Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms.

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow.

Analysis of magnetic resonance spectroscopy relative metabolite ratios in mild traumatic brain injury and normative controls.

INTRODUCTION: We evaluated magnetic resonance spectroscopy (MRS) in United States military personnel with persistent symptoms after mild traumatic brain injury (mTBI), comparing over time two groups randomized to receive hyperbaric oxygen or sham chamber sessions and a third group of normative controls. METHODS: Active-duty or veteran military personnel and normative controls underwent MRS outcome measures at baseline, 13 weeks (mTBI group only), and six months. Participants received 3.0 Tesla brain MRS for analysis of water-suppressed two-dimensional (2D) multivoxel 1H-MRS of the brain using point resolved spectroscopy (PRESS) with volume selection localized above the lateral ventricles and within the brain parenchyma, of which one voxel was chosen in each hemisphere without artifact. Script-based automatic data processing was used to assess N-acetylaspartate (NAA), creatine (Cr), and choline (Cho). Metabolite ratios for white matter were then calculated for NAA/Cr (Area), Cho/Cr (Area), and Cho/NAA (Area). These ratios were compared using standard analysis methodology. RESULTS: There were no observable differences between participants with mTBI and normative controls nor any observable changes over time in the NAA/Cr (area), Cho/Cr (area), and Cho/NAA (area) ratios. Similarly, the control and injured participants were indistinguishable. DISCUSSION: While participants with mild TBI showed no difference in MRS compared to normative controls, our results are limited by the few voxels chosen and potentially by less sensitive MRS markers.

A composite outcome for mild traumatic brain injury in trials of hyperbaric oxygen.

INTRODUCTION: Global outcomes can strengthen inferences from clinical trials. We evaluate global outcomes for persistent post-concussive symptoms (PCS) after mild traumatic brain injury (mTBI) in two clinical trials of hyperbaric oxygen (HBO2) in United States service members. METHODS: During study design, outcomes of symptom, cognitive, and functional impairments planned for a trial of HBO2 for PCS (HOPPS) were weighted and grouped into different domains to formulate the composite outcome total score. The composite outcome was compared between the intervention groups in HOPPS and those in a subsequent HBO2 trial (BIMA) for validation. Additionally, two post hoc global outcome measures were explored, including one composed of components that demonstrated favorable characteristics in both studies and another via components used in another TBI randomized trial (COBRIT). RESULTS: In total, 143 active-duty or veteran military personnel were randomized across the two studies. Composite total scores improved from baseline for HBO2 (mean ± SD -2.9±9.0) and sham (-2.9±6.6) groups in HOPPS but did not differ significantly between groups (p=0.33). In BIMA, 13-week changes from baseline favored the HBO2 group (-3.6±6.4) versus sham (-0.3±5.2; p=0.02). No between-group differences were found when COBRIT composite scoring was applied to BIMA. Overall, HBO2 effects were maximized when the post hoc global measure derived from both studies was applied to the data. CONCLUSIONS: Composite total scores in HOPPS and BIMA were consistent with primary study results. The global measures considered may offer utility as endpoints to achieve maximal HBO2 effect in future trials of the mTBI population. IDS: clinicaltrials.gov Identifiers NCT01611194 (BIMA) and NCT01306968 (HOPPS).

Extended follow-up in a randomized trial of hyperbaric oxygen for persistent post-concussive symptoms.

To date, several Department of Defense (DoD) and civilian studies have evaluated hyperbaric oxygen for mild forms of traumatic brain injury. Prior to the DoD-sponsored "Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA)" trial, none included post-intervention follow-up beyond three to six months. Post-hoc attempts at long-term follow-up were complicated by low participation and potential self-selection bias. BIMA planned for follow-up through 12 months but was amended to add post-concussive and post-traumatic stress disorder, quality of life, pain, depression, anxiety, and alcohol use assessments at 24 and 36 months. A total of 42 of 71 BIMA participants consented to extendedfollow-up, and 40 and 14 completed a 24- or 36-month visit, respectively, representing an overall response rate of 59% and 20%. Participants who completed extended follow-up were similar to the study group that did not in terms of demographics, perceived intervention allocation, and initial response to intervention. There were no significant differences at 24 or 36 months between intervention groups, and group mean scores were near pre-intervention values. This return to baseline could be due to waning treatment effect, selection bias, or participant or perception effects. Though BIMA implemented several participant retention strategies, more frequent participant contact and increased compensation might improve long-term retention in future studies. clinicaltrials.gov Identifier NCT01611194.

Hyperbaric oxygen for mTBI-associated PCS and PTSD: Pooled analysis of results from Department of Defense and other published studies.

BACKGROUND: Some clinical trials report improvement in persistent post-concussive symptoms (PCS) with hyperbaric oxygen (HBO2) following mild traumatic brain injury (mTBI), but questions remain regarding the utility of HBO2 for PCS, the effects of HBO2 on post-traumatic stress disorder (PTSD), and the influences of sham control exposures. METHODS: A systematic review and pooled analysis was conducted to summarize available evidence for HBO2 in mTBI-associated PCS ± PTSD. Data aggregated from four Department of Defense (DoD) studies with participant-level data (n=254) were grouped into pooled HBO2 and sham intervention groups. Changes from baseline to post-intervention on PCS, PTSD, and neuropsychological measures were assessed using linear mixed models to evaluate main intervention and intervention-by-baseline PTSD effects. Potential dose-response relationships to oxygen partial pressures were investigated. Intervention effects from three other published studies with summary-level participant data (n=135) were also summarized.. RESULTS: Pooled DoD data analyses indicated trends toward improvement favoring HBO2 for PCS (Rivermead Total Score: -2.3, 95% CI [-5.6, 1.0], p=0.18); PTSD (PTSD Checklist Total Score: -2.7, 95% CI [-5.8, 0.4], p=0.09); and significant improvement in verbal memory (CVLT-II Trial 1-5 Free Recall: 3.8; 95% CI [1.0, 6.7], p=0.01). A dose-response trend to increasing oxygen partial pressure was also found, with a greater HBO2 effect in mTBI-associated PTSD suggested. The direction of results was consistent with other published studies. CONCLUSION: A definitive clinical trial, with an appropriate control group, should be considered to identify the optimal HBO2 dosing regimen for individuals with mTBI-associated PTSD ± PCS.

Sleep assessment in a randomized trial of hyperbaric oxygen in U.S. service members with post concussive mild traumatic brain injury compared to normal controls.

STUDY OBJECTIVE: In this exploratory, double-blind, longitudinal sham-controlled trial of hyperbaric oxygen (HBO2) for military personnel with post concussive mild traumatic brain injury (mTBI), self-reports and objective measures of sleep-wake disturbances were assessed and compared to normals. METHODS: Self-reports consisting of Pittsburg Sleep Quality Index (PSQI), sleep diary, screening for obstructive sleep apnea (OSA) risk, restless legs syndrome (RLS), cataplexy, and objective actigraphic measures of sleep-wake were obtained on 71 military personnel with mTBI [baseline, 13 weeks and six months post-randomization (post-intervention)], of which 35 met post-traumatic stress disorder (PTSD) criteria, and 75 healthy volunteers (baseline). Baseline between-group and follow-up changes from baseline overall and within subgroups were evaluated. Mild TBI was defined as consisting of head injury associated loss of consciousness (<24 h), post-traumatic amnesia, and neurological deficits. RESULTS: Sleep quality by self-reports was markedly degraded in the mTBI group at baseline compared to a normative cohort; insomnia 87.3 versus 2.8%, OSA risk 70% versus 1.3%, RLS 32.4% versus and 2.7%. (all p-values <0.001), but actigraphy measures did not differentiate between groups. HBO2 compared to sham treatment improved self-reports of PSQI sleep measures, reports (five out of eight at 13-weeks and two out of eight at six-months). However, other sleep-wake measures were not different. CONCLUSIONS: Perceived sleep quality was markedly disrupted in mTBI military personnel and sleep-wake disturbances were prevalent compared to a normative cohort. HBO2 relative to sham improved some measures of sleep quality on the PSQI, but other measures of sleep were not significantly different.

Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial.

BACKGROUND: In prior military randomized trials, participants with persistent symptoms after mild traumatic brain injury (TBI) reported improvement regardless of receiving hyperbaric oxygen (HBO2) or sham intervention. This study's objectives were to identify outcomes for future efficacy trials and describe changes by intervention. METHODS: This Phase II, randomized, double-blind, sham-controlled trial enrolled military personnel with mild TBI and persistent post-concussive symptoms. Participants were randomized to receive 40 HBO2 (1.5 atmospheres absolute (ATA), ⟩99% oxygen, 60 minutes) or sham chamber sessions (1.2 ATA, room air, 60 minutes) over 12 weeks. Participants and evaluators were blinded to allocation. Outcomes assessed at baseline, 13 weeks and six months included symptoms, quality of life, neuropsychological, neurological, electroencephalography, sleep, auditory, vestibular, autonomic, visual, neuroimaging, and laboratory testing. Participants completed 12-month questionnaires. Intention-to-treat results are reported. RESULTS: From 9/11/2012 to 5/19/2014, 71 randomized participants received HBO2 (n=36) or sham (n=35). At baseline, 35 participants (49%) met post-traumatic stress disorder (PTSD) criteria. By the Neurobehavioral Symptom Inventory, the HBO2 group had improved 13-week scores (mean change -3.6 points, P=0.03) compared to sham (+3.9 points). In participants with PTSD, change with HBO2 was more pronounced (-8.6 vs. +4.8 points with sham, P=0.02). PTSD symptoms also improved in the HBO2 group, and more so in the subgroup with PTSD. Improvements regressed at six and 12 months. Hyperbaric oxygen improved some cognitive processing speed and sleep measures. Participants with PTSD receiving HBO2 had improved functional balance and reduced vestibular complaints at 13 weeks. CONCLUSIONS: By 13 weeks, HBO2 improved post-concussive and PTSD symptoms, cognitive processing speed, sleep quality, and balance function, most dramatically in those with PTSD. Changes did not persist beyond six months. Several outcomes appeared sensitive to change; additional studies are warranted.

Simple and Procedural Reaction Time for Mild Traumatic Brain Injury in a Hyperbaric Oxygen Clinical Trial.

Simple reaction time (SRT) and procedural reaction time (PRT) are speed-of-processing tasks in the Automated Neuropsychological Assessment Metrics (ANAM) that may be sensitive to mild traumatic brain injury (mTBI). The investigators measured SRT and PRT throughput (correct responses per minute) at baseline, 6 weeks, and 13 weeks in military personnel with mTBI randomized to local care or 40 chamber sessions (sham-1.2 atmospheres absolute [ATA] air, hyperbaric oxygen-1.5 ATA O2). Scores were assessed at baseline using univariate analysis of variance and across time with repeated measures methods. Data reported as throughput standard scores (mean = 100, SD = 15). Seventy-two participants with ongoing symptoms after mTBI enrolled in the study (three female, median age 31 years, mean three lifetime concussion events, most recent mTBI 23 months prior). Sixty-four had Automated Neuropsychological Assessment Metrics data at 13 weeks. SRT and PRT throughput standard scores were comparable across groups at baseline. Over time, SRT scores did not change in the hyperbaric oxygen or sham groups and decreased in the local care group. PRT throughput standard scores increased from baseline to mid-intervention and decreased from mid-intervention to postintervention in all groups. Repeated measures change over time in SRT (p = 0.23), and PRT (p = 0.17) scores were not different among groups. This study may be underpowered to detect statistically significant change.

Executive summary: The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) Study.

The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) study, sponsored by the Department of Defense and held under an investigational new drug application by the Office of the Army Surgeon General, is one of the largest and most complex clinical trials of hyperbaric oxygen (HBO2) for post-concussive symptoms (PCS) in U.S. military service members.

Hyperbaric oxygen for mild traumatic brain injury: Design and baseline summary.

The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) study, sponsored by the Department of Defense, is a randomized double-blind, sham-controlled clinical trial that has a longer duration of follow-up and more comprehensive assessment battery compared to recent HBO2 studies. BIMA randomized 71 participants from September 2012 to May 2014. Primary results are expected in 2017. Randomized military personnel received hyperbaric oxygen (HBO2) at 1.5 atmospheres absolute (ATA) or sham chamber sessions at 1.2 ATA, air, for 60 minutes daily for 40 sessions. Outcomes include neuropsychological, neuroimaging, neurological, vestibular, autonomic function, electroencephalography, and visual systems evaluated at baseline, immediately following intervention at 13 weeks and six months with self-report symptom and quality of life questionnaires at 12 months, 24 months and 36 months. Characteristics include: median age 33 years (range 21-53); 99% male; 82% Caucasian; 49% diagnosed post-traumatic stress disorder; 28% with most recent injury three months to one year prior to enrollment; 32% blast injuries; and 73% multiple injuries. This manuscript describes the study design, outcome assessment battery, and baseline characteristics. Independent of a therapeutic role of HBO2, results of BIMA will aid understanding of mTBI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Neuropsychological assessments in a hyperbaric trial of post-concussive symptoms.

Results of studies addressing the effect of mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) on symptoms and neuropsychological assessments are mixed regarding cognitive deficits in these populations. Neuropsychological assessments were compared between U.S. military service members with mTBI only (n=36) vs. those with mTBI÷ PTSD (n=35) from a randomized interventional study of mTBI participants with persistent post-concussive symptoms (PCS). The mTBI group endorsed worse symptoms than published norms on PCS, PTSD and pain scales (⟩50% abnormal on Neurobehavioral Symptom Inventory (NSI), PTSD Checklist-Civilian, McGill Pain Questionnaire-Short Form) and some quality of life domains. Worse symptom reporting was found in the mTBI÷ PTSD group compared to mTBI (e.g., mean NSI total score in mTBI 27.5 (SD=12.7), mTBI÷ PTSD 39.9 (SD=13.6), p⟨0.001). The mTBI÷PTSD group performed worse than mTBI on the Weschler Adult Intelligence Scale digit span (mean difference -1.5, 95% CI[-2.9,-0.1], p=0.04) and symbol search (mean difference -1.5, 95% CI[-2.7,-0.2], p=0.03) and Grooved Pegboard (dominant hand mean difference -7.0, 95% CI[-11.5,-2.4], p=0.003; non-dominant mean difference -9.8, 95% CI[-14.9,-4.7], p⟨0.001). Differences were detected in ANAM simple reaction time (p=0.04) and mathematical processing (p=0.03) but not verbal fluency or visuospatial memory assessments. Results indicate increased symptom severity and some cognitive deficits in mTBI÷ PTSD compared to mTBI alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Hyperbaric oxygen for persistent post-concussive symptoms: long-term follow-up.

We report results of an observational cohort study investigating long-term follow-up in participants from two completed United States military trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms (PCS), as well as challenges in recruitment and retention in active-duty military personnel. After informed consent, participants completed an electronic survey assessing PCS, post-traumatic stress disorder (PTSD), anxiety, depression and quality of life. Of 132 HBO2 study participants, 40 (30%) completed the survey (42 could not be contacted; 50 were lost to follow-up or declined). All were male, age 28.1 ±6.6 years (mean ±1SD). Time to follow-up was 39.2 ±6.1 months. At follow-up, participants reported continued symptoms of PTSD, depression, anxiety and reduced quality of life. Among DARPA/VCU study participants, total PCS scores worsened in the 1.5 atmospheres absolute (ATA) equivalent HBO2 group (mean change 7.4 ±15.8) and improved in the sham (-8.0 ±7.7) and 2.0 atmospheres absolute equivalent HBO2 groups (-3.3 ±7.4). Individual changes varied widely, range -23 to +28 points. In participants from the HOPPS study, total PCS scores worsened in all groups: local care (10.5 ±8.7), sham (7.9 ±11.9) and 1.5 ATA HBO2 (1.0 ±19.4). In this limited, cross-sectional sample, PCS and PTSD symptoms did not appear to improve over time by descriptive analyses. Low participation rates and potential response bias limit our ability to perform statistical hypothesis testing and to draw conclusions from these data. Future studies should prospectively plan longitudinal follow-up and regular engagement with participants to minimize attrition.