StrokeNet: Rationale, Overview, Objectives, Priorities, Status

Joe Broderick

Yuko Palesch

NIH StrokeNet Overview

• NINDS created StrokeNet in late 2013 (fully funded in 4/2014) to prioritize, harmonize, and efficiently conduct NINDS funded clinical trials in stroke prevention, treatment, and recovery

• Direct response to the recommendations of the Stroke Progress Review Group and NINDS Stroke Planning efforts in 2012 that identified a need and the opportunity to establish a stroke trial network infrastructure

• Designed to support early exploratory phase 2 to confirmatory phase 3 trials

• Provides the infrastructure to streamline trials through the use of a centralized IRB and master trial contracts and to provide centralized support for data management, integration, and data sharing

NIH StrokeNet

Census Region: West Midwest South Northeast

UW Medicine/ Harborview Med. Ctr.

NorCal Research RCC

Stanford Stroke Center

Los Angeles-So. California Regional NIH StrokeNET UCSD Stroke Center

U Utah RCC

U Minnesota RCC

U Iowa RCC

U Wisconsin

Chicago Stroke Trials Consortium

Michigan StrokeNet

NIH Cleveland Stroke Trials Collaborative

Ohio State WexnerRCC

U Cincinnati RCC

Vanderbilt U Medical Ctr

Georgia StrokeNet

Miami RCC Gulf Regional Area Stroke Programs

So. Caroline Collaborative Alliance for Stroke Trials

Stroke National Capital Area Network for Research

UPMC Stroke Institute

G. Philadelphia NIH StrokeNet

New England RCC

Stroke Trials Network of Columbia and Cornell

NY City Collaborative RCC

www.NIHStrokeNet.org

Leadership Structure of StrokeNet

www.NIHStrokeNet.org

EXECUTIVE Committee

STEERING Committee

OPERATIONS Committee

NINDS / Scientific Advisory

Leadership

Data

Management

Center

Medical University of

South Carolina

National Coordinating

Center and Central

Pharmacy

University of Cincinnati

Regional Coordinating

Centers ( N = 25 )

Satellite Sites / Clinical

Performace Sites

Protocol Awarded

Centers

NON - Network

CORES

Imaging

Training

ADVISORY

COMMITTEES WORKING

GROUPS

Acute Stroke

Prevention

Rehab / Recovery

DSMB

Central IRB

University of Cincinnati

~284 Hospitals

Ethics and Competing Trials

Minority Recruitment

Interventional Management

Joe Broderick, MD

Yuko Palesch, PhD

StrokeNet Hospitals

StrokeNet Population Coverage by Group and Distance

National Coordinating Center

University of Cincinnati

College of Medicine (COM)

Department of Neurology and Rehabilitation

Medicine

NCC Operations Center within University of Cincinnati

StrokeNet National Coordinating Center (NCC)

Contact PI (Broderick) Co-PIs (Khatri, Brott, Cramer)

NCC Organizational Chart

Trial Design, Feasibility Assessment, Scientific and Clinical Expertise

Operational Infrastructure

Educational Core (Kleindorfer,

Marshall)

Working Groups

Imaging Core

Feasibility

Advisory Groups

Operational Infrastructure (UC) PI Broderick

NCC Organizational Chart

Contracts and Legal Liaison

(Sparks)

Clinical Research Administrative

Directors Spilker, Frasure

Central IRB (Linke, Brown)

Trial Project Managers

Pharmacy (Dill)

Financial Manager (Carey)

Administrative Specialist

(Beckman)

cIRB liaison (Roll)

Process of Trial Concept to Trial Start

• Trials can arise from Working Groups within StrokeNet or from outside StrokeNet

• Process involves interaction with Protocol PIs along the entire way but with the bulk of the focus of the working groups and Executive Committee on scientific input (not review) and trial feasibility within the network

StrokeNet Trial Development Process

Applicant submits and discusses initial concept with

NINDS

Applicant discusses concept with Working Group and

submits Concept Proposal NINDS ESC Approval

Feasibility review and

development of budget

Submission for Scientific

Peer Review

Council Review

Final Protocol development with Network

cIRB approval GO!!

Trial Process –DEFUSE III As Example

Step Date Step Date Approval NINDS ESC 5/7/2014 Working Group Summary 2/6/2015

Acute Working Group 5/7/2014 Executive Committee Summary 2/9/2015

Feasibility Assessment Completed from Sites

6/13/2014 Submission for NIH Review 3/5/2015

Working Group Summary 6/16/2014 NINDS Council Review 9/10/2015

Executive Committee Summary 6/18/2014

Submission for NIH Review 7/5/2014

Presentation of MR CLEAN 10/29/2014

NIH Review 11/2014

Second Feasibility Assessment Begun

1/16/2015

Feasibility Survey/Population Assessment –Prevention Trial

Feasibility Survey

• Feasibility recommendation to StrokeNet Exec Committee: 122 clinical sites willing to participate and provide approximately 5 subjects per years.

• 81 sites expressed substantial or extreme enthusiasm about participating in this novel and important study.

• 80 StrokeNet sites would be sufficient to meet trial goals to recruit 806 patients over 2 years.

Population Assessment

• Summary of Eligibility Analysis Within a Population: 10.7% of ischemic stroke patients were eligible for this trial within a population.

• Estimation does not include the proportion of patients with atrial cardiopathy, a less common and extremely important exclusion for this study.

• 24% of all ischemic stroke patients had any left atrial enlargement described (which may include the excluded “mild” LAE), of which 46 (2% of all stroke cases) were otherwise eligible for the study.

Trials Currently Underway in the Network

MISTIE INTRACEREBRAL HEMORRHAGE TRIAL Does faster clot removal in ICH give better patient outcomes?

Diffusion and Perfusion Weighted Imaging Evaluation for Understanding Stroke Evolution TRIAL

Trials Submitted for Peer Review = 7

Trial Domain Submitted

DEFUSE 3 (X2) Acute June 2014 & March 2015*

ICTUS 2-3 Acute October 2014

MOST (X2) Acute October 2014 & July 2015

PICASSO Prevention February 2015

ARCADIA Prevention June 2015

*Trial Awarded in mid-September

Trials in Development/Pending Submission = 12 Trial Domain Anticipated submission

IMPACT Acute October 2015

PreLIMBS Acute October 2015

CREST-H (Ancillary study) Prevention October 2015

ICTuS 3 Acute Resubmission in development

PICASSO Prevention Resubmission in development

DOSER Rehab and Recovery In development

C-PAP Prevention In development

SATURN Prevention In development

Tempo-EMS Acute February 2016

ARREST Prevention In development

LARIAT Prevention February 2016

I WITNESS Acute February 2016

NIH StrokeNet Training Core

2014-2015 Didactic Webinars Date Topic Speaker Institution Moderator Attendance

Aug28 Next Generation Drugs for Neuroprotection

in Acute Ischemic Stroke

B McLaughlin Vanderbilt Tirschwell 66

Sept 25 Thrombolysis in pediatric stroke R Ichord U Penn Tirschwell 79

Oct 30 Neuroimaging Characterization of Brain

Plasticity in Aging and Stroke

V Prabhakaran U Wisc Liebeskind 95

Nov 20 Cell-Based Therapies for Stroke S Savitz UT Houston Marshall 79

Jan 29 Gloves Off for Acute Stroke Management

“New Combatants”: Fellow case

presentations to 2 Stroke Experts

H Adams/G Albers

and Fellows

U Iowa/

Stanford

Kleindorfer 85

Feb 26 Telemedicine in Practice and Research L Schwamm MGH Marshall 131

Mar 26 Aphasia and Language Recovery R Lazar Columbia Marshall 55

April 30 Post Stroke Fatigue K Becker UW Kleindorfer 77

May 28 High Resolution Cerebrovascular Vessel Wall

Imaging

T Hatsukami UW Liebeskind 67

Professional Development Webinars 2015-16

Date Topic Speaker Time Institution Moderator

July 27

Monday

Writing your CV & Biosketch

(updated with new format)

Dawn Kleindorfer 4:00 Cincinnati

Aug 20

Thursday

Approval Process for Medical

Devices in Stroke

Wade Smith 2:00 UCSF Tirschwell

Sept 30

Wednesday

How to Present your Data Enrique Leira 3:00 Iowa Kleindorfer

Oct 20

Tuesday

Creating a Study Budget Joe Broderick

Judy Spilker

1:30 Cincinnati Kleindorfer

Nov 12

Thursday

Grant Writing Steve Greenberg 1:00 MGH Marshall

National Data Management Center (NDMC)

Medical University of South Carolina (MUSC)

College of Medicine (COM)

Department of Public Health Sciences (DPHS)

NDMC Location

Data Coordination Unit (DCU)

StrokeNet National Data Management Center (NDMC)

Contact PI (Palesch) Co-PI (Zhao)

Clinical Advisor (Jauch)

Operations Director (Dillon)

Neuroimaging Core* Biostatistics Core

Data Management Core Site Monitors

NDMC Organizational Chart

Neuroimaging Advisor (George)

* In conjunction with the NCC

Network Development SOPs Working Groups RCC Site Visits Interaction with Global Networks

Project Development Feasibility Surveys Trial Designs Budgeting Project Development Tracking

Information Management RCC, Clinical Sites, Investigators Regulatory Documents Neuroimaging Tracking

NDMC Infrastructure Work Scope

Pre-Implementation Protocol, CRF, and SAP development Study database setup in WebDCU™ Integration of randomization into WebDCU™

Implementation Data management and QA Site Monitoring Neuroimaging tracking Interim reports and analyses Interaction with DSMB as unblinded statistician Blinded statistical input (if needed)

Post-Implementation Database lock Analyses and publications Submission of Public Use Data Sets (PUDS)

NDMC Project Work Scope

WebDCU™ - a CTMS

We manage:

Study Subjects

Clinical Sites

Overall Project

CRF Data

and the StrokeNet

Compliance with Common Data Elements (CDE)

Central Neuroimaging Repository at LONI

Neuroimaging Collection

Imaging Registration in WebDCU™

Subject Enrollment in WebDCU™

Imaging Upload to LONI

Notification to Central Reader

QA Pass?

Imaging Download and Review by Central Reader

Central Review Data Entry into WebDCU™

NO YES

NDMC Biostatistical Core

Randomization in WebDCU™

Challenges

• Balance the portfolio with clinical trials in stroke treatment, prevention and recovery. Competing enrollments between types of trials

• The field and culture of stroke recovery and rehabilitation is new to multicenter clinical trials. Lack of experienced leadership, inclusion of other non-neurology specialties, impact upon variable reimbursement for PT/OT/speech.

• Broader use of Collaborative Research and Development Agreements (CRADA) between NINDS and industry partners

Plans

• Implement trials quickly as they are approved for funding

• Expedite number of high-quality trial proposals – particularly in stroke recovery/rehabilitation.

• Enhance collaborations with international colleagues (global stroke network – trial collaborations), industry (STAIR conference adjacent in time and place to StrokeNet meeting in October), and pre-clinical scientists (possible renewal of focused “Princeton-like” conference – needs funding source).

• Grow and develop educational programs

NIH StrokeNet Working Groups by Domain

NIH StrokeNet NCC Cores

Top 3 Gaps Acute Treatment

Based on the above, we have forwarded the following top 3 vote getters for priority gaps to the StrokeNet Executive Committee (8 gaps identified by group):

1. Prehospital neuroprotection for ischemic stroke

2. Endovascular mechanical thrombectomy for ischemic stroke in beyond 6h patients with imaging selection

3. Any hyperacute therapy for ICH (top single suggestion pro- coagulants in ICH

4. Six of the 8 gaps are represented by ongoing StrokeNet Trials, already submitted, or submitted by October, 2015.

Bolded = ongoing or submitted trial, or in development within StrokeNet

Top 3 Gaps Prevention 1. Optimizing medical management for secondary stroke prevention including research on innovative systems to maximize delivery of care and strategies to bolster self-management skills, self- efficacy, medication adherence, and lifestyle change. 2. Developing more effective early and long-term interventions for stroke subtype-specific secondary prevention among high risk patients with intracranial atherosclerosis, cardioembolic stroke, small vessel disease (ischemic strokes and intracerebral hemorrhage), and cryptogenic infarcts including personalized pharmacogenetic approaches for antithrombotic medication selection. 3. Improving primary prevention strategies including interventions for subclinical leukoarisosis progression/silent stroke, vascular cognitive impairment, asymptomatic aneurysms, and peri-operative stroke.

Top 3 - Recovery-rehabilitation Gaps

1. Understand and document the effects of activity-based interventions, with particular reference to issues of content, dose, and timing.

2. Establish biomarkers of restorative events

3. Increase the number of viable Recovery & Rehabilitation applications.

Ongoing Clinical Trials in RCCs in 2/2014 (n=245*)

33

21

24

167

Number of Trials

Acute

Prevention

Biomarker

Recovery and Rehabilitation

* 2/2014: Out of the 669 ongoing ‘Stroke Trials’ listed on clinicaltrials.gov

Single RCC Studies versus Multi-Center Studies (n=245)

2 – Not approved by ESC 11 - Redirected as not suitable for NIH

StrokeNet

1 - approved for funding

Over 40 projects proposed thus far 28 full concept proposals submitted to NINDS

•Treatment: 10 •Prevention: 8 •Recovery: 10

.

8- Concepts submitted to ESC 6- Approved by ESC 6- Applications submitted for peer-

review

Activities of the Training Core

• Supervision of the RCC Training Programs • Ensure that adequate focus on stroke research

• Education plans with milestones for progress due prior to trainee arrival • All approved last year, with two requiring more information for the core’s review

• Mid-year progress reports • Reviewed, no significant issues noted

• Final Progress Report • Including information about their next position and success in research so far, contact

information

Metrics for Measuring Success of Training Core • Webinar Attendance and Attendee Surveys

• Research Presentations by Trainees

• Final Trainee Survey

• Trainees themselves! • Publications

• Future participation in research • Academic institutions

• Participation in clinical trials/clinical research

• 24/25 of 2014-15 trainees reported their next position was in academia and will be “significantly involved” in research

• Writing/receiving grants

Interactions with Other Networks • NETT – meeting regularly with leadership – collaborations on trials

• NeuroNEXT – supportive enrollment in Rhapsody trial.

• cIRB • Working with cIRB for VAMC for those StrokeNet satellite sites who are part of

StrokeNet – first of its kind • Collaborations with NeuroNEXT, CTSA, and other cIRBs

• AHA • GWTG database – working to incorporate these data as part of data for feasibility

survey of StrokeNet sites (Lee Schwamm, Joe Broderick, Dawn Kleindorfer)

• Global Stroke Alliance • Two meetings in person of national stroke networks leadership. Quarterly meetings

by phone • Planned second meeting with Japanese network in 2016 • Discussing with Australian Stroke Network about DEFUSE III collaboration

Advisory Committees

1) Ethics and Competing Trials Committee (Dr. Jennifer Majersik) – written guideline

2) The Minority Recruitment and Retention Advisory Committee under the direction of B. Boden Albala and Dawn Kleindorfer to assist in the development of strategies to address women and minority recruitment needs in SN grant proposals.

3) The Interventional Advisory Committee was expanded and activated under the direction of Colin Derdeyn and Sam Zaidat to assist in addressing the changes in clinical practice and potential trial design necessitated by the positive findings in the recent endovascular trials.

4) Pediatric Stroke Committee – Chair is Heather Fullerton, MD, and awaiting first potential trial