1. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 1 R. Scott Miller, M.D., COL, US Army Director, Hyperbaric Oxygen Research Program US Army Medical Materiel Development Activity Ft. Detrick, MD PRIMARY OUTCOMES FROM RANDOMIZED, MULTI-CENTER TRIAL OF HBO 2 1.5 ATA FOR POST CONCUSSION SYNDROME 15 JUNE 2013

2. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 2 DISCLAIMER "Opinions, interpretations, conclusions, and recommendations are those of the presenter and are not necessarily endorsed by the other members of the HBO 2 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. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 3 Concussions in the Military 70-80% or more fully recover before 3 months Epilepsy – double the risk within 5 years Second impact syndrome – in children, risk of rapid fatal brain swelling, if first concussion has not yet resolved Cumulative effects if multiple concussions Post-concussion syndrome – Ongoing symptoms > three months after injury

4. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 4 Post-concussion Syndrome (PCS) Headache Dizziness Fatigue Irritability Trouble concentrating Memory problems Sleep problems Changes in personality Apathy Difficulty managing emotional stress PTSD N=232 68.2% 2.9% 16.5% 42.1% 6.8% 5.3% 10.3% 12.6% TBI N=227 66.8% Chronic Pain N=277 81.5% Adapted from Lew, et al, Journal of Rehabilitative Research and Development, 46 (6), 2009, pp. 697-702

5. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 5 HBO 2 for PCS Target Product Profile Hyperbaric oxygen is being evaluated for the treatment of post-concussion syndrome (PCS) Relief of concussion symptom severity Improvement in quality of life for individuals with Post Concussion Syndrome Relief of Post Traumatic Stress Disorder (PTSD) symptom severity in individuals with co-morbid PTSD and PCS PCS has a neurologic and psychiatric component

6. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 6 MRMC Multi-Center Trial: 1.5 ATA HBO 2 vs. Sham vs. Routine TBI Care Funded by DHP RDT&E through MOMRP Conducted to GCP standards under IND 104,678 Four sites, randomized, double blinded, sham- controlled trial – Fort Carson, Camp Lejeune, Camp Pendleton and Fort Gordon – Enrolled military with post–concussion symptoms > 4 months after from TBI – Treated at local military hospital; no travel – Study ran from Jan 11 - Dec 12 Doses Selected: Active: 1.5 ATA 100% O 2 for 60 min X 40 sessions over 10 weeks plus TBI care Sham: 1.2 ATA room air, for 60 min X 40 sessions over 10 weeks plus TBI care oxygen equivalent (~2 L/min via NC) Comparator: Routine TBI care Blind appears maintained by post study questionnaire Outcome Measures: Pre/post intervention Primary: Concussions Symptoms NSI – self-reported questionnaire PRQ – self-reported questionnaire Secondary: PTSD Symptoms: PCL–C (self-report questionnaire) Sleep, pain, depression and anxiety symptoms HRQoL measures – Satisfaction with Life Survey Short Form 36 Health Survey Test of memory malingering (effort) Neurologic: Sharpened Romberg; Smell testing Psychomotor: Grooved Pegboard ANAM (automated cognitive function battery) Cognitive Test Battery - Stroop- CVLT-II - TMT- BVMT-R - D-KEFS- WTAR 1 year follow-up planned, but not presented today

7. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 7 Local Care (n=23) Sham (n=25) HBO 2 1.5 (n=24) Age, mean 30.431.432.5 Sex (% male) 96%92%96% Enlisted 91%96% Completed some college 65%72%63% # TBIs, mean 3.44.13.2 Most Recent TBI < 1 year 73%48%58% Baseline NSI score 33.632.634.3 % PTSD (SCID) 78%68%54% Baseline PCL-C score 51.853.548.5 Results: Demographics 1.5 ATA HBO 2 vs. Sham vs. Routine TBI Care 323 Calls to recruiting center 133 Not eligible/ interested 161 Referred to sites for consent 72 Enrolled 61 Not eligible 17 Withdrew

8. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 8 Results: Safety and Tolerability 1.5 ATA HBO 2 vs. Sham vs. Routine TBI Care Overall HBO 2 1.5 ATA was very well tolerated 1500 chamber sessions administered No seizures or serious adverse events Adverse Events: 15 related adverse events among 116 total adverse events 2 (4%) Withdrawals from Chamber Sessions 1 - claustrophobia/panic attack 1 – worsened headaches Adverse EventShamHBO 2 1.5 Sinus Squeeze40 Ear Pain/Mild Barotrauma14 Worsening/New Onset Headaches12

9. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 9 Concussion Symptoms Rivermead Post Concussion Symptom Questionnaire Improvement from Baseline – Intention to Treat Improvement from Baseline – Per Protocol - No differences in immediate symptom responses between HBO 2 and sham - Both were statistically superior to local TBI care arm, and showed maximal improvement when all 40 sessions were completed

10. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 10 Concussion Symptoms Neurobehavioral Symptom Inventory (NSI) Improvement from Baseline – Intention to Treat Improvement from Baseline – Per Protocol - No differences in immediate symptom responses between HBO 2 and sham - Both were statistically superior to local TBI care arm, and showed maximal improvement when all 40 sessions were completed

11. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 11 PTSD Symptoms PTSD Checklist- Civilian Improvement from Baseline – ITT - By per protocol analysis, there were no differences between HBO 2 and sham with reductions of 9.5 and 12.8 points, respectively - Reductions of > 8 are clinically relevant

12. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 12 Health Related Quality of Life Short Form 36 Health Survey Change from Baseline – Health Concepts (ITT) - Also no difference between HBO2 and sham on Satisfaction with Life Scale with both showing modest improvement

13. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 13 Summary In this study, standard local care offered no improvement during the 3 month observation period Randomization to the chamber (either sham or placebo) offered statistical and in some measures clinically significant improvement over local routine TBI care This explains the anecdotal findings reported Hyperbaric oxygen at 1.5 ATA for 40 sessions offered no statistical benefit over sham in immediate relief of PCS symptoms Could be typical placebo response or low dose oxygen effect

14. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 14 HBO 2 Multi-Center Trial Team Thank You! MRMC Multicenter Study USAMMDA Walter Reed Army Institute of Research Evans Army Community Hosp/10 th SF Group Naval Hospital Camp Lejeune Naval Hospital Camp Pendleton Eisenhower Army Medical Center LDS Hospital/University of Utah Denver VAMC/Center of Mental Illness Research Henry M. Jackson Foundation EmpiriStat Inc. OxyHeal Health Group Dr. Lin Weaver, LDS Hospital/University of Utah Ms. Sue Churchill, LDS Hospital/University of Utah Ms. Kayla Deru, LDS Hospital/University of Utah Dr. Lisa Brenner, MIRECC, Denver VAMC Dr. Nazanin Bahraini, MIRECC, Denver VAMC Ms. Leah Russell, MIRECC, Denver VAMC Ms. Maria Devore, MIRECC, Denver VAMC Dr. Scott Mooney, Eisenhower Army Medical Center Dr. Jack Rigg, Eisenhower Army Medical Center COL Mike Madsen, Eisenhower Army Medical Center LTC Rob Price, Evans Army Community Hospital CDR Laura Grogan, Evans Army Community Hospital LCDR Virginia Skiba, Naval Hospital Camp Lejeune CPT Corinna Bartos, Naval Hospital Camp Lejeune LCDR Jason Gordon, Naval Hospital Camp Lejeune CDR Jim Caviness, Naval Hospital Camp Pendleton Dr. Margaret Ryan, Naval Hospital Camp Pendleton Dr. Nicole Close, EmpiriStat Dr. Brian Hetzell, PPD and our coordinators and technicians

15. UNCLASSIFIEDrobert.s.miller@us.army.mil USAMMDA - Developing Quality Medical Products for U.S. Forces 15 A hyperbaric oxygen session with oxygen hoods in multi-place chamber Equalizing middle ear pressure Monoplace Chamber HBO 2 as a Drug