Hyperbaric Oxygen Therapy for Traumatic Brain Injury

Overseen By Harry Van Loveren, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of South Florida

Must not be taking: Antabuse, Disulfuram, Acetazolamide, others

Disqualifiers: Pregnancy, Bipolar, Schizophrenia, Epilepsy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 44

Duration: 12 weeks

420 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this blinded, adaptive, randomized, placebo-controlled clinical trial is to investigate the use of hyperbaric oxygen as a therapy to treat mild to moderate traumatic brain injury in Veterans and active military. The main questions it aims to answer are: * Does Hyperbaric Oxygen Therapy (HBOT) reduce neurobehavioral symptoms? (Aim 1) * How many HBOT sessions are needed to achieve a significant reduction in neurobehavioral symptoms? (Aim 2) * Does HBOT reduce posttraumatic stress disorder (PTSD) symptoms? (Aim 3) Exploratory objectives will explore if there are changes in: 1.) cognitive functioning using neuropsychological tests and the National Institutes of Health (NIH) toolbox, 2.) inflammation biomarkers in blood, 3.) microbiome in stool samples, 4.) electroencephalogram (EEG), 5.) sleep characteristics, and 6.) fMRI. Research will compare HBOT therapy to a placebo condition to see if HBOT works to treat neurobehavioral symptoms. The placebo condition is a chamber that remains unpressurized and has 21% oxygen. Participants will: 1. Complete baseline assessments to determine eligibility. 2. Attend 40 sessions of HBOT or placebo (normal air) within 12 weeks. 3. Complete questionnaires and interviews throughout the course of the study. 4. Complete a 2-week post treatment visit

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes certain medications that could cause oxygen toxicity, like Antabuse, Disulfuram, Acetazolamide, Sulfamylon, bleomycin, cisplatin, and doxorubicin. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment Hyperbaric Oxygen Therapy for Traumatic Brain Injury?

Research suggests that Hyperbaric Oxygen Therapy (HBOT) may help improve oxygen supply to the injured brain, potentially reducing brain damage and improving outcomes for patients with traumatic brain injury. Studies indicate that HBOT can enhance oxygen delivery to brain tissue, which might help preserve brain function and reduce disability. ^{1 2 3 4 5}

Is hyperbaric oxygen therapy generally safe for humans?

Hyperbaric oxygen therapy is generally considered safe, but some people may experience side effects like ear or sinus pain, anxiety from being in a confined space, low blood sugar, oxygen toxicity, or seizures. These side effects are rare, and the treatment is usually well-tolerated. ^{1 6 7 8 9}

How is hyperbaric oxygen therapy different from other treatments for traumatic brain injury?

Hyperbaric oxygen therapy (HBOT) is unique because it involves breathing pure oxygen in a pressurized chamber, which can improve oxygen supply to the injured brain and potentially reduce brain damage. Unlike other treatments, it does not rely on drugs and may offer additional brain-preserving effects when combined with standard care. ^{1 2 5 10 11}

Eligibility Criteria

This trial is for U.S. Service Members and Veterans aged 18-75 with a history of mild to moderate traumatic brain injury at least one year old, who can consent, tolerate lying down in the HBOT environment for an hour, and speak English. They must have chronic TBI symptoms as indicated by specific test scores.

Inclusion Criteria

I am a U.S. Service Member or Veteran aged 18-75.

I can read, write, and speak English.

I can understand and agree to the study's procedures and risks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

2 visits (in-person)

Treatment

Participants undergo 40 sessions of HBOT or placebo over 12 weeks

12 weeks

40 visits (in-person)

Mid-treatment Assessment

Participants complete a mid-treatment assessment after 20 sessions

1 week

1 visit (in-person)

Post-treatment Assessment

Participants complete assessments 2 weeks after the last treatment session

2 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Hyperbaric Oxygen Treatment

Trial Overview The study tests if Hyperbaric Oxygen Therapy (HBOT) reduces neurobehavioral and PTSD symptoms in these individuals compared to a placebo (normal air). It involves attending 40 sessions within 12 weeks and completing assessments before, during, after treatment, and two weeks post-treatment.

Participant Groups

Group I: HBOT Group Experimental Treatment 1 Intervention

HBOT chamber pressurized to 2.0 ATA with 100% oxygen

Group II: Placebo/Sham Group Placebo Group 1 Intervention

HBOT chamber that remains unpressurized and has 21% oxygen

Hyperbaric Oxygen Treatment is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Hyperbaric Oxygen Therapy for:

• Carbon monoxide poisoning
• Decompression sickness
• Diabetic foot ulcers
• Wound healing

Approved in European Union as Hyperbaric Oxygen Therapy for:

• Carbon monoxide poisoning
• Decompression sickness
• Diabetic foot ulcers
• Wound healing
• Radiation necrosis

Approved in Canada as Hyperbaric Oxygen Therapy for:

• Carbon monoxide poisoning
• Decompression sickness
• Diabetic foot ulcers
• Wound healing

Who Is Running the Clinical Trial?

University of South Florida

Lead Sponsor

Trials

433

Recruited

198,000+

James A. Haley Veterans' Hospital (JAHVH)

Collaborator

Trials

1

Recruited

420+

Findings from Research

Hyperbaric oxygen therapy (HBOT) may offer a potential mortality benefit for certain subgroups of traumatic brain injury (TBI) patients, as one study showed a decrease in mortality from 31% in controls to 17% in the HBOT group, although results were conflicting across studies.

Adverse events associated with HBOT, such as seizures and pulmonary symptoms, were reported, but the overall evidence regarding its effectiveness and safety remains insufficient, highlighting the need for more high-quality research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy for traumatic brain injury: a systematic review of the evidence. McDonagh, M., Helfand, M., Carson, S., et al.[2019]

Hyperbaric oxygen therapy (HBOT) significantly reduced the risk of death in patients with traumatic brain injury, with a relative risk of 0.69, indicating that treating seven patients with HBOT could prevent one additional death.

However, HBOT did not show a significant improvement in favorable clinical outcomes, suggesting that while it may help with survival, it does not necessarily lead to better recovery or quality of life for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury. Bennett, MH., Trytko, B., Jonker, B.[2018]

In a study involving 42 patients with severe traumatic brain injury, the combination of hyperbaric oxygen (HBO2) and normobaric hyperoxia (NBH) significantly increased brain tissue oxygen levels and improved markers of cerebral metabolism compared to standard care.

The combined HBO2/NBH treatment resulted in a 26% reduction in mortality and a 36% improvement in favorable outcomes, indicating its potential as an effective therapeutic strategy for severe TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. Rockswold, SB., Rockswold, GL., Zaun, DA., et al.[2015]

Hyperbaric oxygen therapy (HBOT) administered after moderate traumatic brain injury (mTBI) significantly improved cognitive function in mice, showing similar performance to control (sham) groups, indicating its potential efficacy as a treatment.

Both immediate and delayed HBOT treatments (administered 3 hours and 7 days post-injury, respectively) prevented neuronal loss and other negative biochemical changes associated with mTBI, suggesting a long therapeutic window for neuroprotection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immediate and delayed hyperbaric oxygen therapy as a neuroprotective treatment for traumatic brain injury in mice. Baratz-Goldstein, R., Toussia-Cohen, S., Elpaz, A., et al.[2022]

In a review of over 1.5 million hyperbaric oxygen therapy treatments, only 0.68% were linked to adverse events, indicating that serious complications are rare.

The most common issues reported were barotrauma and confinement anxiety, while severe events like oxygen toxicity occurred in less than 0.05 per 1000 treatments, suggesting that HBO therapy is a safe and low-risk treatment when following proper protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Analysis of Adverse Events in Hyperbaric Oxygen Therapy (2012-2015): Lessons Learned From 1.5 Million Treatments. Jokinen-Gordon, H., Barry, RC., Watson, B., et al.[2022]

In a study of 1,308 patients receiving hyperbaric oxygen (HBO2) therapy, five seizure episodes were reported during 10,425 treatments, indicating a low but notable risk of seizures, particularly in patients with carbon monoxide poisoning and arterial gas embolism.

Despite the occurrence of seizures, none of the patients experienced lasting effects, suggesting that while seizures can happen during HBO2 therapy, the overall safety profile remains high, and clinicians should be prepared to manage such events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Seizure during hyperbaric oxygen therapy: experience at a single academic hospital in Korea. Lee, CH., Choi, JG., Lee, JS., et al.[2021]

Hyperbaric oxygen (HBO) treatment for traumatic brain injury (TBI) may enhance cellular recovery by improving mitochondrial function, rather than just increasing oxygen availability as previously thought.

Administered at 1.5 ATA for 60 minutes, HBO treatment appears to be safe and does not cause oxygen toxicity, suggesting its potential as a therapeutic option for severe brain injuries, although further large-scale studies are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen in traumatic brain injury. Rockswold, SB., Rockswold, GL., Defillo, A.[2022]

Hyperbaric oxygen therapy (HBOT) is associated with a higher incidence of adverse effects (30.11%) compared to control groups (10.43%), particularly when the treatment involves more than 10 sessions or chamber pressures exceed 2.0 ATA.

The most common side effect reported was ear discomfort, indicating that while HBOT can be beneficial, careful monitoring for adverse reactions is necessary, especially under specific conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects of hyperbaric oxygen therapy: a systematic review and meta-analysis. Zhang, Y., Zhou, Y., Jia, Y., et al.[2023]

Hyperbaric oxygen (HBO) therapy may help improve biochemical parameters in patients with traumatic brain injuries, as demonstrated in a case report of a 23-year-old man with a severe gunshot wound.

The study suggests that HBO therapy could be a beneficial treatment option to reduce secondary complications following traumatic brain injury, although further research is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical response to hyperbaric oxygen treatment of a transhemispheric penetrating cerebral gunshot injury. Thelin, EP., Bellander, BM., Nekludov, M.[2020]

Hyperbaric oxygen (HBO) therapy significantly reduces neuronal apoptosis in a mouse model of acute traumatic brain injury (TBI), indicating its potential as a therapeutic intervention.

The mechanism of HBO's protective effect involves the reversal of changes in key proteins associated with apoptosis, specifically through the Akt/GSK3β/β-catenin signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy attenuates neuronal apoptosis induced by traumatic brain injury via Akt/GSK3β/β-catenin pathway. He, H., Li, X., He, Y.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy for traumatic brain injury: a systematic review of the evidence. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Hyperbaric Oxygen and Outcomes Following the Brain Injury: A Systematic Review. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Immediate and delayed hyperbaric oxygen therapy as a neuroprotective treatment for traumatic brain injury in mice. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

A Retrospective Analysis of Adverse Events in Hyperbaric Oxygen Therapy (2012-2015): Lessons Learned From 1.5 Million Treatments. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Seizure during hyperbaric oxygen therapy: experience at a single academic hospital in Korea. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen in traumatic brain injury. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse effects of hyperbaric oxygen therapy: a systematic review and meta-analysis. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Biochemical response to hyperbaric oxygen treatment of a transhemispheric penetrating cerebral gunshot injury. [2020]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy attenuates neuronal apoptosis induced by traumatic brain injury via Akt/GSK3β/β-catenin pathway. [2022]