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 dtamariz@med.miami.edu 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?