Efficacy of hyperbaric oxygen treatment in veterans and service members with traumatic brain injury—a study protocol for a blinded three-stage group sequential randomized controlled trial

Traumatic brain injury (TBI) is common amongst Veterans and Military Service Members (V/SM), with 510,000 diagnosed with a TBI between 2000 and 2024, of which 82% were mild and 12% moderate. Hyperbaric oxygen therapy (HBOT) is considered a potential intervention for the management of mild/moderate TBI. However, the results from previous randomized controlled trials (RCTs) assessing the efficacy of HBOT for managing mild/moderate TBI are inconclusive due to several reasons, including lack of a priori power analyses, design considerations, and inappropriate comparators. The primary objective of this study is to assess the efficacy of HBOT compared to placebo/sham in reducing chronic neurobehavioral symptoms in participants with chronic mild to moderate TBI. This is a single-center blinded group sequential superiority randomized controlled trial (RCT). All consecutive United States (USA) V/SM with a history of mild or moderate TBI with persistent neurobehavioral symptoms (≥ 22 on the Neurobehavioral Symptom Inventory) at a year or more post-injury will be eligible for inclusion. HBOT medical grade oxygen pressurized to 2.0 Atmospheres Absolute (ATA) with Sechrist 3600H/HR monoplace hyperbaric chambers will be compared to a sham group of 1.0 ATA (normobaric) with oxygen delivered at 21% (normal oxygen concentration in room air) for approximately 60 min. The primary outcome is the post-intervention Neurobehavioral Symptom Inventory (NSI) score. Secondary outcomes are the number of HBOT dives needed to achieve a reduction in NSI score and to assess the impact of HBOT on post-traumatic stress disorder (PTSD) symptoms using the PTSD Checklist for DSM-5 (PCL-5). The study aims to enroll 420 subjects with an expected dropout rate of 20%. The study will determine the efficacy of HBOT at 2.0 ATA in reducing long-term neurobehavioral symptoms in V/SM with histories of mild to moderate TBI. This information will assist participants, providers, and policy members in managing chronic neurobehavioral symptoms after TBI. NCT06581003 (registered on 8/28/2024) https://clinicaltrials.gov/study/NCT06581003?term=NCT06581003&rank=1