1. Neurological Emergency Treatment Trials Network Overview of the new network nett.umich.edu

2. Overview 1.The Problem - Neurological Emergencies 2.Developing a Solution 3.The Nuts and Bolts - NETT 4.Impact

3. 1. Neurological Emergencies Spectrum of pathology High burden of disease Importance of early treatment

4. Neurotrauma: Brain & Spinal Cord Injury Stroke: Ischemic & Hemorrhagic Status Epilepticus CNS Infections: Meningitis & Encephalitis Anoxic Brain Injury Others: Bell’s Palsy, Headache, etc. Neurological Emergencies Spectrum of Pathology

5. Neurological Emergencies High Burden of Disease Acute Ischemic Stroke 200 per 100,000 people Mortality 17% at 30 days 1 st Yr cost $91,000 /patient Kissela B et al. Stroke 2004;35(2):426-31. Klijn CJ et al. Lancet Neurol 2003;2(11):698-701. Taylor TN, Drugs 1997;54 Suppl 3:51-7 Williams GR et al, Stroke 1999;30(12):2523-8 Intracerebral hematoma 15 per 100,000 people Mortality 50% at 30 days 1 st Yr cost $124,000 /patient Taylor TN, Drugs 1997;54 Suppl 3:51-7 Broderick JP, et al. J Neurosurg 1993;78(2):188-91 Qureshi AI et al. N Engl J Med 2001;344(19):1450-60

6. Neurological Emergencies High Burden of Disease Traumatic Brain Injury 100 per 100,000 people Mortality 29% at 30 days 1 st Yr cost $136,000 /patient NIH Consensus Panel, JAMA 1999;282(10):974-83. Brown AW, et al. NeuroRehabilitation 2004;19(1):37-43. CDC Fact Sheet: Traumatic Brain Injury (NCIPC), 2005 Spinal Cord Injury 4 per 100,000 people Mortality 20% at 30 days 1 st Yr cost $200,000 /patient Sekhon LH, et al. Spine 2001;26(24 Suppl):S2-12.

7. Neurological Emergencies High Burden of Disease Status Epilepticus 40 per 100,000 people Mortality 22% at 30 days 1 st Yr cost $40,000 /patient Bassin S, et al. Crit Care 2002;6(2):137-42 Claassen J, et al. Neurology 2002;58(1):139-42 DeLorenzo RJ, et al. Neurology 1996;46(4):1029-35 Penberthy LT, et al. Seizure 2005;14(1):46-51 Wu YW, et al. Neurology 2002;58(7):1070-6 Subarachnoid Hemorrhage 6 per 100,000 people Mortality 50% at 30 days 1 st Yr cost $228,000 /patient Taylor TN, Drugs 1997;54 Suppl 3:51-7 Broderick JP, et al. J Neurosurg 1993;78(2):188-91 Schievink WI. N Engl J Med 1997;336(1):28-40

8. Importance of Early Treatment Lessons Learned National Acute Spinal Cord Injury Study (NASCIS) Methylprednisolone I (1979-84) – enrolled up to 48 hours, negative II (1984-90) – enrolled up to 12 hours, negative…. ….but positive in subset treated <8 hours III (1990-97) – enrolled up to 12 hours, negative Bracken MB, et al. JAMA 1984;251:45-52, Bracken MB, et al. N Engl J Med 1990;322:1405-11 Bracken MB, et al. JAMA 1997;277:1597-604

9. Importance of Early Treatment Lessons Learned Thrombolytics in Acute Ischemic Stroke t-PA and streptokinase ECASS (I-II) up to 6 hours, mean 4:24 negative MAST (I+E) up to 6 hours, mean 4:36negative NINDS up to 3 hours, mean 1:59positive NINDS Stroke Study Group. N Engl J Med. 1995; 333:1581–7 MAST-E Study Group. N Engl J Med. 1996; 335:145–50, MAST-I Group. Lancet. 1995; 346:1509–14 Hacke W, et al. JAMA. 1995; 274:1017–25, Hacke W, et al. Lancet. 1998; 352:1245–51

10. 2. Developing a solution Boots on the ground Multi-disciplinary composition Emergence of a network Design for the future

11. Boots on the ground Emergency Medicine driven Neurological emergencies are treated in the initial minutes and hours after arrival mainly by emergency physicians. The ED is a challenging and chaotic environment in which to conduct research. Emergency physicians represent the “boots on the ground”, those on the front line with the manpower and expertise to conduct research in the ED.

12. Multi-disciplinary composition Neurology, Neurosurgery, EMS, Neuro Critical Care, and Trauma Research encompassing a continuum of care that starts in the ambulance or in the emergency department and continues in the ICU, in the OR, on the stroke unit, or in the clinic. Network leadership, Hub PI’s, and Trial PI’s represent a range of specialties.

13. Multi-disciplinary collaborations Workforce by Specialty in the US 12,000 adult neurologists* 1,500 pediatric neurologists 3,500 neurosurgeons 4,000 hospital emergency departments 22,000 emergency physicians *30% in solo private practice

14. Emergence of a network Oct 2003First organizational NET*2 meeting Mar 2004NIH conference on ENTCN 2004-2005NET*2 planning/pilot grant applications Nov 2005RFA for NETT Coordinating Center Apr 2006RFA for NETT Hubs and SDMC Aug 2006NETT Coordinating Center awarded

15. Design for the future Large simple trial designs Streamlined protocols Collect only essential data (short case report forms) High enrollment – lower per-patient costs

16. Design for the future Emphasis on intervention Focus on phase III intervention trials Patient-oriented readily-applicable results Diverse enrollment (patients & practice environments)

17. Design for the future Consent issues Exception to informed consent for emergency research Optimize methods that respect human subjects Dedicate network resources to facilitate local efforts Help develop centralized IRB review

18. 3. Nuts and Bolts What – the mission and vision Who – the participants Why – the incentives How – the organizational structure When – the time line

19. Mission The mission of the Neurological Emergencies Treatment Trials (NETT) Network is to improve outcomes of patients with acute neurological problems through innovative research focused on the emergent phase of patient care.

20. Vision NETT will engage clinicians and providers at the front lines of emergency care to conduct large, simple multi-center clinical trials to answer research questions of clinical importance. The NETT structure will be utilized to achieve economies of scale enabling cost effective, high quality research.

21. NETT Coordinating and Hub Sites

22. Investigators Initiated Studies –Incentives and Limitations –Application Process Industry Sponsored Studies –Network / Investigator Design Study Selection Investigator Initiated Studies

23. Incentives –Investigator receives the trial award –Scientific control, credit, authorship preserved –Infrastructure already established Limitations –Fewer funds stay at investigators institution –Commitment to stay within the network

24. Study Selection Investigator Initiated Studies Process –NETT Trial Guidelines –Clinical Trial Subcommittee & NETT-AG –Administrative Consultation –Submission for Scientific Review

25. Study Selection Industry Sponsored Studies Network / Investigator Design –Scientific Control –Shared Economies of Scale –No Direct Subsidy –NETT-AG solicits scientific review

26. Hub and Spoke design Spoke CCC Hub Spoke 17 Hubs Approximately 41-70 Spokes Hence a total of up to 80+ enrolling sites

27. SDMC DSMB NETT-AG NINDS Scientific Program Director Site MgmtOperations Trial MgmtLeadership Hubs Trial PI CCC

28. Timeline Several simultaneous trials Staggered planning / enrollment

29. How much does it cost? Grant support of NETT FY 2006FY 2007-10 DirectTotalDirectTotal CCC U01 $1M$1.5M$4M$6M SDMC U01 $500K$750M$2M$3M Hubs U10 $200K$300K$800K$1.2M All 17$3.4M$5.1M$13.6M$20.4M Total$5.1M$7.7M$20.4M$30.6M $25.5M Direct $38.3M Total over 5 years

30. 4. Impact Opportunity to advance care of patients with neuro-emergencies Large NIH investment in emergency medicine clinical research Re-engineering the clinical research enterprise

31. nett.umich.edu

32. Priming the pipeline RAMPART INTERACT ProTECT NABPS

33. Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) Paramedic treatment of status epilepticus Standard treatment is IV benzodiazepine IV starts difficult / dangerous in the convulsing patient Best IV agent, lorazepam, impractical for EMS IM treatment is faster and easier Best IM agent, midazolam, is practical for EMS

34. Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) IM midazolam autoinjector v. IV lorazepam Double dummy blinded design Exception to consent for emergency research Outcome: termination of seizure prior to ED arrival Sample 800 patients (400 per group) Intention to treat, non-inferiority analysis

35. US-Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-US) Hematoma expansion is associated with worse outcomes in patients with ICH Very early elevated BP may contribute to acute hematoma expansion Acute hypertension is common with ICH Optimal BP targets in patients with ICH are unknown

36. US-Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-US) Compare systolic target of 140 vs. 180 mmHg US modification of study originally designed in Austraila by our current collaborators Phase II Trial, feasibility / safety primary outcomes Sample 400 patients (200 per arm)

37. Hub pre-RFA slides

38. What does an application need? We don’t really know Enrollment Experience Collaboration

39. Enrollment Sufficient patient volume Access to diverse diagnoses –Adults and children –Neurotrauma, TBI and SCI –Stroke, ischemic and hemorrhagic –Seizure, meningitis, anoxic injury Local infrastructure

40. Experience ED clinical trials (any disease) Institutional track record Cross disciplinary research

41. Collaboration Emergency Medical Services Spokes –Diversity –Buy in Cross disciplinary –Emergency Medicine –Neuro-Critical Care –Neurology / Neurosurgery –Trauma surgery

42. Spokes Don’t have to use all spokes for all trials Look for areas of concentration –Trauma –Stroke –EMS expertise

43. Budget suggestions Include all effort needed to: –Set up the program –Prepare potentially complex IRB apps –Enroll subjects in two trials, best guess –Collect and report data –Provide informatics support Include –Travel to investigator meetings

44. Resources RFA for the 3 components ENCTN final report UM CCC application Links to all available at http://sitemaker.umich.edu/NETT

45. Simple Version

46. What is NETT? Neurological Emergencies Treatment Trials A new clinical trials network dedicated to: –Cross-disciplinary cooperation –Interventions in minutes not hours –Large simple trial streamlined trial designs

47. How will NETT work? Hub and Spoke Design –Large –Scalable Public Utility Model –Open –Economical

48. What kinds of questions? Does very early intensive blood pressure lowering prevent hematoma expansion and improve outcome in patients with ICH? The INTERACT trial

49. What kinds of questions? Does a lower dose of thrombolytic plus a glycoprotein inhibitor improve efficacy and reduce bleeding complications compared to standard dose thrombolysis? The CLEAR trial

50. What kinds of questions? Can progesterone infusion improve survival and neurological outcome in patients with traumatic brain injury? The ProTECT trial

51. What kinds of questions? Can IM midazolam stop seizures as effectively as IV lorazepam in the prehospital care of status epilepticus? The RAMPART trial

52. What kinds of questions? Whatever question you want to ask…

53. What’s the impact? Opportunity to advance care of patients with neuro-emergencies Large NIH investment in emergency medicine clinical research Re-engineering the clinical research enterprise

54. How will you be involved? As a Practitioner As a Hub co-investigator As a Trial investigator

55. Alternate Slides

56. NETT Impact High level of enthusiasm by the academic emergency medicine community for high- quality, non-pharma driven clinical research. High public visibility of treatment-oriented clinical research.

57. NETT Benefits and Risks Immediate invigoration of neurologic community Broader involvement of trainees in research Large number of trials in the pipeline NETT will lead to efficient research in many diseases Tight budget Small numbers of Hubs Scientific review committee tough and less interested in practical trials

59. Special Challenges to studying Neurological Emergencies Urgency: recruitment in minutes not hours Multiple disciplinary involvement: EMS, emergency medicine, neurology, pediatrics, neurosurgery, radiology, traumatology, rehabilitation, others Conditions complicate informed consent

60. Defining Principals Very early enrollment Diverse enrollment, hub and spoke design Large simple trials

61. Operational Principals Streamlined operations Technological efficiencies when possible Centralized outcome assessments Clinical translation

63. Neurological Emergency Treatment Trials Network

64. Burden of Neurological Emergencies Disorder Incidence per 100,000 Mortality 30-day %Cost* thousands $ Acute Ischemic Stroke20017$91 Intracerebral hemorrhage1550$124 Subarachnoid hemorrhage650$228 Traumatic brain injury10029$136 Spinal cord injury420$200 Bacterial meningitis1.512$8 Status epilepticus4022$40 Anoxic brain injury7.580$50** *Per patient in first year, **Rehabilitation only