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Neurological Emergency Treatment Trials Network. Overview of the new network nett.umich.edu. Overview. The Problem - Neurological Emergencies Developing a Solution The Nuts and Bolts - NETT Impact. 1. Neurological Emergencies. Spectrum of pathology High burden of disease

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neurological emergency treatment trials network
Neurological EmergencyTreatment Trials Network

Overview of the new networknett.umich.edu

overview
Overview
  • The Problem - Neurological Emergencies
  • Developing a Solution
  • The Nuts and Bolts - NETT
  • Impact
1 neurological emergencies
1. Neurological Emergencies
  • Spectrum of pathology
  • High burden of disease
  • Importance of early treatment
slide4

Neurological EmergenciesSpectrum 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

200 per 100,000 people

Mortality 17% at 30 days

1st 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

1st 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

Neurological EmergenciesHigh Burden of Disease
neurological emergencies high burden of disease6
Traumatic Brain Injury

100 per 100,000 people

Mortality 29% at 30 days

1st 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

1st Yr cost $200,000 /patient

Sekhon LH, et al. Spine 2001;26(24 Suppl):S2-12.

Neurological EmergenciesHigh Burden of Disease
neurological emergencies high burden of disease7
Status Epilepticus

40 per 100,000 people

Mortality 22% at 30 days

1st 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

1st 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

Neurological EmergenciesHigh Burden of Disease
importance of early treatment lessons learned
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 <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 learned9
Importance of Early TreatmentLessons Learned

Thrombolytics in Acute Ischemic Stroket-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
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
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.
multi disciplinary composition neurology neurosurgery ems neuro critical care and trauma
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 PI’s, and Trial PI’s represent a range of specialties.
multi disciplinary collaborations workforce by specialty in the us
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

emergence of a network
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
Design for the futureLarge 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
Design for the futureEmphasis on intervention
  • Focus on phase III intervention trials
  • Patient-oriented readily-applicable results
  • Diverse enrollment (patients & practice environments)
design for the future consent issues
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
3 nuts and bolts
3. Nuts and Bolts
  • What – the mission and vision
  • Who – the participants
  • Why – the incentives
  • How – the organizational structure
  • When – the time line
mission
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
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. 

slide22

Study SelectionInvestigator Initiated Studies

  • Investigators Initiated Studies
    • Incentives and Limitations
    • Application Process
  • Industry Sponsored Studies
    • Network / Investigator Design
study selection investigator initiated studies
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
study selection investigator initiated studies24
Study SelectionInvestigator Initiated Studies
  • Process
    • NETT Trial Guidelines
    • Clinical Trial Subcommittee & NETT-AG
    • Administrative Consultation
    • Submission for Scientific Review
study selection industry sponsored studies
Study SelectionIndustry Sponsored Studies
  • Network / Investigator Design
    • Scientific Control
    • Shared Economies of Scale
    • No Direct Subsidy
    • NETT-AG solicits scientific review
hub and spoke design
Hub and Spoke design

Spoke

17 Hubs

Approximately 41-70 Spokes

Hence a total of up to 80+ enrolling sites

Hub

Spoke

CCC

Spoke

slide27

Scientific

Program

Director

NINDS

NETT-AG

Trial

PI

CCC

Leadership

Trial Mgmt

Site Mgmt

Operations

Hubs

DSMB

SDMC

timeline
Timeline
  • Several simultaneous trials
  • Staggered planning / enrollment
4 impact
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
priming the pipeline
Priming the pipeline
  • RAMPART
  • INTERACT
  • ProTECT
  • NABPS
r apid a nticonvulsant m edication p rior to ar rival t rial rampart
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
r apid a nticonvulsant m edication p rior to ar rival t rial rampart34
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
us inte nsive blood pressure r eduction in a cute c erebral hemorrhage t rial interact us
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 inte nsive blood pressure r eduction in a cute c erebral hemorrhage t rial interact us36
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)
what does an application need
What does an application need?
  • We don’t really know
  • Enrollment
  • Experience
  • Collaboration
enrollment
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
Experience
  • ED clinical trials (any disease)
  • Institutional track record
  • Cross disciplinary research
collaboration
Collaboration
  • Emergency Medical Services
  • Spokes
    • Diversity
    • Buy in
  • Cross disciplinary
    • Emergency Medicine
    • Neuro-Critical Care
    • Neurology / Neurosurgery
    • Trauma surgery
spokes
Spokes
  • Don’t have to use all spokes for all trials
  • Look for areas of concentration
    • Trauma
    • Stroke
    • EMS expertise
budget suggestions
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
Resources
  • RFA for the 3 components
  • ENCTN final report
  • UM CCC application
  • Links to all available at

http://sitemaker.umich.edu/NETT

what is nett
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
How will NETT work?
  • Hub and Spoke Design
    • Large
    • Scalable
  • Public Utility Model
    • Open
    • Economical
what kinds of questions
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 questions49
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 questions50
What kinds of questions?

Can progesterone infusion improve survival and neurological outcome in patients with traumatic brain injury?

The ProTECT trial

what kinds of questions51
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 questions52
What kinds of questions?

Whatever question you want to ask…

what s the impact
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
How will you be involved?
  • As a Practitioner
  • As a Hub co-investigator
  • As a Trial investigator
nett impact
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.
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

NETT Benefits and Risks
special challenges to studying neurological emergencies
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
defining principals
Defining Principals
  • Very early enrollment
  • Diverse enrollment, hub and spoke design
  • Large simple trials
operational principals
Operational Principals
  • Streamlined operations
  • Technological efficiencies when possible
  • Centralized outcome assessments
  • Clinical translation