PI: KAPUR, JAIDEEP
Title: Established Status Epilepticus Treatment Trial (ESETT)
Received: 10/24/2013
FOA: PAR13-278
Competition ID: FORMS-C
FOA Title: NINDS Phase III Investigator-Initiated Efficacy Clinical Trials (U01)
1 U01 NS088034-01
Dual:
IPF: 1526402
Organization: UNIVERSITY OF VIRGINIA
Former Number:
Department: Neurology
IRG/SRG: ZNS1 SRB-G (74)
AIDS: N
Expedited: N
Subtotal Direct Costs
(excludes consortium F&A)
Year 1: 4,488,108
Year 2: 3,248,392
Year 3: 3,250,257
Year 4: 2,786,085
Year 5: 2,690,266
Animals: N
Humans: Y
Clinical Trial: Y
Current HS Code: 44
HESC: N
New Investigator: N
Early Stage Investigator: N
Senior/Key Personnel:
Organization:
Role Category:
Jaideep Kapur
The Rector and Visitors of the University
of Virginia
PD/PI
Robert Silberleit
University of Michigan
MPI
James Chamberlain
Children's Research Institute
MPI
Daniel Lowenstein
UCSF
Other (Specify)-co-leader, clinical
adjudication core
Shlomo Shinnar
Albert Einstein College of Medicine
Other (Specify)-co-leader, clinical
adjudication core
James Cloyd
University of Minnesota
Other (Specify)-leader, pharmacology
core
Elizabeth Jones
The University of Health Science Center
Houston
Other (Specify)-EFIC consultant
Mark Conaway
The Rector and Visitors of the University
of Virginia
Other (Specify)-Biostatistician
Nathan Fountain
The Rector and Visitors of the University
of Virginia
Other (Specify)-clinical adjudicator
Hannah Cock
St. George's University of London
Other (Specify)-clinical adjudicator
William Barsan
University of Michigan
Other (Specify)-NETT PI
Gerhard Bauer
University of California, Davis
Other (Specify)-GMP Manufacturing
Appendices
Informed consent,Availability of subjects,Sites,Protoco
Council: 05/2014
Accession Number: 3629773
OMB Number: 4040-0001
Expiration Date: 06/30/2016
APPLICATION FOR FEDERAL ASSISTANCE
3. DATE RECEIVED BY STATE
SF 424 (R&R)
1. TYPE OF SUBMISSION*
❍ Pre-application
State Application Identifier
4.a. Federal Identifier
● Application
❍ Changed/Corrected
b. Agency Routing Number
Application
2. DATE SUBMITTED
Application Identifier
c. Previous Grants.gov Tracking Number
5. APPLICANT INFORMATION
The Rector and Visitors of the University of Virginia
Legal Name*:
Office of Sponsored Programs
Department:
School of Medicine
Division:
PO Box 400195
Street1*:
Street2:
City*:
County:
State*:
Charlottesville
Albemarle
VA: Virginia
Province:
Country*:
ZIP / Postal Code*:
USA: UNITED STATES
22904-4195
Organizational DUNS*: 065391526
Person to be contacted on matters involving this application
Prefix: Mr.
First Name*: Stewart
Middle Name: P.
Position/Title:
Street1*:
Street2:
Assistant Dean for Research Administration
PO Box 400195
City*:
County:
State*:
Charlottesville
Albemarle
VA: Virginia
Province:
Country*:
ZIP / Postal Code*:
USA: UNITED STATES
22904-4195
Phone Number*: 434-924-8426
Last Name*: Craig
Fax Number: 434-924-8725
Suffix:
Email: [email protected]
6. EMPLOYER IDENTIFICATION NUMBER (EIN) or (TIN)*
546001796
7. TYPE OF APPLICANT*
H: Public/State Controlled Institution of Higher Education
Other (Specify):
Small Business Organization Type
❍ Women Owned
❍ Socially and Economically Disadvantaged
8. TYPE OF APPLICATION*
If Revision, mark appropriate box(es).
● New
❍ Resubmission
❍ A. Increase Award
❍ Renewal
❍ Continuation
❍ Revision
Is this application being submitted to other agencies?*
9. NAME OF FEDERAL AGENCY*
National Institutes of Health
❍ B. Decrease Award
❍ C. Increase Duration
❍ D. Decrease Duration ❍ E. Other (specify) :
❍Yes
●No
What other Agencies?
10. CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER
93.583
TITLE: Refugee and Entrant Assistance_Wilson/Fish Program
11. DESCRIPTIVE TITLE OF APPLICANT'S PROJECT*
Established Status Epilepticus Treatment Trial (ESETT)
12. PROPOSED PROJECT
Start Date*
07/01/2014
Tracking Number: GRANT11508883
13. CONGRESSIONAL DISTRICTS OF APPLICANT
Ending Date*
06/30/2019
VA-005
Funding Opportunity Number: PAR-13-278 . Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
SF 424 (R&R) APPLICATION FOR FEDERAL ASSISTANCE
Page 2
14. PROJECT DIRECTOR/PRINCIPAL INVESTIGATOR CONTACT INFORMATION
Prefix: Dr.
First Name*: Jaideep
Middle Name:
Professor
Position/Title:
Organization Name*: The Rector and Visitors of the University of Virginia
Neurology
Department:
School of Medicine
Division:
PO Box 800394
Street1*:
Street2:
City*:
County:
State*:
Charlottesville
Albemarle
VA: Virginia
Province:
Country*:
ZIP / Postal Code*:
USA: UNITED STATES
22908-8394
Last Name*: Kapur
Suffix:
Phone Number*: 434-924-5312
Fax Number: 434-982-1726
15. ESTIMATED PROJECT FUNDING
16.IS APPLICATION SUBJECT TO REVIEW BY STATE
EXECUTIVE ORDER 12372 PROCESS?*
a. YES ❍ THIS PREAPPLICATION/APPLICATION WAS MADE
$21,388,532.00
AVAILABLE TO THE STATE EXECUTIVE ORDER 12372
$0.00
PROCESS FOR REVIEW ON:
$21,388,532.00
DATE:
$0.00
b. NO
❍ PROGRAM IS NOT COVERED BY E.O. 12372; OR
a. Total Federal Funds Requested*
b. Total Non-Federal Funds*
c. Total Federal & Non-Federal Funds*
d. Estimated Program Income*
Email*: [email protected]
● PROGRAM HAS NOT BEEN SELECTED BY STATE FOR
REVIEW
17. By signing this application, I certify (1) to the statements contained in the list of certifications* and (2) that the statements herein
are true, complete and accurate to the best of my knowledge. I also provide the required assurances * and agree to comply with
any resulting terms if I accept an award. I am aware that any false, fictitious, or fraudulent statements or claims may subject me to
criminal, civil, or administrative penalties. (U.S. Code, Title 18, Section 1001)
● I agree*
* The list of certifications and assurances, or an Internet site where you may obtain this list, is contained in the announcement or agency specific instructions.
18. SFLLL or OTHER EXPLANATORY DOCUMENTATION
File Name:
19. AUTHORIZED REPRESENTATIVE
Prefix: Mr.
First Name*: Stewart
Middle Name: P.
Assistant Dean for Research Administration
Position/Title*:
Organization Name*: The Rector and Visitors of the University of Virginia
Office of Sponsored Programs
Department:
School of Medicine
Division:
PO Box 400195
Street1*:
Street2:
City*:
County:
State*:
Charlottesville
Albemarle
VA: Virginia
Province:
Country*:
ZIP / Postal Code*:
USA: UNITED STATES
22904-4195
Phone Number*: 434-924-8426
Last Name*: Craig
Fax Number: 434-924-8725
Email*: [email protected]
Signature of Authorized Representative*
Stewart Craig
20. PRE-APPLICATION
File Name:
Suffix:
Date Signed*
10/24/2013
Mime Type:
21. COVER LETTER ATTACHMENT File Name:1273-Cover.pdf Mime Type: application/pdf
Tracking Number: GRANT11508883
Funding Opportunity Number: PAR-13-278 . Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
424 R&R and PHS-398 Specific
Table Of Contents
Page Numbers
SF 424 R&R Cover Page-----------------------------------------------------------------------------------------
1
Table of Contents-------------------------------------------------------------------------
3
Performance Sites---------------------------------------------------------------------------------------------
5
Research & Related Other Project Information------------------------------------------------------------------
12
Project Summary/Abstract(Description)-----------------------------------------------------
13
Project Narrative-------------------------------------------------------------------------
14
Facilities & Other Resources--------------------------------------------------------------
15
Other Attachments-------------------------------------------------------------------------
56
1271-IND_119756_Acknowledgment_Letter---------------------------------
56
1272-Milestone_Plan---------------------------------------------------
62
Research & Related Senior/Key Person--------------------------------------------------------------------------
65
Research & Related Budget Year - 1----------------------------------------------------------------------------
117
Research & Related Budget Year - 2----------------------------------------------------------------------------
120
Research & Related Budget Year - 3----------------------------------------------------------------------------
123
Research & Related Budget Year - 4----------------------------------------------------------------------------
126
Research & Related Budget Year - 5----------------------------------------------------------------------------
129
Budget Justification------------------------------------------------------------------------------------------
132
Research & Related Cumulative Budget--------------------------------------------------------------------------
152
Research & Related Budget Consortium Budget (Subaward 1)----------------------------------------------------
153
Research & Related Budget Consortium Budget (Subaward 2)----------------------------------------------------
170
Research & Related Budget Consortium Budget (Subaward 3)----------------------------------------------------
187
Research & Related Budget Consortium Budget (Subaward 4)----------------------------------------------------
204
Research & Related Budget Consortium Budget (Subaward 5)----------------------------------------------------
221
Research & Related Budget Consortium Budget (Subaward 6)----------------------------------------------------
239
Research & Related Budget Consortium Budget (Subaward 7)----------------------------------------------------
256
Research & Related Budget Consortium Budget (Subaward 8)----------------------------------------------------
274
Research & Related Budget Consortium Budget (Subaward 9)----------------------------------------------------
292
Research & Related Budget Consortium Budget (Subaward 10)---------------------------------------------------
310
Research & Related Budget Consortium Budget (Subaward 11)---------------------------------------------------
327
Research & Related Budget Consortium Budget (Subaward 12)---------------------------------------------------
344
Research & Related Budget Consortium Budget (Subaward 13)---------------------------------------------------
363
Research & Related Budget Consortium Budget (Subaward 14)---------------------------------------------------
380
Research & Related Budget Consortium Budget (Subaward 15)---------------------------------------------------
400
Research & Related Budget Consortium Budget (Subaward 16)---------------------------------------------------
418
Research & Related Budget Consortium Budget (Subaward 17)---------------------------------------------------
436
Research & Related Budget Consortium Budget (Subaward 18)---------------------------------------------------
454
Table of Contents
Page 3
Contact PD/PI: Kapur, Jaideep
Research & Related Budget Consortium Budget (Subaward 19)---------------------------------------------------
471
Research & Related Budget Consortium Budget (Subaward 20)---------------------------------------------------
488
PHS398 Cover Page Supplement----------------------------------------------------------------------------------
506
PHS 398 Research Plan-----------------------------------------------------------------------------------------
508
Specific Aims-----------------------------------------------------------------------------
509
Research Strategy-------------------------------------------------------------------------
510
Human Subjects Section--------------------------------------------------------------------
522
Protection of Human Subjects------------------------------------------
522
Women & Minorities----------------------------------------------------
533
Planned Enrollment Report---------------------------------------------
534
Children--------------------------------------------------------------
535
Multiple PI Leadership Plan---------------------------------------------------------------
536
Bibliography & References Cited-----------------------------------------------------------
537
Consortium/Contractual--------------------------------------------------------------------
545
Letters Of Support------------------------------------------------------------------------
546
Resource Sharing Plans--------------------------------------------------------------------
580
Appendix
Number of Attachments in Appendix: 4
Table of Contents
Page 4
Contact PD/PI: Kapur, Jaideep
OMB Number: 4040-0010
Expiration Date: 06/30/2016
Project/Performance Site Location(s)
Project/Performance Site Primary Location
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
The Rector and Visitors of the University of Virginia
Duns Number:
0653915260000
Street1*:
PO Box 800394
Street2:
City*:
County:
State*:
Charlottesville
Albemarle
VA: Virginia
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
22908-8394
Project/Performance Site Congressional District*:
VA-005
Project/Performance Site Location 1
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
The Regents of the University of Michigan
0731335710000
3003 S. State Street
Street2:
City*:
Ann Arbor
County:
State*:
MI: Michigan
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
48109-1274
Project/Performance Site Congressional District*:
Project/Performance Site Location 2
MI-012
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Brown University
0757109960000
593 Eddy Street
Street2:
City*:
Providence
County:
State*:
RI: Rhode Island
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
02903-4923
Project/Performance Site Congressional District*:
Tracking Number: GRANT11508883
RI-002
Page 5
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
Project/Performance Site Location 3
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
A. I duPont Hospital for Children of the Nemours
Foundation
0380049410000
1600 Rockland Road
Street2:
City*:
Wilmington
County:
State*:
DE: Delaware
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
19803-3607
Project/Performance Site Congressional District*:
Project/Performance Site Location 4
DE-001
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
University of Utah
0090953650000
75 South 2000 East
Street2:
City*:
Salt Lake
City
County:
State*:
UT: Utah
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
84112-8930
Project/Performance Site Congressional District*:
Project/Performance Site Location 5
UT-002
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Baylor College
0511133300000
One Baylor Plaza
Street2:
City*:
Houston
County:
State*:
TX: Texas
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
77030-3411
Project/Performance Site Congressional District*:
Tracking Number: GRANT11508883
TX-009
Page 6
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
Project/Performance Site Location 6
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
The Research Institute at Nationwide Children's
Hospital
1472129630000
700 Children's Drive
Street2:
City*:
Columbus
County:
State*:
OH: Ohio
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
43205-2664
Project/Performance Site Congressional District*:
Project/Performance Site Location 7
OH-003
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
The Trustees of Columbia University in the City of
New York
6218898150000
630 West 168th Street, Box 49
Street2:
City*:
New York
County:
State*:
NY: New York
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
10032-3702
Project/Performance Site Congressional District*:
Project/Performance Site Location 8
NY-013
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Regents of the University of California, Davis
0471200840000
1850 Research Park Drive, Suite 300
Street2:
City*:
Davis
County:
State*:
CA: California
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
95618-6153
Project/Performance Site Congressional District*:
Tracking Number: GRANT11508883
CA-003
Page 7
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
Project/Performance Site Location 9
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Wayne State University
0019622240000
5057 Woodward, Suite 13201
Street2:
City*:
Detroit
County:
State*:
MI: Michigan
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
48202-4051
Project/Performance Site Congressional District*:
Project/Performance Site Location 10
MI-013
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Regents of the University of Minnesota
5559179960000
200 Oak Street SE, Suite 450
Street2:
City*:
Minneapolis
County:
State*:
MN: Minnesota
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
55455-2070
Project/Performance Site Congressional District*:
Project/Performance Site Location 11
MN-005
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Medical College of Wisconsin
9376390600000
8701 Watertown Plank Road
Street2:
City*:
Milwaukee
County:
State*:
WI: Wisconsin
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
53226-3548
Project/Performance Site Congressional District*:
Project/Performance Site Location 12
WI-005
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
Cincinnati Children's Hospital Medical Center
Tracking Number: GRANT11508883
Page 8
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
DUNS Number:
Street1*:
0712849130000
3333 Burnet Avenue
Street2:
City*:
Cincinnati
County:
State*:
OH: Ohio
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
45229-3039
Project/Performance Site Congressional District*:
Project/Performance Site Location 13
OH-001
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
St. George's University of London
2321670980000
Cramer Terrace
Street2:
City*:
London
County:
State*:
Province:
Country*:
Zip / Postal Code*:
GBR: UNITED KINGDOM
SW17 0RE
UK
Project/Performance Site Congressional District*:
Project/Performance Site Location 14
UK-000
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
The University of Health Science Center Houston
8007715940000
7000 Fannin, UCT 1006
Street2:
City*:
Houston
County:
State*:
TX: Texas
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
77030-5401
Project/Performance Site Congressional District*:
Project/Performance Site Location 15
TX-009
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Albert Einstein College of Medicine
1105217390000
1300 Morris Park Avenue
Street2:
Tracking Number: GRANT11508883
Page 9
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
City*:
Bronx
County:
State*:
NY: New York
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
10461-1900
Project/Performance Site Congressional District*:
Project/Performance Site Location 16
NY-014
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
The Regents of the University of California, San
Francisco
0948783370000
3333 California Street, Suite 315
Street2:
City*:
San
Francisco
County:
State*:
CA: California
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
94143-6215
Project/Performance Site Congressional District*:
Project/Performance Site Location 17
CA-012
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Washington University
0685522070000
660 South Euclid Ave.
Street2:
City*:
St. Louis
County:
State*:
MO: Missouri
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
63110-1010
Project/Performance Site Congressional District*:
Project/Performance Site Location 18
MO-001
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
UT Southwestern Medical Center
8007715450000
5323 Harry Hines Blvd.
Street2:
City*:
Dallas
County:
Tracking Number: GRANT11508883
Page 10
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
State*:
TX: Texas
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
75390-9105
Project/Performance Site Congressional District*:
Project/Performance Site Location 19
TX-030
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
University of Pittsburgh
0045143600000
123 University Place
Street2:
City*:
Pittsburgh
County:
State*:
PA: Pennsylvania
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
15213-2303
Project/Performance Site Congressional District*:
Project/Performance Site Location 20
PA-014
❍ I am submitting an application as an individual, and not on behalf of
a company, state, local or tribal government, academia, or other type of
organization.
Organization Name:
DUNS Number:
Street1*:
Children's Research Institute
1439835620000
111 Michigan Avenue, NW
Street2:
City*:
Washington
County:
State*:
DC: District of Columbia
Province:
Country*:
Zip / Postal Code*:
USA: UNITED STATES
20010-2916
Project/Performance Site Congressional District*:
File Name
DC-098
Mime Type
Additional Location(s)
Tracking Number: GRANT11508883
Page 11
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
OMB Number: 4040-0001
Expiration Date: 06/30/2016
RESEARCH & RELATED Other Project Information
1. Are Human Subjects Involved?* ● Yes
❍ No
1.a. If YES to Human Subjects
Is the Project Exempt from Federal regulations?
❍ Yes
If YES, check appropriate exemption number:
If NO, is the IRB review Pending?
● Yes
● No
1
2
3
4
5
6
❍ No
IRB Approval Date:
Human Subject Assurance Number
2. Are Vertebrate Animals Used?*
❍ Yes
00006183
● No
2.a. If YES to Vertebrate Animals
Is the IACUC review Pending?
❍ Yes ❍ No
IACUC Approval Date:
Animal Welfare Assurance Number
3. Is proprietary/privileged information included in the application?*
❍ Yes
● No
4.a. Does this project have an actual or potential impact - positive or negative - on the environment?*
❍ Yes
● No
4.b. If yes, please explain:
4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an ❍ Yes
❍ No
environmental assessment (EA) or environmental impact statement (EIS) been performed?
4.d. If yes, please explain:
5. Is the research performance site designated, or eligible to be designated, as a historic place?*
❍ Yes
● No
❍ Yes
● No
5.a. If yes, please explain:
6. Does this project involve activities outside the United States or partnership with international
collaborators?*
6.a. If yes, identify countries:
6.b. Optional Explanation:
Filename
7. Project Summary/Abstract*
1267-Abstract_Final.pdf
Mime Type: application/pdf
8. Project Narrative*
1268-Project_narrative.pdf
Mime Type: application/pdf
9. Bibliography & References Cited 1269-References.pdf
Mime Type: application/pdf
10.Facilities & Other Resources
Mime Type: application/pdf
1270-Resources.pdf
11.Equipment
12. Other Attachments
Tracking Number: GRANT11508883
1271Mime Type: application/pdf
IND_119756_Acknowledgment_Letter.pdf
1272-Milestone_Plan.pdf
Mime Type: application/pdf
Page 12
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
Benzodiazepine-refractory status epilepticus (Established Status Epilepticus, ESE) is a
relatively common emergency condition with several widely used treatments. There are no
controlled, randomized, blinded clinical trials to compare the efficacy and tolerability of currently
available treatments of ESE. This and the accompanying Statistical and Data Management
Center (SDMC) application describe the ESE treatment trial (ESETT), which is designed to
determine the most effective and/or the least effective treatment of ESE among patients older
than two years by comparing three arms: fosphenytoin (FOS), levetiracetam (LEV), and
valproic acid (VPA). This is a multicenter, randomized, double-blind, Bayesian adaptive, Phase
III comparative effectiveness trial. Up to 795 patients will be randomized initially 1:1:1 and
response-adaptive randomization will occur after 300 patients have been recruited.
Randomization will be stratified by three age groups, 2-18, 19-65, and 66 years and older. The
primary outcome measure is cessation of clinical seizure activity and improving mental status,
without serious adverse effects or further intervention at 60 min after administration of study
drug. Each subject will be followed until discharge or 30 days from enrollment. This trial will
include interim analyses for early success and futility. This trial will be considered a success if
the probability that a treatment is the most effective is greater than 0.975 or the probability that a
treatment is the least effective is greater than 0.975 for any treatment. This will be the first
phase III clinical trial of ESE in children and adults.
Project Summary/Abstract
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Project Narrative
Status epilepticus (SE), consisting of prolonged seizures, is a neurological emergency that can
result in brain injury or even death. Patients in SE are initially treated with benzodiazepines, but
approximately 33% do not respond to these drugs; these patients are considered to have
established SE (ESE). ESE treatment trial (ESETT) seeks to determine which drug, among
Fosphenytoin, Levetiracetam and Valproic acid, is the most effective (or least effective) in
terminating ESE.
Project Narrative
Page 14
Contact PD/PI: Kapur, Jaideep
RESOURCES
University of VirginiaOffice: Dr. Kapur’s office is located in Cobb Hall room 2003. The building houses many resources for clinical
research. These include the Clinical trials office, office of translational research. Offices of clinical trials
coordinators for the Department of Neurology, the SHINE clinical trial group and the UVA NEUROnext clinical
coordinator offices are located in Cobb hall.
Offices for Program manager, ESETT Support Group (ESG), Research & administrative assistant and IT
specialist will be located in Cobb hall.
Ms Emily Gray Grant and Financial manager is located in the next building in McKim Hall. She has access to
all the software including institution wide Oracle- database for grant management.
Computer: All offices will be provided with computers, with appropriately loaded software to manage the trial.
The University has site licenses for most commonly used software. University provides fast internet access,
and is building large digital data storage (Big data) capabilities.
We have access to institutional IRB, which has experience with EFIC trials.
Please note that UVA is NOT a recruiting site.
Facilities & Other Resources
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University of Michigan
The following section highlights relevant resources of both the University of Miami and the Neurologic
Emergencies Treatment Trials (NETT) Network. The NETT resources include the NETT Clinical
Coordinating Center (NETT CCC), the NETT Hub Complexes, and resources at Northwestern University
available through the NETT CCC infrastructure award. The resources of the NETT Statistical and Data
Management Center (SDMC) are provided in the companion SDMC ARCTIC application.
The mission of the NETT is to improve outcomes of patients with acute neurologic problems through innovative
research focused on the emergent phase of patient care. The NETT Clinical Coordinating Center (NETT CCC)
is located within the Department of Emergency Medicine at the University of Michigan, a public institution with
a commitment to improving the public health by advancing medical research, providing excellent clinical care,
and educating the clinicians and investigators of the future. Dr. Barsan, the Principal Investigator, Dr.
Silbergleit, director of study operations management, and Drs. Will Meurer and Lewis Morgenstern, provide
leadership to the operations of the NETT CCC. The University of Michigan is uniquely positioned to function
as NETT Clinical Coordinating Center. The University provides an opportunity to collaborate with a plethora of
intellectually gifted scientists in an environment of cutting-edge technologies. The University has lent its full
support to our endeavors. A detailed description of the resources is provided below.
CLINICAL:
There are 865 inpatient beds in the University of Michigan Hospitals, and over 40,000 patient admissions per
year. The Emergency Department has 80,000 patient visits yearly. Emergency Medicine, Neurology, and
Neurosurgery have a strong clinical collaboration including a successful Stroke Program and JCAHO
certification as a Primary Stroke Center. The University has a long tradition of excellence in patient care and
U.S. News & World Report ranked the UM 17th overall in its honor roll of the nation's best hospitals in 2011.
ANIMAL:
N/A
COMPUTER:
Extensive computing resources throughout the medical campus and elsewhere in the institution provide
outstanding access to information resources, data analysis tools, and unprecedented connectivity to other
institutions. The medical library has among the most extensive collection of online references in the country.
The NETT CCC personnel utilize a combination of Dell Optiplex 745 and 620 Latitude machines, all with Intel
Core 2 Duo processors. Each NETT CCC computer utilizes Microsoft XP operating systems, and utilizes up to
date software packages including Adobe Creative Suite, Visio, and Microsoft Project. Computers are
connected to the University of Michigan computer network, high-speed internet access. The NETT network
website includes a virtual conference room for NETT study members. The virtual conference room is
supported by Adobe Acrobat Connect Professional. This software program allows for increased
communication and the ability to collaborate on study documents in real time.
OFFICE:
The NETT CCC is housed within a state of the art office suite in the Domino’s Farms office complex, which is
approximately four miles east of the UM Medical Campus. The office suite occupies 4000 sq. feet and
contains a two 4-in-one business machines, two photocopiers, three black-and-white and two color printers.
The NETT CCC includes investigators and research staff with full administrative and clerical support. The
conference room located in the suite is equipped with current video and tele-conferencing equipment, and
many internet connections. All NETT personnel are provided with a Dell computing station equipped with
necessary word processing, presentation, and data management software, high-speed internet access and Email. The office suite also provides secure, wireless internet access for NETT CCC staff.
Facilities & Other Resources
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Department of Emergency Medicine at the University of Michigan
The Department of Emergency Medicine was established in 1999, after being a Section in the Department of
Surgery prior to that. The Department has over 75 full time faculty members and is responsible for the
operation of 3 separate emergency departments: Adult ED at U. Michigan, Pediatric ED at U. Michigan, and
the Hurley Medical Center ED in Flint, Michigan. Over 160,000 patients are seen annually at all 3 sites. The
Department has established research programs in Neurological Emergencies, Injury Research, Pediatric
Emergency research (PECARN), Operations Management and Sepsis. The Department has been in the top 2
for NIH funding for Departments of Emergency Medicine for the past 4 years. Four emergency medicine
faculty are members of the multidisciplinary Brain Injury Group along with faculty from Neurology and
Neurosurgery. All acute stroke interventions are directed by members of the Brain Injury group.
Center for Rehabilitation Outcomes & Assessment Research (ROAR)
The Center for Rehabilitation Outcomes & Assessment Research (ROAR) within the Department of Physical
Medicine and Rehabilitation conducts studies that improve the assessment of health, functioning, and quality of
life (QOL) for individuals receiving medical rehabilitation. This laboratory was recently founded and currently
consists of an interdisciplinary group of four PhD level Professors and two MA level Research Associates.
The Center develops and validates new outcomes measurement instruments targeted for rehabilitation
populations. Current activities include a U-01 Roadmap project to test and validate the Patient Reported
Outcomes Measurement System (PROMIS) for children with disabilities, large scale measurement initiatives
including the NIH Toolbox for Neurological and Behavioral Functioning, the Neuro-QOL, a large 5-year,
collaborative R-01 (NICHD and NINDS) to develop a patient reported outcomes measurement system for use
in SCI research and practice, and a collaborative SCI Model System grant to develop a measure of functional
ability and activity limitations for individuals with SCI. ROAR also has funding from the National Institute on
Disability and Rehabilitation Research (NIDRR) to develop a similar patient reported outcomes measurement
system for individuals with Traumatic Brain Injury as part of the TBI Model Systems Program and NIDRR’s
Field Initiated Research grant program. The project is designed to adapt and validate the NIH Toolbox for use
in clinical rehabilitation populations (e.g., SCI, TBI, and Stoke). ROAR is housed in the newly acquired North
Campus Research Complex that consists of 30 buildings encompassing nearly 2 million square feet of
sophisticated laboratory facilities and administrative space.
Online Education and Collaboration Tools
The UM has the most advanced and adaptable online education systems available to learners on-campus and
around the world, through as a partner in the Sakai project, the result of many years of collaboration working in
partnership with Indiana University, MIT, Stanford, the uPortal Consortium, and the Open Knowledge Initiative
(OKI). Other online efforts have been organized directly through the UM health system. The resulting tools
available to this network are the CTools, UM.Lessons, MLearning, and Program for Education and Evaluation
in Responsible Research and Scholarship (PEERRS) which facilitate web-based education training for trials
conducted within the NETT network.
Current NETT education modules include:
Facilities & Other Resources
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NETT Hub Complexes
The NETT network has acknowledged the importance of enrolling patients in both large academic centers and
community hospital emergency departments. The NETT employs a multi-center “hub and spoke” model for
study conduct and recruitment. Regional academic hubs located in tertiary care facilities in the region provide
the research, training, and clinical infrastructure for the spokes, i.e. nearby collaborating community hospitals
with investigators but without full time research staff or advanced care capabilities. Each of the NETT hub
complexes, with an average of five regional spokes, was chosen through a competitive funding mechanism of
the NIH. Each hub complex has identified resources and satisfied the question of their ability to conduct
research in the competitive application process.
Each hub complex offers computers and internet access, twenty first century laboratory facilities, point-of-care
testing instruments, and adequate office space for research study staff. Each hub complex employs
experienced research coordinators within the various research divisions of the hub complex. Additional
responsibilities of the research coordinators include verification of patient enrollment and data collection
processes. The NETT shared resource pool means we avoid the need to employ study-specific individuals to
screen and enroll patients over the enrollment period of a clinical trial. The NETT hub complexes experience
over 5 million Emergency Department visits per year. Specific attributes and descriptions of clinical resources
for each hub complex are reported below.
1.
Hub Complex - Emory University, David Wright, MD, Principal Investigator
The NETT Southeastern Collaborative (NETT SEC) located at Emory University facilitates high-quality
clinical trials in a wide variety of neurological diseases (cerebrovascular disorders, epileptic seizures, acute
infections of the CNS, acute neuromuscular disorders and trauma) in adults or children. The NETT SEC
brings together an extensive array of high volume urban and sub-urban hospitals with a well-established
tract record of expertise and experience in conducting groundbreaking research in neurological
emergencies in a multiracial region. The hub complex has a strong relationship with the neurologists within
their hub complex. Dr. Frankel, a neurologist and co-investigator for the hub complex, has trained a
majority of the neurologists with whom they are collaborating.
2.
Hub Complex - Massachusetts General Hospital, Joshua Goldstein, MD, Principal Investigator
Massachusetts General Hospital (MGH) is the third oldest general hospital in the United States. It is a
1,057 bed tertiary care hospital. It is a Level I adult trauma, pediatric trauma, and burn center, with
approximately 47,000 inpatient admissions per year. The MGH Hub Complex includes Brigham and
Women’s Hospital, Beth Israel Deaconess Medical Center, Boston Medical Center, Children’s Hospital
Boston and Partners Healthcare. Partners Healthcare is an integrated health care system that offers
patients a continuum of coordinated high-quality care. It is one of the largest charitable diversified health
care organizations in the United States, and has the largest non-university-based, non-profit, private
medical research enterprise in the United States. Partners cares for 21% of the Eastern Massachusetts
population (1.3 million total patients per year). The communities served by Partners are socio-economically
diverse. The system also includes Boston EMS and Boston Medflight. All sites have 24/7 laboratory
facilities, 24/7 inpatient pharmacies, including a pharmacist available in-hospital 24/7.
3.
Hub Complex - Medical College of Wisconsin, Thomas Aufderheide, MD, Principal Investigator
The Milwaukee Regional Medical Center (MRMC), partnering with its major teaching affiliates, Froedtert
Memorial Lutheran Hospital (FMLH) and Children’s Hospital of Wisconsin (CHW), and other healthcare
providers on campus, comprise the State of Wisconsin’s largest regional medical center, serving
southeastern Wisconsin and Northern Illinois. The Milwaukee hub complex blueprint capitalizes on the
Medical College of Wisconsin’s enormous infrastructure and expertise as a major Regional Stroke Center
and deploys a cadre of collaborative centers, faculty, and community medical resources in emergency
medicine, the neurosciences (neurology and neurosurgery), interventional neuro-radiology, trauma surgery,
pediatrics, and related subspecialties, such as intensive and acute medicine, and physiatry.
Facilities & Other Resources
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4.
Hub Complex – New York Presbyterian Hospital, Stephan Mayer, MD, Principal Investigator
The Department of Emergency Medicine at New York-Presbyterian Hospital provides around the clock
expert care to 55,000 patients annually, about 13,000 of whom are subsequently admitted to inpatient
services. NYPH provides state-of-the-art evaluation and treatment for patients with a full spectrum of
emergency medical needs. The Children's Hospital at New York-Presbyterian also provides a level of
expertise and range of services and resources dedicated to children in need of emergency care.
5.
Hub Complex – Ohio State University, Michel Torbey, MD, Principal Investigator
The Ohio State University (OSU) Medical Center, one of the largest and most comprehensive medical
centers in the country that includes the College of Medicine and its schools of Allied Medical Professions
and Biomedical Science, six hospitals, more than a dozen research institutes and primary and specialty
care facilities throughout central Ohio. The Medical Center includes a unified physician practice;
representing more than 700 pre-eminent physicians and a network of community-based primary and
subspecialty care facilities that manage more than 900,000 patient visits each year. OSUMC provides
health care services to infants, children and adults through its 5 in-patient facilities and integrated network
of more than 30 community-based clinic and practices throughout Ohio. In 2010, more than 2,000,000
patient care contacts were made through the OSU Health Systems, reflecting the enormous potential for
clinical and translational research activity. Adjacent to OSU Medical Center is Ohio State’s James Cancer
Hospital and Solove Research Institute, a dedicated cancer hospital and research center with its own
governance structure separate from but coordinated with the Medical Center. Clinical studies that require
complex specimen collection and processing or unique patient testing requirements will be done in the
OSU CCTS directed Clinical Research Center Studies where data collection closely embeds in clinical care
will be performed in the clinical research space that is integrated within actual clinics within Departments of
Neurology, Neurological Surgery, and Physical Medicine and Rehabilitation.
6.
Hub Complex – Oregon Health and Sciences University, Robert Lowe, MD, Principal Investigator
Oregon Health & Science University (OHSU) has Schools of Medicine, Nursing, Dentistry, Pharmacy, and
Science & Engineering as well as a tertiary care hospital, dozens of primary care and specialty clinics,
children’s development and rehabilitation center, and 38 research and interdisciplinary centers. The OHSU
BRAINETT consortium includes four EDs with a combined annual census of 216,000 patient visits and was
formed specifically for NETT trials.. All BRAINETT investigators and staff have office space within their
departments.
7.
Hub Complex - Stanford University, James Quinn, MD, Principal Investigator
Stanford University is a private institution committed to improving public health through research and
excellent clinical care. Emergency medicine, neurology and neurosurgery all have strong clinical, teaching
and research departments. The neurology department has a nationally recognized stroke center and the
hospital is JCAHO certified stroke center. The Division of Emergency Medicine provides a dedicated team
of physicians, nurses and other health professionals to provide an extraordinary level of knowledge, skill
and compassion to every patient they serve. Stanford is a Level I Adult & Pediatric Trauma Center - the
highest level possible. Stanford University Medical Center is the only Trauma Center in our county with this
designation and verification; and serves as a regional trauma center for northern and central California, as
well as adjacent states.
Facilities & Other Resources
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8.
Hub Complex - State University of New York Downstate, Steven Levine, MD, Principal Investigator
The State University of New York (SUNY) Downstate Medical Center is within federally designated
underserved areas and serves a large minority population. The infrastructure of the Hub at SUNY
Downstate Medical Center, with joint experienced leadership from Emergency Medicine and Neurology,
has established 2 large spokes: Lincoln Hospital (south Bronx), serving primarily Hispanics, and
Maimonides Medical Center (Brooklyn), one of the largest independent teaching hospitals in the US. The
Hub Complex investigators and clinicians are experts in critical care, neurosurgery, Trauma, Stroke, and
Epilepsy Centers, Neuroradiology, Rehabilitation and Community Engagement/ Disparities Research. The
combined annual ED volume of over 350,000 visits, with over 3,500 neurological emergencies. Strengths
include the extremely diverse, large patient pool, extensive NIH clinical trials experience, detailed ED visit
data from all hospitals, acute telemedicine experience, expertise in exemption from informed consent, and
well-established, extensive community networks and engagement.
9.
Hub Complex - Temple University, Nina Gentile, MD, Principal Investigator
The Temple University Health System delivers health care on a region-wide basis through a network of
academic and community hospitals, medical school and community based physicians, nursing homes, and
home care services. Temple University Health System provides access to an exceptional group of
physicians in every specialty and primary care field. Temple is uniquely positioned to perform quality acute
care research and provide education in neurological emergencies. TUHS (Temple University Hospital,
Temple Children's Medical Center, Episcopal Hospital, and Northeastern Hospitals) and HUH are located
in North Philadelphia in predominantly African-American and Hispanic communities. More than 75% of the
community served by Temple University Hospitals is African– American and over 15% is Hispanic.
10.
Hub Complex - University of Arizona, Kurt Denninghoff, MD, Principal Investigator
The AzNETT includes an interdisciplinary team of emergency physicians, neurologists, neurosurgeons,
coordinators, program managers and information technologists with specific expertise in the conduct of
emergent clinical trials. Team members in both the hub complex and the 12 spoke sites have
demonstrated a long-term commitment to advancing the national research infrastructure as it relates to the
interdisciplinary study of emergent illness. The Hub Complex includes the University Medical Center,
Arizona's only academic medical center and Southern Arizona's only Level 1 Trauma Center.
11.
Hub Complex - University of California, Los Angeles, Jeffrey Saver and Sidney Starkman, MD,
Principal Investigators
The Los Angeles Neurological Emergencies Treatment Trials Hub and Spoke Network brings together a
consortium of 29 EMS Provider Agencies and 38 specialty receiving hospitals in the country's largest and
most diverse County in a Hub and Spoke network designed to perform phase 3 trials with high rates of
recruitment and participation of a substantial number of patients including women, Hispanic-Americans,
African-Americans, and other minority populations. In Los Angeles, the hospitals in the proposed Hub and
Spoke Network will care for over 95,000 acute neurologic emergency patients during the 5 year Award
Cycle.
12.
Hub Complex - University of California, San Francisco, Claude Hemphill, MD, Principal
Investigator
Patients in the SF-NET are cared for by prehospital paramedics, emergency physicians and other
emergency personnel, critical care, neurology and neurosurgery physicians. Each hospital involved in the
network has an emergency department, CT scanners, operating rooms, and an intensive care unit capable
of providing appropriate care. The team of investigators coordinating SF-NET represents clinical care and
clinical research experts across specialties pertinent to the treatment and study of neurological
emergencies.
Facilities & Other Resources
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13.
Hub Complex - University of Cincinnati, Arthur Pancioli, MD, Principal Investigator
The Department of Emergency Medicine is nationally and internationally renowned after decades of
academic productivity and leadership. The hub complex was built on prior experience with a highly
effective, scalable hub and spoke system based out of the University of Cincinnati College of Medicine.
The key elements of this structure include an interdisciplinary team of emergency physicians, neurologists,
neurosurgeons, neuroradiologists, physiatrists, pre-hospital providers, pediatricians, trauma surgeons, and
intensivists all with specific expertise in the conduct of emergent clinical trials. The UC hub complex
system has tremendous enrollment capabilities and specifically has the ability to enroll patients in both our
large academic center as well as our community hospital emergency departments. The Hub Complex
structure is able to capture the entire span of the patient demographic as well as the gamut of neurological
disease processes.
14.
Hub Complex - University of Kentucky, Roger Humphries, MD, Principal Investigator
The University of Kentucky (UK) is a public, state-assisted institution located in Lexington, Kentucky. The
Chandler Medical Center is one of only 10 academic health centers nationwide composed of all six schools
of the health professions: dentistry, medicine, nursing, pharmacy, health sciences, and public health.
Research faculty, staff, and students are involved in more than 2,000 externally funded sponsored projects
each year in addition to countless numbers of scholarly research projects throughout the university's 16
academic and professional colleges. The hub complex encompasses six non-urban affiliate spoke
hospitals located in rural environments will be participating in the UK NETT Clinical Site Hub.
15.
Hub Complex - University of Maryland, Barney Stern, MD, Principal Investigator
The University of Maryland Medical Center (UMMC) has comprehensive clinical services, as expected of a
tertiary, academic health center. The UMMC is a major referral center in the mid-Atlantic region. Within
the Shock Trauma facility is a 12-bed neurotrauma ICU and a 12-bed neurotrauma intermediate care unit.
UMMC also houses a NIH-funded GCRC and has a research pharmacy. The University of Maryland hub
has 11 spoke hospitals including the world-renowned Johns Hopkins University School of Medicine, Johns
Hopkins Hospital (JHH) and Johns Hopkins Bayview Medical Center (JHBMC).
16.
Hub Complex - University of Minnesota, Michelle Biros, MD, Principal Investigator
The Minnesota Hub is directed by the Department of Emergency Medicine, with support from the
Department of Neurology, and other neuro-clinicians, intensivists, trauma surgeons, pediatricians and
primary care providers. The Spoke leadership also consists of Emergency Medicine physicians, with the
support of local neurologists, neurosurgeons and primary care physicians. The University of Minnesota
hospital laboratories have research readiness and can be contracted to process and run or store and ship
specimens to the NETTS Coordinating Center, if required by the specific research protocol. All Spokes
have 24-hour lab facilities to run routine tests. All have lab capabilities to process store and ship
specimens that require special testing. The Hub Principle Investigator Dr. Michelle Biros, and the hub coInvestigator is Dr. David Anderson, facilitate personnel education on basic research concepts, issues of
protection of human subjects in research, and specifics related to each study protocol.
17.
Hub Complex - University of Pennsylvania, Jill Baren, MD, Principal Investigator
The Hospital of the University of Pennsylvania (HUP) is a Level 1 Trauma Center. There is a CT scanner
directly adjacent to the ED. All patient rooms have critical care monitoring capabilities and can
accommodate patients with any medical or surgical neurological emergency. The nursing staff is clinically
well trained and many have previous experience working in other critical care units. Department of
Neurology is the oldest in the country, founded in 1871. It has a long tradition of excellence in neurological
care, neurological research, and neurological education in both adult and pediatric neurology. The
Department of Neurology at the University of Pennsylvania comprises over 60 faculty specializing in all
areas of neurology, specifically including stroke, neurocritical care, epilepsy, neuromuscular disease,
demyelinating disease, neurovirology/encephalitis, and headache, both in adults and in children.
Facilities & Other Resources
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18.
Hub Complex - University of Pittsburgh, Clifton Calloway, MD, Principal Investigator
The University of Pittsburgh Medical Center (UPMC) is one of the largest and most diverse non-profit
integrated healthcare delivery and financing system in the nation with a network of 20 hospitals and 30
outpatient physical rehabilitation facilities. The UPMC inpatient facilities include a major academic and
tertiary hub, specialty facilities (Magee-Women’s Hospital, UPMC Rehabilitation Hospital, Western
Psychiatric Institute and Clinic, Eye and Ear Institute, and Children’s Hospital), and community hospitals.
The UPMC health system has approximately 4,200 licensed beds and 2,800 beds in service, with an
approximate annual volume of 187,000 admissions. The UPMC primary service area includes the 29
counties of western Pennsylvania, with a population base of 4.2 million people. Close to 4 million outpatient
visits occur yearly in the academic and community practices, with more than 750,000 specialty visits occur
in specialty practices. UPMC provides an excellent setting for studying large and varied patient populations
including NIH priority populations.
19.
Hub Complex - University of Texas-Houston, Elizabeth Jones, MD, Principal Investigator
University of Texas (UT)-Houston Department of Emergency Medicine is committed to improving our
specialty through evidence based medicine, innovative research, clinical excellence, and promoting
collaboration among faculty and colleagues at the University of Texas, and to focus on the clinical
strengths of our three emergency departments; the Harris County hospital, LBJ Hospital, and our level one
trauma center, the Memorial Hermann Hospital. The Department's clinical researchers established a
Departmental Research Focus. The purpose of this focus is to provide a singular mission for the
development and execution of research within the Department. Resources and personnel may then be
more effectively positioned for the benefit of the residents, faculty and students engaged in research.
20.
Hub Complex – Virginia Commonwealth University, Joseph Ornato, MD, Principal Investigator
Virginia Commonwealth University Medical Center (VCUMC) boasts the first designated Level I Trauma
Center in the state of Virginia (in 1981), among a current total of five. It is the only state-designated Level I
Trauma Center in the Central Virginia region. Trauma patients requiring admission may arrive by ground
transport (e.g., EMS services) or by rotor-wing aircraft. VCUMC’s air transport, LifeEvac, has been
operating since spring 2001, and additional air ambulance service (Medflight) through the state police.
Specialized training and credentialing for nurses, EMS personnel, and physicians are available, as well as
training for paramedics through VCUMC’s credentialed EMT-Paramedic Program. The Neuroscience ICU
at the VCUMC contains 14 beds dedicated to brain and spinal cord injury and is shared by neurosurgery
and neurology. The Department of Physical Medicine and Rehabilitation (PM&R) offers comprehensive inpatient and outpatient rehabilitation for the residual effects of an acute neurological injury.
21.
Hub Complex - Wayne State University, Robert Welch, MD, Principal Investigator
The Detroit Medical Center (DMC) is the leading academically integrated delivery system in metropolitan
Detroit and the largest health care provider in southeast Michigan. The DMC has more than 2,000 licensed
beds, 3,000 affiliated physicians, and is the teaching and clinical research site for Wayne State University
School of Medicine, the nation’s fourth largest medical school. Our medical experts are nationally
recognized and have a reputation for excellence. Patients are drawn to our world-class in neurosciences,
stroke treatment and rehabilitation. The DMC continues to meet the health care needs of a growing
community. The DMC, consisting of Children’s Hospital of Michigan, Detroit Receiving Hospital, Harper
University Hospital/Hutzel Women’s Hospital, Huron Valley-Sinai Hospital, and Sinai-Grace Hospital, offer
the best in medical research and development, advanced technology and optimum clinical services.
Facilities & Other Resources
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Northwestern University
The Department of Medical Social Sciences (MSS) at Northwestern University receives funding to serve as a
standing NETT resource to assist with the design and collection of patient reported outcomes in NETT clinical
trials. The MSS conducts multidisciplinary health outcomes management and patient-centered clinical
research at Northwestern University’s Feinberg School of Medicine. Established in March, 2009 under the
direction of Dr. David Cella, MSS aims to establish itself as a leader in advancing and applying
outcomes/effectiveness research to improve patient care and influence policy. MSS bridges clinical activity and
health outcomes research across multiple Departments, Centers and Institutes at Northwestern University.
Strong academic ties make possible comprehensive and state-of-the-art health outcomes development and
assessment activity, including collaborations in disease management, prevention and control that utilize
innovative health information technology applications. MSS provides faculty with opportunities to interact with
many successful clinical investigators and with multiple venues to conduct his clinical research activities. All
MSS investigators are fully integrated into its administrative and educational pursuits. MSS is comprised of
approximately 14 doctoral level scientists (PhDs), 12 Master’s level senior and junior staff, 15 Bachelor’s level
staff and several administrative personnel with educational and research backgrounds in health and social
psychology, behavioral science, medical sociology, health economics, psychometrics, biostatistics, and
information technology. MSS has a large centralized library of over 350 individual outcomes measures as well
as a centralized literature bank of well over 8,000 publications available for researchers’ use.
Facilities & Other Resources
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Children’s Research Institute
Division of Emergency Medicine
Children’s National Medical Center (CNMC) is the Department of Pediatrics for the
George Washington University School of Medicine and Health Sciences. Children’s
Hospital is the 280-bed acute care hospital of CNMC, serving as the major pediatric referral
center for the Washington, DC metropolitan region and the southern half of Maryland. The
Emergency Medicine and Trauma Center (EMTC) at Children’s National is among the
largest free-standing pediatric emergency departments (EDs) in the nation. The EMTC
has an annual volume of >100,000 visits and accounts for >70% of all admissions to
Children’s National (including nearly 1000 annually for asthma alone). With > 1200
trauma admissions annually, it is the designated pediatric trauma center for the District of
Columbia and one of two pediatric trauma centers for the State of Maryland.
There is a 34-bed PICU. The dedicated pediatric transport team brings over 5000
children annually from other regional hospitals. The ED patient population is
predominantly minority & Medicaid. Patients cared for by subspecialists include
suburban and rural patients referred from a catchment area of approximately 90 miles
radius. The Division of Emergency Medicine is the largest clinical division in the
Department of Pediatrics, with 32 faculty, 9 fellows, and over 50 pediatricians providing
clinical care. All pediatric subspecialties are represented. The EMTC faculty includes
nine federally funded investigators and a long record of academic productivity and
mentoring and includes national experts in risk adjustment, genomics and proteinomics,
health services research and delivery, and injury prevention.
Clinical Research Institute
The Children’s Research Institute (CRI) is the research arm of Children’s National.
Faculty members involved in funded research carry titles as Investigators in one of CRI’s
6 interdisciplinary research centers; those with clinical responsibilities also are members
of a clinical division within Children’s National. CRI is physically located on 5 floors of
the main hospital building, encompassing 120,000 sq. ft. of space, of which
approximately 90,000 is laboratory space, and the remainder faculty offices, the research
animal facility and clinical research unit. CRI has its own Board of Trustees, and all
external grants are administered through CRI offices.
Children’s National consistently ranks among the top 10% of Departments of
Pediatrics/Children’s Hospitals in terms of NIH funding. CRI currently holds a grant
portfolio in excess of $52 million/year, $38 million of which comes from the NIH. This
represents a seven-fold increase in NIH funding in the past 10 years, and a four-fold
increase in overall funding in the last 10 years. This funding is divided almost equally
between clinical and translational research, with particular strengths in multidisciplinary
teams in five areas: 1) neuroscience and behavioral medicine; 2) genetic medicine; 3)
cancer and immunology; 4) clinical trials and experimental therapeutics; and 5)
community research. Examples include NIH Center grants held by Children’s National
investigators: Rare Diseases Clinical Research Center (RDCRC), Wellstone Muscular
Facilities & Other Resources
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Dystrophy Research Center, Center for Research in Child Health Disparities,
Collaborative Pediatric Critical Care Research Network (CPCCRN), Pediatric
Pharmacology Research Unit, Intellectual and Developmental Disabilities Research
Center (IDCRC), and the Pediatric Emergency Medicine Applied Research Network
(PECARN).
Clinical activities at Children’s National are organized into six interdisciplinary
Clinical Centers: Primary Care, Hospital-based Specialties, Neuroscience and Behavioral
Medicine, Surgical Care, Heart and Lung, and Cancer and Blood Disorders. Each of
these Centers is led by a pediatric faculty member with funded research activities. These
Centers have a natural affinity for the six CRI interdisciplinary Research Centers:
Cancer/Immunology/Cell Biology; Genetic Medicine; Neuroscience; Clinical and
Community Research Molecular Physiology; and Surgical Research. This arrangement
has led to enhanced translational research opportunities.
The George Washington University (GWU) and Children’s National have been
affiliated for over three decades, with Children’s National serving as the Department of
Pediatrics for GWU, and its faculty holding full-time faculty appointments. Founded in
1821, the GWU School of Medicine and Health Sciences (SMHS) includes four
programmatic areas: the School of Medicine, the Department of Clinical Management
and Leadership, the Department of Health Care Science, and the Department of Nursing
Education. Although not primarily recognized for its clinical research, GWU SMHS has
impressive strengths in mechanistic biomedical research (T1), and there are already
strong educational programs integrating Children’s National with basic science
departments at GWU, exemplified by the multidisciplinary Institute for Biological
Sciences and by the recently developed Department of Integrative Systems Biology at
GWU, sited at Children’s National. The GWU SPHHS provides an educational program
distributed across seven departments with its faculty members bringing nationally
recognized expertise in methods of community and health services/policy research
(T2/T3).
Core Laboratories at Children’s National--Through the Translational Technologies and
Resources Component of Children’s CTSA, investigators have access to a host of
translational core laboratories at Children’s National.
Cores Made Available through the CTSI.
CORE
FUNCTION/TECHNOLOGY
Research Animal
Facility (RAF)
The RAF currently is a 7000 sq.ft. predominantly rodent facility with a 3000 cage
limit. It is being expanded to 12,000 sq. ft., increasing caging capacity to 7000
and with a new imaging facility to be completed in Dec. 2011. The RAF provides
space, equipment, and care of laboratory animals that is AALAC accredited and
fully compliant with federal regulations.
Exceeds CDC/NIH guidelines for laboratory research with hazardous agents
capable of respiratory transmission; suitable for conversion to a BSL-3 facility.
The services are broad (covering most aspects of DNA, RNA, protein, and
molecular bioinformatics) but highly integrated. All personnel and equipment are
housed in the Research Center for Genetic Medicine on the fifth floor of
Children’s National/CRI. The goal of the core is to provide access to expertise in
molecular/genomic technologies and bioinformatics. We provide research
resources, training and collaborative opportunities in highly parallel and/or high
BSL-2 plus facility
Genomic/Proteomic
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Preclinical Imaging
Bioanalytic
Flow cytometry
Translational
Pathology Core
Cellular Imaging
throughput DNA, mRNA, and proteomics methods. In addition, we provide
translational bioinformatics expertise to integrate molecular and clinical data.
Both private and public interfaces are designed and supported.
The preclinical (animal) imaging core supports protocol development, imaging
strategy consultation, post processing analysis, image interpretation, reporting,
and archiving. Equipment includes In-Vivo High-Resolution Ultrasound, ATR
Fluorescence Imager, PET/SPECT/CT, Fluorescence Imaging,
Bio-Luminescence Imaging, 7T MRI Scanner
Tandem mass spectrometry and HPLC technology for analyte evaluation-includes
3TMS and 4HPLCs
The two state-of-the-art TM
instruments that we currently
utilize are the Becton
TM
Dickinson FACS
Calibur
and
Cytopeia
Influx
High
speed Cell Sorter. The
FACSCaliburTM supports a wide variety of applications in research environments
such as cell cycle analysis, intracellular cytokine production. The Cytopeia
inFlux™ sorter has very high sensitivity and can analyze cells at speeds greater
than 200,000 events per second.
The goal of the core is to provide resources, support and training for tissue based
research requiring human or animal tissue processing, staining, cryosections,
immunohistochemistry, in situ hybridization, digital slide
imaging for morphometric or archival purposes and laser capture
microdissection. The core staff also supports the training of research personnel in
the development of new assays. Quality control of assays is provided by
pathology faculty.
Provides access to a 3 multiphoton microscope system. The infrared ultra-fast
pulse laser enables deep imaging in living tissue without phototoxic effects
inherent to visible laser or confocal microscope systems
The Center for Translational Science includes over two dozen faculty members from a
variety of backgrounds in clinical and health services research. They range from pediatric
sub-specialists to generalists to psychologists and social scientists. They study a wide range
of pediatric health issues.
Our investigators pursue studies in numerous areas united by one or more of the
following themes: (1) identifying the means by which the organization and delivery of
health-care are related to its effectiveness; (2) improving the quality of health-care for
children, with a special attention on improving health disparities experienced by urban and
disadvantaged populations; and (3) characterizing the circumstances, behaviors, risk status,
and health/mental health of children and families in the context of their communities.
Multi-center collaborations are aimed at improving healthcare across the spectrum
of clinical care from the inpatient setting to the community:
• Pediatric Emergency Care Applied Research Network (PECARN).
Led at CNMC/CRI by James Chamberlain, MD, WBCARN (Washigton Boston
Chicago Applied Research Network) is one of 6 nodes that comprise a larger
national network called the Pediatric Emergency Care Applied Research Network
(PECARN). Funded by an EMSC- Network Development Demonstration
Program cooperative agreement awarded in 2001 and renewed in 2005 and 2011,
the goal of this network is to provide a framework for conducting meaningful and
rigorous pediatric research on the prevention and management of acute illness and
injury in children.
WBCARN Nodal Structure. The CARN node is made up of 1 research node
center and 2 regional hospital emergency department affiliates (HEDAs)
Children’s National Medical Center serves as the research node center for the
following HEDAs- Boston Children’s Hospital and Lurie Children’s Hospital in
Chicago. WCARN hospitals collectively serve over 225,000 patients per year.
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Patients served by these hospitals represent a broad range of racial and ethnic as
well as socio-economic backgrounds.
WBCARN has a dedicated research coordinator for each of its HEDAs who is
centrally overseen by the nodal administrator for PECARN and the nodal
manager for WBCARN based at Children’s National Medical Center. There is
research coverage for WBCARN-related research up to16 hours per day,
depending on the needs of PECARN studies being conducted at each site.
WBCARN research coordinators receive site-specific and research-specific
training for each of the research protocols for which they are responsible as well
as generalized training on Human Subjects Protections and Good Clinical
Practice. WBCARN has a quality assurance plan that calls for the WBCARN
nodal manager to conduct a site monitoring visit of each of the WBCARN sites
twice per year.
•
•
•
Collaborative Pediatric Critical Care Research Network (CPCCRN). Led at
CNMC/CRI by its Site Principal Investigator David Wessel and formerly by
Murray Pollack, this NIH-funded collaborative research network of six premier
pediatric ICUs has been funded to investigate the pathophysiology of pediatric
critical illness and potential therapies best studied in a multi-institutional context.
Initially, CNMC has focused on two aims that are major needs of PICUs as well as
pediatrics. Aim 1 is to develop and to validate a rapid and reliable measure of
functional status applicable to all ages of children. This aim has been successfully
completed and will enable the inclusion of morbidity in large-scale pediatric
studies. Aim 2 is to develop a predictor of three PICU outcomes: death, survival
with low functional status, and survival with adequate functional status. This Aim
is scheduled for study in the near future. Completion of Aim two will result in a
paradigm shift in the way we can compare medical care and outcomes across
different institutions. The network has sponsored an additional four projects since
January 2006: a core data project, two bereavement studies, and a prevention trial in
stress-induced immune suppression.
Washington-Baltimore Center to Improve Child Health Disparities. Funded by the
NIH and led at CNMC by Denice Cora-Bramble, MD, MBA, this program is
designed to build a multi-disciplinary center addressing three problems broadly
affecting disadvantaged children, particularly those of color, in the Washington,
DC, metro region: violence exposure, substance abuse, and obesity/Type II
diabetes. In addition, core facilities within the Center provide a variety of services
to junior investigators as well as training/mentoring to junior investigators who are
themselves minorities or who are investigating issues pertinent to health disparities.
Inner City Asthma Consortium (ICAC). With support from the National Institute of
Allergy and Infectious Diseases (NIAID), the ICAC consists of ten national sites
and provides infrastructure for investigator-initiated studies of multiple clinical and
translational aspects of immuno-monitoring and immuno-therapy among urban,
disadvantaged, and largely minority children with moderate to severe asthma. Led
at Children’s National by Dr. Teach, the ICAC provides biostatistical and
operational support to its Steering Committee, a group of 15 principal investigators
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Contact PD/PI: Kapur, Jaideep
who plan and implement its studies. Recently completed efforts include an analysis
of obesity as a determinant of the inflammatory response in asthma, the role of
exhaled nitric oxide in asthma management, and the role of an IgE-blocking
antibody in the management of children and adolescents with asthma and
documented perennial allergies.
Pediatric Clinical Research Center at CNMC--In 2000, when the GCRC of Children’s
National was first funded by NCRR, it contained 2 patient rooms, an infusion room, a
sample preparation room, a small conference room, and GCRC staff offices, totaling
3,205 sq ft. In preparation for implementing the Clinical Translational Science Award,
awarded to CNMC in July, 2010,(detail provided below), CNMC recently renovated a
unit contiguous to the existing GCRC space at a cost of over $1 million to serve as a
5,880 sq ft. inpatient and outpatient unit of the new PCIR. This added 3 new patient
treatment rooms, 2 patient interview rooms, a full nursing station, a conference room, a
second specimen processing area, and a patient/family waiting room. Additional rooms
now house an array of testing equipment including a BOD POD® (air displacement
plethysmograph), Ultima CardiO2™ metabolic cart and treadmill (energy expenditure
studies at rest and VO2 maximum), a spirometer and exhaled nitric oxide detector, and
the Quantitative Measurement System for muscle strength.
This new space and the increased number of nurses and research assistants permit
the PCIR to support a larger number of diverse and complex on-site studies.
Collectively, the PCIR research staff at CNMC GCRC includes a Director of Research
Nursing, a Nurse Manager, 2 research nurse practitioners, 2 research nurses, 3 research
assistants, and a bionutritionist.
Clinical research nursing has been established recently as an institution-wide CNMC
Nursing Competency. Already, selected clinical nurses in CNMC's Regional Outpatients
Clinics have been trained in principles of research nursing and nursing research. This
will support their participation in participant recruitment and research interactions with
participants at sites conveniently located for patient families. Inpatient and outpatient
nurses who have completed the required research competencies will be able to collect
data or obtain timed specimens as required by the research protocol, while being attentive
to the standards for the responsible conduct of research. In addition, nursing research is
being promoted throughout the hospital with a total of 18 nurse-led, IRB-approved
studies now in process. Nurse investigators will also be supported to develop and
implement studies which they lead. For example, this year a nurse-led, federally funded
multi-site investigation is examining the ability of children and adolescents to complete
web-based questionnaires about symptoms and disease signs.
Clinical and Translational Science Institute--In July 2010, Children’s National Medical
Center was awarded the prestigious Clinical and Translational Science Award (CTSA)
grant, from the National Center for Research Resources (NCRR), to establish the Clinical
and Translational Science Institute at Children’s National (CTSI-CN). This is the first,
and to date, only, such funding awarded directly to a freestanding children’s
hospital and recognizes our outstanding strengths in clinical and translational
research. The CTSI-CN collaborates with investigators from diverse schools and
programs at George Washington University, our partner in the award. In addition, RTI
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International is providing specialized expertise in evaluation to support the CTSI-CN.
Resources of the CTSI-CN are wide-ranging and include, for example, genomic
capabilities supporting mechanistic translational investigators, biostatistical and study
design assistance, pilot funding, community engagement, and clinical research nursing
and study support. All the capabilities of the CTSI-CN can be accessed through a system
of guides and an investigator portal (PIBEAR) being rapidly implemented in the first
months of funding. A prominent feature of the CTSI-CN is the expansion of clinical and
translational research education and training. The Mentored Career Development
Component (KL2) of the CTSA grant is supporting research career development of
clinical researchers who have recently completed professional training and who are
commencing basic, translational and/or clinical research. The goal of CTSA KL2
component is to foster the discipline of clinical research and to expedite clinical and
translational research. In addition, it provides curricular, mentoring, and research support
for trainees in all clinical and translational research training programs, and offers a
Masters Degree in Clinical and Translational Science through George Washington
University, the first in the Washington, DC, area.
Facilities & Other Resources
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UCSF
UCSF Epilepsy Center
Dr. Lowenstein has his own dedicated office that includes computers, internet connection,
phone lines, printer, and other standard equipment and supplies. Clinical research space
includes four research fellow cubicles in which each have computers, wireless internet, and
access to all standard desktop research equipment and supplies. Also, two 400 sq. ft. rooms for
clinical research personnel, and that include computers, printers, phones and a small
conference room.
UCSF Office of Research
This office provides effective and efficient infrastructure for scientific research at UCSF. It
provides guidance and oversight of all regulatory aspects of research, including conflict of
interest and environmental health and safety. It ensures that UCSF adheres to high ethical
standards in the conduct of research and meets the federal, state, and municipal regulations.
The Office also assists researchers in obtaining extramural funds and manages intellectual
property.
UCSF Library
GALEN is the Digital Library of the University of California San Francisco. PubMed@UCSF is
publicly available, but access to full text articles is limited to computers on the UCSF network or
approved offsite computers. It provides access to MEDLINE database and other NLM
databases, and is strong in areas of clinical and basic sciences, nursing, dentistry, and health
care planning and administration from 1966 to the present. References published between 1958
and 1965 can be viewed through OLDMEDLINE. The MELVYL Catalog is used to locate books
at all UC libraries, and California Periodicals to find journals/titles at other UC, CSU and
California libraries. Many other important databases are available, including Current Contents,
BIOSIS, and PsycINFO. The library also houses the Center for Tobacco Control Research and
Education (CTCRE), is a campus-wide center that provides a focal point for work of 30 faculty
members from all four schools at UCSF and the School of Public Health at University of
California, Berkeley. The work of the Center spans policy and historical research, economics,
public health interventions, basic science (particularly around secondhand smoke and nicotine
pharmacology) and clinical interventions.
Computer Resources
Computer staff members develop and maintain the School’s computing infrastructure and carry
out the School’s programming needs, including web page construction and maintenance, and
statisticians provide analytical and design consultation. Information Technology Services
provides a campus-wide high-speed network infrastructure, which allows investigators to access
a wide variety of computing technologies. Because the UCSF campus is geographically diverse,
ITS uses a high speed SONNET Ring backbone infrastructure to allow virtually instantaneous
access to campus computing resources from any campus location, including a number of
clinical facilities affiliated with UCSF. The computing capabilities of the campus are constantly
growing and expanding. Computing resources are conveniently located throughout the campus. Facilities & Other Resources
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Montefiore Medical Center/Albert Einstein College of Medicine
Clinical: Montefiore Medical Center is a tertiary care hospital which is the University Hospital for the Albert
Einstein College of Medicine. It has a separate Children’s hospital with its own busy emergency room, a 14
bed PICU and a 10 bed (6 children and 4 adult) epilepsy unit. There are 9 child neurologists, 6 of whom have
specific expertise and additional training in epilepsy. Montefiore’s intensivists and pediatric neurologists are
experienced in managing status epilepticus and receive patients with this condition from surrounding
community hospitals. There are child neurologists on call at all times to manage neurological emergencies,
including seizures. Pediatric neuropsychologists are available to test children both clinically and in research
protocols. There is an active and fully equipped EEG laboratory. The division of Neuroradiology has two 1.5
Tesla GE MRI systems and a 3.0 Tesla Philips machine with enhanced capabilities for research. The 1.5
Tesla machine is GE Sigma LX MRI system (LX software Release 8.3) with an echo speed gradient system.
The staff has expertise performing and interpreting pediatric MRIs in general and those related to epilepsy in
particular. In addition the Einstein/Montefiore CTSA and Clinical Research Center offer a setting geared for
clinical research. The Einstein NeuroNEXT center of excellence for Clinical Trials in Neurology of which Dr
Shinnar is the PD and co-PI, also offers resources that assist in cohort retention and execution of complex
studies. While we will not be a recruiting site, these resources speak to the experience with performing status
epilepticus studies.
Computer: Dr Shinnar has a personal computer as well as 2 research computers. There is dedicated space on
the hospital network for his research files which are secure and backed up. The computer is password
protected and the research data sits ona separate “I” drive that is not physically located on the computer but is
in the central computing space of the hospital. If the computer is stolen, that data would remain secure as not
physically on the computer. The computers in Dr Shinnar’s area (are all networked. We have a SAS license
through the Albert Einstein College of Medicine (Montefiore is the University Hospital for Einstein). More
sophisticated computing needs can be met through the hospital biostatistics and computer departments and
through our CTSA.
Office: Over 1000 square feet of space are provided to Dr Shinnar and his team in the Epilepsy and Pediatric
Neurology division at Montefiore. This includes separate offices for Dr Shinnar and 4 members of his research
team.. A dedicated research exam room is also provided.
Facilities & Other Resources
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University of Minnesota
The University of Minnesota is a major research institution with a strong tradition of education and
public service. The faculty and facilities at the University of Minnesota will provide an excellent
environment for the proposed research. The College of Pharmacy has faculty who are leading experts
on drug design, delivery, therapy and policy.
Dr. James Cloyd is the Director of the Center for Orphan Drug Research at the University of Minnesota.
Dr. Cloyd, an expert in the area of neuropharmacology, directs a fully-equipped, secured, 1500 sq. foot
laboratory designed to support drug analysis and related research. Computer resources include both
PC and MacIntosh desktop computers with Ethernet linkages to University mainframe computers.
Pharmacokinetic software packages, including WinNonLin, NONMEM, and ADAPT, are available and
routinely used by laboratory personnel to conduct pharmacokinetic analyses as are several statistical
software applications (SPSS, SAS, STATA). Mathematical modeling (MATLAB) and data graphing
software is also available.
UC Davis GMP facility
Laboratory: The GMP laboratory at UC Davis Medical Center is a 6000 square foot, multi-use, 6
manufacturing suite, Class 10,000 laminar air flow clean room facility. Not only can it be used for the
manufacturing of cellular products under Good Tissue Practice and Good Manufacturing Practice, it is
also compliant with USP 797 regulations and can be used for the manufacturing of other therapeutics
for clinical use. All 6 manufacturing rooms are independent of each other, 6 different products can be
manufactured without interfering with each other. The facility features one-way personnel, product and
waste flow. The manufacturing, entry and exit areas are separated by air pressure gradients. Validated,
switchable room pressurization allows for the manufacturing of aerosolizable products in pressure sink
manufacturing rooms. An elaborate interlock system controls opening and closing of access doors,
which avoids cross-contamination of products by air turbulences. The GMP facility features an
electronically controlled and automatically monitored environment, with manual 7 day / week manual
monitoring on top of it. A strict QC/QA program with environmental cleaning and monitoring procedures
is in place to assure freedom from microbiological contamination. This premiere facility provides a state
of the art environment for the manufacturing of novel therapeutics for human clinical applications. The
GMP facility has been presented to the FDA in Type C pre-facilities meeting.
Equipment: The laboratory is equipped with 8 Baker recirculating biosafety cabinets and 2 total
exhaust Baker biosafety cabinets, one Beckman high speed centrifuge, one Beckman ultracentrifuge, 6
Beckman table top centrifuges, 6 Eppendorf microfuges, 4 Chart liquid nitrogen freezers with
associated dewars, 4 Sanyo -80 deg. Celsius freezers, 3 Sanyo -20 deg Celsius freezers, 3 VWR
refrigerators, one Gardenier controlled rate freezer, 10 Sanyo dual stacking incubators, one Miltenyi
CliniMacs clinical grade magnetic cell separator, one clinical grade BD FACS Aria Fluorescent
Activated Cell Sorter in a UC Davis designed, dedicated biosafety cabinet, one New Brunswick
bacterial shaker, one vanGahlen GMP grade hot cell for the manufacturing of clinical grade PET
reagents, one clinical grade GE FPLC station, one Olympus fluorescent microscope, 6 Olympus
inverted microscopes, and one bar code scanner inventorying station. All equipment is validated and
continuously monitored.
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Office: The GMP administrative office has a main office for 6 technicians an adjacent office for the
director. The office is equipped with 4 computer work stations that are networked on the secured UC
Davis Health System which also provides HIPPA compliant secure data transfer, storage and back up,
is equipped to store all written documentation needed for GMP manufacturing and allows for small
group meetings.
Other: The UC Davis GMP facility maintains a 500 square foot Quality Control (QC) laboratory
adjancent to the GMP facility. It is a CLIA certified laboratory with the capability of performing all
needed QC tests on the facility and the final product for patient administration. This laboratory is
equipped with a Baker biosafety cabinet, a clinical grade Sysmex blood analyzer, a clinical grade BD
FACS Calibur analyzer, a Beckman table top centrifuge, an Eppendorf microfuge, a Sanyo dual
stacking incubator, a Sanyo -80 deg Celsius freezer, a Sanyo -20 deg Celsius freezer, a VWR
refrigerator, and an upright and inverted Olympus microscope.
Administration and Regulatory: The UC Davis GMP facility generates all documentation needed for
GMP manufacturing of products, which includes Standard Operating Procedures (SOPs), Batch
Records, Certificates of Analysis, Chain of Custody documentation and others. It also has established
approved facility rates for work performed for inside and outside clients. All administrative duties for the
facility are accomplished by the director and the GMP facility staff., The GMP facility director also
oversees all communications with the Food and Drug Administration, preparation and submission of
pre-pre, pre-IND and IND packages, interactions with the NIH Recombinant DNA Advisory Committee
(RAC) and assures compliance. Several investigator initiated INDs have been approved by the FDA,
and product manufacturing for them is currently ongoing. The UC Davis GMP also facility holds a State
of California Drug Manufacturing License.
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Facilities and Resources
Washington University
Washington University in St. Louis founded in 1853, is a research-intensive university giving balanced attention
to undergraduate, graduate, and professional study, and to research. It is a medium-sized university, varied in
its program offerings, yet small enough to encourage interaction among faculty and students. Through the
years, 18 Nobel laureates have been associated with the University. Today it is ranked among the nation’s top
research intensive universities as judged by the following criteria: amount of federal funding received for
research; the proportion of faculty members serving as advisors to governmental agencies and policy-making
bodies; the volume of faculty publications and creative works; and the number of faculty members holding
positions on editorial boards of professional journals.
Washington University in St. Louis School of Medicine:
Washington University School of Medicine (WUMS) is one of the premier medical schools in the United
States. There have been 17 Nobel laureates associated with WUMS and 14 of the faculty are members of
the prestigious National Academy of Sciences. WUMS has a longstanding commitment and an excellent
history in the training of investigators in basic sciences and clinical sciences. At the predoctoral level, WUMS
has a Medical Scientist Training Program (MSTP; M.D. /Ph.D.) that accepts up to 20 of the nation’s most
promising students per year, and a Masters/M.D. program that accepts up to six students per year. At the
postdoctoral level, WUMS and the affiliated medical center have highly regarded residency and fellowship
training programs in nearly every specialty and subspecialty. In addition, there are 41 training grants in the
medical school.
Institute of Clinical and Translational Sciences (ICTS): The Washington University ICTS was developed
as a result of funding through a CTSA award to Washington University. The ICTS programs, cores and
services were selected to provide an integrated and broad group of new and existing resources to support
investigators at each phase of the clinical or translational research process, and provide a unified venue for
training in clinical and translational research. Cores and services related to research development include:
Business Development Core; Center for Biomedical Informatics; Center for Clinical Research Ethics; Center
for Human Genetics & Genomics; Center for Proteomics & Mass Spectroscopy; Research Design &
Biostatistics Group; Regulatory Support Center; Center for Translational Pathology & Tissue Banking; and the
Clinical Research Core Laboratory. Cores related to research training include: the Clinical Research Training
Center and the Career Development & Translational Research in Pediatrics. The Center for Applied Research
Sciences is also a major component of the ICTS. Dr. Leonard is a member of the ICTS.
Center for Biomedical Informatics: The Center for Biomedical Informatics (CBMI) was established in 2007
as a joint partnership between Washington University in St. Louis (WU) and BJC HealthCare to consolidate
and organize disparate informatics groups. The CBMI is a multi-departmental initiative that spans many
schools such as Engineering and Medicine at WU. Furthermore, the CBMI has extensive collaborations with
WU centers and institutes and partnerships with global informatics initiatives and other academic centers in
the region. The CBMI is charged with develop and maintain the electronic infrastructure needed to facilitate
clinical and translational research in a safe and ethical manner and in full compliance with prevailing
regulations and promoting the use of electronic resources to maximize the safety and quality of patient care at
WU and BJC practice sites and to ensure that advances in medical science are translated into improvements
in patient care as rapidly as possible.
Clinical Studies Data Management: Our primary data management tool will be ClinPortal. ClinPortal is a webbased, clinical studies data management system. Using a graphical front end, ClinPortal dynamically builds
case report forms within the context of a user defined study calendar that drives the study’s data collection
workflow. ClinPortal may also be used to manage clinical data derived from disease oriented groups or
disease-specific patient cohorts. An Oracle database on the backend securely stores PHI in compliance with
HIPAA and IRB regulations. The query tool shares data among ClinPortal studies and across companion
applications (caTissue and CIDER) rendering results in identified and de-identified fashion based on the
authorization of the user. ClinPortal is an n-tiered application certified for use under Linux Red Hat Enterprise
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AS 4.0 or higher with IE 6/7 or Firefox 2.0 and using Oracle as the database. ClinPortal includes an Application
Programming Interface (API) that is caCORE-like.
Security Architecture: To ensure patient privacy and compliance with HIPAA regulations, storage of data
based on this object model is generally separated into two components. Protected health information (e.g.
HIPAA identifiers) is stored behind the university approved, hardware firewalled network, and de-identified
clinicopathology, profiling, and genome annotation data are either stored on a publicly accessible network
(profiling and genome annotation) or are made available through dynamic filtering of the identified database.
Furthermore, each application employs fine grained, instance or record level security to users of the system.
For example, in ClinPortal, the principal investigator of a tissue collection protocol has access to all the
identified information of participants enrolled under that protocol, while other users only have de-identified
access. Thus, access is context specific to each user and individual collection protocols such that it supports
both the regulatory guidelines (e.g. HIPAA and patient privacy) and proprietary (intellectual property)
concerns.
Resources of the Biomedical Informatics Module: The bioinformatics laboratory (Dr. Nagarajan) currently
occupies two facilities. One Nagarajan lab occupies approximately 1,700 square feet of modern research
biomedical informatics space in the Cortex Building (4320 Forest Park Avenue, Suite 211). The second
Nagarajan lab located in Building 4444 (4444 Forest Park Avenue, Suite 6300) and occupies 1,000 square
feet. This includes ten carrels, each capable of being occupied by up to four programmer analysts, a
dedicated server room, and two dedicated conference rooms where face to face, voice, web, and video
conferences take place. The Nagarajan Labs house forty-two high-end Windows XP workstations, which have
dual multi-core processors, 2-4 GB RAM, at least 146GB hard drive, and a DVD-RW drive. Programming
IDEs installed on these machines include Borland Builder 6.0 Enterprise Edition, Microsoft Visual Studio.NET
Architect, Kylix 3.0 Enterprise Edition, Borland JBuilder Enterprise Edition, Eclipse 3.4, and ActivePerl 5.8. All
machines also have Oracle 10g Client installed. Xerox Phaser 8400 DP and 8550 DP color printers are
networked and present in the lab for printing purposes. Multiple servers (~60) are available to store, serve,
and back up clinical, genomic, and annotation data.
WUSM Department of Pediatrics: The department maintains a rich and supportive environment for research.
Pediatric investigators had $22,817,000 (total costs) in NIH funding during FY2011. Several multidisciplinary
projects are funded by the NIH, including the Child Health Research Center of Excellence (K12-HD01487). In
addition to 14 clinical divisions, the Department of Pediatrics is divided into three research units based on
research discipline: Patient-Oriented Research, Developmental Biology and Genetics, and Pathobiology. The
offices and laboratories of the Developmental Biology and Genetics and Pathobiology Units are located in the
227,000 square feet McDonnell Pediatric Research Building (MPRB), adjacent to SLCH, BJH, and WUSM.
WUSM Division of Pediatric Emergency Medicine (PEM): The Division of Emergency Medicine was established
with Dr. Jaffe as its first Chief in 1991. The Division has clinical responsibility for medical care of approximately
55,000 children annually in the St. Louis Children’s Hospital Emergency Department. It also provides
administrative direction for the child abuse pediatrics program. The 16 faculty members of the Division have
established a milieu of active clinical investigation which provides the role-models and a supportive environment
for the training of physician-scientists. The Division holds more than $2.5 million in extramural funding. The
division had 26 original publications and abstracts in 2012. The Division established the Pediatric Emergency
Medicine Research Assistant Program (PEMRAP) in 2002. This educational program is also an important resource
for patient-oriented research. Undergraduate Washington University students obtain advanced biology course
credit for working as research assistants in the Pediatric Emergency Department. On average there are 20 to 40
students per semester, who have enrolled more than 6,000 clinical research subjects in ongoing clinical research
projects.
The administrative offices of the Division of Emergency Medicine are located in the new Northwest Tower (9th
Floor). The area occupied by the Division is located on the north side of the Tower with 11 windowed offices and 4
inner offices. Each faculty office is approximately 125 square feet. Two faculty members are located on the 10th
Floor of the Northwest Tower in the PORU. There are three Fellow offices, which are designed to accommodate
three fellows each. At this time, two offices accommodate three fellows and one office accommodates two fellows.
Two clerical staff members support the activities of the Division members and are also located in this area. A
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workroom containing Division files, copier, shredder and fax machine are also located in this area. Three
conference rooms are available on the 9th Floor.
Computer Facilities
The PI’s office is equipped with a Dell Optiplex 760 PC with two 24-inch monitors, a black-and-white HP laser
printer, and a color HP laser printer. The Department of Pediatrics operates a network, supported by a
campus-wide Gigabit backbone, which includes 1,800 end users in numerous buildings across the WUSM
campus. The Pediatric Computing Facility includes 50 servers with a 25-TB storage area network
(expandable to 150 TB) and a mirroring off-site Disaster Recovery facility, and supplies software and updates.
There are dedicated technical and help desk staff available for on-site repairs and telephone support.
Other
Patient-Oriented Research Unit: The Patient-Oriented Research Unit (PORU) of the Department of
Pediatrics facilitates interaction among clinical or patient-oriented investigators from the Department. The CoUnit Leaders of PORU are Jane M. Garbutt, MBChB, MHSc and Leonard Bacharier, M.D. Dr. Garbutt is a
Research Associate Professor of Medicine and Pediatrics, and the Director of the Mentored Training Program
in Clinical Investigation for the Clinical Research Training Center (CRTC). Dr. Garbutt is an established clinical
investigator at Washington University in St. Louis. Dr. Bacharier is a Professor of Pediatrics, Unit Leader,
Patient Oriented Research Unit and Clinical Director, Division of Allergy, Immunology and Pulmonary
Medicine. Dr. Bacharier is co-principal investigator for the NHBLI’s AsthmaNET, a multi-centered network
examining novel therapeutic approaches to asthma in children and adults. He is an investigator in the
Childhood Asthma Research and Education (CARE) Network, an NHLBI-funded multi-centered network
examining novel therapeutic strategies in children with asthma. As well as a co-investigator in the Childhood
Asthma Management Program. He was a recipient of the Samuel R. Goldstein Leadership Award in Medical
Student Education from Washington University in St. Louis School of Medicine.
Although not solely a geographic entity, the PORU has dedicated space located in 22,000 square feet on the
10th floor of the NWT. Within this area are private offices for the Unit Leaders, the Unit Administrator, and the
Unit Manager of Financial Operations, The Statistician, and 16 other investigators, as well as cubicle-like
workspaces for other staff. There are locked NIH computer rooms, three locked storerooms for study
medications and supplies, four conference rooms, and two work areas with state-of-the-art copy
machine/FAX/printers. The administrative core personnel of PORU assist clinical investigators in the
Department in organizing and processing applications, progress reports and budgets for grants and contracts,
and with submission of human studies protocols to the Internal Review Board (IRB). PORU staff members are
not responsible for the services related to patient care outside of the arena of clinical investigation.
In addition to administrative support, the PORU serves as an academic unit for the interaction and
collaboration of clinical investigators within the Department of Pediatrics. PORU hosts regularly scheduled unit
conferences at which investigators present and discuss ongoing and planned research projects and grant
submissions with other members of the Unit and the Department. These conferences are open to all members
of the Department of Pediatrics and have been well attended by faculty, fellows and staff from numerous
Divisions in the Department as well as by members of the Division of Health Behavior Research of the
Departments of Pediatrics and Internal Medicine. There are also periodic coordinator sessions at which guest
speakers are invited to present seminars on study related topics, as well as sessions for coordinators to share
and exchange ideas about their study processes. These conferences provide an excellent forum for
discussion of patient-oriented research and epidemiologic studies from their early stages of development and
into the implementation phase.
St. Louis Children’s Hospital: St. Louis Children’s Hospital (SLCH) was founded in 1879 and the oldest
pediatric hospital west of the Mississippi River and the seventh oldest children’s hospital in the United States.
SLCH is the major pediatric hospital for the BJC Health System, Inc., and its only tertiary care children’s
hospital, and is the primary pediatric teaching hospital for Washington University in St. Louis School of
Medicine. SLCH has been recently ranked among the top pediatric hospitals in the nation by U.S. News and
World Report and by Child magazine. SLCH has 250 licensed beds including 75 NICU, 39 PICU, and 12
Cardiac ICU beds, and a Level 1 Pediatric Trauma Center. SLCH has about 275,000 patient visits per year.
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Washington University Adult Epilepsy Center and Pediatric Epilepsy Center
The Washington University Epilepsy centers provide state-of-the-art epilepsy care and facilities for both adult
and pediatric populations. The Washington University Adult Epilepsy Center is staffed by four adult
epileptologists and one adult epilepsy fellow. The Washington University Pediatric Epilepsy Center includes
seven pediatric epileptologists and two pediatric epilepsy fellows. Both centers have a very large referral
population. The new onset seizure clinic, staffed by two Pediatric Epilepsy Nurse Practitioners who work in this
role full time, sees more than 500 new pediatric patients per year. The pediatric center in particular has taken
part in recent NIH funded multi-center studies (Childhood Absence Epilepsy Study and EPGP (Epilepsy
Genome/Phenome Project) where it was a substantial contributor and subject recruitment source.
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Hospital Emergency Department Affiliate (HEDA) – Medical College of Wisconsin (MCW),
Children’s Hospital of Wisconsin
The Medical College of Wisconsin is a private free-standing medical college dedicated to
fostering leadership and excellence in Education, Research, Patient Care, and Community
Service. The Department of Pediatrics specializes in educating and training physicians desiring
to serve the health care needs of children, youth, and families. The Department has
approximately 317 faculty members, making it the largest department at MCW. The
Department has achieved national and international recognition because of excellence and
innovative initiatives of its faculty members. Prominent among clinical initiatives are the
Midwest Children’s Cancer Center, Center for the Advancement of Underserved Children, and
Project Ujima, a violence intervention program. In 2011, the Department of Pediatrics was
ranked 21th in NIH funding ($11,844,958) among other pediatric departments. The Children’s
Hospital of Wisconsin (CHW) is the primary teaching hospital for the department.
i. Division of Emergency Medicine The Division of EM has numerous multi-center studies both within and outside of PECARN
including observational studies, clinical trials, and health services research. Of the 11 full-time
faculty actively engaged in research, 6 have advanced degrees in public health or epidemiology.
MCW has trained a cadre of future researchers in PEM. In the past five years, two of our faculty
have held NIH career development awards (K08 and K23), five have participated in the MCW
K30 Clinical Research Scholars Program and currently 5 of our 9 fellows have completed or are
currently enrolled in the Master of Science in Epidemiology Program. The ED is a Level 1
designated trauma center, evaluates 63,000 patients per year and is has a fully integrated
electronic health record (EPIC) since November, 2013.
ii. Qualifications of PECARN PI and Others – David Brousseau MD, MS, HEDA PI Dr. Brousseau is Professor of Pediatrics at the Medical College of Wisconsin (MCW) with a
Masters degree in Epidemiology. . He received a Career Development Award (K08) from the
Agency for Healthcare Research and Quality in 2006, and has successfully transitioned that
award to an NIH funded R01. He is currently the Principal Investigator for a multi-center,
randomized, placebo-controlled clinical trial occurring within PECARN. The study was funded
as part of the EMSC PAR from NICHD. He is also Co-Investigator for an ancillary R01, funded
by NHLBI, assessing quality of life outcomes from the same parent trial. The trial is assessing a
new potential pain treatment for children presenting with sickle cell pain crisis. In addition to his
independent research funding, Dr. Brousseau directs the MCW Physician Scientist medical
school pathway, which provides mentored research experiences for students interested in
pursuing careers as clinician-scientists. Dr. Brousseau also served as Program Director for the
PEM Fellowship at MCW from 2006-2011. He has extensive experience mentoring students,
fellows and junior faculty in research. He has over 40 peer-reviewed publications, including first
author publications in JAMA (Acute Care Utilization and Rehospitalizations for Sickle Cell
Disease)45and Annals of Emergency Medicine (Treatment of Pediatric Migraine Headaches: A
Randomized, Double-Blind Trial of Prochlorperazine versus Ketorolac)46. His track record of
mentorship is highlighted by the fact that 13 of his publications are first authored by trainees.
iii. Research Resources & Partnerships – CTSI –
The Clinical and Translational Science Institute is an NIH-funded infrastructure to support
education, collaboration, and research in clinical and translational science. The CTSI supports
research and collaboration, develops and coordinates training opportunities, funds clinical and
translational research, and promotes collaboration.
Faculty members serve on local and state levels in EMSC programs and committees, including
Co-Chair of the state Committee on PEM. There are close links with the pre-hospital EMS
system as well; one of the faculty members is Pediatric Medical Director for Milwaukee County
EMS and serves on the county and state EMS committees. Our Division maintains close ties
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with the Department of Emergency Medicine, whose faculty includes well-funded investigators
in pre-hospital care who have led or participated in such landmark studies as the Public Access
to Defibrillators (PAD) Trial, the Resuscitation Outcomes Consortium, and the Neurologic
Emergencies Treatment Trial (NETT).
iv. Divisional Infrastructure –
The division has a pool of 3 full time Research Assistants supervised by a Program Coordinator
to accomplish ED study coverage for enrollment of 95 hours a week. These RA’s are trained to
enroll and coordinate the study activities for all the proactive divisional studies. Two important
quality control systems in place are the research database in MS ACCESS which is a repository
of general study information (funding sources, latest documents, project status and enrollment
logs). Additionally within this are complete lists of IRB approved data, protocol violations and deidentified data on screening failures and full enrollment logs. Research Assistants maintain
tracking logs of their work on projects on each component of the work, which enhances
performance management of the staff.
v. IRB Approval Process The MCW IRB full board meets twice a month, on the 1st and third Wednesdays (2 IRB
committees). Based on a recent IRB analysis, the average review period from submission to
approval for Full committee is 31 days and Expedited is 30 days. There are no other reviews
required prior to IRB submission.
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A.I. DuPont Hospital for Children of the Nemours Foundation
RESEARCH FACILITIES
Lecture hall and meeting rooms for groups of varying size are included in the hospital
proper, Research and Administration Building, and Rockland Center One and available
to all research staff for meetings, journal clubs, and formal lecture/symposia series
CLINICAL FACILITIES
Although the Alfred I. duPont Hospital for Children began as primarily an orthopedic
hospital and research institute, we are now a full-service children’s hospital. The hospital
operates as a private, non-profit entity of The Nemours Foundation. The hospital houses
200 beds and had approximately 275,000 outpatient visits in 2007. The
hematology/oncology division treats 60 – 70 new patients annually and continues to
provide services for existing patients. In addition, Nemours has three clinical centers in
Florida that treat cancer patients: Jacksonville, Orlando and Pensacola. These centers
provide a larger population of patients and tumor samples than are typically available to
researchers in the smaller states such as Delaware. All studies involving human subjects
are overseen by institutional review boards (IRBs), with the Delaware IRB being directed
by Dr. Carlos Rosé.
PROJECTS and CORES
Specific facilities for the projects and cores for the NCCCR are described below. All
facilities for the performance of the research described are located on the campus of the
Alfred I. duPont Hospital for Children in four buildings: 1) Rockland Center One, 2) the
Research and Administration Building, 3) the Life Science Center (described under
animal facilities above), and 4) the main hospital building. Major equipment available to
COBRE investigators within Alfred I duPont Hospital for Children is shown in the Table
at the end of this document.
Computer: Each investigator's office and laboratory are equipped with PCs and/or
Apple Macintosh computers with access to Internet and intranet through Ethernet and/or
wireless connections. Standard programs available on the institution’s intranet (e.g.,
word processing, spreadsheet, statistical analysis, SPSS). In addition, the Bioinformatics
Core supports an independent research network that provides local data storage and
backup, email, and web services as well as connections to the University of Delaware,
allowing access to the University of Delaware library holdings.
SHARED FACILITIES, ON-SITE
The Bioinformatics Core provides networked data storage, management, and analysis
facilities including networked servers, a cluster computer, and trained staff to assist in a
broad range of analysis procedures using an array of commercial and open source
applications. This core has recently been enhanced by recruitment of a statistician who
will provide critical statistical services to NCCCR investigators. The bioinformatics core
has developed a tracking and evaluation program for NCCCR mentoring. Each of these
core facilities is staffed through a combination of institutional and COBRE funds (through
the CPR). Use of these core facilities will be available to NCCCR investigators on a feefor-service basis.
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Major equipment at the Alfred I duPont Hospital for Children:
High-speed centrifuges
Ultracentrifuges
Micro-ultracentrifuge
Speed-Vac centrifuge units (3)
 BioRad electroporation unit
 Amaxa electroporation unit
 UV/Vis Spectrophotometers
Leica Automated Fluorescent Microscope
w/Hamamatsu cooled CCD camera
KODAK In-Vivo Imaging System FX PRO
Leica TC/SP2 Confocal Microscope w/live cell
imaging enclosure and Sutter Instr.
microinjection/perfusion apparatus
Leica TC/SP5 Confocal Microscope w/live cell
imaging enclosure
3i Total Internal Reflection Microscope with live cell
imaging enclosure
Leica CTR MIC laser dissection microscope
Luminometer
Luminex 200 system with IS 2.3 software
Applied Biosystem 310 Genetic Analyzer
Applied Biosystem 3130XL Genetic Analyzer
Applied Biosystem 7900HT real-time PCR system
Li-Cor Sequencer (2)
Biotage PSQ 96 MA pyrosequencer
ND-1000
Bioanalyzer
Affymetrix GeneChip Scanner 3000
ChemiImager 440 (Alpha Innotech Corporation)
Biomek 2000 robotic workstation
Victor X4 Multilabel Plate Reader (Perkin-Elmer)
Fluorimeter (BioRad)
2D gel system (BioRad & Pharmacia)
Dodeca gel tanks (2)
Liquid Scintillation Counter (2)
Gamma counter
Biologic HR chromatography system
BioRad LP protein purification workstation
Waters FPLC protein purification system
Waters HPLC system w/Empower software for data
analysis
Geliance 600 Imaging System (Perkin-Elmer)
PE Cytofluor 4000 microplate fluorimeter
Biotek microplate spectrophotometer
PE Luminometer/spectrophotometer plate reader
Electric Cell Impedance Sensing system (ECIS
1600R) (Applied BioPhysics)
Molecular Dynamics Storm Phosphorimager
system
Molecular Dynamics Typhoon Phosphor & Fluorescent imager system
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Cincinnati Children’s Hospital Medical Center
Laboratory: N/A
Clinical: Cincinnati Children’s Hospital Medical Center (CCHMC) is a free-standing children’s hospital with
587 beds and over 33,000 annual admissions that houses the Department of Pediatrics for the University of
Cincinnati College of Medicine (UC). CCHMC is the primary provider of inpatient, subspecialty and emergency
care in Greater Cincinnati and the surrounding counties serving over 2 million people. CCHMC has an
extensive clinical and research community and is committed to promoting and expanding pediatric research
and quality improvement. CCHMC is ranked second nationally among US pediatric institutions receiving NIH
funding and in 2012 received $120 million from the NIH. CCHMC received Magnet status by the American
Nurses Credentialing Center in 2009. In the U.S. News and World Report’s 2010 Best Children’s Hospitals
issue, CCHMC was one of eight pediatric hospitals in the United States included and ranked in the top 10 for
all pediatric subspecialties. This rich clinical and research environment offers numerous opportunities for new
investigators.
Cincinnati Children’s Hospital Medical Center Research Foundation (CCRF) has 822 faculty members
engaged in basic, clinical and translational research and thus is one of the largest pediatric research
institutions in the country. They are committed to promoting the advancement of science and medicine as well
as career advancement of young investigators while being a leader in improving pediatric quality of care and
safety. In 2012, the faculty collectively published 1425 manuscripts. CCRF has dedicated research space
encompassing almost one million square feet and is comprised of:
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
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52 academic divisions and departments
26 available research cores
$106.5 million in NIH research funding
$173 million in sponsored research programs
136 research fellows
Graduate programs in Molecular and Developmental Biology and Immunology
Departments to enhance research and research compliance: Center for Clinical and Translational
Science and Training (CCTST); Center for Technology Commercialization (CTC); Office for Clinical and
Translational Research (OCTR); Office of Research Compliance and Regulatory Affairs (ORCRA);
Sponsored Programs Office (SPO)
The Division of Pediatric Emergency Medicine is responsible for managing two large emergency departments
and three urgent care facilities together with annual visits of over 151,000 pediatric and adolescent patients.
The primary emergency department (Avondale) is a Level 1 Trauma Center and had over 92,000 visits in
2012. The Liberty Township campus had over 34,000 visits in 2012 and is located in a suburb approximately
21 miles north of Cincinnati. These sites will be the location of the proposed research. Over 40 full-time
faculty are members of the Division of Pediatric Emergency Medicine, and several have research agendas with
aims to improve healthcare delivery among the ED population. The Division is dedicated to providing travel
support to all faculty members who have research abstracts accepted for presentations at national meetings,
thus supporting the academic dissemination of research findings.
The Division has a sophisticated infrastructure of research personnel who assist emergency medicine
investigators with all aspects of their research. The Research Team consists of a Research Manager, nine
Clinical Research Coordinators (CRCs), a Regulatory Coordinator and 2 Grants Specialists. The Research
Manager assists with formulating and maintaining research budgets, initial study design and determining the
feasibility of the study. The Grant specialists aid with the development of grants and well as post-grant
management. The Regulatory coordinator ensures that the study follows all internal IRB requirements, federal,
state and internal regulations. The CRCs work directly with the investigators to develop a manual of
operations for each study, enroll patients, and maintain documentation and research forms in compliance with
Federal HIPAA and human subjects regulations.
The Division is also an active participant in the Pediatric Emergency Care Applied Research Network
(PECARN) which is the first federally funded pediatric emergency medicine research network in the United
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States. Dr. Rich Ruddy, the Division Director at CCHMC, is the nodal administrator of the HOMERUN node of
PECARN and works to conduct high-priority, multi-institutional research on the prevention and management of
acute illnesses and injuries in children and adolescents.
Animal: N/A
Computer: Dr. Babcock has a personal laptop computer with Microsoft Word, Excel, Access, PowerPoint,
Outlook Email, SAS and a personal printer. The computers at CCHMC are linked to a Novell Server that is
supported by the Department of Information Systems at CCHMC. All servers are backed-up daily and provide
secure space for data storage.
Office: Dr. Babcock has her own private office which is approximately 120 square feet within the 12,000
square feet of office space provided to the Division of Emergency Medicine. The office has two large file
cabinets providing ample space for research related materials, and both the office and the file cabinets can be
locked. The Division offices are located on the main hospital campus in a building directly across the street
from the main hospital. This space provides work areas for the Division faculty, staff, support staff and clinical
research coordinators as well as 1 large and 2 medium sized conference rooms equipped with state-of-the art
audiovisual equipment.
Core/Shared Facilities:
Center for Clinical and Translational Science and Training (CCTST): The CCTST was established by the UC
College of Medicine in October 2005 with a goal to serve and support the educational needs of the entire
clinical and translational research community of the University of Cincinnati Academic Health Center (AHC).
The CCTST is located on CCHMC campus and provides support for clinical and translational research as well
as guidance on grant preparation, research design and implementation. In 2009, the CCTST was awarded the
NIH Clinical and Translational Science Award (CTSA) for the AHC. This award enabled the CCTST to create a
center for clinical and translational research at our academic health center including CCHMC and UC. As a
result, the CCTST now provides services including biostatistical support, biomedical informatics, data
management, regulatory support, manuscript and grant preparation, and inpatient and outpatient clinical
research services for adult and pediatric studies. The CCTST provides opportunities for peer support and
interaction through the “K Club” which provides guidance on career development issues to career grant
awardees in the University of Cincinnati AHC.
The James M. Anderson Center for Health Systems Excellence: The James M. Anderson Center for Health
Systems Excellence was established in 2010 to dramatically expand our work in transformational
improvement. By working collaboratively, the Anderson Center works to improve outcomes for children and
adolescents, challenges conventional thinking, shares ideas, knowledge and data openly and builds
improvement capability and enables leadership development of the next generation. Additionally, the Center
works to foster collaboration across the organization and community, establishes partnerships with the
community, the private and public sector, and integrates with and serves the organization. Central to their
mission is to support Greater Cincinnati in becoming the healthiest region for children. This center offers
numerous opportunities to interact with colleagues and peers through the Quality Improvement and Health
Services Research Seminars offered monthly. Additionally, several nationally recognized speakers are
brought to this Center to share their information and experiences with the CCHMC community.
Library: The Edward L. Pratt Library supports CCHMC through providing information for patient care, teaching
and research. The library opened in 1931 with the founding of the Cincinnati Children's Research Foundation.
The library houses 5,400 print books and approximately 220 journal subscriptions; over 60 electronic books
and more than 30,000 journal titles are available online through the Pratt Library. The staff includes three
master’s-degree librarians, one paraprofessional librarian, and one experienced assistant.
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Children’s Hospital of Pittsburgh at University of Pittsburgh Medical Center (UPMC)
The Department of Pediatrics moved into a new $625 million, 1.5 million square foot,
269-bed hospital in 2009. Children’s Hospital of Pittsburgh (CHP) is one of eight pediatric
hospitals in the United States named to U.S. News & World Report's Honor Roll of America’s
“Best Children’s Hospitals” for 2010–2011. CHP ranked 10th in total dollars ($22.3 million) and
seventh in number of awards from the NIH for the fiscal year 2008. It was designated a 2009
Top Hospital for the second straight year by the Leapfrog Group (an independent patient safety
organization) It has been recognized by KLAS, an independent health care research
organization, as the number one pediatric hospital in its use of health care information
technology and was the first pediatric hospital in this country to achieve Stage 7 recognition
from the Health Information Management Systems Society (HIMSS) for its electronic medical
record. The primary catchment area includes 5.5 million residents and comprises the regions of
western Pennsylvania, eastern Ohio, and West Virginia
Dr. Robert Hickey is the site Principal Investigator for the Pediatric Emergency Care
Applied Research Network (PECARN) at Children’s Hospital of Pittsburgh of UPMC, and
directly supervises a Research Administrator and three Research Coordinators. There is
Research Coordinator coverage 16 hours per day during the week plus 8 hours on the
weekends.
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Nationwide Children’s Hospital
Nationwide Children’s is a free-standing children’s hospital with 427 licensed beds. It is the sole
pediatric tertiary care facility in Central Ohio and serves a population of 2.8 million, with one
million in the pediatric and adolescent age groups. It is recognized as one of the nation’s 10
largest free-standing pediatric research centers based on National Institutes of Health funding.
In 2009 and 2010, it received $64.8 million and $69.4 million, respectively, in external funding,
with a significant (30.9%) increase in NIH funding. The 62-bed Emergency Department (ED) at
Nationwide Children’s was ranked by Child (now, Parents) magazine as first in the nation for
overall outstanding emergency care in 2006 and third both in 2008 and 2010. The ED is a level
1 Pediatric Trauma Center and the nation’s third busiest pediatric emergency department
(NACHRI data). When restricted to children younger than 19 years of age, Emergency Services
(ED and Urgent Care Centers) had 125,020 visits in 2012. For the main ED, alone, in 2012
there were 84,896 visits. The section of Emergency Medicine comprises: 26 attending
physicians, 28 urgent care physicians, 8 fellows, 7 nurse practitioners, 4 research
coordinators/nurse and 43 undergraduate research assistants. The members of the section
dedicate themselves to the provision of state-of-the-art acute pediatric care in a family-centered
environment, and to research that benefits the children of our community and beyond.
Nationwide Children’s ED research infrastructure is highly engaged and embedded in the flow of
our clinical care. We are highly committed to collaboration. Currently, these efforts include
intramural and extramural projects with many partners, including our vigorous participation in
PECARN (the Pediatric Emergency Care and Applied Research Network), which was and
recently refunded in August, 2011. Selected, relevant multi-center trials studying neurologic
outcomes in children, which we are currently or recently participating in include: (1)
Progesterone for Traumatic Brain Injury in Children: Planning a Clinical Trial; (2) Implementation
of the PECARN traumatic brain injury prediction rules using electronic health record-based
clinical decision support: An interrupted time series trial; (3) Fluid Therapy and Cerebral Injury in
Pediatric Diabetic Ketoacidosis (Fluid Therapy in DKA); (4) Therapeutic Hypothermia after
Pediatric Cardiac Arrest (THAPCA); as well as, (5) Age Specific Screen for Ethanol and
Substance Status.
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UT Southwestern Medical Center/Children’s Medical Center Dallas:
Clinical:
This study will utilize the resources of the Level 1 Emergency Department at Children's Medical
Center of Dallas. These resources include all those necessary for the standard management of
infants and children with status epilepticus.
Laboratory:
This study will utilize the resources of the laboratory Children’s Medical Center of Dallas per the
study protocol. This laboratory includes all the needed resources for the expectations of this
study and is available all hours of study recruitment.
Computer:
Standard computing equipment is available for study team use. Non-standard computer or
electronic equipment will be provided for in the study budget.
Office:
An office is available for the PI and study coordinator. Office areas available include standard
office equipment with phone and internet. The areas are quiet and available for use at any time
necessary.
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University of Utah
The University of Utah enjoys a national standing among top research institutes, including worldwide research
ties. The University promotes high academic standards and professional practice, while fostering creativity and
diversity. State-of-the-art facilities are easily accessed by students, faculty and staff and the University employs
experienced and diverse faculty. This program will utilize the University of Utah’s facilities and resources as
well as collaborate with skilled faculty that will be instrumental for a successful program.
OFFICE
Dr. Maija Holsti, the Principal Investigator, and the research coordinators associated with the project have
secure offices located in the Williams Building in the Research Park area of university campus. The offices are
equipped with personal computers, access to laser printer (HP LaserJet), software for writing (Microsoft Word,
EndNote), statistical analysis, and high-speed internet access. The offices include adequate locked file storage
and shelf space. Fax, phone, and copy facilities are readily accessible. A central secure computing facility is
sponsored by the University and an Intranet network allows for secure high-speed, interactive terminal access,
file transfer, electronic mail, and connections to University and World-Wide databases over the Internet. Per
University of Utah policy, all laptops and removable drives are encrypted.
CLINICAL
Intermountain Healthcare, Primary Children’s Medical Center (PCMC) is a 289-bed state-of the-art
children’s hospital owned by Intermountain Healthcare, located on the University of Utah Campus, and
physically connected to the University Hospital by a pedestrian bridge. PCMC is the primary inpatient and
outpatient specialty teaching site for residency programs and the only tertiary care center in the Intermountain
West serving Utah, Idaho, Wyoming, Nevada, and Montana. US News and World Report recently ranked it as
one of the nation’s best children’s hospitals, recognizing them nationally in 7 of 10 pediatric subspecialties. The
Emergency Department has 35 patient beds with a surge capacity for 42 and operates 3 care pods with
variable scheduling based on the time of day and year. The ED has an annual census of over 40,000 patients
with an inpatient admission rate of about 23%, providing for a large population base of recruitment for study
participants.
The Pharmacy at Primary Children’s Medical Center offers inpatient and outpatient pharmacy services as
well as dedicated research pharmacy support. The inpatient pharmacy is staffed 24/7. The inpatient pharmacy
is fully USP 797 compliant with an ISO 7 clean room and ISO 5 hoods. The inpatient pharmacy at PCMC
established an Investigational Drug Service (IDS) program in 2001, employing a full time IDS Pharmacist. This
service supports investigator, network, and corporate sponsored clinical drug trials.
LABORATORY
The Laboratory Research Studies Department at PCMC provides specimen processing and/or send-out
assistance for all IRB approved research studies. The department includes specialists who create requisitions
specific to each study, set up proper billing procedures, process, store, and ship each sample according to
study specific protocols. Processing ranges from simple centrifuge of blood specimens to performing complex
procedures outlined in the individual study protocol and manual of operations. Several options are available for
storing and shipping samples in batches, including a -80 degree Celsius freezer, a -20 degree Celsius freezer,
and standard refrigeration.
OTHER
University of Utah, Department of Pediatrics. Pediatrics is the second largest department in the School of
Medicine and one of the largest pediatric departments in the country. It is organized in a matrix of 24 divisions
and programs with four dedicated enterprises: Academic, Clinical, Education, and Research. The Department
has over 270 faculty representing all aspects of general and subspecialty pediatrics care.
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The Division of Pediatric Emergency Medicine exclusively staffs the Emergency Department at PCMC. The
Division employs 24 board certified/eligible Attending Physicians, 8 Pediatricians, and 7 Fellow physicians. As
a faculty member of the Division of Pediatric Emergency Medicine, Dr. Holsti will have full access to the
Division’s research infrastructure including a Research Manger, 3 Research Coordinators, 2 Research
Assistants, and a Project Manager. The Division has been a member of PECARN since it’s inception over 10
years ago and has contributed to the network’s enrollment efforts as a high recruitment center for several
studies including a recent seizure study with similar recruitment activities to the proposed effort. The Division
supports a 24/7 on-call system that allows for patient enrollment support for the ED at all hours. Division
research activities include collaborative relationships with nurse administration and other clinical staff at PCMC
providing for ongoing staff training and recruitment support.
The Academic Associates Program was developed to address several challenges related to clinical research
including mentoring future investigators and providing cost-effective, in-house enrollment support for clinical
trials. As a part of the program, students receive didactic sessions on the principles of clinical research during
an 8-hour orientation and subsequent weekly sessions. Course performance is based on professionalism,
informed consent proficiency, screening and enrollment accuracy, and examinations that assess knowledge of
clinical research principles including informed consent and privacy. Students assists with identification,
screening and enrollment for clinical studies located in the emergency department, intensive care unit,
inpatient wards, and outpatient clinics at the University of Utah and Primary Children’s Medical Center.
Students who participate in all four courses offered within the program are eligible to declare a minor in
pediatric research. For this project, the Academic Associate students will be trained to identify eligible patients,
notify the study coordinator, and provide support to the clinical staff until the coordinators arrive.
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Brown University
Clinical and Academic Environment:
Rhode Island Hospital is a 719-bed non-for-profit facility located in Providence, Rhode Island. Founded in
1863 with a donation from Moses Brown Ives, the hospital continues its mission of being “at the forefront of
patient care by creating, applying, and sharing the most advanced knowledge in health care,” to this day.
Rhode Island Hospital is the major teaching hospital of the Warren Alpert Medical School at Brown University,
and is a national leader in research. Rhode Island Hospital also houses Hasbro Children’s Hospital, the
region’s major pediatric care center.
The Department of Emergency Medicine at Brown Medical School was established in 2004 with the
mission of providing high-quality emergency patient care, excellent education, and state-of-the-art research.
Under the leadership of Chair and Physician-in-Chief Dr. Brian Zink, the department is rated among the top 10
percent of the nation’s educational programs in Emergency Medicine, with approximately 400 medical
graduates applying for 12 residency positions each year.
Emergency Medicine physicians staff the EDs at Rhode Island Hospital and Hasbro Children’s Hospital, as
well as the ED at Miriam Hospital. Faculty members hold joint appointments in the departments of Internal
Medicine, Surgery, Pediatrics, and Community Health at Brown Medical School, as well as the Division of
Engineering at Brown University, and are dedicated to both providing high-quality instruction to medical
students and residents and advancing health care through innovative research.
The academic department has a strong research program, with more than 140 peer-reviewed publications over
the past 5 years and more than $4 million in annual grant funding (total costs), which ranks it among the top
departments of emergency medicine for external funding among academic Departments of Emergency
Medicine. Currently active within the Department are five R01 awards which support both clinical and basic
science research. Faculty members also currently hold one Department of Defense grant, two K23 awards,
one K01 award, one SAEM Research Training Grant, one SAEM Research Fellowship, one Lifespan
Development grant, and three Lifespan Risk Management awards. Three industry-sponsored trials are active
in the Emergency Department, and two studies are active in the HRSA-funded PECARN program in the
pediatric ED at Hasbro Children’s Hospital. The majority of these grants are multi-disciplinary in nature,
collaborating with other departments -- both clinical and non-clinical -- utilizing expertise within and outside of
Brown.
Infrastructure within the Department of Emergency Medicine includes fourteen full time research support
positions, including a Senior Research Administrator, a Clinical Research Program Administrator, a Research
Nurse, a Data Management specialist, and nine in-hospital research assistants, to aid with the department's
research initiatives. These research assistants will assist in identifying potential participants for the project and
initializing the consent process. The availability of this infrastructure will assist the research team in all aspects
of this proposal, from concept development to data analysis.
The Rhode Island Hospital Emergency Department is the only Level 1 trauma center in southeastern New
England. The Anderson ED, serving adult patients, encompasses 50,000 square feet, including 74 private
treatment rooms, a dedicated chest pain unit, a cardiac catheterization suite, a fast track area, and critical care
rooms. Two ED-dedicated CT scanners are positioned in the center of the department. Last year over 150,000
patients were treated in the Anderson ED.
Hasbro Children’s Hospital (HCH) at Rhode Island Hospital is the major pediatric teaching hospital for the
Alpert Medical School of Brown University. The Hasbro Emergency Department is located on the Ground Floor
of the HCH and is the pediatric Level 1 Trauma Center for Rhode Island, Southeastern Massachusetts, and
Eastern Connecticut. A dozen regional hospitals routinely refer patients to the Hasbro Emergency Department.
The facility includes 24 individual treatment beds and 4 holding unit beds, 10 “over flow”/urgent care beds, as
well as a private family room which is ideal for confidential conversations and participant interactions. The
annual HCH emergency department volume exceeds 50,000 patients, making it the second busiest pediatric
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emergency department in New England. The Hasbro ED is staffed 24/7 by specialists trained in Pediatric
Emergency Medicine.
The Neurological Emergencies Research Program is a consortium of physicians and research associates
from Neurology, Diagnostic Imaging, Neurosurgery, and Emergency Medicine who support clinical trials
research. The program supervises five full time Research Assistants who assist in clinical trials, such as
POINT, ProTECT III/BioProTECT, HiDef, as well as new studies in traumatic brain injury, hydrocephalus,
TIA/stroke, and neurocritical care. The Neurological Emergencies research team is available 24 hours a day,
seven days a week to assess in subject recruitment and maintenance of the study protocols.
Faculty and Staff have office space in the Department of Emergency Medicine. The offices are hard-wired for
high-speed network and internet access. The co-PIs, program manager and research assistants all have
dedicated office facilities with similar services at the same locations. The Emergency Medicine Office Suite
also contains three conference areas (ranging from 8-seats to 30 seats) available for team meetings.
Research assistants additionally have dedicated office space with lockable filing cabinets and computer access
in a research office within Rhode Island Hospital, immediately adjacent to the HCH. Available software
includes: Microsoft Office (Word, Excel, PowerPoint, Access), DatStat™, SAS, Stata, and EndNote. The
project has a dedicated network drive within the Rhode Island Hospital network that is accessible only to
project personnel and is backed up daily to a remote drive.
MedHost software is used within the emergency departments for patient tracking and documentation.
MedHost provides real-time information regarding patient age, complaint, and other demographics from the
time that a patient presents to the emergency department. Numerous MedHost workstations (both fixed and
portable) are located throughout the emergency department as well as within the Pediatric Emergency
Medicine office suite and in the Emergency Medicine Research Assistants’ office. Project research assistants
use tablet computers to securely screen potential patients and to complete baseline measures for those
enrolled. This blend of information technologies permits effective and secure data collection, transmission,
storage, and analysis. These resources provide the research team with the facilities necessary for research
development, research implementation, analysis, and preparation of data reports and manuscripts.
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Setting, Population and Staffing
The Pediatric Emergency Department (PED) of New-York Presbyterian Morgan Stanley
Children's Hospital (CHONY) provides technologically advanced emergency medical care to ill
and injured children in the Washington Heights community as well as the surrounding and tristate area. Washington Heights is among the most economically distressed, under-resourced,
densely populated and ethnically diverse areas of the city.
The CHONY PED patient population insurance coverage is 65% all-government, 5% private,
and 30% self-pay. The PED offers a full range of primary, tertiary and quaternary sub-specialty
care 24 hours a day, seven days a week. Subspecialty trained Pediatric Emergency Medicine
physicians staff the PED at all times. The CHONY PED is a Level I trauma center and was one
of the first in the region to have 24 hour a day / seven days a week coverage by these physician
specialists. The nursing staff is all specifically trained in emergency pediatrics. Over the past
eight years, the PED volume has increased a dramatic 40%, and currently provides care for
approximately 50,000 children annually.
Research Resources
The PED has a stable research infrastructure that has enabled the fellows and faculty to
conduct substantive prospective research. In addition to multiple PEM investigators who
conduct research, this infrastructure includes a full-time research coordinator specific for the ED
division. Additionally, the Division of PEM has a Research Assistant Program which provides
coverage of the ED for 23 hours / day seven days each week with volunteer post-baccalaureate
student research assistants. These assistants commit to a minimum of one year of service. This
support has enabled the CHONY ED to enroll patients into prospective multi-center studies with
a capture rate of 75-96%.
Collaborative Research
The Division of PEM has a strong history of collaborative research, including efforts within and
external to the institution. PEM research has included collaborations with the majority of
divisions within the Department of Pediatrics (e.g. Divisions of Infectious Disease, Pulmonology,
and Critical Care) as well as studies conducted with the Department of Biomedical Informatics
and the School of Nursing. Additionally, the Division of PEM is privileged to be one leading site
of the Pediatric Emergency Care Applied Research Network (PECARN), created in October of
2001. PECARN is the first federally-funded, Health Resources and Services Administration,
multi-institutional network for research in pediatric emergency medicine. The goal of this
network is to conduct meaningful and rigorous multi-institutional research into the prevention
and management of acute illnesses and injuries in children and youth across the continuum of
emergency medicine health care. PECARN (www.pecarn.org) provides the leadership and
infrastructure needed to promote multi-center studies and support research collaboration among
investigators.
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Texas Children’s Hospital
Texas Children’s Hospital (TCH), is a tertiary care children’s hospital that provides specialty and
subspecialty care to children in southeast Texas in addition to patients referred from multiple
U.S. locales and international cities. Approximately 80,000 pediatric patients per year are
treated in the Emergency Department (ED). Other than critically ill transported patients, all
admissions to TCH are processed through the ED at TCH. The tertiary nature of the hospital
allows for a rich clinical exposure to a large number of childhood disease diagnoses.
The campus of TCH is located among 5 buildings in the Texas Medical Center which are
connected by bridges. Inpatient care is delivered in 2 of those towers among 582 beds, making
TCH the largest free-standing children’s hospital in the country. Clinical care is delivered by over
40 general and subspecialty pediatric services, providing the highest level of skilled care in the
region. As a designated nursing magnet, ancillary staff services are equally robust to provide a
spectrum of clinical support services. As the pediatric partner to Baylor College of Medicine,
TCH and Baylor have sustained a long history of academic-clinical partnership in a plethora of
research studies.
The Section of Emergency Medicine at Baylor College of Medicine has academic and
administrative offices housed on the campus of Texas Children’s Hospital within the Texas
Medical Center and in close proximity to the investigators’ research labs. Within these
complexes of 50 offices is a separate Pediatric Emergency Medicine Research Office that
occupies 14 offices and 19 work stations. Research technicians, administrative and secretarial
personnel, information technology personnel, and database specialists are housed in these
offices. The physical layout of offices within offices allow for the provision of security of
confidential patient information in either paper or computer form. Human subjects data, once
collected in the emergency department setting is then processed and stored in these offices and
is accessible only to key research personnel.
The TCH Emergency Department also has a cadre of coordinators and assistants to support the
conduct of PECARN research including a team of 7 trained research coordinators providing 1214 hours per day of ED coverage on weekdays and 8-10 hours per day on weekends, an
Academic Associates program in partnership with University of Houston for which college credit
is offered that provides formal training in clinical research. An average of 10 basic and 4
advanced students rotate through PEM quarterly. As part of their course work, students enroll
patients into ED research studies.
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UC Davis
The emergency department is housed in a spectacular, state-of-the-art 68-bed facility, and is
staffed by 28 emergency medicine and pediatric emergency medicine faculty who supervise the
training of the following residents: emergency medicine, family medicine, internal medicine,
pediatrics, physical medicine and rehabilitation, and surgery. The ED annual census is 65,000
visits, with an admission rate of 30% for adult patients and 20% for pediatric patients. We are
the only designated Level 1 Trauma Center in the Region, and the only Pediatric Trauma
Center. Emergency services range from resuscitation and stabilization of the critically ill or
injured patient, with access to the highest technology in advanced airway management
techniques and equipment, to treating common fractures and infections. Procedures commonly
performed in our ED include intubations, central line placement, chest tube insertion, complex
wound repair, closed reduction of fractures and dislocations, lumbar punctures, thrombolytic
administration, advanced stroke management, and surgical drainage of soft tissue abscesses.
These services are provided with the full support of advanced technology, such as rapid helical
computerized tomography (CT), magnetic resonance imaging (MRI), bedside ultrasound,
angiography and dedicated emergency laboratory and radiology services 24 hours a day. Each
patient room in the UC Davis emergency department is equipped with a sliding glass door for
patient privacy and confidentiality. The Department of Emergency Medicine employs a staff of
two full-time Research Managers, two full-time Senior Clinical Research Coordinators, six fulltime Clinical Research Coordinators and one part-time Clinical Research Coordinator. All
research staff are trained in compliance with federal and institutional requirements for the
protection of human subjects.
All staff (investigators and research coordinator) have access to Dell desktop computers with
Microsoft Network and Office programming. Investigators also have access to appropriate
software. Data security is ensured with state-of-the-art computer infrastructure and coordination
of its network infrastructure and security with the Health Sciences Campus (HSC) information
systems at the UC Davis medical center. This provides firewall hardware, automatic network
intrusion detection, and the expertise of dedicated security experts working at UCDMC. Network
equipment includes three high-speed switches and two hubs. User authentication is centralized
with two Windows domain servers. Communication over public networks is encrypted with
virtual point-to-point sessions using secure socket layer (SSL) or virtual private network (VPN)
technologies, both of which provide at least 128 bit encryption.
Dr. Vance maintains an office space located within the Emergency Department Administrative
Office (Patient Support Services Building, Room 2100) which is located on the medical center
campus and near the Emergency Department. The Research Coordinator (to be designated)
will have designated office space in the off-site research building housing the research staff of
the Pediatric Emergency Care Applied Research Network (PECARN) (the Western Fairs
Building at 2500 Stockton Blvd.). All staff have access to internet, fax, copy, and print
capabilities within the office.
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Wayne State University/Children’s Hospital of Michigan
Clinical Environment: The Children’s Hospital of Michigan (CHOM) emergency department (ED) has been
a Level 1 Trauma Center for pediatrics since 1992 and is equipped to handle the most severe injuries and
illnesses. The ED is comprised of nearly 21,000 square feet of space with 52 exam rooms, which include three
resuscitation bays; four negative pressure rooms, two positive pressure rooms, and all but 13 of the beds are
fully enclosed private exam rooms. Thirty-two pediatric emergency physicians and pediatricians staff the ED.
Twenty physicians are board certified in Pediatric Emergency Medicine, ten are all certified in Pediatrics as
well, and two are dual certified in both Emergency Medicine and Pediatric Emergency Medicine. There are
58.5 nurse FTEs and 25 FTEs patient care associates and 7 nurse practitioners. The ED is the primary
training site for residents from pediatrics, emergency medicine, osteopathic programs, family practice
and internal medicine along with the third and fourth year medical students from Wayne State University
School of Medicine. The ED has one of the longest running accredited Pediatric Emergency Medicine
Fellowship program in the US, second largest PEM fellowship program in the country, and with an average of 4
PEM fellows a year, currently 12 PEM fellows, the largest fellowship program at CHM. The PEM training at
CHM has been exemplary as evidenced by a board certification rate of > 85% for first time takers.
The CHOM ED is a state-of-art facility with an electronic patient tracking system, electronic medical records
(EMR) and digital imaging system that enhance patient care. CHOM is also one of the few Children’s Hospitals
in the country that has achieved HIMSS Analytics EMR Adoption Model level 6 certification; this is the
penultimate level before having a completely integrated EMR (level 7). These electronic resources have
allowed researchers to quickly identify and approach patients and patient families for research enrollment.
Scientific Environment: Wayne State University (WSU) is among the nation’s top public universities for total
research expenditures ($257.2 million total; $251.8 million in science and engineering), ranking 52nd among
public universities and colleges, according to the National Science Foundation. WSU houses the Perinatology
Research Branch, a 165.9 million dollar award that helps fund critical perinatal and maternal-fetal medical
research by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the
National Institutes of Health.
CHOM is ranked among the nation’s top 30 hospitals in the U.S. News & World Report’s 2010-11 edition of
Best Children’s Hospitals. Parents' magazine (www.parents.com) just came out with its annual ranking of
children's hospital where we were ranked on 6 pediatric specialty areas, one of them being emergency care.
Our ED was ranked 6th in the country.
Clinical Research Facilities: The Pediatric Emergency Medicine Research (PEMR) has staff composed of a
research and grants manager, certified clinical research coordinators, research assistants, undergraduate and
graduate student assistants that are available on site and/or on-call for several different studies. We have
devoted office space with 10 work stations and separate locked filing storage room. When enrolling in the ED
each PEMR team member has access to a laptop or tablet to aid ED enrollment. We have generous lab
facilities for processing and storing samples available to us 24 hours a day, 7 days a week. A member of the
PEMR staff serves on the Emergency Department Nurse Practice Council to ensure research procedures are
reviewed and adapted to the bust ED environment to ensure successful colorations and completions of clinical
projects in the ED.
Network and Multi-Center Research:
Children’s Hospital of Michigan and the Department of Pediatrics at Wayne State University have key
collaborations with several different pediatric research networks including the Pediatric Emergency Care
Applied Research Network (PECARN), the Collaborative Pediatric Critical Care Research Network (CCPRCN)
and the National Institute of Child Health and Human Development Neonatal Research Network (NICHD
NRN). We have also begun work in partnership with the global consortium of pediatric emergency medicine
research networks, Pediatric Emergency Research Networks (PERN) which includes PECARN.
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Dr. Mahajan, the site PI for this project, serves as the Co-Investigator for the Great Lakes Emergency Medical
Services for Children Research Node (GLEMSCRN) of PECARN. PECARN was created by the Emergency
Medical Services for Children (EMSC) program and the Maternal and Child Health Bureau (MCHB) of the
Health Resources and Services Administration (HRSA). The goal of the PECARN network is to conduct high
priority multi-institutional research into the prevention and management of acute illnesses and injuries in
children and youth of all ages across the continuum of emergency medicine health care and to promote the
health of children in all phases of care. Currently, we have 3 PECARN and 2 PERN active enrolling under the
guidance of our PEMR staff.
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring MD 20993
IND 119756
IND ACKNOWLEDGEMENT
Jaideep Kapur, MBBS, Ph.D
Department of Neurology, Box 800394
University of Virginia-Health Sciences Center
Charlottesville, VA 22908-0394
Dear Dr. Kapur:
We acknowledge receipt of your Investigational New Drug Application (IND) submitted under
section 505(i) of the Federal Food, Drug, and Cosmetic Act (FDCA). Please note the following
identifying data:
IND NUMBER ASSIGNED:
119756
SPONSOR:
Jaideep Kapur, MBBS, Ph.D
PRODUCT NAME(S):
Fosphenytoin Injection
Levetiracetam Injection
Valproic acid Injection
DATE OF SUBMISSION:
September 16, 2013
DATE OF RECEIPT:
September 17, 2013
You may not initiate studies in humans until 30 days after the date of receipt shown above unless
we notify you sooner that you may proceed. If, on or before October 17, 2013, we identify
deficiencies in the IND that require correction before human studies begin or that require
restriction of human studies, we will immediately notify you verbally or in writing that
(1) clinical studies may not be initiated under this IND ("clinical hold") or (2) certain restrictions
apply to clinical studies under this IND (“partial clinical hold”). If we place your human studies
on clinical hold, you will be notified in writing of the reasons and the information necessary to
correct the deficiencies. In the event of such notification, you must not initiate or you must
restrict such studies until you have submitted information to correct the deficiencies, and we
have subsequently notified you that the information you submitted is satisfactory.
It has not been our policy to object to a sponsor, upon receipt of this acknowledgement letter,
either obtaining supplies of the investigational drug or shipping it to investigators listed in the
IND. However, if the drug is shipped to investigators, they should be reminded that studies may
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IND 119756
Page 2
not begin under the IND until 30 days after the IND receipt date or later if the IND is placed on
clinical hold.
FDAAA TITLE VIII RESPONSIBILITIES
You are also responsible for complying with the applicable provisions of sections 402(i) and (j)
of the Public Health Service Act (PHS Act) [42 USC §§ 282 (i) and (j)], which was amended by
Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public
Law No, 110-85, 121 Stat. 904).
Title VIII of FDAAA amended the PHS Act by adding new section 402(j) [42 USC § 282(j)],
which expanded the current database known as ClinicalTrials.gov to include mandatory
registration and reporting of results for applicable clinical trials of human drugs (including
biological products) and devices.
In addition to the registration and reporting requirements described above, FDAAA requires that,
at the time of submission of an application under section 505 of the FDCA, the application must
be accompanied by a certification that all applicable requirements of 42 USC § 282(j) have been
met. Where available, the certification must include the appropriate National Clinical Trial
(NCT) numbers [42 USC § 282(j)(5)(B)].
You did not include such certification when you submitted this application. You may use Form
FDA 3674, “Certification of Compliance, under 42 U.S.C. § 282(j)(5)(B), with Requirements of
ClinicalTrials.gov Data Bank,” [42 U.S.C. § 282(j)] to comply with the certification requirement.
The form may be found at http://www.fda.gov/opacom/morechoices/fdaforms/default.html.
In completing Form FDA 3674, you should review 42 USC § 282(j) to determine whether the
requirements of FDAAA apply to any clinical trial(s) referenced in this application. Please note
that FDA published a guidance in January 2009, “Certifications To Accompany Drug, Biological
Product, and Device Applications/Submissions: Compliance with Section 402(j) of The Public
Health Service Act, Added By Title VIII of the Food and Drug Administration Amendments Act
of 2007,” that describes the Agency’s current thinking regarding the types of applications and
submissions that sponsors, industry, researchers, and investigators submit to the Agency and
accompanying certifications. Additional information regarding the certification form is available
at:
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCA
ct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/uc
m095442.htm. Additional information regarding Title VIII of FDAAA is available at:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-014.html. Additional information for
registering your clinical trials is available at the Protocol Registration System website
http://prsinfo.clinicaltrials.gov/.
When submitting the certification for this application, do not include the certification with other
submissions to the application. Submit the certification within 30 days of the date of this letter.
In the cover letter of the certification submission clearly identify that it pertains IND 119756
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IND 119756
Page 3
submitted on September, and that it contains the FDA Form 3674 that was to accompany that
application.
If you have already submitted the certification for this application, please disregard the above.
ADDITIONAL IND RESPONSIBILITIES
As sponsor of this IND, you are responsible for compliance with the FDCA
(21 U.S.C. §§ 301 et. seq.) as well as the implementing regulations [Title 21 of the Code of
Federal Regulations (CFR)]. A searchable version of these regulations is available at
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm. Your responsibilities
include:
x
Reporting any unexpected fatal or life-threatening suspected adverse reactions to this
Division no later than 7 calendar days after initial receipt of the information
[21 CFR 312.32(c)(2)].
If your IND is in eCTD format, submit 7-day reports electronically in eCTD format via the
FDA Electronic Submissions Gateway (ESG). To obtain an ESG account, see information
at the end of this letter.
If your IND is not in eCTD format:
x
you should submit 7-day reports by a rapid means of communication, preferably by
facsimile or email. You should address each submission to the Regulatory Project Manager
and/or to the Chief, Project Management Staff;
x
if you intend to submit 7-day reports by email, you should obtain a secure email account
with FDA (see information at the end of this letter);
x
if you also send copies of these reports to your IND, the submission should have the
same date as your facsimile or email submission and be clearly marked as “Duplicate.”
x
Reporting any (1) serious, unexpected suspected adverse reactions, (2) findings from other
clinical, animal, or in-vitro studies that suggest significant human risk, and (3) a clinically
important increase in the rate of a serious suspected adverse reaction to this Division and to
all investigators no later than 15 calendar days after determining that the information
qualifies for reporting [21 CFR 312.32(c)(1)]. If your IND is in eCTD format, submit 15day reports to FDA electronically in eCTD format via the ESG. If your IND is not in eCTD
format, you may submit 15-day reports in paper format; and
x
Submitting annual progress reports within 60 days of the anniversary of the date that the
IND became active (the date clinical studies were permitted to begin) [21 CFR 312.33].
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Page 4
CHARGING FOR AN INVESTIGATIONAL DRUG
We remind you that, under 21 CFR 312.8(a)(3), you may not charge for this investigational drug
without prior written authorization from FDA.
GOOD LABORATORY PRACTICE
All laboratory or animal studies intended to support the safety of this product should be
conducted in compliance with the regulations for "Good Laboratory Practice for Nonclinical
Laboratory Studies" (21 CFR 58). If such studies have not been conducted in compliance with
these regulations, provide a statement describing in detail all differences between the practices
used and those required in the regulations.
ENVIRONMENTAL ASSESSMENT
Box 13, item 7 of form FDA 1571 requests that either an "environmental assessment," or a
"claim for categorical exclusion" from the requirements for environmental assessment, be
included in the IND. If you did not include a response to this item with your application, please
submit one. Information on environmental assessments is available in the guidance
“Environmental Assessment of Human Drugs and Biologics.” This document is available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm070561.pdf.
SUBMISSION REQUIREMENTS
Cite the IND number listed above at the top of the first page of any communications concerning
this application. Each submission to this IND must be provided in triplicate (original plus two
copies). Please include three originals of all illustrations that do not reproduce well. Send all
submissions, electronic or paper, including those sent by overnight mail or courier, to the
following address:
Food and Drug Administration
Center for Drug Evaluation and Research
Division of Neurology Products
5901-B Ammendale Road
Beltsville, MD 20705-1266
All regulatory documents submitted in paper should be three-hole punched on the left side of the
page and bound. The left margin should be at least three-fourths of an inch to assure text is not
obscured in the fastened area. Standard paper size (8-1/2 by 11 inches) should be used; however,
it may occasionally be necessary to use individual pages larger than standard paper size.
Non-standard, large pages should be folded and mounted to allow the page to be opened for
review without disassembling the jacket and refolded without damage when the volume is
shelved. Shipping unbound documents may result in the loss of portions of the submission or an
unnecessary delay in processing which could have an adverse impact on the review of the
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submission. For additional information, see
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Drug
MasterFilesDMFs/ucm073080.htm.
Secure email between CDER and sponsors is useful for informal communications when
confidential information may be included in the message (for example, trade secrets or patient
information). If you have not already established secure email with the FDA and would like to
set it up, send an email request to [email protected]. Please note that secure email may
not be used for formal regulatory submissions to applications (except for 7-day safety reports for
INDs not in eCTD format).
The FDA Electronic Submissions Gateway (ESG) is the central transmission point for sending
information electronically to the FDA and enables the secure submission of regulatory
information for review. If your IND is in eCTD format, you should obtain an ESG account. For
additional information, see
http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/.
If you have any questions, contact me, via telephone at (301) 796-5068 or via email at
[email protected].
Sincerely,
{See appended electronic signature page}
Laurie Kelley, PA-C
Regulatory Project Manager
Division of Neurology Products
Office of Drug Evaluation I
Center for Drug Evaluation and Research
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--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------LAURIE A KELLEY
09/24/2013
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Milestone Plan:
a) Completion of start‐up activities: 12 months. Individual sites require 6-12 months to complete Exception
from Informed Consent activities (EFIC) and IRB approval.
b) Enrollment of the first subject: 9 Months
c) Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study subjects, including women, minorities and children (as appropriate):
When all sites are operational we will recruit 16-20 patients each month. Following table is constructed
assuming that we will recruit 795 patients to complete the study. However, it is possible that adaptive
Bayesian design would result in fewer patients being recruited to answer the question. This is addressed in
simulations below.
End of Year
1
2
3
4
5
Enrollment (Absolute)
Enrollment (%) Assuming 795 max.
Note this is an adaptive design
study
3%
25%
50%
75%
100%
25
199
400
600
795
d) Completion of data collection: Year 5.
e) Completion of primary endpoint and secondary endpoint data analyses 6 months after completion of
recruitment
f) Completion of final study report 12 months after completion of recruitment
g) Adaptive designs, allowed under this mechanism, should include a pre‐specified adaptation plan that allows for clear go/no‐go decisions Interim Monitoring: Interim monitoring for success and futility will begin after 400 patients have been enrolled
and will be repeated after every additional 100 patients are enrolled. Thus, interim analyses will be performed
after 400, 500, 600, and 700 patients.
1) This trial will stop early for success if we have identified the maximum effective treatment with at least
97.5% probability.
2) There are two early futility criteria.
The first futility rule will stop the trial early if all treatment arms have a clinically unacceptable response
rate. This trial may stop early for futility if there is a low probability, less than 5%, that any of the three
treatment arms is achieving a response rate of at least 25%.
The second futility rule will stop the trial early if all treatments are performing similarly and we will be
unable to identify a most effective or least effective treatment. This trial will stop early for futility if the
predictive probability of identifying either the most effective or the least effective treatment at the
maximum sample size is less than 5%.
Potential scenarios for early termination were simulated:
Simulation Details Table 1. Response Rate Scenarios Considered 1272-Milestone_Plan
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Contact PD/PI: Kapur, Jaideep
Drug A Drug B
Drug C
Null 50% 50% 50% One Good Treatment 50% 50% 65% Two Good Treatments 50% 65% 65% One Middle One Good 50% 57.5% 65% All Bad 25% 25% 25% All Really Bad 10% 10% 10% Note table 2 below suggests that the trial may end with fewer patients than planned 795, under many
scenarios:
Table 2. Mean Allocation (Proportion of Total Mean Allocation)
Null Total N
Drug A
Drug B Drug C 508 169 (33%) 169 (33%) 169 (33%) 484 127 (26%) 127 (26%) 231 (47%) 684 115 (17%) 284 (41%) 284 (41%) 592 123 (22%) 190 (32%) 279 (47%) 522 174 (33%) 174 (33%) 174 (34%) 400 133 (33%) 133 (33%) 133 (34%) 50% ‐ 50% ‐ 50% One Good 50% ‐ 50% ‐ 65% Two Good 50% ‐ 65% ‐ 65% One Middle One Good 50% ‐ 57.5% ‐ 65% All Bad 25% ‐ 25% ‐ 25% All Really Bad 10% ‐ 10% ‐ 10% All interim analysis results will be considered confidential and only presented to the Data and Safety Monitoring
Board in a formal report prepared by the unblinded statistical team at the SDMC. Following review of both the
1272-Milestone_Plan
Page 63
Contact PD/PI: Kapur, Jaideep
interim analysis results and safety data, the DSMB will make a recommendation regarding the above
decisions. See Human Subjects section for more information on the DSMB.
1272-Milestone_Plan
Page 64
Contact PD/PI: Kapur, Jaideep
OMB Number: 4040-0001
Expiration Date: 06/30/2016
RESEARCH & RELATED Senior/Key Person Profile (Expanded)
PROFILE - Project Director/Principal Investigator
Prefix: Dr.
First Name*: Jaideep
Middle Name
Suffix:
Last Name*: Kapur
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
The Rector and Visitors of the University of Virginia
Neurology
School of Medicine
PO Box 800394
Country*:
Zip / Postal Code*:
USA: UNITED STATES
22908-8394
Charlottesville
Albemarle
VA: Virginia
Phone Number*: 434-924-5312
Fax Number: 434-982-1726
E-Mail*: [email protected]
Credential, e.g., agency login: jkapur
Project Role*: PD/PI
Other Project Role Category:
Degree Type: PhD; MB
Degree Year: 1988; 1985
File Name
Mime Type
1255-Biosketch_Kapur.pdf
Attach Biographical Sketch*:
application/pdf
Attach Current & Pending Support:
PROFILE - Senior/Key Person
Prefix: Dr.
Middle Name
First Name*: Robert
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
University of Michigan
Emergency Medicine
Country*:
Zip / Postal Code*:
USA: UNITED STATES
48109-5700
Suffix:
Last Name*: Silberleit
University Hospital Floor B1 Reception Emergency
1500 E Medical Center Dr SPC 5301
Ann Arbor
MI: Michigan
Phone Number*: 734-936-6666
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login: silbergleit
Project Role*: PD/PI
Other Project Role Category:
Degree Type: MD
Degree Year: 1992
File Name
Attach Biographical Sketch*:
Mime Type
1256-Biosketch_SILBERGLEIT.pdf application/pdf
Attach Current & Pending Support:
Tracking Number: GRANT11508883
Page 65
Funding Opportunity Number: PAR-13-278 . Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
PROFILE - Senior/Key Person
Prefix: Dr.
Middle Name
First Name*: James
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
Children's Research Institute
Pediatrics and Emergency Med.
Country*:
Zip / Postal Code*:
USA: UNITED STATES
20010-2916
Suffix:
Last Name*: Chamberlain
111 Michigan Ave., NW
Washington
DC: District of Columbia
Phone Number*: 202-476-3253
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login: jchamber
Project Role*: PD/PI
Other Project Role Category:
Degree Type: MD
Degree Year: 1984
File Name
Mime Type
1257-Chamberlain_biosketch.pdf
Attach Biographical Sketch*:
application/pdf
Attach Current & Pending Support:
PROFILE - Senior/Key Person
Prefix: Dr.
Middle Name
First Name*: Daniel
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
UCSF
Neurology
Country*:
Zip / Postal Code*:
USA: UNITED STATES
94143-6215
Suffix:
Last Name*: Lowenstein
3333 California Street
San Francisco
CA: California
Phone Number*: 415-514-6019
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: co-leader, clinical adjudication core
Degree Type: MD
Degree Year: 1983
File Name
Attach Biographical Sketch*:
Mime Type
1258-Biosketch_Lowenstein.pdf
application/pdf
Attach Current & Pending Support:
Tracking Number: GRANT11508883
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2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
PROFILE - Senior/Key Person
Prefix: Dr.
First Name*: Shlomo
Middle Name
Suffix:
Last Name*: Shinnar
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
Albert Einstein College of Medicine
Neurology and Pediatrics
Country*:
Zip / Postal Code*:
USA: UNITED STATES
10461-1900
1300 Morris Park Avenue
Bronx
NY: New York
Phone Number*: 718-920-4378
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: co-leader, clinical adjudication core
Degree Type: PhD, MD
Degree Year: 1977, 1978
File Name
Mime Type
1259-Biosketch_Shinnar.pdf
Attach Biographical Sketch*:
application/pdf
Attach Current & Pending Support:
PROFILE - Senior/Key Person
Prefix: Dr.
Middle Name
First Name*: James
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
University of Minnesota
College of Pharmacy
Country*:
Zip / Postal Code*:
USA: UNITED STATES
55455-2070
Suffix:
Last Name*: Cloyd
200 Oak Street SE, Suite 450
Minneapolis
MN: Minnesota
Phone Number*: 612-624-4609
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: leader, pharmacology core
Degree Type: PharmD
Degree Year: 1976
File Name
Attach Biographical Sketch*:
Mime Type
1260-Biosketch_Cloyd.pdf
application/pdf
Attach Current & Pending Support:
Tracking Number: GRANT11508883
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2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
PROFILE - Senior/Key Person
Prefix: Dr.
First Name*: Elizabeth
Middle Name
Suffix:
Last Name*: Jones
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Associate Professor
The University of Health Science Center Houston
Emergency Medicine
Country*:
Zip / Postal Code*:
USA: UNITED STATES
77030-5401
7000 Fannin, UCT 1006
Houston
TX: Texas
Phone Number*: 713-500-7864
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: EFIC consultant
Degree Type: MD
Degree Year: 1986
File Name
Mime Type
1261-Biosketch_Jones.pdf
Attach Biographical Sketch*:
application/pdf
Attach Current & Pending Support:
PROFILE - Senior/Key Person
Prefix: Dr.
Middle Name
First Name*: Mark
Suffix:
Last Name*: Conaway
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
The Rector and Visitors of the University of Virginia
Public Health Sciences Admin.
School of Medicine
PO Box 800717
Country*:
Zip / Postal Code*:
USA: UNITED STATES
22908-8717
Charlottesville
VA: Virginia
Phone Number*: 434-924-8510
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: Biostatistician
Degree Type: PhD
Degree Year: 1985
File Name
Attach Biographical Sketch*:
Mime Type
1262-Biosketch_Conaway.pdf
application/pdf
Attach Current & Pending Support:
Tracking Number: GRANT11508883
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2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
PROFILE - Senior/Key Person
Prefix: Dr.
First Name*: Nathan
Middle Name
Suffix:
Last Name*: Fountain
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
The Rector and Visitors of the University of Virginia
Neurology
School of Medicine
PO Box 800394
Country*:
Zip / Postal Code*:
USA: UNITED STATES
22908-8394
Charlottesville
VA: Virginia
Phone Number*: 434-243-6281
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: clinical adjudicator
Degree Type: MD
Degree Year: 1989
File Name
Mime Type
1263-Biosketch_Fountain.pdf
Attach Biographical Sketch*:
application/pdf
Attach Current & Pending Support:
PROFILE - Senior/Key Person
Prefix: Dr.
First Name*: Hannah
Middle Name
Suffix:
Last Name*: Cock
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Reader in Clinical Neurology
St. George's University of London
Clinical Sciences
Country*:
Zip / Postal Code*:
GBR: UNITED KINGDOM
SW17 0RE UK
Cranmer Terrace
London
Phone Number*: +44 20 8725
Fax Number:
E-Mail*: [email protected]
2002
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: clinical adjudicator
Degree Type: MD
Degree Year: 1996
File Name
Attach Biographical Sketch*:
Mime Type
1264-Biosketch_Cock.pdf
application/pdf
Attach Current & Pending Support:
Tracking Number: GRANT11508883
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2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
PROFILE - Senior/Key Person
Prefix: Dr.
First Name*: William
Middle Name G.
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Professor
University of Michigan
Emergency Medicine
Country*:
Zip / Postal Code*:
USA: UNITED STATES
48106-5700
Suffix:
Last Name*: Barsan
24 Frank Lloyd Wright Dr.
Lobby H, Suite 3100
Ann Arbor
MI: Michigan
Phone Number*: 734-232-2142
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: NETT PI
Degree Type: MD
Degree Year: 1975
File Name
Mime Type
1265-Biosketch_Barsan.pdf
Attach Biographical Sketch*:
application/pdf
Attach Current & Pending Support:
PROFILE - Senior/Key Person
Prefix: Dr.
First Name*: Gerhard
Middle Name
Position/Title*:
Organization Name*:
Department:
Division:
Street1*:
Street2:
City*:
County:
State*:
Province:
Director
University of California, Davis
GMP Facility
Country*:
Zip / Postal Code*:
USA: UNITED STATES
95817-2305
Suffix:
Last Name*: Bauer
2921 Stockton Blvd.
Sacramento
CA: California
Phone Number*: 916-703-9305
Fax Number:
E-Mail*: [email protected]
Credential, e.g., agency login:
Project Role*: Other (Specify)
Other Project Role Category: GMP Manufacturing
Degree Type: BS
Degree Year: 1990
File Name
Attach Biographical Sketch*:
Mime Type
1266-Biosketch_Bauer.pdf
application/pdf
Attach Current & Pending Support:
Tracking Number: GRANT11508883
Page 70
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2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
BIOGRAPHICAL SKETCH
Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
Jaideep Kapur
POSITION TITLE Professor
eRA COMMONS USER NAME jkapur
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION
DEGREE
(if applicable)
YEAR(s)
FIELD OF STUDY
University of Delhi, New Delhi, India
M.B., B.S
1985
Medicine
University of Virginia, Charlottesville, VA
Ph.D.
1988
Neuroscience
Eastern Virginia School of Medicine, Norfolk, VA
Internship
1989
Internal Medicine
Medical College of Virginia, Richmond, VA
Residency
1992
Neurology
University of Michigan, Ann Arbor, MI
Fellowship
1993
Epilepsy/EEG
A. PERSONAL STATEMENT Early in my career I hypothesized that GABA-A receptors in the
hippocampus are altered during early status epilepticus. This was based on some paired pulse
inhibition and binding experiments that I had performed as a graduate student and my experience in
treating patients with status epilepticus as a resident in Richmond. Most of the drugs we were using
had actions on GABA -A receptors. During my residency, I was fortunate to work with Doug Coulter and
make some initial observations supporting the idea that GABA-A are modified during status epilepticus.
Later I was able to show that alterations in GABA-A receptor properties correlate in time with
development of benzodiazepine resistance in whole animals. These studies showed that as status
epilepticus lasts longer benzodiazepines become less effective. Later studies demonstrated activity
dependent trafficking of synaptic GABA-A receptors. After doing two decades of research on basic
mechanisms of status epilepticus I find it frustrating that the treatment of status epilepticus has not
changed much. There is no scientifically proven treatment for benzodiazepine refractory status
epilepticus. With this background, I was delighted to be invited to participate in designing ESETT. The trial grew
out of London-Innsbruck colloquia on Status Epilepticus organized by Drs. Simon Shorvon & Eugen
Trinka, which are biennial meetings of all status epilepticus investigators. Originally two trials with
similar design were conceived, one in Europe lead by Drs. Hannah Cock and Simon Shorvon and
second one in the US lead by Dr. Daniel Lowenstein. The British Health Agency did not support the
European trial and that group joined the US group. In December 2010, Dr. Daniel Lowenstein decided
to step down from the leadership of US ESETT in order to focus on an internation Center without walls
on epilepsy genetics (EPI4K), the investigator group selected me to lead ESETT. Since then, I have
organized and lead regular teleconferences and meetings of the ESETT investigator group to plan and
prepare the protocol, design the study in collaboration with Adaptive Design group (ADAPT-IT), form a
partnership with PECARN and prepare Investigational New Drug application. In these activities my
scientific and clinical training have been complemented by my leadership and administrative
experience). I served as the President of the American Epilepsy Society (first and second VP before
that), and as Vice Chair of Department of Neurology, and currently serve as Director of Neuroscience
Center of Excellence, University of Virginia.
I lack experience managing large clinical trials, therefore we have chosen Multiple PI mechanism with
Drs. Robert Silbergleit and James Chamberlain as Joint PIs. Dr. Silbergleit was a PI of Rapid
Anticonvulsant Medication Prior to Arrival Trial (RAMPART), and Dr. James Chamberlain lead the Use
Of Lorazepam for the Treatment of Pediatric Status Epilepticus: A Randomized, Double-Blinded Trial of
Lorazepam and Diazepam. In addition, Drs. Daniel Lowenstein and Shlomo Shinnar will serve on
ESETT oversight and steering committee and both of them have extensive experience in designing and
executing clinical trials. We have worked collaboratively over past 3 years in designing this trial. POSITIONS
1993-94
1994-98
1998-01
Lecturer, Department of Neurology, University of Michigan
Assistant Professor, Department of Neurology, University of Michigan
Assistant Professor, Department of Neurology, University of Virginia
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2001-07
2007-2010
2007-current
2010- Current
2012-current
Associate Professor, Department of Neurology, University of Virginia
Harrison Distinguished Professor of Neurology
Professor of Neurology, University of Virginia
Eugene Meyer III Professor of Neuroscience
Director, Neuroscience Center of Excellence
PROFESSIONAL AFFILIATIONS
Society for Neuroscience; American Epilepsy Society; American Academy of Neurology; American Clinical
Neurophysiology Society; American Neurological Association.
PROFESSIONAL ACTIVITIES
Editorial Boards
1996-1999
Epilepsy Advances
1998-2006
Epilepsy research
2001-current
Contributing Editor, Epilepsy Currents
2011-Current
Neurology
2011-Current
Neurosurgery
2013Experimental Neurology
Leadership:
American Epilepsy Society
2002-2004
Board of Directors
2005-2007
Chair, Research and Training Committee, and Ex officio member of the Board
2007-2011
Executive Committee of the Board
2009-2010
President
International League Against Epilepsy
2010
Member, Therapeutics Commission
2011-2017
Member, North American Commission, Chair Education Task Force
Epilepsy Foundation (National)
2001-2009
Professional Advisory Board, Epilepsy Foundation of America
2006-2009
Chair, Research Council.
Epilepsy Research Foundation
2006-2008
Board of Directors
2008-2010
President of the Board of Directors
2010-2013
Board of Directors
Reviewer NIH Initial Review Groups Ad Hoc Member, SBIR, SEP-MDCN, BDCN1, BDCN2, NST, NAME,
CounterACT (1998-Now). Permanent Member NIH IRG Clinical Neuroscience and Disease (2004-2008).
Member Reviewer: Congressionally Directed Medical Research Program (CDMRP-DOD)CURE epilepsy
Foundation, Epilepsy Foundation.
Honors: Research Recognition Award (Basic Science) of American Epilepsy Society (2013), Lennox
Fellowship, American Epilepsy Society (1992); National Science Talent Search Scholarship (1977-84), &
National Merit Scholarship, Government of India (1971).
BIBLIOGRAPHY (15 Publications most relevant to current application):
1) Bleck T, Cock H, Chamberlain J, Cloyd J, Connor J, Elm J, Fountain N, Jones E, Lowenstein D,
Shinnar S, Silbergleit R, Treiman D, Trinka E, Kapur J. The established status epilepticus trial 2013.
Epilepsia. 2013 Sep;54 Suppl 6:89-92. PMCID pending.
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2) Kozhemyakin M, Rajasekaran K, Todorovic M, Kowalski S, Balint C and Kapur J Somatostatin type II
receptor activation inhibits glutamate release and prevents status epilepticus. Neurobiology of Disease
(2013) 54:94-104. PMCID 3628955
3) Rajasekaran K, Todorovic M and Kapur J Calcium permeable AMPA receptors are expressed in a
rodent model of status epilepticus. Annals of Neurology (2012) 72:91-102. PMCID 3408623.
4) Sun J and Kapur J M-type potassium channels modulate Schaffer collateral CA1 glutamatergic synaptic
transmission. Journal of Physiology. (2012) 590:3953-64. PMCID 3476642.
5) Rannals M and Kapur J Homeostatic strengthening of inhibitory synapses is mediated by the
accumulation of GAB-A receptors. Journal of Neuroscience (2011) 31:17,701-12. PMCID 3396123
6) Goodkin HP and J Kapur The impact of diazepam's discovery on the treatment and understanding of
status epilepticus Epilepsia. (2009) 50:2011-8. PMCID 2844441
7) Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, and Kapur J Subunit-specific trafficking of GABAA
receptors during status epilepticus. Journal of Neuroscience (2008) 28: 2527-2538. PMCID2880323
8) Goodkin HP, Yeh J-L, and Kapur J Status epilepticus increases the intracellular accumulation of
GABAA receptors. Journal of Neuroscience (2005) 25: 5511-5520. PMCID 2878479
9) Mangan PS and Kapur J, Factors underlying bursting behavior in a network of cultured hippocampal
neurons exposed to zero magnesium. Journal of Neurophysiology (2004) 91: 946-957. PMCID
2892720
10) Yen W, Williamson J, Bertram EH and Kapur J A comparison of 3 NMDA receptor antagonists in the
treatment of prolonged status epilepticus. Epilepsy Research (2004) 59: 43-50. PMCID2892717
11) Borris DJ, Bertram EH and Kapur J, Ketamine controls prolonged status epilepticus. Epilepsy Research
(2000) 42:117-122.
12) Kapur J and. Macdonald RL, Rapid seizure-induced reduction of benzodiazepine and Zn++ sensitivity
of hippocampal dentate granule cell GABAA receptors. Journal of Neuroscience (1997): 17:7532-7540.
13) Kapur J and Coulter DA, Experimental status epilepticus alters GABAA receptor function in CA1
pyramidal neurons. Annals of Neurology, 38, (1995) 893-900.
14) Kapur J, Lothman EW and DeLorenzo RJ, Loss of GABAA receptors during partial status epilepticus.
Neurology, (1994) 44: 2407-2408.
15) Kapur J, and Lothman EW, Loss of recurrent inhibition precedes delayed spontaneous seizures in the
hippocampus after tetanic electric stimulation. Journal of Neurophysiology, (1989) 61: 427-434.
RESEARCH PROJECTS ONGOING OR COMPLETED DURING THE LAST 3 YEARS:
Active Principal Investigator:
1) “Neurosteroid regulation of seizures” Agency NIH, NINDS
Principal Investigator: Jaideep Kapur.
Type: 1RO1 NS44370
Active Period: September 2003 to June 2018.
We propose to accomplish following specific aims: Aim 1) To characterize the impact of progesterone
treatment on glutamatergic synaptic transmission on CA1 pyramidal neurons and dentate granule cells of
naïve and epileptic female rats using a combination of patch clamp electrophysiology and analysis of the
expression of the AMPAR subunits via both biochemical and immunohistochemical techniques. Aim 2) To
characterize the impact of progesterone treatment on GABAergic synaptic transmission on CA1 PN and DGCs
of naïve and epileptic female rats with a similar combination of techniques as in aim 1. Aim 3) To determine
the role of progesterone receptors in progesterone-induced tolerance during progesterone treatment and
withdrawal.
2) "Treatment of status epilepticus” Agency: National Institute of Neurological Disorders and Stroke
Principal Investigator: Jaideep Kapur.
Type: 1RO1 NS040337
Active Period: September 2000 to June, 2015.
Experiments were designed to study the plasticity of AMAPA receptors on hippocampal dentate granule cells
and CA1 pyramidal neurons during two stages of status epilepticus. . In aim 1, experiments are proposed to
define the time course of modification of AMPAR-mediated transmission on CA1 pyramidal neurons and DGCs
during three stages of SE using a combination of patch clamp electrophysiological techniques. In aim 2,
experiments test whether Ca2+ can enter hippocampal neurons during seizures via AMPA receptors. In aim 3,
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Contact PD/PI: Kapur, Jaideep
experiments test whether prolonged seizures and in vitro bursting accelerate internalization of the GluR2
subunit of AMPARs. In aim 4, experiments will compare the efficacy of competitive and non-competitive
AMPAR antagonists and therapeutically available topiramate in terminating early, refractory and
3) NINDS Research Education Program for Residents and Fellows at the University of Virginia
Multi PI Mech-Co PIs: Johnston, K. and Kapur, J.
Type: 1R25NS065733- Active Period 03/03/2009-02/28/2014
This is a training grant to prepare Neurology residents in clinical and bench research.
Completed in last 3 years.
1) Mechanism and treatment of nerve agent-induced seizures, NIH
Principal investigator: Jaideep Kapur.
Type: UO1 Active period current: (06-11).
2) M current-based therapies for nerve agent seizures
Type: PR093963: Investigator initiated peer-reviewed program Congressionally Directed Medical Research
Program (CDMRP) Department of Defense.
Biosketches
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BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Silbergleit, Robert
Professor of Emergency Medicine
eRA COMMONS USER NAME (credential, e.g., agency login)
silbergleit
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
Massachusetts Institute of Technology
Cambridge, MA
University of Michigan Medical School
Ann Arbor, MI
Medical College of Pennsylvania
Philadelphia, PA
George Washington University
Washington, DC
SB
06/88
Life Sciences
MD
06/92
Medicine
Residency
06/95
Emergency Medicine
Research
Fellowship
06/97
Brain Resuscitation
A. Personal Statement
I am an emergency physician with expertise in organizing and conducting clinical trials in the acute care
setting. My past experience is as a translational researcher, working on laboratory animal models of brain
injury and participating in clinical trials in stroke as a site PI and sub-investigator. For the past seven years, I
have been a leading co-investigator in the formation and organization of the Neurological Emergencies
Treatment Trials network where I contribute to the oversight and management of all NETT trials. In the NETT I
have developed specific expertise and experience in investigating initial interventions in patients with status
epilepticus. My clinical trial leadership experience includes being the Co-Prinicpal Investigator, along with Dan
Lowenstein, of the recently completed Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), a
study of prehospital treatment of status epilepticus. RAMPART completed ahead of schedule and
underbudget. I am also a co-investigator in the clinical trial leadership for the Progesterone for Traumatic brain
injury: Experimental Clinical Treatment (ProTECT) trial which is recruiting on schedule with over 834 subjects
enrolled with moderate to severe traumatic brain injury. As in ESETT, enrollment in this trial takes place in the
earliest stages of intervention in the emergency department. In multiple trials I have developed operational
and academic expertise in Exception from Informed Consent (EFIC) for Emergency Research and its conduct
under FDA regulations. These experiences have prepared me well for my responsibilities in the current
application. ESETT has a multiple PI leadership plan, and my role is to serve as the principal investigator
responsible for the clinical coordination of the trial at the NETT CCC. Working together with the other
coordinating center investigators and with the Hub principal investigators, my responsibilities include oversight
of protocol implementation, regulatory management, human subjects’ protection (including EFIC), accrual and
monitoring. I will oversee the day to day operations of the trial, and work closely with the trial project manager
and study monitors.
B. Positions and Honors
Positions and Employment
1995-1997
Adjunct Instructor of Emergency Medicine, George Washington University
1995-1997
Clinical Instructor of Emergency Medicine, Medical College of Pennsylvania
1997-1998
Lecturer, University of Michigan Medical School
1998-2006
Assistant Professor, University of Michigan Medical School
2006-2013
Associate Professor, University of Michigan Medical School
2013Professor, University of Michigan Medical School
Biosketches
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Contact PD/PI: Kapur, Jaideep
Other Experience and Professional Memberships
Selected Research Projects and Clinical Trials
1999-2003
Principal Investigator, Hyperbaric oxygen in rodent models of cerebral ischemia
2006Principal Investigator, Rapid Anticovulsant Medication Prior to Arrival Trial
2005-2006
Co-investigator, Safety of Community Delivery of tPA in Acute Stroke
2005-2006
Co-investigator, GIS System Design for Acute Stroke Treatment in Michigan
2006Co-investigator, Neurological Emergencies Treatment Trials (NETT) Network
2009Co-investigator, Progesterone for the Treatment of Traumatic Brain Injury (ProTECT III)
1997-1998
Site Principal Investigator, HALT Stroke trial
2003-2006
Site Principal Investigator, SAINT II trial, CHANT trial
1998-1999
Site Sub-investigator, GAIN America trial
1998-2000
Site Sub-investigator, Leukarrest trial, Xe CT in Acute Stroke, Pfizer CP 101,606
2000-2004
Site Sub-investigator, IHAST trial, CFAAST trial
2003-2008
Site Sub-investigator, CLEAR trial
2006-2009
Site Sub-investigator, TNK-S2B trial
2005
Panelist investigator, PRACTISE trial
National Grant Review Activities
2002NIH/NINDS Special Emphasis Panels, (SPOTRIAS, NETT, R13, GO), reviewer
2006-2009
American Heart Association Brain 2 Study Section, member
2008-2013
NIH/NINDS-NSDK Clinical Trials Study Section, guest reviewer (08-09), member (09-13)
Editorial Boards and Editorships
2002-2011
Editorial Board Member, Annals of Emergency Medicine
2009
Guest Editor, Emergency Medicine Clinics of North America – February 2009, Vol 27, Issue 1
Journal Peer Reviewer Activities
Brain Research, Stroke, Academic Emergency Medicine, Annals of Emergency Medicine, Journal of Clinical
Anesthesia, Prehospital Emergency Care, BMC Medical Ethics, BMC Trials, BMC Neurology
Professional Society Memberships
Society for Academic Emergency Medicine, American Academy of Emergency Medicine, American Heart
Association / American Stroke Association, Society for Neuroscience, National Association of Emergency
Medical Services Physicians, Neurocritical Care Society, Society for Clinical Trials, Public Responsibility in
Medicine and Research
Honors
1986
1993
1995
1996
2004
2006
2013
Sigma Xi Research Honor Society
Alpha Omega Alpha Honor Society
SAEM National Meeting, Best Resident/Fellow Oral Presentation
Fellow, American Academy of Emergency Medicine
Annals of Emergency Medicine “Top Peer Reviewer” Status
Fellow, Stroke Council, American Heart Association
Society for Clinical Trials, Trial of the Year Award
C. Selected Peer-reviewed Publications (Selected from 78 peer-reviewed publications)
Most relevant to the current application
1. Millikan D, Rice B, Silbergleit R. Emergency treatment of status epilepticus: current thinking. Emerg Med
Clin North Am 2009;27:101-13 PMID: 19218022
2. Silbergleit R, Barsan W. Neurological emergencies. Front Neurol Neurosci 2009;25:163-73 PMID:
19478518
3. McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam Versus Diazepam For The Treatment Of
Status Epilepticus: A Meta-Analysis. Acad Emerg Med 2010;17:575-582, PMID: 20624136
4. Zhao W, Durkalski V, Pauls K, Dillon C, Kim J, Kolk D, Silbergleit R, Stevenson V, Palesch Y. An
Electronic Regulatory Document Management System for a Clinical Trial Network. Contemp Clin Trials
2010;31:27-33 PMID: 19782156
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5. Ubel PA, Silbergleit R. Behavioral equipoise: a way to resolve ethical stalemates in clinical research.
Amer J Bioethics 2011;11(2):1-8 PMID: 21337264
6. Durkalski V, Silbergleit R, Lowenstein D. Challenges in the design and analysis of non-inferiority trials: a
case study. Clin Trials 2011;8(5):601-8 PMID: 21921062
7. Silbergleit R, Lowenstein D, Durkalski V, Conwit R; for the NETT Investigators. RAMPART (Rapid
Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of
intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus
by paramedics. Epilepsia 2011;52 Suppl 8:45-7 PMID: 21967361
8. Le Roux PD, Cooper J, Guntupalli KK, Silbergleit R, Daily J, Geocadin R, Wijman CA, Suarez JI. The
Critical Care Research Networks Experience. Neurocrit Care 2012;16(1):42-54 PMID: 21796494
9. Claassen J, Silbergleit R, Weingart SD, Smith WS. Emergency Neurological Life Support: Status
Epilepticus. Neurocrit Care 2012;17 Suppl 1:73-8 PMID: 22956118
10. Silbergleit R, Biros MH, Harney D, Dickert N, Baren J; on behalf of the NETT Investigators.
Implementation of the Exception From Informed Consent Regulations in a Large Multicenter Emergency
Clinical Trials Network: The RAMPART Experience. Acad Emerg Med 2012;19:448-454 PMID 22506949
11. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; for the NETT
Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med
2012;366(7):591-600 PMID: 22335736
12. McMullan JT, Pinnawin A, Jones E, Denninghoff K, Siewart N, Spaite DW, Zaleski E, Silbergleit R. The 60Day Temperature-Dependent Degradation of Midazolam and Lorazepam in the Prehospital Environment.
Prehosp Emerg Care 2013;17:1-7 PMID: 23148574
13. Silbergleit R, Lowenstein D, Durkalski V, Conwit R; for the NETT Investigators. Lessons from the
RAMPART study-and which is the best route of administration of benzodiazepines in status epilepticus.
Epilepsia 2013;54 Suppl 6:74-7 PMID: 24001080
14. Bleck T, Cock H, Chamberlain J, Cloyd J, Connor J, Elm J, Fountain N, Jones E, Lowenstein D, Shinnar S,
Silbergleit R, Treiman D, Trinka E, Kapur J. The established status epilepticus trial. Epilepsia 2013;54
Suppl 6:89-92 PMID: 24001084
15. Dickert NW, Mah VA, Baren JM, Biros MH, Govindarajan P, Pancioli A, Silbergleit R, Wright DW, Pentz
RD. Enrollment in research under exception from informed consent: The Patients' Experiences in
Emergency Research (PEER) study. Resuscitation. 2013 Apr 16. doi:pii: S0300-9572(13)00214-1.
10.1016/j.resuscitation.2013.04.006. [Epub ahead of print] PMID: 23603291
D. Selected Research Support
5U01NS056975-06
Barsan (PI)
07/2006-08/2011, 09/2011-8/2016
Neurological Emergencies Treatment Trials Network: Clinical Coordinating Center
This grant provides the infrastructure to coordinate multiple simultaneous confirmatory phase randomized
controlled trials of acute interventions for neurological emergencies in a national multicenter research network.
Role: Co-Investigator
5U01NS056975-06S1
Barsan (PI)
07/2006-08/2011, 09/2011-8/2016
Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART)
This trial, awarded as a supplement to the NETT CCC grant, is a randomized controlled non-inferiority trial of
IM midazolam versus IV lorazepam for the treatment of prehospital status epilepticus by paramedics.
Role: Co-principal Investigator
5U01NS073476-02
Barsan et al. (PI)
09/2010-08/2014
Accelerating Drug and Device Evaluation through Innovative Clinical Trial Design-Adaptive Design Trial
This NIH/FDA funded project uses the NETT as a testbed in which to develop, simulate, and quantitatively
assess adaptive confirmatory phase trial designs (including ESETT’s) and to qualitatively evaluate the
development, acceptability, and innovation risks as perceived by various stakeholder groups.
Role: Co-Investigator
1U01NS062778-01A1
Wright (PI)
07/2009-03/2015
Progesterone for Traumatic brain injury-Experimental Clinical Treatment
This is a definitive confirmatory efficacy trial of progesterone versus placebo initiated quickly after moderate to
severe traumatic brain injury and continued for 4 days. The trial is being conducted in the NETT.
Role: Co-Investigator
Biosketches
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BIOGRAPHICAL SKETCH
NAME
POSITION TITLE
Chamberlain, James M.
Professor of Pediatrics and Emergency Medicine
eRA COMMONS USER NAME (credential, e.g., agency login)
jchamber
EDUCATION/TRAINING
INSTITUTION AND LOCATION
Rensselaer Polytechnic Institute, Troy, NY
University of Connecticut, Farmington, CT
University of Maryland, Baltimore, MD
University of Maryland, Baltimore, MD
George Washington University,
Washington, DC
DEGREE
(if applicable)
B.S.
M.D.
Residency
Chief Resident
Fellowship
YEAR(s)
1980
1984
1984-7
1997-8
1988-90
FIELD OF STUDY
Biology
Medicine
Pediatrics
Pediatrics
Pediatric Emergency
Medicine
A. Personal Statement
The objective of this proposal is to perform a randomized controlled trial of three commonly used
anticonvulsant medications for the treatment of benzodiazepine-refractory status epilepticus. Using an
adaptive randomization design, we will compare fos-phenytoin to levetiracetam to valproate for patients
with ongoing generalized status epilepticus after receiving adequate doses of benzodiazepines. To
enroll adequate numbers of pediatric patients, we will capitalize on established relationships with
hospitals in the Pediatric Emergency Care Applied Research Network (PECARN). I am one of 6 nodal
Principal Investigators for the PECARN and I was the PI for a randomized controlled trial of lorazepam
versus diazepam involving the hospitals of PECARN and Children’s Hospital of Dallas. In addition to an
established track record of enrollment in clinical trials, we specific have experience in the use of the
Exception from Informed Consent for Emergency Research under 21 CFR 50.24 for enrolling patients in
the emergency department with status epilepticus.
B. Positions and Honors
Positions and Employment
1990-96
Assistant Professor of Pediatrics. The George Washington University School of Medicine
and Health Sciences. Washington DC.
1995-present Assistant Professor of Emergency Medicine. The George Washington University School
of Medicine and Health Sciences. Washington DC.
1996-2005
Associate Professor of Pediatrics. The George Washington University School of Medicine
and Health Sciences. Washington DC.
2006-present Professor of Pediatrics and Emergency Medicine. The George Washington University
School of Medicine and Health Sciences. Washington DC.
Other Experience and Professional Memberships
1990-2001
Fellowship Director, Pediatric Emergency Medicine. Children’s National Medical Center.
Washington, DC.
2000-present Division Chief of Emergency Medicine. Children’s National Medical Center. Washington,
DC.
Biosketches
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Contact PD/PI: Kapur, Jaideep
2001-present National Steering Committee. Pediatric Emergency Care Applied Research Network.
2002-2004
Vice Chair, National Steering Committee. Pediatric Emergency Care Applied Research
Network.
2003-2006
Associate Medical Director, EMSC National Resource Center.
2004-present Chair, Pediatric Off-Patent Drug Study Steering Committee.
2006-2008
Pediatric Emergency Care Applied Research Network, Liaison to EMSC Partnership for
Children Stakeholders.
2007
Advisory Council, Pediatric Emergency Department Preparedness Guidelines, American
Academy of Pediatrics.
2008-09
Data Safety Monitoring Board. RAMPART Study (RCT of anticonvulsant medications in
prehospital status epilepticus)
2011-present Executive Committee, Pediatric Emergency Research Networks.
Honors
Jan 1999
Oct 2002
Feb 2003
May 2008
May 2010
Society of Critical Care Medicine Educational Scholarship Award. For Vardis R,
Chamberlain JM, Pollack MM. The influence of socioeconomic status on severity of
disease in children. Oral presentation at the Society of Critical Care Medicine.
The C. Robert Chambliss Award for Best Paper. Section on Transport Medicine,
American Academy of Pediatrics. For Freishstat RJ, Klein BL, Teach SJ, Johns CMS,
Arapian LS, Perraut ME, Chamberlain JM. Pediatric Interhospital Transport Utilization
Comparing Referring Hospitals With and Without Pediatric Inpatient Services. Boston,
MA. October 2002.
Lantern Award. Presented by the Government of the District of Columbia, Department of
Health, Maternal and Family Health Administration for working to improve the interface
between emergency departments and primary care providers.
Best Research Award by a Junior Faculty Member. For Ryan LM, Brandoli C, Wright JL,
Freishtat RJ, Tosi L, Hoffman EP, Chamberlain JM. Vitamin D Insufficiency in African
American Children with Forearm Fractures. Children’s National Medical Center Annual
Research Forum.
Clinical Research Mentorship Award, Children's National Medical Center.
C. Selected peer-reviewed publications (in chronological order).
Most relevevant to the current application
1. Chamberlain JM, Singh T, Baren JM, Maio RF. Food and Drug Administration Public Hearing on the
Conduct of Emergency Clinical Research: Testimony of Pediatric Emergency Care Applied
Research Network. Acad Emerg Med published February 25, 2007 as
doi:10.1197/j.aem.2006.11.024. Available at
http://www.aemj.org/cgi/content/full/j.aem.2006.11.024v1. PMID: 17322568
2. Chamberlain JM, Lillis K, Vance C, Brown KM, Fawumi O, Nichols S, Davis CO, Singh T, Baren JM
for the Pediatric Emergency Care Applied Research Network. Perceived challenges to obtaining
informed consent for a time-sensitive emergency department study of pediatric status epilepticus:
Results of two focus groups. Acad Emerg Med 2009;16:763-70. PMID: 19673713
3. Chamberlain JM, Capparelli EV, Brown KM, Vance CW, Lillis K, Mahajan P, Lichenstein R, Stanley
RM, Davis CO, Gordon S, Baren JM, Van den Anker J for the Pediatric Emergency Care Applied
Research Network. The pharmacokinetics of intravenous lorazepam in pediatric patients with and
without status epilepticus. J Pediatr 2012;160:667-672. PMIdL: 22050870
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Additional recent publications of importance to the field (in chronological order)
4. Chamberlain JM, Joseph JG, Slonim A. Reducing Errors and Promoting Safety in Pediatric
Emergency Care. Amb Pediatr 2004;4:55-63.PMID: 14731090
5. Chamberlain JM, Patel KM, Pollack MM, Brayer A, Macias CG, Okada P, Schunk JE for the
Collaborative Research Committee of the Emergency Medicine Section of the American Academy of
Pediatrics. Recalibration of the Pediatric Risk of Admission (PRISA) Score Using a Multi-Institutional
Sample. Ann Emerg Med 2004;43:461-468. PMID: 15039688
6. Ryan LM, Depiero AD, Sadow KB, Warmink CA, Chamberlain JM, Teach SJ, Johns CMS.
Recognition and Management of Pediatric Fractures by Pediatric Residents. Pediatrics
2004;114:1530-1533. PMID: 15574611
7. Freishtat RJ, Klein BL, Teach SJ, Johns CMS, Arapian LS, Perraut MD, Chamberlain JM. Admission
Predictor Modeling in Pediatric Interhospital Transport. Pediatr Emerg Care 2004;20:443-7.
8. Chamberlain JM, Patel KM, Pollack MM. The Pediatric Risk of Hospital Admission (PRISA II) Score:
A Second Generation Severity of Illness Score for Pediatric Emergency Patients. Pediatrics
2005;115:388-395. PMID: 15687449
9. Chamberlain JM, Patel KM, Pollack MM. The Association of Emergency Department Care Factors
With Admission and Discharge Decisions for Pediatric Patients. Journal of Pediatrics 2006;149:644649. PMID: 17095336
10. Chamberlain JM, Joseph JG, Pollack MM. Differences In Severity-Adjusted Pediatric Hospitalization
Rates Are Associated With Race/Ethnicity. Pediatrics 2007; 119: e1319-e1324.
11. Gorelick MH, Knight S, Alessandrini EA, Stanley RM, Chamberlain JM, Kuppermann N, Alpern ER
for the Pediatric Emergency Care Applied Research Network. Lack of Agreement in Pediatric
Emergency Department Discharge Diagnoses from Clinical and Administrative Data Sources. Acad
Emerg Med 2007 14: 646-652. PMID: 17545362
12. Stanley RM, Teach SJ, Mann NC, Alpern ER, Gerardi MJ, Mahajan PV, Chamberlain JM for the
Pediatric Emergency Care Applied Research Network. Variation in ancillary testing among pediatric
asthma patients seen in emergency departments. Acad Emerg Med 2007;4:532-8.
13. Atabaki SM, Stiell IG, Bazarian JJ, Sadow KE, Vu TT, Camarca MA, Berns S, Chamberlain JM. A
clinical decision rule for cranial computed tomography in minor pediatric head trauma. Arch Pediatr
Adolesc Med. 2008;162:439-45. PMID: 18458190
14. Shaw KN, Ruddy RM, Olsen CS, Lillis KA, Mahajan PV, Deam JM, Chamberlain JM for the Pediatric
Emergency Care Applied Research Network. Pediatric patient safety and emergency departments:
Unit characteristics and staff perceptions. Pediatrics 2009;124:485-493. PMID: 19651575
15. Alessandrini EA, Alpern ER, Chamberlain JM, Shea JA, Gorelick MH. A New Diagnosis Grouping
System for Child Emergency Department Visits. Acad Emerg Med 2010;17:204-213. PMID:
20370751
D. Research Support
Ongoing
HHSN275201100017C (Chamberlain JM)
9/1/11-5/31/14
NICHD.
Use of Lorazepam for the Treatment of Pediatric Status Epilepticus.
The purpose of this contract is to pursue FDA approval of lorazepam for the treatment of pediatric status
epilepticus by performing a randomized controlled trial of lorazepam versus diazepam.
U03MC00006-11-00 (Chamberlain JM)
HRSA/MCHB/EMSC
Washington-Boston-Chicago Applied Research Node
Biosketches
9/1/11–8/31/15
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Contact PD/PI: Kapur, Jaideep
The purpose of this grant is to establish the Washington-Boston-Chicago research node of the Pediatric
Emergency Care Applied Research Network.
R01 HS20270-01A1 (Alpern)
1/01/2011-10/31/16
AHRQ
Improving the Quality of Pediatric Emergency Care Using an Electronic Medical Record Registry and
Clinician Feedback.
The overall goal is to establish a data registry from electronic health records to collect and report quality
measures of emergency care provided to children. The project will establish measurable benchmarks
and implement a clinician feedback intervention to improve performance.
Completed
1R01HS019712 (Marcin J)
9/30/10-9/30/13
AHRQ
Factors Associated with Quality of Care Delivered to Children in US EDs.
The purpose of this grant is to validate an implicit measure of emergency care quality and to study the
factors associated with high-quality.
Biosketches
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Contact PD/PI: Kapur, Jaideep
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
eRA COMMONS USER NAME (credential, e.g., agency login)
Professor of Neurology
Daniel H. Lowenstein, MD
LOWENSTEIN
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
University of Colorado
B.A.
1974
Mathematics
The Pennsylvania State University
M.S.
1977
Human Development
University of Victoria
1978
Pre-medical
Harvard Medical School
M.D.
1983
Medicine
Personal Statement
I am a clinician-scient ist with expertise in epilepsy, and particular interests in the genetics of hu man epilepsy,
status epilepticus, and the provision of neurological care in the pre-hospital setting. I have more than 25 yea rs
of experience in the dia gnosis and treatment of patients with epilepsy, and have b een involved in numero us
clinical and translational epilepsy research proje cts. I am Co-Principal Investigator and member of the NETT
Clinical Coordinating Center Executive Committee, and was Co-Principal Investigator with Dr. Rob
ert
Silbergleit for the Rapid Anticonvulsant Medications Prior to Arrival Trial (RAMPART) study. I also was the P.I.
of the Pre-Hospital Treatment of Status Epilepticus (PHTSE) trial, which was the basis for RAMPART. I am the
PI of the Ep ilepsy Phenome/Genome Project (EPGP), an in ternational, multi-institutional, collaborative study
that is collecting detailed phenotype date on 5 ,250 subjects with specific forms of epilepsy, with the aim of
determining the genetic determinants of their disease with whole exome and whole genome sequencing, a nd
serve as PI of two components of the Epi4K Ce nter Without Walls, which is in the process of se quencing at
least 4,000 individuals with epilepsy over the next 4 year s. As Associate Dean for Clinical and Translational
Sciences and a member of the Board of Director s of the UCSF Clinical and Translational Sciences Institute, I
am heavily involved in efforts here at UCSF and nationa lly to improve the clinic al/translational sciences
infrastructure.
Research and Professional Experience:
1978-1979 Research Assistant in Vascular Surgery, Univ. of Colorado School of Medicine
1983-1984 Resident in Pediatrics, Univ. of California, School of Medicine (UCSF)
1984-1986 Resident in Neurology, UCSF
1986-1987 Chief Resident in Neurology, UCSF
1987-1989 Research Fellow in Molecular Biology
1987-2000 Attending Physician, San Francisco General Hospital and Moffit-Long Hospitals
1989-1996 Assistant Professor of Neurology, UCSF
1992-2000 Director, Epilepsy Research Laboratory, UCSF
1993- 2000 Faculty member, UCSF Graduate Program in Neuroscience
1996-1998 Associate Professor of Neurology, Anatomy and Neurosurgery, UCSF
1997-2000 Robert B. and Ellinor Aird Chair in Neurology, UCSF
1998-2000 Professor of Neurology, Anatomy and Neurosurgery, UCSF
2000-2002 Carl W. Walter Professor of Neurology and Dean for Medical Education, Harvard Medical School
2000-2002 Director, Program in Brain Plasticity and Epileptogenesis, Dept. of Neurology, BIDMC
2002Professor of Neurology, UCSF
2002Director, UCSF Epilepsy Center
2003Director, Physician-Scientist Education and Training Programs
2006Associate Dean for Clinical and Translational Sciences
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Honors and Awards:
1973
B.A. with honors in Mathematics, University of Colorado
1976
The Pennsylvania State University Graduate School Fellowship
1987
National Research Service Award - National Institutes of Health
1989
Clinical Investigator Development Award - National Institutes of Health
1991
Epilepsy Foundation of America Research Award
1992
UCSF Academic Senate Distinction in Teaching Award
1992
Klingenstein Fellowship in the Neurosciences
1993
UCSF Kaiser Award for Excellence in Teaching
1994
UCSF Class of 1994 Faculty Teaching Award
1997
American Neurological Association Distinguished Teacher Award
1998
Alpha Omega Alpha Robert J. Glaser Distinguished Teacher Award (AAMC)
2001
American Epilepsy Society Basic Science Research Award
2006
Holly Smith Award for Exceptional Service to the UCSF School of Medicine
2009
UCSF Chancellor’s Award for Public Service
2013
Ambassador for Epilepsy Award, International League Against Epilepsy
2013
“The Last lecture”, University of California, San Francisco
2013
Raymond D. Adams Lecturer, American Neurological Association
C. Selected Peer-Reviewed Publications (selected from >135 peer reviewed articles)
Most Relevant to the Current Application
1. Lowenstein DH, Alldredge BK. Status Epilepticus at an Urban Public Hospital in the 1980s. Neurology
1993;43:483-488. PMID: 8450988
2. Yaffe K, Lowenstein DH. Prognostic Factors in the Use of Pentobarbital Coma for the Treatment of
Refractory Status Epilepticus. Neurology 1993;43:895-900. PMID: 8492944
3. Lowenstein DH, Alldredge, BK. Current Concepts: Status Epilepticus. The New England Journal of
Medicine 1998;338:970-976. PMID: 9521986
4. Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, O’Neil N, Gottwald MD, Ulrich S, Neuhaus JM,
Segal MR, Lowenstein DH. Prehospital Treatment of Status Epilepticus: A Randomized, Controlled Trial
of Paramedic-Administered Benzodiazepine Treatment. The New England Journal of Medicine
2001;345:631-637. PMID: 11547716
5. Parent JM, Valentin VV, Lowenstein DH. Prolonged Seizures Increase Proliferating Neuroblasts in the
Adult Rat Subventricular Zone-Olfactory Bulb Pathway. Journal of Neuroscience 2002;22:3174-3188.
PMID: 11943819
6. Chang BS, Lowenstein DH. Mechanisms of Disease: Epilepsy. The New England Journal of Medicine
2003;349:1257-1266. PMID: 14507951
7. Glaser CA, Gilliam S, Honarmand S, Tureen J, Lowenstein DH, Anderson LJ, Bollen A, Solbrig M.
Refractory Status Epilepticus in Encephalitis. Neurocritical Care 2008;9:74-82. PMID: 18097641
8. Kelley MS, Jacobs MP, Lowenstein DH; NINDS Epilepsy Benchmark Stewards. The NINDS epilepsy
research benchmarks. Epilepsia. 2009;50:579-82. PMID: 19317887
9. Loring DW, Lowenstein DH, Barbaro NM, Fureman BE, Odenkircher J, Jacobs MP, Austin JK, Dlugos DJ,
French JA, Gaillard WD, Hermann BP, Hersdordder DC, Roper SN, Van Cott AC, Grinnon S, Stout A.
Common data elements in epilepsy research: Developme nt and implementation of the NINDS Epilep sy
CDE Project. Epilepsia 2011;52:1186-1191. PMID: 21426327
10. Rossetti AO, Lowenstein DH. Management of refractory status epilept icus in adults: still more questions
than answers. Lancet Neurology 10:922-930, 2011. PMID: 21939901
11. Silbergleit R, Durkalski V, Lowenstein DH, Conwit R, Pancioli A, Palesch Y, Barsan
W and the
Neurological Emergencies Treatment Trials Investigat ors. Intramuscular versus intravenous therapy for
prehospital status epilepticus. The New England Journal of Medicine 366:591-600, 2012. PMID: 22335736
12. The Epi4K Investigators. Epi4K: Gene discovery in 4,000 Genomes. Epilepsia 53:1457-1467, 2012. PMID:
22642626
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13. Nesbitt G, McKenna K, Mays V, Carpenter A, Miller K, Williams M and The E PGP Investigators. The
Epilepsy Phenome/Genome Project (EPGP) informatics pla tform. Journal of Medical Informatics 82:248259, 2013. PMID: 22579394
14. The EPGP Collaborative. The Epilepsy Phenome/Genome Project. Clinical Trials: Journal of the Society for
Clinical Trials 10:568-586, 2013. PMID: 23818435
15. The Epi4K Consortium and the Epilepsy Phenome/Genome Project. De novo mutations in epileptic
encephalopathies. Nature doi: 10.1038/nature12439. [Epub ahead of print] PMID: 23934111
D. Selected Research Support
Ongoing Research Support
U01NS077276 (A118377, fund 21357)
Lowenstein
(PI)
09/30/11 – 08/31/16
Epi4K – Phenotyping and Clinical Informatics Core
This grant supports a core that collects and validates the phenotypic information of various cohorts of patients
with epilepsy from throughout the world, and organizes these data for use in genomic analyses to be carried
out by the Epi4K Center Without Walls.
Role: PI
U01 NS053998 (A106437, fund 30127)
Lowenstein
(PI)
05/01/07 – 04/30/14
The Epilepsy Phenome/Genome Project
The major goal of this project is to carry out a large-scale, national, multi-institutional, collaborative research
project aimed at advancing our understanding of the genetic basis of the most common forms of idiopathic and
cryptogenic epilepsies and a subset of symptomatic epilepsy; i.e. epilepsies that are probably related to
genetic predispositions or developmental anomalies rather than exogenous, acquired factors.
Role: PI
Epilepsy Research Foundation, JHU subcontract (A121063, fund 72802)
Ziai (PI)
06/01/12-05/31/14
Validation of the ANI-SI Dry EEG Headset in Time-Critical Applications
This grant supports a prospective, observational study of the use of a rapid-application EEG headset for the
detection of seizures and status epilepticus in the emergency department and intensive care settings.
Role: Co-Investigator
Epilepsy Study Consortium Inc. (A120617, fund 72697)
Lowenstein, Kuzniecky, French (PIs)
08/01/12-07/31/17
The Human Epilepsy Project (HEP)
The major goal is to carry out a prospective, observational study of selected patients with newly diagnosed
epilepsy, with a focus on the identification of biomarkers associated with the progression of disease and
treatment response.
Role: PI
U01 NS056975, Univ. of Michigan subcontract (A119304, fund 84785)
Barsan and Lowenstein (PIs)
09/01/11 – 08/31/16
Neurological Emergencies Treatment Trials Network (NETT): Clinical Coordinating Center
This grant supports the creation and implementation of a national network of clinical centers capable of
carrying out clinical research to address high priority questions about the diagnosis and treatment of patients
with acute neurological emergencies.
Role: PI
UL1TR000004 (A119683, fund 29571)
Biosketches
Johnston
(PI)
Page 84
Contact PD/PI: Kapur, Jaideep
07/01/12 – 06/20/16
Clinical Translational Science Institute
This program aims to create an integrated academic home that transforms research and education in clinical
investigation and translational science at UCSF and throughout the community.
Role: Co-Investigator
U01 NS77274, Duke subcontract (A119187, fund 72347)
Berkovic, Goldstein, Lowenstein (PIs)
1 of 7 Epi4K: Gene discovery in 4,000 epilepsy genomes
09/01/11-07/30/16
This grant supports the basic administrative functions of the Epi4K Center Without Walls.
Role: PI
U01 NS056975 Silbergleit and Lowenstein (PIs)
09/01/11 – 08/31/16
Rapid Anticonvulsant Medication Prior to Arrival (RAMPART) Trial
This grant supports a prospective, controlled trial of the efficacy and safety of intramuscular midazolam versus
intravenous lorazepam in the pre-hospital treatment of convulsive status epilepticus.
Role: PI
Biosketches
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Contact PD/PI: Kapur, Jaideep
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
SHLOMO SHINNAR, MD, PHD
PROFESSOR OF NEUROLOGY, PEDIATRICS
AND EPIDEMIOLOGY AND POPULATIONS
HEALTH
eRA COMMONS USER NAME (credential, e.g., agency login)
SSHINNAR123
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
COLUMBIA UNIVERSITY, NYC, NY
ALBERT EINSTEIN COL OF MED, BRONX, NY
ALBERT EINSTEIN COL OF MED, BRONX, NY
BA
PHD
MD
1971
1977
1978
PHYSICS
NEUROPHYSIOLOGY
MEDICINE
PERSONAL STATEMENT;
The goal of the proposed clinical trial is to determine the optimal therapy for Established Status Epilepticus
ESE) defined as status epilepticus that has not responded to appropriate doses of benzodiazepines. Drugs to
be compared are intravenous fosphenytoin, Leviteracetam and valproate. The study will include both children
and adults. This is a double blind randomized clinical trial. My role is to be a member of the executive
committee with participation in all functions of that committee. I will also co-direct the phenomenology core
which will classify the outcomes centrally. I have had longstanding interest and expertise in pediatric status
epilepticus and in clinical trials in children with neurological disorders. I am currently the PI of the FEBSTAT
study (Consequences of Prolonged Febrile Seizures in Childhood (NS 43209) where I also direct the
phenomenology core. I also serve on the executive committee of the Childhood Absence Epilepsy trial (PI:
Glauser, NS045911) where I also direct the phenomenology core. That trial successfully recruited 454 children
with newly diagnosed childhood absence into an RCT. I have had considerable experience with multicenter
trials and have classified over 1000 cases of pediatric epilepsy as part of NIH funded trials. I expect this to be a
productive and fruitful collaboration.
PROFESSIONAL EMPLOYMENT:
Academic Appointments
Albert Einstein College of Medicine, Bronx, NY
1983-1988 -Assistant Professor of Neurology and Pediatrics
1988-1993 -Associate Professor of Neurology and Pediatrics
1993-Professor of Neurology and Pediatrics
2006-Professor of Epidemiology and Population Health
Montefiore Medical Center, Bronx, NY
2002-Hyman Climenko Professor of Neuroscience Research
1986- Director, Comprehensive Epilepsy Management Center
1983-1986
Co-Director
1994Attending in Neurology and Pediatrics
1983-1989
Assistant Attending in Neurology and Pediatrics
1989-1994
Associate Attending in Neurology and Pediatrics
BOARD CERTIFICATION:
1979
National Board of Medical Examiners
1984
American Board of Pediatrics
1984
American Board of Psychiatry and Neurology: (Child Neurology)
1996-2015
Added qualification in Clinical Neurophysiology
AWARDS AND HONORS:
1989
American Epilepsy Society Research Recognition Award
Biosketches
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Contact PD/PI: Kapur, Jaideep
2011
2013
CURE New Yor Epilepsy Research Leadership Award
JAvits Neuroscience Investigator Award (for FEBSTAT - NS
43209)
SELECTED PROFESSIONAL ACTIVITIES:
American Epilepsy Society – Board: Councilor 1993-1995, ex-officio 2006-2008; 2012- current
Pediatric Guidelines Taskforce 1994-2013 ; Awards Committee 2000-2008, chair-2004-2008;
American Academy of Neurology: Epilepsy section- chair 2006-2008, chair elect 2004-2006
Epilepsy Foundation of America, Task Force on Consensus Statement on Convulsive Status Epilepticus
1991-1995; 2003-2007
Montefiore Medical Center Institutional Review Board: 1985- , vice chair 1989- , chair 2010Albert Einstein College of Med, Committee on Clinical Investigations : 1987- , vice chair 1989NINDS study section – Clinical Trials NSD-K, member 2005-2009
SELECTED PUBLICATIONS RELEVANT TO THIS TRIAL:
1. Shinnar S, Pellock JM, Moshe SL, Maytal J, O'Dell C, Driscoll SM, Alemany M, Newstein D, DeLorenzo
RJ. In whom does status epilepticus occur: Age-related differences in children. Epilepsia 1997;38:907-914.
2. Sillanpaa M, Shinnar S. Status epilepticus in a population-based cohort with childhood-onset epilepsy in
Finland. Ann Neurol 2002; 52:303-310. PMID: 12205642
3. Glauser TA, Cnaan A, Shinnar S, HIrtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC for
the Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid and lamotrigine in childhood
absence epilepsy. N Engl J Med 2010;362:790-799.
4. Hesdorffer DC, Shinnar S, Lewis DV, Moshe SL, Nordli DR Jr, Pellock JM, MacFall J, Shinnar RC, Masur D,
Frank LM, Epstein LG, Litherand MS, Seinfeld S, Bello JA, Chan S, Bagiella E, Sun S and the FEBSTAT study
team. Design and Phenomenology of the FEBSTAT Study. Epilepsia 2012; 53:1471-1480. PMID: 22742587
NIHMS#379528
5. Shinnar S, Bello JA, Chan S, Hesdorffer DC, Lewis DV, MacFall J, Pellock JM, Nordli DR, Frank LM, Moshe
SL, Gomes W, Shinnar RC, Sun S for the FEBSTAT Study Team. MR Imaging abnormalities following Febrile
Status Epilepticus in Children: The FEBSTAT Study Neurology. 2012;79:871-877 PMID: 22843278
PMCID: PMC3425848
ADDITIONAL 10 REFERENCES
1. Maytal J, Shinnar S, Moshe SL, Alvarez LA. Low morbidity and mortality of status epilepticus in children.
Pediatrics 1989; 83:323-331.
2. Shinnar S, Maytal J, Krasnoff L, Moshe SL. Recurrent status epilepticus in children. Ann Neurol
1992;31:598-604.
3. Dodson WE, DeLorenzo RJ, Pedley TA, Shinnar S, Treiman DM, Wannamaker BB. The treatment of
convulsive status epilepticus: Recommendations of the Epilepsy Foundation of America's working group on
status epilepticus. JAMA 1993;270:854-859.
4.. Berg AT, Shinnar S, Levy SR, Testa FM. Status epilepticus in children with newly diagnosed epilepsy. Ann
Neurol 1999;45:618-623.
5. Haut SR, Shinnar S, Moshe SL, O'Dell C, Legatt AD. The association between seizure clustering and
convulsive status epilepticus in patients with intractable complex partial seizures. Epilepsia 1999;1832-1834.
6. Shinnar S, Berg AT, Moshe SL, Shinnar R. How long do new onset seizures in children last? Ann Neurol
2001;49:659-664.
7. Berg AT, Shinnar S, Testa FM, Levy SR, Frobish D, Smith SN. Status epilepticus after the initial diagnosis
of epilepsy in children. Neurology 2004;631027-1034. PMID: 15452294
8. Sillanpaa M, Shinnar S. Long-Term Mortality in Childhood-Onset Epilepsy. N Engl J Med 2010;363:25222529.
9. Nordli DR Jr, Moshe SL, Shinnar S, Hesdorffer DC, Sogawa S, Pellock JM, Lewis DV, Frank LM, Shinnar
RC, Sun S. Acute EEG findings in children with febrile status epilepticus: Results of the FEBSTAT study.
Neurology 2012; 79:2180-2186 PMID: 23136262
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10. Holland K, Shinnar S. Status epilepticus in children. Handb Clin Neurol 2012; 108:795-812. PMID:
22939066.
Ongoing Research Support: .
Project Number:
R01 NS 43209-01A1 Shlomo Shinnar (PI)
Source:
NIH/NINDS
Title:
Consequences of Prolonged Febrile Seizures in Childhood
Dates:
2/1/03-5/1/137
To examine the consequences of febrile status epilepticus and clarify the relationship between febrile
epilepticus, mesial temporal sclerosis and subsequent epilepsy and cognitive impairment.
Project Number:
Source:
RO1-NS045911 Tracey Glauser (Principal Investigator)
NIH/NINDS
9/30/03-6/31/14
Title:
Treatment of Childhood Absence Epilepsy Study
To look at factors which contribute to treatment failure, either due to lack of seizure control or development of
dose limiting side effects in childhood absence epilepsy comparing ethosuximide, valproic acid and lamotrigine
monotherapy. Dr Shinnar is a member of the executive committee and director of the phenomenology, EEG
and neuropsychology cores.
Project Number:
Source:
1401DK066174 S. Furth (Principal Investigator)
NIH/NINDS
7/1/09-6/30/14
Title:
Prospective Study of Chronic Kidney Disease in Children
To determine the risk factors for accelerated decline in renal function; incidence, nature, magnitude and
temporal evolution of impaired brain function and structure; prevalence of risk factors for cardiovascular
disease and implications of growth failure and its treatment on morbidity in children with chronic kidney
disease. Dr Shinnar is a consultant to this study.
Project Number:
1U10NS077308-01 Shlomo Shinnar and Richard Lipton Co-Pis
Project Title:
Einstein Center for Excellence in Clinical Trials in Neuroscience (Neuro-NEXT)
Dates of Approved
9/30/2011 – 8/31/2018
Project
Source:
NINDS
One of 25 centers funded nationally to be part of the NeuroNEXT network and conduct clinical trials in
Neuroscience with an emphasis on Phase 2 trials.
Project Number:
1 P20 NS080185, PI: James O McNamara MD, Duke University
Project Title:
Prevention of Temporal Lobe Epilepsy
Dates of Approved
2012-2015
Project:
Source:
NINDS
A center without walls to study prevention of temporal lobe epilepsy. Dr Shinnar is a coinvestigator who is
providing input from the FEBSTAT study
Project Number:
R01 NS066929, PI: Janet Soul MD, Boston Children’s Hospital
Source:
NINDS
Title:
Pilot trial of Bumetanide for Neonatal Seizures
Biosketches
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Contact PD/PI: Kapur, Jaideep
Dates:
2010-2015
A pilot study to assess the safety and efficacy of bumetanide in the treatment of neonatal seizures. Dr Shinnar
is a member of the steering committee.
NIH/NINDS P20 NS080181
PI: Jerome Engel Jr MD, UCLA
The Epilepsy Bioinfomatics Study (EpiBioS) 2012-2015
Source:
NINDS
No support
A planning grant to design a center without walls to eventually do antiepeliptogeneses trials focusing on post
traumatic epilepsy.
Biosketches
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BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Cloyd, James
Weaver Endowed Chair for Orphan Drug
Development, Professor and Director, Center for
eRA COMMONS USER NAME (credential, e.g.,
Orphan Drug Research College of Pharmacy,
agency login)
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as
nursing include postdoctoral training and residency training if applicable )
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if
applicable)
Purdue University, West Lafayette, IN
B.S.
1971
Pharmacy
University of Kentucky, Lexington, KY
PharmD
1976
Clinical Pharmacy
University of Kentucky, Lexington, KY
Residency
1976
Clinical Pharmacy
University of Washington, Seattle, WA
Post-Doc
Fellowship
1985-86
Clinical
Pharmacokinetics
A. Personal Statement
The focus of my research is the clinical pharmacology of CNS drugs. These studies have included laboratory
investigations of drug solubility, stability, and pharmacology; drug safety and pharmacokinetics in healthy
volunteers and patients; and efficacy trials. Among the clinical trials I’ve designed and directed are Phase I
and III studies or rectal diazepam for seizure emergencies. Most recently my research group has initiated
studies in dogs and healthy human volunteers investigating the pharmacokinetics and pharmacodynamics of
benzodiazepines and benzodiazepine prodrugs as rescue therapy and the potential use of intravenous
topiramate for neonatal seizures. This background provides me with the expertise and experience to evaluate
the potential clinical value of compounds with anti-seizure activity identified through laboratory screening as
well as the design, execution, and analysis of Phase I-IV trials.
B. Positions and Honors
Postions
1976 – 1980
Assistant Professor, College of Pharmacy, University of Minnesota.
1976 – 1985
Clinical Pharmacist, Epilepsy Center, St. Paul-Ramsey Medical Center, St. Paul, Minnesota.
1981 – 1993
Associate Professor, College of Pharmacy, University of Minnesota.
1982 – 1996
Head, Department of Pharmacy Practice, College of Pharmacy, University of Minnesota.
1993 – present Professor, College of Pharmacy, University of Minnesota
1996 – 2006
Director, Epilepsy Research and Education Program, College of Pharmacy
2000 – 2006
Associate Dean for Research, College of Pharmacy
2006 – 2007
Co-director, Epilepsy Research and Education Program
2004 – present
Weaver Endowed Chair for Orphan Drug Development and Director, Center for Orphan
Drug Development
2007 - present Director, Center for Orphan Drug Research
Honors
1981
1988
1991
1992
1997
Morse-Amoco Foundation Award, University of Minnesota
(Outstanding University Teacher)
Distinguished Alumnus Award, Purdue University School of Pharmacy
Fellow-American College of Clinical Pharmacy
Education Award-American College of Clinical Pharmacy
Academy of Distinguished Teachers-University of Minnesota
Biosketches
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Contact PD/PI: Kapur, Jaideep
2000
Association
2005
Fellow-Academy of Pharmaceutical Research and Science, American Pharmacists
Research Achievement Award-American Pharmacists Association
Biosketches
Page 91
Contact PD/PI: Kapur, Jaideep
C. Selected Peer-reviewed Publications (of 100)
Driefuss FE, Rosman NP, Cloyd JC, Pellock JM, Kuzniecky RI, Lo WD, Matsuo F, Sharp GB, Conry JA,
Bergen DC, Bell WE. A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures.
NEJM, 338:1869-75, 1998.
Cloyd JC, Lalonde R, Beniak TE, Novack GD. A Single Blind, Crossover Comparison of the Pharmacokinetics
and Cognitive Effects of a New Rectal Diazepam Gel with Intravenous Diazepam. Epilepsia, 39(5):520-526,
1998
Cloyd JC, Dutta S, Cao G, Walch JK, Collins SD, Granneman GR, et al. Valproate Unbound Fraction and
Distribution Volume Following Rapid Infusions in Patients with Epilepsy. Epilepsy Research, 2003; 53:19-27.
PMID: 12576164
Ahn JE, Cloyd JC, Brundage RC, Marino SE, Conway JM, Ramsay RE, White JR, Musib LC, Rarick JO,
Birnbaum AK, Leppik IE. Phenytoin Half-Life and Clearance during Maintenance Therapy in Adults and
Elderly with Epilepsy, Neurology, 71:38-43, 2008
Ivaturi VD, Riss JR, Kriel RL, Cloyd JC. Pharmacokinetics and tolerability of intranasal diazepam and
midazolam in healthy adult volunteers. Acta Neurol Scand, 2009; Nov;120(5):353-7
Marino SE, Leppik IE, Birnbaum AK, Conway JM, Musib LC, Brundage RC, Ramsay RE, Pennel PB, White JR,
Gross CR, Rarick JO, U Mishra U, Cloyd JC. Steady-state Carbamazepine Pharmacokinetics following Oral
and Stable-Labeled Intravenous Administration in Epilepsy Patients: Effect of Race and Sex. Clin Pharmacol
Ther. 2012 Mar;91(3):483-8
Hardy BT, Patterson EE, Cloyd JM, Hardy RM, Leppik IE. Double-masked, placebo-controlled study of
intravenous levetiracetam for the treatment of status epilepticus and acute repetitive seizures in dogs. J Vet
Intern Med. 2012 Mar-Apr;26(2):334-40
Puranik YG, Birnbaum AK, Marino SE, Ahmed G, Cloyd JC, Remmel RP, Leppik IE, Lamba JK. Association of
carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in
patients with epilepsy.
Pharmacogenomics. 2013 Jan;14(1):35-45
Ivaturi V, Kriel R, Brundage R, Loewen G, Mansbach H, Cloyd J. Bioavailability of Intranasal vs. Rectal
Diazepam, Epilepsy Res. 2013 Feb;103(2-3):254-61
Clark AM, Kriel RL, Leppik IE, Marino SE, Mishra U, Brundage RC, Cloyd JC. Intravenous topiramate:
comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers. Epilepsia. 2013
Jun; 54(6):1099-1105
Clark AM, Kriel RL, Leppik IE, White JR, Henry TR, Brundage RC, Cloyd JC. Intravenous topiramate: Safety
and pharmacokinetics following a single dose in patients with epilepsy or migraines taking oral topiramate.
Epilepsia. 2013, Jun; 54(6): 1106-11
Agarwal SK, Kriel RL, Brundage RC, Ivaturi VD, Cloyd JC. A pilot study assessing the bioavailability and
pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers. Epilepsy
Res. 2013 Aug;105(3):362-7.
Bleck T, Cock H, Chamberlain J, Cloyd J, Connor J, Elm J, Fountain N, Jones E, Lowenstein D, Shinnar S,
Silbergleit R, Treiman D, Trinka E, Kapur J. The established status epilepticus trial 2013. Epilepsia. 2013
Sep;54 Suppl 6:89-92
Coles LD, Patterson EE, Sheffield WD, Mavoori J, Higgins J, Michael B, Leyde K, Cloyd JC, Litt B, Vite C,
Biosketches
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Worrell GA. Feasibility study of a caregiver seizure alert system in canine epilepsy. Epilepsy Res. 2013 Aug
17.
D. Research Support-Current
GlaxoSmithKline, “Differential Pharmacological Effect of Ezogabine on Canine EEGs”, 2013-14, Cloyd JC (PI)
Paralyzed Veterans of American and Medtronic, “Two-way Crossover of Oral and Inrtavenous Baclofen”, 201314, Cloyd, JC (co-PI)
Department of Defense, “Identifying New Therapies for Infantile Spasms”, 2013-2016, Galanopoulou A (PI),
Cloyd, JC (Co-PI)
NHLBI 1R01HL103927-01A1, “Phase II Clinical Trial to Evaluate the Benefits of Postconditioning in STEMI”,
2011-2012, Traverse, JH (PI), Cloyd, JC (Co-I)
NINDS 1R21NS072166-01, “Canine Status Epilepticus: A Translational Platform for Human Therapeutic
Trials”, 2010-2013, Leppik (PI), Cloyd, JC (Co-PI)
Genzyme, “Development of a Pharmacotherapy and Pharmacogenetics of Inherited
Metabolic Disease Post-PharmD Fellowship”, 2010-14, Utz J, PI; Cloyd JC, (Co-PI)
Biosketches
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BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Jones, Elizabeth Blanchard, MD
Associate Professor of Emergency Medicine
eRA COMMONS USER NAME (credential, e.g., agency login)
joneseb
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
Louisiana State University, Baton Rouge, LA
LSU School of Medicine, Shreveport, LA
Medical College of Virginia, Richmond, VA
Carolinas Medical Center, Charlotte, NC
BS
MD
05/1982
06/1986
06/1989
06/1999
Biochemistry
Medicine
Internal Medicine
Emergency Medicine
A. Personal Statement
I have many experiences that qualify me to contribute to the ESETT. I have been in the Department of
Emergency Medicine at UT Houston for 14 years. I have experience in EMS, both as the medical director of
an EMS agency and as the medical director of an EMS community college program. For the past 6 years, I
have been the PI of our NETT project. I created our SETNETT organization, set up four studies in our area
and trained staff and co-investigators in the UT Department of Emergency Medicine. Under my guidance the
SETNETT has become one of the top NETT hubs. I have more than met the requirements of a hub PI. I
currently serve on the NETT Operations Committee which meets by conference call weekly. I serve on the
NETT Hub-Spoke Relations Committee. I have successfully obtained community approval for 2 EFIC studies
in 3 large cities in Texas, involving more than 30 hospitals and IRBs. I am a member of the planning
committee for the ESETT.
B. Positions and Honors
Positions
1999 – Present Society of Academic Emergency Medicine
1999 – Present Harris County Society of Emergency Physicians
1999 - Present Associate Professor, Department of Emergency Medicine, University of Texas Medical School
at Houston, Emergency Department Faculty, Memorial Hermann Hospital—Texas Medical Center, Research
Faculty, Memorial Hermann Hospital – Southwest, Emergency Department faculty, Lyndon Baines Johnson
General Hospital
2009 – Present Harris County Medical Society
Certifications
American Board of Internal Medicine, September 13, 1989
American Board of Emergency Medicine, October, 2001, recertified November, 2010
ACLS, Course Director, 1992 – Present
ATLS, Instructor, 1994 – 2004
ATLS, 1994 – Present
PALS, Instructor, 1998 – Present
Biosketches
Page 94
Contact PD/PI: Kapur, Jaideep
Professional Organizations
American College of Physicians, 1986-1996
Honors and Awards
Memorial Hermann Healthcare System, Hero Award, June 9, 2001.
The University of Texas Medical School at Houston, Master Teacher, 2002 – 2003, 2005 – 2006.
The University of Texas Medical School at Houston, Dean’s Award for Excellence in Teaching, 2003, 2004
Award of Appreciation, 2004 Biomedical Engineering Students
Department of Emergency Medicine, Chief’s Award, 2005
C. Peer-Reviewed Publications
1. McMullen JT, Pinnawin A, Jones E, Denninghoff, et al. The 60-day temperature dependant degradation of
midazolam and lorazepam in the pre-hospital environment. Prehosp Emerg Care. 2013 Jan-Mar; 17 (1) 1-7.
2. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W for the NETT
Investigators. Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus. NEJM. 2012;
366(7): 591-600
3. Martin-Schild S, Albright KC, Tanksley J, Pandav V, Jones EB, Grotta JC, Savitz SI. Zero on the NIHSS
does not equal the absence of stroke. Ann Emerg Med. 2011; 57: 42-45
4. Jones EB, Chambers KM, Luis H. Thoracic trauma: Initial treatment and radiographic evaluation.
Emergency Medicine Reports, Vol 22, No 18, 2001
5. Jones EB, Robinson D. Unstable angina. Emergency Medicine Reports, Vol 21, No 10, May 8, 2000
6. Jones EB, Marshall E, Ornato JP, et al. Frequency of unfavorable cardiac events documented by routine
telemetry after uncomplicated percutaneous transluminal coronary angioplasty. Am J Cardiol, 1993; 71: 122930
7. Jones EB, Gonzalez ER, Boggs JG, et al. Safety and efficacy of rectal prochlorperazine for the treatment
of migraine in the emergency department. Ann Emerg Med, 1994; 24: 237-241
8. Chambers KA, Jones EB, Haro L. Thoracic trauma: Non-cardiac injuries. Emergency Medicine Reports.
Vol 22, No 19, 2001
9. Haro L, Jones EB, Chambers KA. Thoracic trauma: Cardiovascular injuries. Emergency Medicine
Reports. Vol 22, No 20, 20.
D. On-Going Support
U10NS058930
Jones (PI)
09/01/2007 – 07/31/2017
Neurological Emergencies Treatment Trials Southeast Texas Clinical Site Hub. Principal Investigator, Group of
17 centers funded to establish centers to conduct emergency neurological research.
Role: PI
U01NS040406
Ginsberg (PI)
06/01/2006 – 05/31/2013
Albumin in Acute Stroke Trial (ALIAS) 2, Site Principal Investigator, Multicenter study of albumin versus
placebo in acute stroke
Role: Co-I
U01NS056975
Barsan (PI)
08/01/2008 – 07/31/2012
Rapid Anti-convulsant Medication Prior to Arrival Trial (RAMPART): Multicenter study of pre-hospital use of IM
midazolam versus IV lorazepam for treatment of status epilepticus,data collection complete.
Role: Co-I
U01NS062778
Wright (PI)
Biosketches
07/01/2010 – 06/30/2013
Page 95
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Progesterone for the Treatment of Traumatic Brain Injury (ProTECT): Multicenter study of IV progesterone
versus placebo for moderate to severe acute traumatic brain injury.
Role: Co-I
U01NS062835
Barsan (PI)
06/01/2010 – 08/31/2013
Platelet-oriented Inhibition in New TIA and minor ischemic stroke (POINT) Trial: Multicenter study of
clopidogrel and aspirin versus aspirin alone for prevention of stroke following transient ischemic attack.
Role: Co-I
U01NS069498
Johnston (PI)
08/01/2011 – 07/31/2013
Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial: Multicenter study of targeted glucose control
(treatment group-IV insulin with target 80-130mg/dL) verses control therapy of sub q insulin plus basal insulin
with target glucose less than 180 mg/dL in acute ischemic stroke.
Role: Co-I
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BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Mark R. Conaway
Professor
Translational Research and Applied Statistics
University of Virginia
eRA COMMONS USER NAME (credential, e.g., agency login)
mconaway
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
Grinnell College, Grinnell, Iowa
University of Minnesota, Minneapolis, Mn
BA
PhD
1980
1985
Mathematics
Statistics
A. Personal Statement
This project is a multi-center randomized clinical trial and I will serve as the statistician blinded to study results.
I have expertise in the design and analysis of both early stage and randomized clinical trials. Prior to joining the
faculty at the University of Virginia, I was a faculty member in the statistical center of the Cancer and Leukemia
Group B (CALGB), a cooperative cancer group coordinating multi-center oncology trials. As a faculty member
at UVA, I have been the principal statistician for randomized trials in oncology, neurology and critical care
medicine.
B. Positions and Honors
PROFESSIONAL EXPERIENCE
1985-1989
Assistant Professor, Dept of Statistics and Actuarial Science, University of Iowa
1989-1990
Visiting Assistant Professor, Dept of Biostatistics, Harvard School of Public Health
1990-1991
Assistant Professor, Dept of Statistics and Actuarial Science, University of Iowa
1991-1994
Assistant Professor, Div of Biometry, Duke University Medical Center, Durham, NC
1994-1996
Associate Professor, Div of Biometry, Duke University Medical Center, Durham, NC
1996-2002
Associate Professor, Div of Biostatistics and Epidemiology, The University of Virginia
2002-2003
Professor, Div of Biostatistics and Epidemiology, The University of Virginia
2003–2008
Director, Div of Biostatistics and Epidemiology, The University of Virginia
2008-2011
Professor, Div of Biostatistics and Epidemiology, The University of Virginia
2011-present
Professor, Translational Research and Applied Statistics, University of Virginia
2012
Fellow, American Statistical Association
C. Selected Peer-reviewed publications (of 180 total)
1. Conaway, M. (1989) ``Conditional Likelihood Methods for Repeated Categorical Responses'', Journal
of the American Statistical Association, 84, 53- 62.
2. Conaway, M. (1990) ``A Random Effects Model for Binary Data'', Biometrics, 46, 317 - 328.
3. Conaway, M.(1992) ``The Analysis of Repeated Categorical Measurements Subject to Nonignorable
Nonresponse''. Journal of the American Statistical Association, 87, 817-824.
4. Conaway, M. (1993) ``Nonignorable Nonresponse Models for Time Ordered Categorical Responses''
Applied Statistics, 42, 105-112.
5. Conaway, M. and Petroni, G. (1995) ``Bivariate Sequential Designs for Phase II Trials.'' Biometrics, 51,
656-664. PMID: 7662852
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6. Conaway, M. and Petroni, G. (1996) ``Designs for Phase II Trials Allowing for a Trade-Off Between
Response and Toxicity.'' Biometrics, 52, 1375-1386. PMID:8962459
7. Kantoff P., Halabi, S., Conaway, M., et al. (1999) ''Hydrocortisone with or without mitoxantrone in men
with hormone-refractory prostate cancer: Results of Cancer and Leukemia Group B 9182 study. Journal
of Clinical Oncology 17:2506-2517. PMID: 10561316
8. Dawson, N., Conaway, M., Halabi S, et al. (2000) '' A randomized study comparing standard versus
moderately high dose megestrol acetate in advanced prostate cancer: Cancer and Leukemia Group B
(CALGB) study 9181.'' Cancer, 88,4: 825-832. PMID: 10679652
9. Conaway,M , Dunbar, S., and Peddada, S. (2004) “Designs for single or multiple agent phase I trials”,
Biometrics, 60, 661-669. PMID: 15339288
10. Wolf, A., Conaway, M., Crowther, J., Hazen, K., Nadler, J., Oneida, B., and Bovbjerg, V. (2004)
Translating Lifestyle Intervention to Practice in Obese Patients with Type 2 Diabetes: Improving Control
with Activity and Nutrition (ICAN) , Diabetes Care 27 (7): 1570-1576 PMID: 15220230
11. Willson DF, Thomas NJ, Markovitz BP, Bauman LA, DiCarlo JV, Pon S, Jacobs BR, Jefferson LS,
Conaway MR, Egan EA, and members of the Pediatric Acute Lung Injury and Sepsis Investigators
(PALISI) (2005) “Effect of Exogenous Surfactant (Calfactant) in Pediatric Acute Lung Injury, Journal of
the American Medical Association 293 (4): 470-476 PMID: 15671432
12. Stevenson, R., Conaway, M., Chumlea, WC, Rosenbaum, P., Fung, E., Henderson, R., Worley, G.,
Liptak, G., O’Donnell, M., Samson-Fang, L., and Stallings, V. (2006) “Growth and Health in Children
with Moderate-Severe Cerebral Palsy”, Pediatrics, Vol 118, Number 3, 1010-1018. PMID: 16950992
13. Willson DF, Thomas NJ, Tamburro R, Truemper E, Truwit J, Conaway M, Traul C, Egan EE; in
collaboration with Pediatric Acute Lung and Sepsis Investigators Network. (2013) The Relationship of
Fluid Administration to Outcome in the Pediatric Calfactant in Acute Respiratory Distress Syndrome
Trial. Pediatric Critical Care Medicine. 2013 Aug 6. [Epub ahead of print] PMID: 23925143
14. Wages, N. , Conaway, M. and O’Quigley, J. (2011) Continual reassessment method for partial
ordering, Biometrics. Mar 1. [epub ahead of print] PMID: 21361888. PMC3141101
15. Wages NA, Conaway MR (2013) Specifications of a continual reassessment method design for phase I
trials of combined drugs. Pharmaceutical Statistics. 2013 Jul;12(4):217-24 PMID: 23729323. NIHMSID:
498868. PMCID: PMC3771354
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D. Research Support
ACTIVE
5R01CA142859-02 (Conaway)
07/2010 - 12/2013
NIH-NCI
Designs for Phase I Trials for Combinations of Agents
Role: Principal investigator
This proposal develops novel designs for phase I trials that include multiple therapeutic agents
5R01HL075792-09 (Kramer)
04/2013 - 03/2016
NIH/NHLBI
Comprehensive Magnetic Resonance in PAD
Role: Co-investigator
The goal of the study is to develop diagnostic methods in PAD that allow study of progression and regression
of disease.
5P30CA044579-20 (Weber)
07/1997 - 01/2016
NIH /NCI
Cancer Center Support Grant (Biostatistics Core)
Role:Co-investigator
Specific Aim: This is to support investigators in the UVA Cancer Center in the design and analysis of studies
related to cancer.
1U01NS069498-01A1 (Johnston)
09/01/11-03/31/16
NIH-NINDS
Stroke Hyperglycemia Insulin Network Effort (SHINE)
Role: Co-investigator
This is a proposal for a multi-center clinical trial of glucose control for patients with ischemic stroke.
2P01CA104106-06 (Paschal)
04/2011-03/2016
Signalling and Progression in Prostate Cancer
NIH-NCI
Role: Co-investigator
This is a renewal of a program project that explores the role of signaling molecules in the progression of
prostate cancer.
Gates Foundation (Petri)
Performance of Rotavirus and Oral polio Vaccines In Developing countries
Role: Co-investigator
The goal of the study is to understand the spectrum of biologic reasons for failure of the oral vaccines for polio
and rotavirus.
7P01HL055798-16 (Hedrick)
07/01/12-6/30/17
Immune Cells in Atherosclerosis and Vascular Disease
NIH-NHLBI
Role: Co-investigator
This program project grant centers around the immunobiology of atherosclerosis, with the goal of
understanding how macrophages and lymphocytes communicate in the aortic wall to modulate atherogenesis.
Completed
R01 NS050192-01 (Johnston, KC)
NIH-NINDS
Glucose Regulation in Acute Stroke (GRASP)
Role: co-I
This is a multicenter, randomized, controlled pilot clinical trial.
Biosketches
09/2005 - 05/2010
Page 99
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5U01HL088925-04 (Kron/Johnston)
07/2007 – 06/2012
NIH/NHLBI/NINDS
Network for CT Surgical Investigations in Cardiovascular Medicine
Role: Co-investigator
This is a network of institutions doing cardiovascular surgery clinical trials.
Biosketches
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BIOGRAPHICAL SKETCH
Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Nathan Benjamin Fountain
Professor of Neurology
eRA COMMONS USER NAME (credential, e.g., agency login)
NBF2PNIH
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION
University of Iowa, Iowa City, Iowa
University of Iowa College of Medicine
University of Virginia
University of Virginia
University of Virginia
University of Virginia
DEGREE
(if applicable)
YEAR(s)
FIELD OF STUDY
B.S.
M.D.
Intern
Residency
Fellowship
Fellowship
1985
1989
1989-1990
1990-1993
1993-1994
1994-1996
Zoology
Medicine
Internal Medicine
Neurology
Clinical Neurophysiology
Experimental Epilepsy
A. Personal Statement
Dr. Fountain has extensive experience in epilepsy clinical trials of drugs and devices, which will benefit his
role in scientific design and practical implementation of the project. He has a long-standing research with
publications in treatment of status epilepticus, EEG and especially nonconvulsive status epileptics. Dr.
Fountain has an extensive history of successful NIH and industry sponsored epilepsy research with a welldeveloped clinical research program infrastructure. He has designed and been the multisite PI for multiple
studies and conducted more than 50 clinical trials.
B. Positions and Honors
Positions
1992-1993
Chief Resident, Department of Neurology, University of Virginia Health, Charlottesville, VA
7/96-6/01
Assistant Professor, Neurology, University of Virginia School of Medicine, Charlottesville, VA
7/01-6/09
Associate Professor, Neurology, University of Virginia School of Medicine, Charlottesville, VA
10/97-present Director, F.E. Dreifuss Comprehensive Epilepsy Program, University of Virginia,
10/97-Present Director, EEG/Epilepsy Fellowship, University of Virginia, Charlottesville, VA
2/98-Present Director, Children Specialty Services Neurology Clinics, UVA, Charlottesville, VA
7/09-Present Professor, Neurology, University of Virginia School of Medicine, Charlottesville, VA
Honors
1985
1982-1985
1984
1985
1985
1988
1989
1994-1995
1996
2007
2007
2010
Bachelor of Science with Special Honors
Iowa Foundation Scholarships and University of Iowa Honors Society Member
Iowa Undergraduate Scholar
University of Iowa Certificate of Achievement/Collegiate Scholar
Medical Student Research Fellowship
University of Iowa Class of 1934 Academic Scholarship
Barry Freeman Fellowship for study in Papua New Guinea
Epilepsy Foundation of America Clinical Research Fellowship Grant
Alpha Omega Alpha Medical Honor Society
Best Doctors in America
Visiting Professorship, Ain Shams University, Cairo, Egypt, October 15-19, 2007
Visiting Professorship, Anshan Changda Hospital, Anshan, China, November 20-24, 2010
Other Experience and Professional Memberships
Biosketches
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Grant and Federal Review Committees
1998-1999
Scientific Review Committee, Comitato Telethon Grants, Rome, Italy
2000
Israel Science Foundation
2002
Georgian -U.S. Civilian Research and Development Foundation
2004
CDC Quality of Epilepsy Care Grant Review Panel, 2004-R19
2006
Epilepsy Quality of Care Measures, Expert Review Panel, Boston University
2007
CDC Epidemiology of Epilepsy Grant Review Panel, 2007-R05
2008-present Chairman, FDA Peripheral and CNS Drugs Advisory Committee
2009
CDC Special Emphasis Grant Review Panel
2010-present Epilepsy Foundation Research Grant Review Committee
Professional Societies: National Offices and Committees
1999-2004
Epilepsy Education Committee, American Academy of Neurology
2001-2004
Annual Course Committee, American Epilepsy Society
2001-2002
Practice Parameter Reviewer Network, American Academy of Neurology
2002-2004
Scientific Program Committee, American Epilepsy Society
2003
Ad Hoc Reviewer, Clinical Policies Committee, American College of Emergency Physicians
2005-present National Association of Epilepsy Centers, Board of Directors (Treasurer 2010-2012, VP 2012-)
2005-present Critical Care Monitoring Committee, American Clinical Neurophysiology Society
2006
NAEC Epilepsy Quality Care Indicators Committee
2007-2010
Annual Course Committee, American Epilepsy Society
2007-present Professional Advisory Board (PAB), Epilepsy Foundation (of America), Chair-elect (2011-)
2008-present Web Publishing Committee of Content Advisory Committee, Epilepsy Foundation PAB
2008-present Advocacy Committee, Epilepsy Foundation PAB
2008-2010
AAN Epilepsy Quality Care Indicators Work Group, Co-Chair
2002-2008
Epilepsy Foundation of Virginia, President
2003-2013
Virginia Neurological Society, Executive Committee; Councilor (03-05), Treasurer (05-07), Vice
President (07-09), President elect (09-11), President (11-13 )
2011-present Epilepsy Research Foundation, Board of Directors
A. Selected peer-reviewed publications (Selected from 92 publications)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Fountain, N.B., Lothman, E.W. Pathophysiology of status epilepticus. Journal of Clinical
Neurophysiology 1995;12(4):326-342.
Fountain, N.B., Eberhard, D.A. Primary angiitis of the CNS associated with cerebral amyloid angiopathy:
report of two cases and review of the literature. Neurology 1996;46;190-197.
Bear, J., Fountain, N.B., Lothman, E.W. Responses of the superficial entorhinal cortex in vitro in slices
from naive and chronically epileptic rats. Journal of Neurophysiology 1996;76(5):2928-2940.
Fountain, N.B., Kim, J.S., Lee, S.I. Sleep deprivation activates epileptiform discharges independent of the
activating effects of sleep. Journal of Clinical Neurophysiology 1998;15(1):69-75.
Fountain, N.B., Bear, J., Bertram, E.H., Lothman, E.W. Responses of deep entorhinal cortex are
epileptiform in an electrogenic rat model of chronic temporal lobe epilepsy. Journal of Neurophysiology
1998;80:230-240.
Bertram, E.H., Zhang D.X., Mangan P., Fountain, N., Rempe D. Functional anatomy of limbic epilepsy - a
proposal for central synchronization of a diffusely hyperexcitable network. Epilepsy Research
1998;32:194 205.
Fountain, N.B., Lopes, M.B.S. Control of primary angiitis of the CNS associated with cerebral amyloid
angiopathy by cyclophosphamide alone. Neurology 1999;52(3):660-662.
Quigg, M., Fountain, N.B. Conduction aphasia elicited by stimulation of the left posterior superior
temporal gyrus. Journal of Neurosurgery, Neurology & Psychiatry 1999;66:393-396.
Fountain, N.B., Adams, R. E. Midazolam treatment of acute and refractory status epilepticus. Clinical
Neuropharmacology 1999;22(5):261 267.
Fountain, N.B. Status epilepticus: risk factors and complications. Epilepsia 2000;41(Suppl 2):S23-S30.
Laxer K, and Ganaxolone Presurgical Study Group. Assessment of ganaxolone anticonvulsant activity
using a randomized double-blind, presurgical trial design. Epilepsia 2000;41(9):1187-1194.
Biosketches
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12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Frucht M.M., Quigg, M., Schwaner, C., Fountain, N.B. Distribution of seizure precipitants among epilepsy
syndromes. Epilepsia 2000;41:1534-1539.
Fountain, N.B., Waldman, W.A. Effects of benzodiazepines on triphasic waves: Implications for
nonconvulsive status epilepticus. Journal of Clinical Neurophysiology, 2001;18(4):345-352.
Pellock JM, Glauser TA, Bebin EM, Fountain NB, Ritter FJ, Coupez RM, Shields WD. Pharmacokinetic
Study of Levetiracetam in Children. Epilepsia 2001;42(12):1574-1579.
Glauser TA, Pellock JM, Bebin EM, Fountain NB, Ritter FJ, Jensen CM, Shields WD. Efficacy and safety
of levetiracetam in children with partial seizures: an open-label trial. Epilepsia 2002;43:518-524.
Quigg MS, Armstrong RF, Farace E, Fountain NB. Quality of life outcome is associated with cessation
rather than reduction of psychogenic nonepileptic seizures. Epilepsy and Behavior 2002;3:455-459.
Gullapalli D, Fountain NB. Clinical correlation of occipital intermittent rhythmic delta activity (OIRDA).
Journal of Clinical Neurophysiology, 2003;20(1):35 41.
Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status
epilepticus. Neurology 2003;61:1066-1073.
Fountain, N.B., May A.C. Epilepsy and Athletics. Clinics in Sports Medicine 2003;33(3):605-616.
Kirby D, Fountain NB, Quigg MS. Standardized mental status testing for nonconvulsive status epilepticus.
American Journal of Electroneurodiagnositc Technology 2004;44(3):199-201.
Sahoo SK, Fountain NB. Epilepsy in football players and other land based contact/collision sport athletes:
when can they participate and is there an increased risk? Current Sports Medicine Reports,
2004;3(5):284-5.
Fountain NB, Conry JA, Rodríguez-Leyva I, Gutierrez-Moctezuma J, Salas E, Coupez R, Stockis A, Lu Z.
Prospective Assessment of Levetiracetam Pharmacokinetics During Dose Escalation in 4- to 12-Year-Old
Children With Partial-Onset Seizures on Concomitant Carbamazepine or Valproate. Epilepsy Research
2007;74:60-69.
Biton V, Rosenfeld WE, Whitesides J, Fountain NB, Vaiciene N, Rudd GD. Intravenous lacosamide as
replacement for oral lacosamide in patients with partial-onset seizures (SP616). Epilepsia
2008;49(3):418–424.
Sachdeo RC, Fountain NB, Montouris GD, Beydoun A, Hull RP, Doty P, Rudd GD. Maximum tolerated
dose of oral lacosamide as adjunctive therapy for partial-onset seizures: results from an open-label trial,
2008, submitted.
Fountain NB, Van Ness PC, Swain-Eng R, Tonn S, Bever CT Jr, et al. Quality improvement in neurology:
AAN epilepsy quality measures: Report of the Quality Measurement and Reporting Subcommittee of the
American Academy of Neurology. Neurology 2011;76(1):94-99.
Morrell MJ and RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of
medically intractable partial epilepsy. Neurology 2011;77(13):1295-304.
Engel J Jr, et al. Early randomized surgery for epilepsy trial (ERSET). JAMA 2012;307(9):922-930.
Fountain NB, Krauss G, Isojarvi J, Dilley D, Doty P, Rudd GD. Safety and tolerability of adjunctive
lacosamide IV loading dose for in lacosamide-naïve patients with partial-onset seizures. Epilepsia
2013;54(1):58-65.
Wicks P, Fountain NB. Patient Assessment of Physician’s Performance of Epilepsy Quality Care
Measures. Neurology Clinical Practice 2012:2;335-342.
Hirsch LJ, Laroche SM, Gaspard N, Gerard E, Svoronos A, Herman ST, Mani R, Arif H, Jette N, Minazad
Y, Kerrigan JF, Vespa P, Hantus S, Claassen J, Young GB, So E, Kaplan PW, Nuwer MR, Fountain NB,
Drislane FW. American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology:
2012 version. J Clin Neurophysiol 2013;30:1-27
C. Research Support
(From 6 NIH, 3 Foundation, and 42 Industry Sponsored Grants)
Ongoing Research Support
U01 NS 053998
D. Lowenstein, R. Kuzniecky (co-PI)
Epilepsy Phenome/Genome Project.
Biosketches
11/1/10-12/31/12
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Contact PD/PI: Kapur, Jaideep
This is a multicenter study to collect phenotype characteristics and genotype information from people with
defined epilepsy, intended to identify epilepsy risk genes through techniques such as whole exon sequencing.
Role: Co-investigator, 5%
R01 NS 058634-01A2
N. Barbaro, M. Quigg (co-PIs)
1/1/09-12/31/14
NIH-NINDS
Radiosurgery verus Open Surgery for Epilepsy (ROSE) trial. This is a multicenter, randomized, blinded
controlled trial of radiosurgery versus standard temporal lobectomy for temporal lobectomy due to mesial
temporal sclerosis.
Role: Co-investigator, 5%
SANTE
R. Fisher (PI)
7/1/05-6/30/12
Medtronic
Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE)
This study is a randomized controlled double-blind trial of electrical stimulation of the anterior nucleus of the
thalamus as treatment for intractable partial-onset seizures in adults. No overlap is anticipated.
Role: Co-Investigator, 1%
Neuropace Pivotal Trial
M. Morrell (PI)
7/1/06-6/30/12
Neuropace
This study is a randomized controlled double-blind trial of responsive neurostimulation from an intracranial
electrical device as treatment for intractable partial-onset seizures in adults. No overlap is anticipated.
Role: Co-Investigator, 1%
Completed Research Support (Investigator-initiated; last 3 years)
R01-39466
A. Herzog (PI)
7/01/07-6/30/09
NIH-NINDS
Progesterone therapy for women with Epilepsy
This was a randomized controlled double-blind trial of progesterone as treatment for intractable partial-onset
seizures in women subcategorized by the presence of catamenial seizures.
Role: Co-Investigator
U01 NS042372
J. Engel (PI)
10/1/04-9/30/06
NIH
Early Randomized Surgical Epilepsy Trial (ERSET)
This was a randomized clinical trial to compare the efficacy of anterior temporal lobectomy to standard medical
therapy.
Role: Co-Investigator
Biosketches
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BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Hannah Rutherford Cock
Reader in Clinical Neurology
Honorary Consultant Neurologist
eRA COMMONS USER NAME (credential, e.g., agency login)
hannahrc
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
University of London, UK
University of London, UK
BSc (i)
MBBS
06/86
06/89
University of London, UK
MD
05/96
London Deanery, UK
CST
01/01
Physiology
Medicine & Surgery
Research Doctorate,
Neuroscience
Completion Specialist
Training, Neurology
A. Personal Statement
The goal of the proposed research is to undertake a multicenter, randomized double blind trial to determine the
comparative effectiveness and safety of fos phenytoin, levetiracetam and valproate in subjects with
benzodiazepine-refractory (established) status epileptics. I have been instrumental in developing this project
from the outset, developed from an initial workshop at an international status epilepticus colloquium in 2009. I
have an established reputation in epilepsy research and status epilepticus in particular, with a change in
emphasis from laboratory to clinical research and teaching following the birth of a disabled child in 2006. I chair
the UK Epilepsy Research Network interventions & therapeutics Clinical Study Group, am a member of the
International League Against Epilepsy (ILAE) status epilepticus classification taskforce, and represent the ILAE
Commission for European Affairs on the Epilepsy Advocacy Europe Joint task force. I am the lead for status
epilepticus guidelines (clinical and pharmacy) in my own regional neuroscience centre, and undertake expert
witness/consultancy work in medicolegal and industry contexts, including specifically around the management
of status epilepticus. I have experience managing and working within multidisciplinary research and clinical
teams, including adhering to protocols, timescales and budgets. Although we had originally hoped to undertake
the work in Europe as well as USA, differences in ethics and licensing rules pose barriers, and it has become
clear that it is most appropriate to build on the existing successes of NETT and PECARN in the USA in order to
deliver the goal. I also have considerable experience in trial recruitment and site management in my host
institution, in secure electronic communications/data handling, and in working collaboratively on international
projects including as European Neurological Society Teaching Course Director, and a clinical lead for the elearning project ebrain. In summary, I have been involved in the development of this project from the outset,
and my clinical and research skills make me ideally suited to undertaken the proposed role as a member of the
blinded clinical adjudication core.
B. Positions and Honors
List in chronological order previous positions, concluding with the present position. List any honors. Include
present membership on any Federal Government public advisory committee.
2001-2003 Senior Lecturer, Advanced Welcome Fellow Institute of Neurology, University College London
Neurology & Honorary Consultant Neurologist, Epilepsy Group, National Hospital for Neurology, London
11/2000-09/2001 Locum Consultant Epilepsy Group, National Hospital for Neurology & Neurosurgery
Neurology
02/1999-09/2001 Clinical Lecturer, Institute of Neurology and Honorary Registrar, Epilepsy Group, National
Hospital for Neurology & neurosurgery, London
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02/1998-01/1999 Specialist Registra, National Hospital for Neurology & Neurosurgery,London
03/1996-01/1998 Registrar, Royal Free Hospital, Neurology
02/1994–02/1996 MRC Training fellow, Royal Free Hospital, London (Supervisor Prof AHV
Schapira),Neurology (mitochondrial disease)
02/1993 – 01/1994, Medical Registrar, Hillingdon Hospital, London
08/89 – 01/1993, Basic Medical & Surgical training posts, Various London Hospitals.
Current Employment
 Reader in Clinical Neurology, Division Clinical Sciences, St Georges, University of London, Cranmer
Terrace, London SW17 0RE (Senior Lecturer 2003-11, Reader 2011-)
 Honorary Consultant Neurologist, Epilepsy Group, Atkinson Morley Regional Neuroscience Centre, St
George’s NHS Trust, Blackshaw Road, SW17 0QT (2003-)
Current external roles:
 Expert Advisor on Neurology to London Underground Ltd, Occupational Health (2001-).
 Editorial Board, European Journal of Neurology (2013-)
 Executive Committee, European Neurological Society (2006-), Teaching Course Director (2012-)
 Chair, Interventions & Therapeutics Clinical Study Group, UK Epilepsy Research Network (2010 - )
 Clinical Lead, ebrain www.ebrainjnc.com
 Epilepsy Action, Clinical Advisor (2007 – )
 ILAE Status Epilepticus classification taskforce (2010-)
Previous external roles
 Editorial Boards Epilepsia (2009-12); Journal of Neurology (2008-12)
 Chair, Association of British Neurology Trainees, (1998-2000)
Professional memberships
 Fellow of the Royal College of Physicians (2006-), Member (1992-)
 Member International League Against Epilepsy (1999-)
 British Medical Association (1989-)
 Association of British Neurologists (1996-)
 Fellow of the Higher Education Academy (2001-)
 American Academy of Neurology (2006 - )
 Royal Society of Medicine (2008-)
Prizes & Scholarships
 Medical Research Council Scholarship for BSc training
 Douglas Cree Prize for Medicine
 Medical Research Council Clinical Training Fellowship
 Royal Society of Medicine, Section of Neurology, Gordon Holmes Registrar's Prize
 International League Against Epilepsy (UK) Milleneum Young Scientific Investigators Prize
 Wellcome Trust Advanced Training Fellowship
1985
1989
1994
1996
1999
2001
C. Selected Peer-reviewed Publications (selected from 50 peer-reviewed publications)
Most relevant to the current application:
1. Kelso A R C, Cock H R, Status epilepticus. Practical Neurology (2005) 5(6):322-333
2. Acute down-regulation of adenosine A1 receptor activity in status epilepticus. Hamil N E, Cock H R,
Walker MC Epilepsia 2012; 53(1):177-88) PMID: 22150479
3. Established Status Epilepticus Treatment Trial. Cock H R, on behalf of ESETT group Epilepsia (2011)
52(suppl8): 50-52 PMID: 21967363
4. Gibbs, J E, Cock H R. Administration of Levetiracetam after prolonged status epilepticus does not
protect from mitochondrial dysfunction in a rodent model Epilepsy research (2007) 73(2):208-212
PMID: 17085017
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5. Gibbs J E, Walker M C, Cock H R. Levetiracetam: antiepileptic properties and protective effects on
mitochondrial dysfunction in experimental status epilepticus Epilepsia (2006) 47(3):1-10 PMID:
16529608
6. Walker M C, Cross H, Smith S, Young C, Aicardi J, Appleton R, Aylett S, Besag F, Cock H R,
DeLorenzo R, Drislane F, Duncan J S, Ferrie C, Fujikawa D, Gray W P, Kaplan P, Koutroumandis M,
O’Regan M, Plouin P, Sander J W A, Scott R, Shorvon S D, Treiman D, Wasterlain C, Wieshmann U.
Nonconvulsive status epilepticus: Epilepsy Research Foundation Workshop Reports. Epileptic
Disorders (2005) 7(3):253-96 PMID:16162436
7. Cock H R, Schapira AHV. A comparison of lorazepam and diazepam as initial therapy in convulsive
status epilepticus. QJM, (2002) 95:1-7 PMID: 11937649
Additional recent publications of importance to the field (in chronological order)
1. Nilsen K E, Walker M C, Cock H R. Characterisation of the tetanus toxin model of refractory focal
neocortical epilepsy in the rat. Epilepsia (2005) 46(2):1-9 PMID: 15679498
2. Pearce K M, Cock H R. An audit of electroencephalography requests: use and misuse Seizure (2006)
15(3):184-189 PMID: 16488630
3. Nilsen K E, Kelso A R C, Cock H R. Antiepileptic effect of gap junction blockers in a rat model of
refractory focal cortical epilepsy Epilepsia (2006) 47(7): 1169-1175 PMID: 16886980
4. Acceptability and effectiveness of a strategy for the communication of the diagnosis of psychogenic
non-epileptic seizures Hall-Patch L, Brown R, House A, Howlett S, Kemp S, Lawton G, Mayor R, Smith
P, Reuber M and NEST Collaborators Group (Including Cock H R) Epilepsia (2010) 51(1):70-78 PMID:
19453708
5. Screening for Depression in Epilepsy Clinics. A Comparison of Conventional and Visual-Analogue
Methods. Rampling JR, Mitchell AJ, Von Oertzen J, Docker J, Jackson J, Cock HR, Agrawal N.
Epilepsia (2012) 53(10):1713-21 2012 PMID: 22765759
6. Understanding patient perceptions following a psycho-educational intervention for psychogenic nonepileptic seizures. Baxter S, Mayor R, Baird W, Brown R, Cock H, Howlett S, House A, Messina J,
Smith P, Reuber M. Epilepsy and behaviour (2012) 24(3) 487-93 PMID: 22386913
7. Short-term outcome of psychogenic nonepileptic seizures after communication of the diagnosis. Mayor
R, Brown RJ, Cock H, House A, Howlett S, Singhal S, Smith P, Reuber R. Epilepsy and behaviour
(2012); 25(5) 686-71 PMID: 23168089
8. Which Symptoms are indicative of Depression in Epilepsy Settings? An Analysis of the Diagnostic
Significance of Somatic and Non-Somatic Symptoms Journal of Affective Disorders. Mitchel AJ, Iannou
N, Rampling JM, von Oertzen T, Cock HR, Agrawal A. Journal of Affective Disorders (2013)
250(3):861-7 PMID: 23668901
D. Research Support
I have had minimal research support since the birth of my son who has severe disabilities in 2006. I have lead
only one grant application (for a pragmatic status epilepticus trial in Europe) as which was unsuccessful, and
collaborated on one other (as below).
Completed Research Support
 2008 – 2010 Co-Applicant, UK NIHR, Research for patient benefit grant. Non-epileptic Seizures Treatment
(NEST) study: an evaluation of the feasibility of a randomised controlled trial of a psycho-educational
intervention. Principal applicant Dr M Reuber, Sheffield University/Teaching Trust; Co-applicants Dr HR
Cock, Prof A House (Leeds, Liaison Psychiatry), Richard Brown (Manchester, Clinical Psychology), Dr S
Kemp (Leeds, Clinical Psychology), M Bradburn (Sheffield, Statistics), Prof P Smith (Cardiff, Neurologist),
11/08, £185,813 over 26 months

2006-2009 British Medical Association, Vera Down Award 3-nitrotyrosine in cell death and epilepsy.
Awarded to Dr Andrew Kelso (under my sponsorship), £20,000, all attributed to SGUL.

2006 – 2008 Neuroscience Research Foundation A study of the neuromodulatory role of adenosine in
status epilepticus in vivo. Project grant, 04/2006, £25,000 over 2 years all attributed to SGUL
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
2005-2008 St George’s-Royal Holloway Strategic Initiative. A study of the neuromodulatory role of
adenosine in status epilepticus in vitro and in vivo. PhD Studentship, Nicola Hamil, 10/2005, £45,000 over
3 years, all attributed to SGUL

2004-2006 St George’s Hospital Charitable Foundation Fellowship Mechanisms and markers of seizure
related brain damage in vivo. MD Studentship, Andrew Kelso, £110,000, all attributed to SGUL.

2003-2006 Unrestricted Educational Grant, UCB Pharma Pharmaceuticals. Levetiracetam and
neuroprotection in status epilepticus: characterization of biochemical mechanisms. (Dr HR Cock, Dr M
Walker, Dr P Patsalos). £110,000, all attributed to SGUL

2003-2004 Epilepsy Research Foundation Desmond Pond Fellowship, Focal drug treatment and the role
of gap junctions in focal cortical epilepsy. Awarded to Dr K Nilsen (post doctoral fellow) under my
sponsorship, £60,000, all attributed to SGUL

2001-2004 Wellcome Trust Advanced Fellowship: Mechanisms of cell death and neuroprotection following
status epilepticus. £373,200, of which approx £80,000 attributed to SGUL.

2001-2003 Brain Research Trust. Neuronal stem cell grafting as a treatment for focal cortical epilepsy (Dr
HR Cock, Dr MC Walker). £104,354 (UCL)

2001-2003, Unrestricted Educational Grant, R W Johnson Pharmaceutical Research Institute. Topiramate
and its effects in the termination of status epilepticus, £115,000 (Dr MC Walker, Dr PN Patsalos, Dr HR
Cock, UCL)

2001-2002, Unrestricted Educational Grant, UCB Pharma Pharmaceuticals; Development of a clinical
epilepsy database, £20,000, Dr H Cock (UCL).
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BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
William G. Barsan, MD
Professor of Emergency Medicine
eRA COMMONS USER NAME (credential, e.g., agency login)
wbarsan
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
University of Cincinnati, Cincinnati, Ohio
BS
06/72
Biology
Ohio State University, Columbus, Ohio
MD
06/75
Medicine
University of Virginia Hospital, Charlottesville, VA
Residency
06/77
Surgery & Radiology
University of Cincinnati Medical Ctr, Cincinnati, OH
Residency
06/79
Emergency Medicine
A. Personal Statement
As PI of the NETT Clinical Coordinating Center, I helped develop the infrastructure for the NETT and the
policies and procedures for running all aspects of the network. This trial, ESETT is one which is of great
importance to the NETT and other clinical trial networks. The potential implications from the results of this
study include the advancement of knowledge regarding the treatment options for patients suffering from Status
Epilepticus. I will be involved at all levels within the network for this trial, including study design and
development, ongoing management of the trial, financial and contractual arrangements for the network and
maintaining productive collaborations with NINDS, the Statistical and Data Management Center and the
Hubs/Spoke Complexes.
B. Position and Honors
Positions and Employment
1979-1985
Assistant Professor, Dept of Emergency Medicine, Univ of Cincinnati College of Medicine
1981-1984
Residency Coordinator, Dept of Emerg Medicine, Univ of Cincinnati College of Medicine
1985-1991
Associate Professor, Dept of Emergency Medicine, Univ of Cincinnati College of Medicine
1991-1992
Professor, Dept of Emergency Medicine, Univ of Cincinnati College of Medicine
1992-1999
Professor and Section Head, Dept of Emergency Medicine, Univ of Michigan
1999-2012
Professor and Chair, Dept of Emergency Medicine, Univ of Michigan
2012-present Professor, Dept. of Emergency Medicine, Univ of Michigan
Other Experience and Professional Memberships
1985-1993
Society for Academic Emergency Medicine, Board of Directors
1991-1992
Society for Academic Emergency Medicine, President
1993-2001
American Board of Emergency Medicine, Board of Directors
1999-2001
American Board of Emergency Medicine, President
2002-2004
Chair, Board of Trustees, Huron Valley Ambulance
2002-2006
Deputy Editor, Annals of Emergency Medicine
Honors
1986
1992
1995
2003
2004
2004
2005
Founding Member, Greater Cincinnati/Northern Kentucky Stroke Team
Golden Apple Teaching Award, Univ of Cincinnati, Dept of Emergency Medicine
Hal Jayne Academic Excellence Award, presented by SAEM
Elected to the Institute of Medicine, National Academy of Sciences
Peter Rosen Award for Academic Leadership, American Academy of Emergency Physicians
Outstanding Contributions in Research Award, American College of Emergency Physicians
SAEM Leadership Award
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C. Selected Peer-Reviewed Publications (Selected from 90 peer-reviewed publications)
Most relevant to the current application
1. Brott TG, Haley Jr. EC, Levy DE, Barsan W, Broderick J, Sheppard G, Spilker J, Kongable G, Massey S,
Reed R, Marler J. Urgent Therapy for Stroke: Part I. Pilot Study of Tissue Plasminogen Activator
Administered Within 90 Minutes. Stroke 1992;23:632-640. PMID: 1579958
2. Haley EC, Brott T, Sheppard G, Barsan WG, Broderick J, Marler J, et al. Pilot Randomized Trial of Tissue
Plasminogen Activator in Acute Ischemic Stroke. Stroke 1993;24:1000-1004. PMID: 8322373
3. Barsan WG, Brott TG, Broderick J, Haley EC, Levy DE, Marler JR. Urgent Therapy for Acute Stroke: The
Effects of a Stroke Trial on Untreated Patients. Stroke 1994;25:2132-2137. PMID: 7974533
4. The National Institute of Neurological Disorders and Stroke t-PA Stroke Study Group (W.G. Barsan).
Tissue Plasminogen Activator for Acute Ischemic Stroke. N Engl J Med 1995;333:1581-1587. PMID:
7477192
5. National Institute of Neurological Disorders and Stroke (NINDS) t-PA Stroke Study Group (W.G. Barsan, et
al). Generalized Efficacy of t-PA for Acute Stroke. Subgroup Analysis of the NINDS t-PA Stroke Trial.
Stroke 1997;28:2119-2125. PMID: 9368551
6. National Institute of Neurological Disorders and Stroke (NINDS) t-PA Stroke Study Group (W.G. Barsan, et
al). Intracerebral Hemorrhage after Intravenous t-PA Therapy for Ischemic Stroke. Stroke 1997;8:21092118. PMID: 9368550
7. Barsan, W, Pancioli, A, Conwit, R. Executive Summary of the National Institute for Neurological Disorders
and Stroke Conference on Emergency Neurologic Clinical Trials Network. Ann Emerg Med 2004; 44:407412.
8. Papa, L, Kuppermann, N, Lamond, K, Barsan, W, Camargo, C, Ornato, J, Stiell, I, Talan, D. Structure and
function of emergency care research networks: strengths, weaknesses, and challenges. Acad Emerg Med
2009; 995-104. PMID: 19799579
9. Scott PA, Frederiksen SM, Kalbfleisch JD, Xu Z, Caveney, AF, Meurer, WJ, Sandretto A, Holden AB, Haan
MN, Hoeffner EG, Ansari SA, Lambert DP, Jaggi M, Barsan WG, Silbergleit R. Safety of Intravenous
Thrombolytic Use in Emergency Departments without Acute Stroke Teams. Acad Emerg Med. 2010; 17:
1062-1071. PMCID: PMC3058313
10. Cofield, S, Conwit, R, Barsan, W, Quinn, J. Recruitment and Retention of patients into Emergency
Medicine Clinical Trials. Acad Emerg Med 2010; 17:1104-1112 PMCID: PMC3058592
Additional selected and recent publications (in chronological order)
11. Barsan WG, Brott TG, Broderick JP, Haley EC, Levy D, Marler JR. Time of Hospital Presentation in
Patients with Acute Stroke. Archives of Internal Medicine 1993;153:2558-2561. PMID: 7598755
12. Levy DE, Brott TG, Haley EC, Marler JR, Sheppard GL, Barsan W, Broderick JP. Factors Related to
Intracranial Hematoma Formation in Patients Receiving Tissue-type Plasminogen Activator for Acute
Ischemic Stroke. Stroke 1994;25:291-297. PMID: 8303734
13. The Ancrod Stroke Study Investigators (W.G. Barsan). Ancrod for the Treatment of Acute Ischemic Brain
Infarction. Stroke 1994;25:1755-1759. PMID: 8073455
14. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T. Early Hemorrhage Growth in Patients with
Intracerebral Hemorrhage. Stroke 1997;28:1-5. PMID: 8996478
15. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; for the NETT
Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med
2012;366(7):591-600 PMCID:PMC3307101
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D. Research Support
Ongoing Research Support
5U01 NS056975
Barsan (PI)
07/2006-08/2011, 09/2011-8/2016
NIH/NINDS
Neurological Emergencies Treatment Trials Network Clinical Coordinating Center
The goal of the Neurologic Emergencies Treatment Trials (NETT) Network is to improve outcomes of patients
with acute neurologic problems through innovative research focused on the emergent phase of patient care.
Role: Principal Investigator
5U01 NS056975
Barsan (PI)
07/2006-08/2011, 09/2011-8/2016
NIH/NINDS
Rapid Anticonvulsant Medications Prior to Arrival Trial (RAMPART)
The goal of RAMPART is to study will determine if the anti-seizure drug midazolam given via IM stops seizures
as well as the anti-seizure medicine lorazepam given IV, and if there is a difference in the rapidity and safety of
these two medicines given in these different ways.
Role: Co-Investigator
1U01NS062835
Johnston, C. (PI)
9/2009 – 8/2014
NIH/NINDS
POINT: Platelet-Oriented Inhibition in New TIA
The Primary Specific Aim of this randomized, double-blind, multicenter clinical trial is to determine whether
clopidogrel (Plavix) 75 mg/day by mouth after a loading dose of 600 mg is effective in reducing the 90-day risk
of major ischemic vascular events (ischemic stroke, myocardial infarction, and ischemic vascular death) when
initiated within 12 hours of TIA onset in patients receiving aspirin 50-325 mg/day.
Role: Co-Investigator
1U01NS062778 Wright (PI)
7/2009 – 6/2014
NIH/NINDS
Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment
Progesterone is a steroid found to have neuroprotective properties in multiple different animal models of brain
injury. The ProTECT trial will determine the efficacy and confirm safety of this treatment in adults with
moderate to severe TBI.
Role: Co-Investigator
1U01NS073476-01 Barsan, Berry, Lewis (PI)
09/2010-08/2014
NIH/NINDS and FDA
Accelerating Drug and Device Evaluation through Innovative Clinical Trial Design
The use of adaptive trial designs for confirmatory phase clinical trials has the prospect for accelerating the
process of drug and device acceptance and regulatory approval. Four adaptive clinical trials will be designed
for potential use in the NETT. The project will evaluate the process and potential barriers to use of adaptive
designs for confirmatory phase clinical trials.
Role: Principal Investigator
1-U01-NS-069498
Johnston, K. (PI)
08/2011 – 07/2018
NIH/NINDS
Stroke Hyperglycemia Insulin Network Effort (SHINE)
Serve as the Clinical Coordinating Center for a multicenter, prospective, randomized, controlled trial, with
blinded outcomes aims to determine the efficacy and provide further safety data on the use of insulin infusion
therapy for glucose control in hyperglycemic acute ischemic stroke patients. The primary outcome to be
assessed at 90 days will be the difference in favorable outcome measured by the modified Rankin Scale score
in the insulin infusion group compared to the control group.
Role: Co-Investigator
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U01 NS 079077
Gentile (PI)
02/2013 – 01/2014
NIH/NINDS
Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial (I-SPOT)
Serve as the PI for the Clinical Coordinating Center for the multicenter I-SPOT trial. I-SPOT will compare the
effects of strict hyperglycemia control with standard treatment of hyperglycemia on membrane-bound TF-PCA
and markers of blood coagulation in T2DM patients after AIS.
Role: Co-Investigator
1R24TW00889901 Barsan/Donkor (PI)
11/2010 - 8/2014
NIH Fogarty
Ghana Emergency Medicine Collaborative Training Program
The 5 year project will generate a cadre of well-trained EM personnel who will sustain training of EM providers
in Ghana. Approximately 100 nurses, 100 residents and 40 EMS providers will undergo training over the 5 year
period. 900 medical students will be educated about EM. Exposure to research methodology will produce
residency graduates fluent in research methods and capable conducting locally-based research. Ultimately, the
in-country program will improve retention of EM providers and decrease preventable acute injury and illness
related deaths in Ghana.
Role: Co-Investigator
1U01NS062091
Qureshi (PI)
10/2013 - 7/2015
NINDS/NIH
Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-II: A Phase III Randomized
Multicenter Clinical Trial of Blood Pressure Reduction for Hypertension in Acute Intracerebral Hemorrhage
ATACH-II is a multicenter, randomized, concurrently-controlled, parallel arms design to determine the
therapeutic benefit of intensive SBP treatment (SBP<140 mmHg) compared with standard SBP treatment
(SBP<180 mmHg) in reducing the proportion of patients with death and disability (mRS of 4-6) at Day 90
among subjects with ICH treated within 4.5 hours of symptom onset. Dr. Barsan, in collaboration with Dr.
Quresh, will oversee the Clinical Coordination for the US sites participating in this trial.
Role: Co-Investigator
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BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Gerhard Bauer
Assistant Adjunct Professor, Laboratory Director,
GMP Facility
eRA COMMONS USER NAME (credential, e.g., agency login)
gbauer
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
Undergraduate School, Wieselburg, Austria
School of Medicine, University of Vienna, Austria
Educational Evaluation for the United States
(Foundation for International Studies, Seattle,
WA)
Matura
1976
Scientific track, major
biology
Absolutorium
1980
Medicine
Bachelor of
Science
Evaluated
1990
Medicine
A. Personal Statement:
Gerhard Bauer is an associate professor and director of the Good Manufacturing Practice (GMP) facility at the
UC Davis Stem Cell Program within the UC Davis School of Medicine. He is a nationally and internationally
recognized expert in designing and operating academic GMP facilities, and in developing GMP processes for
the manufacturing of cellular, products and drug formulations for human administration. His state of the art
GMP facility at UC Davis has been recognized to be among the best GMP facilities in the US. He is an expert
in the development of novel drug formulations, as has been demonstrated by the FDA approval of two drug
formulations he developed and tested for investigator initiated clinical trials of traumatic brain injury and
Alzheimer’s disease. He is uniquely qualified for this application due to his background in GMP manufacturing
and testing of novel drug formulations and their FDA approval for clinical trials.
B. Positions and Honors:
FEDERAL INSTITUTE OF SERUM CONTROLS
Branch for Blood and Serum Products, Vienna, Austria, 1982 – 1990 Research Associate
UNIVERSITY OF MARYLAND AT BALTIMORE
School of Medicine, Department of Microbiology, Baltimore, Maryland, 1990 – 1993 Research Scientist
THE JOHNS HOPKINS UNIVERSITY
Department of Molecular Microbiology and Immunology, Baltimore, Maryland, 1993 - 1995 Research
Scientist
CHILDRENS HOSPITAL LOS ANGELES
Division of Research Immunology / Bone Marrow Transplantation, Los Angeles, California, 1995 – 2001
CITY OF HOPE NATIONAL MEDICAL CENTER
Division of Virology, Duarte, California, 2001 - 2002 Research Faculty, Support Scientist, Supervisor of
the Gene Vector Evaluation Lab
WASHINGTON UNIVERSITY IN ST. LOUIS
School of Medicine, St. Louis, Missouri, 2002 – 2006
Laboratory Director GMP Facility, Core Co-Director
UNIVERSITY OF CALIFORNIA DAVIS
School of Medicine, Stem Cell Program, Sacramento, CA, 2006 – present
Assistant Adjunct Professor
Laboratory Director GMP Facility
Honors:
American Society of Gene Therapy Member (1997 – present)
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Washington University Institutional Review Board Member (2002 - 2005)
Washington University Institutional Biosafety Committee Member (2003 - 2005)
UC Davis Translational Research Integration and Compliance Committee (TRICC) Member (2005 - present)
UC Davis Medical School Admissions Committee Member UC Davis (2008 – present)
UC Davis Institutional Biosafety Committee Member and Vice Chair (2008 - present)
C. Selected peer-reviewed publications 22 out of 40
1) Targeted Transduction of CD34+ Cells by Transdominant Negative Rev-expressing Retrovirus Yields
Partial Anti-HIV Protection of Progeny Macrophages.
Davis, B.R.; Saitta, F.P.; Bauer, G.; Bunnell, B.A.; Morgan, R.A., Schwartz, D.H. Hum Gene Ther, 1998, May
20, 9(8): 1197-1207
2) Inhibition of Human Immunodeficiency Virus-1 (HIV-1) Replication after Transduction of
Granulocyte-colony Stimulating Factor Mobilized CD34+ Cells from HIV-1 Infected Donors Using
Retroviral Vectors Containing Anti-HIV-1 Genes.
Bauer, G.; Valdez, P.; Kearns, K.; Bahner, I.; Wen, S.F.; Zaia, J.A.; Kohn, D.B. Blood, 1997, April 1, 89(7):
2259 -2267
3) Increased Gene Transfer into Human CD34+ Progenitor Cells Using Retroviral Vectors Produced by
a Canine Packaging Cell Line. Bauer, G.; Sauter, S.; Ibanez, C.; Rice, C.R.; Valdez, P.; Jolly, D.; Kohn, D.B
Biol Blood Marrow Transplant 1998, 4(3): 119-127
4) Stable Transduction of Quiescent CD34(+)CD38(-) Human Hematopoietic Cells by HIV-1-based
Lentiviral Vectors.
Case, SS.; Price, M.A.; Jordan, C.T.; Yu, X.J.; Wang, L.; Bauer, G.; Haas, D.L.; Xu, D.; Stripecke, R.; Naldini,
L.; Kohn, D.B.; Crooks, G.M. Proc Natl Acad Sci USA, 1999, Mar 16, 96(6): 2988-2993
5) A Clinical Trial of Retroviral-mediated Transfer of a Rev-responsive Element Decoy into CD34(+)
Cells from the Bone Marrow of Human Immunodeficiency Virus-1-infected Children.
Kohn, D.B.; Bauer, G.; Rice, C.R.; Rothschild, J.C.; Carbonaro, D.A., Valdez, P.; Hao, Q.L.; Zhou, C.; Bahner,
I.; Kearns, K.; Brody, K.; Fox, S.; Haden, E.; Wilson, K.; Salata, K.; Dolan, C.; Wetter, C.; Aguilar-Cordova, E.;
Church, J. Blood, 1999, Jul 1, 94(1): 368-371
6) Gene Therapy for Pediatric AIDS. Bauer G., Selander D., Engel B., Carbonaro D., Csik S., Rawlings S.,
Church J., Kohn D.B. Ann N Y Acad Sci, 2000 Nov; 918:318-29.
7) Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells.
Lee, N.S.; Dohjima, T.; Bauer, G.; Li, H.; Li, M.J.; Ehsani, A.; Salvaterra, P.; Rossi, J. Nature Biotechnol. 2002,
May 20(5):500-5.
8) The Design and Construction of a GMP Facility for Cellular and Gene Therapy in an Academic Center
- Implementing New Regulatory Requirements.
Bauer, G.; Nolta, J.; Walker, J.; Devine, S.; DiPersio, J. Stem Cell and Cellular Therapy, March 2003, Vol.1,
No.1, 54-61
9) In Vivo Biosafety Model to Assess Risk of Adverse Events from Retroviral and Lentiviral Vectors.
G Bauer, M Dao, S Case, P Herrbrich, J Arevalo, T Meyerrose, X Wang, S Csik, D Skelton, D B. Kohn, and J
Nolta. Mol Ther. 2008;16:1308-1315, Epub 2008 May 06.
10) Specific transduction of HIV susceptible cells for CCR5 knockdown and resistance to HIV infection:
a novel method for targeted gene therapy and intracellular immunization.
Anderson, J., Walker, J., Nolta, J., Bauer, G. J Acquir Immune Defic Syndr. 2009 Oct 1;52(2):152-61.
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11) Pre-integration HIV-1 inhibition by a combination lentiviral vector containing a chimeric TRIM5alpha
protein, a CCR5 shRNA, and a TAR decoy.
Anderson JS, Javien J, Nolta JA, Bauer G. Mol Ther. 2009 Dec;17(12):2103-14. Epub 2009 Aug 18.
12) Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors.
Meyerrose T, Olson S, Pontow S, Kalomoiris S, Jung Y, Annett G, Bauer G, Nolta JA. Adv Drug Deliv Rev.
2010 Sep 30;62(12):1167-74. Epub 2010 Oct 13.
13) Mesenchymal stem cells for the treatment of neurodegenerative disease.
Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Regen Med. 2010 Nov;5(6):933-46.
14) Generation of HIV-1 Resistant and Functional Macrophages From Hematopoietic Stem Cell-derived
Induced Pluripotent Stem Cells.
Kambal A, Mitchell G, Cary W, Gruenloh W, Jung Y, Kalomoiris S, Nacey C, McGee J, Lindsey M, Fury B,
Bauer G, Nolta JA, Anderson JS. Mol Ther. 2011 Mar;19(3):584-93. Epub 2010 Nov 30.
15) Concise review: induced pluripotent stem cell-derived mesenchymal stem cells: progress toward
safe clinical products.
Jung Y, Bauer G, Nolta JA. Stem Cells. 2012 Jan;30(1):42-7.
16) Genetically Engineered Mesenchymal Stem Cells as a Proposed Therapeutic for Huntington's
Disease.
Olson SD, Pollock K, Kambal A, Cary W, Mitchell GM, Tempkin J, Stewart H, McGee J, Bauer G, Kim HS,
Tempkin T, Wheelock V, Annett G, Dunbar G, Nolta JA. Mol Neurobiol. 2012 Feb;45(1):87-98. Epub 2011 Dec
9.
17) Long-term Effects of Intravitreal Injection of GMP-grade Bone Marrow Derived CD34+ Cells in NODSCID Mice with Acute Ischemia-Reperfusion Injury.
Park SS, Caballero S, Bauer G, Shibata B, Roth A, Fitzgerald PG, Forward KI, Zhou P, McGee J, Telander
DG, Grant MB, Nolta JA. Invest Ophthalmol Vis Sci. 2012 Jan 12. [Epub ahead of print]
18) Generation of an HIV-1 resistant immune system with CD34+ HSCs transduced with a triple
combination anti-HIV lentiviral vector.
Walker JE, Chen RX, McGee J, Nacey C, Pollard RB, Abedi M, Bauer G, Nolta JA, Anderson JS. J Virol. 2012
Mar 7. [Epub ahead of print]
19) A Roadmap for Academic Health Centers to Establish Good Laboratory Practice-Compliant
Infrastructure.
Adamo JE, Bauer G, Berro M, Burnett BK, Hartman KA, Masiello LM, Moorman-White D, Rubinstein EP,
Schuff KG.
Acad Med. 2012 Mar;87(3):279-284.
20) Fighting HIV with stem cell therapy: one step closer to human trials? Anderson JS, Bauer G.Expert
Rev Anti Infect Ther. 2012 Oct;10(10):1071-3.
21) CD25 Pre-selective Anti-HIV Vectors for Improved HIV Gene Therapy. Kalomoiris S, Lawson J, Chen
RX, Bauer G, Nolta J, Anderson JS. Hum Gene Ther Methods. 2012 Dec 6. [Epub ahead of print]
22) Good Manufacturing Practices (GMP) manufacturing of advanced therapy medicinal products: a
novel tailored model for optimizing performance and estimating costs. Abou-El-Enein M, Römhild A,
Kaiser D, Beier C, Bauer G, Volk HD, Reinke P. Cytotherapy. 2013 Mar;15(3):362-83. doi:
10.1016/j.jcyt.2012.09.006.
Book Chapters:
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1) Nolta J, Bauer G, and Sands M. Animal models for clinical gene therapy trials. In Translational and
Experimental Clinical Research. Philadelphia: Lippincott Williams & Wilkins; Schuster, Daniel P. and William J.
Powers, eds. 2005.
2) Meyerrose TM, Rosova I, Dao MA, Herrbrich P, Bauer G, and Nolta JA. Establishment and transduction of
primary human stromal/ mesenchymal stem cell monolayers. Chapter 2, Genetic Engineering of Mesenchymal
Stem Cells. Kluwer Academic Publishers, Dordrecht, the Netherlands. Nolta JA (Editor). February 2006.
Selected Clinical Trials (by RAC number): 9602-147 Transduction of CD34+ Cells from the Bone Marrow of
HIV-1 Infected Children: Comparative Marking by an RRE Decoy and a Neutral Gene. (Kohn) Phase I
completed. 9604-153 Transduction of CD34+ Autologous Peripheral Blood Progenitor Cells from HIV-1
Infected Persons: a Phase I Study of Comparative Marking Using a Ribozyme Gene and a Neutral Gene.
(Kohn) Phase I completed. 1202-1153 Stem Cell Gene Therapy for HIV in AIDS Lymphoma Patients. (Abedi)
Phase I ongoing.
Recent INDs: IND 14848 (Sept.2011): Autologous Cord Blood for Traumatic Brain Injury. IND 13307
(Nov.2011): Autologous CD34+ Cells for Intravitreal Injection.
D. Research Support
Ongoing Research Support:
UC Davis Startup Funds Bauer Lab
CIRM Disease Team Award
Subcontract GMP manufacturing
iPS therapy for epidermolysis bullosa
Bauer PI
Bauer, PI
9/2006 – present
5/2010 - 5/2014
CIRM Disease Team Award
MSC therapy for Huntington’s disease
Wheelock, PI
10/2012-10/2016
CIRM Disease Team Award
MSC therapy for critical limb ischemia
Laird, PI
10/2012-10/2016
James B. Pendleton Charitable Trust
Equipment grant for HIV gene therapy research
Bauer PI
9/2013 - present
Bauer PI
2/2010
Completed Research Support:
James B. Pendleton Charitable Trust
Equipment grant for HIV gene therapy research
Biosketches
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PHS 398 Research Plan
Please attach applicable sections of the research plan, below.
OMB Number: 0925-0001
1. Introduction to Application
(for RESUBMISSION or REVISION only)
2. Specific Aims
1274-Specific_Aims.pdf
3. Research Strategy*
1275-Research_Strategy.pdf
4. Progress Report Publication List
Human Subjects Sections
5. Protection of Human Subjects
1276-Human_Subjects.pdf
6. Inclusion of Women and Minorities
1277-Women_ Minorities.pdf
7. Inclusion of Children
1278-Children.pdf
Other Research Plan Sections
8. Vertebrate Animals
9. Select Agent Research
10. Multiple PD/PI Leadership Plan
1279-Multiple_PD_Final.pdf
11. Consortium/Contractual Arrangements
1280-Consortium_Arrangements.pdf
12. Letters of Support
1281-Letters.pdf
13. Resource Sharing Plan(s)
1282-Resource_Sharing_Plan.pdf
Appendix (if applicable)
14. Appendix
1283-Protocol.pdf
1284-Informed_Consent.pdf
1285-Availability_of_Subjects.pdf
1286-sites.pdf
Tracking Number: GRANT11508883
Page 508
Funding Opportunity Number: PAR-13-278. Received Date:
2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
SPECIFIC AIMS
This application describes a clinical trial to find the best available treatment of convulsive status epilepticus
(SE) that is unresponsive to adequate doses of benzodiazepines, established status epilepticus (ESE). SE is a
prolonged self-sustaining seizure or recurrent seizures without recovery of consciousness. There are
approximately 120,000-180,000 episodes of convulsive SE each year in the US, affecting individuals of all
ages. The primary goal of SE treatment is prompt termination of seizures because the risk of adverse
consequences of SE, including refractoriness, systemic complications, neurological injury and death, increase
with increasing seizure duration. SE is initially treated with benzodiazepines based on evidence from three
double-blind, randomized, controlled clinical trials. Approximately one third of SE patients continue to have
seizures despite administration of adequate doses of benzodiazepines. Despite the common use of
intravenous fosphenytoin (FOS), valproic acid (VPA) or levetiracetam (LEV) for the treatment of ESE worldwide, there are no class I clinical trials comparing the efficacy of these medications in this setting. A largescale, retrospective analysis of protocol-driven treatment of ESE suggested that VPA was superior to LEV but
not phenytoin (PHT). FOS is most commonly used agent in US, though all three drugs are recommended.
Experts, Cochrane reviews, and professional associations have recommended that a prospective randomized
trial is necessary to determine the best available treatment of ESE.
A group of experienced investigators who have designed and successfully executed phase III clinical trials and
research in SE (including PreHospital Treatment of Status Epilepticus (PHTSE), Rapid Anticonvulsant
Medication Prior to Arrival Trial (RAMPART), Febrile Status Epilepticus study (FEBSTAT) and Use Of
Lorazepam for the Treatment of Pediatric Status Epilepticus: A Randomized, Double-Blinded Trial of
Lorazepam and Diazepam) have worked with two major research networks and an adaptive clinical trial design
team to organize the ESE treatment trial (ESETT)6,88,44,81,15. ESETT tests the hypothesis that among FOS,
LEV and VPA at least one drug is 15% superior to another for safe clinical resolution of ESE. The study is
designed to accomplish the following specific aims:
Aim 1: To determine the most effective or least effective treatment of ESE by comparing three arms:
FOS, LEV, and VPA.
Aim 2: To further understand impact of three drugs on secondary outcomes: time to termination of
clinical seizures, intubation or admission to ICU within 24 hours of enrollment mortality, cessation of
SE and serious adverse effects analyzed separately.
Aim 3: To ensure that the trial is informative for treatment of ESE in children by describing the
effectiveness and rate of adverse reactions of these drugs in children.
Emergency Departments (ED) from two experienced and successful networks: Neurology Emergency
Treatment Trials network (NETT) and Pediatric Emergency Care Applied Research Network (PECARN) will
recruit patients older than 2 years of age with ESE. Patients who are witnessed to have a clinically apparent
seizure after already having received an adequate dose of benzodiazepines for generalized, tonic-clonic
convulsion(s) will be eligible for recruitment under exception from informed consent (EFIC) rules. Patientswill
be enrolled under the exception from informed consent (EFIC) for emergency research regulations. Because of
differences in etiology of SE and suspected differences in adverse effect profiles, randomization will be
stratified by three age groups (2-18, 19-65, 66 and older). Pre-randomized drug vials in kits will be available in
the ED drug refrigerator for infusion of either FOS 20 mg/Kg, or VPA 40 mg/Kg, or LEV 60 mg/Kg, dose
increasing up to a maximum weight of 75 Kg, then fixed. Infusion will occur over 10 minutes, and patients will
be evaluated for end of clinical seizures, responsiveness, need for further seizure medications, hypotension
and arrhythmias at 20 and 60 minutes from start of infusion. The primary outcome is clinical cessation of
status epilepticus, without recurrent seizures, life-threatening hypotension or cardiac arrhythmia, or use of
additional anti-seizure medications within 1 hour of the start of study drug infusion. The study is a randomized,
blinded, response-adaptive, three-arm comparative effectiveness design. The initial 300 patients will be
randomized in a 1:1:1 ratio (100 each arm) and then response-adaptive randomization will be used to allocate
subsequent patients. When the total sample size is 795, there will be 90% power to identify the most effective
and/or the least effective treatment when one treatment arm has a true response rate of 65% and the true
response rate is 50% in the other two arms. ESETT will also measure the effectiveness of FOS, LEV and VPA
for the treatment of ESE in children. It will also describe serious adverse event rate by treatment group and
age group.
Specific Aims
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2. SIGNIFICANCE
There are approximately 120,000-180,000 episodes of convulsive SE each year in the US, affecting individuals
of all ages, and one-third of them do not respond to benzodiazepines. Despite the significant morbidity and
mortality associated with ESE, there is currently no scientific evidence to guide the treatment of ESE. SE
results in additional economic costs of more complex and prolonged medical care, and early and effective
treatment reduces ICU admission rates 76,6,88. ESETT will determine how to best treat SE unresponsive to
benzodiazepines in both children and adults, and therefore promises to have a major impact on clinical
practice.
3. INNOVATION
1) This will be the first randomized, controlled, blinded trial to determine the best available treatment of ESE, a
neurological emergency associated with neurological injury, systemic complications and death.
2) ESETT will inform the treatment of SE in children. A common problem with novel treatments, including
those for SE, is that they are first tested in adults and then, after a prolonged period, may be tested and
approved in children. Although lorazepam is commonly recommended for treatment of SE in children, a
clinical trial to test its efficacy in children occurred more than a decade after two trials in adults6,97. This issue
has been addressed by the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity
Act (PREA) – to encourage more pediatric studies of drugs used for children. According to the Institute of
Medicine and the Food and Drug Administration (FDA), key issues involved in using drugs in children that have
been tested and approved for adults is lack of data on efficacy, toxicity and pharmacokinetics. ESETT brings
together teams pediatric neurologists and pediatric emergency medicine specialists with expertise in SE, and
its design includes weight-based pediatric drug dosing, consideration of pharmacokinetics, age-stratified
randomization and sample size to ensure that it will measure effectiveness and toxicity of FOS, LEV and VPA
when they are used for the treatment of ESE in children.
3) The specific features of the ESETT design are detailed in the accompanying Statistical Data Management
Center application and include: 1) response-adaptive randomization (RAR); 2) frequent interim assessments;
and, 3) a Bayesian approach. The Bayesian approach provides a probability statement for the scientific
question of interest: “Which treatment is the best treatment?” The use of response adaptive randomization
benefits patients by randomizing a higher proportion of patients to the superior treatment arm and gives us
better estimates of the safety profile for the superior treatment (by randomizing more patients to this arm). On
average, this design uses fewer patients and has higher power than an analogous trial with fixed
randomization. In addition to answering the key clinical question of which treatment to choose for established
status epilepticus, implementation of this design will provide important information for the clinical trial
community regarding future directions for adaptive designs for phase III trials.
4. APPROACH
4.1 Background
4. 1. 1) DEFINITION OF THE PROBLEM: SE is defined as a prolonged, self-sustaining seizure or recurrent
seizures without recovery of consciousness between seizures56. In epidemiological studies, seizures lasting 30
minutes are considered status epilepticus, whereas more recent treatment studies have used a duration of 510 minutes55,88. Several lines of evidence suggest that seizures lasting more than 5-10 minutes are unlikely to
terminate without treatment 82,83,3,56. Epidemiological studies carried out in Richmond, VA measured an
incidence of SE of 41/100,00 and estimated a corrected incidence of 61/100,00023. Based on these studies,
there are approximately 120,000-180,000 episodes of convulsive SE each year in the US. SE is particularly
common in children and the elderly84,95. It complicates many neurological and systemic illnesses24,23, and the
mortality associated with SE is estimated as 19%23. Although this mortality is determined in large part by the
underlying etiology, the occurrence and duration of ongoing SE contribute to mortality 109,70,96. Whereas the 30
day mortality of SE lasting 10-29 minutes is 2.9%, mortality is estimated to be from 19-27% for SE lasting >30
minutes 22,23,97,53,109.
In addition to mortality, longer duration SE is associated with brain damage. There is unequivocal evidence
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that prolonged SE in experimental animals causes widespread injury to the brain, including the hippocampus,
cortex and other structures 65,63,16,106,54. Within the hippocampus CA3 and CA1 layers and hilar interneurons
are particularly vulnerable 91,90,35. Autopsy studies from humans who suffered SE have also suggested brain
damage due to prolonged SE, but they were confounded by coexisting causes of SE 19,21,37. However, recent
MRI findings from FEBSTAT clearly indicate that SE, but not simple febrile seizures, cause T2 signal increase
in the human hippocampus81. Furthermore, EEG abnormalities are common in children with febrile SE. Finally,
more prolonged SE is associated with development of resistance to benzodiazepines116,83,97. Thus, although
multiple different etiologies such as infection, tumors, fever, brain malformations, preexisting epilepsy and
metabolic disorders cause SE, the primary goal of initial treatment is prompt termination of seizures because
adverse consequences of SE increase as seizures last longer54,64,63,16. Early termination of SE can limit
development of refractory SE, neurological injury and mortality in experimental animals36,48. In tow clinical
trials, PHTSE and RAMPART, early termination of SE was associated with reduced ICU admission rates6,88.
In treatment guidelines based on three randomized blinded clinical trials97,6,88,12,62,52, benzodiazepines are the
agents of choice for the initial treatment of convulsive SE. However, these trials also demonstrated that 30-40
% of convulsive SE patients do not respond to benzodiazepines6,97,88. Patients in SE who have not responded
to benzodiazepines are considered to have established status epilepticus (ESE).
4.1.2) BIOLOGICAL BASIS OF BENZODIAZEPINE REFRACTORINESS: Benzodiazepines act on GABAA
receptors and enhance inhibitory synaptic transmission39. In experimental animals, benzodiazepines terminate
seizures effectively if they are given soon after the start of seizures, when the electroencephalogram (EEG)
demonstrates recurrent seizures and behavioral seizures are mild. Benzodiazepines are less effective in
treating longer lasting SE, especially after discrete electrographic seizures have merged and 10 or more
minutes have elapsed since the onset of a generalized tonic-clonic seizure48,103,105,46. Studies further reveal
that inhibitory synaptic transmission mediated by GABAA receptors is reduced in the hippocampi of animals in
ESE47,48,42,94,68. Biochemical studies show a decrease in the number of functional receptors on the postsynaptic membrane in the hippocampi of animals in ESE41,42,94,68. This rapid receptor plasticity is believed to
be mediated by prolonged seizures, which activate many second messenger pathways 73,13. In summary,
prolonged seizures modify GABAA receptors and lead to ESE.
4.1.3) ANIMAL DATA: FOS and PHT are not effective in termination of benzodiazepine refractory SE in animal
model ESE. In an electrical stimulation model where excitatory inputs to the hippocampus were stimulated
(perforant path) for 60 minutes, the resulting in animal model ESE was not terminated by phenytoin (50 mg/Kg)
given intravenously 58,59. LEV administered alone reduced the duration of perforant path stimulation–induced
animal ESE57 suppressed behavioral seizures, but EEG seizures continued unabated. VPA is effective in
terminating refractory SE induced by Cobalt/ Homocysteine102. A new VPA derivative is highly effective in
terminating experimental refractory SE induced by cholinergic stimulation114.
4.1.4) RATIONALE FOR COMPARING FOS, LEV AND VPA: FOS, LEV and VPA are commonly used for the
treatment of ESE and there is clinical and scientific equipoise in this setting, which can only be addressed by a
clinical trial 98,12,99,18,80,86. Current guidelines recommend use of IV FOS, LEV or VPA12. Historically phenytoin
(PHT) (or FOS) was the most commonly used AED for the treatment of ESE because few other AEDs were
available in the intravenous formulation. However rapid intravenous administration of FOS (or PHT) can lead
to hypotension, cardiac arrhythmias and with respect to PHT (though not FOS) purple glove syndrome if
extravasation occurs. The effectiveness of FOS in terminating ESE has also not been established98.
Intravenous formulations of VPA and LEV, which became available in the last decade, can be safely
administered rapidly50,4,77,78,100. Multiple publications reporting the treatment of ESE with LEV or VPA have
emerged99,98,85. An analysis of publications until 2009 reported that 707 patients with LEV, with a success rate
of about 70%99. In ESE, the efficacy of LEV was reported as 51.7 % in one study7 and 73.2% in another
study100. VPA has been used for the treatment of SE in prospective or retrospective series and two randomized
open trials98. An analysis of these trials reported that 693 adults or children in SE had been safely treated with
VPA and with a response rate ranging from 60- 83%. A pilot prospective randomized open study reported a
trend towards superiority of VPA to phenytoin in treatment of SE67. Another study reported that VPA controlled
SE refractory to PHT71. Among neurologists surveyed by the Neurocritical Care Society (U.S.), FOS is the
most commonly used drug for the treatment of ESE80. In a retrospective analysis of charts of patients in SE
admitted to neurocritical care units, FOS (or PHT) was the most commonly used drug for the treatment of
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ESE18. A survey of Pediatric ED physicians belonging to PECARN showed that the majority of physicians use
FOS for the treatment of ESE (unpublished).
In a larger-scale, retrospective analysis of protocol-driven treatment of ESE, 187 episodes were identified in
which PHT, LEV or VPA was given after benzodiazepines
Established SE
failed. SE did not respond to 25.4% of cases treated with
Figure 1
PHT
VPA, 41.4% treated with FOS, and 48.3% treated with LEV
7
LEV
(see Figure 1 - Alvarez) . Importantly, this was an open,
Alvarez
VPA
nonrandomized trial, and the severity of SE in VPA treated
patients may have been less than the other two groups,
which may explain part of the relative effectiveness of VPA
Tripathi
in the study7. Two ESE treatment studies were open,
randomized, prospective studies. In the first study (see
Figure 1 - Tripathi) 100 82 patients were randomized to IV
Agarwal
LEV or IV VPA after they had failed diazepam treatment of
40
60
80
100
SE. Status epilepticus was terminated by IV LEV in 30
% Patients in which SE was controlled
(37%) patients and VPA in 28 (34%) patients, a difference
100
that was again not significant . In the second study (see
Figure 1 - Agarwal)4, one hundred patients aged two or older who had failed IV diazepam were randomized to
either 20 mg/Kg of VPA or 20 mg/Kg PHT. SE was controlled in 44 (88%) patients treated with VPA and 42
(81%) patients treated with PHT; a difference that was not significant4. In summary, one large head-to-head
comparison of these three agents raised the possibility that VPA is superior to LEV for the treatment of ESE,
and two other studies showed no significant differences.
Expert evaluation of the published data suggest that VPA (Class IIa level A) may be superior to FOS (Class IIa
level B), which may be superior to (LEV class IIb level C), this analysis was the basis of most current
guidelines from the neurocritical care society, which recommend all three drugs12. The available pilot data is
sufficient to estimate clinically relevant effect size (see section 5.1 and accompanying design application), and
preclude the need to undertake any further pilot studies.
4.1.5) SAFETY & PHARMACOKINETICS OF INTRAVENOUS FOS/PHT: Although FOS (or PHT) is the most
commonly used and recommended treatment of ESE, there are concerns that the drug causes hypotension
and cardiac arrhythmia in patients28,10. In the original pharmacokinetics
studies, where the drug was infused at the rate of 50 mg/Kg, significant
decreases in blood pressure requiring a reduction in the infusion rate were
observed. This was a particular problem in the elderly, where hypotension
occurred in > 50% of patients older than 7020. Hypotension was much less
common in children and adults up to the age of 4020,9. In a direct
comparison, patients older than 50 or with atherosclerotic cardiovascular
disease had a higher risk for hypotension than younger patients without
vascular disease 28. The FOS package insert warns about these effects
and recommends administration at a maximum rate of 150 mg/min.
The pharmacokinetics of FOS (1200 mg) administered to adults at the rate
of 150 mg PE /min is illustrated in figure 232, showing unbound(free)
phenytoin plasma concentrations following administration. These remain
in the 2.0- 3.0 mg/L range 90 minutes after administration. The accepted
therapeutic range of unbound plasma concentration is 1 to 2 mg/L.
Patients receiving a single dose of FOS (1500 mg) are expected to
maintain a free phenytoin concentration above 2 mg/L for 90 to 120
Figure 2
minutes. In children, infusion of 18 mg/Kg FOS resulted in a peak serum
concentration of 1.5 mg/L within 5 minutes72. Finally, a study comparing the pharmacokinetics of PHT
following IV administration of FOS in children and adults showed that total plasma concentration of PHT was
within the therapeutic range for shorter duration in children compared to adults 93. It is thus reasonable in the
patient who has stopped seizing to wait for 1 hour from start of infusion to start or restart anti-seizure
medication.
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4.1.6) SAFETY AND PHARMACOKINETICS OF INTRAVENOUS LEV: Intravenous LEV has been used for 8
years and as yet no serious adverse effects requiring intervention have been reported 77,78,98,66,5. The
recommended dose of LEV in children up to 40 Kg is 20-60 mg/Kg per day (package insert). In adults, the
recommended dose range is 1-3 g per day, but higher doses up to 6g per day are commonly used. The safety
of rapid intravenous administration of LVT has been assessed.
Intravenous doses of 2500 mg have been administered over 5
minutes and doses of 4000 mg have been given over 15 minutes
safely in adults77. The common adverse effects in these patients
were dizziness, somnolence, irritability and headache77. In prior
pharmacokinetics studies with 4000 mg LEV, the serum concentration
of LEV reached a peak concentration (80-160 mg/L) within 15
minutes, and levels remained above 40 mg/L for 12 hours77. Although
IV LEV is approved for use in individuals 16 and older, there are data
on its pharmacokinetics and safety in children. In critically ill children
(2-16), LEV concentrations were in the expected range based on the
Figure 3
administered dose and aligned with the predictions derived from a
model built on oral pediatric pharmacokinetics and oral and intravenous pharmacokinetics in
adults 75,110,38,2,1. In children with epilepsy on anticonvulsants, the pharmacokinetics of IV LEV was similar to
that observed after oral administration of LEV in children taking VPA or carbamazepine 110,33. Intravenous LEV
is well tolerated in critically ill children with SE or recurrent seizures 1,2. Children have a shorter mean half-life
and more rapid LEV clearance than adults (package insert), 75,38,33. Given these data, subjects weighing up to
75 Kg will receive a loading dose of 60 mg/kg over 10 minutes, and those weighing 75 Kg or more will receive
a fixed dose of 4500 mg over 10 minutes.
4.1.6) SAFETY AND PHARMACOKINETICS OF VPA: Although there are adverse reactions associated with
chronic administration of VPA, no acute adverse reaction requiring intervention has resulted from a single
intravenous dose of VPA113,51,67,100,101,112. Here we discuss chronic VPA toxicity literature to emphasize that
none of these occur following a single dose. In a series of reviews of hepatotoxicity associated with VPA,
Dreifuss and colleagues concluded that the primary risk of fatal hepatic dysfunction (1/500) was in children 0 to
2 years old receiving valproate as polytherapy. The risk declined with age and
Figure 4
was low in patients receiving valproate as monotherapy (1/37,000). Of note,
variants of the polymerase c gene (POLG) have been associated with the risk
of VPA-induced hepatotoxicity, only in context of chronic use of the drug92.
However, POLG mutations are extraordinarily rare and testing for them has
not become routine prior to initiation of VPA therapy, though some institutions
do screen. No hepatic fatalities occurred in patients above the age of 10 years
receiving valproate as monotherapy31,29,14. Children below age 2 and those
with known or suspected metabolic encephalopathy, hepatic dysfunction are
excluded from ESETT.
Children born to mothers taking high doses of VPA during pregnancy have a
higher than expected incidence of birth defects and their cognitive function is
lower than expected at ages 3 and 4.5 111,61,60. These risks are associated
with chronic administration of high dose VPA; there is no evidence that single
dose of VPA given during pregnancy can cause these birth defects78. Women
known to be pregnant are excluded from study. Overall the life threatening
nature of ESE and the fact that only single dose of VPA will be used in the
study would suggest that potential benefits of VPA outweigh its toxicity.
Recommended VPA dose ranges from 15-45 mg/kg/day. VPA is often
administered rapidly by the intravenous route. In one study it was administered at a rate of up to 10
mg/Kg/minute for doses up to 30 mg/Kg51. In another study in children it was given at rates up to 11
mg/Kg/min for dose up to 40 mg/Kg101,113. The most common adverse events were injection site pain, pain with
infusion, dizziness and somnolence. Published pharmacokinetics data50 suggest that, at these doses, serum
VPA levels will peak between 150-200 mg/L within minutes of administration and then remain in the 50-150
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mg/L range for the next 4 hours (see Figure 4). In children, the pharmacokinetics of rapid administration of IV
VPA conforms to models developed using oral VPA in children and oral and intravenous VPA in adults 115.
Recent studies suggest that the pharmacokinetics of IV VPA is also safe in acutely ill children with recurrent
seizures and in those with epilepsy 11,79. Based on these considerations, subjects weighing up to 75 Kg will
receive a loading dose of 40 mg/kg over 10 minutes, and those weighing 75 Kg or more will receive a fixed
dose of 3000 mg over 10 minutes.
4.1.7) RATIONALE FOR EXCLUDING PHENOBARBITAL AND LACOSAMIDE Phenobarbital has been used
for the treatment of ESE and was considered as an alternative treatment. However, phenobarbital is a
sedative anticonvulsant, with action on GABAA receptors, which will depress consciousness of patients already
treated with benzodiazepines. Heavy sedation would make the determination of primary outcome difficult and
would increase the likelihood of intensive care and intubation to protect the airway. IV lacosamide was
considered and literature on its use for ESE treatment was reviewed45,34. The drug is not included in this trial
because dose and safety of rapid infusion has not been established in children. Discussions with the
manufacturer suggested that safety and dosing data for children will not be available for at least 3-4 years.
Finally, for trial to be feasible, a maximum of 3 drugs could be tested. FOS, LEV and VPA are the drugs with
the most solid evidence and the 3 most widely used in the US and thus were chosen over lacosamide.
4.2 Preliminary data
4.2.1) ESETT WILL BE EXECUTED BY A COLLABORATION OF TWO MAJOR FEDERALLY-FUNDED
RESEARCH NETWORKS, NETT AND PECARN: NETT is organized to conduct large simple trials to reduce
the burden of very acute injuries and illnesses affecting the brain, spinal cord, and peripheral nervous system.
Within NETT there are 18 hubs, associated spoke hospitals, a Clinical Coordination Center (CCC) at the
University of Michigan, and a Statistical and Data Management Center (SDMC) at the Data Coordinating Unit
(DCU) of the Medical University of South Carolina, Charleston. NETT recently completed an SE study: “Rapid
Anticonvulsant Medication Prior to Arrival Trial (RAMPART)”.
Figure 5
PECARN conducts meaningful and rigorous multi-institutional research
into the prevention and management of acute illnesses and injuries in
children and youth across the continuum of emergency medicine health
care. PECARN consists of a Data Coordinating Center at University of
Utah, six Research Node Centers (RNCs), and 17 Hospital Emergency
Department Affiliates (HEDAs). PECARN has recently completed an SE
study in children: “Use of lorazepam for the treatment of pediatric status
epilepticus: A randomized, double-blinded trial of lorazepam and
diazepam”. The following presents the data on the ability of the NETT and
PECARN networks to conduct a large RCT of ESE.
4.2.2) RAMPART: Performed under the leadership of Drs. Robert Silbergleit and Daniel Lowenstein, the
RAMPART study was a randomized double-blind non-inferiority trial that compared the efficacy of
intramuscular midazolam with that of intravenous lorazepam for children and adults in SE88. RAMPART
involved 4314 paramedics, 33 EMS agencies, and 79 receiving hospitals across the US, and was conducted
under Exception From Informed Consent (EFIC) regulations87. Recruitment was completed in 22 months (i.e. in
half the predicted time, figure 5) and 2145 patients were assessed for eligibility. 1023 patients were enrolled
and randomized,130 were excluded from intention-to-treat analysis owing to repeat enrollment, and 893 were
assigned to the treatment group89. Among patients assigned to the treatment group, 488 (54%) were men, 453
(51%) were black, 106 (12%) were Hispanic, 588 (66%) had epilepsy, and the precipitating cause of SE was
non-compliance or discontinuation of anticonvulsant therapy in 278 (31%), idiopathic or breakthrough SE in
242 (27%) and lowered seizure threshold in 62 (7%). Patients in SE weighing > 40 Kg were treated with either
10 mg of intramuscular midazolam or 4 mg of IV lorazepam, and drug doses were adjusted for those weighing
13-40 Kg. The primary outcome was termination of seizures before arrival in the emergency department
without the need for paramedics to provide rescue therapy. In intention to treat analysis, 73.4 + 4.1% patients
treated with IM midazolam and 63.5 + 5.4 % treated with IV lorazepam were successfully treated. IM
midazolam was thus at least as effective and safe as IV lorazepam. Treatment with benzodiazepines failed in
282 (32%) of the patients, and ESETT seeks to find the best treatment for this group that failed to respond to
adequate doses of benzodiazepines. The definition of “adequate doses” of benzodiazepines for ESETT is
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based on those used in the RAMPART trial.
4.2.3) Use of lorazepam for the treatment of pediatric status epilepticus: A randomized, double-blinded
trial of lorazepam and diazepam. Dr. James Chamberlain oversaw this double-blind, randomized EFIC trial
at 12 sites using the PECARN infrastructure. Children 3 months to 17 years of age with generalized convulsive
SE were randomized to receive either 0.1 mg/kg lorazepam (max 4 mg) or diazepam 0.2 mg/kg (max 8 mg) by
slow IV push. Half this dose was repeated at 5 minutes if needed. The primary efficacy outcome was cessation
of SE by 10 minutes with no recurrence by 30 minutes. The primary safety outcome was the need for assisted
ventilation. 275 children were enrolled, and no differences were found in either efficacy (Drug A 74% versus
Drug B 71%) or safety (Drug A 16% versus Drug B 17.6%). With the exception of sedation (Drug A 50%, Drug
B 66.9%), all secondary efficacy and safety outcomes were similar.
4.3 Study Plan
4.3.1) OVERVIEW: ESETT is designed as a simple study, where patients are enrolled, randomized and treated
with either FOS, LEV or VPA, and the primary outcome is determined in the ED, an hour after enrollment,
using clinical criteria previously employed in two phase III trials of SE. The key information about the study,
study drug, and a study device will be available in a box stored in the ED drug refrigerator. Figure 6 below
explains the study flow.
Figure 6
Standard Care
Intervention Period
Standard Care
00:00
01:00
-00:30 to -00:05
primary outcome assessment
- 23:55
cumulative dose of 23:30
benzodiazepine
must enrollment/randomization
00:20
be ≥ adequate with last dose given
rescue
medication
given if ongoing sz
> 5 and < 30 min prior to study treatment
ICT
B
ED
B
00:20 - 01:00
rescue if sz recurs or prn
B
23:00
Speculative
timing of ictus (ICT), ED arrival
23:01:38
- 23:52:00
(ED), and benzo doses (B)
If sz’s are continuing or recurring
clinical team assesses eligibility.
Kits are randomized ahead. Clinical
team pulls “use next” kit (by age tier)
23:53
and prepares infusion
Study team is activated
00:10 - 00:20
observe without intervention
01:10
00:00 - 00:10
study drug infusion
Enrollment and
randomization are
defined as time of
infusion start
On arrival study team takes over data
collection and initiates efforts to notify
and seek consent from LAR
4.3.2) RATIONALE BEHIND INCLUSION CRITERIA: This study will recruit children ages 2-18, adults ages
19-65 and elderly age 66 and older. The current treatment protocols for SE in children older than 2 years of
age are similar to those in adults and elderly, regardless of the etiology52,12,85. A recent review of published
clinical trials concluded that the efficacy of anti-seizure medications in adults predicts the efficacy of these
medications in the pediatric population (ages 2-18) for partial onset seizures 74. Based on studies of the
pathophysiology of SE, it is believed that refractoriness to benzodiazepines results from ongoing seizure
activity regardless of etiology and age, and the goal of therapy is to terminate ongoing seizures 48,40,41,69,16.
While the frequency of different etiologies is different in children than in adults, the range of etiologies of SE
are similar in children and adults with the exception of febrile SE, which is unique to children25,24,23,84,83.
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Approximately half of all SE episodes occur in children, and children have the second highest incidence of SE
among all age groups84,96,95. The highest incidence is in the elderly, but elderly constitute a smaller fraction of
the total US population than children107. Finally, people aged 19-65 have a lower incidence of SE than
children or elderly, but constitute the largest fraction of the US population, therefore this group contributed a
large number of cases (approximately 45%) to a recent SE clinical trial (RAMPART)88. SE occurs more
commonly in the black population and based on experience with RAMPART, we expect that more patients of
that race will be enrolled23.
4.3.4) INCLUSION CRITERIA:
a. Any patient aged 2 or older who is witnessed to have clinically apparent recurrent or ongoing convulsive
activity in the ED and has already received adequate dose of benzodiazepines in the past 5-30 minutes
for a witnessed generalized tonic-clonic seizure. The seizure and its initial treatment may have occurred
prior to arrival in the ED.
b. Adequate doses of benzodiazepines are as follows: For patients >40kg - diazepam 10 mg IV, lorazepam 4
mg IV or midazolam 10mg IV or IM. For patients between 10-40 kg - diazepam 0.3 mg/kg IV, lorazepam
0.15 mg/kg IV and midazolam 0.3 mg/kg IV or IM. The drugs may have been administered in two or more
divided doses. These doses are based on published clinical trials, as well as clinical practice97,6,49,15,88.
c. Patients taking PHT, LEV or VPA for epilepsy or other reasons are eligible to participate, because patients
in SE are often found to have sub-therapeutic anticonvulsant levels. An additional dose of anticonvulsant
is very unlikely to cause toxicity and harm, and there is no consensus whether ESE in patients with
epilepsy is best treated with the anticonvulsant the patient is already taking or an alternative
anticonvulsant.
4.3.5) EXCLUSION CRITERIA:
a. Patients below age 2 years. These patients are excluded for three reasons. First, SE in the first year of life
tends to have very different etiologies than SE in patients older than one year84.Second, >90% of febrile
SE occurs in children <2 years and febrile SE accounts for more than two-thirds of SE in the second year
of life84. As febrile SE may have a different etiology, pathophysiology and drug responsiveness compared
to the other etiologies of SE, we did not want to have a large number of febrile SE cases in the trial.
Thirdly, though there are no data to suggest a single dose is unsafe, there are more concerns about use
of VPA in the very young due to toxicity with chronic use. Metabolic disorders associated with VPA
hepatotoxicity are commonly diagnosed by age 2, and the highest risk of VPA hepatotoxicity is in this age
group31,29,14 Finally, logistically including children under 2 years would have required another set of
medications as the median weight of a 2 year old is 12 kg and this would have significantly complicated
the trial.
b. Pregnant women and prisoners. These individuals cannot participate in trials carried out in Health and
Human Services funded research under Exception From Informed Consent (EFIC) rules.
c. Treatment with propofol, etomidate, ketamine or another sedative with anticonvulsant properties (except
benzodiazepines) after initial seizure. These drugs will prevent the determination of the primary outcome
and can themselves terminate ESE.
d. Intubation. Intubated patients are often sedated with drugs that have anticonvulsant properties, and cannot
be assessed for one aspect of the study’s primary outcome: improving responsiveness.
e. Acute post traumatic seizures. Treatment of trauma takes precedence and often requires intubation.
f. Known contraindication to study drugs including allergy, metabolic disorders, pancreatitis, liver disease,
hypotension. Given that it is a single dose for treatment of a life threatening disorder, and that this
information may not be known at the time of presentation, no screening is feasible and only those patients
with KNOWN contraindication are excluded.
g. Hypoglycemia < 50 mg/dL, hyperglycemia > 400 mg/dL. Underlying cause for these needs to be treated.
h. Cardiac arrest and post-anoxic seizures. The outcome for recovery of consciousness is poor, and these
patients require other treatments such as hypothermia.
4.3.6) PITFALLS: Despite the similarities, there are important differences between children, adults and the
elderly with regards to frequency of etiologies and outcome84,24,108,95. Elderly patients have much higher
mortality than children and a have higher incidence of hypotension and arrhythmia associated with FOS107. It
is possible that efficacy or tolerability of the study drugs will be age-related, and we have therefore planned for
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age-stratified randomization of the three study drugs. Furthermore, simulations have been run to test the
feasibility of age-stratified randomization in concert with response adaptive randomization.
4.3.7) CONSENT (EXCEPTION FROM): Patients will be enrolled under Exception from Informed Consent
(EFIC) in all cases. Obtaining prospective informed consent is not feasible for many reasons. SE patients are
unconscious and unable to understand and consent for research. Morbidity and mortality increase with
increasing duration of seizure95,23,81,71. Therefore, we cannot ethically delay therapy or study procedures solely
for the purpose of obtaining consent from family members. SE cannot be identified prospectively as more than
50% of patients who have SE have never had a seizure before23. Even in patients with epilepsy, it is not
possible to predict who will have SE. Both NETT and PECARN have successfully conducted SE trials under
EFIC87,88. A more detailed rationale for EFIC and process for obtaining community consent is described in the
protocol and human subjects section.
4.3.8) RANDOMIZATION: Due to the emergency nature of ESE, randomization must not delay treatment. To
complete the randomization quickly, the study kits will be pre-assigned using a central randomization process
via a web site (WebDCU) maintained by the NETT Data Coordinating Center. The centralized randomization
process will be stratified by age group (2-18 years, 19-65 years, and greater than 65 years). The “Step
Forward” web-based randomization is enabled because ESETT is a blinded study.
4.3.9) ENROLLMENT: Prior to enrollment at each site, the appropriate treatment kits for each of the three age
group strata are designated with a “Next” flag. When a subject is enrolled into the study, the site staff goes to
the stock of study drug kits and takes the drug kit with the “Next” flag on it, for the appropriate age stratum.
The drug study kit will contains: 1) a 100 ml vial containing either FOS, VPA, or LEV; 2) the tubing for IV
administration; 3) study device (described below); 4) length-based weight/dose estimation tape (similar to
Broselow tape).
4.3.10) THE STUDY DEVICE , an iTouch (Apple) device with an ESETT app loaded on
Figure 7
it (Figure 7), will be started by the treating physician and will guide the team through
the initial phase of the study. The study device will serve the following functions:
a. Time keeper: The device records the time of onset of infusion of the study drug.
Using an alarm, the device reminds the treating team to record the patient’s clinical
state 20 minutes and 60 minutes after the onset of infusion.
b. Outcome record: Although the primary source document for the study is the
patient’s medical record, the study device will also record the clinical state of the
patient at 20 minutes and 60 minutes (primary outcome) after the onset of drug
infusion. This will serve as a fail-safe mechanism for determination of the primary
outcome.
c. Voice recording: Once the infusion button is switched “on”, the device will record
sound for 60 minutes from the start of the infusion. This will provide further record of
the primary outcome. The study device will be kept at the patient’s bedside from the start of the study until
retrieved by the coordinator or another member of the study team.
4.3.11) INTERVENTION: The drugs will be formulated by the GMP Facility of the Institute for Regenerative
Cures (School of Medicine University of California, Davis) under supervision of Dr. Gerhard Bauer and James
Cloyd (head of the Pharmacology Core), as follows: FOS 16.66 mg/ml, VPA 33.33 mg/ml and LEV 50 mg/ml
concentration. The drugs will be packaged in a 100 ml vials, labeled at Davis using WebDCU-generated data
labels, shipped to study site under refrigeration, and placed inside the study boxes on site. The dose will be
FOS 20 mg/kg, VPA 40 mg/kg, and LEV 60 mg/kg up to a weight of 75 kg. At 75 kg the maximum safe dose
for a 10 minute infusion period for adults is reached. A 10 kg patient would receive drug infusion at the rate of
1.2 ml/minute and those weighing 75 Kg or more will receive drugs at an infusion rate of 9 ml/minute.
RATIONALE: The goal is to administer the maximum safe dose of each drug over 10 minutes. The rate
limiting agent is FOS (i.e. both VPA and LEV can in principle be administered at slightly faster rates). For FOS,
the FDA boxed warning in the package insert recommends that FOS be administered at a maximum rate of
150 mg/min, fixing the maximum dose to 1500 mg. Given that the recommended FOS dose for the treatment
of SE is 20 mg/Kg, patients weighing 75 Kg or less will receive 20 mg/Kg FOS and those weighing more will
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receive the maximum safe dose of 1500 mg. If hypotension or cardiac arrhythmias occur during the FOS
infusion, the treating physician can reduce the rate of infusion by 50% and deliver the drug over 20 minutes.
LEV dose will be 60 mg/kg up to a maximum of 4500 mg and VPA dose will be 40 mg/kg up to a maximum of
3000 mg.
4.3.12) PRIMARY OUTCOME DETERMINATION: The primary outcome for the study is clinical cessation of
status epilepticus, without recurrent seizures, life-threatening hypotension or cardiac arrhythmia, or the use of
additional anti-seizure medications within 60 minutes of the start of study drug infusion. Clinical cessation of
SE consists of absence of clinical seizures and improving mental status. The patient will be observed for 20
minutes after start of infusion to evaluate for end of clinically apparent seizures and time of termination of
seizures will be noted. If clinically apparent seizures continue or recur after 20 minutes, further intervention
with an anticonvulsant medication is indicated. The patient’s mental status will be evaluated 20 and 60 minutes
after start of drug infusion. The patient will be observed for hypotension and cardiac arrhythmias for at least
60 minutes. Following definitions apply:
a. Start of study drug infusion: Time when the study drug infusion pump is switched on.
b. Clinical cessation of SE: absence of clinical seizures and improving mental status.
c. No improvement in mental status: Patient’s responsiveness to verbal command or noxious stimuli has
not improved 1 hour after the start of infusion of the study drug compared to the examination performed at
20 minutes from the start of drug infusion.
d. Life-threatening hypotension: Within 1 hour of start of infusion of the study drug, systolic blood
pressure remains below specified levels on two consecutive readings at least 10 minutes apart and
remains below specified levels for more than 10 minutes despite reduced drug infusion rate or its
termination and a fluid challenge. “Specified levels” for systolic blood pressure are 90 mmHg in adults
and children older than 13 years old, 80 mmHg in children 7 to 12 years old, and 70 mmHg in children 2 to
6 years of age.
e. Life-threatening cardiac arrhythmia: Any arrhythmia that occurs within 1 hour of start of infusion of the
drug that persists despite reducing rate of drug infusion, or that requires termination with chest
compressions, pacing, defibrillation, or use of an anti-arrhythmic agent or procedure.
f. Further intervention: administration of any of the following anti-seizure or sedative medications for
recurrent seizures or any other reason, by any route, within one hour after the start of study drug infusion:
carbamazepine, clobazam, dexmedetomidine, diazepam, ethosuximide, etomidate, ezogabine, felbamate
fosphenytoin, gabapentin, ketamine, lacosamide, lamotrigine, levetiracetam, midazolam, methohexital,
oxcarbamazepine, pentobarbital, phenobarbital, phenytoin, propofol, pregabalin, primidone, rufinamide,
thiopental, tiagabine, topiramate, valproic acid or valproate, vigabatrin, zonisamide.
4.3.13) RATIONALE: The primary outcome is a combined measure of efficacy (clinical cessation of SE) and
absence of serious adverse effects. The definition of clinical cessation of SE used in ESETT is based on that
used in the PHTSE6 and RAMPART88 studies to determine the primary outcome. In these two blinded studies,
ED physicians were able to clinically determine the cessation of SE. We chose a composite primary outcome
and included no improvement in mental status as failure to meet primary outcome, for several reasons. The
first is the difficulty in separating seizure cessation from adverse effect of sedation. Approximately 15-20% of
convulsive SE becomes non-convulsive after treatment26, and patients can become unresponsive due to
sedation caused by the study drugs. Thus, an unresponsive patient who no longer has clinically evident
seizures could still be in non-convulsive SE, sedated by drugs, or both. It is not possible to separate this
adverse effect from the primary outcome. Second, an important goal of this study is to identify the drugs
having fewest adverse effects, which will likely be associated with reduced admission to ICU. For example,
anesthetics will terminate seizures in all patients but cause unacceptable side effects: deep sedation, coma
and respiratory depression requiring intubation. Third, FOS, which is the current treatment of choice for
benzodiazepine-refractory SE, carries a risk of hypotension and cardiac arrhythmia; however the frequency
and seriousness of this adverse effect in patients with SE are unknown. If another drug has efficacy similar to
FOS in terminating SE but has a significantly lower risk of significant adverse effects, this finding will lead to a
change in clinical practice.
Although study drugs are administered over 10 minutes, we expect that the termination of clinical seizure
activity will take up to 20 minutes based on the pharmacokinetic properties of all three study drugs. FOS must
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be converted to PHT by enzyme action and then it reaches a peak brain concentration in 30 minutes 104.
Similarly, following intravenous injection, the brain entry of LEV takes 20-30 minutes,27 whereas VPA brain
concentration peaks within 10 minutes43.
4.3.14) ROLE OF EEG: We considered the possibility of using EEG to determine the primary outcome.
However, this was not feasible for several reasons. Many participating centers do not have access to 24 hour
EEG. Furthermore, even in centers where EEG is available, technicians are on call from home and application
of a complete set of EEG leads, and obtaining 20 minutes of recording will typically not occur within the time
window of 60 minutes. There are emerging techniques for rapid EEG recording using novel electrode
configurations and recording devices, however none of them have been sufficiently validated for use in this
study. If a promising rapid EEG recording technology emerges during the study, we will test its reliability in an
ESETT ancillary study.
4.4) Aim 2: To further understand impact of three drugs on secondary outcomes: time to termination
of clinical seizures, intubation or admission to ICU within 24 hours of enrollment mortality, cessation
of SE and serious adverse effects analyzed separately.
4.4.1 MEASUREMENT OF CLINICAL CHARACTERISTICS AND SECONDARY OUTCOMES: A Clinical
Adjudication Core, consisting of Drs. Lowenstein, Shinnar, Fountain and Cock will monitor the consistency of
primary determined locally, determine secondary outcomes, and categorize the clinical characteristics of the
patients. All records will be reviewed from across the country to ensure that primary outcomes are being
determined in a consistent fashion across sites. For each case being reviewed, the Core will determine:
a. the etiology of status epilepticus:
b. the time interval between onset of seizures and treatment in each patient controlled;
c. the duration of seizures from the start of study drug infusion;
d. whether failure to meet primary outcome was due to life-threatening hypotension or cardiac arrhythmia,
continued seizures or continued unresponsiveness;
The sites, with assistance from the Clinical Coordination Center, will prepare a package of data on each patient
and make it available to the Clinical Adjudication Core through WebDCU. The package will consist of the ED
records including the ambulance call sheet, the admission note, neurology consult note, and reports of CT,
MRI or EEG if obtained. Any reference to study drug or patient name in the medical record will be redacted by
the site clinical coordinator and confirmed by Clinical Coordination Center.
Two adjudicators will review the data independently and enter etiology, estimated time to treatment, estimated
time to termination of seizures and reason for failure (if relevant) in a discrete element chart on WebDCU. If
there is disagreement between the two adjudicators, then one of the two Core leaders not involved in the
original review will make a final determination, in consultation with the two adjudicators. To attain consistency
of review by four adjudicators, a set of 20 test records will be reviewed by each adjudicator and discussed
before the start of patient enrollment. The adjudicators will be blinded to treatment assignment.
4.4.2) MAINTAINING THE BLIND: Patients and ED study team members will be blinded to the treatment
assignment, as are the PI and Clinical Coordinating Center. Blinding is provided by the use of the same color
of formulations, drug packaging, and method of drug administration in every subject. The blind is maintained
until the primary outcome has been entered into the central database (electronically) at the Statistical and Data
management Center. Secondary outcomes are determined by a blinded Clinical Adjudication Core or evident
from the clinical course.
4.4.3) PROTECTING PATIENTS: Once the initial treatment of ESE is complete (and outcome recorded), the
patient is expected to be transferred to inpatient floor or ICU the treating team. The treating team can
determine the identity of study drug by calling a toll free number; provided the primary outcome has been
recorded centrally. Unblinding is considered necessary to allow appropriate care for the patients following the
ED-based intervention specified by the trial. If the study drug has been successful in terminating SE, then this
agent is commonly continued for 16-48 hours until a long-term anti-seizure drug has been started. AED levels
are needed for appropriate management. If the study drug failed to terminate SE, then the treating team would
want to use a drug that was not used for treating the patient.
4.4.4) PITFALLS: The concern with unblinding is that a study physician could potentially become aware of the
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drugs used and primary outcome. However, each site is expected to recruit a small number of patients (46/year on average), so it is extremely unlikely that the same ED physician will recruit enough patients to gain
any insight into a treatment effect. To probe this, however, each physician will be asked to guess which drug
they administered when entering the primary outcome, to test the validity of blinding.
4.5) Aim 3. The following efforts are made to ensure that the trial will be informative about safety and
efficacy of FOS, LEV and VPA in the treatment of ESE in children.
a. Experts in pediatric SE, Drs. Shlomo Shinnar and James Chamberlain helped design the trial. They have
helped define inclusion criteria, primary and secondary outcomes, and pediatric-appropriate doses of study
drugs, study design. They will help oversee the execution of the trial. Involvement of the PECARN network
with specific experience in pediatric ED trials also helps ensure that the pediatric component will be
successful.
b. Eligibility criteria: In defining benzodiazepine refractoriness in children, experts considered published data
in pediatric SE, ongoing studies and current clinical practice in pediatric EDs and out of hospital
treatment52,30,8.
c. Study drug doses adjusted for children. In children, the drugs are being dosed by weight.
d. Age-stratified randomization of drugs. Despite similarities in the pathophysiological mechanisms, there are
important differences between children, adults and elderly with regards to frequency of etiologies and
outcome 84,24,108,95. Although there is no prior evidence to suggest that treatment effectiveness will differ by
age, it is possible that efficacy and/or tolerability of the study drugs will turn out to be age-related; therefore
three age groups will be balanced with regards to drug allocation. At each interim analysis, the interaction
between age group and treatment group will be tested. If there is evidence of an interaction then response
adaptive randomization will be stopped, and randomization will revert to equal allocation until the end of the
trial.
e. Hypotension and cardiac arrhythmias associated with PHT or FOS are more common in patients older than
50 and those with atherosclerotic vascular disease 20,10,9. It is therefore possible that the rate of serious
adverse reactions will be much less common in children than in adult population. We will analyze the
frequency of adverse effects (hypotension, cardiac arrhythmias) as a function of age.
f.
Subanalysis of primary outcome in children: ESETT plans to recruit a minimum of 336 children to
determine the effectiveness of these drugs in children. A sample size of 336 will have 80% power to detect
a 20% difference in primary outcome between drugs. It is expected that these drugs will terminate seizures
at similar rates in children as in adults. The pathophysiology of ESE in children older than 2 years is
similar to that in adults. Furthermore, a systematic review of published clinical trials recently concluded
that the efficacy of anti-seizure medications in adults can be used to predict the efficacy of these
medications in the pediatric population (ages 2-18) for partial onset seizures74.
5 STATISTICS & FEASIBILITY
5. 1) SAMPLE SIZE CALCULATION: Details of study design are in the accompanying application. Sample size
impacts feasibility and is therefore discussed here. Based on a recent study7 and expert evaluation of all
currently published data on the treatment of ESE, we assumed that the worst drug will be effective in 50% of
the patients. The recently completed RAMPART study for the initial treatment of SE was designed with the
assumption that an absolute difference of 10% or less would be considered to not be clinically significant (i.e.
the non-inferiority margin). There is broad consensus among experts that, for a second treatment, a difference
of 15% would indicate clear superiority of one of the drugs over others, and will be sufficient to change clinical
practice. The posterior probabilities that each treatment is the most and least effective treatment will be
calculated using Bayesian methods based on a uniform prior for each treatment’s success rate, and a
conjugate beta-binomial model17. This trial will be considered a success if the probability that a treatment is the
most effective is greater than 0.975 or the probability that a treatment is the least effective is greater than 0.975
for any treatment. A sample size of 795 provides 90% power to identify the most effective or the least effective
treatment when one treatment arm has a true response rate of 65% and the true response rate is 50% in the
other two arms (a 15% difference in response rates). The false positive rate of this trial is the probability of
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incorrectly identifying either a most effective treatment and/or a least effective treatment. Under simulation the
false positive rate was determined to be less than 0.05 under a variety of scenarios.
5.2 ENROLLMENT: To complete this trial successfully, we have made careful plans to recruit 795 patients
over 4.5 years, with 6 months allotted at the outset for start-up and EFIC). Two carefully performed,
independent estimates suggest that on average each site will be able to recruit 4-6 patients per year ESETT.
Drs. Jennifer Langer and Nathan Fountain reviewed charts of all patients evaluated in the University of Virginia
ED for diagnosis of SE, seizures or epilepsy over a period of 12 months and found that 12 patients would be
eligible for ESETT (i.e. benzodiazepine-resistant SE) each year. We conservatively assume that 33-50% of
eligible patients will be recruited, i.e. a medium-sized hospital will recruit 4-6 patients per year, thus requiring
40 medium-sized hospitals to participate. Drs. John Betjemann and Daniel Lowenstein at University of
California, San Francisco reviewed charts of patients enrolled in RAMPART and estimated that each NETT
hub enrolled approximately 4 patients per year in RAMPART who would be eligible for ESETT. Less rigorous
feasibility analysis was a survey of 22 NETT hubs and PECARN sites who were asked to estimate the number
of SE patients evaluated in ED, based on diagnostic code 345.3 or their databases. These sites estimated that
they collectively evaluate 7736 patients with SE each year, which would suggest that 300- 400 patients could
be recruited to ESETT each year. However, these surveys are less reliable than thorough chart reviews and
we have planned according to more conservative estimates provided by chart review. These studies suggest
that approximately 40 centers can complete the study in 4 years of enrollment, with the first year devoted to
EFIC and startup (40 centers X 4 years X 4-6 patients per year = 640-960). There will be 22 NETT hubs, and
17 PECARN sites participating. Children age 2-18 will be recruited by both PECARN & NETT sites. PECARN
sites will recruit children whereas many NETT sites will recruit adults and children. We expect that 336
children will be recruited before recruitment is complete for the overall study; however we will continue the
study to recruit sufficient number of children if necessary.
5.3 NETT SITES: Emory University, Henry Ford Hospital, Massachusetts General Hospital, Medical College
of Wisconsin, New York Presbyterian, Ohio State University, Oregon Health and Science University, Stanford
University Medical Center, State University of New York, Downstate Medical Center, Temple University,
University of Arizona, University of California, Los Angeles, University of California, San Francisco, University
of Cincinnati, University of Kentucky, University of Maryland, University of Minnesota, University of
Pennsylvania, University of Pittsburgh, University of Texas medical’s school at Houston, Virginia
Commonwealth University, and Wayne State University. In this group, 12 sites participated in a SE trial under
EFIC (RAMPART), ED refrigerators and programmable infusion pumps are widely available. Median time to
EFIC approval is 8 months.
5.4 PECARN SITES: 16 PECARN sites and University of Texas Southwestern Medical Center at Dallas have
agreed to participate. Several PECARN sites are also NETT sites and will be managed jointly. Hasbro
children’s medical Center Brown University, Children’s Hospital of Pennsylvania, University of Pennsylvania,
CS Mott Hospital at University of Michigan, Nemeur’s medical clinic DuPont Hospital, , University of Utah
primary Children’s Hospital, Baylor College of Medicine, St. Louis Children’s Hospital, Washington University,
Children’s Hospital of Michigan, Wayne state University, University of Cincinnati, Ohio State University,
Nationwide Children’s, Children’s Hospital of New York, University of California, Davis, Medical College of
Wisconsin, Children’s National Medical Ctr., George Washington University, University of Pittsburgh. There are
10 sites with previous experience with a SE treatment trial. Median time for EFIC clearance for this network is
10 months, and ED refrigerators and programmable pumps are widely available.
5.5 TRIAL MANAGEMENT: A detailed plan for managing and leading the trial is presented in the budget
justification section. We have already identified the site for drug formulation, filed an Investigational New Drug
(IND) application with FDA.
5.6 DISSEMINATION OF TRIAL RESULTS: The trial results will be disseminated via publications, AES, AAN
and Status epilepticus conference presentations, and websites and through the lay press and other methods
required under the EFIC process. Efforts will be made to influence practice by engaging guideline writing
committees.
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PROTECTION OF HUMAN SUBJECTS
4.1.1 Risks to Human Subjects
(a) Human Subjects Involvement, Characteristics, and Design.
This Human Subjects Research involves an NIH-Defined Phase III Clinical Trial. The study
population consists of individuals aged 2 years old and older suffering from convulsive status
epilepticus with seizures continuing despite treatment with adequate doses of benzodiazepines.
The study population will consist of males and females of all ethnicities and races. A maximum
of 795 subjects will be enrolled.
Patients will be enrolled in the Emergency Departments (ED) from two experienced and
successful networks--Neurology Emergency Treatment Trials network (NETT) and Pediatric
Emergency Care Applied Research Network (PECARN). There will be NETT 22 hubs and 17
PECARN sites participating. Each NETT hub will also recruit patients from its network of spoke
hospitals. PECARN sites will recruit children age 2-18, whereas many NETT sites will recruit
both children and adults.
We expect that 336 children will be recruited before recruitment is complete for the overall
study, however we will continue the study to recruit sufficient number of children if necessary.
NETT hubs are Emory University, Henry Ford Hospital, Massachusetts General Hospital,
Medical College of Wisconsin, New York Presbyterian, Ohio State University, Oregon Health
and Science University, Stanford University Medical Center, State University of New York,
Downstate Medical Center, Temple University, University of California, Los Angeles, University
of California, San Francisco, University of Cincinnati, University of Kentucky, University of
Maryland, University of Minnesota, University of Pennsylvania, University of Pittsburgh,
University of Texas Medical School at Houston, Virginia Commonwealth University, and Wayne
state University.
The PECARN sites are Hasbro children’s medical Center Brown University, Children’s Hospital
of Pennsylvania, University of Pennsylvania, CS Mott Hospital at University of Michigan,
Nemeur’s medical clinic DuPont Hospital, University of Texas Southwestern medical Center at
Dallas, University of Utah primary Children’s Hospital, Baylor College of Medicine, St. Louis
Children’s Hospital, Washington University, Children’s Hospital of Michigan, Wayne state
University, University of Cincinnati, Ohio State University, Nationwide Children’s, Children’s
Hospital of New York, University of California, Davis, Medical College of Wisconsin, Children’s
National Medical Ctr., George Washington University, University of Pittsburgh.
Detailed Eligibility Criteria
Inclusion criteria

Any patient aged 2 or older who is witnessed to have clinically apparent recurrent or
ongoing convulsive activity in the ED and has already received adequate dose of
benzodiazepines in the past 5-30 minutes for a witnessed generalized tonic-clonic
seizure. The seizure and its initial treatment may have occurred prior to arrival in the ED.
Exclusion criteria


Patients below age 2 years.
Women known to be pregnant and prisoners.
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





Treatment with propofol, etomidate, ketamine or another sedative with anticonvulsant
properties (except benzodiazepines) after initial seizure.
Intubation.
Acute post traumatic seizures.
Known contraindication to study drugs including allergy, metabolic disorders,
pancreatitis, liver disease, hypotension.
Hypoglycemia < 50 mg/dL, hyperglycemia > 400 mg/dL.
Cardiac arrest and post-anoxic seizures.
Special vulnerable populations
Fetuses, neonates, women known to be pregnant, prisoners, institutionalized individuals are
excluded from the study. We will not require a pregnancy test prior to randomization. ESE is an
emergency and needs to be treated without delay. In current clinical practice treatment would
not be delayed for a pregnancy test. It is very unlikely that one dose of drug would damage a
fetus and this must be balanced against the damage to the mother and fetus caused by
prolonged SE.
Children 2-18 are included. Rationale: Children are especially vulnerable to SE. Approximately
half of all SE episodes occur in children, and children have the second highest incidence of SE
among all age groups (the highest incidence is in the elderly, but elderly constitute a smaller
fraction of total US population than children). Although children with SE have a lower morbidity
and mortality compared to older patients and the frequency of different etiologies is different
than in adults, the etiologies are similar with the exception of febrile SE, which is unique to
children. Except for infants, the treatment protocols for children are similar to those in adults.
There is no scientific evidence guiding the treatment of ESE in children. ESETT will help define
the best available treatment of ESE in children.
Assignment to treatment group
Patients will be randomly assigned to a treatment group. Due to the emergency nature of ESE,
randomization assignment must not delay treatment. To complete the randomization quickly, the
study kits will be pre-randomized using a “Step Forward” central randomization process via a
web site (WebDCU) maintained by the NETT Statistical and Data Management Center.
Randomization will be stratified by age group (2-18 years, 19-65 years, and greater than 65
years). Randomization will initially be allocation in a 1:1:1 ratio, and once 300 patients are
enrolled, randomization probabilities will be response-adaptive.
Rationale for the interventions’ dose, frequency and administration
The goal is to administer via intravenous route the maximum safe dose of each drug (FOS,
LEV, VPA) over 10 minutes. FOS will be administered at a dose of 20 mg/Kg up to a weight of
75 Kg for a maximum dose of 1500 mg. LEV will be administered at a dose of 60 mg/kg up to a
weight of 75 kg for a maximum dose of 4500 mg. VPA will be administered at a dose 40 mg/kg
up to 75 Kg weight with a maximum dose of 3000 mg.
The sites listed above will enroll patients, administer study drug, determine primary outcome,
record clinical information and transmit enter it into the study database via webDCUTM managed
by the ESETT Statistical and Data Management Center. The ESETT Clinical Coordination
Center will perform site monitoring to ensure consistency and completeness of the data
collected.
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(b) Sources of Materials.
No biological materials (including blood samples) will be obtained during this study. Only
clinical data regarding clinical history, clinical course, diagnostic tests, and clinical outcomes will
be collected. Study information will be collected from the patient’s medical record and from the
Study device used during the study treatment. Data will be collected on each subject and
recorded on case report forms at each individual site. The clinical center staff is responsible for
timely entry of required data into the study database via WebDCU™. The NETT Network
Statistical and Data Management Center (SDMC) will handle data management for this trial.
The WebDCU™ is a user-friendly menu-driven system with built-in warnings and rules to
facilitate the data collection process and ensure sufficient quality control. The database will be
developed in Microsoft SQL server based on the approved Case Report Forms (CRFs). During
the design of the database, automated consistency checks and data validation rules will be
programmed to check for potential data errors, including missing required data, data out of prespecified range, data conflicts and disparities within and among the CRFs. All validation rules
will be outlined in the Data Management Plan that will be generated by the SDMC. The data are
managed, including data queries, by the SDMC using the secure ESETT Trial website.
The ESETT Trial will be conducted in compliance with guidelines for HIPAA protections at each
clinical center. All study investigators at the clinical centers must ensure that the confidentiality
of personal identifiers and all personal medical information of study participants will be
maintained at all times. All efforts will be made to keep study subject information private. Each
enrolled subject will have a unique study identifier assigned to them. The SDMC computers and
servers will only house de-identified information (i.e., names, ssn, medical record numbers will
not be collected), rather the subject will be tracked during the study period through the assigned
unique identifier. All collected information regarding a given subject will be stored using the
unique identification code. Only the appropriate local site study personnel and Clinical Research
Associates (i.e. monitors) will have access to a subject’s personal identifying information.
Source documents and case report forms (CRFs) will remain at the participating sites. All data
will be stored in a manner that is HIPAA compliant, without the ability to track the information
back to a specific subject except through a password protected system. All study personnel will
have Protection of Human Research Subjects certification.
In addition to the study database, the SDMC provides the clinical center staff access (via
password) to a standard set of web-enabled tools, including subject visit calendar, subject
accrual reports, CRF completion status, and outstanding DCR status pertaining to their
respective centers. These tools allow the staff to receive regular updates on overall study
status, new external information relevant to the Trial, Committee meetings calendar, etc.
The WebDCU™ uses SSL encryption methods that allow a secured Internet transfer. Backup
tapes of data collected on the WebDCU™ are generated on a daily basis. All SDMC server
systems used in the management and storage of clinical trial data are maintained on site at the
limited access offices of the MUSC Data Center, where safety issues such as virus, power cutoff, hardware failure, fire, flood, earthquake and theft are professionally addressed.
The study will be conducted in accordance with the ICH Guidelines for Good Clinical Practice
and all relevant local, national and international regulations. Data quality monitoring will
performed continuously. Out of range and logical errors are identified at the time of data entry.
External site visits will be conducted periodically by the NETT Project Monitor of the Clinical
Coordinating Center in accordance with the NETT monitoring standard operating procedures
(SOPs) http://nett.umich.edu. In brief, the primary purpose of the site visit is to confirm that local
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regulatory documents are being properly maintained, and to compare data reported on case
report forms with source documents, including documentation of informed consent and proper
reporting of adverse events. Site visits will be conducted after the first two subjects are entered
at site and annually thereafter unless additional monitoring trips are needed. At each site visit,
the records of all subjects will be reviewed for a completed informed consent document, and the
records of a minimum of 10% of the subjects enrolled since the prior site visit will be reviewed
against source documents for all data elements. The subjects to be reviewed will be selected
randomly by the SDMC. During a review, the NETT Project Monitor compares the data entered
into the study database to the individual subject source (whether electronic medical records, or
original or copied paper charts) records.
Data Collection Schedule
Day 1
Eligibility
X
Randomization
X
Primary outcome
X
Demographics
X
Post enrollment consent to continue Documentation X**
Day 2
X
Study Box Data device upload to WebDCUTM
X
Probable cause of status epilepticus
X
X
Adverse Events
X
X
Intubation within 24 hours of enrollment
X
X
Time to termination of clinical seizures
X
X
Admission to ICU within 24 hours of enrollment
Hospital D/C*
X
X
X
End of Study
X
*
Hospital Discharge or 30 days from enrollment if still in the hospital.
**
Or earliest opportunity if not possible in the ED
(c) Potential Risks.
For FOS, the FDA boxed warning in the package insert recommends that FOS be administered
at a maximum rate of 150 mg/min, fixing the maximum dose to 1500 mg. Given that the
recommended FOS dose for the treatment of SE is 20 mg/Kg, patients weighing 75 Kg or less
will receive 20 mg/Kg FOS and those weighing more will receive the maximum safe dose of
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1500 mg. If hypotension or cardiac arrhythmias occur during the FOS infusion, the treating
physician can reduce the rate of infusion by 50% and deliver the drug over 20 minutes.
Although FOS (or PHT) is the most commonly used and recommended treatment of ESE, there
are concerns that the drug causes hypotension and cardiac arrhythmia(Binder et al.
1996;Donovan and Cline 1991). In the original pharmacokinetics studies, where the drug was
infused at the rate of 50 mg/Kg, significant decrease blood pressure (requiring reduction
infusion rate) occurred most commonly in elderly. Greater than > 50 % of patients older than
70 had significant hypotension(Cranford et al. 1978). Hypotension can occur in children and
adults up to the age of 40, but it is less common(Appleton and Gill 2003;Cranford, Leppik,
Patrick, Anderson, & Kostick 1978). In a direct comparison, patients older than 50 or with
atherosclerotic cardiovascular disease had a higher risk for hypotension than younger patients
without vascular disease(Donovan & Cline 1991). The FOS package insert warns of this effect.
Cardiac arrhythmias may occur with FOS infusion at all rates, but are much more common
when FOS is infused at rates > 150mg/min. FOS will be infused at a maximum of 150mg/min
and patient blood pressure and cardiac rhythym will be continually monitored during drug
administration.
Another possible safety concern is the time from study drug infusion until the determination of
the primary outcome. Patients receiving a single dose of FOS (1500 mg) are expected to
maintain a free phenytoin concentration above 2 mg/L for 90 to 120 minutes. It is thus
reasonable in the patient who has stopped seizing to wait for 1-2 hours from start of infusion to
start or restart anti-seizure medication. In another study, Infusion of 18 mg/Kg FOS in children
resulted in a peak serum concentration of 1.5 mg/L within 5 minutes (Ogutu et al. 2003).
Pharmacokinetics of PHT following intravenous administration of FOS was compared in adults
and children(Tanaka et al. 2013). In pediatric patients, total plasma concentration of PHT was
within the therapeutic range for shorter duration than in adult patients. Given these limitations,
children will be given a larger, weight based dose than adults.
Intravenous LEV has been used for 8 years and as yet no serious adverse effects requiring
intervention have been reported (Aiguabella et al. 2011;Misra et al. 2011;Ramael et al.
2006a;Ramael et al. 2006b;Trinka 2009). The recommended dose of LVT in children up to 40
Kg is 20-60 mg/Kg per day (package insert). In adults, the recommended dose range is 1-3 g
per day, but higher doses up to 6g per day are commonly used. The safety of rapid intravenous
administration of LVT has been assessed. Intravenous doses of 2500 mg have been
administered over 5 minutes and doses of 4000 mg have been given over 15 minutes safely in
adults(Ramael, Daoust, Otoul, Toublanc, Troenaru, Lu, & Stockis 2006a). The common
adverse effects in these patients were dizziness, somnolence, irritability and headache(Ramael,
Daoust, Otoul, Toublanc, Troenaru, Lu, & Stockis 2006a). Based on these considerations,
subjects weighing up to 75 Kg will receive a loading dose 60 mg/kg over 10 minutes. Those
weighing 75 Kg or more will receive a fixed dose of 4500 mg over 10 minutes. Based on prior
pharmacokinetics studies, the peak serum concentration of LVT should reach a peak
concentration (80-160 mg/L) within 15 minutes, and levels will stay above 40 mg/L for 12
hours(Ramael, Daoust, Otoul, Toublanc, Troenaru, Lu, & Stockis 2006a). Although IV LEV is
approved for use in individuals 16 and older, there is data on its pharmacokinetics, and safety in
children. In critically ill children (2-16) observed levetriacetam concentrations were in the
expected range based on the administred dose and aligned with the predictions derived from a
model built on oral pediatric pharmacokinetics and oral and intravenous pharmacokinetics in
adults (Abend et al. 2009a;Abend et al. 2009b;Glauser et al. 2007;Pellock et al. 2001;Weinstock
et al. 2013). In children with epilepsy on anticonvulsants, the pharmacokinetics of IV LEV was
similar to that observed after oral administration of LEV in children taking VPA or
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carbamazepine (Fountain et al. 2007;Weinstock, Ruiz, Gerard, Toublanc, Stockis, Farooq,
Dilley, Karmon, Elgie, & Schiemann-Delgado 2013). Children have a shorter mean half-life and
more rapid LEV clearance than adults (package insert), (Fountain, Conry, Rodriguez-Leyva,
Gutierrez-Moctezuma, Salas, Coupez, Stockis, & Lu 2007;Glauser, Mitchell, Weinstock, Bebin,
Chen, Coupez, Stockis, & Lu 2007;Pellock, Glauser, Bebin, Fountain, Ritter, Coupez, & Shields
2001). Intravenous LEV is well tolerated in critically ill children, with SE or recurrent seizures
(Abend, Florance, Finkel, Licht, & Dlugos 2009a;Abend, Monk, Licht, & Dlugos 2009b).
Although there are adverse reactions associated with chronic administration of VPA, no acute
adverse reaction requiring intervention has resulted from a single intravenous dose of
VPA(Limdi et al. 2005;Misra et al. 2006;Tripathi et al. 2010;Venkataraman and Wheless
1999;Wheless et al. 2004;Wheless and Treiman 2008). Here we discuss chronic VPA toxicity
literature to emphasize that none of these occur following a single dose. In a series of reviews of
hepatotoxicity associated with VPA, Dreifuss and colleagues concluded that the primary risk of
fatal hepatic dysfunction (1/500) was found to be in children 0 to 2 years old receiving valproate
as polytherapy. The risk declined with age and was low in patients receiving valproate as
monotherapy (1/37,000). No hepatic fatalities occurred in patients above the age of 10 years
receiving valproate as monotherapy(Bryant, III and Dreifuss 1996;Dreifuss et al. 1987;Dreifuss
et al. 1989). There are also no reports of hepatotoxicity associated with a single dose of VPA.
Variants of the polymerase c gene (POLG) hve been associated with the risk of VPA-induced
hepatotoxicity(Stewart et al. 2010). However, POLG mutations are extraordinarily rare and
testing for them has not become routine prior to initiation of VPA therapy, though some
institutions do screen. Clearly, in the context of acute SE, screening is not possible even in
those institutions whose practice is to screen. While there is a variability of presentation of
POLG mutations, the majority are early onset. It is now believed that many of the fatalities
reported by Dreifuss were POLG mutations. Children under age 2 are excluded from ESETT.
Even in the context of POLG or any other susceptible mutation, all the case reports are in the
setting of chronic use. While it is conceivable that a single dose could also cause liver toxicity, it
is very unlikely even in a child with POLG. Thus, to the best of our knowledge, a single dose of
VPA , as is planned in ESETT, should be safe. In the retrospective series to date (see above),
IV VPA has some of the best evidence for efficacy including children, arguing for its inclusion in
ESETT. Children below age 2 and those with known or suspected metabolic encephalopathy
are excluded from ESETT.
Children born to mothers taking high doses of VPA during pregnancy have a higher than
expected incidence of birth defects and their cognitive function is lower than expected at ages 3
and 4.5 (McVearry et al. 2009;Meador et al. 2009;Werler et al. 2011). These risks are
associated with chronic administration of high dose VPA; there is no evidence that single dose
of VPA given during pregnancy can cause these birth defects(Ramael, De, Toublanc, Otoul,
Boulanger, Riethuisen, & Stockis 2006b). Women known to be pregnant are excluded from
study. Overall the life threatening nature of ESE and the fact that only single dose of VPA will be
used in the study would suggest that potential benefits of VPA outweigh its toxicity.
Recommended VPA dose ranges from 15-45 mg/kg/day. VPA is often administered rapidly by
the intravenous route. In one study it was administered at a rate of up to 10 mg/Kg/minute for
doses up to 30 mg/Kg(Limdi, Shimpi, Faught, Gomez, & Burneo 2005). In another study in
children it was given at rates up to 11 mg/Kg/min for dose up to 40 mg/Kg(Venkataraman &
Wheless 1999;Wheless, Vazquez, Kanner, Ramsay, Morton, & Pellock 2004). The most
common adverse events were injection site pain, pain with infusion, dizziness and somnolence.
Based on these considerations, subjects weighing up to 75 Kg will receive a loading dose of 40
mg/kg over 10 minutes. Those weighing 75 Kg or more will receive a fixed dose of 3000 mg
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over 10 minutes. Based on published pharmacokinetic data(Limdi et al. 2007), serum VPA
levels will peak between 150-200 mg/L within minutes of administration and then remain in the
50-150 mg/L range for the next 4 hours (see Figure 4). Pharmacokinetics of IV VPA has been
studied in children with epilepsy (Birnbaum et al. 2003;Panomvana Na et al. 2006;Ramsay et al.
2003;Visudtibhan et al. 2011;Williams et al. 2012). Recent studies suggest that the
pharmacokinetics of rapid intravenously administered VPA conforms to models developed
using oral VPA in children and oral and intravenous VPA in adults (Williams, Jayaraman,
Swoboda, & Barrett 2012). Intravenous VPA is safe in acutely ill children with recurrent
seizures and in those with epilepsy (Birnbaum, Kriel, Norberg, Wical, Le, Leppik, & Cloyd
2003;Ramsay, Cantrell, Collins, Walch, Naritoku, Cloyd, & Sommerville 2003).
4.1.2 Adequacy of Protection Against Risks
(a) Recruitment and Informed Consent (Exception)
Patients will be enrolled under Exception from Informed Consent (EFIC) in all cases. Obtaining
prospective informed consent is not feasible because SE patients are unconscious and unable
to understand and provide consent for research. Because morbidity and mortality increase with
increasing time of seizure, so we cannot ethically delay therapy or study procedures solely for
the purpose of obtaining consent from family members. As more than 50% of SE patients have
never had a seizure before, it would not be feasible to prospectively enroll epilepsy patients in
the trial. Even in patients with epilepsy it is not possible to predict who will have SE. As part of
the EFIC process, community consultation and public disclosure will occur prior to the start of
the trial.
It is well established that morbidity and mortality in convulsive SE are related to the duration of
the seizure. Therefore, it is not possible to delay therapy or study procedures solely for the
purpose of obtaining consent. Research involving patients who have emergency conditions
presents an ethical dilemma. Protecting patient autonomy through the informed consent
process is one of the cornerstones of ethical research. But in a true emergency it is not ethical
to withhold treatment while obtaining study consent. This conundrum makes it almost
impossible to performed conventionally-consented clinical research in the many life-threatening
conditions.
In SE, the patient cannot give consent and the patient’s legally authorized representative(LAR)
is not available in the short time frame required. Even when an LAR is available, meaningful
informed consent is impossible to obtain because of the time constraints and the emotional
distress caused by witnessing convulsive SE. In SE, time to treatment is especially critical.
Inability to obtain informed consent can limit the ability to discover the optimal treatment for this
critical and life-threatening condition. Because informed consent is not possible within the
therapeutic window, all patients will be enrolled in the study under the exception from informed
consent. Study investigators will then aggressively try to locate an LAR. When the LAR is
located or the patient is able to consent, the LAR or patient will be approached to obtain
permission to continue the study. A draft of the model consent form is attached as an appendix.
Prior to enrolling patients at any study sites, the site investigators will obtain local Institutional
Review Board (IRB) approval. Sites will be expected to comply with their local IRB practices to
ensure adequate protection of patient/study subject rights. This will typically require annual
reporting and reviews of study subject enrollment, outcomes, and adverse events. Informed
consent form templates will be provided for sites to aid in the submission process, and to ensure
consistency in the consent process between centers. The ESETT Clinical Coordination Center
will assist sites with their local IRB submission and consent revisions.
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Applicability of EFIC to the Trial and Compliance with FDA Requirements (21 CFR 50.24)
FDA regulations cite specific circumstances in which EFIC is appropriate. The ESETT trial
fulfills these requirements for emergency research. SE is a life-threatening situation. Population
studies of the incidence of SE report an incidence of between 41-61/100,000. The mortality rate
is estimated to be 17%. Available medications are unsatisfactory for the treatment of SE. The
Cochrane review of anticonvulsant therapy for SE found eleven studies with 2017 subjects. The
review concluded that lorazepam was the most effective agent and will terminate SE in 60-70%
of patients. From 30-40% of patients do not respond to first-line therapy for SE. No
prospective, blinded randomized controlled trial has compared treatments for seizures refractory
to initial benzodiazepine treatment. Current published guidelines recommend treatment with
FOS, or VPA with LEV as alternatives(Brophy et al. 2012;Loddenkemper and Goodkin
2011;Meierkord et al.). However, there are small, open-label randomized studies that suggest
the potential efficacy of VPA over LEV in treatment ESE(Alvarez et al. 2011). A series of
observational studies suggest that that LEV and VPA are safe and effective in the treatment of
ESE (Trinka 2009;Trinka 2011).
Obtaining prospective informed consent is not feasible for acute SE patients because SE
patients are unconscious and unable to understand and consent for research. Morbidity and
mortality increase with increasing time of seizure. Therefore, we cannot ethically delay therapy
or study procedures solely for the purpose of obtaining consent. SE cannot be identified
prospectively. More than 50% of patients who have SE have never had a seizure before. Even
in patients with epilepsy it is not possible to predict who will have SE.
This research could not be carried out without an EFIC because treatment for ESE needs to
begin immediately upon ED arrival. Since ESE patients are unable to consent for themselves
and there is not time to obtain consent from an LAR, all patients must be enrolled under EFIC.
Informed consent requires that the LAR have time to understand the material presented, be able
to ask questions and have time to think about what the patient would want. This is not possible
in 5-10 minutes during a very stressful time. In ESE, time to treatment is especially critical.
Inability to obtain informed consent can limit the ability to discover better treatments for this
critical and life-threatening condition.
(b) Protection Against Risk
Additional protections associated with conducting a trial under 21 CFR 50.24 are the following:
a)
Community Consultation—The community will be consulted prior to the initiation of
research. With guidance from the site-specific IRB, the community will be asked to give
their opinions of the research through 6 possible mechanisms—community meetings,
town hall meetings, focus groups, meetings with established community advisory
boards, in-person surveys, and random-digit dialing surveys. The type of community
consultation used will be determined by the IRB for the local site. The number of
consultations required will also be determined by the local IRB. After review of the
results of the community consultation, the local IRB will decide if the community supports
the research.
b)
Community consultation participants and others in the community will be able to opt out
of the study at the each meeting or by contacting the site. We will use bracelets for this
purpose. We will offer “opt-out” bracelets at each community consultation event. These
bracelets will also be available by calling each site. Enrolling sites will be trained to
check for these opt-out bracelets prior to study enrollment.
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c)
At the conclusion of the study, we will report the results of the study back to all
community groups consulted.
d)
Public Disclosure before the trial—The study public disclosure will include a clear
statement that informed consent will not be obtained for subjects prior to enrollment, a
balanced description of the risks and benefits of the study, a synopsis of the research
protocol and study design, methods of identifying potential study subjects, a list of
participating sites/institutions and instructions about how to receive an “opt-out” bracelet
for the study. We will place ads in community newspapers, set up a study website and
issues press releases about the study. Each site IRB will determine the type and form of
local public disclosure.
f).
Public Disclosure after the Trial—After the trial, we will place ads in all outlets used for
public disclosure before the trial, place results on the study website and issue a press
release. All sites will also conduct local public disclosure as required by the site’s IRB.
g)
Plan for consent after enrollment—After study enrollment, study personnel will attempt to
obtain consent for use of data and follow-up from the patient if possible. Otherwise, the
study personnel will attempt to locate the patient’s LAR. Standard consent processes
will be used.
h)
Plan for contact of the LAR—Sites will consult their hospital registration representative
for contact of Legally Authorized Representatives (LAR) or family members and will
aggressively seek informed consent for the patient’s participation in the trial as soon as
possible after enrollment. If necessary other hospital resources such as social work will
be contacted to help identify the patient’s LAR. Attempts to contact the LAR will be
documented.
I)
Establishment of an independent data and safety monitoring committee -- we will
establish an independent safety monitoring committee for ongoing review of the conduct
of the study, adverse events, efficacy and safety.
Additional Protections for Children
Expert in pediatric SE, Drs. Shlomo Shinnar and James Chamberlain helped to define the
inclusion criteria, primary and secondary outcomes, and pediatric-appropriate doses of study
drugs, and study design with careful consideration of children. The primary analysis will test for
an interaction of treatment group with age group. Safety outcomes such as frequency of
adverse effects (hypotension, cardiac arrhythmias) will also be monitored by age group.
4.1.3 Potential Benefits of the Proposed Research to Human Subjects and Others
There may or may not be a direct medical benefit to individual research participants. However,
subjects may benefit from the research because SE is a life-threatening condition, and the
interventions being studied are currently in use despite lack of evidence of their comparative
efficacy. The risks of the study procedures are reasonable given that all are FDA-approved
medications and are currently in clinical use. Studies in experimental animals reveal that LEV
can terminate experimental ESE but FOS, the current treatment of choice fails to do so
(Mazarati et al. 1998;McDonough et al. 2004;Prasad et al. 2002).
4.1.4 Importance of Knowledge to be Gained
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There are approximately 120,000-180,000 episodes of convulsive SE each year in the US,
affecting individuals of all ages, and one-third of them do not respond to benzodiazepines
(ESE). Despite the significant morbidity and mortality associated with ESE, as well as the
additional economic costs of more complex and prolonged medical care, there is currently no
scientific evidence to guide the treatment of ESE. ESETT will determine how to best treat SE
unresponsive to benzodiazepines in both children and adults, and therefore promises to have a
major impact on clinical practice.
4.1.5
Data and Safety Monitoring Plan
All patients in the ESETT Trial will be closely monitored. Sites will be expected to comply with
their local IRB practices to ensure adequate protection of the subject rights. This typically
requires annual reporting and reviews of study subject enrollment, outcomes, and adverse
events. An independent Data and Safety Monitoring Board (DSMB) appointed by the NINDS will
provide ongoing evaluation of safety data as well as the overall conduct of the trial. A Safety
Monitoring Plan will be established in collaboration with the SDMC and the ESETT Executive
Committee during Year 1. The DSMB will be formed by the NINDS as per institute guidelines.
The DSMB members will have a meeting with the study team prior to study commencement to
discuss the protocol as well as content and format of the DSMB reports.
The SDMC statisticians will generate Data and Safety Monitoring (DSMB) Reports
semiannually or more frequently as needed. This review will aid in identifying any safety issues
that may need to be addressed. All adverse events occurring within 24 hours of treatment and all
serious adverse events occurring during study participation will be collected in the study
database. The Clinical PIs will be notified in real-time (automatic email notification upon data
entry at the site) of all SAEs and will be required to provide a timely review of relatedness and
expectedness of the specific SAE. Adverse events (including SAEs) will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA) dictionary. Certain adverse events are
anticipated with fos-phenytoin treatment: occurrence of life threatening hypotension or
arrhythmia. These AEs are included as part of the primary outcome and their occurrence will
make the primary outcome a treatment failure. In addition, the rate of expected AEs by
treatment group will be included in each DSMB report. All MedDRA coded AEs and SAEs will
be summarized in terms of frequency of the event, number of subjects having the event, and
severity and relatedness to treatment. Unadjusted relative risks will be provided with two-sided
95% confidence intervals. Stopping one of the treatment arms due to harm may be considered
by the DSMB at any time, and guidance will be provided in terms of providing the unadjusted
relative risks and their 95% confidence intervals.
In addition to AEs/SAEs, each semiannual DSMB report will include cumulative summary
statistics on enrollment and retention; baseline characteristics; protocol violations; and data
management/quality information (e.g., timeliness and completeness of data entry by the clinical
sites, number of data queries generated and resolved). The DSMB may issue recommendations
regarding study conduct when concerns arise that may threaten participant safety or study
integrity. In addition the SDMC will generate Interim Monitoring Reports according to the
planned interim analyses for the DSMB to review. The DSMB will follow the trial stopping rules
for efficacy or futility as described in the ESETT Study Design. The SDMC statisticians will
generate two version of the DSMB report. The statistics for the ‘Closed Session’ DSMB Reports
are provided by treatment group (partially blinded as group A, B, or C), and will be made
Protection of Human Subjects
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Contact PD/PI: Kapur, Jaideep
available to the DSMB only. The ‘Open Session’ DSMB report contains aggregated statistics
only, i.e., not by treatment group, and is made available to the ESETT Executive Committee.
4.1.6 ClinicalTrials.gov Requirements
The trial will be registered with ClinicalTrails.Gov and updates will be maintained in a timely
manner. The trial’s results will be registered in clinicaltrials.gov within one year of completion of
the trial.
Protection of Human Subjects
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Contact PD/PI: Kapur, Jaideep
Inclusion of Women and Minorities
Participation in the ESETT trial of all eligible subjects of both genders and all minorities will be
encouraged. We expect the demographics of the subjects enrolled to reflect that of populations
of patients suffering from established status epilepticus at the participating centers. SE occurs
more commonly in the black population, thus, we expect that more patients of that race will be
enrolled overall. Enrollment rates by gender, race, and ethnicity will be monitored via periodic
reports of the demographic information entered on the screening log.
While many different barriers to participation of minorities in clinical research exist among
different segments of the population, if trial investigators continually examine and evaluate
methods to overcome barriers to participation, recruitment of diverse populations should be
successful. Using a variety of possible methods, community consultations will be conducted
prior to the initiation of the ESETT trial. Where possible, research team members whose racial,
ethnic, and language backgrounds are similar to those of the potential study participants will
participate in local community consultation activities to help establish a greater sense of trust
among potential study participants.
Clinically important sex/gender, racial, and ethnic differences in the best (or worst) treatment are
not expected. However, statistical analyses will explore whether differences due to gender,
race, or ethnicity may exist. These exploratory analyses are planned for both efficacy and safety
outcomes and are described in the SDMC analysis plan.
Women & Minorities Inclusion
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Contact PD/PI: Kapur, Jaideep
OMB Number: 0925-0002
Planned Enrollment Report
This report format should NOT be used for collecting data from study participants.
Study Title:
Established Status Epilepticus Treatment Trial (ESETT)
Domestic/Foreign:
Domestic
Comments:
Racial Categories
Ethnic Categories
Not Hispanic or Latino
Female
Male
Hispanic or Latino
Female
Male
Total
American Indian/Alaska Native
4
4
0
0
8
Asian
18
18
0
0
36
Native Hawaiian or Other Pacific Islander
1
1
0
0
2
Black or African American
195
196
1
1
393
White
129
129
47
47
352
More than One Race
0
0
2
2
4
Total
347
348
50
50
795
Study 1 of 1
Page 534
Tracking Number: GRANT11508883
Funding Opportunity Number: PAR-13-278. Received Date: 2013-10-24T16:15:52.000-04:00
Contact PD/PI: Kapur, Jaideep
Inclusion of Children
Children older than 2 years old are included in the ESETT trial. The clinical issues explored in
this trial are relevant to the treatment of established status epilepticus in both children and
adults. The inclusion of children is important to make certain the results of this trial can be used
to inform treatment of this large population of patients. The ESETT team’s pediatric
neurologists and pediatric emergency medicine specialists with expertise in SE have helped to
develop the proposed design which includes weight-based pediatric drug dosing and agestratified randomization. The current treatment protocols for SE in children older than 2 years of
age are similar to those in adults and elderly, regardless of the etiology.(Brophy, Bell, Claassen,
Alldredge, Bleck, Glauser, Laroche, Riviello, Jr., Shutter, Sperling, Treiman, & Vespa
2012;Loddenkemper & Goodkin 2011;Shorvon 2011) Children younger than 2 were excluded
due to differences in etiology (e.g. febrile) and concerns about VPA hepatotoxicity in the very
young.
Inclusion Of Children
Page 535
Contact PD/PI: Kapur, Jaideep
Multiple PD/PI Leadership Plan
The three Principal Investigators, Jaideep Kapur, James Chamberlain, and Robert Silbergleit
will direct this trial cooperatively together with Jordan Elm, the PI of the associated SDMC grant
application. Although leadership and decision making will be collaborative, the distinct primary
domains and responsibilities of the three PI’s of this proposal are separately defined.
Dr. Kapur will be the liaison principal investigator, and will have the overall responsibility for
project organization and administration. He will also be responsible for oversight of the clinical
management of the trial, by chairing the Oversight and Steering committee. He will participate in
site initiation and in training of investigators, in collaboration with Clinical project a manager (see
details in the budget justification section).
Dr. Chamberlain will be the Principal Investigator representing the PECARN network. In
collaboration with the ESETT PIs, he will oversee of protocol implementation, regulatory
management, human subjects’ protection, accrual and monitoring at participating PECARN
sites.
Dr. Silbergleit will be the principal investigator responsible for the clinical coordination of the trial
at the NETT CCC. He will work closely with the other NETT coordinating center investigators
and with the Hub principal investigators. His responsibilities include oversight of protocol
implementation, regulatory management, human subjects’ protection, accrual and monitoring.
He will oversee the day to day operations of the trial, and work closely with the trial project
manager and study monitors.
All PI’s share responsibility for the scientific integrity of the study, overall study management,
and interpretation and dissemination of the study findings. Any disagreements over study
matters are expected to be resolved collaboratively among the PI’s and with the NETT and
PECARN network leaderships, but if necessary final decisions will be determined by majority
vote of the three PI’s.
Detailed trial management plan is in the budget justification section.
Multiple PI Leadership Plan
Page 536
Contact PD/PI: Kapur, Jaideep
Reference List 1. Abend, N. S., Florance, N., Finkel, R. S., Licht, D. J., and Dlugos, D. J. Intravenous levetiracetam terminates refractory focal status epilepticus . Neurocrit.Care(2009) 10: 83‐86. 2. Abend, N. S., Monk, H. M., Licht, D. J., and Dlugos, D. J. Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures . Pediatr.Crit Care Med.(2009) 10: 505‐510. 3. Afra, P., Jouny, C. C., and Bergey, G. K. Duration of complex partial seizures: an intracranial EEG study . Epilepsia.(2008) 49: 677‐684. 4. Agarwal, P., Kumar, N., Chandra, R., Gupta, G., Antony, A. R., and Garg, N. Randomized study of intravenous valproate and phenytoin in status epilepticus . Seizure.(2007) 16: 527‐532. 5. Aiguabella, M., Falip, M., Villanueva, V., de la Pena, P., Molins, A., Garcia‐Morales, I., Saiz, R. A., Pardo, J., Tortosa, D., Sansa, G., and Miro, J. Efficacy of intravenous levetiracetam as an add‐on treatment in status epilepticus: a multicentric observational study . Seizure.(2011) 20: 60‐64. 6. Alldredge, B. K., Gelb, A. M., Isaacs, S. M., Corry, M. D., Allen, F., Ulrich, S., Gottwald, M. D., O'Neil, N., Neuhaus, J. M., Segal, M. R., and Lowenstein, D. H. A comparison of lorazepam, diazepam, and placebo for the treatment of out‐of‐hospital status epilepticus . N.Engl.J.Med.(2001) 345: 631‐637. 7. Alvarez, V., Januel, J. M., Burnand, B., and Rossetti, A. O. Second‐line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam . Epilepsia(2011) 52: 1292‐1296. 8. Appleton, R., Sweeney, A., Choonara, I., Robson, J., and Molyneux, E. Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus . Dev.Med.Child Neurol.(1995) 37: 682‐688. 9. Appleton, R. E. and Gill, A. Adverse events associated with intravenous phenytoin in children: a prospective study . Seizure.(2003) 12: 369‐372. 10. Binder, L., Trujillo, J., Parker, D., and Cuetter, A. Association of intravenous phenytoin toxicity with demographic, clinical, and dosing parameters . Am.J.Emerg.Med.(1996) 14: 398‐401. 11. Birnbaum, A. K., Kriel, R. L., Norberg, S. K., Wical, B. S., Le, D. N., Leppik, I. E., and Cloyd, J. C. Rapid infusion of sodium valproate in acutely ill children . Pediatric Neurology(2003) 28: 300‐303. 12. Brophy, G. M., Bell, R., Claassen, J., Alldredge, B., Bleck, T. P., Glauser, T., Laroche, S. M., Riviello, J. J., Jr., Shutter, L., Sperling, M. R., Treiman, D. M., and Vespa, P. M. Guidelines for the evaluation and management of status epilepticus . Neurocrit.Care(2012) 17: 3‐23. 13. Brunig, I., Penschuck, S., Berninger, B., Benson, J., and Fritschy, J. M. BDNF reduces miniature inhibitory postsynaptic currents by rapid downregulation of GABA(A) receptor surface expression . European Journal of Neuroscience(2001) 13: 1320‐1328. 14. Bryant, A. E., III and Dreifuss, F. E. Valproic acid hepatic fatalities. III. U.S. experience since 1986 . Neurology(1996) 46: 465‐469. 15. Chamberlain, J. M., Altieri, M. A., Futterman, C., Young, G. M., Ochsenschlager, D. W., and Waisman, Y. A References Cited
Page 537
Contact PD/PI: Kapur, Jaideep
prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children . Pediatric Emergency Care(1997) 13: 92‐94. 16. Chen, J. W., Naylor, D. E., and Wasterlain, C. G. Advances in the pathophysiology of status epilepticus . Acta Neurol.Scand.Suppl.(2007) 186:7‐15.: 7‐15. 17. Connor J.T, Elm J.J., and Broglio KR. Bayesian Adaptive Trials for Comparative Effectiveness Research: An
Example in Status Epilepticus . Journal of Clinical Epidemiology(2013) : ‐. 18. Cook, A. M., Castle, A., Green, A., Lesch, C., Morrison, C., Rhoney, D., Parker, D., Jr., Tesoro, E., Brophy, G., Goodwin, H., Gokun, J., Makii, J., McAllen, K., Bledsoe, K., Sangha, K., Weant, K., Liang, N., and Murphy‐
Human, T. Practice variations in the management of status epilepticus . Neurocrit.Care(2012) 17: 24‐30. 19. Corsellis, J. A. and Bruton, C. J. Neuropathology of status epilepticus in humans . Adv.Neurol.(1983) 34: 129‐139. 20. Cranford, R. E., Leppik, I. E., Patrick, B., Anderson, C. B., and Kostick, B. Intravenous phenytoin: clinical and pharmacokinetic aspects . Neurology(1978) 28: 874‐880. 21. DeGiorgio, C. M., Tomiyasu, U., Gott, P. S., and Treiman, D. M. Hippocampal pyramidal cell loss in human status epilepticus . Epilepsia(1992) 33: 23‐27. 22. DeLorenzo, R. J., Garnett, L. K., Towne, A. R., Waterhouse, E. J., Boggs, JG, Morton, L., Choudhry, M. A., Barnes, T., and Ko, D. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes . Epilepsia(1999) 40: 164‐169. 23. DeLorenzo, R. J., Hauser, W. A., Towne, A. R., Boggs, J. G., Pellock, J. M., Penberthy, L., Garnett, L., and Ko, D. A prospective, population‐based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology(1996) 46: 1029‐1035. 24. DeLorenzo, R. J., Pellock, J. M., Towne, A. R., and Boggs, J. G. Epidemiology of status epilepticus . J.Clin.Neurophysiol.(1995) 12: 316‐325. 25. DeLorenzo, R. J., Towne, A. R., Pellock, J. M., and Ko, D. Status epilepticus in children, adults, and the elderly . Epilepsia(1992) 33 Suppl 4: S15‐S25. 26. DeLorenzo, R. J., Waterhouse, E. J., Towne, A. R., Boggs, J. G., Ko, D., Delorenzo, G. A., Brown, A., and Garnett, L. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus . Epilepsia(1998) 39: 833‐840. 27. Doheny, H. C., Ratnaraj, N., Whittington, M. A., Jefferys, J. G., and Patsalos, P. N. Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat . Epilepsy Research(1999) 34: 161‐168. 28. Donovan, P. J. and Cline, D. Phenytoin administration by constant intravenous infusion: selective rates of administration . Ann.Emerg.Med.(1991) 20: 139‐142. 29. Dreifuss, F. E., Langer, D. H., Moline, K. A., and Maxwell, J. E. Valproic acid hepatic fatalities. II. US experience since 1984 . Neurology(1989) 39: 201‐207. 30. Dreifuss, F. E., Rosman, N. P., Cloyd, J. C., Pellock, J. M., Kuzniecky, R. I., Lo, W. D., Matsuo, F., Sharp, G. B., Conry, J. A., Bergen, D. C., and Bell, W. E. A comparison of rectal diazepam gel and placebo for acute repetitive seizures . N.Engl.J.Med.(1998) 338: 1869‐1875. 31. Dreifuss, F. E., Santilli, N., Langer, D. H., Sweeney, K. P., Moline, K. A., and Menander, K. B. Valproic acid hepatic fatalities: a retrospective review . Neurology(1987) 37: 379‐385. References Cited
Page 538
Contact PD/PI: Kapur, Jaideep
32. Fischer, J. H., Patel, T. V., and Fischer, P. A. Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures . Clin.Pharmacokinet.(2003) 42: 33‐58. 33. Fountain, N. B., Conry, J. A., Rodriguez‐Leyva, I., Gutierrez‐Moctezuma, J., Salas, E., Coupez, R., Stockis, A., and Lu, Z. S. Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4‐ to 12‐
year‐old children with partial‐onset seizures on concomitant carbamazepine or valproate . Epilepsy Research(2007) 74: 60‐69. 34. Fountain, N. B., Krauss, G., Isojarvi, J., Dilley, D., Doty, P., and Rudd, G. D. Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide‐naive patients with partial‐onset seizures . Epilepsia(2012) 54: 58‐65. 35. Fujikawa, D. G. The temporal evolution of neuronal damage from pilocarpine‐induced status epilepticus . Brain Research(1996) 725: 11‐22. 36. Fujikawa, D. G. Prolonged seizures and cellular injury: understanding the connection . Epilepsy Behav.(2005) 7 Suppl 3: S3‐11. 37. Fujikawa, D. G., Itabashi, H. H., Wu, A., and Shinmei, S. S. Status epilepticus‐induced neuronal loss in humans without systemic complications or epilepsy . Epilepsia(2000) 41: 981‐991. 38. Glauser, T. A., Mitchell, W. G., Weinstock, A., Bebin, M., Chen, D., Coupez, R., Stockis, A., and Lu, Z. S. Pharmacokinetics of levetiracetam in infants and young children with epilepsy . Epilepsia(2007) 48: 1117‐1122. 39. Goodkin, H. P. and Kapur, J. The impact of diazepam's discovery on the treatment and understanding of status epilepticus . Epilepsia(2009) 50: 2011‐2018. 40. Goodkin, H. P., Liu, X, and Holmes, G. L. Duration, not age, determines the efficacy of diazepam in terminating secondarily generalized status epilepticus . Epilepsia(2002) 43: 73‐73. 41. Goodkin, H. P., Yeh, J. L., and Kapur, J. Status epilepticus increases the intracellular accumulation of GABAA receptors . Journal of Neuroscience(2005) 25: 5511‐5520. 42. Goodkin, Howard P., Joshi, Suchitra, Mtchedlishvili, Zakaria, Brar, Jasmit, and Kapur, Jaideep. Subunit‐Specific Trafficking of GABAA Receptors during Status Epilepticus . Journal of Neuroscience(2008) 28: 2527‐2538. 43. Hammond, E. J., Perchalski, R. J., Villarreal, H. J., and Wilder, B. J. In vivo uptake of valproic acid into brain . Brain Research(1982) 240: 195‐198. 44. Hesdorffer, D. C., Shinnar, S., Lewis, D. V., Moshe, S. L., Nordli, D. R., Jr., Pellock, J. M., Macfall, J., Shinnar, R. C., Masur, D., Frank, L. M., Epstein, L. G., Litherland, C., Seinfeld, S., Bello, J. A., Chan, S., Bagiella, E., and Sun, S. Design and phenomenology of the FEBSTAT study . Epilepsia(2012) 53: 1471‐1480. 45. Hofler, J. and Trinka, E. Lacosamide as a new treatment option in status epilepticus . Epilepsia(2013) 54: 393‐
404. 46. Jones, D. M., Esmaeil, N., Maren, S., and Macdonald, R. L. Characterization of pharmacoresistance to benzodiazepines in the rat Li‐Pilocarpine model of status epilepticus . Epilepsy Research(2002) 50: 301‐
312. 47. Kapur, J. and Coulter, D. A. Experimental status epilepticus alters GABAA receptor function in CA1 pyramidal neurons . Annals of Neurology(1995) 38: 893‐900. 48. Kapur, J. and Macdonald, R. L. Rapid Seizure‐Induced Reduction of Benzodiazepine and Zn2+ Sensitivity of References Cited
Page 539
Contact PD/PI: Kapur, Jaideep
Hippocampal Dentate Granule Cell GABAA Receptors . Journal of Neuroscience(1997) 17: 7532‐7540. 49. Leppik, I. E., Derivan, A. T., Homan, R. W., Walker, J., Ramsay, R. E., and Patrick, B. Double‐blind study of lorazepam and diazepam in status epilepticus . JAMA(1983) 249: 1452‐1454. 50. Limdi, N. A., Knowlton, R. K., Cofield, S. S., Ver Hoef, L. W., Paige, A. L., Dutta, S., and Faught, E. Safety of rapid intravenous loading of valproate . Epilepsia(2007) 48: 478‐483. 51. Limdi, N. A., Shimpi, A. V., Faught, E., Gomez, C. R., and Burneo, J. G. Efficacy of rapid IV administration of valproic acid for status epilepticus . Neurology(2005) 64: 353‐355. 52. Loddenkemper, T. and Goodkin, H. P. Treatment of pediatric status epilepticus . Curr.Treat.Options.Neurol.(2011) 13: 560‐573. 53. Logroscino, G., Hesdorffer, D. C., Cascino, G., Annegers, J. F., and Hauser, W. A. Short‐term mortality after a first episode of status epilepticus . Epilepsia(1997) 38: 1344‐1349. 54. Lothman, E. The biochemical basis and pathophysiology of status epilepticus . Neurology(1990) 40: 13‐23. 55. Lowenstein, D. H., Alldredge, B. K., Allen, F., Neuhaus, J., Corry, M., Gottwald, M., O'Neil, N., Ulrich, S., Isaacs, S. M., and Gelb, A. The prehospital treatment of status epilepticus (PHTSE) study: design and methodology . Control Clin.Trials(2001) 22: 290‐309. 56. Lowenstein, D. H., Bleck, T., and Macdonald, R. L. It's time to revise the definition of status epilepticus . Epilepsia(1999) 40: 120‐122. 57. Mazarati, A. M., Baldwin, R., Klitgaard, H., Matagne, A., and Wasterlain, C. G. Anticonvulsant effects of levetiracetam and levetiracetam‐diazepam combinations in experimental status epilepticus . Epilepsy Research(2004) 58: 167‐174. 58. Mazarati, A. M., Baldwin, R. A., Sankar, R., and Wasterlain, C. G. Time‐dependent decrease in the effectiveness of antiepileptic drugs during the course of self‐sustaining status epilepticus . Brain Research(1998) 814: 179‐185. 59. McDonough, J. H., Benjamin, A., McMonagle, J. D., Rowland, T., and Shih, T. M. Effects of fosphenytoin on nerve agent‐induced status epilepticus . Drug Chem.Toxicol.(2004) 27: 27‐39. 60. McVearry, K. M., Gaillard, W. D., VanMeter, J., and Meador, K. J. A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy . Epilepsy Behav.(2009) 16: 609‐616. 61. Meador, K. J., Baker, G. A., Browning, N., Clayton‐Smith, J., Combs‐Cantrell, D. T., Cohen, M., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., and Loring, D. W. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs . N.Engl.J.Med.(2009) 360: 1597‐1605. 62. Meierkord, H., Boon, P., Engelsen, B., Gocke, K., Shorvon, S., Tinuper, P., and Holtkamp, M. EFNS guideline on the management of status epilepticus in adults . Eur.J.Neurol.(2010) 17: 348‐355. 63. Meldrum, B. S. Neuropathological consequences of chemically and electrically induced seizures . Ann.N.Y.Acad.Sci.(1986) 462: 186‐193. 64. Meldrum, B. S., Vigouroux, R. A., and Brierley, J. B. Systemic factors and epileptic brain damage. Prolonged seizures in paralyzed, artificially ventilated baboons . Arch.Neurol.(1973) 29: 82‐87. 65. Meldrum, B. S., Vigouroux, R. A., Rage, P., and Brierley, J. B. Hippocampal lesions produced by prolonged References Cited
Page 540
Contact PD/PI: Kapur, Jaideep
seizures in paralyzed artificially ventilated baboons . Experientia(1973) 29: 561‐563. 66. Misra, U. K., Kalita, J., and Maurya, P. K. Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study . J.Neurol.(2011) : ‐. 67. Misra, U. K., Kalita, J., and Patel, R. Sodium valproate vs phenytoin in status epilepticus: a pilot study . Neurology(2006) 67: 340‐342. 68. Naylor, D. E., Liu, H., and Wasterlain, C. G. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus . Journal of Neuroscience(2005) 25: 7724‐7733. 69. Naylor, D. E., Liu, H., and Wasterlain, C. G. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus . Journal of Neuroscience(2005) 25: 7724‐7733. 70. Neligan, Aidan and Shorvon, Simon D. Frequency and Prognosis of Convulsive Status Epilepticus of Different Causes: A Systematic Review . Archives of Neurology(2010) 67: 931‐940. 71. Nordli, D. R., Jr., Moshe, S. L., Shinnar, S., Hesdorffer, D. C., Sogawa, Y., Pellock, J. M., Lewis, D. V., Frank, L. M., Shinnar, R. C., and Sun, S. Acute EEG findings in children with febrile status epilepticus: Results of the FEBSTAT study . Neurology(2012) 79: 2180‐2186. 72. Ogutu, B. R., Newton, C. R., Muchohi, S. N., Otieno, G. O., Edwards, G., Watkins, W. M., and Kokwaro, G. O. Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus . Br.J.Clin.Pharmacol.(2003) 56: 112‐119. 73. Pal, S., Sun, D., Limbrick, D., Rafiq, A., and DeLorenzo, R. J. Epileptogenesis induces long‐term alterations in intracellular calcium release and sequestration mechanisms in the hippocampal neuronal culture model of epilepsy . Cell Calcium(2001) 30: 285‐296. 74. Pellock, J. M., Carman, W. J., Thyagarajan, V., Daniels, T., Morris, D. L., and D'Cruz, O. Efficacy of antiepileptic drugs in adults predicts efficacy in children: a systematic review . Neurology(2012) 79: 1482‐1489. 75. Pellock, J. M., Glauser, T. A., Bebin, E. M., Fountain, N. B., Ritter, F. J., Coupez, R. M., and Shields, W. D. Pharmacokinetic study of levetiracetam in children . Epilepsia(2001) 42: 1574‐1579. 76. Penberthy, L. T., Towne, A., Garnett, L. K., Perlin, J. B., and DeLorenzo, R. J. Estimating the economic burden of status epilepticus to the health care system . Seizure.(2005) 14: 46‐51. 77. Ramael, S., Daoust, A., Otoul, C., Toublanc, N., Troenaru, M., Lu, Z. S., and Stockis, A. Levetiracetam intravenous infusion: a randomized, placebo‐controlled safety and pharmacokinetic study . Epilepsia(2006) 47: 1128‐
1135. 78. Ramael, S., De, Smedt F., Toublanc, N., Otoul, C., Boulanger, P., Riethuisen, J. M., and Stockis, A. Single‐dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple‐dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects . Clin.Ther.(2006) 28: 734‐744. 79. Ramsay, R. E., Cantrell, D., Collins, S. D., Walch, J. K., Naritoku, D. K., Cloyd, J. C., and Sommerville, K. Safety and tolerance of rapidly infused Depacon. A randomized trial in subjects with epilepsy . Epilepsy Research(2003) 52: 189‐201. 80. Riviello, J. J., Jr., Claassen, J., Laroche, S. M., Sperling, M. R., Alldredge, B., Bleck, T. P., Glauser, T., Shutter, L., Treiman, D. M., Vespa, P. M., Bell, R., and Brophy, G. M. Treatment of Status Epilepticus: An International Survey of Experts . Neurocrit.Care(2012) : ‐. References Cited
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81. Shinnar, S., Bello, J. A., Chan, S., Hesdorffer, D. C., Lewis, D. V., Macfall, J., Pellock, J. M., Nordli, D. R., Frank, L. M., Moshe, S. L., Gomes, W., Shinnar, R. C., and Sun, S. MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study . Neurology(2012) 79: 871‐877. 82. Shinnar, S., Berg, A. T., Moshe, S. L., and Shinnar, R. How long do new‐onset seizures in children last? Annals of Neurology(2001) 49: 659‐664. 83. Shinnar, S., Hesdorffer, D. C., Nordli, D. R., Jr., Pellock, J. M., O'Dell, C., Lewis, D. V., Frank, L. M., Moshe, S. L., Epstein, L. G., Marmarou, A., and Bagiella, E. Phenomenology of prolonged febrile seizures: results of the FEBSTAT study . Neurology(2008) 71: 170‐176. 84. Shinnar, S., Pellock, J. M., Moshe, S. L., Maytal, J., O'Dell, C., Driscoll, S. M., Alemany, M., Newstein, D., and DeLorenzo, R. J. In whom does status epilepticus occur: age‐related differences in children . Epilepsia(1997) 38: 907‐914. 85. Shorvon, S. The treatment of status epilepticus . Curr.Opin.Neurol.(2011) 24: 165‐170. 86. Shorvon, S. Guidelines for status epilepticus: are we there yet? Neurocrit.Care(2012) 17: 1‐2. 87. Silbergleit, R., Biros, M. H., Harney, D., Dickert, N., and Baren, J. Implementation of the exception from informed consent regulations in a large multicenter emergency clinical trials network: the RAMPART experience . Acad.Emerg.Med.(2012) 19: 448‐454. 88. Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., and Barsan, W. Intramuscular versus intravenous therapy for prehospital status epilepticus . N.Engl.J.Med.(2012) 366: 591‐600. 89. Silbergleit, R., Lowenstein, D., Durkalski, V., and Conwit, R. RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double‐blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics . Epilepsia(2011) 52 Suppl 8: 45‐47. 90. Sloviter, R. S. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the "dormant basket cell" hypothesis and its possible relevance to temporal lobe epilepsy . Hippocampus.(1991) 1: 41‐66. 91. Sloviter, R. S. On the relationship between neuropathology and pathophysiology in the epileptic hippocampus of humans and experimental animals. Hippocampus(1994) 4: 250‐253. 92. Stewart, J. D., Horvath, R., Baruffini, E., Ferrero, I., Bulst, S., Watkins, P. B., Fontana, R. J., Day, C. P., and Chinnery, P. F. Polymerase gamma gene POLG determines the risk of sodium valproate‐induced liver toxicity . Hepatology(2010) 52: 1791‐1796. 93. Tanaka, J., Kasai, H., Shimizu, K., Shimasaki, S., and Kumagai, Y. Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers . Eur.J.Clin.Pharmacol.(2013) 69: 489‐497. 94. Terunuma, M., Xu, J., Vithlani, M., Sieghart, W., Kittler, J., Pangalos, M., Haydon, P. G., Coulter, D. A., and Moss, S. J. Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus . J Neurosci.(2008) 28: 376‐384. 95. Towne, A. R. Epidemiology and outcomes of status epilepticus in the elderly . Int.Rev.Neurobiol.(2007) 81:111‐
27.: 111‐127. 96. Towne, A. R., Pellock, J. M., Ko, D., and DeLorenzo, R. J. Determinants of mortality in status epilepticus . Epilepsia(1994) 35: 27‐34. References Cited
Page 542
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97. Treiman, D. M., Meyers, P. D., Walton, N. Y., Collins, J. F., Colling, C., Rowan, A. J., Handforth, A., Faught, E., Calabrese, V. P., Uthman, B. M., Ramsay, R. E., and Mamdani, M. B. A Comparison of four treatments for generalized convulsive status epilepticus . New England Journal of Medicine(1998) 339: 792‐798. 98. Trinka, E. What is the relative value of the standard anticonvulsants: Phenytoin and fosphenytoin, phenobarbital, valproate, and levetiracetam? Epilepsia(2009) 50 Suppl 12: 40‐43. 99. Trinka, E. What is the evidence to use new intravenous AEDs in status epilepticus? Epilepsia(2011) 52 Suppl 8: 35‐38. 100. Tripathi, M., Vibha, D., Choudhary, N., Prasad, K., Srivastava, M. V., Bhatia, R., and Chandra, S. P. Management of refractory status epilepticus at a tertiary care centre in a developing country . Seizure.(2010) 19: 109‐
111. 101. Venkataraman, V. and Wheless, J. W. Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients . Epilepsy Research(1999) 35: 147‐153. 102. Walton, N. Y. and Treiman, D. M. Experimental secondarily generalized convulsive status epilepticus induced by D,L‐homocysteine thiolactone . Epilepsy Research(1988) 2: 79‐86. 103. Walton, N. Y. and Treiman, D. M. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam . Exp.Neurol.(1988) 101: 267‐275. 104. Walton, N. Y. and Treiman, D. M. Efficacy of ACC‐9653 (a phenytoin prodrug) in experimental status epilepticus in the rat . Epilepsy Research(1990) 5: 165‐168. 105. Wang, N. C., Good, L. B., Marsh, S. T., and Treiman, D. M. EEG stages predict treatment response in experimental status epilepticus . Epilepsia(2009) 50: 949‐952. 106. Wasterlain, C. G., Fujikawa, D. G., Penix, L., and Sankar, R. Pathophysiological mechanisms of brain damage from status epilepticus . Epilepsia(1993) 34 Suppl 1: S37‐S53. 107. Waterhouse, E. J. and DeLorenzo, R. J. Status epilepticus in older patients: epidemiology and treatment options . Drugs Aging(2001) 18: 133‐142. 108. Waterhouse, E. J., Garnett, L. K., Towne, A. R., Morton, L. D., Barnes, T., Ko, D., and DeLorenzo, R. J. Prospective population‐based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia . Epilepsia(1999) 40: 752‐758. 109. Waterhouse, E. J., Vaughan, J. K., Barnes, T. Y., Boggs, J. G., Towne, A. R., Kopec‐Garnett, L., and DeLorenzo, R. J. Synergistic effect of status epilepticus and ischemic brain injury on mortality . Epilepsy Research(1998) 29: 175‐183. 110. Weinstock, A., Ruiz, M., Gerard, D., Toublanc, N., Stockis, A., Farooq, O., Dilley, D., Karmon, Y., Elgie, M. J., and Schiemann‐Delgado, J. Prospective Open‐Label, Single‐Arm, Multicenter, Safety, Tolerability, and Pharmacokinetic Studies of Intravenous Levetiracetam in Children With Epilepsy . J.Child Neurol.(2013) : ‐. 111. Werler, M. M., Ahrens, K. A., Bosco, J. L., Mitchell, A. A., Anderka, M. T., Gilboa, S. M., and Holmes, L. B. Use of antiepileptic medications in pregnancy in relation to risks of birth defects . Ann.Epidemiol.(2011) 21: 842‐850. 112. Wheless, J. W. and Treiman, D. M. The role of the newer antiepileptic drugs in the treatment of generalized convulsive status epilepticus . Epilepsia(2008) 49 Suppl 9: 74‐78. References Cited
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113. Wheless, J. W., Vazquez, B. R., Kanner, A. M., Ramsay, R. E., Morton, L., and Pellock, J. M. Rapid infusion with valproate sodium is well tolerated in patients with epilepsy . Neurology(2004) 63: 1507‐1508. 114. White, H. S., Alex, A. B., Pollock, A., Hen, N., Shekh‐Ahmad, T., Wilcox, K. S., McDonough, J. H., Stables, J. P., Kaufmann, D., Yagen, B., and Bialer, M. A new derivative of valproic acid amide possesses a broad‐
spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage . Epilepsia(2012) 53: 134‐146. 115. Williams, J. H., Jayaraman, B., Swoboda, K. J., and Barrett, J. S. Population pharmacokinetics of valproic acid in pediatric patients with epilepsy: considerations for dosing spinal muscular atrophy patients . J.Clin.Pharmacol.(2012) 52: 1676‐1688. 116. Yaffe, K. and Lowenstein, D. H. Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus . Neurology(1993) 43: 895‐900. References Cited
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Consortium/Contractual Arrangements
The University of Virginia has made arrangements with selected clinical institutions in North America to
complete the human subject portion of this proposal. Selected clinical institutions are active participants in one
or both of the PECARN and NETT networks. MUSC is submitting a partnering application and will function as
the Statistical Center. University of Michigan will serve as the Site Coordinating Center.
The appropriate programmatic and administrative personnel of each institution involved in this grant application
are prepared to establish the necessary inter-institutional agreements that will ensure compliance with all
pertinent Federal regulations and policies.
We plan to establish subcontracts with the following institutions:
Institution
University of Michigan
University of Pittsburgh
University of Texas Southwestern Med. Ctr.
Children’s National Med. Ctr.
Washington University
Brown University
A.I. DuPont Hospital for Children of the
Nemours Foundation
University of Utah
Baylor College
The Research Institute at Nationwide
Children’s Hospital
Children’s Hospital of New York
University of California, Davis
Wayne State University
University of Minnesota
Medical College of Wisconsin
Cincinnati Children’s Hospital Medical Center
St. George’s University of London
The University of Health Science Center
Houston
Albert Einstein College of Medicine
University of California, San Francisco
Consortium/Contractual
Role
Clinical Coordinating Center for NETT and PECARN
PECARN site
PECARN site
Administrative Core and PECARN site
PECARN site
PECARN site
PECARN site
PECARN site
PECARN site
PECARN site
PECARN site
PECARN site
PECARN site
Pharmacology Core
PECARN site
PECARN site
Clinical Adjudication Core
Clinical Adjudication Core
Administrative Core and Clinical Adjudication Core
Administrative Core and Clinical Adjudication Core
Page 545
Contact PD/PI: Kapur, Jaideep
Neu
urologica
al
Eme
ergenciess
Trea
atment
Tria
als
Clinica
al Coordinating Center
Universsity of Michigan
Departmentt of Emergenc
cy Medicine
N
Neuro Emergen
ncies Research
Universitty of Michigan
24 Frank Lloyyd Wright Dr.
Lobby H, Suite 3100
Ann Arb
bor, MI 48106
7734-232-2142
Fax7734-232-2122
Septeember 23, 201
13
William
m G. Barsan, MD
Principal
P
Investigator
Daniel Lowenstein,
L
MD
Lewis Morgenstern,
M
MD
Arth
hur Pancioli, MD
Robertt Silbergleit, MD
D, PhD
Jaideeep Kapur, MD
Profeessor
Depaartment of Neurology
University of Virg
ginia
Valerie Stevenson, BAS, CCRP
Adm
ministrative Director
Statisttical Data Manag
gement Center
Medicaal University of Sou
uth Carolina
Yuk
ko Palesch, PhD
Re: ESETT
E
Trial
Dear Jaideep ,
Principal
P
Investigator
Valeriee Durkalski, PhD
Nation
nal Institute of Neurological
N
Disord
ders and Stroke
Robin Conwit, MD
Scientiffic Program Director
Scott
S
Janis, PhD
Administratiive Program Director
Hub P
Principal Investig
gators
Tom Aufderheide,
A
MD
Medical College of Wisconsin
Jill Baren,
B
MD, MBE
Unive
ersity of Pennsylvania
Michellee Biros, MD, MS
On behalf of the Neurological
N
E
Emergencies Treatment Trrials network, I am writing
g
in strrong support of
o the grant appplication to conduct ESE
ETT, a random
mized clinical
trial to
t select the optimal
o
seconnd-line anticonnvulsant meddication in thee management
of paatients with beenzodiazepinee-refractory sstatus epilepticus in the em
mergency
deparrtment. This trial has the eenthusiastic eendorsement oof the NETT Steering
Comm
mittee which includes the NETT leaderrship at the Clinical Coorddinating
Centeer, the Statistiical and Dataa Managemennt Center, the NINDS, and all the Hub
Princcipal Investigaators. A list oof identified ccross disciplinnary site inveestigators for
this trrial has been provided for the consortiuum section off the applicatioon's research
plan.
Un
niversity of Minnesota
Clifton W. Calllaway, MD, PhD
Temple Un
niversity of Pittsburgh
Kurt Denninghoff, MD
University of Arizona
Nina
N
Gentile, MD
Temple University
Joshua N. Gold
dstein, MD, PhD
Massachussetts General Hospital
J. Claude Hemphilll, III, MD, MAS
University of Caliifornia, San Francisco
Roger Humphries,
H
MD
University
U
of Kentucky
Eliza
abeth Jones, MD
University of Texas
Steven
n R. Levine, MD
SUNY Down
nstate Medical Center
ESET
TT is a naturaal continuatio n of the workk that NETT bbegan in RAM
MPART to
optim
mize the very early deliveryy of anticonvu
vulsants as a strategy to impprove the
outco
omes of patien
nts with statuus epilepticus.. This trial truuly leveragess our
netwo
ork’s ability to
t perform higgh quality ranndomized clinnical trials in the hectic
envirronment of the emergency department rresuscitation bbay in the firsst minutes of
hospiital care. Ourr multidiscipllinary organizzation ensuress that subjectss are followed
d
appro
opriately throughout their ccourse in the ICU and hosppitalization. ESETT will
beneffit from the effficiencies off scale inherennt in our estabblished infrasstructure and
our other
o
on-going
g clinical trialls. As co-PI oof the ADAPT-IT project, we thought
that ESETT
E
was a clinical trial that could cleearly benefit from an adapptive design.
We believe
b
that th
he re-design oof the trial using adaptive cclinical trial m
methodology
as paart of the ADA
APT-IT proje ct in NETT hhas been of grreat value.
Christopher Lew
wandowski, MD
Henry
y Ford Health System
Robert Lowe,
L
MD, MPH
Oregon Health
h & Science University
The human
h
and fin
nancial costs of status epillepticus are im
mportant. Wee are eager to
work
k with you to select
s
and possitively impacct the treatmeent of these paatients.
Step
phan Mayer, MD
New York Presbyterian
P
Hospital
Joseph
h P. Ornato, MD
Sinceerely,
Virginia Comm
monwealth University
Arth
hur Pancioli, MD
Un
niversity of Cincinnati
Jamees V. Quinn, MD
Stanford University
Jeeffrey Saver, MD
University of Ca
alifornia, Los Angeles
Barn
ney J. Stern, MD
Un
niversity of Maryland
Williiam Barsan, MD
M
Princcipal Investigaator, NETT C
CCC
Michel To
orbey, MD, MPH
Ohio
O
State University
Robert Welch, MD
Wayne
W
State University
Da
avid Wright, MD
Emory University
Letters Of Support
Page 546
nett.um
mich.edu
u
Contact PD/PI: Kapur, Jaideep
Letters Of Support
Page 547
Contact PD/PI: Kapur, Jaideep
Letters Of Support
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Letters Of Support
Page 549
Contact PD/PI: Kapur, Jaideep
UNIVERSITY OF CALIFORNIA, DAVIS
BERKELEY  DAVIS  IRVINE  LOS ANGELES  MERCED  RIVERSIDE  SAN DIEGO  SAN FRANCISCO
SANTA BARBARA  SANTA CRUZ
GMP FACILITY
September 23, 2013
To: James Cloyd, PharmD
Professor and Lawrence C. Weaver Endowed Chair
Orphan Drug Development
College of Pharmacy
University of Minnesota
Minneapolis, MN 55455
Email: [email protected]
Phone: (612) 624-4609
Fax: (612) 626-9985
RE: Letter of Support for ….
Dear Dr. Cloyd,
As the Director of the UC Davis GMP facility, I am writing to indicate that our institution and the GMP
Facility strongly support this opportunity to manufacture the drug formulations for your important clinical
study.
With more than two decades of GMP manufacturing and regulatory experience in the US and abroad, I
will be happy to provide our services and my expertise for GMP manufacturing and regulatory support. I
have helped to successfully initiate many investigator INDs for novel indications and have manufactured
the GMP grade products for these studies. Audits conducted for these INDs indicated “no deviations
found”.
I also designed and have been directing, for the last 3 years, the largest academic GMP facility in Northern
California. The UC Davis GMP facility is a state of the art clean room facility that has been designed to
manufacture a variety of clinical grade products needed by academic researchers for investigator initiated
clinical trials. We are currently manufacturing novel drug formulations for two such clinical trials.
We will be happy to GMP manufacture Fosphenytoin (FOS), Levetiracetam (LVT) and Valproic Acid
(VPA) formulations for you. Our GMP facility staff will also provide Quality Control and Quality
Assurance for the manufacturing process and the final products.
Letters Of Support
Page 578
Contact PD/PI: Kapur, Jaideep
UNIVERSITY OF CALIFORNIA, DAVIS
BERKELEY  DAVIS  IRVINE  LOS ANGELES  MERCED  RIVERSIDE  SAN DIEGO  SAN FRANCISCO
SANTA BARBARA  SANTA CRUZ
We are looking forward to a strong and fruitful collaboration with you.
Sincerely,
Gerhard Bauer
Laboratory Director GMP Facility
Adjunct Assistant Professor
Stem Cell Program, School of Medicine
University of California Davis
Institute For Regenerative Cures (IRC)
2921 Stockton Blvd., Room 1345
Sacramento, CA 95817
Tel: (916) 703 9305
Fax: (916) 703 9310
[email protected]
Letters Of Support
Page 579
Contact PD/PI: Kapur, Jaideep
Resource Sharing Plan
The primary results of the clinical trial will be disseminated by publication in the peer reviewed
medical literature. In accordance with the NIH Public Access Policy, the investigators will
submit an electronic version of their final, peer-reviewed manuscripts (directly or through the
publisher) to the National Library of Medicine’s PubMed Central, no later than 12 months after
the official date of publication.
The trial will be registered with http://www.clinical trials.gov, and results of ESETT will be
reported there within a year of trial completion as is consistent with the requirements for
applicable clinical trials per FDAAA 801 requirements.
After completion of the study and dissemination of primary study results, a public use dataset
will be created. The public use dataset will be made available for download through a platform
to be designated by the NINDS. The public use dataset, along with the study protocol, the data
dictionary, and a brief set of instructions (“Readme” file) will be provided.
Data Sharing Plan: Upon completion of the study and dissemination of primary study results,
the analysis data files will be made available for scientific research purposes, along with the
final version of the study protocols, the data dictionary, and a brief instruction (“Readme”
file). The datasets will be made available within 1 year of when the primary manuscripts are
accepted for publication. The rationale for the timeline is to ensure that priority is given to the
study investigators in manuscript development. The study datasets generated from the
WebDCU™ study database will subscribe to the common data elements as much as possible.
This should facilitate the sharing and the use of these datasets among the study investigators.
The public use data files and the accompanying documents will be made available through the
NINDS data repository.
Procedure: Each dataset will be stripped of all personal identifiers and will undergo deidentification process (see below). Furthermore, the SDMC statisticians will create derived
variables that would be needed in the analyses. The analysis data files will be made available in
SAS. Once they become available, any researcher (study investigator or otherwise) wishing to
receive the ESETT Public Use Data Files must contact the NINDS.
De-identification: In compliance with the HIPAA regulations, the analysis data files that will be
made publicly available will undergo the following de-identification process:





delete study ID numbers and assign a random number to each subject
delete hub/spoke ID numbers and assign a random number to each hub/spoke
delete investigator or assessor name/ID
convert all dates and times (e.g., birth date, death date, end of study date) to the number of
days/minutes from the date and time of randomization.
delete all comment fields
Resource Sharing Plans
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