1. Edward Sloan, MD, MPH, FACEP ED Ischemic Stroke Patient Neuroprotection: What neuroprotection strategies do we utilize and what might be the role of NXY-059?

2. Edward Sloan, MD, MPH, FACEP 2006 Advanced Emergency & Acute Care Medicine and Technology Conference 2006 Advanced Emergency & Acute Care Medicine and Technology Conference

3. Edward Sloan, MD, MPH, FACEP Emergency Medicine Associates Atlantic City, NJ September 26-27, 2006

4. Edward Sloan, MD, MPH, FACEP Edward P. Sloan, MD, MPH FACEP Professor Department of Emergency Medicine University of Illinois College of Medicine Chicago, IL

5. Edward Sloan, MD, MPH, FACEP Attending Physician Emergency Medicine University of Illinois Hospital Our Lady of the Resurrection Hospital Chicago, IL

6. Edward Sloan, MD, MPH, FACEP Disclosures NovoNordisk, King Pharmaceuticals, UCB Pharma Advisory Boards NovoNordisk, King Pharmaceuticals, UCB Pharma Advisory Boards Eisai Speakers’ Bureau Eisai Speakers’ Bureau ACEP Clinical Policies Committee ACEP Clinical Policies Committee ACEP Scientific Review Committee ACEP Scientific Review Committee Executive Board, Foundation for Education and Research in Neurologic Emergencies Executive Board, Foundation for Education and Research in Neurologic Emergencies

7. Edward Sloan, MD, MPH, FACEP Global Objectives Maximize patient outcome Maximize patient outcome Utilize health care resources well Utilize health care resources well Optimize evidence-based medicine Optimize evidence-based medicine Enhance ED practice Enhance ED practice

8. Edward Sloan, MD, MPH, FACEP Sessions Objectives State key questions and concepts State key questions and concepts Why perform neuroprotection? Why perform neuroprotection? What global neuroprotections? What global neuroprotections? What specific therapies? What specific therapies? What lies ahead? What lies ahead?

9. Edward Sloan, MD, MPH, FACEP Case Presentation… 64 year old presents to ED Trouble using L hand and speech Symptoms for last 90 minutes No headache or trauma History of TIA x 1, similar symptoms Hx DM, smoker No recent illness

10. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant Specific neuroprotectants tested SAINT-I clinical trial showed benefit Specific questions to be addressed

11. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume

12. Edward Sloan, MD, MPH, FACEP Stroke Volume and Outcome Vessel occlusion Infarct core Ischemic penumbra How large is the core in the ED? What is the penumbra conversion? Do ED therapies limit infarct growth?

13. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size

14. Edward Sloan, MD, MPH, FACEP Limiting Stroke Volume Enhance perfusion Treat hypoxia, hypotension Limit ischemic cascade effects Prevent complications the astonis hing results Compare the results with a conventional training protocol. Most people do at least two exercises per muscle group, perform three sets and perhaps 12 or 15 reps per set. Allowing just five seconds per rep, that makes for at least 36 minutes of exercise per workout. This is usually done three times per week. So in six weeks, a conventional program would involve 648 minutes of exercise. That's 42 times more than the subjects in our study. Are your results in the last six weeks 42 times better than theirs? I doubt it. perform ance improve ment Remember, these golfers were exercising in a way that did not involve stretching or moving the weight over a full range of motion. So how did this affect a full range of motion activity like a golf drive? Every one of them showed an improvement. The increase in drive distance varied from 5 to 31 yards. Keep in mind that these subjects had been golfing for up to 40 years and had handicaps as low as eleven. So getting any improvement in golfers who already play at this level is impressive. Getting it with 14 minutes of exercise spread over six weeks is truly revolutionary. The fact is every sport -- even a finesse sport like golf -- is improved by an increase in strength. Muscles are responsible for all movement in the body and stronger muscles deliver more power to every aspect of movement, irrespective of its range of motion.increase in strength Since this study, I've gone on to improve this method of training. Further research showed that static hold times could be reduced to even less than what the golfers used. Workouts can be spaced further apart as a trainee gets stronger. I work with advanced trainees who train once every six weeks, yet they gain strength on every exercise each time they work out. The weights they hoist are enormous. I believe the time is coming when most people will have a better understanding of the role of proper, efficient strength training methods and frequency. For the guy who wants maximum results with minimum time invested, an ultra-brief but ultra-intense workout will be performed about as often as he gets a haircut. Anything more is just lifting weights as a busy work hobby. Train smart!

15. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra

16. Edward Sloan, MD, MPH, FACEP Aggressively Rx Ischemic Penumbra Maximize cerebral perfusion Provide optimal substrates, O2 Avoid cell death Maintain intact blood brain barrier

17. Edward Sloan, MD, MPH, FACEP Cerebral Perfusion CPP = MAP - ICP Cerebral perfusion pressure Mean arterial pressure Intracranial pressure

18. Edward Sloan, MD, MPH, FACEP Cerebral Perfusion CPP = MAP - ICP If MAP = 110 mmHg, ICP 10 mmHg CPP then equals 100 mmHg Cerebral blood flow auto-regulation CPP maintained over range of MAPs Pathological ICP elevations limited

19. Edward Sloan, MD, MPH, FACEP Mean Arterial Pressure 120 / 75MAP = 90 mmHg 210 / 120MAP = 150 mmHg 180 / 110MAP = 97 mmHg How much MAP therapy is OK? What agents provide best Rx? How to avoid watershed infarct?

20. Edward Sloan, MD, MPH, FACEP Watershed Infarct wa·ter·shed (wô t r-sh d) n. 1. A ridge of high land dividing two areas that are drained by different river systems. Also called water parting. 2. The region draining into a river, river system, or other body of water. 3. A critical point that marks a division or a change of course; a turning point: watershed infarction n. Infarction of the cerebral cortex in an area of blood supply between two major cerebral arteries.

21. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant

22. Edward Sloan, MD, MPH, FACEP ED MD: Best Neuroprotectant

23. Edward Sloan, MD, MPH, FACEP ED MD: Best Neuroprotectant Available 24/7

24. Edward Sloan, MD, MPH, FACEP ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct

25. Edward Sloan, MD, MPH, FACEP ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly

26. Edward Sloan, MD, MPH, FACEP ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly Focus on acute interventions

27. Edward Sloan, MD, MPH, FACEP ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly Focus on acute interventions Know our limitations

28. Edward Sloan, MD, MPH, FACEP ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly Focus on acute interventions Know our limitations We can be trained

29. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway

30. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway ETI, rapid sequence induction

31. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension

32. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension

33. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities

34. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities Diagnose and lower elevated ICP

35. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities Diagnose and lower elevated ICP Prevent and treat seizures

36. Edward Sloan, MD, MPH, FACEP ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities Diagnose and lower elevated ICP Prevent and treat seizures We first do no harm

37. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant Specific neuroprotectants tested

38. Edward Sloan, MD, MPH, FACEP Stroke Pathophysiology, Neuroprotectants

39. Edward Sloan, MD, MPH, FACEP Stroke Pathophysiology, Neuroprotectants Lubeluzole Fosphenytoin Sipatrigine Riluzole Lamotrigine Lifarizine Maxipost

40. Edward Sloan, MD, MPH, FACEP Stroke Pathophysiology, Neuroprotectants

41. Edward Sloan, MD, MPH, FACEP Aptiganel Selfotel GV-150526 CP-101606 Eliprodil ACPC ACEA 1021 Dizocilpine Dextromethorphan NBQX Magnesium Stroke Pathophysiology, Neuroprotectants

42. Edward Sloan, MD, MPH, FACEP Stroke Pathophysiology, Neuroprotectants

43. Edward Sloan, MD, MPH, FACEP Stroke Pathophysiology, Neuroprotectants GM 1 Piracetam Tirilizad PEG SOD PNA Enlimomab Citicoline CX295 Ceresine

44. Edward Sloan, MD, MPH, FACEP Stroke Pathophysiology: Free Radical Formation

45. Edward Sloan, MD, MPH, FACEP Stroke Pathophysiology: Free Radical Formation Tirilazad Citicoline Ebselen NXY-059

46. Edward Sloan, MD, MPH, FACEP Neuroprotection 1955-2000 Neuroprotective Agents Tested 49 RCTs Performed 114 Patients Enrolled 21,445 Trials with Positive Results 0 Kidwell CS et al. Stroke 32(6):1349-59. This year, first positive primary endpoint trial Trials of Neuroprotection Agents in Stroke: 1955-2000

47. Edward Sloan, MD, MPH, FACEP Why have neuroprotection agents failed in human trials? Wrong theoretical concept Wrong theoretical concept Treatment initiated too late Treatment initiated too late Stroke heterogeneity Stroke heterogeneity Wrong drug action Wrong drug action Doses too low Doses too low Trials underpowered Trials underpowered Wrong outcome measures Wrong outcome measures Insensitive statistical techniques Insensitive statistical techniques

48. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant Specific neuroprotectants tested SAINT-I clinical trial showed benefit

49. Edward Sloan, MD, MPH, FACEP NXY-059 (Cerovive) 2006;354(6):588-600.

50. Edward Sloan, MD, MPH, FACEP NXY – 059 Characteristics NXY-059 (Cerovive) is an intravenous, nitrone-based, free radical trapping agent NXY-059 (Cerovive) is an intravenous, nitrone-based, free radical trapping agent Preclinical trials positive in rats/primates Preclinical trials positive in rats/primates Effective after 4 hours of ischemia Effective after 4 hours of ischemia Significant dose response Significant dose response

51. Edward Sloan, MD, MPH, FACEP SAINT I Trial (Stroke – Acute Ischemic – NXY-059 Treatment) RCT Design RCT Design 72 hr treatment window 72 hr treatment window NXY-059 vs placebo NXY-059 vs placebo Target plasma concentration ~260 μM Target plasma concentration ~260 μM 158 centers across 24 countries 158 centers across 24 countries Europe, Asia, Australia, New Zealand, South Africa Europe, Asia, Australia, New Zealand, South Africa Lees KR et L. N Engl J Med 2006;354(6):588-600.

52. Edward Sloan, MD, MPH, FACEP SAINT I Trial (Stroke – Acute Ischemic – NXY-059 Treatment) Eligibility Eligibility CT/MR consistent with AIS CT/MR consistent with AIS Previous independence Previous independence NIHSS ≥6 including limb weakness NIHSS ≥6 including limb weakness t-PA permitted t-PA permitted < 6hr ictus to treatment < 6hr ictus to treatment Forced allocation to achieve mean time from onset to start of treatment ≤ 4 hrs Forced allocation to achieve mean time from onset to start of treatment ≤ 4 hrs Lees KR et L. N Engl J Med 2006;354(6):588-600.

53. Edward Sloan, MD, MPH, FACEP SAINT I Primary Outcome Variable: Change in Modified Rankin Scale Bedridden, incontinent, requires constant care Needs assistance with walking and attending to bodily needs Requires some help, but can walk without assistance Unable to do some previous activities, but independent Symptomatic, but performing previous activities Symptom free 0 1 2 3 4 5 Not bedridden Able to walk without assistance Able to look after self Able to do all usual activities Symptom free Bedridden / Death At 90 Days Lees KR et L. N Engl J Med 2006;354(6):588-600.

54. Edward Sloan, MD, MPH, FACEP SAINT I Secondary Outcome Variables mRS at 7 and 30 days mRS at 7 and 30 days NIHSS change on days 7 and 90 NIHSS change on days 7 and 90 Barthel Index on days 7, 30, and 90 Barthel Index on days 7, 30, and 90 Safety Safety Day 90 SIS-16 and Four Domains Day 90 SIS-16 and Four Domains Day 90 EQ-5D Day 90 EQ-5D Lees KR et L. N Engl J Med 2006;354(6):588-600.

55. Edward Sloan, MD, MPH, FACEP Primary Outcome (ITT): mRS at 90 Days Lees KR et L. N Engl J Med 2006;354(6):588-600.

56. Edward Sloan, MD, MPH, FACEP Primary Outcome (Per Protocol): mRS at 90 Days Lees KR et L. N Engl J Med 2006;354(6):588-600.

57. Edward Sloan, MD, MPH, FACEP NXY-059 Number Needed to Treat: Benefit Using mRS Shift Analysis Lowest Possible 7.9 Highest Possible 16.7 Expert Panel 9.8 8.7 – 10.9 Saver J. UCLA Stroke Center

58. Edward Sloan, MD, MPH, FACEP NXY-059 Number Needed to Treat: Benefit Using Outcome Dichotomy mRSNNT 0 vs 1-6 23 0-1 vs 2-6 42 0-2 vs 3-6 48 0-3 vs 4-6 28 Saver J. UCLA Stroke Center

59. Edward Sloan, MD, MPH, FACEP SAINT I Clinical Endpoints Endpoint P Value Rankin shift 0.038 Rankin dichotomized 0.17 Improvement in NIHSS 0.86 Barthel Index dichotomized 0.14 Stroke Impact Scale 0.08 Euro QOL Index 0.06 QOL Visual Analogue Scale 0.05

60. Edward Sloan, MD, MPH, FACEP # Patients AE=adverse event; SAE=serious adverse event; DAE=discontinued due to adverse event. Lees KR, et al. New Engl J Med. 2006;354:588-600. Nxy-059 Safety: Adverse Events

61. Edward Sloan, MD, MPH, FACEP 0 10 20 30 40 50 60 70 80 52 16 6 31 20.9% 6.4% 12.9% 2.5% 15.4% Placebo + rt-PA (n=249) NXY-059 + rt-PA (n=240) Asymptomatic ICH* Symptomatic ICH* P=0.036 ICH After IV tPA Thrombolysis: (SAINT –I Post Hoc Analysis) 27.3% Patients (n) *NINDS definition; ICH=intracerebral hemorrhage P<0.005 (total ICH) Lees KR, et al. New Engl J Med. 2006;354:588-600.

62. Edward Sloan, MD, MPH, FACEP ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant Specific neuroprotectants tested SAINT-I clinical trial showed benefit Specific questions to be addressed

63. Edward Sloan, MD, MPH, FACEP Neuroprotectant Questions Will SAINT-II reproduce results?

64. Edward Sloan, MD, MPH, FACEP Neuroprotectant Questions Will SAINT-II reproduce results? Will the NNT be comparable?

65. Edward Sloan, MD, MPH, FACEP Neuroprotectant Questions Will SAINT-II reproduce results? Will the NNT be comparable? Will safety data be comparable?

66. Edward Sloan, MD, MPH, FACEP Neuroprotectant Questions Will SAINT-II reproduce results? Will the NNT be comparable? Will safety data be comparable? Will the tPA / ICH data compare?

67. Edward Sloan, MD, MPH, FACEP Neuroprotectant Questions Will SAINT-II reproduce results? Will the NNT be comparable? Will safety data be comparable? Will the tPA / ICH data compare? How to explain BBB information?

68. Edward Sloan, MD, MPH, FACEP Neuroprotectant Questions Will SAINT-II reproduce results? Will the NNT be comparable? Will safety data be comparable? Will the tPA / ICH data compare? How to explain BBB information? What cost will the results justify?

69. Edward Sloan, MD, MPH, FACEPConclusions We provide neuroprotection Neuroprotection reduces infarct volume, complications New neuroprotection data Interesting data related to IV tPA Ischemic stroke care enhanced Patient outcomes improved

70. Edward Sloan, MD, MPH, FACEP Questions? www.FERNE.org edsloan@uic.edu 312 413 7490 ferne_ema_2006_sloan_neuroprotection_092606_pending 6/3/2016 4:40 AM