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Bullock, Ross


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Bullock, Ross

  1. 1. Neuroprotection Trials in Traumatic Brain Injury -2011 Ross Bullock, MD, PhD. Director, Neurotrauma,- University of Miami /Jackson Memorial Hospital, Miami.
  2. 2. TBI Clinical Trials--recent, and ongoing….2011 Clinical trials .Gov n= 307 ,33 acute, 13 observational) <ul><li>Progesterone … Protect III Trial…“NETT”-Ongoing, BHR Pharma- SyNAPSe –ongoing.. </li></ul><ul><li>Estrogen-Premarin-UT southwestern </li></ul><ul><li>Factor VII..Novonordisk-Completed </li></ul><ul><li>Hypothermia After Acute Traumatic Brain Injury (NABIS:HIIR) –Completed ,B-HYPO” Japan..completed </li></ul><ul><li>Erythropoetin in Severe TBI…X 2 </li></ul><ul><li>Hypertonic saline –prehospital/ER…NHLB consortium..results? </li></ul><ul><li>Citicholine “COBRIT” NICHD consortium..Ongoing.. </li></ul><ul><li>Neuren NNZ 2566-INTREPID--Ongoing </li></ul><ul><li>Decompressive craniotomy…RESCUE ICP…(DECRA completed) </li></ul><ul><li>Oxycyte….Perfluorocarbon…Ongoing </li></ul><ul><li>Cyclosporin –ABIC—unfunded? </li></ul><ul><li>Solvay SL339…endothelin antagonist/anti apoptotic ..(ABIC)-prematurely stopped </li></ul><ul><li>Stem cells—Egypt N=80, uncontrolled, UT Houston, children n=10.. </li></ul><ul><li>Hyperbaric Oxygen—Chronic TBI. X 4….acute TBI-unfunded… </li></ul><ul><li>Laser light therapy..” Photothera” </li></ul><ul><li>bright light and exercise-chronic-NIH </li></ul><ul><li>Normothermia and Diclofenac..Italy, acute </li></ul><ul><li>Normoglycemia and Neurological Outcome –U of Louisville </li></ul><ul><li>Preventing Epilepsy After Traumatic Brain Injury With Topiramate (PEPTO)—U Penn.. </li></ul><ul><li>Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR-RCT)aust,NZ </li></ul><ul><li>Vasopressin Versus Catecholamines for Cerebral Perfusion Pressure Control in Brain Injured Trauma Patients (AVP) Magnesium sulphate in TBI—U of Washington..completed, </li></ul><ul><li>Brain 0xygen –directed therapy…BOOST..UT Dallas/Parklands </li></ul><ul><li>Mannitol vs Hypertonic saline..X3 </li></ul><ul><li>COSBID—EcoG…for Spreading depolarisations.. </li></ul>
  3. 3. Blast injury….Pathomechanism poorly understood.. Fulminant brain swelling, and delayed “Vasospasm”…. The DOD Effect on TBI research..2007-~$120m 2008 ~$90m…
  4. 4. “ Per Ardua ad Virtutam” 8 Major Consortia for TBI trials….Over 300 centers… NICHD TBI trials Cosortium…CDP choline trial-8 centers NETT…… progesterone “Protect “ trial-~17major centers.. NHLBI ….Hypertonic saline, prehospital DOD new PTSD/TBI Consortium.. 10 centers… LABIC—Latin American Brain Injury Centers.. ANZICS consortium….DECRA..17 centers ABIC…~50 centers.. EBIC….
  5. 5. Protect III <ul><li>Emory University—David Wright. </li></ul><ul><li>Collaborators: </li></ul><ul><li>Henry Ford Hospital Emory University Collaborators: Henry Ford Hospital Medical College of Wisconsin New York Presbyterian Hospital Oregon Health and Science University Stanford University Temple University University of Arizona University of California University of Cincinnati University of Kentucky University of Maryland University of Minnesota - Clinical and Translational Science Institute University of Texas University of Pennsylvania Virginia Commonwealth University Wayne State University </li></ul>N=1140, NIH NINDS sponsored, using the NETT consortium…GCS4-12, within 4hrs of injury… BHR Pharma , parallell phase III in US, EU…
  6. 6. “ Those who do not learn from the lessons of History, are Doomed to repeat the mistakes of the past” Winston Churchill
  7. 8. Requirement for successful phase III TBI Trials- The 6 “Koch’s Postulates”… <ul><li>Mechanism shown in animal models.. </li></ul><ul><li>Drug /agent reverses damage in animals </li></ul><ul><li>mechanism shown in human TBI </li></ul><ul><li>brain penetration </li></ul><ul><li>Safety/tolerability shown in humans with TBI </li></ul><ul><li>Use drug sensitive end points </li></ul>
  8. 9. Nelfinavir - study 506 Mean changes from Baseline in CD4 cell cycle Clinical Trials in HIV/AIDS…600 trials, to get to HAART …
  9. 10. Hand-held battlefield ready and EMT use Point-of-Care Clinical laboratory platforms Biomarker Assay for CNS injury The Banyan vision… In Collaboration with Device Manufacturers TBI Biomarker Diagnostic
  10. 11. Kobeissy, et al. Wang . Differential proteomic analysis of traumatic brain injury biomarker study using CAX-PAGE/RPLC-MSMS method. Mol. Cell. Proteomics 5: 1887-1898. Neuroproteomic Biomarker Discovery ”high throughput screening”… Naïve vs. Injured
  11. 12. Time Post Injury (hours) SBDP120 (ng/ml) Time Post Injury (hours) CSF Serum SBDP120 in TBI.. SBDP120 (ng/ml)
  12. 13. Successful Trials in clinical Neuroscience <ul><li>“ Stroke” -~155 phase III trials… </li></ul><ul><li>rTPA Thrombolysis - NIH </li></ul><ul><li>Carotid Endarterectomy - NIH </li></ul><ul><li>Hypothermia—global brain ischemia </li></ul><ul><li>after cardiac arrest…EU, Au mrc. </li></ul><ul><li>Spinal Cord Injury - NASCIS II -NIH </li></ul><ul><li>Multiple Sclerosis - Interferon </li></ul><ul><li>AIDS Protease Inhibitors/Anti-Retrovirals </li></ul><ul><li>Over 600 phase II-III trials in AIDS/HIV… </li></ul><ul><li>~23 in TBI…!! </li></ul>
  13. 14. Bcl-2 Bax Human CEREBRAL CONTUSIONS LOW POWER NNZ 2566— active against delayed apoptotic mechanisms, in Human TBI?—Neurotrophin? T B I HIGH POWER
  14. 15. N = Neuronal cell body V = Blood vessel Blk arrow = Astrocyte Dbl arrow = normal oligo Blk pointer = unraveled myelin Arrowhead = swollen axonal figures Open arrow = microglia Star = amorphous crystallized material 3d 15d 3mo 9mo 12mo Control Bramlett, et al.—apoptotic cell death delayed up to I year, after TBI..
  15. 16. 1 hour post injury.. GCS 13 6 hours after injury.. GCS 6 ICP High.. Delayed intracerebral hemorrhage due to coagulopathy..the Nemesis of “Polytrauma”
  16. 17. Schematic representation of PFC emulsion particle distribution within the capillary increasing the surface area for O2 transport to the entire blood volume. Can PFC’s increase Brain oxygenation, by Non Erythrocyte Oxygen transport, in compressed, deformed capillaries? RBC’s PFC Emulsion Particles
  17. 18. Effect of Hyperoxia on Regional Oxygenation and Metabolism after severe Human TBI … Nortje et al, Crit Care Med 2008 :36, 273-281
  18. 19. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. Rockswold GL , Ford SE , Anderson DC , Bergman TA , Sherman RE . Division of Neurosurgery, Hennepin County Medical Center, Minneapolis, Minnesota. The authors enrolled 168 patients with closed-head trauma into a prospective trial to evaluate the effect of hyperbaric oxygen in the treatment of brain injury.. Hyperbaric oxygen was administered to the treatment group in a monoplace chamber every 8 hours for 1 hour at 1.5 atm absolute; this treatment course continued for 2 weeks or until the patient was either brain dead or awake. An average of 21 treatments per patient was given. Outcome was assessed by blinded independent examiners. The entire group of 168 patients was followed for 12 months, with two patients lost to follow-up study. The mortality rate was 17% for the 84 hyperbaric oxygen-treated patients and 32% for the 82 control patients (chi-squared test, 1 df, p = 0.037). Among the 80 patients with an initial GCS score of 4, 5, or 6, the mortality rate was 17% for the hyperbaric oxygen-treated group and 42% for the controls (chi-squared test, 1 df, p = 0.04). Analysis of the 87 patients with peak intracranial pressures (ICP) greater than 20 mm Hg revealed a 21% mortality rate for the hyperbaric oxygen-treated patients, as opposed to 48% for the control group (chi-squared test, 1 df, p = 0.02 ). J Neurosurg. 1992 Jun;76(6):929-34
  19. 20. The NIH-NINDS Trial of ICP Monitoring, in Bolivia,LABIC… 4 hospitals, PRCT..~350 pts
  20. 21. Human TBI …and COSBID.. suppression of large amplitude delta activity (e.g. PLEDs) EEG DC 1 s 1 min Chi-square p<0.001 N=72, MIA= 2 nd highest enroller 68% 25% >38.0 23% 58% 35.0-38.0 10% 17% < 35.0 Temp during CSD All temps during monitoring Temperature ranges
  21. 22. Explained Variance Nagelkerke’s R 2 Univariate Analysis-outcome * * * * Significance at p<0.05
  22. 24. <ul><li>Australia and NZ </li></ul><ul><li>The Alfred Royal Melbourne Hospital Royal Adelaide Hospital Royal Perth Hospital Sir Charles Gairdner Hospital Nepean Hospital John Hunter Hospital Royal North Shore Hospital Liverpool Hospital Wollongong Hospital Princess Alexandra Hospital Gold Coast Hospital Flinders Medical Centre Auckland Hospital Waikato Hospital Wellington Hospital </li></ul><ul><li>Saudi Arabia </li></ul><ul><li>King Fahad National Guard Hospital Canada </li></ul><ul><li>Hamilton General hospital Vancouver General Hospital Sunnybrook Medical Centre Royal Columbian Hospital India </li></ul><ul><li>Christian Medical College, </li></ul><ul><li>Ludhiana </li></ul>160 enrolled…NEMJ,march 2011 Early bifrontal decompression, Vs medical management No benefit from surgery…more disabled and vegetative outcomes.. Craniectomy patients had less time with ICP above the treatment threshold (P<0.001), fewer interventions for increased ICP, and fewer days in ICU than standard care (P<0.001). However, craniectomy patients had more unfavorable outcomes (70% vs. 51%; Odds Ratio (OR) 2.21; 95% Confidence Intervals (CI) 1.14-4.26; P=0.02), worse GOSE scores (OR 1.84; 95% CI 1.05-3.24; P=0.03), and more severely disabled survivors (63% vs. 40%; P=0.01). The treatment effect was similar after adjustment for pre-specified potential confounders. Mortality at 6 months was similar in the two treatment groups (18% vs. 19%).
  23. 25. Cambridge – 34 Leeds – 20 Royal London – 12 Newcastle – 11 Southampton – 10 Singapore – 8 Milan, Italy – 6 Manchester – 6 Saudi Arabia – 5 Edmonton, Canada – 5 Calgary, Canada – 4 Hong-Kong – 4 Old Church – 4 Plymouth – 4 Hurstwood Park – 3 Kings College – 3 Pavia, Italy – 3 Barcelona, Spain – 2 Livorno, Italy – 1 Malaysia – 1 Oxford – 1 Queen’s Square – 1 Swansea – 1 Ulm, Germany - 1 The study has recruited 150 patients to date! Well done everyone!! The top five recruiting centres are Cambridge, Leeds, Royal London, Newcastle and Southampton. Please continue recruiting all 150 patients recruited, by june 2008! DECRA Study…Melbourne,Australia, 210 pts, ~70 entered…J Cooper, G Rosenfeld
  24. 26. Photothera …the Allure of the Laser..
  25. 27. Alvarez-Buylla, et al, Nature,427, feb 2004,740-744
  26. 28. Cell proliferation at the site of injury Chirumamilla et al., 2002,J Neurotrauma
  27. 29. Age-related cell proliferation Underlying mechanisms
  28. 30. MWM Performance following intra-ventricular infusion of EGF –for 7days—byAlzet minipump.. <ul><li>Endogenous neuroprogenitor </li></ul><ul><li>Stimulation… </li></ul><ul><li>Mesenchymal stem cells, IV, IT </li></ul><ul><li>Embryonal stem cells… </li></ul><ul><li>Intraparenchymal </li></ul><ul><li>Fetal neuroprogenitor cells.. </li></ul><ul><li>Autologous neuroprogenitor </li></ul><ul><li>Expansion.. </li></ul>
  29. 31. Nestin—marker of progenitor cells Tuj1-- MAP 2.. SPION labelling… Human “Neural stem cells” after TBI....n=31 Mouse NPC’s..SOX 2 positive cells..
  30. 32. Severe TBI-- Does it all make a difference? <ul><li>Mortality rates falling….~80% before WWII.. </li></ul><ul><ul><li>60% in 1960’s, 40% in 1980’s ~20% in 2000…. </li></ul></ul><ul><ul><li>Most cost effective surgical procedure of all is craniotomy for EDH… </li></ul></ul>Probability of death…severe TBI-2007