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Neurological Emergency Treatment Trials Network

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Title: Neurological Emergency Treatment Trials Network


1
Neurological EmergencyTreatment Trials Network
Overview of the new networknett.umich.edu
2
Overview
  • The Problem - Neurological Emergencies
  • Developing a Solution
  • The Nuts and Bolts - NETT
  • Impact

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

4
Neurological EmergenciesSpectrum of Pathology
  • Neurotrauma Brain Spinal Cord Injury
  • Stroke Ischemic Hemorrhagic
  • Status Epilepticus
  • CNS Infections Meningitis Encephalitis
  • Anoxic Brain Injury
  • Others Bells Palsy, Headache, etc.

5
Neurological EmergenciesHigh Burden of Disease
  • Acute Ischemic Stroke
  • 200 per 100,000 people
  • Mortality 17 at 30 days
  • 1st Yr cost 91,000 /patient
  • Kissela B et al. Stroke 200435(2)426-31.
  • Klijn CJ et al. Lancet Neurol 20032(11)698-701.
  • Taylor TN, Drugs 199754 Suppl 351-7
  • Williams GR et al, Stroke 199930(12)2523-8
  • Intracerebral hematoma
  • 15 per 100,000 people
  • Mortality 50 at 30 days
  • 1st Yr cost 124,000 /patient
  • Taylor TN, Drugs 199754 Suppl 351-7
  • Broderick JP, et al. J Neurosurg
    199378(2)188-91
  • Qureshi AI et al. N Engl J Med 2001344(19)1450-6
    0

6
Neurological EmergenciesHigh Burden of Disease
  • Traumatic Brain Injury
  • 100 per 100,000 people
  • Mortality 29 at 30 days
  • 1st Yr cost 136,000 /patient
  • NIH Consensus Panel, JAMA 1999282(10)974-83.
  • Brown AW, et al. NeuroRehabilitation
    200419(1)37-43.
  • CDC Fact Sheet Traumatic Brain Injury (NCIPC),
    2005
  • Spinal Cord Injury
  • 4 per 100,000 people
  • Mortality 20 at 30 days
  • 1st Yr cost 200,000 /patient
  • Sekhon LH, et al. Spine 200126(24 Suppl)S2-12.

7
Neurological EmergenciesHigh Burden of Disease
  • Status Epilepticus
  • 40 per 100,000 people
  • Mortality 22 at 30 days
  • 1st Yr cost 40,000 /patient
  • Bassin S, et al. Crit Care 20026(2)137-42
  • Claassen J, et al. Neurology 200258(1)139-42
  • DeLorenzo RJ, et al. Neurology 199646(4)1029-35
  • Penberthy LT, et al. Seizure 200514(1)46-51
  • Wu YW, et al. Neurology 200258(7)1070-6
  • Subarachnoid Hemorrhage
  • 6 per 100,000 people
  • Mortality 50 at 30 days
  • 1st Yr cost 228,000 /patient
  • Taylor TN, Drugs 199754 Suppl 351-7
  • Broderick JP, et al. J Neurosurg
    199378(2)188-91
  • Schievink WI. N Engl J Med 1997336(1)28-40

8
Importance of Early TreatmentLessons 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 lt8 hours
  • III (1990-97) enrolled up to 12 hours,
    negative
  • Bracken MB, et al. JAMA 198425145-52, Bracken
    MB, et al. N Engl J Med 19903221405-11
  • Bracken MB, et al. JAMA 19972771597-604

9
Importance of Early TreatmentLessons Learned
  • Thrombolytics in Acute Ischemic Stroket-PA and
    streptokinase
  • ECASS (I-II) up to 6 hours, mean 424 negative
  • MAST (IE) up to 6 hours, mean 436 negative
  • NINDS up to 3 hours, mean 159 positive
  • NINDS Stroke Study Group. N Engl J Med. 1995
    33315817
  • MAST-E Study Group. N Engl J Med. 1996
    33514550, MAST-I Group. Lancet. 1995
    346150914
  • Hacke W, et al. JAMA. 1995 274101725, Hacke W,
    et al. Lancet. 1998 352124551

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

11
Boots on the groundEmergency 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 compositionNeurology,
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 PIs, and Trial PIs
    represent a range of specialties.

13
Multi-disciplinary collaborationsWorkforce 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 2003 First organizational NET2 meeting
  • Mar 2004 NIH conference on ENTCN
  • 2004- 2005 NET2 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

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

16
Design for the futureEmphasis on intervention
  • Focus on phase III intervention trials
  • Patient-oriented readily-applicable results
  • Diverse enrollment (patients practice
    environments)

17
Design for the futureConsent 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
Study SelectionInvestigator Initiated Studies
  • Investigators Initiated Studies
  • Incentives and Limitations
  • Application Process
  • Industry Sponsored Studies
  • Network / Investigator Design

23
Study SelectionInvestigator 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

24
Study SelectionInvestigator Initiated Studies
  • Process
  • NETT Trial Guidelines
  • Clinical Trial Subcommittee NETT-AG
  • Administrative Consultation
  • Submission for Scientific Review

25
Study SelectionIndustry 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
17 Hubs Approximately 41-70 Spokes Hence a total
of up to 80 enrolling sites
Hub
Spoke
CCC
Spoke
27
Scientific Program Director
NINDS
NETT-AG
Trial PI
CCC
Trial Mgmt
Leadership
Site Mgmt
Operations
Hubs
DSMB
SDMC
28
Timeline
  • Several simultaneous trials
  • Staggered planning / enrollment

29
How much does it cost? Grant support of NETT
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 MedicationPrior 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 MedicationPrior 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 dont 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
  • Dont 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
Whats 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

58
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59
Special Challenges to studyingNeurological
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

62
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63
Neurological EmergencyTreatment Trials Network
64
Burden of Neurological Emergencies
65
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