mTBI Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms
Condition: Traumatic Brain Injury With Brief Loss of Consciousness; Post-Concussion Syndrome
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Post-Concussion Syndrome; Unconsciousness
Intervention: Hyperbaric oxygen (HBO2) at 1.5 atms; Sham control 1.2 atms
Intervention description: The Hyperbaric oxygen (HBO2) at 1.5 atms (active) group (hyperbaric oxygen-chamber compressed to 1.5 atm abs and breathing 100% oxygen). Each participant should complete 40 sessions over the course of 12 weeks, one session per day, five per week.; The chamber will be compressed with air to 1.2 atm abs to simulate the active group. Participants will don a hood and breathe 21% oxygen (room air). Each participant will complete 40 sessions, one session per day, five sessions per week, within 12 weeks following randomization. Breathing air at a pressure of 1.2 atm abs is equivalent to inhaling 25% oxygen at sea level pressure (1.0 atm abs).
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 71.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: HBO2; HBOT; mTBI; Brain injury; PCS; PTSD; hyperbaric oxygen

Summary:

      Purpose of this study is to investigate the mechanisms of action of hyperbaric oxygen therapy
      for persistent post-concussive symptoms after mild tramatic brain injury
    

Eligibility criteria:

        Inclusion Criteria

          -  On active duty (TRICARE beneficiary) at the time of consent and through the 6-month
             visit or a Veteran, as well as Active Duty military who become Veterans after
             enrollment.

          -  Men and women 18-65 years of age at the time of study enrollment.

          -  Able to equalize middle ear pressure in a test of chamber pressure and tolerate the
             chamber environment.

          -  Able to speak and read English, as primary language.

          -  Agrees to and appears able to participate in all outcome assessments.

          -  Agrees to provide blood samples for clinical lab tests.

          -  Demonstrates the ability to offer informed consent and signs the study informed
             consent document.

          -  Participants stationed or living outside the Colorado Springs/Denver, Colorado area
             must be willing and able to travel. A reliable companion may accompany the participant
             if travel supervision is required.

          -  Active duty participants must obtain a letter of support from a supervisor or
             commanding officer prior to the outcome assessments (and travel, if necessary) to the
             OAC.

        Participants must have a history of at least one (minimum requirement) mild traumatic brain
        injury (mTBI) with persistent symptoms that meets all the following criteria:

          -  Brain injury that occurred more than 3 months prior to baseline screening at the local
             site, with the most recent injury occurring no more than 5 years prior to
             randomization.

          -  Most recent traumatic brain injury (TBI) occurred on active duty.

          -  TBI was caused by non-penetrating trauma or blast exposure.

          -  TBI resulted in at least one of the following at the time of injury: a period of loss
             of or a decreased level of consciousness (up to 30 minutes); a loss of memory for
             events immediately before or after the injury (up to 24 hours); or alteration in
             mental state at the time of the injury (becoming dazed or confused).

          -  Has current complaints of TBI symptoms such as headache, dizziness, or cognitive or
             affective problems that score at least 3 post-concussive symptoms as assessed by the
             OSU TBI-ID.

          -  Has received current standard of care pharmacologic and nonpharmacologic interventions
             for TBI and any concomitant post traumatic stress disorder (PTSD) with no significant
             change in psychoactive therapy for at least 1 month.

          -  Creatinine level that is less than or equal to the EACH laboratory's upper limit of
             normal. If the creatinine level exceeds the EACH laboratory's upper limit of normal,
             participants cannot have a CT scan due to risk of contrast dye-induced renal failure.
             Such participants may be randomized but must be approved by the Study Director.

        Exclusion Criteria:

          -  Prisoners.

          -  Pregnant Women.

          -  Minors.

          -  Individuals whose most recent TBI was sustained during illegal activity.

          -  Potential active duty participants stationed >1 hour outside the designated
             recruitment area of a participating local site will be excluded unless the command
             authorizes temporary relocation and appropriate relocation resources.

          -  Potential Veteran participants who live >1 hour outside the designated recruitment
             area of a participating local site, must be willing and able to travel to the local
             site to participate in all required local site visits without additional financial
             assistance than that which is described in the Veteran Payment Schedule (consent
             attachment C).

          -  Active duty individuals with anticipated prolonged TAD/TDY or deployment within 6
             months of study enrollment will be excluded.

          -  Veterans with anticipated prolonged travel or relocation within 6 months of study
             enrollment will be excluded.

        An individual with any of the following characteristics will be excluded from this study
        based on contraindications to hyperbaric pressurization and hyperbaric oxygenation or other
        study assessment measures:

          -  Women who are pregnant or who plan to become pregnant during the study period.

          -  Women who are breastfeeding.

          -  Women of childbearing potential who do not agree to practice an acceptable form of
             birth control during the study period.

          -  Epilepsy or seizure disorder not stable on anticonvulsant therapy (stable defined as 6
             months seizure-free).

          -  Inability to protect airway or requires frequent suctioning.

          -  Known or suspected perilymphatic fistula.

          -  Presence of tracheostomy (due to limitations in autoinflation of the middle ear
             space).

          -  Diabetes (risk of hypoglycemia).

          -  Creatinine level that exceeds 1.5 times the EACH laboratory's upper limit of normal.

          -  A diagnosis (from patient report or medical record evidence within one year) of
             untreated clinical hypo- or hyperthyroidism.

          -  Allergy to iodine-based contrast dye (exclusion criteria for neuroimaging assessment
             measures only).

          -  Presence of implanted device (e.g., cardiac defibrillator, intrathecal drug delivery
             device, cochlear implant, pacemaker, stents or aneurysm clips) that poses increased
             risk to the participant during hyperbaric exposure or magnetic resonance imaging
             (MRI). Any implanted device must be cleared through the manufacturer for exposure to
             hyperbaric pressure and 3.0 Tesla MRI.

          -  Participants who must travel to altitudes greater than 10,000 feet during chamber
             session intervention.

          -  Paratroopers who are unable to suspend activity during chamber exposures.

          -  An individual who has had refractive eye surgery within the last 90 days.

          -  Any brain injury not of traumatic etiology, such as stroke or drug-induced coma.

          -  Heart failure with ejection fraction < 50% (due to increased risk for precipitating
             acute lung edema during exposure to HBO2).

          -  Emphysema, chronic bronchitis, or bullous lung disease (due to risk for pulmonary
             barotrauma during hyperbaric decompression).

          -  Asthma not well controlled.

        An individual with any of the following characteristics will be excluded from this study
        based on confounding of the outcome measures:

          -  Those who are unable to participate fully in outcome assessments unless randomization
             is reviewed and approved (in writing) by the study director.

          -  Vision uncorrectable to 20/50 (monocular vision acceptable).

          -  Dynavision within 30 days of screening.

          -  Deafness in both ears defined as 90 dB HL or greater, through the speech frequencies
             of each of 500 Hz, 1 kHz, 2 kHz and 4 kHz in each ear; this is determined by a
             baseline measurement of pure tone air conduction thresholds.

          -  Participant self-report or documented diagnosis of psychiatric disorders in the
             medical record within the last year of any of the following: schizophrenia,
             dissociative disorder, or bipolar disease.

          -  Anxiety or claustrophobia precluding participation in the hyperbaric chamber sessions
             or neuroimaging procedures.

          -  Verifiable neurodegenerative disease (e.g., Alzheimer's disease, multiple sclerosis,
             senile dementia).

          -  Presence of chronic debilitating disease (e.g., end-stage renal disease, end-stage
             liver disease, diabetes with sequelae).

          -  Documented unresolved anemia, with anemia defined as hematocrit less than 30%.

          -  History, by self-report, of receiving therapeutic ionizing radiation to the head.

          -  Foreign material in head that would interfere with brain imaging (e.g., MRI or
             computed tomography [CT]), unless randomization has been cleared by the study
             director.

          -  Foreign (unknown composition) or metallic/ferromagnetic material within the individual
             that poses risk from MRI, unless randomization has been cleared by the study director.

          -  History, by self report, of illicit drug use, except remote (prior to military
             enlistment) non-habitual (habitual is considered greater than weekend) use of
             marijuana.

          -  History, by self report or medical record in the last year, of alcohol abuse.
             Prospective participants who have been sober for the last 90 days prior to screening
             may be eligible based on the site principal investigator determination.

          -  Current positive urine test for an illicit substance(s).

          -  Any condition or use of prescribed medication in which, in the opinion of the
             investigator, participation in this study would impact the safety of the individual.

          -  Brain injury of moderate or severe degree: duration of loss of consciousness at the
             time of injury greater than 30 minutes, duration of post-traumatic amnesia greater
             than 24 hours, or brain injury of a penetrating etiology.

          -  Any lifetime history of penetrating brain injury.

          -  Active malignancy, prior malignancy (except basal cell carcinoma) within the last 5
             years, or any prior treatment with bleomycin (trade name Blenoxane). Prior treatment
             with doxorubicin (trade name Adriamycin) is acceptable as long as an echocardiography
             following treatment is normal.

          -  Unable to abstain from caffeine or tobacco products for at least a 2-hour interval.

          -  Concurrent enrollment in an alternate interventional trial.

          -  Unable or unwilling to cease participation in sports in which another head injury is
             likely (e.g., mixed martial arts, boxing) during the study period.

          -  Diagnosis of Meniere's disease by self-report or medical record evidence within one
             year.

          -  Pre-TBI history of significant dizziness (lasting more than 1 day).

        A prospective participant with any of the following characteristics will be excluded from
        this study to protect blinding:

          -  Prior treatment with HBO2 for TBI or PCS.

          -  Prior HBO2 treatment for indications other than TBI or PCS within the last 3 months.

          -  Experienced hyperbaric chamber inside attendant (anyone deemed to have experience with
             hyperbaric pressurization that could compromise their blind to allocation).

          -  Technical, military, or occupational divers.