Efficacy of Hyperbaric Oxygen Treatment in Veterans and Service Members with Traumatic Brain Injury - A Study Protocol for a Blinded Group Sequential Randomized Controlled Trial

Efficacy of Hyperbaric Oxygen Treatment in Veterans and Service Members with Traumatic Brain Injury - A Study Protocol for a Blinded Group Sequential Randomized Controlled Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of Hyperbaric Oxygen Treatment in Veterans and Service Members with Traumatic Brain Injury - A Study Protocol for a Blinded Group Sequential Randomized Controlled Trial Dawn Neumann, Ambuj Kumar, Harry van Loveren This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6874662/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Mar, 2026 Read the published version in Trials → Version 1 posted 6 You are reading this latest preprint version Abstract Background: 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 y 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. Methods: This is a single-center blinded group sequential superiority randomized controlled trial (RCT). All consecutive US 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 minutes. The primary outcome is the post-intervention Neurobehavioral Symptom Inventory (NSI) score. Secondary outcomes is 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%. Discussion: 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. Trial Registration: NCT06581003 (registered on 8/28/2024) https://clinicaltrials.gov/study/NCT06581003?term=NCT06581003&rank=1 Traumatic brain injury Veterans Hyperbaric Oxygen Therapy Neurobehavioral Symptoms Post-Traumatic Stress Figures Figure 1 Background and rationale Traumatic brain injury (TBI), defined as a neurological insult due to an external force that disrupts brain function (e.g., falls, motor vehicle accidents, assault, and blast injuries)( 1 ), is common amongst Veterans and Military Service Members (V/SM).( 2 ) The Department of Defense (DoD) reported more than 510,000 service members were diagnosed with a TBI between 2000 and 2024, of which 82% were classified as mild and 12% as moderate.( 2 ) While the majority of those with mild TBI make a full return to baseline functioning without intervention, a substantial minority of about 20% continue to report long-term post-concussive symptoms with considerable distress.( 3 – 5 ) Given the prevalence of these long-term, neurobehavioral symptoms post-TBI, it is critical to identify acceptable, evidence-based interventions for these individuals. One intervention still under investigation for the treatment of neurobehavioral symptoms is hyperbaric oxygen therapy (HBOT). HBOT has generated substantial interest among V/SM for managing neurobehavioral symptoms associated with TBI.( 6 ) HBOT delivers 100% medical-grade oxygen inside a chamber where the air pressure is raised to at least 1.4 times greater than normal atmospheric pressure at sea level to increase oxygen supply to blood and tissues.( 7 ) It has been theorized that HBOT reduces inflammation and promotes the healing of neurological damage incurred by TBI due to the boosted delivery of oxygen.( 8 ) However, evidence for the efficacy of HBOT in improving persistent neurobehavioral symptoms in individuals with chronic mild and moderate TBI has been mixed.( 9 – 12 ) Some studies have found pre/post improvements in neurobehavioral symptoms and cognitive deficits in participants with mild TBI.( 10 ) However, these pre-post findings are prone to regression to the mean phenomena and cannot be considered reliable to consider HBOT an effective treatment for TBI symptoms. In a systematic review, Parr and colleagues synthesized results from three RCTs comparing HBOT to sham-controls in military participants with mild TBI( 12 – 15 ), and found no differences in post-treatment neurobehavioral symptoms between participants randomized to HBOT or the sham-control arm.( 12 ) Two additional studies published after the Parr synthesis are worth noting. The study by Wolf et al. randomized 25 military participants with mild TBI to 2.4 Atmospheres Absolute (ATA) or room air 1.3 ATA (sham) for thirty 90-minute sessions. The HBOT arm did not have better post-treatment neurobehavioral symptoms than the sham arm.( 16 ) In contrast, the most recent RCT (n = 49) by Weaver et al which used 1.5 ATA found a significant improvement in NSI compared to sham treatment.( 17 ) However, the study did not achieve their targeted accrual (n = 150) and had substantial attrition. Therefore, despite the statistically significant findings, these results are inconclusive. In short, the results from previous studies are conflicting and could be attributed to various limitations including, lack of power analysis,( 15 ) insufficient accrual and retention,( 17 ) adherence to the protocol,( 17 ) and poor controls.( 10 , 16 ) Furthermore, the strength of evidence was graded as low due to risk of bias and imprecision.( 12 ) Another issue relates to difference in number of sessions and the atmospheric pressure used.( 12 , 16 , 17 ) The abovementioned limitations in the extant literature prevent researchers and clinicians from understanding whether HBOT effectively reduces neurobehavioral symptoms in individuals with TBI. Furthermore, there is uncertainty related to the number of HBOT dives needed to achieve a response in mild/moderate TBI patients. The current trial seeks to overcome these key limitations by adequately powering the study with a large sample and using an inactive placebo to clarify the efficacy of HBOT in V/SM with chronic neurobehavioral symptoms after mild to moderate TBI. Objectives The primary objective of this study is to determine if HBOT, compared to placebo/sham, is associated with a reduction in chronic neurobehavioral symptoms in patients with chronic mild to moderate TBI. The secondary objectives are to 1) determine the number of HBOT dives needed to achieve a significant reduction in neurobehavioral symptoms after TBI and 2) assess the efficacy of HBOT versus placebo/sham in reducing post-traumatic stress disorder (PTSD) symptoms. Trial design The trial design is a blinded group sequential superiority randomized controlled trial (RCT). The aim is to assess the efficacy of HBOT (chamber pressurized to 2.0 ATA with 100% oxygen) to a placebo/sham (HBOT chamber that remains unpressurized with 21% oxygen, except for the ascent and descent, which lasts 16 minutes) in V/SM with chronic symptoms after mild to moderate TBI. The flow of participants in this trial will be reported according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines (Fig. 1 ).( 18 ) METHODS: participants, interventions, and outcomes Study setting This single-site study will be conducted at the University of South Florida Morsani College of Medicine’s HBOT Center located on the University of South Florida Health campus in Tampa, Florida. Eligibility criteria All consecutive US V/SM with histories of mild or moderate TBI (score of 2–4 on the OSU TBI Identification Method)( 19 ) at least one year before their study participation with persistent neurobehavioral symptoms (≥ 22 on the Neurobehavioral Symptom Inventory) will be eligible for inclusion. Other inclusion criteria are: 18–75 years of age; ability to read, write, and speak English; provide informed consent; tolerate lying down in HBOT environment for one hour; no scuba diving within the last month; and no HBOT within the previous three months. Participants will be excluded for health conditions that could pose a safety concern if treated with HBOT. The following three screening stages will be used to rule out conditions that would deem the participant ineligible: 1) Prescreening interview for basic criteria, such as age, U.S. Military involvement, exposure to HBOT in the last three months, obvious medical conditions that would preclude eligibility (e.g., respiratory problems or seizures); 2) self-report of medical history collected after consent; and 3) a comprehensive physical exam conducted by an advanced practitioner or the study medical director during baseline. Reasons for exclusion are: pregnant (determined by urine pregnancy test) or plans to become pregnant during the study period; currently lactating and breast-feeding; history of retinal repair; active malignancy, tumor-related chemotherapy within the past six-months, or therapeutic radiation to the central nervous system within the prior year; bipolar disorder type I or schizophrenia (determined by self-report and medication review); chronic use of supplemental oxygen or hypoxemia; emphysema with carbon dioxide retention; untreated asthma/bronchial obstruction/pulmonary blebs or bronchospasm; evidence of recent/untreated pneumothorax; pneumocephalus; upper respiratory infection; viral infection (e.g. high fever); congestive heart failure (ejection fraction < 40%); implanted devices not cleared for hyperbaric pressurization; history of middle ear surgery / disorders or evidence of noncompliant tympanic membrane (until corrected); optic neuritis; congenital spherocytosis; epilepsy and/ or seizures; current suicidal intent as measured by ≥ 3 on the Columbia-Suicide Severity Rating Scale Screener; and Antabuse and other medications that would predispose to oxygen toxicity or known to increase drug toxicity, which are disulfuram, acetazolamide, sulfamylon; bleomycin, cisplatin, and doxyrubicin. Concurrent clinical trial participation precludes participants from inclusion. Who will take informed consent? The principal investigator, project managers, research assistants, and independent evaluators will complete the informed consent process. All V/SM initially undergo a phone screen, which starts with a brief description of the RCT and its goals, followed by screening questions related to initial eligibility as V/SM, history of TBI including present and past symptoms, ability and availability to attend 40 HBOT dives, and assessment of exclusion parameters. Following the phone screen, participants will be invited to learn about the study via an informed consent session conducted by phone, virtual meeting platform, or in-person. All potential participants will also receive a hard or electronic copy of the Informed Consent Form (ICF). The consenting team member will review the study's risks and benefits and ensure the participant understands the research. We anticipate the ICF session will last an average of 30 minutes, but participants will be given as much time as needed to consider the study. The participant can schedule a second appointment if desired. After reviewing the ICF with a study team member, the participant may discuss the clinical trial with family and friends before deciding to participate. The research team will be available to answer questions about the study. If the participant wants to join the study, the consenting team member will have the individual sign the ICF via e-Florence (21 CFR Part 11 compliant system) or on-site. Interventions The study has two arms: HBOT (treatment) and sham/ placebo. For both arms, participants will complete 40 dives in Sechrist 3600H/HR Monoplace chambers (Sechrist Industries Inc, Anaheim, CA) within 12 weeks, with ideal daily week-day sessions. Total treatment session time (including time for changing into a hospital gown, pre/post recording of blood pressure, heart rate, etc.) is estimated at approximately 90 minutes. Total time in the monoplace HBOT chambers, including time for descent and ascent, is expected to be approximately 76 minutes; the intervention and placebo are 60 minutes). Participants will receive $ 50 for each dive to compensate for their time and improve adherence to the dive protocol. HBOT Arm : The experimental group will undergo HBOT at a pressure of 2.0 ATA. Oxygen will be delivered at 100% for approximately 60 minutes. The descent will be conducted with 100% oxygen over approximately 10 minutes until a depth and pressure of 2.0 ATA is reached. A curvilinear (slowly at first then gaining speed once the pressure change is decreased) descent will be used to reduce the incidence of barotrauma. Once at depth, the subject will be exposed to 100% oxygen at 2 ATA for approximately 60 minutes. Upon completion of the treatment, the chamber will slowly be lowered back to atmospheric pressure for approximately six minutes. Sham/placebo Arm : The sham intervention will use 1.0 ATA (normobaric) pressure and 21% oxygen delivery (normal oxygen concentration in room air) for approximately 60 minutes. During the approximate 10-minute descent phase of the procedure, the operator will increase pressure to simulate pressurized oxygen by exercising the tympanic membrane with no more than 1.3 ATA. This process will require the participants to clear their ears similar to the intervention arm, which decreases their ability to detect if they are in the treatment or placebo group. After the participant clears their ears, the chamber operator will reduce the pressure back to 1.0, and the participant will receive normal air for the approximately 60-minute-long procedure. After approximately 60 minutes, the chamber operator will pressurize the chamber to no greater than 1.3 ATA and decompress it within approximately 6 minutes. Criteria for discontinuing allocated interventions Any participant can withdraw from the trial at any time. An enrolled participant would become ineligible to continue in the study if s/he sustained an injury during the study that would prohibit completion, any change in circumstance that would render the participant unable to meet the inclusion criteria, or ineligibility determined by a medical physician on the research study team. Participants can also withdraw from the study due to any related Adverse events (AE) or Serious Adverse Events (SAE) that investigators/data safety monitoring committee deems warranting withdrawal of the subject (e.g., new TBI since enrollment) or non-availability to attend sessions in a timely manner. Participants who start the HBOT/sham sessions but do not complete all dives will be encouraged to complete the assessments following the intention-to-treat principle. Reasons for dropouts/withdrawal will be recorded. Outcomes Primary outcome Neurobehavioral Symptom Inventory (NSI). ( 20 ) Post-intervention NSI score is the primary outcome measure. Briefly, NSI is a 22-item self-report measure used to evaluate the severity of neurobehavioral symptoms after TBI. Using a four-point Likert scale (none to very severe), participants rate the degree to which they were disturbed by somatic/sensory, affective, and cognitive symptoms in the last two weeks. Scores range from 0–88 with acceptable reliability and validity.( 21 ) A score of 22 or greater was selected as an inclusion criterion in consistency with a similar RCT assessing the efficacy of HBOT for post-concussive symptoms.( 10 ) The published minimal detectable change is 5.70.( 22 ) The NSI was chosen as the primary outcome measure because it is a widely used and sensitive measure for detecting change( 23 ) in post-TBI neurobehavioral symptoms. The NSI is a common outcome in TBI HBOT trials. Secondary outcomes The number of HBOT dives needed to achieve a significant reduction in neurobehavioral symptoms after TBI. The goal is to determine if there is an optimal threshold for the number of HBOT dives to achieve a response as measured by NSI. PTSD Checklist for DSM-5 (PCL-5).( 24 ) Post-intervention PCL-5 score is the secondary outcome measure. It is a 20-item self-rated survey for measuring PTSD symptoms. Each item corresponds to the diagnostic criteria of PTSD. Participants indicate the degree to which they have been bothered by each symptom in the past week, ranging from 0 (not at all) to 4 (extremely). PCL5 is applied generally to any traumatic event. Psychometric properties indicate the PCL-5 is a valid instrument for PTSD symptoms.( 24 ) Participant timeline STUDY PERIOD Timepoint Enrollment Allocation Post-allocation (every 5th Dive) Closeout -t1 -t2 0 t1 t2 t3 t4 t5 t6 t7 t8 t9 ENROLLMENT Consent Eligibility screen1 Eligibility screen 2 Allocation X X X X INTERVENTION HBOT Sham/Placebo 40 dives in 12 weeks 40 dives in 12 weeks ASSESSMENTS Subject characteristics, medical history, military history X NSI X X X X X X X X X X PCL-5 X X X X X X X X X X Recruitment The following recruitment methods will be used for this study: study flyers will be posted on social media platforms, distributed at local or statewide events, and distributed at various healthcare provider offices; HBOT clinical trial website; patient referral by their treating physicians; and clinicaltrials.gov. Additionally, a healthcare administrative database from the James A. Haley Veterans' Hospital (JAHVH) and University of South Florida (USF) Health will be used to identify all V/SM with a TBI diagnosis. Individuals with a TBI diagnosis at JAHVH and USF Health will be sent letters notifying them about the study and the study website where they can choose to securely enter their contact information. Assignment of Intervention: Allocation and Blinding Random sequence generation: A block-stratified method using the PASS computer program( 25 ) will be used for the generation of the randomization sequence stratified for TBI severity (mild, moderate). The block size will be random. Allocation concealment: The allocation concealment will be ensured by central randomization via the REDCap( 26 ) randomization module, where the assignment table will be uploaded. REDCap will assign a treatment group to each participant. Once a participant meets eligibility criteria, an HBOT technician enters the participants' information into REDCap and receives the treatment assignment. All consecutive consenting participants who pass the baseline assessments will be randomized to one of the two study groups in a 1:1 allocation ratio. Blinding: Participants will be blinded to conditions to reduce performance bias. To minimize detection bias, investigators, Independent Evaluators (IE), and data analysts will also be blinded to treatment conditions (i.e. HBOT or placebo/sham group). Treatments will be coded (e.g., A or B) in the database. Because the primary outcome measure data will be collected using a self-report questionnaire, the possibility of interpretation does not exist. Only in case of safety issues could the participants' assignment be unblinded. All participants will be unblinded after the 2-week post-treatment assessment. To assess the adequacy of blinding participants, all participants will complete a Group Allocation Belief form during the post-treatment visit to evaluate if participants could correctly identify the random group allocation. Data collection and management Data collection for the primary (NSI) and secondary (PCL-5) outcome measures occur at baseline, every 5th dive, and at the 2-week post-treatment assessment. Data for the NSI and PCL-5 are collected via electronic surveys in REDCap and are completed directly by the subject. The IEs, which include Clinical Research Associates and Advanced Practitioners, are responsible for the collection of this data. Participants are paid stipends for baseline, mid-point assessments, and post-treatment assessments. With permission, assessments will still be performed on participants who withdraw from treatment. Data monitoring This study has two forms of ongoing monitoring. First, this study is monitored quarterly by an independent study monitor from USF Research Integrity & Compliance Quality Improvement Program. Second, this study also reports to the Data Safety Monitoring Board (DSMB). The DSMB is an independent multidisciplinary group of researchers, physicians, methodologists and biostatisticians. DSMB meetings are held annually, and interim reports are sent quarterly to the Board members. The DSMB is comprised of six external experts not employed at USF with complementary areas of expertise, including TBI (n = 3), HBOT (n = 2), clinical trials and translational research (n = 3), neurobehavioral outcomes (n = 2), and military research (n = 1). Adverse Events and Serious Adverse Events Monitoring. Study staff systematically monitor all AEs, SAEs, and unanticipated problems involving risk to participants or others (UPIRSOs) throughout the study. AEs are defined as any untoward physical or psychological event in a human subject that occurs after consent through the end of the subject's study participation. AEs include new events that were not present prior to the subject's participation in the intervention or events that were present before the study intervention started but notably increased in severity. The primary study staff member interacts with the participant to assess and document the participant's health status at each visit by asking if anything has changed in their health or medications since their last visit. Each participant has a safety log, which is used to record any AEs or SAEs. The study team, including the principal investigator and medical team members, reviews all AEs, SAEs and UPIRSOs to determine their relation to the intervention (e.g., Unrelated, Unlikely, Possible, Probable, and Definite). SAEs and other UPIRSOs are reported to the DSMB, IRB, Food and drug administration (FDA), and the funder in accordance with reporting requirements. Sample size calculations The proposed study is a blinded three-stage, group sequential adaptive RCT. The primary outcome is the difference between the experimental (HBOT) and placebo/sham arms on NSI total scores at 2 weeks post-treatment. At post-treatment, we expect the HBOT group to have a mean NSI score of 27.3, placebo/sham group a mean of 33, with a standard deviation (SD) for a single observation of 17. To detect the smallest meaningful difference of 5.7 between groups at post-treatment, 168 participants per group is needed for a total N = 336. With an expected dropout rate of 20%, we plan to randomize N = 420. This is a group sequential study design, and three interim analyses are planned accordingly. For early detection of efficacy, the first of three planned interim analyses will be performed after the accrual of 84 patients (42 per group) complete 40 dives and the 2 weeks post-intervention assessment. The second and third interim analyses are planned after accrual and completion of 40 HBOT/Sham dives by 168 (84 per group) and 252 (126 per group) participants, respectively. The final analysis is planned after the accrual of all 336 participants (168 per group). Accounting for dropouts/withdrawals, the planned accrual is 105 for the first, 210 for the second, 315 for the third interim analysis, and 420 participants (Fig. 1 ) for the final analysis. The sample sizes for the three interim analyses are based on alpha errors of 0.01%, 0.55%, and 2.19% for the first, second, and third interim analyses, respectively. Statistical analysis All interim and final analyses for the primary and secondary outcomes associated with improvement will be based on the intent-to-treat (ITT) principle, which includes all randomized participants. For safety or adverse events, all analyses will be performed according to the per-protocol principle, including participants who successfully completed this clinical trial according to the plan. The participant characteristics will be summarized as average, standard deviation, minimum and maximum values for continuous data, and frequency and percentage for categorical data. The difference in participant characteristics across the compared groups will be assessed using the Chi-Square test, Fisher's exact test, or independent samples t -test, as applicable. The difference in the efficacy associated with the compared interventions will be assessed at 2 weeks post the last dive using the independent samples t-test and summarized as mean difference (MD) along with 95% confidence intervals (CI). The statistical significance is set at 0.01% for the first interim analysis, 0.55% for the second interim analysis, 2.19% for the third interim analysis and 5% for the final analysis. If any interim analyses show a significant beneficial effect with HBOT, the randomization will stop, and all subjects will be offered HBOT. The data collection will continue, and the analyses will be pre-post instead of comparative. If there is no efficacy at the first interim analysis, we will continue the study without adaptation unless significant side effects are found for HBOT. For participants lost to follow-up (i.e., missing data), the last observation carried forward method will be used, including the baseline status and the status at the last visit. All analyses will be performed using the IBM SPSS statistical analysis package.( 27 ) Because this is an RCT, we expect the groups to be balanced at baseline for the interim and final analysis. However, in case of baseline imbalance between the compared groups, we will use a generalized linear model with compared treatments as the main effect and baseline status as a covariate. Additionally, we will apply the mixed-model repeated measures (MMRM) method to measure the change from baseline to each post-baseline assessment during the treatment period. Additional per-protocol analyses will be conducted, including a modified ITT group of participants who attended at least 75% of HBOT dives (30 dives) and an efficacy group of participants who completed all 40 dives according to the protocol. The secondary outcome to determine the optimal number of HBOT dives required to achieve a response will be assessed using the receiver operating curve analysis and summarized as the area under the curve along with 95% CI. PTSD may play moderating roles in treatment response and will be examined with sensitivity analyses. Ethical Considerations and Dissemination This study is approved by the Institutional Review Board (IRB) at USF (IRB# 6819). The United States FDA has authorized the use of HBOT under investigational new drug (IND)/ investigational device exemption (IDE; IND/ IDE #: 172640). All participants provide a verbal consent before prescreening and sign an ICF before additional data collection. For transparency, this study is registered on Clinicaltrials.gov (NCT06581003). Participants who are randomized to the sham and complete the full study protocol will be offered the opportunity to receive 40 HBOT dives locally or at an approved clinic after unblinding. Any anomalies or abnormalities that present a risk to the participant's health (e.g., elevated blood pressure) identified during the assessments will be reported to the participant. The participant may also be offered referrals for appropriate clinical evaluation and care based on existing standards of care. Results will be disseminated via peer-reviewed scientific journals and conferences. Findings will also be posted on ClinicalTrials.gov. Discussion The efficacy of HBOT has been previously assessed in RCTs. However, the previous trials had limitations that make the results inconclusive, including inadequately powered RCTs, high dropout rates, and challenges with treatment adherence due to significant time to complete 40 dives. The goal of the current RCT is to address the previous studies limitations and provide evidence about whether HBOT is effective at reducing neurobehavioral symptoms after a mild or moderate TBI in V/SM. If efficacy is established, the results will also inform participants, providers, and policy makers about the optimal number of HBOT dives needed for a clinically-relevant response. Trial Status Initial approval was 07/16/25. Current status is: Protocol version # 5 (submitted 02/18/2025), which was approved 03/24/2025. Recruitment began: 09/18/2024 Approximate date recruitment will end: 06/01/2027 Abbreviations AEs Adverse Events AUC Area Under the Curve ATA Atmosphere Absolute CO 2 Carbon Dioxide COPD Chronic Obstructive Pulmonary Disease CI Confidence Interval CITI Collaborative Institutional Training Initiative C-SSRSS Columbia Suicide Severity Rating Scale Screener DSMB Data Safety Monitoring Board DVBIC Defense and Veterans Brain Injury Center DOD Department of Defense DSM-5 Diagnostic and Statistical Manual of Mental Disorders − 5 FDA U. S. Food and Drug Administration fMRI Functional Magnetic Resonance Imaging HIPAA Health Insurance Portability and Accountability Act HBOT Hyperbaric Oxygen Therapy IE Independent Evaluators III Individually Identifiable Information ICF Informed Consent Form IRB Institutional Review Board ITT Intent-to-treat IDE Investigational Device Exemption JAHVH James A. Haley Veteran’s Hospital mTBI Mild TBI MMRM Mixed Model Repeated Measures NIH National Institutes of Health NSI Neurobehavioral Symptom Inventory OEF Operation Enduring Freedom OIF Operation Iraqi Freedom OND Operation New Dawn OSU TBI Ohio State University TBI Identification Method PCL-5 PTSD Checklist-5 PTSD Posttraumatic Stress Disorder PI Principal Investigator PHI Protected Health Information RCT Randomized Controlled Trial ROC Receiver Operating Curve R&DC Research and Development Committee SAE Serious Adverse Events SD Standard Deviation SOP Standard Operating Procedure SI Suicide Intent TBI Traumatic Brain Injury UPIRSOs Unanticipated Problems Involving Risk to Participants or Others US United States USF University of South Florida VA Veteran’s Administration Declarations Ethics Approval and Consent to participate: This study is approved by the Institutional Review Board (IRB) at USF (IRB# 6819). Written, informed consent to participate will be obtained from all participants. The United States FDA has authorized the use of HBOT under investigational new drug (IND)/ investigational device exemption (IDE; IND/ IDE #: 172640). Consent for Publication. All have reviewed content and have provided consent for publication of this manuscript Availability of data and materials. Data will be made available upon request provide proper data use agreements are in place. Competing interests: Directly related to this HBOT study, several authors’ received support from the State of Florida funding via their institutions (DN, AK, HvL, JW, JD, KD, RK, JM, SRM, TR, NS, MS, MT, AT, JW, HY, FRY). Some authors receive fees for consultation (MM, JW), expert testimony (MS, JW), honorarium (MS), or for royalties or licenses (MS), and/or own stock (MM). MS, NS, AW, JW, FRY serve on advisory boards or workshop groups. Funding. The State of Florida funded this multi-year randomized clinical trial through the legislative appropriations process during state fiscal years 22-24. The subsequent budgets were signed by the Governor and the funding was allocated to the USF Morsani College of Medicine to conduct the five-year trial. Authors’ contribution. All authors contributed to obtaining funding, design of the study, review of the study design, obtaining required approvals, and/or ongoing conduct of the trial. Acknowledgements : Below we acknowledge the individuals who comprise the USF HBOT for Veterans with TBI Collaborative Group (alphabetical order) F Y Bowling USSOCOM [email protected] Joseph Dituri, PhD University of South Florida, Morsani College of Medicine [email protected] Keith Dombrowski, MD University of South Florida, Morsani College of Medicine [email protected] Rachel Karlnoski, PhD University of South Florida, Morsani College of Medicine [email protected] Kelli Kessack University of South Florida, Morsani College of Medicine [email protected] Jorge Mendoza Veteran Shannon R. Miles, PhD James A. Haley Veterans’ Hospital [email protected] Max Mokin, MD, PhD University of South Florida, Morsani College of Medicine [email protected] Tea Reljic, MS, MPH University of South Florida, Morsani College of Medicine [email protected] Paul Sanberg, MD, PhD Co-I University of South Florida, Morsani College of Medicine [email protected] Nathan Schilaty, DC, PhD University of South Florida, Morsani College of Medicine [email protected] Michael Schoenberg, PhD University of South Florida, Morsani College of Medicine [email protected] Mala Trivedi, MD University of South Florida, Morsani College of Medicine [email protected] Athanasios Tsalatsanis, PhD University of South Florida, Morsani College of Medicine [email protected] Narayan Viswanadhan, MD James A. Haley Veterans’ Hospital [email protected] Alison Willing, PhD University of South Florida, Morsani College of Medicine [email protected] Chris Wilson USSOCOM [email protected] Jason Wilson, MD, PhD University of South Florida, Morsani College of Medicine [email protected] Hariom Yadav, PhD University of South Florida, Morsani College of Medicine [email protected] Fayyadh Yusuf, PhD University of South Florida, Morsani College of Medicine [email protected] References Centers for Disease Control and Prevention. TBI: Get the FactsFebruary 19. 2025. Available from: http://www.cdc.gov/ncipc/tbi/TBI.htm . doi: https://www.cdc.gov/traumaticbraininjury/get_the_facts.html Military Health System. DOD TBI Worldwide Numbers 2023 [Available from: https://health.mil/Military-Health-Topics/Centers-of-Excellence/Traumatic-Brain-Injury-Center-of-Excellence/DOD-TBI-Worldwide-Numbers Belanger HG, Curtiss G, Demery JA, Lebowitz BK, Vanderploeg RD. Factors moderating neuropsychological outcomes following mild traumatic brain injury: a meta-analysis. J Int Neuropsychol Soc. 2005;11(3):215–27. Lagace-Legendre C, Boucher V, Robert S, Tardif PA, Ouellet MC, de Guise E, et al. Persistent Postconcussion Symptoms: An Expert Consensus-Based Definition Using the Delphi Method. J Head Trauma Rehabil. 2021;36(2):96–102. Quinn DK, Mayer AR, Master CL, Fann JR. Prolonged Postconcussive Symptoms. Am J Psychiatry. 2018;175(2):103–11. Kim Peterson D, Bourne J, Anderson E, Boundy HM. Evidence Brief: Hyperbaric Oxygen Therapy (HBOT) for Traumatic Brain Injury and/or Post-traumatic Stress Disorder. Washington (DC): Department of Veterans Affairs (US); 2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499535/ Gottfried I, Schottlender N, Ashery U. Hyperbaric Oxygen Treatment-From Mechanisms to Cognitive Improvement. Biomolecules. 2021;11(10). Liu H-y, Shang Y-h. Effect of guipizide maleate with hyperbaric oxygen therapy on neurophysiology and coagulation indices in patients with severe craniocerebral injury Tropical. J Pharm Res. 2023;22(7):1483–8. Harch PG. Systematic Review and Dosage Analysis: Hyperbaric Oxygen Therapy Efficacy in Mild Traumatic Brain Injury Persistent Postconcussion Syndrome. Front Neurol. 2022;13:815056. Harch PG, Andrews SR, Rowe CJ, Lischka JR, Townsend MH, Yu Q, et al. Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome: a randomized controlled trial. Med Gas Res. 2020;10(1):8–20. Miskin BM, Fox LA, Abou-Al-Shaar H, Bin-Alamer O, Goertz A, Lipin CT, et al. Hyperbaric Oxygen Therapy for the Management of Mild and Moderate Traumatic Brain Injury: A Single-Center Experience. World Neurosurg. 2023;176:e357–70. Parr NJ, Anderson J, Veazie S. Evidence Brief: Hyperbaric Oxygen Therapy for Traumatic Brain Injury and/or Post-traumatic Stress Disorder. VA Evidence-based Synthesis Program Reports. Washington (DC)2021. Cifu DX, Hart BB, West SL, Walker W, Carne W. The effect of hyperbaric oxygen on persistent postconcussion symptoms. J Head Trauma Rehabil. 2014;29(1):11–20. Miller RS, Weaver LK, Bahraini N, Churchill S, Price RC, Skiba V, et al. Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms: a randomized clinical trial. JAMA Intern Med. 2015;175(1):43–52. Weaver LK, Wilson SH, Lindblad AS, Churchill S, Deru K, Price RC, et al. Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial. Undersea Hyperb Med. 2018;45(2):129–56. Wolf G, Cifu D, Baugh L, Carne W, Profenna L. The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury. J Neurotrauma. 2012;29(17):2606–12. Weaver LK, Ziemnik R, Deru K, Russo AA. A double-blind randomized trial of hyperbaric oxygen for persistent symptoms after brain injury. Sci Rep. 2025;15(1):6885. Butcher NJ, Monsour A, Mew EJ, Chan AW, Moher D, Mayo-Wilson E, et al. Guidelines for Reporting Outcomes in Trial Reports: The CONSORT-Outcomes 2022 Extension. JAMA. 2022;328(22):2252–64. Corrigan JD, Bogner J. Initial reliability and validity of the Ohio State University TBI identification method. J Head Trauma Rehabil. 2007;22(6):318–29. Cicerone KD, Kalmar K. Persistent postconcussion syndrome: The structure of subjective complaints after mild traumatic brain injury. J Head Trauma Rehabil. 1995;10(3):1–17. Silva MA. Review of the Neurobehavioral Symptom Inventory. Rehabil Psychol. 2021;66(2):170–82. Silva MA, Barwick FH, Kretzmer TS, Vanderploeg RD, Belanger HG. Reliable change indices for the Neurobehavioral Symptom Inventory and Brief Symptom Inventory-18 in a mild traumatic brain injury sample. Clin Neuropsychol. 2013;27(4):539–646. Scarlett E, Lu LH, Cummings LD, Bowles AO. Neurobehavioral Symptom Inventory Item-Level Change Complements the Reliable Change Method. J Head Trauma Rehabil. 2023;38(4):E312–7. Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. J Trauma Stress. 2015;28(6):489–98. PASS. 2025 Power Analysis and Sample Size Software. Kaysville, Utah, USA: NCSS, LLC; 2025. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42(2):377–81. IBM corp. IBM SPSS Statistics for Windows Version 29. Armonk, NY: IBM Corp; 2025. Tables Table 1 Participant Timeline STUDY PERIOD Timepoint Enrollment Allocation Post-allocation (every 5th Dive) Closeout -t1 -t2 0 t1 t2 t3 t4 t5 t6 t7 t8 t9 ENROLLMENT Consent Eligibility screen1 Eligibility screen 2 Allocation X X X X INTERVENTION HBOT Sham/Placebo 40 dives in 12 weeks 40 dives in 12 weeks ASSESSMENTS Subject characteristics, medical history, military history X NSI X X X X X X X X X X PCL-5 X X X X X X X X X X Supplementary Files FillableSPIRITOutcomes2022ChecklistwithSPIRIT2013.pdf Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2026 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 24 Dec, 2025 Reviewers agreed at journal 17 Jul, 2025 Reviewers invited by journal 10 Jul, 2025 Editor invited by journal 10 Jul, 2025 Editor assigned by journal 12 Jun, 2025 First submitted to journal 11 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6874662","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":483479023,"identity":"aa7ec627-1a6a-4cb7-b11e-9608820f46d9","order_by":0,"name":"Dawn Neumann","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDCCA1Da/nwziCkhQ7wWhhvHEkBaeEjQciDHAEQR1sJ3u/mY1I2aO3mMDWc+v7pRY8HDwH746AZ8WiTvHEuTzjn2rJiZuXebdc4xoMN40tJu4NNicCPHTDqH7XBiG8PZbcY5bEAtEjxmBLTkf5PO+Xc4sYch55lxzj+itOSwSee2HU6cwZDD/Di3jQgtkjfSjK1z+w4nbpA4Zsac2yfBw0bIL3w3kh/ezvkG1MLf/Phzzrc6OX72w8fwakEGbBJgkljlIMD8gRTVo2AUjIJRMHIAAElcTWAwtcqMAAAAAElFTkSuQmCC","orcid":"","institution":"University of South Florida Morsani College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Dawn","middleName":"","lastName":"Neumann","suffix":""},{"id":483479024,"identity":"0d2eb062-9d02-4a0e-86cb-080f5884620a","order_by":1,"name":"Ambuj Kumar","email":"","orcid":"https://orcid.org/0000-0003-1260-6694","institution":"University of South Florida College of Medicine: University of South Florida Morsani College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ambuj","middleName":"","lastName":"Kumar","suffix":""},{"id":483479025,"identity":"51a294be-bd7f-458c-93e5-bd4113fd8259","order_by":2,"name":"Harry van Loveren","email":"","orcid":"","institution":"University of South Florida College of Medicine: University of South Florida Morsani College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Harry","middleName":"van","lastName":"Loveren","suffix":""}],"badges":[],"createdAt":"2025-06-11 20:07:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6874662/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6874662/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-026-09645-z","type":"published","date":"2026-03-25T16:12:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86674219,"identity":"56e8f867-57d0-4af3-a98b-743053be4ef1","added_by":"auto","created_at":"2025-07-14 11:52:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37973,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eParticipant Flow\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1Studyflow.png","url":"https://assets-eu.researchsquare.com/files/rs-6874662/v1/1549a186b988d87b7fc4c25f.png"},{"id":105755937,"identity":"c99c2573-8798-4214-980f-cf4529223ee6","added_by":"auto","created_at":"2026-03-30 16:33:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1031853,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6874662/v1/a0ecb870-7e39-4300-bd90-aca664a89074.pdf"},{"id":86675522,"identity":"4cc716f2-1601-4d11-99ef-836c575e09bf","added_by":"auto","created_at":"2025-07-14 12:00:25","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":233585,"visible":true,"origin":"","legend":"","description":"","filename":"FillableSPIRITOutcomes2022ChecklistwithSPIRIT2013.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6874662/v1/0a525f58616a92e2e2736053.pdf"}],"financialInterests":"","formattedTitle":"Efficacy of Hyperbaric Oxygen Treatment in Veterans and Service Members with Traumatic Brain Injury - A Study Protocol for a Blinded Group Sequential Randomized Controlled Trial","fulltext":[{"header":"Background and rationale","content":"\u003cp\u003eTraumatic brain injury (TBI), defined as a neurological insult due to an external force that disrupts brain function (e.g., falls, motor vehicle accidents, assault, and blast injuries)(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), is common amongst Veterans and Military Service Members (V/SM).(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) The Department of Defense (DoD) reported more than 510,000 service members were diagnosed with a TBI between 2000 and 2024, of which 82% were classified as mild and 12% as moderate.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) While the majority of those with mild TBI make a full return to baseline functioning without intervention, a substantial minority of about 20% continue to report long-term post-concussive symptoms with considerable distress.(\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Given the prevalence of these long-term, neurobehavioral symptoms post-TBI, it is critical to identify acceptable, evidence-based interventions for these individuals.\u003c/p\u003e\u003cp\u003eOne intervention still under investigation for the treatment of neurobehavioral symptoms is hyperbaric oxygen therapy (HBOT). HBOT has generated substantial interest among V/SM for managing neurobehavioral symptoms associated with TBI.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) HBOT delivers 100% medical-grade oxygen inside a chamber where the air pressure is raised to at least 1.4 times greater than normal atmospheric pressure at sea level to increase oxygen supply to blood and tissues.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) It has been theorized that HBOT reduces inflammation and promotes the healing of neurological damage incurred by TBI due to the boosted delivery of oxygen.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) However, evidence for the efficacy of HBOT in improving persistent neurobehavioral symptoms in individuals with chronic mild and moderate TBI has been mixed.(\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Some studies have found pre/post improvements in neurobehavioral symptoms and cognitive deficits in participants with mild TBI.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) However, these pre-post findings are prone to regression to the mean phenomena and cannot be considered reliable to consider HBOT an effective treatment for TBI symptoms. In a systematic review, Parr and colleagues synthesized results from three RCTs comparing HBOT to sham-controls in military participants with mild TBI(\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), and found no differences in post-treatment neurobehavioral symptoms between participants randomized to HBOT or the sham-control arm.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Two additional studies published after the Parr synthesis are worth noting. The study by Wolf et al. randomized 25 military participants with mild TBI to 2.4 Atmospheres Absolute (ATA) or room air 1.3 ATA (sham) for thirty 90-minute sessions. The HBOT arm did not have better post-treatment neurobehavioral symptoms than the sham arm.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) In contrast, the most recent RCT (n\u0026thinsp;=\u0026thinsp;49) by Weaver et al which used 1.5 ATA found a significant improvement in NSI compared to sham treatment.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) However, the study did not achieve their targeted accrual (n\u0026thinsp;=\u0026thinsp;150) and had substantial attrition. Therefore, despite the statistically significant findings, these results are inconclusive. In short, the results from previous studies are conflicting and could be attributed to various limitations including, lack of power analysis,(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) insufficient accrual and retention,(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) adherence to the protocol,(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and poor controls.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) Furthermore, the strength of evidence was graded as low due to risk of bias and imprecision.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Another issue relates to difference in number of sessions and the atmospheric pressure used.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThe abovementioned limitations in the extant literature prevent researchers and clinicians from understanding whether HBOT effectively reduces neurobehavioral symptoms in individuals with TBI. Furthermore, there is uncertainty related to the number of HBOT dives needed to achieve a response in mild/moderate TBI patients. The current trial seeks to overcome these key limitations by adequately powering the study with a large sample and using an inactive placebo to clarify the efficacy of HBOT in V/SM with chronic neurobehavioral symptoms after mild to moderate TBI.\u003c/p\u003e\n\u003ch3\u003eObjectives\u003c/h3\u003e\n\u003cp\u003eThe primary objective of this study is to determine if HBOT, compared to placebo/sham, is associated with a reduction in chronic neurobehavioral symptoms in patients with chronic mild to moderate TBI. The secondary objectives are to 1) determine the number of HBOT dives needed to achieve a significant reduction in neurobehavioral symptoms after TBI and 2) assess the efficacy of HBOT versus placebo/sham in reducing post-traumatic stress disorder (PTSD) symptoms.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eTrial design\u003c/h2\u003e\u003cp\u003eThe trial design is a blinded group sequential superiority randomized controlled trial (RCT). The aim is to assess the efficacy of HBOT (chamber pressurized to 2.0 ATA with 100% oxygen) to a placebo/sham (HBOT chamber that remains unpressurized with 21% oxygen, except for the ascent and descent, which lasts 16 minutes) in V/SM with chronic symptoms after mild to moderate TBI. The flow of participants in this trial will be reported according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"METHODS: participants, interventions, and outcomes","content":"\u003cp\u003e\u003cem\u003eStudy setting\u003c/em\u003e This single-site study will be conducted at the University of South Florida Morsani College of Medicine\u0026rsquo;s HBOT Center located on the University of South Florida Health campus in Tampa, Florida.\u003c/p\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003eAll consecutive US V/SM with histories of mild or moderate TBI (score of 2\u0026ndash;4 on the OSU TBI Identification Method)(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) at least one year before their study participation with persistent neurobehavioral symptoms (\u0026ge;\u0026thinsp;22 on the Neurobehavioral Symptom Inventory) will be eligible for inclusion. Other inclusion criteria are: 18\u0026ndash;75 years of age; ability to read, write, and speak English; provide informed consent; tolerate lying down in HBOT environment for one hour; no scuba diving within the last month; and no HBOT within the previous three months.\u003c/p\u003e\u003cp\u003eParticipants will be excluded for health conditions that could pose a safety concern if treated with HBOT. The following three screening stages will be used to rule out conditions that would deem the participant ineligible: 1) Prescreening interview for basic criteria, such as age, U.S. Military involvement, exposure to HBOT in the last three months, obvious medical conditions that would preclude eligibility (e.g., respiratory problems or seizures); 2) self-report of medical history collected after consent; and 3) a comprehensive physical exam conducted by an advanced practitioner or the study medical director during baseline. Reasons for exclusion are: pregnant (determined by urine pregnancy test) or plans to become pregnant during the study period; currently lactating and breast-feeding; history of retinal repair; active malignancy, tumor-related chemotherapy within the past six-months, or therapeutic radiation to the central nervous system within the prior year; bipolar disorder type I or schizophrenia (determined by self-report and medication review); chronic use of supplemental oxygen or hypoxemia; emphysema with carbon dioxide retention; untreated asthma/bronchial obstruction/pulmonary blebs or bronchospasm; evidence of recent/untreated pneumothorax; pneumocephalus; upper respiratory infection; viral infection (e.g. high fever); congestive heart failure (ejection fraction\u0026thinsp;\u0026lt;\u0026thinsp;40%); implanted devices not cleared for hyperbaric pressurization; history of middle ear surgery / disorders or evidence of noncompliant tympanic membrane (until corrected); optic neuritis; congenital spherocytosis; epilepsy and/ or seizures; current suicidal intent as measured by \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;3 on the Columbia-Suicide Severity Rating Scale Screener; and Antabuse and other medications that would predispose to oxygen toxicity or known to increase drug toxicity, which are disulfuram, acetazolamide, sulfamylon; bleomycin, cisplatin, and doxyrubicin. Concurrent clinical trial participation precludes participants from inclusion.\u003c/p\u003e\n\u003ch3\u003eWho will take informed consent?\u003c/h3\u003e\n\u003cp\u003eThe principal investigator, project managers, research assistants, and independent evaluators will complete the informed consent process. All V/SM initially undergo a phone screen, which starts with a brief description of the RCT and its goals, followed by screening questions related to initial eligibility as V/SM, history of TBI including present and past symptoms, ability and availability to attend 40 HBOT dives, and assessment of exclusion parameters. Following the phone screen, participants will be invited to learn about the study via an informed consent session conducted by phone, virtual meeting platform, or in-person. All potential participants will also receive a hard or electronic copy of the Informed Consent Form (ICF). The consenting team member will review the study's risks and benefits and ensure the participant understands the research. We anticipate the ICF session will last an average of 30 minutes, but participants will be given as much time as needed to consider the study. The participant can schedule a second appointment if desired. After reviewing the ICF with a study team member, the participant may discuss the clinical trial with family and friends before deciding to participate. The research team will be available to answer questions about the study. If the participant wants to join the study, the consenting team member will have the individual sign the ICF via e-Florence (21 CFR Part 11 compliant system) or on-site.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eThe study has two arms: HBOT (treatment) and sham/ placebo. For both arms, participants will complete 40 dives in Sechrist 3600H/HR Monoplace chambers (Sechrist Industries Inc, Anaheim, CA) within 12 weeks, with ideal daily week-day sessions. Total treatment session time (including time for changing into a hospital gown, pre/post recording of blood pressure, heart rate, etc.) is estimated at approximately 90 minutes. Total time in the monoplace HBOT chambers, including time for descent and ascent, is expected to be approximately 76 minutes; the intervention and placebo are 60 minutes). Participants will receive \u003cspan\u003e$\u003c/span\u003e50 for each dive to compensate for their time and improve adherence to the dive protocol.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHBOT Arm\u003c/span\u003e: The experimental group will undergo HBOT at a pressure of 2.0 ATA. Oxygen will be delivered at 100% for approximately 60 minutes. The descent will be conducted with 100% oxygen over approximately 10 minutes until a depth and pressure of 2.0 ATA is reached. A curvilinear (slowly at first then gaining speed once the pressure change is decreased) descent will be used to reduce the incidence of barotrauma. Once at depth, the subject will be exposed to 100% oxygen at 2 ATA for approximately 60 minutes. Upon completion of the treatment, the chamber will slowly be lowered back to atmospheric pressure for approximately six minutes.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSham/placebo Arm\u003c/span\u003e: The sham intervention will use 1.0 ATA (normobaric) pressure and 21% oxygen delivery (normal oxygen concentration in room air) for approximately 60 minutes. During the approximate 10-minute descent phase of the procedure, the operator will increase pressure to simulate pressurized oxygen by exercising the tympanic membrane with no more than 1.3 ATA. This process will require the participants to clear their ears similar to the intervention arm, which decreases their ability to detect if they are in the treatment or placebo group. After the participant clears their ears, the chamber operator will reduce the pressure back to 1.0, and the participant will receive normal air for the approximately 60-minute-long procedure. After approximately 60 minutes, the chamber operator will pressurize the chamber to no greater than 1.3 ATA and decompress it within approximately 6 minutes.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eCriteria for discontinuing allocated interventions\u003c/h2\u003e\u003cp\u003eAny participant can withdraw from the trial at any time. An enrolled participant would become ineligible to continue in the study if s/he sustained an injury during the study that would prohibit completion, any change in circumstance that would render the participant unable to meet the inclusion criteria, or ineligibility determined by a medical physician on the research study team. Participants can also withdraw from the study due to any related Adverse events (AE) or Serious Adverse Events (SAE) that investigators/data safety monitoring committee deems warranting withdrawal of the subject (e.g., new TBI since enrollment) or non-availability to attend sessions in a timely manner. Participants who start the HBOT/sham sessions but do not complete all dives will be encouraged to complete the assessments following the intention-to-treat principle. Reasons for dropouts/withdrawal will be recorded.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003cp\u003e\u003cem\u003eNeurobehavioral Symptom Inventory (NSI).\u003c/em\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) Post-intervention NSI score is the primary outcome measure. Briefly, NSI is a 22-item self-report measure used to evaluate the severity of neurobehavioral symptoms after TBI. Using a four-point Likert scale (none to very severe), participants rate the degree to which they were disturbed by somatic/sensory, affective, and cognitive symptoms in the last two weeks. Scores range from 0\u0026ndash;88 with acceptable reliability and validity.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) A score of 22 or greater was selected as an inclusion criterion in consistency with a similar RCT assessing the efficacy of HBOT for post-concussive symptoms.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) The published minimal detectable change is 5.70.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) The NSI was chosen as the primary outcome measure because it is a widely used and sensitive measure for detecting change(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) in post-TBI neurobehavioral symptoms. The NSI is a common outcome in TBI HBOT trials.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSecondary outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eThe number of HBOT dives needed to achieve a significant reduction in neurobehavioral symptoms after TBI. The goal is to determine if there is an optimal threshold for the number of HBOT dives to achieve a response as measured by NSI.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePTSD Checklist for DSM-5 (PCL-5).(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) Post-intervention PCL-5 score is the secondary outcome measure. It is a 20-item self-rated survey for measuring PTSD symptoms. Each item corresponds to the diagnostic criteria of PTSD. Participants indicate the degree to which they have been bothered by each symptom in the past week, ranging from 0 (not at all) to 4 (extremely). PCL5 is applied generally to any traumatic event. Psychometric properties indicate the PCL-5 is a valid instrument for PTSD symptoms.(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\n\u003ch3\u003eParticipant timeline\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"13\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"12\" nameend=\"c13\" namest=\"c2\"\u003e\u003cp\u003eSTUDY PERIOD\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTimepoint\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eEnrollment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAllocation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"8\" nameend=\"c12\" namest=\"c5\"\u003e\u003cp\u003ePost-allocation\u003c/p\u003e\u003cp\u003e(every 5th Dive)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003eCloseout\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-t1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-t2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003et1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003et2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003et3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003et4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003et5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003et6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003et7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003et8\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003et9\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e\u003cb\u003eENROLLMENT\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eConsent\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEligibility screen1\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEligibility screen 2\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eAllocation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eINTERVENTION\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eHBOT\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSham/Placebo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"8\" nameend=\"c12\" namest=\"c5\"\u003e\u003cp\u003e\u003cb\u003e40 dives in 12 weeks\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"8\" nameend=\"c12\" namest=\"c5\"\u003e\u003cp\u003e\u003cb\u003e40 dives in 12 weeks\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eASSESSMENTS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSubject characteristics, medical history, military history\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNSI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePCL-5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cb\u003eX\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eRecruitment\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe following recruitment methods will be used for this study: study flyers will be posted on social media platforms, distributed at local or statewide events, and distributed at various healthcare provider offices; HBOT clinical trial website; patient referral by their treating physicians; and clinicaltrials.gov. Additionally, a healthcare administrative database from the James A. Haley Veterans' Hospital (JAHVH) and University of South Florida (USF) Health will be used to identify all V/SM with a TBI diagnosis. Individuals with a TBI diagnosis at JAHVH and USF Health will be sent letters notifying them about the study and the study website where they can choose to securely enter their contact information.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eAssignment of Intervention: Allocation and Blinding\u003c/h2\u003e\u003cp\u003eRandom sequence generation: A block-stratified method using the PASS computer program(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) will be used for the generation of the randomization sequence stratified for TBI severity (mild, moderate). The block size will be random.\u003c/p\u003e\u003cp\u003eAllocation concealment: The allocation concealment will be ensured by central randomization via the REDCap(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) randomization module, where the assignment table will be uploaded. REDCap will assign a treatment group to each participant. Once a participant meets eligibility criteria, an HBOT technician enters the participants' information into REDCap and receives the treatment assignment. All consecutive consenting participants who pass the baseline assessments will be randomized to one of the two study groups in a 1:1 allocation ratio.\u003c/p\u003e\u003cp\u003eBlinding: Participants will be blinded to conditions to reduce performance bias. To minimize detection bias, investigators, Independent Evaluators (IE), and data analysts will also be blinded to treatment conditions (i.e. HBOT or placebo/sham group). Treatments will be coded (e.g., A or B) in the database. Because the primary outcome measure data will be collected using a self-report questionnaire, the possibility of interpretation does not exist. Only in case of safety issues could the participants' assignment be unblinded. All participants will be unblinded after the 2-week post-treatment assessment. To assess the adequacy of blinding participants, all participants will complete a Group Allocation Belief form during the post-treatment visit to evaluate if participants could correctly identify the random group allocation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eData collection and management\u003c/h2\u003e\u003cp\u003eData collection for the primary (NSI) and secondary (PCL-5) outcome measures occur at baseline, every 5th dive, and at the 2-week post-treatment assessment. Data for the NSI and PCL-5 are collected via electronic surveys in REDCap and are completed directly by the subject. The IEs, which include Clinical Research Associates and Advanced Practitioners, are responsible for the collection of this data. Participants are paid stipends for baseline, mid-point assessments, and post-treatment assessments. With permission, assessments will still be performed on participants who withdraw from treatment.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eData monitoring\u003c/h2\u003e\u003cp\u003eThis study has two forms of ongoing monitoring. First, this study is monitored quarterly by an independent study monitor from USF Research Integrity \u0026amp; Compliance Quality Improvement Program. Second, this study also reports to the Data Safety Monitoring Board (DSMB). The DSMB is an independent multidisciplinary group of researchers, physicians, methodologists and biostatisticians. DSMB meetings are held annually, and interim reports are sent quarterly to the Board members. The DSMB is comprised of six external experts not employed at USF with complementary areas of expertise, including TBI (n\u0026thinsp;=\u0026thinsp;3), HBOT (n\u0026thinsp;=\u0026thinsp;2), clinical trials and translational research (n\u0026thinsp;=\u0026thinsp;3), neurobehavioral outcomes (n\u0026thinsp;=\u0026thinsp;2), and military research (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e\u003cp\u003eAdverse Events and Serious Adverse Events Monitoring. Study staff systematically monitor all AEs, SAEs, and unanticipated problems involving risk to participants or others (UPIRSOs) throughout the study. AEs are defined as any untoward physical or psychological event in a human subject that occurs after consent through the end of the subject's study participation. AEs include new events that were not present prior to the subject's participation in the intervention or events that were present before the study intervention started but notably increased in severity. The primary study staff member interacts with the participant to assess and document the participant's health status at each visit by asking if anything has changed in their health or medications since their last visit. Each participant has a safety log, which is used to record any AEs or SAEs. The study team, including the principal investigator and medical team members, reviews all AEs, SAEs and UPIRSOs to determine their relation to the intervention (e.g., Unrelated, Unlikely, Possible, Probable, and Definite). SAEs and other UPIRSOs are reported to the DSMB, IRB, Food and drug administration (FDA), and the funder in accordance with reporting requirements.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eSample size calculations\u003c/h2\u003e\u003cp\u003eThe proposed study is a blinded three-stage, group sequential adaptive RCT. The primary outcome is the difference between the experimental (HBOT) and placebo/sham arms on NSI total scores at 2 weeks post-treatment. At post-treatment, we expect the HBOT group to have a mean NSI score of 27.3, placebo/sham group a mean of 33, with a standard deviation (SD) for a single observation of 17. To detect the smallest meaningful difference of 5.7 between groups at post-treatment, 168 participants per group is needed for a total N\u0026thinsp;=\u0026thinsp;336. With an expected dropout rate of 20%, we plan to randomize N\u0026thinsp;=\u0026thinsp;420. This is a group sequential study design, and three interim analyses are planned accordingly. For early detection of efficacy, the first of three planned interim analyses will be performed after the accrual of 84 patients (42 per group) complete 40 dives and the 2 weeks post-intervention assessment. The second and third interim analyses are planned after accrual and completion of 40 HBOT/Sham dives by 168 (84 per group) and 252 (126 per group) participants, respectively. The final analysis is planned after the accrual of all 336 participants (168 per group). Accounting for dropouts/withdrawals, the planned accrual is 105 for the first, 210 for the second, 315 for the third interim analysis, and 420 participants (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) for the final analysis. The sample sizes for the three interim analyses are based on alpha errors of 0.01%, 0.55%, and 2.19% for the first, second, and third interim analyses, respectively.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll interim and final analyses for the primary and secondary outcomes associated with improvement will be based on the intent-to-treat (ITT) principle, which includes all randomized participants. For safety or adverse events, all analyses will be performed according to the per-protocol principle, including participants who successfully completed this clinical trial according to the plan. The participant characteristics will be summarized as average, standard deviation, minimum and maximum values for continuous data, and frequency and percentage for categorical data. The difference in participant characteristics across the compared groups will be assessed using the Chi-Square test, Fisher's exact test, or independent samples \u003cem\u003et\u003c/em\u003e-test, as applicable. The difference in the efficacy associated with the compared interventions will be assessed at 2 weeks post the last dive using the independent samples t-test and summarized as mean difference (MD) along with 95% confidence intervals (CI). The statistical significance is set at 0.01% for the first interim analysis, 0.55% for the second interim analysis, 2.19% for the third interim analysis and 5% for the final analysis. If any interim analyses show a significant beneficial effect with HBOT, the randomization will stop, and all subjects will be offered HBOT. The data collection will continue, and the analyses will be pre-post instead of comparative. If there is no efficacy at the first interim analysis, we will continue the study without adaptation unless significant side effects are found for HBOT. For participants lost to follow-up (i.e., missing data), the last observation carried forward method will be used, including the baseline status and the status at the last visit. All analyses will be performed using the IBM SPSS statistical analysis package.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eBecause this is an RCT, we expect the groups to be balanced at baseline for the interim and final analysis. However, in case of baseline imbalance between the compared groups, we will use a generalized linear model with compared treatments as the main effect and baseline status as a covariate. Additionally, we will apply the mixed-model repeated measures (MMRM) method to measure the change from baseline to each post-baseline assessment during the treatment period.\u003c/p\u003e\u003cp\u003eAdditional per-protocol analyses will be conducted, including a modified ITT group of participants who attended at least 75% of HBOT dives (30 dives) and an efficacy group of participants who completed all 40 dives according to the protocol.\u003c/p\u003e\u003cp\u003eThe secondary outcome to determine the optimal number of HBOT dives required to achieve a response will be assessed using the receiver operating curve analysis and summarized as the area under the curve along with 95% CI.\u003c/p\u003e\u003cp\u003ePTSD may play moderating roles in treatment response and will be examined with sensitivity analyses.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eEthical Considerations and Dissemination\u003c/h2\u003e\u003cp\u003e This study is approved by the Institutional Review Board (IRB) at USF (IRB# 6819). The United States FDA has authorized the use of HBOT under investigational new drug (IND)/ investigational device exemption (IDE; IND/ IDE #: 172640). All participants provide a verbal consent before prescreening and sign an ICF before additional data collection. For transparency, this study is registered on Clinicaltrials.gov (NCT06581003). Participants who are randomized to the sham and complete the full study protocol will be offered the opportunity to receive 40 HBOT dives locally or at an approved clinic after unblinding. Any anomalies or abnormalities that present a risk to the participant's health (e.g., elevated blood pressure) identified during the assessments will be reported to the participant. The participant may also be offered referrals for appropriate clinical evaluation and care based on existing standards of care.\u003c/p\u003e\u003cp\u003eResults will be disseminated via peer-reviewed scientific journals and conferences. Findings will also be posted on ClinicalTrials.gov.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe efficacy of HBOT has been previously assessed in RCTs. However, the previous trials had limitations that make the results inconclusive, including inadequately powered RCTs, high dropout rates, and challenges with treatment adherence due to significant time to complete 40 dives. The goal of the current RCT is to address the previous studies limitations and provide evidence about whether HBOT is effective at reducing neurobehavioral symptoms after a mild or moderate TBI in V/SM. If efficacy is established, the results will also inform participants, providers, and policy makers about the optimal number of HBOT dives needed for a clinically-relevant response.\u003c/p\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eTrial Status\u003c/h2\u003e\u003cp\u003eInitial approval was 07/16/25. Current status is: Protocol version # 5 (submitted 02/18/2025), which was approved 03/24/2025.\u003c/p\u003e\u003cp\u003eRecruitment began: 09/18/2024\u003c/p\u003e\u003cp\u003eApproximate date recruitment will end: 06/01/2027\u003c/p\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003ctable id=\"Tabb\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eAEs\u003c/div\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eAdverse Events\u003c/div\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eAUC\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eArea Under the Curve\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eATA\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eAtmosphere Absolute\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCarbon Dioxide\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCOPD\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eChronic Obstructive Pulmonary Disease\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eConfidence Interval\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCITI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCollaborative Institutional Training Initiative\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eC-SSRSS\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eColumbia Suicide Severity Rating Scale Screener\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eDSMB\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eData Safety Monitoring Board\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\nDVBIC\u003c/div\u003e\n\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eDefense and Veterans Brain Injury Center\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eDOD\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eDepartment of Defense\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eDSM-5\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eDiagnostic and Statistical Manual of Mental Disorders \u0026minus;\u0026thinsp;5\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eFDA\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eU. S. Food and Drug Administration\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003efMRI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eFunctional Magnetic Resonance Imaging\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHIPAA\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHealth Insurance Portability and Accountability Act\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHBOT\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHyperbaric Oxygen Therapy\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIE\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIndependent Evaluators\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIII\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIndividually Identifiable Information\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eICF\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eInformed Consent Form\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIRB\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eInstitutional Review Board\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eITT\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntent-to-treat\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIDE\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eInvestigational Device Exemption\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eJAHVH\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eJames A. Haley Veteran\u0026rsquo;s Hospital\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003emTBI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eMild TBI\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eMMRM\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eMixed Model Repeated Measures\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eNIH\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eNational Institutes of Health\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eNSI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eNeurobehavioral Symptom Inventory\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOEF\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOperation Enduring Freedom\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOIF\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOperation Iraqi Freedom\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOND\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOperation New Dawn\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOSU TBI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eOhio State University TBI Identification Method\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePCL-5\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePTSD Checklist-5\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePTSD\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePosttraumatic Stress Disorder\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePrincipal Investigator\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePHI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eProtected Health Information\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eRCT\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eRandomized Controlled Trial\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eROC\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eReceiver Operating Curve\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eR\u0026amp;DC\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eResearch and Development Committee\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSAE\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSerious Adverse Events\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSD\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eStandard Deviation\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSOP\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eStandard Operating Procedure\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSuicide Intent\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eTBI\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eTraumatic Brain Injury\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eUPIRSOs\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eUnanticipated Problems Involving Risk to Participants or Others\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eUS\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eUnited States\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eUSF\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eUniversity of South Florida\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eVA\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eVeteran\u0026rsquo;s Administration\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics Approval and Consent to participate:\u0026nbsp;\u003c/em\u003eThis study is approved by the Institutional Review Board (IRB) at USF (IRB# 6819). Written, informed consent to participate will be obtained from all participants. \u0026nbsp;The United States FDA has authorized the use of HBOT under investigational new drug (IND)/ investigational device exemption (IDE; IND/ IDE #: 172640).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for Publication.\u0026nbsp;\u003c/em\u003eAll have reviewed content and have provided consent for publication of this manuscript\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials.\u003c/em\u003e Data will be made available upon request provide proper data use agreements are in place.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests:\u0026nbsp;\u003c/em\u003eDirectly related to this HBOT study, several authors\u0026rsquo; received support from the State of Florida funding via their institutions (DN, AK, HvL, JW, JD, KD, RK, JM, SRM, TR, NS, MS, MT, AT, JW, HY, FRY). Some authors receive fees for consultation (MM, JW), expert testimony (MS, JW), honorarium (MS), or for royalties or licenses (MS), and/or own stock (MM). \u0026nbsp;MS, NS, AW, JW, FRY serve on advisory boards or workshop groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding.\u0026nbsp;\u003c/em\u003eThe State of Florida funded this multi-year randomized clinical trial through the legislative appropriations process during state fiscal years 22-24. The subsequent budgets were signed by the Governor and the funding was allocated to the USF Morsani College of Medicine to conduct the five-year trial.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; contribution.\u0026nbsp;\u003c/em\u003eAll authors contributed to obtaining funding, design of the study, review of the study design, obtaining required approvals, and/or ongoing conduct of the trial.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eBelow we acknowledge the individuals who comprise the USF HBOT for Veterans with TBI Collaborative Group (alphabetical order)\u003c/p\u003e\n\u003cp\u003eF Y Bowling\u003c/p\u003e\n\u003cp\u003eUSSOCOM\u0026nbsp;\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eJoseph Dituri, PhD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eKeith Dombrowski, MD\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eRachel Karlnoski, PhD\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eKelli Kessack\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eJorge Mendoza\u003c/p\u003e\n\u003cp\u003eVeteran\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShannon R. Miles, PhD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJames A. Haley Veterans\u0026rsquo; Hospital\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eMax Mokin, MD, PhD\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u0026nbsp;\u003c/p\u003e\n\u003cp\[email protected]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTea Reljic, MS, MPH\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003ePaul Sanberg, MD, PhD \u0026nbsp; \u0026nbsp;Co-I\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u0026nbsp;\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eNathan Schilaty, DC, PhD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u0026nbsp;\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eMichael Schoenberg, PhD\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected] \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMala Trivedi, MD\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAthanasios Tsalatsanis, PhD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u0026nbsp;\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eNarayan Viswanadhan, MD\u003c/p\u003e\n\u003cp\u003eJames A. Haley Veterans\u0026rsquo; Hospital \u0026nbsp;\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eAlison Willing, PhD\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eChris Wilson\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUSSOCOM\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eJason Wilson, MD, PhD\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eHariom Yadav, PhD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e\n\u003cp\u003eFayyadh Yusuf, PhD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUniversity of South Florida, Morsani College of Medicine\u003c/p\u003e\n\u003cp\[email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCenters for Disease Control and Prevention. TBI: Get the FactsFebruary 19. 2025. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.cdc.gov/ncipc/tbi/TBI.htm\u003c/span\u003e\u003cspan address=\"http://www.cdc.gov/ncipc/tbi/TBI.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. doi: https://www.cdc.gov/traumaticbraininjury/get_the_facts.html\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMilitary Health System. DOD TBI Worldwide Numbers 2023 [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://health.mil/Military-Health-Topics/Centers-of-Excellence/Traumatic-Brain-Injury-Center-of-Excellence/DOD-TBI-Worldwide-Numbers\u003c/span\u003e\u003cspan address=\"https://health.mil/Military-Health-Topics/Centers-of-Excellence/Traumatic-Brain-Injury-Center-of-Excellence/DOD-TBI-Worldwide-Numbers\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBelanger HG, Curtiss G, Demery JA, Lebowitz BK, Vanderploeg RD. Factors moderating neuropsychological outcomes following mild traumatic brain injury: a meta-analysis. J Int Neuropsychol Soc. 2005;11(3):215\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLagace-Legendre C, Boucher V, Robert S, Tardif PA, Ouellet MC, de Guise E, et al. Persistent Postconcussion Symptoms: An Expert Consensus-Based Definition Using the Delphi Method. J Head Trauma Rehabil. 2021;36(2):96\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQuinn DK, Mayer AR, Master CL, Fann JR. Prolonged Postconcussive Symptoms. Am J Psychiatry. 2018;175(2):103\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim Peterson D, Bourne J, Anderson E, Boundy HM. Evidence Brief: Hyperbaric Oxygen Therapy (HBOT) for Traumatic Brain Injury and/or Post-traumatic Stress Disorder. Washington (DC): Department of Veterans Affairs (US); 2018. 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Front Neurol. 2022;13:815056.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarch PG, Andrews SR, Rowe CJ, Lischka JR, Townsend MH, Yu Q, et al. Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome: a randomized controlled trial. Med Gas Res. 2020;10(1):8\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiskin BM, Fox LA, Abou-Al-Shaar H, Bin-Alamer O, Goertz A, Lipin CT, et al. Hyperbaric Oxygen Therapy for the Management of Mild and Moderate Traumatic Brain Injury: A Single-Center Experience. World Neurosurg. 2023;176:e357\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eParr NJ, Anderson J, Veazie S. Evidence Brief: Hyperbaric Oxygen Therapy for Traumatic Brain Injury and/or Post-traumatic Stress Disorder. VA Evidence-based Synthesis Program Reports. Washington (DC)2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCifu DX, Hart BB, West SL, Walker W, Carne W. The effect of hyperbaric oxygen on persistent postconcussion symptoms. J Head Trauma Rehabil. 2014;29(1):11\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiller RS, Weaver LK, Bahraini N, Churchill S, Price RC, Skiba V, et al. Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms: a randomized clinical trial. JAMA Intern Med. 2015;175(1):43\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWeaver LK, Wilson SH, Lindblad AS, Churchill S, Deru K, Price RC, et al. Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial. Undersea Hyperb Med. 2018;45(2):129\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWolf G, Cifu D, Baugh L, Carne W, Profenna L. 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Armonk, NY: IBM Corp; 2025.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eParticipant Timeline\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth colspan=\"12\" align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSTUDY PERIOD\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTimepoint\u003c/div\u003e\n \u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eEnrollment\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv 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\u003c/table\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Traumatic brain injury, Veterans, Hyperbaric Oxygen Therapy, Neurobehavioral Symptoms, Post-Traumatic Stress","lastPublishedDoi":"10.21203/rs.3.rs-6874662/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6874662/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e 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 y 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. \u0026nbsp;\u0026nbsp;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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This is a single-center blinded group sequential superiority randomized controlled trial (RCT). All consecutive US 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 minutes. The primary outcome is the post-intervention \u003cem\u003eNeurobehavioral Symptom Inventory (NSI)\u003c/em\u003e score. Secondary outcomes is 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%. \u003cbr\u003e\n \u003cstrong\u003eDiscussion:\u003c/strong\u003e 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eNCT06581003 (registered on 8/28/2024) https://clinicaltrials.gov/study/NCT06581003?term=NCT06581003\u0026amp;rank=1\u003c/p\u003e","manuscriptTitle":"Efficacy of Hyperbaric Oxygen Treatment in Veterans and Service Members with Traumatic Brain Injury - A Study Protocol for a Blinded Group Sequential Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 11:52:20","doi":"10.21203/rs.3.rs-6874662/v1","editorialEvents":[{"type":"communityComments","content":1},{"type":"decision","content":"Minor revision","date":"2025-12-24T14:17:05+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-07-17T09:19:12+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-10T11:33:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Trials","date":"2025-07-10T11:18:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-12T11:08:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-06-11T16:07:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a94c762f-8af6-4576-a1cd-c06038dc1451","owner":[],"postedDate":"July 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:28:02+00:00","versionOfRecord":{"articleIdentity":"rs-6874662","link":"https://doi.org/10.1186/s13063-026-09645-z","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-03-25 16:12:56","publishedOnDateReadable":"March 25th, 2026"},"versionCreatedAt":"2025-07-14 11:52:20","video":"","vorDoi":"10.1186/s13063-026-09645-z","vorDoiUrl":"https://doi.org/10.1186/s13063-026-09645-z","workflowStages":[]},"version":"v1","identity":"rs-6874662","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6874662","identity":"rs-6874662","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}