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Welcome to the Welcome to the
Conference Call – New NETT Hub PIsFriday, October 12, 2007
9:00-10:00 am PDT / 12:00-1:00 pm EDTToll free dial-in number: (888) 242-1836
ACCESS CODE: 4905767
• Overview of network structure Dr. Barsan 15 min.• Hub Performance measures Dr. Barsan• Flow of Funds Valerie Stevenson 5 min.• Regulatory Document collection Dr. Pancioli 5 min.
•
• ALIAS trial Dr. Pancioli 15 min.– NETT vs. “legacy” sites V. Stevenson– Protocol training opportunities Joy Pinkerton– Start up activities Melissa Falb
• RAMPART Robert Silbergleit 5 min.– Brief description of trial
• Need for in-person meetings and training Pancioli/All 5 min.• Questions/comments All 10 min.
Neurological EmergencyTreatment Trials Network
Overview of the new network
nett.umich.edu
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 futureEmphasis on intervention
•Focus on phase III intervention trials
•Patient-oriented readily-applicable results
•Diverse enrollment (patients & practice environments)
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
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.
• Investigators Initiated Studies– Incentives and Limitations– Application Process
• Industry Sponsored Studies– Network / Investigator Design
Study SelectionInvestigator 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 SelectionInvestigator Initiated Studies
• Process
– NETT Trial Guidelines
– Clinical Trial Subcommittee & NETT-AG
– Administrative Consultation
– Submission for Scientific Review
Study SelectionIndustry Sponsored Studies
• Network / Investigator Design
– Scientific Control
– Shared Economies of Scale
– No Direct Subsidy
– NETT-AG solicits scientific review
Timeline
• Several simultaneous trials
• Staggered planning / enrollment
NETT Organizational
Structure
Hubs
SDMCCCC
NINDS
Clinical Coordinating Center
• PI: William Barsan • Co-PI: Dan Lowenstein • Co-Investigators: Lewis Morgenstern, Art Pancioli,
Robert Silbergleit, Phillip Scott, Angela Caveney, Bruno Giordani
• Administrative Staff: Lori Avers, Valerie Stevenson • Site Management: Melissa Falb, Donna Harsh, Irene
Ewing• Education: Joy Pinkerton• Human Subjects Protection: Deneil Kolk
Leadership Administration
BarsanLowenstein
Bylaws, Contracts, Budgets, Compliance, Reports, Coordination of Units, Promotion of network within EM
and Neurology communities
Liaison to NAG & Scientific Program Director
Site Management
Pancioli
Recruitment, Training, Certification, Screening, Enrollment,
Monitoring,
Liaison to Hub investigators
Study Operations
Silbergleit
MOP, Human Subjects Protection, Outcome Assessment, Centralized Data, Telemedicine,
Liaison to SDMC and DSMB
TrialManagement
Morgenstern
Trial Solicitation, Scientific Review, Publications, Clinical Translation Unit.
Liaison to Trial Investigators and NSD-K
CCC Internal Advisory Committee
CCC
Statistical and Data Management Center (SDMC) Medical University of South Carolina
• PI: Yuko Palesch• Co-PI: Valerie Durkalski• Co-Investigators: Renee Martin; Patrick Mauldin;
Sharon Yeatts; Wenle Zhao• Staff: Wayne Andrus; Catherine Dillon; Jaemyung
Kim; Rick Leinster; Keith Pauls; Teddy Redmon; Christopher Rhodes.
Data Management
Statistics
WebDCUTM
SDMC
Data processing
Data query generation and monitoring
Data validation
Site contact
Training
Report generation
Archiving
Protocol design
SAP development
DSMB report generation
Analyses
Database development
PM tools development
Central randomization
Maintenance
W. Zhao
V. Durkalski, C. Dillon
Y. Palesch, V. Durkalski
National Institute of Neurological Disorders and Stroke (NINDS )
• NINDS Assoc Director Clinical Trials: John Marler• Scientific Program Director : Robin Conwit• Administrative Program Director: Scott Janis• Grants Management: Gavin Wilkom• Scientific guidance-SDMC:Peter Gilbert
NINDS
Robin Conwit, MDScientific Program Director
Scientific Guidance
Gavin WilkomFunding Management
Peter Gilbert, PhDScientific Guidance-SDMC
Scott Janis, PhD Administrative Program Director
Liaison
NETT-Advisory Group
NETT DSMB
Scientific leadership
Promote the mission of the NINDS
Identify needs & develop new initiatives
Coordinate Funding
Grants Management
NINDS
Leadership
Administrative
The Hard Work!
HUB COMPLEXES
Hubs
Develop operational plans Patient recruitment, treatment, and follow-upComplete and accurate data collection Participate in writing manuscripts Adhere to a common study protocol for each trialAttend training and investigator meetingsProtect human subjects Ensure adequate representation Assist data audits and other quality control proceduresProvide research infrastructure & monitoring of spokes
HUB COMPLEXES
SpokesParticipate in studies requiring
larger sample size
Hubs and Investigators
Columbia University/NY Presbyterian Stephan Mayer, MDEmory University David Wright, MDHenry Ford Hospital Christopher Lewandowski, MDMedical College of Wisconsin Thomas Aufderheide, MDOregon Science and Health University Robert Lowe, MDStanford University James Quinn, MDTemple University Nina Gentile, MDUniversity of Arizona Kurt Denninghoff, MDUniversity of California SF Claude Hemphill, MDUniversity of Cincinnati Arthur Pancioli, MDUniversity of Kentucky Roger Humphries, MDUniversity of Maryland Barney Stern, MDUniversity of Minnesota Michelle Biros, MDUniversity of Pennsylvania Jill Barren, MDUniversity of Texas-Houston Elizabeth Jones, MDVirginia Commonwealth University Joseph Ornato, MDWayne State University Robert Welch, MD
Hubs
SDMCCCC
NINDS
Hubs NINDS
SDMCCCC
SteeringCommittee
Steering Committee
• Activities– Consider modifications and approve final
versions of protocols and operations– Supervise overall execution of the trial– Provide input on generating and approving study
policies– Plan and draft study-related publications
• Members– Members of the Executive Committee– Hub Principal Investigators
Hubs NINDS
SDMCCCC
Steering
Exec
Executive Committee• Activities
– Oversee administrative functions– Ensure effective communication and collaboration
among Hubs– Formulate and maintain standards for the network– Responsible for integration of all elements of the
network, including all regulatory compliance– Advocates, represents, and promotes mission of the
network • Members
– William Barsan (Chair), Robin Conwit, Catherine Dillon, Valerie Durkalski, Dan Lowenstein, Lewis Morgenstern, Yuko Palesch, Art Pancioli, Robert Silbergleit, Valerie Stevenson
Hubs NINDS
SDMCCCC
Steering
Exec
Spokes
Hubs NINDS
SDMCCCC
Steering
Exec
Spokes NAG
Network Advisory Group• Activities
– Oversight of the network– Give final approval to
• trial protocols• modifications to the protocols• the overall budget• plans for analysis
• Members – Appointed and organized by NINDS (TBD)– Experts in Emergency Medicine and Neurology– NINDS officials with expertise in clinical trials
• Forwards reports and recommendations to NINDS
Hubs NINDS
SDMCCCC
Steering
Exec
Spokes NAG
Specimen
Pharmacy
Imaging
Hubs NINDS
SDMCCCC
Steering
Exec
Spokes NAG
Specimen
Pharmacy
Imaging
DSMB
Data and Safety Monitoring Board (DSMB)
• Members
– Appointed by NINDS (TBD)
• Activities
– Monitor safety and performance and to review interim analyses in the NETT Network clinical trials
• Depending on the specific trials selected, more than one DSMB may be required
Hubs NINDS
SDMCCCC
Steering
Spokes NAG
Specimen
Pharmacy
Imaging
DSMBExec
OperationsCommittee
Network Operations Committee
• Activities
– Oversees the day-to-day operational issues of both study management and site management
– Responsible for the operational aspects of the individual trials such as regulatory compliance, monitoring and maximizing recruitment
– Responsible for the integration of the Hub and Spoke System by providing education, guidance and feedback to Network personnel
• Members– Catherine Dillon, Valerie Durkalski, Irene Ewing, Melissa Falb,
Donna Harsh, Deneil Kolk, Yuko Palesch, Art Pancioli, Joy Pinkerton, Robert Silbergleit, Valerie Stevenson,
Hubs NINDS
SDMCCCC
Steering
Exec
Spokes NAG
Specimen
Pharmacy
Imaging
DSMB
OperationsCommittee
InternalAdvisory
Internal Advisory Committee
• Activities– Provide independent consultation and
guidance to the CCC and the EC
• Members – Dr. Bob Adams (Chair)– Dr. Arthur Kellerman– Dr. Roger Lewis – Dr. Raj Narayan
Hubs NINDS
SDMCCCC
Steering
Exec
Spokes NAG
Specimen
Pharmacy
Imaging
DSMB
OperationsCommittee
InternalAdvisory
TrialPI
Report Card
Category Weight Points Criteria Reporting Responsibility
1. IRB proposals, renewals & amendments submitted / approved on time & sent to CCC
10 % 10 On time 5 0-120 day “late” 0 > 120 delay
CCC Site Manager will track and report
2. “Essential Documents Binder” completeness
10 % 10 Complete 5 Minor deficiencies 0 Major deficiencies
CCC monitor will track and report
3. Participation in research studies which are appropriate for the facility #
20 %
20 ≥ 80% participation 15 ≥ 60 % participation 10 ≥ 40% participation 5 ≥ 20% participation
CCC Site Manager will report
4. Enrollment success (% eligible)
30 %
30 Top quartile of sites 20 Second quartile 10 Third quartile of sites 0 Fourth quartile of sites
Data collected from screening logs by SDMC
5. Data entry is timely (within 10 days) and accurate (<10% query rate).
10 % 10 Meets 0 Does not Meet
SDMC
6. Meets site monitoring recommendation on time (within 6 weeks)
10 % 10 Meets 0 Does Not Meet
CCC monitor will track and report
7. Team contributions of site PI leadership, participation in network activities, attendance at meetings, etc.
10 % 10 Excellent 5 Adequate 0 Insufficient
CCC monitor will track and report
# Studies deemed inappropriate for site or where there is conflict with other research are exempted from the denominator.
Spoke
Spoke
Color Key for Flow Of FundsInfrastructure awards directly from NINDS
Subcontracts with Trial PI
Subcontract with NETT CCC
Subcontract with Hub ** Source of funding depends on type of agency providing the service
Hubs
SDMC
CCC
NINDS
Centralizedpharmacy
or trialservices**
Trial PIFunds from
R01
Regulatory Document Management
An Outside View of the System
Clinic
al H
ub
Clinic
al S
poke
Study Protocol
Inve
stig
ator
Participating Hub/Spoke
Subject Phase/Visit
CRF Data
Hub/Spoke Document
Investigator Document
SAE/MedWatch
Enrollment Randomization
Drug/D
evic
e
Distri
bution
Study Calendar
Study Database
Clinical Data Monitoring
Study Progress Report
Clinical Data Report
Study Payment Management
CentralPharmacy
DSMB
MSM
SDMC
CCC
ExecutiveCommittee
Centra
l Sco
ring
Centra
l Im
agin
g
Specimen Tracking
Central Lab
Score Expert
Image Reader
Hub/SpokeStaff
SteeringCommittee
NINDS
An Inside View of the System
Clinical Hub Clinical SpokeStudy Protocol Investigator
Participating Hub/Spoke
Subject Phase/Visit
CRF Data
Hub/Spoke Document
Investigator Document
SAE/MedWatch
Enrollment Randomization
Drug/Device Distribution
Study Calendar
Study Database
Clinical Data Monitoring
Study Progress Report
Clinical Data Report
Study Payment Management
Central Scoring
Central ImagingSpecimen Tracking
ALIAS
Primary ObjectiveTo ascertain whether 2g/kg 25% human serum albumin (ALB) therapy confers neuroprotection in acute ischemic stroke over and above the best standard of care.
ALIASALIASALIAS
Rationale (cont’d)• Exhibits proven and robust efficacy• Targets multiple injury mechanisms • Has minimal risk of adverse effects• Can be easily administered without complicated
laboratory tests
ALIASALIASALIAS
Study Design• Two studies: thrombolysis and non-thrombolysis
cohorts• Multi-center, randomized, double-blinded, saline-
controlled parallel study• In-person follow-up assessment at 3 months• Telephone follow-up assessments at 1-, 6-, 9-,
and 12-month• Sample size of 900 for each cohort• 3 planned interim analyses
ALIASALIASALIAS
Primary Outcome MeasureModified Rankin Scale score of 0 or 1, OR NIHSS score of 0 or 1 at 3 months from randomization
ALIASALIASALIAS
Secondary Outcome Measures• Barthel Index, Stroke-Specific Quality of Life, and
Trail Making at 3 months• EuroQol at 3 months and 1 year• Stroke-free status through 1 year
Main Eligibility Criteria• Acute ischemic stroke• Age >=18 years• NIHSS score at baseline >=6• Initiation of study drug within 5 hours of stroke
onset• No history of or medical exam results with cardiac
problems (particularly CHF/pulmonary edema)• Informed consent
ALIASALIASALIAS
Study Drug Kit
ALIASALIASALIAS
NETT vs. “Legacy” ALIAS sites
• Sites already participating in ALIAS (legacy) do not need to re-establish a new subcontract with the NETT CCC
• May receive “credit” for augmenting legacy site enrollment– Note subjects that were enrolled through NETT efforts
ALIAS Start up activities
• Identify individuals and obtain WebDCU training• Obtain mRS and NIHSS certification
– Required for all staff clinically evaluating subjects or administering assessments
• Up-to-date HIPAA and Human Subjects Protection• Review protocol and Manual of Procedures • Submit ALIAS Regulatory Documents• IRB-approved Informed Consent Form
– NOTE: send a copy of your ICF template to Dr. Tamariz at the University of Miami for review, prior to local submission, at [email protected] or (305) 968-0766
ALIAS Protocol Training Opportunities
• Web cast on NETT website (http://sitemaker.umich.edu/nett/education)
• PI tele-cast • In-person meeting?• Train the trainer• Training slide set
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
• 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 700 patients (350 per group)
• Intention to treat, non-inferiority analysis
Rapid Anticonvulsant MedicationPrior to Arrival Trial (RAMPART)
Hypotheses
Primary• IM midazolam is as effective as IV lorazepam at
stopping convulsions prior to ED arrival
Secondary• Convulsions stop more rapidly with treatment
with IM midazolam versus IV lorazepam• There is no difference in safety between the two
treatments
Inclusion criteria
• Continuous or repeated convulsive seizure activity for > 5 minutes
• Patient is still seizing
• Estimated weight > 13 kg
Exclusion criteria
• Major trauma precipitating seizure• Hypoglycemia• Known allergy to midazolam or lorazepam• Sensitivity to benzodiazepines• Cardiac arrest or heart rate <40 beats/minute• Known pregnancy• Prisoner
Intervention - Dose
• Two packages in each box, Child dose and Adult dose• Each package has one IM injector, one IV dose, one of
which is active, the other is dummy
• Child (13- 39 kg) – Lorazepam 2 mg or Midazolam 5 mg• Adult (40 kg and up)– Lorazepam 4 mg or Midazolam 10 mg
• Midazolam is in an autoinjector• Lorazepam is given IV
RAMPART Datalogger
Providing data loggers, stepper controllers, data acquisition and custom engineering services to customers worldwide
Intervention
• Medic arrives on scene and evaluates patient• Ask bystanders duration of seizure and trauma• Look for medic alert jewelry • Check glucose and vital signs• For children, check estimated weight• If criteria are met, study box is opened to enroll• Medic states that entry criteria are met• Select child dose or adult dose based on weight• Give IM medication and verbalize
Intervention (continued)
• Start IV, give IV med, and verbalize• Monitor vital sings and transport• Verbalize if convulsions stop• At 10 minute after treatment, provide “rescue”
meds per local protocol if still seizing en route, verbalize that med was given
• At ED arrival, verbalize whether patient is still seizing or not
ED and inpatient treatment
Attempt standardized post-intervention care
For further seizures in the ED or secondary treatment of prior status…
• Lorazepam 0.05-0.1 mg/kg plus
• Phenytoin or Fosphenytoin 18-20 mg/kg
ED and inpatient treatment
If seizures continue then…
• Intubate and ventilate, keep ≤ 37°C• Consider vecuronium 0.1 mg/kg• Then add:
– Midazolam 0.2 mg/kg then 1.2 ug/kg/min or– Propofol 1 mg/kg then 1-5 mg/kg/hr or– Pentobarbital 5-15 mg/kg over 1 hr, then 0.5-5 mg/kg/hr
• Admit to ICU, early EEG monitoring
Study Activity and Data Collection
• Study team activated on ED arrival of subject• Investigator or coordinator in ED
– Collect the data logger– Complete as many CRF items as possible– Approach subject or family for consent to continue to
collect and use data
• Restock ambulance with new study kit • Follow patient in hospital for AE’s
– Collect remaining data at discharge
Primary outcome
• Proportion of subjects with termination of clinically evident seizure determined at arrival in the Emergency Department (ED) after a single dose of study medication.
• Non-inferiority analysis designed to detect greater than 10% absolute difference in proportion with termination at ED arrival.
Secondary outcomes
• Rapidity of seizure termination• Frequency of subsequent tracheal intubation• Frequency and duration of ICU and hospital stay
Exception to Informed Consent
• Community Consultation• Public Notification
• Local Context• Centralized Support
• Local Outreach – attend community meetings• Patient Focus Groups – survivors and clinics
Need for in-person
meetings and training?