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

Phase 2

Completed

Conditions: Traumatic Brain Injury With Brief Loss of Consciousness
Post-Concussion Syndrome

Interventions: Drug: Hyperbaric oxygen (HBO2) at 1.5 atms
Drug: Sham control 1.2 atms

Registration Number: NCT01611194

Lead Sponsor: U.S. Army Medical Research and Development Command

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 71

Inclusion Criteria

Not provided

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.

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HBO2 at 1.5 Atomspheres Absolute (ATA)	Hyperbaric oxygen (HBO2) at 1.5 atms	Hyperbaric oxygen (HBO2) at 1.5 atms. Stratified by site and time from injury (less than one year versus one year or more), in which participants are randomized. Each participant will complete 40 sessions, one session per day, five sessions per week, within 12 weeks following randomization.
Sham Control (1.2 Atomspheres)	Sham control 1.2 atms	Sham control 1.2 atms. 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).

Primary Outcome Measures

Name	Time	Method
Summary of Treatment-Emergent Adverse Events	months 3, 6, 4, 5 and 7-12. Extended f/u up to 36 months	Safety was evaluated in-person during the first 3 months and at month 6, and via telephone follow-up calls at months 4, 5, and 7-12. Extended annual follow-up continued for up to 36 months through January 2016.
Summary of Study Intervention-Related Adverse Events	months 3, 6, 4, 5 and 7-12. Extended f/u up to 36 months	Safety was evaluated in-person during the first 3 months and at month 6, and via telephone follow-up calls at months 4, 5, and 7-12. Extended annual follow-up continued for up to 36 months through January 2016.

Secondary Outcome Measures

Name	Time	Method
Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ, RPQ3 and RPQ13) - Baseline (ITT Population)	Baseline	RPQ/RPQ-3 was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-3 ranges from 0-12 and access a subset of symptoms. RPQ-13 ranges from 0-52 and access's 13 remaining symptoms. Analyses of the RPQ-3 and RPQ-13 domain scores are presented separately. For each of the RPQ-3, RPQ-13, and RPQ total scales, the scores were derived by totaling the corresponding question scores for each domain.
Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ) - Change From Baseline (Per Protocol (PP) Population)	Baseline to month 24 and month 36	RPQ was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. For the RPQ total scales, the scores were derived by totaling the corresponding question scores for each domain and change from baseline.
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)	Baseline	RPQ/RPQ-3 was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-3 ranges from 0-12 and access a subset of symptoms. RPQ-13 ranges from 0-52 and access's 13 remaining symptoms. Analyses of the RPQ-3 and RPQ-13 domain scores are presented separately. For each of the RPQ-3, RPQ-13, and RPQ total scales, the scores were derived by totaling the corresponding question scores for each domain.
Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ3) - Change From Baseline (ITT Population)	Baseline to week 13, Months 6 and 12	RPQ-3 was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-3 ranges from 0-12 and access a subset of symptoms. Analyses of the RPQ-3 domain scores are presented separately. For the RPQ-3 total scales, the scores were derived by totaling the corresponding question scores for each domain and it's change from baseline.
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)	Baseline to 24 months and 36 months	RPQ was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-13 ranges from 0-52 and access's 13 remaining symptoms. Analyses of the RPQ-13 domain scores are presented separately. For RPQ-13 total scales, the scores were derived by totaling the corresponding question scores for each domain and change from baseline.
Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ) - Change From Baseline (ITT Population)	Baseline to week 13, Months 6 and 12	RPQ was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. The scores were derived by totaling the corresponding question scores for each domain and it's change from baseline.
Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ13) - Change From Baseline (ITT Population)	Baseline to week 13, Months 6 and 12	RPQ was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-13 ranges from 0-52 and access's 13 remaining symptoms. Analyses of the RPQ-13 domain scores are presented separately. For RPQ-13 total scales, the scores were derived by totaling the corresponding question scores for each domain and change from baseline.
Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ3) - Change From Baseline (Per Protocol (PP) Population)	Baseline to month 24 and month 36	RPQ-3 was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-3 ranges from 0-12 and access a subset of symptoms. Analyses of the RPQ-3 domain scores are presented separately. For the RPQ-3 total scales, the scores were derived by totaling the corresponding question scores for each domain and change from baseline.
Presence of Post Concussion Symptoms Following Traumatic Brain Injury Using The Rivermead Post-Concussion Symptom Questionnaire (RPQ13) - Change From Baseline (Per Protocol (PP) Population)	Baseline to month 24 and month 36	RPQ was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-13 ranges from 0-52 and access's 13 remaining symptoms. Analyses of the RPQ-13 domain scores are presented separately. For RPQ-13 total scales, the scores were derived by totaling the corresponding question scores for each domain change from baseline.
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)	Baseline to 24 months and 36 months	RPQ was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. For the RPQ total scales, the scores were derived by totaling the corresponding question scores for each domain and change from baseline.
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)	Baseline to 24 months and 36 months	RPQ-3 was created to measure the severity of post-concussion symptoms following traumatic brain injury. Scale compares any current symptoms to pre-injury levels to account for potential symptom exacerbation due to the TBI. The RPQ is the most commonly used clinical measure for mild TBI research because it is simple and reflects psychosocial function. The RPQ is intended to measure the presence and severity of 16 of the most commonly reported post-concussion symptoms found in the literature. The RPQ scale includes 16 common post-concussion symptom items whose responses range from "0= Not experienced at" to "4= A severe problem". Total range is 0 to 64. RPQ-3 ranges from 0-12 and access a subset of symptoms. Analyses of the RPQ-3 domain scores are presented separately. For the RPQ-3 total scales, the scores were derived by totaling the corresponding question scores for each domain and change from baseline.

Trial Locations

Locations (5): TBI Program/HBO2 Research Program Madigan Healthcare system
🇺🇸
Tacoma, Washington, United States
Outcomes Assessment Center, Evans Army Community Hospital
🇺🇸
Colorado Springs, Colorado, United States
Evans Army Community Hospital / Hyperbaric Medicine Complex
🇺🇸
Fort Carson, Colorado, United States
Camp Lejeune
🇺🇸
Jacksonville, North Carolina, United States
Joint Base Lewis-McChord
🇺🇸
Fort Lewis, Washington, United States

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