Clinical trial NCT01611194: mTBI Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms
Official title: Brain Injury and Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms After Mild Traumatic Brain Injury (BIMA) Protocol
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Traumatic Brain Injury With Brief Loss of Consciousness
Post-Concussion Syndrome
Keywords: HBO2
HBOT
mTBI
Brain injury
PCS
PTSD
hyperbaric oxygen
Lead sponsor: U.S. Army Medical Research and Development Command
Sponsor class: FED
First posted: 2012-06-04
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief 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

Detailed description: 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.

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.

Primary outcomes:
measure: Summary of Treatment-Emergent Adverse Events
timeFrame: months 3, 6, 4, 5 and 7-12. Extended f/u up to 36 months
measure: Summary of Study Intervention-Related Adverse Events
timeFrame: months 3, 6, 4, 5 and 7-12. Extended f/u up to 36 months
Secondary outcomes:
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ, RPQ3 and RPQ13) - Baseline (ITT Population)
timeFrame: Baseline
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ, RPQ3 and RPQ13) - Baseline (Per Protocol (PP) Population)
timeFrame: Baseline
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ) - Change From Baseline (ITT Population)
timeFrame: Baseline to week 13, Months 6 and 12
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ3) - Change From Baseline (ITT Population)
timeFrame: Baseline to week 13, Months 6 and 12
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ13) - Change From Baseline (ITT Population)
timeFrame: Baseline to week 13, Months 6 and 12
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ) - Change From Baseline (Per Protocol (PP) Population)
timeFrame: Baseline to week 13, Months 6 and 12
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ3) - Change From Baseline (Per Protocol (PP) Population)
timeFrame: Baseline to week 13, Months 6 and 12
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ13) - Change From Baseline (Per Protocol (PP) Population)
timeFrame: Baseline to week 13, Months 6 and 12
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ) - Change From Baseline: 24 and 36 Months (ITT Population)
timeFrame: Baseline to 24 months and 36 months
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ3) - Change From Baseline: 24 and 36 Months (ITT Population)
timeFrame: Baseline to 24 months and 36 months
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ13) - Change From Baseline: 24 and 36 Months (ITT Population)
timeFrame: Baseline to 24 months and 36 months
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ) - Change From Baseline (Per Protocol (PP) Population)
timeFrame: Baseline to month 24 and month 36
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ3) - Change From Baseline (Per Protocol (PP) Population)
timeFrame: Baseline to month 24 and month 36
measure: Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ13) - Change From Baseline (Per Protocol (PP) Population)
timeFrame: Baseline to month 24 and month 36
Other outcomes:
Locations:
city: Colorado Springs
country: United States
facility: Outcomes Assessment Center, Evans Army Community Hospital
state: Colorado
city: Fort Carson
country: United States
facility: Evans Army Community Hospital / Hyperbaric Medicine Complex
state: Colorado
city: Jacksonville
country: United States
facility: Camp Lejeune
state: North Carolina
city: Fort Lewis
country: United States
facility: Joint Base Lewis-McChord
state: Washington
city: Tacoma
country: United States
facility: TBI Program/HBO2 Research Program Madigan Healthcare system
state: Washington
Study officials:
affiliation: Intermountain Health Care, Inc.
name: Lindell Weaver, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Weaver LK, Churchill S, Wilson SH, Hebert D, Deru K, Lindblad AS. A composite outcome for mild traumatic brain injury in trials of hyperbaric oxygen. Undersea Hyperb Med. 2019 BIMA Special Edition No. Feb;46(3):341-352.
citation: Churchill S, Deru K, Weaver LK, Wilson SH, Hebert D, Miller RS, Lindblad AS. Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms. Undersea Hyperb Med. 2019 BIMA Special Edition No. Feb;46(3):331-340.
citation: Hart BB, Wilson SH, Churchill S, Deru K, Weaver LK, Minnakanti M, Lindblad AS. Extended follow-up in a randomized trial of hyperbaric oxygen for persistent post-concussive symptoms. Undersea Hyperb Med. 2019 BIMA Special Edition No. Feb;46(3):313-327.
citation: Wetzel PA, Lindblad AS, Mulatya C, Kannan MA, Villmar Z, Gitchel GT, Weaver LK. Eye tracker outcomes in a randomized trial of 40 sessions of hyperbaric oxygen or sham in participants with persistent post concussive symptoms. Undersea Hyperb Med. 2019 BIMA Special Edition No. Feb;46(3):299-311.
citation: Walker JM, Mulatya C, Hebert D, Wilson SH, Lindblad AS, Weaver LK. 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. Sleep Med. 2018 Nov;51:66-79. doi: 10.1016/j.sleep.2018.06.006. Epub 2018 Jun 30.
citation: Wetzel PA, Lindblad AS, Raizada H, James N, Mulatya C, Kannan MA, Villamar Z, Gitchel GT, Weaver LK. Eye Tracking Results in Postconcussive Syndrome Versus Normative Participants. Invest Ophthalmol Vis Sci. 2018 Aug 1;59(10):4011-4019. doi: 10.1167/iovs.18-23815.
citation: Meehan A, Searing E, Weaver LK, Lewandowski A. Baseline vestibular and auditory findings in a trial of post-concussive syndrome. Undersea Hyperb Med. 2016 Aug-Sept;43(5):567-584.
citation: Wilson SH, Weaver LK, Lindblad AS. Neuropsychological assessments in a hyperbaric trial of post-concussive symptoms. Undersea Hyperb Med. 2016 Aug-Sept;43(5):585-599.
citation: Walker JM, James NT, Campbell H, Wilson SH, Churchill S, Weaver LK. Sleep assessments for a mild traumatic brain injury trial in a military population. Undersea Hyperb Med. 2016 Aug-Sept;43(5):549-566.
citation: Mirow S, Wilson SH, Weaver LK, Churchill S, Deru K, Lindblad AS. Linear analysis of heart rate variability in post-concussive syndrome. Undersea Hyperb Med. 2016 Aug-Sept;43(5):531-547.
citation: Williams CS, Spitz MC, Foley JF, Weaver LK, Lindblad AS, Wierzbicki MR. Baseline EEG abnormalities in mild traumatic brain injury from the BIMA study. Undersea Hyperb Med. 2016 Aug-Sept;43(5):521-530.
citation: Williams CS, Weaver LK, Lindblad AS, Kumar S, Langford DR. Baseline neurological evaluations in a hyperbaric trial of post-concussive syndrome. Undersea Hyperb Med. 2016 Aug-Sept;43(5):511-519.
citation: Weaver LK, Chhoeu A, Lindblad AS, Churchill S, Wilson SH. Hyperbaric oxygen for mild traumatic brain injury: Design and baseline summary. Undersea Hyperb Med. 2016 Aug-Sept;43(5):491-509.