mTBI Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms

Active duty military personnel and Veterans received for 60-minute daily chamber sessions in
which they received HBO2, 1.5 atmospheres absolute (ATA), or sham intervention (1.2 ATA, room
air) for post concussion syndrome (PCS).

The study is to provide a rationale for the selection of outcome assessments to serve as
primary and secondary endpoints for a pivotal randomized clinical trial of hyperbaric oxygen
for the treatment of PCS. The participants will undergo a comprehensive battery of symptom
and quality of life assessments. The distribution of response, change in response over time,
homogeneity of variance across subgroups, and relationships between outcome measures will be
compared by treatment assignment with a cohort from a study of similar design among a normal
study population.

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.