Overarching Challenge: There is currently no FDA-approved medication for the treatment of TBI. Safe and efficacious pharmacological interventions for chronic TBI in OEF/OIF/OND veterans are urgently needed. Our research group recently demonstrated that a novel neurosteroid (pregnenolone) is a safe and well-tolerated therapeutic candidate. Pregnenolone is a naturally occurring molecule that is synthesized in the brain, adrenals, and other tissues. It is sold as a dietary supplement in the U.S. (although over-the-counter formulations are not required to meet FDA IND standards for purity, and we will thus have pregnenolone custom-synthesized for the proposed clinical trial). Pregnenolone appears to be effective in reducing TBI sequelae and pain symptoms at a dose of 500 mg in our prior studies (Marx et al., 2016; Naylor et al., 2020), and it is possible that higher doses of pregnenolone will produce even greater relief of TBI symptoms and further enhance functional outcomes. We therefore propose to investigate maximal well-tolerated doses of pregnenolone as a safe and non-habit-forming new medication for TBI sequelae, potentially representing a clinical breakthrough.

Objective And Rationale: We already hold an FDA IND for the use of pregnenolone for chronic TBI (FDA IND #78,270) and have extensive experience with pharmacological interventions (holding a total of six FDA INDs for neurosteroid and other small molecule therapeutics). We are also very fortunate to have access to the VA Mid-Atlantic Mental Illness, Research, Education, and Clinical Center (MIRECC) Post-Deployment Mental Health Study (PDMH), which enrolled over 3,800 OEF/OIF/OND Veterans (of whom 94% have provided permission to be recontacted for future research studies). Enrollment for the proposed project is thus eminently feasible. This clinical trial will randomly divide a total of 108 OEF/OIF/OND-Era Veterans with a history of chronic TBI into two groups (approximately 54 participants per group). One group will receive pregnenolone (starting at 500 mg and increasing to maximal well-tolerated doses up to 2,000 mg), and the other will receive placebo (no active study medication). We will determine how TBI-related sequelae change over the 8-week study period. In addition, we will investigate the biological effects of pregnenolone by drawing a blood sample at each study visit to characterize how pregnenolone and other molecules change over the course of treatment and potentially predict clinical improvement. The proposed biomarker-informed randomized controlled trial with a novel intervention for TBI will potentially yield new knowledge that could prevent or mitigate TBI symptoms and co-occurring psychological health conditions and identify predictive biomarkers of clinical outcome.

Impact On Service Member Health and Well-Being: This innovative randomized controlled trial in OEF/OIF/OND Veterans with a history of chronic complex TBI investigating a novel pharmacological intervention is supported by extensive biomarker and clinical data and could rapidly lead to pivotal Phase 3 studies and FDA approval at an accelerated timeframe. This study could also identify biomarkers of risk and resilience that predict TBI sequelae and therapeutic response and could translate into an urgently needed safe and efficacious new treatment for Veterans with a history of chronic complex TBI.