reported sleep with BCAA supplementation.

• Publisher: Oxford University Press
• Subject: Clinical trials / Protocol Papers / Sleep / Traumatic brain injury