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

Phase 2

Completed

• Conditions: Traumatic Brain Injury; Post-concussive Symptoms
• Interventions: Drug: hyperbaric oxygen; Other: sham hyperbaric air

• Registration Number: NCT01306968
• Lead Sponsor: U.S. Army Medical Research and Development Command

Brief Summary

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

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.

Study Timeline

• Study Start: 2011-02
• Study First Submitted: 2011-02-24
• Study First Submitted QC: 2011-03-01
• Study First Posted: 2011-03-02
• Primary Completion: 2012-08
• Study Completion: 2012-08
• Results First Submitted: 2014-07-16
• Status Verified: 2014-08
• Results First Submitted QC: 2014-08-25
• Last Update Submitted: 2014-08-25
• Results First Posted: 2014-09-05
• Last Update Posted: 2014-09-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 79

Inclusion Criteria

• Volunteers must have history of at least one mild traumatic brain injury (mTBI) with persistent symptoms that meets all the following criteria:

  • Brain injury that occurred more than 4 months prior to enrollment, with the most recent injury occurring no earlier than October 7, 2001.
  • Most recent traumatic brain injury occurred while serving on active duty, and while deployed to the United States (US) Central Command (USCENTCOM).
  • 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).

• Volunteers must also meet all the following criteria:

  • 18-65 years old at the time of study enrollment.
  • A 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 Ohio State University (OSU) Traumatic Brain Injury (TBI) Identification (ID) Method interview
  • Has received current local care pharmacologic and non-pharmacologic interventions for TBI and any concomitant posttraumatic stress disorder (PTSD) with no significant change in therapy for at least 1 month
  • 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.

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Exclusion Criteria

• History of brain injury of moderate or severe degree: duration of loss of consciousness at the time of injury greater than 30 minutes, or duration of post-traumatic amnesia greater than 24 hours, or brain injury of a penetrating etiology.
• History of brain injury not of traumatic etiology, such as stroke or drug-induced coma.
• Prior treatment with HBO2.
• Hyperbaric chamber inside attendant, professional (paid)underwater diver (commercial, operational/ military, instructor), or technical diver.
• 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;
• Those who are unable to participate fully in outcome assessments (Blind in one or both eyes; Deaf in one or both ears; or Ambulation with assistive devices
• Pre-existing diagnosis of a psychotic disorder(s): schizophrenia, dissociative disorder, and bipolar disease.
• Verifiable degenerative mental disease (e.g., Alzheimer's disease, multiple sclerosis, senile dementia).
• Epilepsy or seizure disorder requiring anticonvulsants.
• Active malignancy, prior malignancy (except basal cell carcinoma) within the last 5 years.
• 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 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 (lithium, cisplatin, doxorubicin, or bleomycin) in which receipt of HBO2 would impact the safety of the individual.
• Anticipated administrative separation, prolonged temporary assigned duty (TAD/TDY) or deployment within 3 months after randomization
• Claustrophobia (unwilling or unable to enter hyperbaric chamber).
• Inability to protect airway or requires frequent suctioning; presence of tracheostomy
• 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).
• 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HBO2 Group	hyperbaric oxygen	Routine PCS care supplemented with hyperbaric oxygen (HBO2) at the dose of 1.5 ATA for 60 minutes administered over 40 sessions given daily Monday through Friday
Sham Group	sham hyperbaric air	Routine PCS care supplemented with an otherwise identical sham hyperbaric air exposure at 1.2 atmospheres absolute (ATA)

Primary Outcome Measures

Name	Time	Method
Change in Post-concussion Symptom Scores Using RPQ - Intent to Treat	Follow-up Visit 2; Day 56 (up to day 100) for groups not recieving HBO2, Day 70 for groups recieving HBO2	Means for the change from baseline to follow-up visit 2
Post-Intervation Post-concussion Symptom Scores Using RPQ - Intent to Treat	Follow-up Visit 2; Day 56 (up to day 100) for groups not recieving HBO2, Day 70 for groups recieving HBO2	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.
Change in Post-concussion Symptom Scores Using RPQ - Per Protocol Population	Follow-up Visit 2; Day 56 (up to day 100) for groups not recieving HBO2, Day 70 for groups recieving HBO2	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.
Post-Intervation Post-concussion Symptom Scores Using RPQ - Per Protocol Population	Follow-up Visit 2; Day 56 (up to day 100) for groups not recieving HBO2, Day 70 for groups recieving HBO2	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.

Trial Locations

Locations (5)

Naval Hospital Camp Pendleton; 🇺🇸 Camp Pendleton, California, United States

Eisenhower Army Medical Center; 🇺🇸 Fort Gordon, Georgia, United States

Evans Army community Hospital Fort Carson; 🇺🇸 Fort Carson, Colorado, United States

Naval Hospital Camp Lejeune; 🇺🇸 Camp Lejeune, North Carolina, United States

Study Coordinating Center, LDS Hospital; 🇺🇸 Salt lake City, Utah, United States