Hyperbaric Oxygen Research
The U. S. Army Medical Materiel Development Activity (USAMMDA) is leading an effort to determine if hyperbaric oxygen is of benefit in the treatment of chronic symptoms of mild traumatic brain injury (TBI) or post-concussion syndrome (PCS).
For the Army, the Hyperbaric Oxygen (HBO2) Therapy clinical trials focus on research related to the development of treatment modalities using HBO2 for chronic post-concussion syndrome after mild traumatic brain injury (mTBI). Each study has its own emphasis, looking into efficacy, safety, duration, treatment dose and various neurological assessments of the effect of HBO2 for this condition.
Three HBO2 human clinical trials were designed to evaluate the effectiveness of HBO2 treatments for Service Members who have experienced one or more concussions and who are symptomatic at, or after, the time of post-deployment health reassessments: 1- A pilot phase II (narrow population safety and effectiveness) study of hyperbaric oxygen for persistent post-concussive symptoms after mild traumatic brain injury (HOPPS), 2- Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (BIMA), and 3- Development of Normative Datasets for Assessments Planned for Use in Patients with Mild Traumatic Brain Injury (Normal). Previously, the U.S. Air Force and U.S. Navy, the latter with the sponsorship of Defense Advanced Research Projects Agency (DARPA), each conducted a phase II pilot study evaluating the effects of HBO2 treatment on service members with mTBI. Each of these Department of Defense (DoD) -sponsored study efforts were incorporated into the meta-analysis conducted in Fiscal Year (FY) 2017. Separately, the Army also sponsored a retrospective, Long Term Follow-up (LTFU) study that focused on the lessons learned from long-term follow-up of subjects enrolled in the DoD primary HBO2 trials. To support the Army-sponsored protocols, four HBO2 study sites were established within the Military Health System. Each of the research sites consisted of a hyperbaric oxygen chamber enclosed in a mobile trailer, a second mobile trailer for testing and evaluation of the subjects, and a third subject staging trailer.
The DOD and the Army remain committed to seeking and conducting research and development efforts for evidence-based therapies for the treatment of mTBI due to injuries during military service and other visible and invisible medical consequences of war.
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Completed, manuscript published and final clinical study report submitted to the Food and Drug Administration (FDA) in June 2015.
Exploratory study: To develop a potential composite outcome measure from the selected assessment tools for future validation
Primary Objective: To obtain a point estimate of the mean change in scores and associated variance of the Rivermead Post-Concussive Symptom Questionnaire using the RPQ-3 scale within groups across time from baseline in order to use this information for sample size calculation in a Phase III trial of hyperbaric oxygen in the same population.
Secondary objectives: To obtain a point estimate of the mean change in scores and associated variance of a second candidate primary outcome measure (for future pivotal study), the Neurobehavioral Symptom Inventory (NSI), within study groups across time from baseline in order to estimate the sensitivity of the instrument to detect changes in postconcussive symptoms. Conclusion: Hyperbaric oxygen augmenting routine TBI care showed no improvement over a sham procedure in concussion or posttraumatic stress disorder (PTSD) symptom relief using either the RPQ or Neurobehavioral Symptom Inventory (NSI) patient reported outcome measures. Results in the per protocol analysis (completed all 40 sessions) were similar to the intention-to-treat analysis. Both chamber procedures (HBO2 and sham) showed relative symptomatic improvement to the comparator group continuing routine TBI care only, suggestive of a placebo effect. The results of this study do not support conducting a Phase 3 trial.
HOPPS primary manuscript was published online in Journal of the American Medical Association "Internal Medicine November 2015
Subject participation is completed and final clinical study report submitted to the FDA in July 2017, primary manuscript submitted for consideration to a peer review journal in October 2017 in addition to numerous secondary manuscripts being written. Undersea and Hyperbaric Medical Society, Undersea and Hyperbaric Medicine Journal Volume 43, Number 5, Special Issue 2016: BIMA. This special issue, "Brain Injury and Mechanisms of Action of Hyperbaric Oxygen (HBO2) for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) Study", was published November 2016 and summarizes results and findings in baseline publications for the BIMA study in addition to reporting on the Long-Term Follow-up Study, and non-HBO2 interventions for mild TBI.
Exploratory study: The study attempted to identify potential confounding variables in evaluating and treating PCS. An evaluation of the test-retest variability of these assessments has been explored separately in a normal study population to differentiate meaningful clinical changes within the PCS population.
Primary Objective: Under an Investigational New Drug (IND) held by the Office of the Army Surgeon General (IND 104,678), this study (BIMA) obtained pilot data that will complement results from another pilot study (HOPPS). Results from BIMA and HOPPS will be used to select primary and secondary endpoints for a subsequent phase III efficacy trial of hyperbaric oxygen versus sham control for the treatment of PCS. Ideal endpoint candidates will have properties that suggest an association with a neurologic mechanism.
Additionally, this study has describe the brain function and anatomy of active duty personnel and Veterans with PCS who are symptomatic at least three months but no more than five years after mild traumatic brain injury using a comprehensive battery of assessments, across time, in groups randomized to receive intervention (HBO2) or sham control, and explore potential associations between changes in function, anatomy, and participant reported outcomes.
Secondary objectives: To evaluate safety of the proposed hyperbaric oxygen and sham interventions; to identify practical issues in instituting assessments among participants with PCS and to address related logistical considerations prior to initiating the pivotal study; and to compare outcome assessment results to a normative population, without history of TBI, comprehensively assessed in a similar fashion in a companion study. Approximately six-thousand (6,000) bio-specimen samples collected during the BIMA and Normal studies are stored for future research at SRISAI Biopharmaceutical Solutions, LLC
Conclusion (Clinical Study Report IND 104678, Study S-11-17): The BIMA study is characterized by its double blind design, high intervention adherence rate, and high retention rate through month 12 following randomization. Bias due to informative missing data and unblinding are unlikely confounders in the results from this study through month 12. This study was small and designed to be exploratory, without a single predefined primary outcome measure. Lack of power to detect clinically meaningful changes and spurious statistically significant differences due to the quantity of outcome measures are important shortcomings in interpretation. The results suggest the intervention was unlikely to be harmful. The concentration of statistically significant reductions in persistent post concussive symptoms in those randomized to hyperbaric oxygen with concomitant PTSD as measured across multiple self-reported instruments requires further study. The observed effect was no longer present at month six after randomization (approximately three months following the intervention completion period) or month 12 following randomization (approximately nine months following the intervention period completion).
Subject participation is completed and final statistical report is completed.
Exploratory study: The purpose of this study was to estimate properties of assessments that would be used to evaluate the efficacy of HBO2 in studying post concussive syndrome due to mild TBI. The normative data set will be compared to results from other HBO2 research program studies.
Primary Objective: To develop a database from normal healthy participants for the same outcomes used in a program of studies of HBO2 versus sham control in participants with persistent PCS; to characterize the distribution of responses and change in responses over time for each of the outcomes and to examine associations between measures within a given normal participant and across participant characteristics such as age and gender; and to evaluate the test-retest reliability of a series of assessments anticipated for use in the primary, secondary, and exploratory outcomes of this program of studies.
Secondary objectives: To compare normative values to results from randomized exploratory studies of HBO2 vs sham control in participants with persistent PCS; examine relationships between outcome measures from normal participants (with respect to clinical equivalence, participant burden, and risk) and compare to associations observed in randomized exploratory studies of HBO2 vs sham control in participants with persistent post-concussive symptoms.
Conclusion: This study conducted a comprehensive evaluation of the responses for a battery of outcomes when measured in a normative population by assessing their consistency from baseline to follow-up time points, concurrent validity, and comparability across subgroups. Though this study was exploratory in nature, it provided evidence of assessments that maintained high reliability over time, particularly for the neuropsychological, visual systems, and neuroimaging domains, and identified males and select age subgroups as potential sources of the instabilities of measures over time that were observed in the other domains. With the baseline abnormalities that were noted in this study for some assessments at baseline, especially for clinical neuroimaging findings and Sharpened Romberg measures, the degree to which the above results generalize to a truly healthy population may be limited.
Study completed and executive summary was submitted in July 2015; U.S. Army Medical Research and Materiel Command Institutional Review Board provided the study closure memo in September 2015.
Observational cohort study: The purpose of this study was to investigate long-term follow-up of participants from two completed U.S. military trials of HBO2 for persistent PCS, as well as challenges in recruitment and retention in active duty military personnel.
Primary Objective: To assess differences in changes from initial HBO2 study baseline in persistent symptoms of mTBI and PTSD among participants who received HBO2 intervention, sham intervention, and local care (where applicable) for the prior HBO2 studies individually. In this context, baseline refers to the time point immediately prior to exposure to HBO2, sham, or local care intervention. Secondary objectives: To assess differences between pooled active and sham intervention groups across studies in quality of life, depression, and anxiety at the long-term follow-up time point.
Conclusion: In this small group of individuals receiving HBO2, sham chamber sessions, or local care for PCS as a result of military service, PCS and PTSD symptoms did not appear to resolve over time. However, possible conclusions from this data set are constrained by the low participation rate and possible response bias. Future studies should consider prospective planning of longitudinal follow-up and regular engagement with participants to minimize attrition.
- The U.S. Air Force study is complete and did not show any statistically significant benefit from high dose HBO2 (2.4 atmospheres absolute [ATA]) relative to a sham air exposure in symptom relief and neurocognitive testing beyond the equivalent of what would be observed from placebo effects. The study results were published in the Journal of Neurotrauma, November 2012 and the Undersea and Hyperbaric Medicine Journal, November-December 2012.
- The USN/VCU/VA study testing low dose HBO2 (1.5 and 2.0 ATA) is complete and showed no statistically significant benefit relative to a sham air exposure. Outcome measures of this study focused on symptom relief and neurocognitive testing. The study results were published in the Journal of Head Trauma and Rehabilitation, September 2013.
In June 2014 the HBO2 PMO contracted the Samueli Institute, a non-profit research institute, to conduct a literature search to explore the efficacy of HBOT for patients suffering from the consequences of TBI, and develop recommendations based on the current state of the evidence for its clinical use, implementation, as well as next steps for the field. They also reviewed and analyzed the impact of mixed study results and identify the validity of reported placebo effects. This work resulted in a white paper titled, "Is Hyperbaric Oxygen Therapy Effective for Traumatic Brain Injury?", a Rapid Evidence Assessment of the Literature (REAL) & Recommendations for the Field.
The following was published in the report:
- Improvements in mTBI outcomes shown within the groups receiving HBO2, as well as the sham treatment in the DOD-funded studies cannot be ignored.
- Samueli discussed the debate on what constitutes a true sham for HBO2. Specifically, the report stated that a true sham treatment may have to be done with normal atmospheric pressure and that more research is needed to be confident that a sham is not a therapeutic treatment.
- The report concludes that for mTBI, there is not enough evidence to make comparisons between standard care and HBO2 therapy, while fully acknowledging that the improvements in the treatment groups cannot be ignored. The report calls for further research to define the "active agent" no matter if it is the oxygen level, pressure, duration, frequency, length, ritual, non-specific placebo effects or other unidentified factor.
- Louisiana State University (LSU) / Harch Study as of October 17, 2017 "The primary specific aim is to determine whether 40 1.5 ATA (atmospheres absolute) HBOT's can improve symptoms and cognitive function in military veterans with mild-moderate TBI/PCS with PTSD. As of September 26, 2017: 150 subjects have been screened, 42 subjects have completed the protocol; three (3) are in treatment; one (1) subject is in the control period; three (3) are in the two-month follow-up period post-hyperbaric oxygen treatment and two (2) additional subjects are scheduled for final in-person screening next week. The total accrual goal is 59 subjects at LSU.