Neurological Emergency Treatment Trials Network Overview of the

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

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

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

Neurological Emergencies Spectrum of Pathology • 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 High Burden of Disease Acute Ischemic Stroke Intracerebral hematoma 200 per 100, 000 people 15 per 100, 000 people Mortality 17% at 30 days Mortality 50% at 30 days 1 st Yr cost $91, 000 /patient 1 st Yr cost $124, 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 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

Neurological Emergencies High Burden of Disease Traumatic Brain Injury Spinal Cord Injury 100 per 100, 000 people 4 per 100, 000 people Mortality 29% at 30 days Mortality 20% at 30 days 1 st Yr cost $136, 000 /patient 1 st Yr cost $200, 000 /patient NIH Consensus Panel, JAMA 1999; 282(10): 974 -83. Brown AW, et al. Neuro. Rehabilitation 2004; 19(1): 37 -43. CDC Fact Sheet: Traumatic Brain Injury (NCIPC), 2005 Sekhon LH, et al. Spine 2001; 26(24 Suppl): S 2 -12.

Neurological Emergencies High Burden of Disease Status Epilepticus Subarachnoid Hemorrhage 40 per 100, 000 people 6 per 100, 000 people Mortality 22% at 30 days Mortality 50% at 30 days 1 st Yr cost $40, 000 /patient 1 st Yr cost $228, 000 /patient Bassin S, et al. Crit Care 2002; 6(2): 137 -42 Claassen J, et al. Neurology 2002; 58(1): 139 -42 De. Lorenzo 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 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

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

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: 36 negative NINDS up to 3 hours, mean 1: 59 positive 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

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

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.

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.

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

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

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

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

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

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

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.

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.

NETT Coordinating and Hub Sites

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

Study Selection Investigator Initiated Studies • 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

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

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

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

Scientific Program Director NETT-AG NINDS CCC Leadership Trial Mgmt Trial PI Site Mgmt Operations Hubs DSMB SDMC

Timeline • Several simultaneous trials • Staggered planning / enrollment

How much does it cost? Grant support of NETT FY 2006 FY 2007 -10 Direct Total $1 M $1. 5 M $4 M $6 M SDMC U 01 $500 K $750 M $2 M $3 M Hubs U 10 $200 K $300 K $800 K $1. 2 M All 17 $3. 4 M $5. 1 M $13. 6 M $20. 4 M $5. 1 M $7. 7 M $20. 4 M $30. 6 M CCC U 01 Total $25. 5 M Direct $38. 3 M Total over 5 years

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

nett. umich. edu

Priming the pipeline • RAMPART • INTERACT • Pro. TECT • NABPS

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

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

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

US-Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-US) • Compare systolic target of 140 vs. 180 mm. Hg • 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)

Hub pre-RFA slides

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

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

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

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

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

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

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

Simple Version

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

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

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

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

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

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

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

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

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

Alternate Slides

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

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

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

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

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

Neurological Emergency Treatment Trials Network

Burden of Neurological Emergencies Disorder Incidence per 100, 000 Mortality 30 -day %Cost* thousands $ Acute Ischemic Stroke Intracerebral hemorrhage Subarachnoid hemorrhage Traumatic brain injury Spinal cord injury Bacterial meningitis Status epilepticus Anoxic brain injury 200 15 6 100 4 1. 5 40 7. 5 17 50 50 29 20 12 22 80 $91 $124 $228 $136 $200 $8 $40 $50** *Per patient in first year, **Rehabilitation only