Welcome to the

1. Welcome to the

2. 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) 242-1836ACCESS 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.

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

4. Design for the futureLarge simple trial designs • Streamlined protocols • Collect only essential data (short case report forms) • High enrollment – lower per-patient costs

5. Design for the futureEmphasis on intervention • Focus on phase III intervention trials • Patient-oriented readily-applicable results • Diverse enrollment (patients & practice environments)

6. 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

7. 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.

8. 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. 

9. Study SelectionInvestigator Initiated Studies • Investigators Initiated Studies • Incentives and Limitations • Application Process • Industry Sponsored Studies • Network / Investigator Design

10. 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

11. Study SelectionInvestigator Initiated Studies • Process • NETT Trial Guidelines • Clinical Trial Subcommittee & NETT-AG • Administrative Consultation • Submission for Scientific Review

12. Study SelectionIndustry Sponsored Studies • Network / Investigator Design • Scientific Control • Shared Economies of Scale • No Direct Subsidy • NETT-AG solicits scientific review

13. Timeline • Several simultaneous trials • Staggered planning / enrollment

14. NETT Organizational Structure

15. Hubs NINDS CCC SDMC

16. 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

17. CCC Leadership Trial Management Administration Barsan Morgenstern Lowenstein Bylaws, Contracts, Budgets, Trial Solicitation, Scientific Compliance, Reports, Coordination of Review, Publications, Clinical Units, Promotion of network within EM Translation Unit. and Neurology communities Liaison to NAG & Scientific Program Director Liaison to Trial Investigators and NSD-K CCC Internal Advisory Committee Site Management Study Operations Pancioli Silbergleit Recruitment, Training, Certification, MOP, Human Subjects Protection, Screening, Enrollment, Outcome Assessment, Monitoring, Centralized Data, Telemedicine, Liaison to Hub investigators Liaison to SDMC and DSMB

18. 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.

19. SDMC WebDCUTM W. Zhao Data Management V. Durkalski, C. Dillon Database development PM tools development Central randomization Maintenance Data processing Data query generation and monitoring Data validation Site contact Training Report generation Archiving Statistics Y. Palesch, V. Durkalski Protocol design SAP development DSMB report generation Analyses

20. 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

21. NINDS Scientific Guidance Administrative Robin Conwit, MD Scientific Program Director Scott Janis, PhDAdministrative Program Director Peter Gilbert, PhD Scientific Guidance-SDMC Gavin Wilkom Funding Management Coordinate Funding Grants Management Scientific leadership Promote the mission of the NINDS Identify needs & develop new initiatives Liaison NINDSLeadership NETT-Advisory Group NETT DSMB

22. HUB COMPLEXES The Hard Work!

23. HUB COMPLEXES Hubs Develop operational plans Patient recruitment, treatment, and follow-up Complete and accurate data collection Participate in writing manuscripts Adhere to a common study protocol for each trial Attend training and investigator meetings Protect human subjects Ensure adequate representation Assist data audits and other quality control procedures Provide research infrastructure & monitoring of spokes Spokes Participate in studies requiring larger sample size

24. Hubs and Investigators Columbia University/NY Presbyterian Stephan Mayer, MD Emory University David Wright, MD Henry Ford Hospital Christopher Lewandowski, MD Medical College of Wisconsin Thomas Aufderheide, MD Oregon Science and Health University Robert Lowe, MD Stanford University James Quinn, MD Temple University Nina Gentile, MD University of Arizona Kurt Denninghoff, MD University of California SF Claude Hemphill, MD University of Cincinnati Arthur Pancioli, MD University of Kentucky Roger Humphries, MD University of Maryland Barney Stern, MD University of Minnesota Michelle Biros, MD University of Pennsylvania Jill Barren, MD University of Texas-Houston Elizabeth Jones, MD Virginia Commonwealth University Joseph Ornato, MD Wayne State University Robert Welch, MD

25. Hubs NINDS CCC SDMC

26. Hubs NINDS SteeringCommittee CCC SDMC

27. 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

28. Hubs NINDS Steering Exec CCC SDMC

29. 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

30. Spokes Hubs NINDS Steering Exec CCC SDMC

31. Spokes NAG Hubs NINDS Steering Exec CCC SDMC

32. 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

33. Spokes NAG Hubs NINDS Steering Exec Imaging CCC SDMC Pharmacy Specimen

34. Spokes NAG Hubs NINDS Steering Exec DSMB Imaging CCC SDMC Pharmacy Specimen

35. 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

36. Spokes NAG Hubs NINDS Steering Exec DSMB Imaging CCC SDMC Pharmacy OperationsCommittee Specimen

37. 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,

38. Spokes NAG Hubs NINDS Steering Exec InternalAdvisory DSMB Imaging CCC SDMC Pharmacy OperationsCommittee Specimen

39. 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

40. Spokes NAG Trial PI Hubs NINDS Steering Exec InternalAdvisory DSMB Imaging CCC SDMC Pharmacy OperationsCommittee Specimen

41. Report Card

42. Centralized pharmacy or trial services** SDMC Color Key for Flow Of Funds Infrastructure 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 NINDS Trial PI Funds from R01 CCC Spoke Hubs Spoke

43. Regulatory Document Management

45. An Outside View of the System CCC NINDS Clinical Hub Clinical Spoke Investigator Hub/Spoke Staff Drug/Device Distribution Steering Committee Study Protocol Clinical Data Report Participating Hub/Spoke Central Pharmacy WebDCU Investigator Document Enrollment Randomization Study Payment Management Executive Committee Central Lab Central Imaging Subject Phase/Visit Study Calendar Specimen Tracking Image Reader MSM Central Scoring SAE/MedWatch CRF Data Clinical Data Monitoring Score Expert DSMB Study Progress Report Hub/Spoke Document Study Database SDMC

46. An Inside View of the System Project Management Study Protocol Clinical Spoke Investigator Clinical Hub Study Payment Management Participating Hub/Spoke Hub/Spoke Document Investigator Document Enrollment Randomization Drug/Device Distribution Study Progress Report Study Calendar Specimen Tracking Central Imaging Subject Phase/Visit SAE/MedWatch CRF Data Clinical Data Monitoring Central Scoring Clinical Data Report Study Database Data Management

47. ALIAS

48. ALIAS Primary Objective To ascertain whether 2g/kg 25% human serum albumin (ALB) therapy confers neuroprotection in acute ischemic stroke over and above the best standard of care. 

49. ALIAS 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

50. ALIAS 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