Neurological Emergency Treatment Trials Network

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Neurological EmergencyTreatment Trials Network
Overview of the new networknett.umich.edu
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Overview

• The Problem - Neurological Emergencies
• Developing a Solution
• The Nuts and Bolts - NETT
• Impact

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1. Neurological Emergencies

• Spectrum of pathology
• High burden of disease
• Importance of early treatment

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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.

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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

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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.

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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

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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

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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

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2. Developing a solution

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

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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.

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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.

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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

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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

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Design for the futureLarge simple trial designs

• Streamlined protocols
• Collect only essential data (short case report
  forms)
• High enrollment lower per-patient costs

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Design for the futureEmphasis on intervention

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

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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

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3. Nuts and Bolts

• What the mission and vision
• Who the participants
• Why the incentives
• How the organizational structure
• When the time line

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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.

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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. 

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NETT Coordinating and Hub Sites
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Study SelectionInvestigator Initiated Studies

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

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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

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Study SelectionInvestigator Initiated Studies

• Process
• NETT Trial Guidelines
• Clinical Trial Subcommittee NETT-AG
• Administrative Consultation
• Submission for Scientific Review

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Study SelectionIndustry Sponsored Studies

• Network / Investigator Design
• Scientific Control
• Shared Economies of Scale
• No Direct Subsidy
• NETT-AG solicits scientific review

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Hub and Spoke design
Spoke
17 Hubs Approximately 41-70 Spokes Hence a total
of up to 80 enrolling sites
Hub
Spoke
CCC
Spoke
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Scientific Program Director
NINDS
NETT-AG
Trial PI
CCC
Trial Mgmt
Leadership
Site Mgmt
Operations
Hubs
DSMB
SDMC
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Timeline

• Several simultaneous trials
• Staggered planning / enrollment

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How much does it cost? Grant support of NETT
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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

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nett.umich.edu
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Priming the pipeline

• RAMPART
• INTERACT
• ProTECT
• NABPS

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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

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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

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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

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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)

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Hub pre-RFA slides
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What does an application need?

• We dont really know
• Enrollment
• Experience
• Collaboration

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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

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Experience

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

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Collaboration

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

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Spokes

• Dont have to use all spokes for all trials
• Look for areas of concentration
• Trauma
• Stroke
• EMS expertise

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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

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Resources

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

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Simple Version
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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

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How will NETT work?

• Hub and Spoke Design
• Large
• Scalable
• Public Utility Model
• Open
• Economical

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What kinds of questions?

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

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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

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What kinds of questions?

• Can progesterone infusion improve survival and
  neurological outcome in patients with traumatic
  brain injury?
• The ProTECT trial

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What kinds of questions?

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

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What kinds of questions?

• Whatever question you want to ask

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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

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How will you be involved?

• As a Practitioner
• As a Hub co-investigator
• As a Trial investigator

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Alternate Slides
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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.

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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

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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

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Defining Principals

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

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Operational Principals

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

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Neurological EmergencyTreatment Trials Network
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Burden of Neurological Emergencies
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