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USAMMDA - Developing Quality Medical Products for U.S. Forces 1 COL R. Scott Miller, M.D., FACP, FIDSA Assistant.

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Presentation on theme: "USAMMDA - Developing Quality Medical Products for U.S. Forces 1 COL R. Scott Miller, M.D., FACP, FIDSA Assistant."— Presentation transcript:

1 USAMMDA - Developing Quality Medical Products for U.S. Forces 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 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 USAMMDA - Developing Quality Medical Products for U.S. Forces 3 Concussions in the Military 70-80% fully recover in 3 months concussions may be complicated by psychological trauma or PTSD

4 USAMMDA - Developing Quality Medical Products for U.S. Forces 4 What is Hyperbaric Oxygen (HBO 2 )? 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 O 2 concentrations in blood and tissues … which FDA considers a drug FDA Approved Indications for HBO 2 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 USAMMDA - Developing Quality Medical Products for U.S. Forces 5 A hyperbaric oxygen session with oxygen hoods in multiplace chamber Equalizing middle ear pressure Monoplace Chamber HBO 2 Administration

6 USAMMDA - Developing Quality Medical Products for U.S. Forces 6 Why HBO 2 ? HBO 2 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 USAMMDA - Developing Quality Medical Products for U.S. Forces 7 HBO 2 for chronic brain injury 1967: Holbach (Germany) – Used 1.5 atm abs for chronic stroke 1973: Holbach and Caroli (Germany) – dose selection – From 1967 to 1973, over 700 HBO 2 sessions for acute brain injury – Examined cerebral glucose metabolism and acid/base balance of the brain in 102 patients that received 267 courses of HBO 2 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 sessions. – SPECT brain imaging showed increased perfusion at selected intervals and clinical improvement noted

8 USAMMDA - Developing Quality Medical Products for U.S. Forces 8 HBO 2 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 HBO 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 USAMMDA - Developing Quality Medical Products for U.S. Forces 9 HBO 2 for TBI Health System Perspectives HBO 2: 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 2003 UMHS Position Statement – insufficient data for endorsement for acute or chronic brain injury 2003 AHRQ – insufficient evidence for TBI, stroke and cerebral palsy 2008 Cochrane Review – insufficient data for acute TBI 2009 VA Review – insufficient data to support use for TBI or PCS

10 USAMMDA - Developing Quality Medical Products for U.S. Forces 10 HBO 2 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 USAMMDA - Developing Quality Medical Products for U.S. Forces 11 Obtaining the Evidence FDA Perspectives U.S. Army Office of the Surgeon General holds the IND #104,678 for testing HBO 2 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 USAMMDA - Developing Quality Medical Products for U.S. Forces 12 HBO 2 in the DoD TBI Research Portfolio Reset Objective Measure of Head Impact Exposure Valid Criteria & Objective mTBI/ Concussion Screening Tool Head Impact/Blast Injury Dosimeter Validated Definition and Technologies: EEG, TCD, Eye Tracking, Vestibular Ocular Assessment, ICP Device, Biomarkers RTD Standards, Evaluation/ Measurement Medications, Novel Interventions Cognitive, Behavioral, and Neurological Assessments (CT, EEG, fMRI, DTI, MRS, etc.) mTBI/ Concussion Recovery mTBI/ Concussion Treatment Evidence-Based Rehabilitation Protocols, Measures of Rehabilitation Progress Portable Fieldable Diagnostic Device (In Theatre & Garrison) Pharmaceutics & Surgical Technology Recovery Timecourse & Rehabilitation Valid RTD Standards & Measures of Rehabilitation mTBI/ Concussion Assessment mTBI/ Concussion Screening (DoD Guidelines) mTBI/ Concussion Screening (DoD Guidelines) RDT&E: Injury Prevention Combat Casualty Care Possible mTBI/ Concussion from Impact or Blast Return to Duty/Disability/Reclassification Assessment mTBI/ Concussion Prevention/ Education & Training Nutraceuticals, Standards for Helmets, Education/CPG’s for Soldiers, Leaders & Service Providers Medical Standards for Protective Equipment Continuing Education and Reinforcement for Soldiers, Leaders and Service Providers Psych Health and Related Symptoms HBO 2

13 USAMMDA - Developing Quality Medical Products for U.S. Forces 13 Multicenter Pivotal Trial? (n=300+) DoD/VA HBO 2 Research Program Jan ‘11Jan ‘13Jul ‘12Jan ‘12Jul’11Jul ‘13 HOPPS IND Pilot Study (n=96) USAFSAM Pilot Study (n=50) VA/VCU/USN Dose Ranging Study (n=60) Outcomes in Normals Study (n=75) Mechanisms of Action Study (BIMA) (n=60) Outcome Validation Project Jan ‘14Jul ‘14Jan ‘15 DSMB IND Filed Type C meeting TMA & UHMS Submission De Novo/ 510K End Phase II Chambers Installation at 4 MTFs We must know these before we start pivotal trial: - sham method validated - dose selection of HBO 2 - outcome measure validated to detect change after intervention - establish range of placebo effect to determine sample size MultiModal Rehab Effectiveness RCT? (n=100)

14 USAMMDA - Developing Quality Medical Products for U.S. Forces 14 HBO 2 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?

15 USAMMDA - Developing Quality Medical Products for U.S. Forces 15 To estimate in pilot studies if HBO 2 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 HBO 2 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 HBO 2 mTBI Research Program Goals

16 USAMMDA - Developing Quality Medical Products for U.S. Forces 16 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 mTBI AND 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

17 USAMMDA - Developing Quality Medical Products for U.S. Forces 17 Co-Morbidities Associated with PCS PTSD n= % 2.9% 16.5% 42.1% 6.8% 5.3% 10.3% 12.6% PCS n= % Chronic Pain n= % Lew, et al 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: % of PCS is an isolated finding

18 USAMMDA - Developing Quality Medical Products for U.S. Forces 18 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

19 USAMMDA - Developing Quality Medical Products for U.S. Forces 19 Cognitive Rehabilitation – IOM Report Oct 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 Treatment of Post Concussion Syndrome

20 USAMMDA - Developing Quality Medical Products for U.S. Forces 20 Evidence for HBO 2 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, HBO 2 remains a promising but unproven therapy for PCS

21 USAMMDA - Developing Quality Medical Products for U.S. Forces 21 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 HBO 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.

22 USAMMDA - Developing Quality Medical Products for U.S. Forces 22 Challenge: Understanding the Placebo Response 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 HBO 2 efficacy can be confirmed Khan 2002: half of all trials of antidepressants later FDA approved showed no benefit over placebo effective placebo response – antidepressants 30-50% anxiolytics 30-50% PTSD treatment 38.5% HBO2 Treatment Interactions with Caring Staff/ Placebo Effects Month stay in New Orleans

23 USAMMDA - Developing Quality Medical Products for U.S. Forces 23 Meta-analysis of placebo-controlled 75 depression trials from 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:

24 USAMMDA - Developing Quality Medical Products for U.S. Forces 24 Challenge: Systemically Measuring 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

25 USAMMDA - Developing Quality Medical Products for U.S. Forces 25 Summary: State of the Science Despite a series of anecdotes and lobbying efforts for the hyperbaric industry, there remains no definitive medical evidence that HBO 2 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

26 USAMMDA - Developing Quality Medical Products for U.S. Forces 26 MHS Partnerships and Info for Wounded Warriors ClinTrials.gov – registry of all clinical trials HBO 2 Information Hotline is available – Warriors can call to get information about any HBO 2 research trial – Info on ongoing DoD and civilian studies USAF Study USAFSAM Wilford Hall Medical Center Hyperion Inc. Navy/VA Study NOMI Pensacola Virginia Commonwealth University McGuire Richmond VAMC 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/Intermountain Healthcare Denver VAMC/Center of Mental Illness Research Henry M. Jackson Foundation EmpiriStat Inc. OxyHeal Health Group Upcoming Studies NICoE Madigan AMC Many new academic partners

27 USAMMDA - Developing Quality Medical Products for U.S. Forces 27 Questions


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