Post-Concussion Syndrome Rehabilitation: Is there a Role for Hyperbaric Oxygen? 4 MAY 2012

1. COL R. Scott Miller, M.D., FACP, FIDSA Assistant Professor of Medicine, USUHS Director, Hyperbaric Oxygen Research Program US Army Medical Materiel Development Activity Ft. Detrick, MD Post-Concussion Syndrome Rehabilitation: Is there a Role for Hyperbaric Oxygen? 4 MAY 2012

2. DISCLAIMER • "Opinions, interpretations, conclusions, and recommendations are those of the presenter and are not necessarily endorsed by the other members of the HBO2 research consortium, the U.S. Army Medical Materiel Development Activity, the U.S. Army Medical Research and Materiel Command, the U.S. Army or the Department of Defense ."

3. Concussions in the Military • 70-80% fully recover in 3 months • concussions may be complicated by psychological trauma or PTSD

4. What is Hyperbaric Oxygen (HBO2)? Intervention in which a patient breathes 100% oxygen intermittently inside a chamber that is pressurized to higher than sea level pressure specifically to pressures of 1.4 atmospheres absolute or higher. creates supraphysiologic O2 concentrations in blood and tissues … which FDA considers a drug FDA Approved Indications for HBO2 Decompression Sickness - Crush Injuries Air/Gas Embolisms - Enhanced Healing of Selected Wounds Carbon Monoxide Poisoning and Smoke Inhalation Intracranial Abscess - Radiation Tissue Damage Gas Gangrene - Skin Grafts and Flaps Necrotizing Soft Tissue Infection - Thermal Burns Osteomyelitis, refractory - Exceptional Blood Loss

5. HBO2Administration Monoplace Chamber A hyperbaric oxygen session with oxygen hoods in multiplace chamber Equalizing middle ear pressure

6. Why HBO2? • HBO2 is a FDA-cleared treatment modality recommended for 14 indications • including carbon monoxide poisoning where acutely it works in part to reduce inflammatory responses in the brain • As an alternative medicine therapy, it has been evaluated for a variety of other neurologic conditions: • acute stroke and stroke rehabilitation • cerebral palsy • autism • anoxic brain injury • acute moderate-severe TBI • TBI rehabilitation

7. 1967: Holbach (Germany) Used 1.5 atm abs for chronic stroke 1973: Holbach and Caroli (Germany) – dose selection From 1967 to 1973, over 700 HBO2 sessions for acute brain injury Examined cerebral glucose metabolism and acid/base balance of the brain in 102 patients that received 267 courses of HBO2 Discovered that 1.5 atm abs was optimal, 2.0 atm abs was adverse 1980: Neubauer and End (Florida) Used 1.5 atm abs for chronic stroke, 2.0 atm abs for acute stroke Subsequently used 1.5 atm abs for other types of chronic brain injury 1994: Harch (LSU) – open label study Used HBOT 1.5 atm abs in chronic brain injury x 40-80 sessions. SPECT brain imaging showed increased perfusion at selected intervals and clinical improvement noted HBO2 for chronic brain injury

8. HBO2 in subacute TBI – limited animal data Mechanisms of action in subacute/chronic TBI are unknown Limited animal data Rat focal cortical contusion model – intervention 30d post injury 3 groups: untreated control sham, normobaric air group HBO2 1.5 ATA x 90 min, 80 sessions given twice daily Endpoint: Morris Water Task Improved spatial learning/memory Increased Blood volume - Hippocampus Harch 2007 Brain Res 1174: 120

9. HBO2 for TBI Health System Perspectives • HBO2: a cleared product and can be prescribed ‘off-label’ • problem is payment/reimbursement • no third party payers will cover acute TBI or brain rehabilitation citing that lack of quality evidence • requires out-of-pocket payments • 2003UMHS Position Statement – insufficient data for endorsement for acute or chronic brain injury • 2003 AHRQ – insufficient evidence for TBI, stroke and cerebral palsy • 2008Cochrane Review – insufficient data for acute TBI • 2009VA Review – insufficient data to support use for TBI or PCS

10. HBO2 for PCS What MHS/TRICARE is Looking For • Evidence of a nationally accepted practice (32 CFR 199.2) • Reliable evidence • well-controlled trials of clinically meaningful endpoints, published in peer-reviewed literature • published formal technology assessments • published reports of national medical associations (i.e. UHMS) • published national medical policy organizations (i.e. AHRQ) • published reports of national expert opinions organizations (i.e. IOM) • NOT anecdotes and case series

11. Obtaining the Evidence FDA Perspectives • U.S. Army Office of the Surgeon General holds the IND #104,678 for testing HBO2 for post-concussion syndrome • FDA considers hyperbaric oxygen a ‘combination product’ • supraphysiologic levels of oxygen (drug) delivered in a Class II medical device (hyperbaric chamber) • Requirements for New Device Application (PMA) • safety collection sufficient in size • 2 randomized, double blind pivotal trials

12. DoD/VA HBO2 Research Program USAFSAM Pilot Study (n=50) We must know these before we start pivotal trial: - sham method validated - dose selection of HBO2 - outcome measure validated to detect change after intervention - establish range of placebo effect to determine sample size VA/VCU/USN Dose Ranging Study (n=60) IND Filed Type C meeting End Phase II De Novo/ 510K HOPPS IND Pilot Study (n=96) TMA & UHMS Submission Outcome Validation Project Mechanisms of Action Study (BIMA) (n=60) Chambers Installation at 4 MTFs Outcomes in Normals Study (n=75) MultiModal Rehab Effectiveness RCT? (n=100) DSMB DSMB DSMB DSMB Multicenter Pivotal Trial? (n=300+) Jan ‘11 Jul’11 Jan ‘12 Jul ‘12 Jan ‘13 Jul ‘13 Jan ‘14 Jul ‘14 Jan ‘15

13. HBO2 for PCS Efficacy Claims being Evaluated • Hyperbaric oxygen is being explored for the restorative treatment of post concussion syndrome • Relief of symptoms • post concussion symptom severity • post traumatic stress disorder symptom severity in individuals with co-morbid PTSD and PCS • Improved cognitive functioning • Improvement in quality of life for individuals with • post concussion syndrome (PCS) • Enhancement of other rehabilitation strategies?

14. To estimate in pilot studies if HBO2 shows benefit above sham control To estimate placebo effect on outcome measures May impact further research funding To develop grade 1 evidence from randomized, sham- controlled trials that demonstrate if HBO2 is safe and effective for treatment of post concussion syndrome If effective and safe: to seek the endorsement of UHMS and TRICARE/VA for treatment of post-concussion syndrome Ultimately submit the data to the FDA for treatment of symptoms and neurocognitive improvement in PCS DoD/VA HBO2mTBI Research Program Goals

15. Post-Concussion Syndrome Lack of a standardized case definition • Using DSM-IV-TR definition • History of concussion (mTBI) - a closed head injury with: • Loss of consciousness for 0-30 minutes – OR • Alteration of consciousness for a moment up to 24 hours - OR • Traumatic amnesia lasting no longer than 1 day • AND • At least 3 symptoms starting or worsening after mTBIAND lasting at least 3 months: • Headaches - Seizures • Dizziness/balance problems - Difficulty with memory or solving problems • Blurred vision - Managing stress or emotional upset • Fatigue or sleep problems - Controlling your temper/irritability • Ringing in your ears

16. Co-Morbidities Associated with PCS Chronic Pain n=277 81.5% PTSD n=232 68.2% 10.3% 16.5% 2.9% 42.1% 12.6% 6.8% 5.3% PCS n=227 66.8% • 8% of PCS is an isolated finding Lew, et al. 2009. Prevalence of Chronic Pain, Posttraumatic Stress Disorder, and Persistent Postconcussive Symptoms in OIF/OEF Veterans: Polytrauma Clinical Triad, Journal of Rehabilitative Research and Development, Vol. 46: 697-702.

17. Treatment of Post Concussion Syndrome • No proven restorative therapy, other than time • Avoidance of recurrent concussion • Skills for coping with disability • Drugs for individual symptom relief Crosby return on hold as concussion symptoms continue Reuters – Wed, Dec 28, 2011

18. Treatment of Post Concussion Syndrome • Cognitive Rehabilitation – IOM Report Oct 2011 • 88 non-coordinated, mostly single-site studies using: • non-standardized interventions; and • non-standardized outcome measures • limited evidence of benefit for post concussion syndrome (single study) • recommended continuing use until more evidence

19. Evidence for HBO2 for PCS/PTSD • Our wounded warriors deserve the best evidence-based medical care that is available • onus on MHS to evaluate off-label uses of traditional and alternative therapies when a treatment gap exists • Despite lots of hype and lobbying efforts, HBO2 remains a promising but unproven therapy for PCS

20. Claims of Efficacy in Case Reports &Case Series in mTBI in Warriors Anecdotal case reports (2009): Harch and Wright SOCOM experience Harch et al reported a case series of 15 warriors with PCS/PTSD in J Neurotrauma Dec 2011 Veterans 1-4 years post mild TBI with chronic symptoms exposed to HBO2 1.5 ATA x 40 days with twice daily dive sessions Assessment pre and immediately post treatment; Up to 51% improvement in self-reported anxiety and depression sx Self-reported ‘improved to normal’: cognition (50 67%); emotional (3261%); physical (4766%) Marked improvement in self-reported sleep ~ 10 % improvement in memory and neurocognitive tests Most retained symptomatic improvement at 6 months.

21. Challenge: Understanding the Placebo Response Month stay in New Orleans • PCS symptoms, like all psychologic • & self-reported outcomes, are • markedly prone to • placebo/Hawthorne effects • RCT control group needed • placebo effects are pharmacologic • without understanding placebo effects, no claims of HBO2 efficacy can be confirmed • Khan 2002: half of all trials of antidepressants later FDA approved showed no benefit over placebo • effectiveplacebo response – antidepressants 30-50% • anxiolytics 30-50% • PTSD treatment 38.5% Interactions with Caring Staff/ Placebo Effects HBO2 Treatment

22. Meta-analysis of placebo-controlled 75 depression trials from 1981-2000 • Successful outcome defined as 50% reduction in Hamilton depression scale • Overall 30% of placebo recipients met the 50% improvement threshold • Individual studies showed up 51% of placebo recipients met a 50% symptom improvement score • Placebo drift: effects are more pronounced in recent studies Walsh BT et al, JAMA 2002; 287: 1840-7

23. Challenge: SystemicallyMeasuring Improvement • As no current therapies exist for post-concussion syndrome, there are no validated outcome measures • Goal to validate outcome measures as scaffold for future clinical trials • Post-concussion symptoms questionnaire • Neurobehavioral Symptom Inventory (NSI) • - Must address confounds of co-morbidities • Global Outcome Score • Possibly, a battery of neurocognitive tests

24. Summary: State of the Science Despite a series of anecdotes and lobbying efforts for the hyperbaric industry, there remains no definitive medical evidence that HBO2 has a therapeutic role in the relief of symptoms or brain dysfunction for warriors with post-concussion syndrome/mild TBI or PTSD. DoD leadership has partnered with the VA and academia to develop a coordinated research program to collect the data to allow evidence-based decision-making

25. MHS Partnerships and Info for Wounded Warriors ClinTrials.gov – registry of all clinical trials HBO2 Information Hotline is available Warriors can call 1-877-445-3199 to get information about any HBO2 research trial Info on ongoing DoD and civilian studies USAF Study USAFSAM Wilford Hall Medical Center Hyperion Inc. MRMC Multicenter Study USAMMDA Walter Reed Army Institute of Research Evans Army Community Hosp/10thSF Group Naval Hospital Camp Lejeune Naval Hospital Camp Pendleton Eisenhower Army Medical Center LDS Hospital/Intermountain Healthcare Denver VAMC/Center of Mental Illness Research Henry M. Jackson Foundation EmpiriStat Inc. OxyHeal Health Group Navy/VA Study NOMI Pensacola Virginia Commonwealth University McGuire Richmond VAMC Upcoming Studies NICoE Madigan AMC Many new academic partners

26. Questions