Welcome to the
Conference Call – New NETT Hub PIs Friday, October 12, 2007  9:00-10:00 am PDT / 12:00-1:00 pm EDT Toll free dial-in numbe...
Neurological Emergency Treatment Trials Network Overview of the new network nett.umich.edu
Design for the future Large simple trial designs <ul><li>Streamlined protocols </li></ul><ul><li>Collect only essential da...
Design for the future Emphasis on intervention <ul><li>Focus on phase III intervention trials </li></ul><ul><li>Patient-or...
Design for the future Consent issues <ul><li>Exception to informed consent for emergency research </li></ul><ul><li>Optimi...
Mission <ul><li>The mission of the Neurological Emergencies Treatment Trials (NETT) Network is to improve outcomes of pati...
Vision <ul><li>NETT will engage clinicians and providers at the front lines of emergency care to conduct large, simple mul...
<ul><li>Investigators Initiated Studies </li></ul><ul><ul><li>Incentives and Limitations </li></ul></ul><ul><ul><li>Applic...
Study Selection Investigator Initiated Studies <ul><li>Incentives </li></ul><ul><ul><li>Investigator receives the trial aw...
Study Selection Investigator Initiated Studies <ul><li>Process </li></ul><ul><ul><li>NETT Trial Guidelines </li></ul></ul>...
Study Selection Industry Sponsored Studies <ul><li>Network / Investigator Design </li></ul><ul><ul><li>Scientific Control ...
Timeline <ul><li>Several simultaneous trials </li></ul><ul><li>Staggered planning / enrollment </li></ul>
NETT Organizational Structure
Hubs SDMC CCC NINDS
Clinical Coordinating Center <ul><li>PI: William Barsan  </li></ul><ul><li>Co-PI: Dan Lowenstein  </li></ul><ul><li>Co-Inv...
Leadership  Administration Barsan Lowenstein Bylaws, Contracts, Budgets,  Compliance, Reports, Coordination of  Units, Pro...
Statistical and Data  Management Center (SDMC)    Medical University of South Carolina <ul><li>PI: Yuko Palesch </li></ul>...
Data Management Statistics WebDCU TM SDMC Data processing Data query generation and monitoring Data validation Site contac...
National Institute of Neurological Disorders and Stroke (NINDS ) <ul><li>NINDS Assoc Director Clinical Trials:   John Marl...
NINDS Robin Conwit, MD Scientific Program Director Scientific Guidance Gavin Wilkom Funding Management   Peter Gilbert, Ph...
The Hard Work! HUB COMPLEXES
Hubs Develop operational plans  Patient recruitment, treatment, and follow-up Complete and accurate data collection  Parti...
Hubs and Investigators <ul><li>Columbia University/NY Presbyterian Stephan Mayer, MD </li></ul><ul><li>Emory University Da...
Hubs SDMC CCC NINDS
Hubs NINDS SDMC CCC Steering Committee
Steering Committee  <ul><li>Activities </li></ul><ul><ul><li>Consider modifications  and approve final versions of protoco...
Hubs NINDS SDMC CCC Steering Exec
Executive Committee <ul><li>Activities </li></ul><ul><ul><li>Oversee administrative functions </li></ul></ul><ul><ul><li>E...
Hubs NINDS SDMC CCC Steering Exec Spokes
Hubs NINDS SDMC CCC Steering Exec Spokes NAG
Network Advisory Group <ul><li>Activities </li></ul><ul><ul><li>Oversight of the network </li></ul></ul><ul><ul><li>Give f...
Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging
Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging DSMB
Data and Safety  Monitoring Board (DSMB )   <ul><li>Members </li></ul><ul><ul><li>Appointed by NINDS (TBD) </li></ul></ul>...
Hubs NINDS SDMC CCC Steering Spokes NAG Specimen Pharmacy Imaging DSMB Exec Operations Committee
Network Operations Committee <ul><li>Activities </li></ul><ul><ul><li>Oversees the day-to-day operational issues of both s...
Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging DSMB Operations Committee Internal Advisory
Internal Advisory Committee   <ul><li>Activities </li></ul><ul><ul><li>Provide independent consultation and guidance to th...
Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging DSMB Operations Committee Internal Advisory Trial PI
Report Card
Spoke Spoke Color Key for Flow Of Funds Infrastructure awards directly from NINDS Subcontracts with Trial PI Subcontract w...
<ul><li>Regulatory Document Management </li></ul>
 
WebDCU An Outside View of the System Clinical Hub Clinical Spoke Study Protocol Investigator Participating Hub/Spoke Subje...
An Inside View of the System Clinical Hub Clinical Spoke Study Protocol Investigator Participating Hub/Spoke Subject Phase...
<ul><li>ALIAS </li></ul>
<ul><li>Primary Objective </li></ul><ul><li>To ascertain whether 2g/kg 25% human serum albumin (ALB) therapy confers neuro...
<ul><li>Rationale (cont’d) </li></ul><ul><li>Exhibits proven and robust efficacy </li></ul><ul><li>Targets multiple injury...
<ul><li>Study Design </li></ul><ul><li>Two studies: thrombolysis and non-thrombolysis cohorts </li></ul><ul><li>Multi-cent...
<ul><li>Primary Outcome Measure </li></ul><ul><li>Modified Rankin Scale score of 0 or 1,  OR  NIHSS score of 0 or 1 at 3 m...
<ul><li>Main Eligibility Criteria </li></ul><ul><li>Acute ischemic stroke </li></ul><ul><li>Age >=18 years </li></ul><ul><...
<ul><li>Study Drug Kit </li></ul>ALIAS
NETT vs. “Legacy” ALIAS sites  <ul><li>Sites already participating in ALIAS (legacy) do not need to re-establish a new sub...
ALIAS Start up activities  <ul><li>Identify individuals and obtain WebDCU training </li></ul><ul><li>Obtain mRS and NIHSS ...
ALIAS Protocol Training Opportunities  <ul><li>Web cast on NETT website (http://sitemaker.umich.edu/nett/education) </li><...
<ul><li>RAMPART </li></ul>
R apid  A nticonvulsant  M edication P rior to  Ar rival  T rial  (RAMPART) <ul><li>Paramedic treatment of status epilepti...
<ul><li>IM midazolam autoinjector v. IV lorazepam </li></ul><ul><li>Double dummy blinded design </li></ul><ul><li>Exceptio...
Hypotheses <ul><li>Primary </li></ul><ul><li>IM midazolam is as effective as IV lorazepam at stopping convulsions prior to...
Inclusion criteria <ul><li>Continuous or repeated convulsive seizure activity for > 5 minutes </li></ul><ul><li>Patient is...
Exclusion criteria <ul><li>Major trauma precipitating seizure </li></ul><ul><li>Hypoglycemia </li></ul><ul><li>Known aller...
Intervention - Dose <ul><li>Two packages in each box, Child dose and Adult dose </li></ul><ul><li>Each package has one IM ...
RAMPART Datalogger Providing data loggers, stepper controllers, data acquisition and custom engineering services to custom...
Intervention <ul><li>Medic arrives on scene and evaluates patient </li></ul><ul><li>Ask bystanders duration of seizure and...
Intervention (continued) <ul><li>Start IV, give IV med, and verbalize </li></ul><ul><li>Monitor vital sings and transport ...
ED and inpatient treatment <ul><li>Attempt standardized post-intervention care </li></ul><ul><li>For further seizures in t...
ED and inpatient treatment <ul><li>If seizures continue then… </li></ul><ul><li>Intubate and ventilate, keep ≤ 37°C </li><...
Study Activity and Data Collection <ul><li>Study team activated on ED arrival of subject </li></ul><ul><li>Investigator or...
Primary outcome <ul><li>Proportion of subjects with termination of clinically evident seizure determined at arrival in the...
Secondary outcomes <ul><li>Rapidity of seizure termination </li></ul><ul><li>Frequency of subsequent tracheal intubation <...
Exception to Informed Consent <ul><li>Community Consultation </li></ul><ul><li>Public Notification </li></ul><ul><li>Local...
<ul><li>Need for in-person  </li></ul><ul><li>meetings and training? </li></ul>
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NETT New Hub PI Teleconference 10-12-07

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  • Replace “Presenter&apos;s Name” with your name. Alternative title slides are available at the end of this presentation in the “alternatives” slide.
  • The FDA and NIH have harmonized a set of regulations that allow an exception to informed consent for emergency research for life-threatening conditions where existing treatments are unsatisfactory and in which the research cannot practicably be conducted with informed consent. These regulations are at 21 CFR 50.24. The key components of these rules are requirements for public notification, community consultation, and consent to remain in the study at the earliest opportunity. The likely need to use emergency exception for multiple trials introduces an opportunity to advance the state of the art and really optimize alternatives to consent that still honor the Belmont reports inherent call to respect human subjects. We will have a chance to figure the best ways to do public notification and community consultation. Dedicated network resources ensure that experience is concentrated, solutions easily shared, and lessons need not be learned over and over again. Materials and contacts created for one trial can be used again for the next. We will work with the NIH and FDA to explore and, if desired, help create a national IRB for emergency research. Perhaps modeled after the National Cancer Institute’s C-IRB initiative, this will be a resource shared by the three Federally funded emergency research networks. The purpose of a C-IRB is to optimize the protection of patients by providing the highest quality review. An emergency research CIRB would have great expertise in emergency research and the application of the regulations at 50.24. It would also ensure equity in review. Greater resources would be freed up at local IRBs to allow them to do a better job at evaluating local context. Participation would be voluntary.
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  • NETT New Hub PI Teleconference 10-12-07

    1. 1. Welcome to the
    2. 2. Conference Call – New NETT Hub PIs Friday, October 12, 2007 9:00-10:00 am PDT / 12:00-1:00 pm EDT Toll free dial-in number: (888) 242-1836 ACCESS CODE: 4905767 <ul><li>Overview of network structure Dr. Barsan 15 min. </li></ul><ul><li>Hub Performance measures Dr. Barsan </li></ul><ul><li>Flow of Funds Valerie Stevenson 5 min. </li></ul><ul><li>Regulatory Document collection Dr. Pancioli 5 min. </li></ul><ul><li>ALIAS trial Dr. Pancioli 15 min. </li></ul><ul><ul><li>NETT vs. “legacy” sites V. Stevenson </li></ul></ul><ul><ul><li>Protocol training opportunities Joy Pinkerton </li></ul></ul><ul><ul><li>Start up activities Melissa Falb </li></ul></ul><ul><li>RAMPART Robert Silbergleit 5 min. </li></ul><ul><ul><li>Brief description of trial </li></ul></ul><ul><li>Need for in-person meetings and training Pancioli/All 5 min. </li></ul><ul><li>Questions/comments All 10 min. </li></ul>
    3. 3. Neurological Emergency Treatment Trials Network Overview of the new network nett.umich.edu
    4. 4. Design for the future Large simple trial designs <ul><li>Streamlined protocols </li></ul><ul><li>Collect only essential data (short case report forms) </li></ul><ul><li>High enrollment – lower per-patient costs </li></ul>
    5. 5. Design for the future Emphasis on intervention <ul><li>Focus on phase III intervention trials </li></ul><ul><li>Patient-oriented readily-applicable results </li></ul><ul><li>Diverse enrollment (patients & practice environments) </li></ul>
    6. 6. Design for the future Consent issues <ul><li>Exception to informed consent for emergency research </li></ul><ul><li>Optimize methods that respect human subjects </li></ul><ul><li>Dedicate network resources to facilitate local efforts </li></ul><ul><li>Help develop centralized IRB review </li></ul>
    7. 7. Mission <ul><li>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. </li></ul>
    8. 8. Vision <ul><li>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.  </li></ul>
    9. 9. <ul><li>Investigators Initiated Studies </li></ul><ul><ul><li>Incentives and Limitations </li></ul></ul><ul><ul><li>Application Process </li></ul></ul><ul><li>Industry Sponsored Studies </li></ul><ul><ul><li>Network / Investigator Design </li></ul></ul>Study Selection Investigator Initiated Studies
    10. 10. Study Selection Investigator Initiated Studies <ul><li>Incentives </li></ul><ul><ul><li>Investigator receives the trial award </li></ul></ul><ul><ul><li>Scientific control, credit, authorship preserved </li></ul></ul><ul><ul><li>Infrastructure already established </li></ul></ul><ul><li>Limitations </li></ul><ul><ul><li>Fewer funds stay at investigators institution </li></ul></ul><ul><ul><li>Commitment to stay within the network </li></ul></ul>
    11. 11. Study Selection Investigator Initiated Studies <ul><li>Process </li></ul><ul><ul><li>NETT Trial Guidelines </li></ul></ul><ul><ul><li>Clinical Trial Subcommittee & NETT-AG </li></ul></ul><ul><ul><li>Administrative Consultation </li></ul></ul><ul><ul><li>Submission for Scientific Review </li></ul></ul>
    12. 12. Study Selection Industry Sponsored Studies <ul><li>Network / Investigator Design </li></ul><ul><ul><li>Scientific Control </li></ul></ul><ul><ul><li>Shared Economies of Scale </li></ul></ul><ul><ul><li>No Direct Subsidy </li></ul></ul><ul><ul><li>NETT-AG solicits scientific review </li></ul></ul>
    13. 13. Timeline <ul><li>Several simultaneous trials </li></ul><ul><li>Staggered planning / enrollment </li></ul>
    14. 14. NETT Organizational Structure
    15. 15. Hubs SDMC CCC NINDS
    16. 16. Clinical Coordinating Center <ul><li>PI: William Barsan </li></ul><ul><li>Co-PI: Dan Lowenstein </li></ul><ul><li>Co-Investigators: Lewis Morgenstern, Art Pancioli, Robert Silbergleit, Phillip Scott, Angela Caveney, Bruno Giordani </li></ul><ul><li>Administrative Staff: Lori Avers, Valerie Stevenson </li></ul><ul><li>Site Management: Melissa Falb, Donna Harsh, Irene Ewing </li></ul><ul><li>Education: Joy Pinkerton </li></ul><ul><li>Human Subjects Protection: Deneil Kolk </li></ul>
    17. 17. Leadership Administration Barsan Lowenstein 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 Trial Management Morgenstern Trial Solicitation, Scientific Review, Publications, Clinical Translation Unit. Liaison to Trial Investigators and NSD-K CCC Internal Advisory Committee CCC
    18. 18. Statistical and Data Management Center (SDMC) Medical University of South Carolina <ul><li>PI: Yuko Palesch </li></ul><ul><li>Co-PI: Valerie Durkalski </li></ul><ul><li>Co-Investigators: Renee Martin; Patrick Mauldin; Sharon Yeatts; Wenle Zhao </li></ul><ul><li>Staff: Wayne Andrus; Catherine Dillon; Jaemyung Kim; Rick Leinster; Keith Pauls; Teddy Redmon; Christopher Rhodes. </li></ul>
    19. 19. Data Management Statistics WebDCU TM 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
    20. 20. National Institute of Neurological Disorders and Stroke (NINDS ) <ul><li>NINDS Assoc Director Clinical Trials: John Marler </li></ul><ul><li>Scientific Program Director : Robin Conwit </li></ul><ul><li>Administrative Program Director: Scott Janis </li></ul><ul><li>Grants Management: Gavin Wilkom </li></ul><ul><li>Scientific guidance-SDMC:Peter Gilbert </li></ul>
    21. 21. NINDS Robin Conwit, MD Scientific Program Director Scientific Guidance Gavin Wilkom Funding Management Peter Gilbert, PhD Scientific 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
    22. 22. The Hard Work! HUB COMPLEXES
    23. 23. 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 HUB COMPLEXES Spokes Participate in studies requiring larger sample size
    24. 24. Hubs and Investigators <ul><li>Columbia University/NY Presbyterian Stephan Mayer, MD </li></ul><ul><li>Emory University David Wright, MD </li></ul><ul><li>Henry Ford Hospital Christopher Lewandowski, MD </li></ul><ul><li>Medical College of Wisconsin Thomas Aufderheide, MD </li></ul><ul><li>Oregon Science and Health University Robert Lowe, MD </li></ul><ul><li>Stanford University James Quinn, MD </li></ul><ul><li>Temple University Nina Gentile, MD </li></ul><ul><li>University of Arizona Kurt Denninghoff, MD </li></ul><ul><li>University of California SF Claude Hemphill, MD </li></ul><ul><li>University of Cincinnati Arthur Pancioli, MD </li></ul><ul><li>University of Kentucky Roger Humphries, MD </li></ul><ul><li>University of Maryland Barney Stern, MD </li></ul><ul><li>University of Minnesota Michelle Biros, MD </li></ul><ul><li>University of Pennsylvania Jill Barren, MD </li></ul><ul><li>University of Texas-Houston Elizabeth Jones, MD </li></ul><ul><li>Virginia Commonwealth University Joseph Ornato, MD </li></ul><ul><li>Wayne State University Robert Welch, MD </li></ul>
    25. 25. Hubs SDMC CCC NINDS
    26. 26. Hubs NINDS SDMC CCC Steering Committee
    27. 27. Steering Committee <ul><li>Activities </li></ul><ul><ul><li>Consider modifications and approve final versions of protocols and operations </li></ul></ul><ul><ul><li>Supervise overall execution of the trial </li></ul></ul><ul><ul><li>Provide input on generating and approving study policies </li></ul></ul><ul><ul><li>Plan and draft study-related publications </li></ul></ul><ul><li>Members </li></ul><ul><ul><li>Members of the Executive Committee </li></ul></ul><ul><ul><li>Hub Principal Investigators </li></ul></ul>
    28. 28. Hubs NINDS SDMC CCC Steering Exec
    29. 29. Executive Committee <ul><li>Activities </li></ul><ul><ul><li>Oversee administrative functions </li></ul></ul><ul><ul><li>Ensure effective communication and collaboration among Hubs </li></ul></ul><ul><ul><li>Formulate and maintain standards for the network </li></ul></ul><ul><ul><li>Responsible for integration of all elements of the network, including all regulatory compliance </li></ul></ul><ul><ul><li>Advocates, represents, and promotes mission of the network </li></ul></ul><ul><li>Members </li></ul><ul><ul><li>William Barsan (Chair), Robin Conwit, Catherine Dillon, Valerie Durkalski, Dan Lowenstein, Lewis Morgenstern, Yuko Palesch, Art Pancioli, Robert Silbergleit, Valerie Stevenson </li></ul></ul>
    30. 30. Hubs NINDS SDMC CCC Steering Exec Spokes
    31. 31. Hubs NINDS SDMC CCC Steering Exec Spokes NAG
    32. 32. Network Advisory Group <ul><li>Activities </li></ul><ul><ul><li>Oversight of the network </li></ul></ul><ul><ul><li>Give final approval to </li></ul></ul><ul><ul><ul><li>trial protocols </li></ul></ul></ul><ul><ul><ul><li>modifications to the protocols </li></ul></ul></ul><ul><ul><ul><li>the overall budget </li></ul></ul></ul><ul><ul><ul><li>plans for analysis </li></ul></ul></ul><ul><li>Members </li></ul><ul><ul><li>Appointed and organized by NINDS (TBD) </li></ul></ul><ul><ul><li>Experts in Emergency Medicine and Neurology </li></ul></ul><ul><ul><li>NINDS officials with expertise in clinical trials </li></ul></ul><ul><li>Forwards reports and recommendations to NINDS </li></ul>
    33. 33. Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging
    34. 34. Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging DSMB
    35. 35. Data and Safety Monitoring Board (DSMB ) <ul><li>Members </li></ul><ul><ul><li>Appointed by NINDS (TBD) </li></ul></ul><ul><li>Activities </li></ul><ul><ul><li>Monitor safety and performance and to review interim analyses in the NETT Network clinical trials </li></ul></ul><ul><li>Depending on the specific trials selected, more than one DSMB may be required </li></ul>
    36. 36. Hubs NINDS SDMC CCC Steering Spokes NAG Specimen Pharmacy Imaging DSMB Exec Operations Committee
    37. 37. Network Operations Committee <ul><li>Activities </li></ul><ul><ul><li>Oversees the day-to-day operational issues of both study management and site management </li></ul></ul><ul><ul><li>Responsible for the operational aspects of the individual trials such as regulatory compliance, monitoring and maximizing recruitment </li></ul></ul><ul><ul><li>Responsible for the integration of the Hub and Spoke System by providing education, guidance and feedback to Network personnel </li></ul></ul><ul><li>Members </li></ul><ul><ul><li>Catherine Dillon, Valerie Durkalski, Irene Ewing, Melissa Falb, Donna Harsh, Deneil Kolk, Yuko Palesch, Art Pancioli, Joy Pinkerton, Robert Silbergleit, Valerie Stevenson, </li></ul></ul>
    38. 38. Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging DSMB Operations Committee Internal Advisory
    39. 39. Internal Advisory Committee <ul><li>Activities </li></ul><ul><ul><li>Provide independent consultation and guidance to the CCC and the EC </li></ul></ul><ul><li>Members </li></ul><ul><ul><li>Dr. Bob Adams (Chair) </li></ul></ul><ul><ul><li>Dr. Arthur Kellerman </li></ul></ul><ul><ul><li>Dr. Roger Lewis </li></ul></ul><ul><ul><li>Dr. Raj Narayan </li></ul></ul>
    40. 40. Hubs NINDS SDMC CCC Steering Exec Spokes NAG Specimen Pharmacy Imaging DSMB Operations Committee Internal Advisory Trial PI
    41. 41. Report Card
    42. 42. Spoke Spoke 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 Hubs SDMC CCC NINDS Centralized pharmacy or trial services** Trial PI Funds from R01
    43. 43. <ul><li>Regulatory Document Management </li></ul>
    44. 45. WebDCU An Outside View of the System Clinical Hub Clinical Spoke Study 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 Pharmacy DSMB MSM SDMC CCC Executive Committee Central Scoring Central Imaging Specimen Tracking Central Lab Score Expert Image Reader Hub/Spoke Staff Steering Committee NINDS
    45. 46. An Inside View of the System Clinical Hub Clinical Spoke Study 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 Imaging Specimen Tracking Project Management Data Management
    46. 47. <ul><li>ALIAS </li></ul>
    47. 48. <ul><li>Primary Objective </li></ul><ul><li>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.  </li></ul>ALIAS
    48. 49. <ul><li>Rationale (cont’d) </li></ul><ul><li>Exhibits proven and robust efficacy </li></ul><ul><li>Targets multiple injury mechanisms </li></ul><ul><li>Has minimal risk of adverse effects </li></ul><ul><li>Can be easily administered without complicated laboratory tests </li></ul>ALIAS
    49. 50. <ul><li>Study Design </li></ul><ul><li>Two studies: thrombolysis and non-thrombolysis cohorts </li></ul><ul><li>Multi-center, randomized, double-blinded, saline-controlled parallel study </li></ul><ul><li>In-person follow-up assessment at 3 months </li></ul><ul><li>Telephone follow-up assessments at 1-, 6-, 9-, and 12-month </li></ul><ul><li>Sample size of 900 for each cohort </li></ul><ul><li>3 planned interim analyses </li></ul>ALIAS
    50. 51. <ul><li>Primary Outcome Measure </li></ul><ul><li>Modified Rankin Scale score of 0 or 1, OR NIHSS score of 0 or 1 at 3 months from randomization </li></ul>ALIAS <ul><li>Secondary Outcome Measures </li></ul><ul><li>Barthel Index, Stroke-Specific Quality of Life, and Trail Making at 3 months </li></ul><ul><li>EuroQol at 3 months and 1 year </li></ul><ul><li>Stroke-free status through 1 year </li></ul>
    51. 52. <ul><li>Main Eligibility Criteria </li></ul><ul><li>Acute ischemic stroke </li></ul><ul><li>Age >=18 years </li></ul><ul><li>NIHSS score at baseline >=6 </li></ul><ul><li>Initiation of study drug within 5 hours of stroke onset </li></ul><ul><li>No history of or medical exam results with cardiac problems (particularly CHF/pulmonary edema) </li></ul><ul><li>Informed consent </li></ul>ALIAS
    52. 53. <ul><li>Study Drug Kit </li></ul>ALIAS
    53. 54. NETT vs. “Legacy” ALIAS sites <ul><li>Sites already participating in ALIAS (legacy) do not need to re-establish a new subcontract with the NETT CCC </li></ul><ul><li>May receive “credit” for augmenting legacy site enrollment </li></ul><ul><ul><li>Note subjects that were enrolled through NETT efforts </li></ul></ul>
    54. 55. ALIAS Start up activities <ul><li>Identify individuals and obtain WebDCU training </li></ul><ul><li>Obtain mRS and NIHSS certification </li></ul><ul><ul><li>Required for all staff clinically evaluating subjects or administering assessments </li></ul></ul><ul><li>Up-to-date HIPAA and Human Subjects Protection </li></ul><ul><li>Review protocol and Manual of Procedures </li></ul><ul><li>Submit ALIAS Regulatory Documents </li></ul><ul><li>IRB-approved Informed Consent Form </li></ul><ul><ul><li>NOTE: send a copy of your ICF template to Dr. Tamariz at the University of Miami for review, prior to local submission, at [email_address] or (305) 968-0766 </li></ul></ul>
    55. 56. ALIAS Protocol Training Opportunities <ul><li>Web cast on NETT website (http://sitemaker.umich.edu/nett/education) </li></ul><ul><li>PI tele-cast </li></ul><ul><li>In-person meeting? </li></ul><ul><li>Train the trainer </li></ul><ul><li>Training slide set </li></ul>
    56. 57. <ul><li>RAMPART </li></ul>
    57. 58. R apid A nticonvulsant M edication P rior to Ar rival T rial (RAMPART) <ul><li>Paramedic treatment of status epilepticus </li></ul><ul><li>Standard treatment is IV benzodiazepine </li></ul><ul><li>IV starts difficult / dangerous in the convulsing patient </li></ul><ul><li>Best IV agent, lorazepam, impractical for EMS </li></ul><ul><li>IM treatment is faster and easier </li></ul><ul><li>Best IM agent, midazolam, is practical for EMS </li></ul>
    58. 59. <ul><li>IM midazolam autoinjector v. IV lorazepam </li></ul><ul><li>Double dummy blinded design </li></ul><ul><li>Exception to consent for emergency research </li></ul><ul><li>Outcome: termination of seizure prior to ED arrival </li></ul><ul><li>Sample 700 patients (350 per group) </li></ul><ul><li>Intention to treat, non-inferiority analysis </li></ul>R apid A nticonvulsant M edication P rior to Ar rival T rial (RAMPART)
    59. 60. Hypotheses <ul><li>Primary </li></ul><ul><li>IM midazolam is as effective as IV lorazepam at stopping convulsions prior to ED arrival </li></ul><ul><li>Secondary </li></ul><ul><li>Convulsions stop more rapidly with treatment with IM midazolam versus IV lorazepam </li></ul><ul><li>There is no difference in safety between the two treatments </li></ul>
    60. 61. Inclusion criteria <ul><li>Continuous or repeated convulsive seizure activity for > 5 minutes </li></ul><ul><li>Patient is still seizing </li></ul><ul><li>Estimated weight > 13 kg </li></ul>
    61. 62. Exclusion criteria <ul><li>Major trauma precipitating seizure </li></ul><ul><li>Hypoglycemia </li></ul><ul><li>Known allergy to midazolam or lorazepam </li></ul><ul><li>Sensitivity to benzodiazepines </li></ul><ul><li>Cardiac arrest or heart rate <40 beats/minute </li></ul><ul><li>Known pregnancy </li></ul><ul><li>Prisoner </li></ul>
    62. 63. Intervention - Dose <ul><li>Two packages in each box, Child dose and Adult dose </li></ul><ul><li>Each package has one IM injector, one IV dose, one of which is active, the other is dummy </li></ul><ul><li>Child (13- 39 kg) – Lorazepam 2 mg or Midazolam 5 mg </li></ul><ul><li>Adult (40 kg and up)– Lorazepam 4 mg or Midazolam 10 mg </li></ul><ul><li>Midazolam is in an autoinjector </li></ul><ul><li>Lorazepam is given IV </li></ul>
    63. 64. RAMPART Datalogger Providing data loggers, stepper controllers, data acquisition and custom engineering services to customers worldwide
    64. 65. Intervention <ul><li>Medic arrives on scene and evaluates patient </li></ul><ul><li>Ask bystanders duration of seizure and trauma </li></ul><ul><li>Look for medic alert jewelry </li></ul><ul><li>Check glucose and vital signs </li></ul><ul><li>For children, check estimated weight </li></ul><ul><li>If criteria are met, study box is opened to enroll </li></ul><ul><li>Medic states that entry criteria are met </li></ul><ul><li>Select child dose or adult dose based on weight </li></ul><ul><li>Give IM medication and verbalize </li></ul>
    65. 66. Intervention (continued) <ul><li>Start IV, give IV med, and verbalize </li></ul><ul><li>Monitor vital sings and transport </li></ul><ul><li>Verbalize if convulsions stop </li></ul><ul><li>At 10 minute after treatment, provide “rescue” meds per local protocol if still seizing en route, verbalize that med was given </li></ul><ul><li>At ED arrival, verbalize whether patient is still seizing or not </li></ul>
    66. 67. ED and inpatient treatment <ul><li>Attempt standardized post-intervention care </li></ul><ul><li>For further seizures in the ED or secondary treatment of prior status… </li></ul><ul><li>Lorazepam 0.05-0.1 mg/kg plus </li></ul><ul><li>Phenytoin or Fosphenytoin 18-20 mg/kg </li></ul>
    67. 68. ED and inpatient treatment <ul><li>If seizures continue then… </li></ul><ul><li>Intubate and ventilate, keep ≤ 37°C </li></ul><ul><li>Consider vecuronium 0.1 mg/kg </li></ul><ul><li>Then add: </li></ul><ul><ul><li>Midazolam 0.2 mg/kg then 1.2 ug/kg/min or </li></ul></ul><ul><ul><li>Propofol 1 mg/kg then 1-5 mg/kg/hr or </li></ul></ul><ul><ul><li>Pentobarbital 5-15 mg/kg over 1 hr, then 0.5-5 mg/kg/hr </li></ul></ul><ul><li>Admit to ICU, early EEG monitoring </li></ul>
    68. 69. Study Activity and Data Collection <ul><li>Study team activated on ED arrival of subject </li></ul><ul><li>Investigator or coordinator in ED </li></ul><ul><ul><li>Collect the data logger </li></ul></ul><ul><ul><li>Complete as many CRF items as possible </li></ul></ul><ul><ul><li>Approach subject or family for consent to continue to collect and use data </li></ul></ul><ul><li>Restock ambulance with new study kit </li></ul><ul><li>Follow patient in hospital for AE’s </li></ul><ul><ul><li>Collect remaining data at discharge </li></ul></ul>
    69. 70. Primary outcome <ul><li>Proportion of subjects with termination of clinically evident seizure determined at arrival in the Emergency Department (ED) after a single dose of study medication. </li></ul><ul><li>Non-inferiority analysis designed to detect greater than 10% absolute difference in proportion with termination at ED arrival. </li></ul>
    70. 71. Secondary outcomes <ul><li>Rapidity of seizure termination </li></ul><ul><li>Frequency of subsequent tracheal intubation </li></ul><ul><li>Frequency and duration of ICU and hospital stay </li></ul>
    71. 72. Exception to Informed Consent <ul><li>Community Consultation </li></ul><ul><li>Public Notification </li></ul><ul><li>Local Context </li></ul><ul><li>Centralized Support </li></ul><ul><li>Local Outreach – attend community meetings </li></ul><ul><li>Patient Focus Groups – survivors and clinics </li></ul>
    72. 73. <ul><li>Need for in-person </li></ul><ul><li>meetings and training? </li></ul>

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