Hyperbaric Oxygen Therapy (HBO2)for Persistent Post-concussive Symptoms After Mild Traumatic Brain Injury (mTBI) (HOPPS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier:
NCT01306968
First received: February 24, 2011
Last updated: October 1, 2012
Last verified: October 2012
  Purpose

This is a Phase II randomized trial designed to describe the magnitude of change between baseline and follow-up outcomes for symptom surveys and a battery of neuropsychological tests administered at time points corresponding before and after 10 weeks over observation in four groups:

  • A military population with post-concussion syndrome (mTBI) receiving local standard care
  • A military population with post-concussion syndrome (mTBI) receiving local standard care and sham hyperbaric oxygen sessions
  • A military population with post-concussion syndrome (mTBI) receiving local standard care and hyperbaric oxygen at 1.5 atmospheres sessions
  • A otherwise similar group with PTSD but no history of TBI receiving local standard care Differences and variability of the tests will be used for determining the optimum primary endpoint(s) for future trial, as well as for refinement of sample size and power calculations for these studies. The groups undergoing hyperbaric sessions will be assigned to receive HBO2 or sham using a randomized, double blind design.

Active duty military (Army, Marine, Navy, Air Force) men and non-pregnant women residing in the United States and who will remain in the military for the entire study period, aged 18-65 years who have been deployed one or more times to the US Central Command since the initiation of Operation Enduring Freedom (October 7, 2001) who either:

  • have been diagnosed with Post Traumatic Stress Disorder (PTSD) as a result of traumatic events that occurred during the qualifying CENTCOM deployment, but have no diagnosed or suspected lifetime brain injuries resulting in loss or alteration of consciousness; OR
  • have been diagnosed with at least one mild brain injury (mTBI) with persistent (> 4 months) symptoms sustained during one or more of those deployments

Condition Intervention Phase
Post-concussive Symptoms
Traumatic Brain Injury
Drug: hyperbaric oxygen
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Pilot Phase II Study of Hyperbaric Oxygen for Persistent Post-concussive Symptoms After Mild Traumatic Brain Injury (HOPPS)

Resource links provided by NLM:


Further study details as provided by U.S. Army Medical Research and Materiel Command:

Primary Outcome Measures:
  • Rivermead Post-Concussion Symptom Questionnaire to measure change from baseline [ Time Frame: Change from Baseline of RPQ/RPQ-3 at time of randomization to Day 28 and Day56 ] [ Designated as safety issue: No ]
    The Rivermead Post-Concussion Symptom Questionnaire (RPQ)/RPQ-3 was created to measure the severity of post-concussion symptoms following traumatic brain injury. The 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 outcome 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.


Secondary Outcome Measures:
  • Neurobehavioral Symptom Inventory (NSI) [ Time Frame: Baseline randomization/Day 28/ Day 56 ] [ Designated as safety issue: No ]

    The Neurobehavioral Symptom Inventory (NSI) is a self-report measure that asks individuals to rate their difficulties with a variety of symptoms.

    Items on the Inventory include: Dizziness, loss of balance, poor coordination, headaches, nausea, visual disturbance, light sensitivity, hearing difficulty, noise sensitivity, body/extremity numbness, altered taste or smell, appetite change, poor concentration, forgetfulness, difficulty making decisions, slowed thinking, fatigue, insomnia, feeling anxious, feeling depressed, irritability and poor frustration tolerance.



Enrollment: 79
Study Start Date: February 2011
Study Completion Date: August 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Cohort 1 (PTSD) Group A
Subjects who have PTSD but have no diagnosed or suspected brain injuries
No Intervention: Cohort 2 (mTBI) Group B
Group B (mTBI LC) (randomized/unblinded): Subjects who have one or more mild traumatic brain injuries with persistent symptoms per the inclusion/exclusion criteria and are randomized to continue to receive local care for mTBI
Experimental: Cohort 2 (mTBI) Group C
Group C (mTBI HBO2) (randomized/blinded): Subjects who have one or more mild traumatic brain injuries with persistent symptoms per the inclusion/exclusion criteria and are randomized to the active intervention (hyperbaric oxygen)
Drug: hyperbaric oxygen

The chamber will be compressed with air to 1.5 atm abs. Once the chamber is compressed to 1.5 atm abs, the subjects will don a hood and breathe 100% oxygen. Hoods will be supplied with oxygen with flows of at least 30 liters per minute and overboard dumping of excess gas. Each subject will complete 40 sessions.

The duration of the hyperbaric oxygen exposures will be 60 minutes (±2 minutes), timed from when the chamber hatch or door closes, and ending when the chamber hatch or door opens ("door-to-door" time equals 60 minutes). The total intervention exposure time is 50 minutes (±2 minutes). The interval to compress to the intervention pressure (1.5 atm abs) and will be 5 minutes (±1 minute). The interval to decompress from the study pressure will be 5 minutes (±1 minute).

Other Name: medical oxygen
Sham Comparator: Cohort 2 (mTBI) Group D
Subjects who have one or more mild traumatic brain injuries with persistent symptoms per the inclusion/ exclusion criteria and are randomized to the sham control
Drug: hyperbaric oxygen
A pressure of 1.2 atm abs will provide an equivalent inhaled oxygen concentration of 25%. The duration of the sham exposures will be 60 minutes (±2 minutes). Each subject will complete 40 sessions.
Other Name: medical oxygen

Detailed Description:

Brain injury due to trauma is very common; nonetheless, no pharmacological therapy is known to improve outcomes. Medications are used to treat symptoms, such as seizures and affective disorders, but are not intended to affect the fundamental problem. If HBO2, which is regularly available and relatively safe, improves outcome in brain-injured subjects by treating the underlying pathophysiology of post-concussive syndrome, this would represent a significant advance in treatment of brain injury. Hyperbaric oxygen (HBO2) has been proposed as a treatment for patients with TBI.

Hyperbaric oxygen is one of the first pharmacologic interventions being tested in this population of individuals with mild TBI and chronic post-concussive symptoms targeted to improve cognition, memory, and functional status. However, much is unknown about how to measure improvement in post-concussive symptoms after an intervention in the targeted active duty population. In preparation for a pivotal efficacy study, the objectives of this study are to characterize two candidate primary outcome tools in our intended study population, the RPQ and the NSI, in order to better estimate the sample size needed to answer the efficacy question.

Agency for Healthcare Research and Quality (AHRQ) conducted a comprehensive review of the literature, interviewed subject matter experts (SME), and conducted focus groups with SMEs to evaluate the evidence for HBO2 for patients with TBI. The AHRQ concluded that "Although they are cited frequently, the case series and time-series studies of HBO2 for TBI patients had serious flaws. There were no high-quality studies of the use of HBO2 to improve function and quality of life in patients with chronic, stable disabilities from TBI. The most important gap in the evidence is a lack of a good quality time-series study or controlled trial of the effects of HBO2 on cognition, memory, and functional status in patients with deficits due to mild chronic TBI." Similarly, the Department of Health and Human Services (DHHS) has not approved HBO2 therapy for the treatment of TBI as a covered condition, citing the lack of supporting evidence for clinical efficacy.

The Defense Centers of Excellence for Psychological Health and Traumatic concluded that sufficient case reports, early safety and feasibility study data, and basic scientific plausibility exist to warrant prompt experimental study of HBO2 in the care of the full spectrum of chronic TBI. This would best be accomplished in a randomized, double-blind, multi-center clinical trial.

This Phase 2 study, through specific study design, inclusion and exclusion criteria, interim and end point analyses, treatment protocols, dose-response and safety issues, evaluation methodologies, safety, and outcome measures address the need for clinical efficacy.

In preparation for the pivotal trial, the purpose of this Phase II study is to describe the magnitude of change between baseline and follow-up outcomes for a battery of neuropsychological tests within groups. A secondary objective is to explore changes across the four groups. Differences and variability of the tests will be used for determining the optimum primary endpoint(s) for the Phase III trial, as well as for refinement of sample size and power calculations for this future study. Recruitment, randomization, blinding, and study and intervention logistics and planning will also be assessed.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:Cohort 1: PTSD with no history of TBI

  • Deployed to the US Central Command (USCENTCOM) between October 7, 2001 through 4 months prior to enrollment, serving on land, no exposure to blast, blunt, or penetrating trauma resulting in brain injury during deployment.
  • On active duty (TRICARE beneficiary) at the time of consent and during study participation.
  • Diagnosed PTSD that occurred as a result of traumatic events that occurred during the qualifying CENTCOM deployment.
  • Stable on pharmacologic and nonpharmacologic interventions, with no significant change in therapy for at least 1 month.
  • 18-65 years old at the time of study enrollment.
  • Willing and committed to comply with the research protocol and complete all outcome measures.
  • Able to self-consent.
  • Able to speak and read English, as primary language.
  • Able to participate in all outcome measures

Cohort 2 mTBI:history of least 1 mTBI with persistent symptoms

  • most recent injury occurring no earlier than October 7, 2001.
  • Most recent traumatic brain injury occurred while serving on active duty.
  • Most recent traumatic brain injury occurred while deployed to the US Central Command (USCENTCOM).
  • Most recent traumatic brain injury occurred while on shore.
  • Most recent traumatic brain injury was caused by blast exposure or blunt trauma.
  • Most recent traumatic brain injury resulted in at least one of the following: 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).
  • On active duty (TRICARE beneficiary) at the time of consent and during study participation.
  • Has current complaints of brain injury 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 local care pharmacologic and nonpharmacologic interventions for TBI and any concomitant PTSD with no significant change in therapy for at least 1 month (to ensure that the participant has received local therapy yet continues to complain of brain injury symptoms, and to accommodate the possible cognitive impact of medications that may be taken for PTSD, depression, and/or anxiety.
  • 18-65 years old at the time of study enrollment.
  • Willing and committed to comply with the research protocol and complete all outcome measures.
  • Able to self-consent. -Able to speak and read English, as primary language.-
  • Able to participate in all outcome measures.
  • Able to equalize middle ear pressure

Exclusion Criteria:

All cohorts and groups will exclude:

  • Prisoners
  • Pregnant women
  • Minors
  • Pregnancy, women who plan to become pregnant during the study period, women who do not agree to practice an acceptable form of birth control during the study period, or women who are breastfeeding; urine hCG will be assayed in all female subjects who could be pregnant prior to study procedures. In addition, point-of-care urine pregnancy testing will be assayed monthly in women of childbearing potential who receive the study intervention (Groups C (mTBI HBO2) and D (mTBI Sham)). If a woman is of childbearing potential, she must agree not to become pregnant for the duration of her study participation. Effective ways to avoid pregnancy include: abstinence, hysterectomy, bilateral oophorectomy, tubal ligation, male condoms, oral or injectable contraceptives, or an intrauterine device.
  • Those who are unable to participate fully in outcome assessments
  • Blind in one or both eyes
  • Deaf in one or both ears
  • Ambulation with assistive devices (e.g., wheelchair, cane, crutches, or walker) Pre-existing (before the participant's enrollment in the study) diagnosis of a psychotic disorder(s): schizophrenia, dissociative disorder, and bipolar disease. (Psychiatric problems, such as depression and anxiety, may be associated with brain injuries; therefore, subjects in Cohort 2 (mTBI) with a brain-injury associated psychiatric disorder will not be excluded. Subjects in Cohort 2 (mTBI) with a psychiatric disorder that was diagnosed before most recent traumatic brain injury will be excluded).
  • Epilepsy or seizure disorder requiring anticonvulsants.
  • Active malignancy, prior malignancy (except basal cell carcinoma) within the last 5 years.
  • Verifiable degenerative mental 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, all types of diabetes with or without sequelae).
  • Documented clinically significant uncorrected anemia
  • Documented sickle cell disease.
  • History of receiving therapeutic ionizing radiation to the head.
  • Verifiable diagnosis of learning disability.
  • Positive urine test for an illicit substance(s).
  • Any condition or use of prescribed medication in which participation in this study would impact the safety of the individual subject.
  • Receiving Dynavision therapy within 30 days prior to enrollment.
  • Anticipated administrative separation, prolonged TAD/TDY or deployment before study completion (3 months after randomization)
  • Service members stationed outside the designated recruitment area without access/permission to stay at local WT Presence of tracheostomy (due to limitations in autoinflation of the middle ear space).
  • Use of lithium (due to possibility of concomitant toxic adverse events with HBO2, specifically hyperexcitability).
  • 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).
  • Active malignancy, prior malignancy (except basal cell carcinoma) within the last 5 years, or any prior treatment with cisplatin (Platinol), doxorubicin (Adriamycin), or bleomycin [Blenoxane] (prior cisplatin, doxorubicin, or bleomycin therapy may increase risk for oxidative stress with inhalation of high concentrations of oxygen).
  • Diabetes (relative contraindication related to risk of hypoglycemia).
  • Presence of implanted device (e.g., cardiac defibrillator, intrathecal drug delivery device, cochlear implant) that poses increased risk to subject during hyperbaric exposure.
  • Prior treatment with HBO2.
  • Experienced underwater diver or hyperbaric chamber inside attendant (anyone deemed to have experience with hyperbaric pressurization that could compromise their remaining blind to allocation.

Additional Exclusion for Cohort 1:

Any lifetime history brain injury of traumatic etiology, any brain injury of anoxic or cerebrovascular etiology, or penetrating brain injury.

Additional exclusion for Cohort 2:

  • Asthma requiring use of routine or rescue medication within the past 30 days
  • Claustrophobia (unwilling or unable to enter hyperbaric chamber).
  • Inability to protect airway or requires frequent suctioning.
  • Presence of tracheostomy (due to limitations in autoinflation of the middle ear space).
  • Use of lithium (due to possibility of concomitant toxic adverse events with HBO2, specifically hyperexcitability).
  • 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).
  • Active malignancy, prior malignancy (except basal cell carcinoma) within the last 5 years, or any prior treatment with cisplatin (Platinol), doxorubicin (Adriamycin), or bleomycin [Blenoxane] (prior cisplatin, doxorubicin, or bleomycin therapy may increase risk for oxidative stress with inhalation of high concentrations of oxygen).
  • Diabetes (relative contraindication related to risk of hypoglycemia).
  • Presence of implanted device (e.g., cardiac defibrillator, intrathecal drug delivery device, cochlear implant) that poses increased risk to subject during hyperbaric exposure.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01306968

Locations
United States, California
Naval Hospital Camp Pendleton
Camp Pendleton, California, United States, 92055
United States, Colorado
Evans Army community Hospital Fort Carson
Fort Carson, Colorado, United States, 80913
United States, Georgia
Eisenhower Army Medical Center
Fort Gordon, Georgia, United States, 30905
United States, North Carolina
Naval Hospital Camp Lejeune
Camp Lejeune, North Carolina, United States, 28547
United States, Utah
Study Coordinating Center, LDS Hospital
Salt lake City, Utah, United States, 84143
Sponsors and Collaborators
U.S. Army Medical Research and Materiel Command
Investigators
Principal Investigator: Scott Miller, MD, COL United States Army Medical Materiel Development Activity
  More Information

No publications provided

Responsible Party: U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier: NCT01306968     History of Changes
Other Study ID Numbers: S-10-09
Study First Received: February 24, 2011
Last Updated: October 1, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by U.S. Army Medical Research and Materiel Command:
mild tramatic brain injury
mTBI
hyperbaric oxygen
post concussive symptoms
active duty military
veterans

Additional relevant MeSH terms:
Brain Injuries
Post-Concussion Syndrome
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Brain Concussion
Head Injuries, Closed
Wounds, Nonpenetrating

ClinicalTrials.gov processed this record on April 15, 2014