Web Coke Hound FOIA Docs

ORDER FOR SUPPLIES OR SERVICES I PAGE OF PAGES
IMPORTANT : Ma rk al l packages and pa pers w ith con tr ac t and/or order numbers. I 1 I 7

1. DATE OF ORDER 2. CONTRACT NO. grany6 6. SH IP TO:
HHSN271201 00 19 I
a. NAME OF CONS IGNEE
09/14/2020
3. ORDER NO . 14.REQU ISITION/ REFERENCE NO.
3WFN MSC 6012
75N95020 F00002 57 599 15
5. ISSUING OFFICE (Address corresp ondence to) b. STREET ADD RESS
Na ti o n al In s t it ut es of Hea l th 3WFN 30 1 Nort h Stones t reet Ave . 6012
Na ti o n al I ns t it ut e on Drug Abuse
Bethesda , MD 20892-7511
c. CITY I d. STATE I e. Z IP CODE

Bethesda MD 20892
7. TO: f. SH IP VIA
a. NAME OF CONTRACTOR
SRI I NTERNATIO NAL : 11 10 101 8. TYPE OF ORDER
b. COMPANY NAME
__, a . PURCHASE Kl b. DELIVERY
c. STREET ADD RESS REFERENCE YOUR:
333 RAVENSWOOD AVENUE 75N9 50 20 F0000 2 Pr oposal Except for billing inst ructio ns on the
reverse, this delive ry order is
subject to instructions contained on
this side only of this form and is
Please furnish the following on the terms issued subject to the terms and
and conditio ns specified on both sides of condi tions of the above -numbered
d. CITY
MENLO PARK
Ie. STATE If . Z IP CODE this order and on the attached sheel , if
anv. includina de liverv as indica ted .
contract.
CA 940253493
9. ACCO UNTING AND APPROPR IATION DATA 10. REQ UISITIONING OFFICE
See Sc hedule Nat i ona l I n st it u te s of Health
11. BUSINESS CLASS IFICATION (Check appropriate box(es)) 12. F.O.B . POI NT
- a. SMALL X] b. OTHER THAN SMALL = c. DISADVANTAGED = d WOMEN -OW NED ~ e. HUBZone
-
f . SERVICE-DISABLED
VETERAN -OW NED
~ g. WOME N-OWN ED SMALL BUSINESS (WOSB)
ELIGIBLE UNDER THE WOSB PROGRAM
7 h. EDWOSB
13 . PLAC E OF 14. GOVERN MENT BIL NO. 15. DELIV ER TO F.O B. POINT 16. DISCOUN T TERMS
O N OR BEFORE 6°at e/
a. INSPEC T ION I b. ACCEP TANCE 07/23/202
Destination Dest in at i on Net 30
17. SCHEDULE /See reverse for Rejections)
QUANTI TY UNIT QUANT ITY

ITEM NO . SUPPL IES OR SERV ICES ORDERED UN IT PR ICE AMOUNT ACC EPTED
(a) (b) (C) (d) (el (/) (g)
Purpose : To award Task Order 75N 95020 F0 0 002
1Propr ietary Info
I unde r ID IQ No . HHSN27 12 0 18 0 00 19 I for
p roprietary lnf o
work as described in t he attached NIDA
Co n t r act Task Order Pa r t I , Section B . Tas k
Descr ip t i on .
Con t in u ed ...
18. SHIPPING POINT 19. GROSS SHIPPI NG WEIG HT 20. INVOIC E NO. 17(h)
TOTAL
(Cont.
pages)
•
21. MAIL INVO ICE TO:
a. NAM E $1 , 256 , 044 . 00

Office of Fina nc ial Man agement
SEE BILLING
INSTRUCTIONS b. STR EET AD DRESS 2115 E J e fferson St
ON REVERSE (or P.O. Box)
MSC 85 00 Sui t e 4B 432 17(i)
GRA ND
•
TOTAL
c. CITY e. Z IP COD E
$1 , 256 , 044 . 00
r .STATE
Bet hesda MD 20892 - 8500
"eda cted by agreement
22. UNIT ED STATES OF
AMER ICA BY (Signature/
AUTHOR IZED FOR LOCA L REPRODUCTION OPTIONAL FORM 347 (Re,. 2/20 12)
PREVIOUS EDITION NOT USAB LE Prescribedby GSAJFAR48 CFR $3.:213,(f)
Obtained via FOIA by White Coat Waste Project

ORDER FOR SUPPLIES OR SERVICES PAGE NO
SCHEDULE - CONTINUATION 2
IM PO RTANT: Mark all packages and papers with contract and or orde r numbers .
DATE OF ORDER I CONTRAC T NO. ORDER NO.
09/1 4/2020 IHHSN271201 800019I I75 N95020F0 000 2
ITEM NO. SUPPLIES/SERV ICES QUAN TITY UNIT UNIT A MOUNT QUA NTITY
ORDERED PRICE ACCEPTED
(a) (b) (c) (d) (e) (f) (g)
Task Or de r Amou nt : $1 , 256 , 044
FY20 , Period o f Performance 09/14 /202 0 to

09/13/2020
Overt im e (pr emi um) pay for ju nior a nd

se ni o r techn icians shal l n ot e x ceed a t otal
o f $ 441. 74 u nd er t h is task o rd er .
Admin Office :
Nation al I n st it u t es of He alt h
Nati onal Institute o n Dr ug Abus e
Bethesda , MD 20892 - 75 11
Pe ri od of Perfo rmanc e : 09/1 4/2 0 20 to
09/13/2021
1 FY20 . Task Order No . 75N95020F00002 . Period 1, 2 5 6 , 044 . 00

o f Performance : September 14 , 202 0 to
September 13 , 2021
De l ivery To : 4123/J ustin Drott
Product/Service Cod e : R49 9
Product/Service Descrip t ion : SOPPORT-
PROFESS I ONAL : OTHER
Pr o j ect Dat a :
120500 . 2020 . 100 . HN61 NIDA OD OFC
DIR . 25505 RESEARCH AND
DEVELOPMEN T .0 7/23/202 0
Account in g I n fo :
0802932020 1DAD. 2020 . 01 . 6100 .HN61000000
C . E . 00182 . 406 . 9999 . 25505 . 610 00001 . 9999
. 9999 . 9999
Fu nde d : $1 , 256 , 044 . 00
TOTA L CARR IED FORWA RD TO 1ST PAGE (ITEM 17(H)) $1 ,256,044 .00
AUTHOR IZED FOR LOCAL REPODUCTION OPTIONAL FORM 348 (Rev . 4/2006)

PREV IOUS EDITION NOT USAB LE
Pre$cribed t1'/GSAFAR(4$ CFR)53..213(')
N01DA-18-8939 Task Order No. 75N95020F00002
TASK ORDER (TO)
Contractor: SRI International T.0.Titlef''"'""'""

Contract No: HHSN271201800019I T.O. No.: 75N95020F00002
T.O. Originator: NIDA , DTMC, Nathan M. Appe l, Ph.D. Contracted Task Area(s): 1, 2, 19
T.O. Type : Cost Reimbursement (Completion)
PART I. INITIATOR'S REQUEST
A. Period of Performance: 12 months from effective date of award.
B. Task Leader:~f_•ct_ed
_b_
y •_gr_=_· _
en_
! -------------~
C. Activity A
D. Activity Description:~F
r_op
-rie
-tar,
_'_w
1 0
_ ___________ ~
Propr
ietary
Info
E. Activity A Deliverables:
a. Draft Study Protocol : The Contractor shall provide the NIDA COR with a Draft Study Protocol within
5 business days of the COR's request. The protocol shall comply with GLP guidelines and have a
clearly written section that describes appropriate statistical methods for analyzing the experimenta l
data. The protocol shal l set forth the experimental and reporting designs in clear detail and be free of
ambiguities , typographica l errors and contradict ions. In-text tables shall be used to supplement
explanations provided in the text of the protocol. The draft protoco l shall clearly state the anticipated
study schedule , including anima l arrival , treatment phase, ante-mortem evaluations, dispositio n of the
animals after the study and report preparation . The Contractor shal l make NIDA-specified changes to
Draft Study Protoco ls and respond within 3 business days of the COR's request. The protocol may

Page 3 of 7
be revised multiple times before it is acceptable to the NIDA.
b. Final Study Protocol: The Contractor shall provide the COR with a Final Study Protoco l within 2
business days of the COR's authorization to issue the Final Study Protocol.
c. Draft Study Report: The Contractor shall provide the COR with an audited Draft Study Report
within 4 weeks after comp letion of the in-life phase of study. The report shall be free of grammatical
and typographical erro rs, shall be clear, and shall be concise and structured like a manuscript for a
reviewed pharmaco logy or tox icology journal. It shall include a title page, abstract, introduction ,
methods , results, discussion , summary and bibliography or references . Tables and/or figures shall be
included after the bibliography, along with a legend page. As the report may be submitted by NIDA to
the FDA, the report shall conform to standards set forth by GLP guidelines. The Contractor shall
make NIDA-specified changes to Draft Study Reports within 5 business days of the COR's request.
The report may be revised multiple times before it is acceptable to the NIDA.
d. Final Study Report: The Final Study Report shall be issued within 10 business days of the COR's
authorization to issue the Final Study Report. It shall conform to GLP Guidel ines. The Contractor
shall issue one indexed and numer ically paginated, continuous from first page to last, bound paper
copy of the comp lete Final Study Report and one each, indexed and numerically paginated,
continuous from first page to last, electronic copy of the complete Final Study report as an Adobe
PDF file and as a Microsoft Word DOC file . The reports shall include all tables and appendices . The
Contractor shall post the electronic versions of the Final Study Report to NIDA's secure server (e.g.,
Livelink) and, in addition , The Contractor shall post a complete set of all data tables as individual files,
to NIDA's secure server . The posted data tables shall be in a format such that the data can be
exported or copied (that is, not PDF or an image format) into other computer programs, such as
Microsoft Excel and GraphPad Prism , for possible subsequent analysis by NIDA. In addition, the
Contractor shall deliver to the NIDA COR the Adobe PDF file , the Microsoft Word DOC file, and the
data tables on electronic storage media such as an external hard drive, USS flash drive, or SD card
with the Final Study Report.
The Contractor shall ensure that all Study Reports are free from spelling , typog raphical, or
grammatical errors. Study Reports containing such errors shall be deemed unacceptable and
returned to the Contractor for correction. A revised report shall be submitted with the date of
the revision.
D. Activity B
. . Descnp
1. ActIvIty . t'I0n: r roprietary Info
Propr ietary Info

Page 4 of 7
!Proprietary Info
2. Activity B Deliverables:
a. Draft Study Protocol: The Contractor shall provide the NIDA COR with a Draft Study Protocol w ith in
5 business days of the COR 's request. The protocol shall comp ly with GLP guidelines and have a
clearly written section that describes appropriate statist ical methods for analyzing the experimental
data . The protoco l shall set forth the experimental and reporting designs in clear detail and be free of
amb iguities , typographical errors and contradictions . In-text tables and time-course graphs shall be
used to supplement explanations provided in the text of the protocol. The draft protocol shall clearly
state the anticipated study schedule, including animal arrival, treatment phase , ante-mortem
evaluat ions, dispos ition of the animals after the study and report preparation . The Contractor shall
make NIDA-specified changes to Draft Study Protocols and respond within 3 business days of the
COR's request. The protocol may be revised multiple times before it is acceptable to the NIDA.
b. Final Study Protocol: The Contractor shall provide the COR with a Final Study Protocol within 2
c. Draft Study Report: The Contractor shall provide the COR with an audited Draft Study Report
within 12 weeks after completion of the final in-life study. The report shall be free of grammatical and
typographical errors , shall be clear , and shall be concise and structured like a manuscript for a

Page s of 7
reviewed pharmaco logy or toxicology journal. It shall include a title page, abstract, introduction,
methods, results, discussion , summary and bibliography or references. Tables and/or figures shall be
make NIDA-specified changes to Draft Study Reports with in 5 business days of the COR's request.
d. Final Study Report: : The Final Study Report shall be issued within 10 business days of the COR 's
authorization to issue the Final Study Report. It shall conform to GLP Guidelines . The Contractor
shall issue one indexed and numer ically paginated, continuous from first page to last, bound paper
continuous from first page to last, electronic copy of the complete Final Study report as an Adobe
PDF file and as a Microsoft Word DOC file. The reports shall include all tables and appendices. The
Livelink) and, in addition , The Contractor shall post a complete set of all data tables as individual files,
to NIDA's secure server. The posted data tables shall be in a format such that the data can be
exported or cop ied (that is, not PDF or an image format) into other computer programs, such as
Microsoft Excel and GraphPad Prism , for possible subsequent analysis by NIDA. In addition , the
Contractor shall deliver to the NIDA COR the Adobe PDF file , the Microsoft Word DOC file, and the
data tables on electronic storage media such as an external hard drive, USB flash drive or SD card,
with the Final Study Report.
The Contractor shall ensure that all Study Reports are free from spelling , typographical , or
returned to the Contractor for correction . A revised report shall be submitted with the date of
the revision.
E. Task Order Deliverable: NIDA will not receive value from this Task Order until Final Study Reports of
all the prescribed activities have been received so the results therein can be considered holistically.
Thus , the contractor shall produce a Comprehens ive Final Study Report summariz ing the results of
the Activ ities conducted under this Task Order. This report may be issued in the form of a Letter
Report to the NIDA COR.
I
F. Task Order Res onse Due Date: Sign Part II and email your response toat
edacted by agreement y 03/20/2020 at 3:00 PM EST. redacted by agreement
'----------'
G . Proposal Instructions: Please complete Part II, "Contractor's Response to TOR FP." In addition, The
Contractor sha ll demonstrate its understanding of this task order by describing the work needed to
perform it. The Contractor also shall propose and itemize costs for preparation and delivery of all
deliverables required under the contract.

Page 6 of 7
SRI International Proposal 20-059R2 341 BDU TORFP N01DA-18-8939
Task Order 75N95020F00002: GLP Interaction Safety Studies in Rats and Dogs July 17, 2020
TASK ORDER PROPOSAL RESPONSE

• r roprietary Info
Contractor: SRI International T.O. Title:
Contract No: HHSN271201800019I T.O Order No: 75N95020F00002 Modification No: 1
T.O. Originator: NIDA DPMCDAr~ e-da-cte_d-by-agr

_ eem
_. _en_! ----~
Statement of Work Task Area{s}: 1 Date Prepared: July 17, 2020
PART II. SRI INTERNATIONAL'S RESPONSE TO TASK ORDER REQUEST FOR

PROPOSAL (TORFP)
r roprietary Info
A. Estimated Cost and Effort:

Under this task order SRI proposes an estimated ~
hours of labor and a total cost-plus fixed
fee of $1,256 ,044 . See Attachment A Estimated Budget for breakdown of each activity cost
details . Detailed description of the approach to be used and of the deliverables for Activity A and
Activity B:
See Attachment B for a detailed description of approach and deliverables.
APPROVAL TO PROCEED: The Contractor will not exceed the estimated T.O. amount or change the T.O.
leader without the prior written approval of the Project Officer and Contracting Officer. The following
_ Accounting and Ae,eroeriation Data are ae,elicable to this Task Order.
r edacted by agreement
For the Contractor: Date: July 17, 2020
(Signature)
Redacted by agreement
Typed Name: I
For the Government
Typed Name:
Contracting Officer

Task Order Proposal Response Page 7 of 7
IMPORTANT : Ma rk al l packages and pa pers w ith con tr ac t and/or order numbers. I 1 I 8

1. DATE OF ORDER 2. CONTRACT NO. grany6 6. SH IP TO:
HHSN271201 00 19 I
03/25/2020
3. ORDER NO . 14.REQU ISITION/ REFERENCE NO.
6001 , NSC , Rockville
75N95020 F0000 1 56 634 15
5. ISSUING OFFICE (Address corresp ondence to) b. STREET ADD RESS
Na ti o n al In s t it ut es of Hea l th Neu roscie nc e Center
Na ti o n al I ns t it ut e on Drug Abuse 6001 Executive Blv d
Bethesda , MD 20 89 2-7 511

Rockville MD 20852
7. TO: f. SH IP VIA
a. NAME OF CONTRACTOR
SRI I NTERNATIO NAL : 11 10101 8. TYPE OF ORDER
b. COMPANY NAME
__, a . PURCHASE Kl b. DELIVERY
333 RAVENSWOOD AVENUE 75N9 50 20 F0000 1 Proposa l Except for billing inst ructions on the
reverse, this delive ry order is
subject to instructions contained on
this side only of this form and is
Please furnish the following on the terms issued subject to the terms and
and condi tions specified on both sides of condi tions of the above -numbered
d. CITY
MENLO PARK
Ie. STATE I f . Z IP CODE this order and on the attached sheel , if
contract.
CA 940253493
9. ACCO UNTING AND APPROPR IATION DATA 10. REQ UISITIONING OFFICE
See Sc hedule Nat i ona l I n st it u te s of Health
11. BUSINESS CLASS IFICATION (Check appropriate box(es)) 12. F.O.B . POI NT
- a. SMALL X] b. OTHER THAN SMALL = c. DISADVANTAGED = d WOMEN -OW NED ~ e. HUBZone
-
f . SERVICE-DISABLED
VETERAN -OW NED
~ g. WOME N-OWN ED SMALL BUSINESS (WOSB)
ELIGIBLE UNDER THE WOSB PROGRAM
7 h. EDWOSB
13 . PLAC E OF 14. GOVERN MENT BIL NO. 15. DELIV ER TO F.O B. POINT 16. DISCOUN T TERMS
O N OR BEFORE 6°at e/
a. INSPEC T ION I b. ACCEP TANCE 03/25/202
Destination Dest in at i on

ITEM NO . SUPPL IES OR SERV ICES ORDERED UN IT PR ICE AMOUNT ACC EPTED
(a) (b) (C) (d) (el (/) (g)
Purpose : To award Task Order 75N 95020 F0 0 001
(In teractio n Safety St udies in Rats a nd
Dogs) unde r ID IQ No . HHSN27 12 0 18 0 00 19 I for
work as described in t he attached NIDA
Co n t r act Task Order Pa r t I ' Section B . Tas k
Descr ip t i on .
Con t in u ed ...
18. SHIPPING POINT 19. GROSS SHIPPI NG WEIG HT 20. INVOIC E NO. 17(h)
TOTAL
(Cont.
pages)
•
a. NAM E $1 , ll3 , 092 . 00

Office of Fina nc ial Man agement
SEE BILLING
INSTRUCTIONS b. STR EET AD DRESS 2115 E J e fferson St
MSC 85 00 Sui t e 4B 432 17(i)
GRA ND
•
TOTAL
c. CITY e. Z IP COD E
$1 , ll3 , 09 2 . 00
r .STATE
Bet hesda MD 20892 - 8500
22. UNIT ED STATES OF Redactedby agreement
AMER ICA BY (Signature/
AUTHOR IZED FOR LOCA L REPRODUCTION

PREVIOUS EDITION NOT USAB LE
-
OPTIONAL FORM 347 (Re,. 2/20 12)
Prescribedby GSAJFAR48 CFR $3.:213,(f)
IM PO RTANT: Mark all packages and papers with contract and or orde r numbers .
DATE OF ORDER I CONTRAC T NO. ORDER NO.
03/25/ 2020 IHHSN271201 800019I I75 N95020F0 0001
ITEM NO. SUPPLIES/SERV ICES QUAN TITY UNIT UNIT A MOUNT QUA NTITY
(a) (b) (c) (d) (e) (f) (g)
Task Or de r Amou nt : $1 , 11 3 , 092
FY20 , Period o f Performance : 03/25 / 2020 to

03/24/2021
Overt im e (pr emium) pay for ju nior a nd

se ni o r techn icians shal l n ot e x ceed a t otal
o f $ 408 . 74 u nd er t hi s task o rd er .
Admin Office :
Nati onal I n st it u t es of He alt h
Nati onal Institute o n Drug Abuse
Bethesda , MD 20892 - 75 11
Pe ri od of Pe rf o rmanc e : 03/25/2020 to
03/24/2021
1 FY20 . Task Order No . 75N95020F0000 1 . Per i od 1, 113 , 092 . 00

o f Performance : Marc h 25 , 2020 - Ma rc h 24 ,
2021 .
De l ivery To : 4123/ J ustin Drott
Product/Service Code : R49 9
Product/Service Descrip t ion : SOPPORT-
PROFESS I ONAL : OTHER
Pr o j ect Dat a :
120500 . 2020 . 100 . HN61 NIDA OD OFC
DIR . 25103
MGMT&S UPPRT-RE SEARCH&DEV. 03/02/2020
Account in g I n fo :
0802932020 1DAD. 2020 . 01 . 6100 .HN61000000
C . E . 00182 . 406 . 9999 . 25103 . 610 00001 . 9999
. 9999 . 9999
Fu nde d : $1 , 1 13 , 09 2 . 00
TOTA L CARR IED FORWA RD TO 1ST PAGE (ITEM 17(H)) $1 ,113,092.00

AUTHOR IZED FOR LOCAL REPODUCTION OPTIONAL FORM 348 (Rev . 4/2006)

PREV IOUS EDITION NOT USAB LE
Pre$cribed t1'/GSAFAR(4$ CFR)53..213(')
N01 DA-18-8939 Task Order
TASK ORDER (TO)
Contractor: SRI International T.O. Title: Interaction Safety Studies in Rats

and Dogs
Contract No: HHSN271201800019I T.O. No.: 75N95020F00001

Modification No.: Q
T .O . O ngIna . NIDA DTMC

. . tor.--~· ~ edacted by agreement
---• .._L
________ ___, Contracted Task Area(s): 1, 2, 19
T.O. Type : Cost reimbursement (Completion)
A. Period of Performance: 12 Months from Award Date
B. Task Leader f~ ed
- a-ct_ed_b,_• a_gr_= _ e_m_______________ ~
C. Activity A
1. Activity Description: Cocaine Interaction Study in Rats (Activity A)
Under Statement of Work (SOW) Task 1, the Contractor shall conduct acute drug interaction studies
in rodents. Specific methods to be used in these studies shall be subject to the approval of the
Contracting Officer's Representative (COR). Under SOW Task 19, the Contractor shall conduct, as
directed by the COR, special in vivo or in vitro toxicology or pharmacokinetic studies, the details of
which cannot be specified in advance of the contract award. Examples include modifications of the
specified protocols in Tasks 1 to 18, inclusive, to allow for a more specialized evaluation of test
articles and development of a protocol with features similar to a clinical situation. The objective of
these studies shall be to determine the safety of a test article in combination with cocaine or
methamphetamine, an opiate or ethanol. For purposes of cost estimation only, assume that a
test article to be designated by the COR will be administered by oral gavage and tested in
combination with cocaine, the interaction article, administered by intravenous (tail vein) injection,
and that the study will be conducted in two sessions. The interval between the test article and
cocaine will be 2 hours. Effects on lethality, behavior (to include convulsions) and clinical
observations shall be assessed. In this study there would be 12 treatment groups comprised of 10
male rats each. Animals would be observed for treatment effects at intervals for as many as 4 hours
on the dosing day and once daily for 3 days thereafter. The animals would be humanely sacrificed
approximately 4 days after dosing. All test article and interaction article dosing solutions shall be
assayed to verify identity and concentration. NIDA requires a complete report for the study. The
study shall be conducted and reported in conformance with Good Laboratory Practice (GLP)
guidelines (CFR Title 21 Part 58).
2. Activity A Deliverables:
a. Draft Study Protocol: The Contractor shall provide the NIDA COR with a Draft Study Protocol within
clearly written section that describes appropriate statistical methods for analyzing the experimental
data. The protocol shall set forth the experimental and reporting designs in clear detail and be free of
ambiguities, typographical errors and contradictions . In-text tables shall be used to supplement
explanations provided in the text of the protocol. The draft protocol shall clearly state the anticipated
study schedule, including animal arrival, treatment phase, ante-mortem evaluations, disposition of the
animals after the study and report preparation. The Contractor shall make NIDA-specified changes to

Page 3 of 8
Draft Study Protoco ls and respond within 3 business days of the COR's request. The protocol may
b. Final Study Protocol: The Contractor shall provide the COR with a Final Study Protocol within 2
business days of the CO R's authorization to issue the Final Study Protocol.
c. Draft Study Report : The Contractor shall provide the COR with an audited Draft Study Report
within 4 weeks after completion of the in-life phase of study. The report shall be free of grammatica l
and typographica l errors, shall be clear , and shall be conc ise and structured like a manuscript for a
reviewed pharmacology or toxicology journal. It shall include a title page, abstract, introduct ion,
methods , results, discuss ion , summary and bibliography or references . Tables and/or figures shall be
the FDA, the report shall conform to sta ndards set forth by GLP guidel ines . The Contractor sha ll
make NIDA-specif ied changes to Draft Study Reports with in 5 business days of the COR's request.
d. Final Study Report: The Final Study Report shall be issued within 10 business days of the COR's
authorization to issue the Final Study Report. It shall conform to GLP Guidelines. The Contractor
shall issue one indexed and numerica lly paginated , continuous from first page to last, bound paper
continuous from first page to last, electron ic copy of t he complete Final Study report as an Adobe
PDF file and as a Microsoft Word DOC file. The reports shall include all tab les and append ices. The
Livelink) and, in addit ion , The Contractor shall post a complete set of all data tables as individual files,
to NIDA's secure server . The posted data tables shall be in a format such that the data can be
Microsoft Excel and GraphPad Prism , for possible subsequent analysis by NIDA. In addition , the
Contractor shall deliver to t he NIDA COR the Adobe PDF file , the Microsoft Word DOC file , and the
data tables on electronic storage media such as an external hard drive CD, DVD, USS flash drive or
SD card, with the Final Study Report.
The Contractor shall ensure that all Study Reports are free from spelling, typographical, or
grammatical errors. Study Reports containing such errors shall be deemed unacceptab le and
returned to the Contractor for correction. A revised report shall be submitted with the date of
the revision.
D. Activity B
1. Activity Description: Cardiovascular Safety Interaction Study in Dogs (Act ivity B)
Under SOW Task 2, the Contractor shall conduct an acute drug interaction study in unrestrained
dogs or monkeys. Specific methods to be used in the study shall be subject to the approval of the
COR. Under SOW Task 19, the Contractor shall conduct, as directed by the COR, special in vivo or
in vitro tox icology or pharmacokinetic studies, the detai ls of which cannot be spec ified in advance of
the contract award . Examples include modifications of the spec ified protocols in Tasks 1 to 18,
inclusive, to allow for a more specialized evaluation of test articles and deve lopment of a protocol
with features similar to a clinical situation . The objective of this study is to evaluate the
cardiovascular safety of a drug (test article) administered via oral gavage and an intravenous drug of
abuse (interaction article), for example , coca ine or methamphetam ine, in unrestrained freely-mov ing,
telemetered beagle dogs and to collect blood for bioanalysis . For purposes of cost estimation
only, assume that the study will be conducted in two phases , bioanalyt ical and interact ion, and use
7 dogs (6 on study and 1 spare). For the bioanalytical phase, animals may be treated with up to 4
different dose levels of the test article at one-week intervals . Blood samples will be collected prior to
dosing and as many as 8 time points after dosing . The blood samp les will be separated by
centrifuga tion and plasma will be collected , divided into 2 aliquots each , and stored frozen for
subsequent bioanalysis. The bioanalysis wil l be wil l performed by a different laboratory. The NIDA

Page 4 of 8
COR will provide The Contractor with instructions for sample collection , process ing, storage and
shipp ing the aliquots to its designated bioanalytical laboratory . The results of the bioana lysis will be
shared with SRI and shall be included in the study report. Telemetry will not be collected in
bioanalytical phase. For the interaction phase, each dog will be instrumented with a surgically
implanted telemetry unit to monitor and report body temperature , hemodynamic parameters (to
include systolic blood pressure , diastolic blood pressure , mean arterial blood pressure and heart
rate) and electrocardiograms (to include PR, QRS , RR, QT, QTc, J-Tpeak, and T-peak-Tend
intervals) and be implanted with a titanium vascular access ort. The general study design of the
interaction phase is similar to that in Stud roprietary info hat SRI conducted for NIDA in
dogs and monkeys, respect ively. In brief, t ere wI e nine treatment sessions. The Contractor will
adm inister combinations of a test article dosed by oral gavage followed by an interaction article
dosed by intravenous infusion. The dose levels of the test and the interaction articles, and interval
between their doses will be specified by the NIDA COR. The intravenous interaction article and its
vehicle will be administered via a surgically implanted vascular access port using a programmab le
infusion pump carried in a jacket or backpack worn by each animal. Typically, each treatment
combination will be separated by at least 5 days. The Contractor shall use infus ion pumps that have
the capacity to record, store and report the actual time , duration and volume of the interact ion article
dose. The Contractor shall inspect those data after each treatment session to ensure that animals
received the entire dose and include the records in the study report . If there is evidence that an
anima l did not receive the appropriate dose of interaction article the SRI Study Director shall inform
the NIDA COR. The NIDA COR will decide whether the anima l that did not receive the appropriate
dose will need to be treated again. Telemetry shall be continuously recorded for at least 1.5 h prior
to test article administration (to establish the base line), after the test article is administered (assume
2 hours), and at least 4 hours after the interaction article is administered . Electrocardiograms shall
be analyzed by a veterinary cardiolog ist or a similarly qualified individ ual. The Contractor shall verify
the patency of the vascular access ports and acclimatize the test anima ls to the jacketing and dosing
regimens prior to initiating the treatment sessions .
The order of the study phases may be reversed , or NIDA may decide not to conduct the bioanalysis
phase. For purposes of cost estimation only assume there will be 6 weeks between the study
phases. In view of these cons iderations The Contractor is asked to provide separate cost estimates
for the bioanalytica l phase and the interaction phase and for 6 weeks of housing between phases .
At the end of the study the anima ls will be humane ly sacr ificed , necropsied , and telemetry
transmitters recovered for refurbishing and future use. NIDA requires a complete report for the
study . The study shall be conducted and reported in conformance with Good Laboratory Practice
(GLP) guidelines (CFR Title 21 Part 58).
2. Activity B Deliverables:
a. Draft Study Protoco l: The Contractor shall provide the NIDA COR with a Draft Study Protocol within
clear ly written section that describes appropr iate statistical methods for analyzing the experimental
data. The protocol shall set forth the experimental and reporting designs in clear detail and be free of
ambiguities, typographica l errors and contradictions . In-text tables shall be used to supplement
explanations provided in the text of the protocol. The draft protocol shall clearly state the anticipated
study schedule, includ ing animal arriva l, treatment phase, ante-mortem evaluations , disposition of the
animals after the study and report preparation . The Contracto r shall make NIDA-specified changes to
Draft Study Protoco ls and respond within 3 business days of the COR 's request. The protocol may be
revised multiple times before it is acceptable to the NIDA.
b. Final Study Protocol : The Contractor shall provide the COR with a Final Study Protocol within 2
c. Draft Study Report: The Contractor shall provide the COR with an audited Draft Study Report within
12 weeks after completion of the final in-life study. The report shall be free of grammatical and
typographical errors , shall be clear , and shall be concise and structured like a manuscr ipt for a

Page 5 of 58
reviewed pharmacology or toxicology journal. It shall include a title page, abstract, introduction,
methods, results, discussion, summary and bibliography or references. Tables and/or figures shall be
make NIDA-specified changes to Draft Study Reports within 5 business days of the COR 's request.
d. Final Study Report: : The Final Study Report shall be issued within 10 business days of the COR 's
authorization to issue the Final Study Report. It shall conform to GLP Guidelines. The Contractor
shall issue one indexed and numerically paginated , continuous from first page to last, bound paper
copy of the complete Final Study Report and one each, indexed and numerically paginated ,
continuous from first page to last , electronic copy of the complete Final Study report as an Adobe
PDF file and as a Microsoft Word DOC file. The reports shall include all tables and appendices. The
Livel ink) and , in addition, The Contractor shall post a complete set of all data tables as individual files,
to NIDA 's secure server. The posted data tables shall be in a format such that the data can be
Microsoft Excel and GraphPad Prism, for possible subsequent analysis by NIDA. In addition, the
Contractor shall deliver to the NIDA COR the Adobe PDF file, the Microsoft Word DOC file, and the
data tables on electronic storage media such as an external hard drive CD , DVD, USS flash drive or
SD card , with the Final Study Report .
The Contractor shall ensure that all Study Reports are free from spelling, typographical, or
returned to the Contractor for correction . A revised report shall be submitted with the date of
the revision.
E. Task Order Deliverable: NIDA will not receive value from this Task Order until Final Study Reports of
all the prescribed activities have been received so the results therein can be considered holistically .
Thus, the contractor shall produce a Comprehensive Final Study Report summarizing the results of
the Activities conducted under this Task Order . This report may be issued in the form of a Letter
Report to the NIDA COR.
edacted by agreement
F. Task Order Res onse Due Date: Si n Part II and email our res onse to t
y 11/29/2019 (12:00
-------------------------'
......
.......,,........._....
G. Proposal Instructions: Please complete Part II, "Contractor's Response to TORFP." In addition , SRI
will demonstrate its understanding of this task order by describing the work needed to perform it. The
Contractor also shall propose and item ize costs for preparation and delivery of all deliverables
required under the contract.

Page 6 of 8
SRI Internat ional Proposal 19-263 341 R 1 BDU TORFP N01 DA-18-8939
Task Order: Interact ion Safety Studies in Rats and Dogs
TASK ORDER PROPOSAL RESPONSE
Contractor: SRI International T.O. Title: Interaction Safety Stud ies in Rats and Dogs
Contract No: HHSN271201800019I T.O Order No: 75N95020F00001 Modification No: Q_

AjRedactedby agreement
T.O. Originator: NIDA, DPMCD 9~-------~
Statement of Work Task Area(s): 1 Date Prepared: January 10, 2020
PART II. SRI INTERNATIONAL'$ RESPONSE TO TASK ORDER REQUEST FOR

PROPOSAL (TORFP)
Under this task order , SRI proposes to perform one interaction safety study in rats and one
cardiovascular safety interact ion study in dogs in response to the TORFP. The objectives of
these studies are to determine the safety of a test article in comb ination with an abused
substance (interaction article) . The estimated period of performance is January 15, 2020
through January 14, 2021; however , the actual start date is contingent upon rece ipt of test
articles from the cl ient.
SRI will perform the Activity A, GLP rat interact ion study. The Activity B, GLP dog telemetry
study, will be outsourced to Charles River Laboratories (CRL) as the hardware and software
currently w ith SRI needs to be updated by the vendors and validated by SRl's QAU before any
work can be performed . CRL at Ashland , OH site has the validated equipment and software to
perform the NIDA required activit ies. Due to these reasons and in the interest of cost and time
for the NIDA , SRI has decided to outsource this GLP dog telemetry study to the lab that
performs this type of study frequently and has previously conducted a NIDA study with similar
study design. SRI will serve as the study monitor for the study .
A. Estimated Cost and Effort:

l_loder this tksk order SRI proposes an estimate~i:: ~ours of labor and a tota l cost of
st
rtem,zed
Co _and fee of ftem
ized
Cost lfor a total cost plus fixed fee of $1,113 ,092 . See Attach ment A
Estimated Budget for breakdown of each activity cost deta ils. Detailed descr iption of the
approach to be used and of the deliverables for Activity A and Activity B:
See Attachment B for a detailed description of approach and del iverables.
APPROVAL TO PROCEED: The Contractor will not exceed the estimated T.O. amount or
change the T.O. leader without the prior written approval of the Project Officer and Contracting
Officer. The following Accounting and Appropriation Data are applicable to this Task Order .

SRI Internat ional Proposal 19-263 341 R 1 BDU TORFP N01 DA-18-8939
Task Order: Interact ion Safety Studies in Rats and Dogs
For the Cont ractor: Lr_ •ct-ed_b_y •_gr_=_· -en-t _____ J------ Date : January 9, 2020
(Signature)
r edacted by agreement
Typed Name:
For the Government: Date:

----------------
Contrac t ina Officer 's Reoresentative (COR)
Kedacted by agreement
Typed Name: Date:

Contracting Officer

NIDA CONTRACT TASK ORDER (T.O.)
Contractor: SRI Internationa l, Inc. T.O. Title: Interaction Safety Studies in Rats
Contract No: HHSN271201800019I T.O. No: HHSN27100001 Modification No.: _Q_
T.O. Originator: NIDA COR Contracted Task Area: _1_
Task Order Type: Completion
A. Period of Performance: September 7, 2018 through September 6, 2019 .
B. Task Description:
Under Task 1, the Contractor shall conduct acute drug interaction studies in rats. Specific methods to be
used in these studies shall be subject to the approval of the COR . The objective of these studies shall be
to determine the safety of the test article in combination with coca ine or methamphetamine , an opiate or
ethanol. For purposes of cost estimation only , please assume that one or more test articles will be
tested in combination with an interaction article . The interact ion article may be a stimulant, such as
cocaine or methamphetamine, or an opiate, such as morphine or methadone . There would be a total of 3
studies. The three studies may use the same interaction article or two studies may use a stimulant and
the third use an opiate or two studies may use an opiate and the third use a stimu lant. The overall study
design is the same. The test article(s) will be administered by oral gavage and tested in combination with
either a stimulant administered by intravenous (tail vein) injection or an opiate administered by
subcutaneous injection. Each study wil l be conducted in two sessions . The interval between test and
interaction articles will be 2 hours. Effects on lethality, convulsions, and clinical observations shall be
assessed . In each study, there would be 12 treatment groups comprised of 10 male rats each . Animals
would be observed for treatment effects at intervals after the test article and for as many as 4 hours after
the interaction article dose on the dos ing day, and once dai ly for 3 days thereafter. There shall be two
mock dos ing sessions to acc limate the animals to handling and gavage. The anima ls would be humane ly
sacrificed approx imate ly 4 days after dosing . All test article and interaction article dosing solutions shall
be assayed to verify ident ity and concentra tion. NIDA requires a complete report for each study and the
requirements for report content and format shall conform to GLP guidelines.
C. Task Leader: reda cted by agreement
D. Deliverables : ~------------~
1. Draft Study Protocol: For each study the Contractor shall provide the COR with a Draft Study
Protoco l in MS Word format within 5 business days of the COR 's request. Overall , the protocol shall
follow GLP guidelines and have a clearly written section that describes appropriate statist ical
methods for analyzing the experimental data . The protocol shall set forth the experimen tal and
reporting designs in clear detai l and be free of ambiguities, typograph ical errors and contradictions.
In-text tables shall be used to supplement exp lanations provided in the text of the protocol. The draft
protocol shall clearly state the anticipated study schedule , including animal arrival , treatment phase,
antemortem evaluations and report preparation. The Contractor shall make NIDA-specified changes
to Draft Study Protocols and respond within 3 business days of the COR's request. The protoco l may
2. Final Study Protocol: The Contractor shall make NIDA-specified changes to Draft Study Protocols,
Page 1 of 6
providing the NIDA COR with a Final Study Protocol in MS Word format within 2 business days of
request.
3. Draft Study Report: The Contractor shall provide the COR with a Draft Study Report with in 4
weeks after completion of all evaluations. Each study shall have a separate report. All Draft Study
Reports must be single, continuously paginated in MS Word format. The report shall be free of
grammatical and typographical errors , shall be clear , and shall be concise and structured like a
manuscript for a reviewed pharmacology or toxicology journal. It shall include a title page, abstract,
introduct ion, methods , results , discussion, summary and bibliography or references. Tables and/or
figures shall be included after the bibliography, along with a legend page . As the reports may be
submitted by NIDA to the FDA, the reports must conform to the general requirements (style and
content) necessary for documentat ion submitted in support of an IND or NOA. Moreover, they shall
conform to the minimum standards set forth by GLP guide lines. The Contractor shall make NIDA-
specified changes to Draft Study Reports within 5 business days of the COR 's request.
4. Final Study Report: The Contractor shall make NIDA-spec ified changes to Draft Study Reports,
providing the COR with a Final Study Report within 10 business days of the COR 's request. The
Contractor shall issue an electronic copy of the comp lete final report as a single , continuous ly
paginated Adobe PDF file to the NIDA COR. A second electronic copy of all Final Study Reports must
in single, continuous ly paginated in MS Word format must be sent to the COR. The reports shall
include all tables and appendices. The Contractor shall post the electronic versions of the Final
Study Report , including all tables and appendices , in an Adobe PDF file and as a Microsoft Word
DOC file to NIDA's secure server (e.g., Livelink) , and The Contractor shall provide a complete set of
all data tables as separate files. The data tables shall be in a format such that the data can be
Microsoft Excel and Graph Pad Prism, for possible subsequent analys is by NIDA. In addition, the
Contractor shall deliver to the NIDA COR the Final Study Report , including all tab les, figures, graphs
and appendices , as an Adobe PDF file and as a Microsoft Word DOC file, and the raw data tables in
a format can be exported or copied (that is, not PDF or an image format) into other computer
programs , such as Microsoft Excel and GraphPad Prism on electronic storage media such as an
external hard drive CD, DVD, USB flash drive or SD card a CD or DVD with the Final Study Report.
5. The Contractor will provide a Letter Report (not-to-exceed 1 page) summarizing the results of all
three activities in Task Order 1 at the end of the task order period in MS Word format.
The Contractor shall ensure that all Study Reports are free from spelling , typographical, or
grammatical errors . Study Reports containing such errors shall be deemed unacceptable and
returned to The Contractor for correction . A revised report shall be submitted with the date of
the revision.
E. Task Order Response Due Date: August 13, 2018 by 3:00 pm Eastern Time.
Page 2 of 6
NIDA CONTRACT TASK ORDER (T.O.)
Contractor: SRI International, Inc. T.O. Title: Interaction Safety Studies in Rats
Contract No: HHSN271201800019I T.O. No: HHSN27100001 Modificat ion No.: _Q_
T.O. Originator: NIDA COR Contracted Task Area: _ 1_
Task Order Type: Completion
PARTI I. CONTRACTOR'S RESPONSE TO T.O. REQUEST

(The Contractor may attach addit ional sheets to this form to present requested data.)
A. Estimated Cost and Effort
Direct Labor - Hourly rbor

Costs
Fringe Benefits - Hourly

Total Direct Labor & Fringe Benefits $41,014
R~c.io Rate
~temized Cost
Overh ead (TEC)
Overh ead (CON)
Total Overhead
tem ized Cost
Premium Labor
Other Direct Costs

Materials and Supplie s
Profession al Travel
Equipment
Consultants
Internal Servi ces
Outside Services
Subcontracts
Total Other Direct Costs $16,830
Subtotal: Direct Labor , Fringe Benefits ,

tem ized Cost
Overh ead , & Other Directs
~
Adjusted Base for SCB temized Cost
SCB
Exclusion (s) From Base For G&A
Adju sted Base for G&A
G&A
Total Proposed Cost Exclud ing Fee

ftem ized Cost
Proposed Fee/Profit ree I
Total Proposed Cost Plus Fee/Profit Per Study $138,148
Total Cost for all Thr ee Activiti es Estima ted Total $414,444
Page 3 of 6
SRl's cost estimate is based on the Task Order provided by NIDA, as well as the following
assumptions:
a. SRI will perform dose stability and concentration verification for the test article.
b. SRI will perform concentration verif ication for the interaction art icle.
c. No additional veterinary services will be required for the conduct of this study.
d. No additional equipment will need to be purchased for the conduct of this study.
B. DELIVERABLES
1. Draft Study Protocol: For each study the Contractor shall provide the COR with a Draft
Study Protocol within 5 business days of the COR's request. Overall, the protocol shall
follow GLP gu idelines and have a clearly written section that describes appropriate
statistical methods for analyzing the experimental data . The protocol shall set forth the
experimental and reporting des igns in clear detail and be free of ambiguities,
typographical errors and contradict ions. In-text tables shall be used to supplement
explanations provided in the text of the protocol. The draft protocol shall clearly state the
ant icipated study schedule, including anima l arrival , treatment phase , antemortem
evaluations and report preparation. SRI shall make NIDA-specif ied changes to Draft
Study Protocols and respond within 3 business days of the COR's request. The protocol
may be revised multip le times before it is acceptable to the NIDA.
2. Final Study Protocol: SRI will provide the COR with a Final Study Protocol within 2
bus iness days of the COR's authorizat ion to issue the Final Study Protocol
3. Draft Study Report: SRI will provide the COR with a Draft Study Report within 4 weeks
after completion of all evaluations. Each study shall have a separate report. The report
sha ll be free of grammatical and typographical errors , sha ll be clear, and shall be
concise and structured like a manuscr ipt for a reviewed pharmaco logy or toxicology
journal. It shall include a title page , abstract, introduction, methods , results, discussion ,
summary and bibliography or references . Tables and/or figures shall be included after
the bibliography, along with a legend page. As the reports may be submitted by NIDA to
the FDA, the reports must conform to the general requirements (style and content )
necessary for documentation submitted in support of an IND or NOA. Moreover , they
sha ll conform to the minimum standards set forth by GLP guidelines. The Contractor
sha ll make NIDA- specified changes to Draft Study Reports within 5 business days of
the COR's request.
4. Final Study Report: The Final Study Report shall be issued within 10 business days of
the COR's authorization to issue. SRI will issue one bound paper copy of the report and
one each electronic copy of the complete final report as an Adobe PDF file and as a
Microsoft Word DOC file. The reports shall include all tables and appendices. SRI will
post the electronic versions of the Final Study Report, including all tables and
appendices , in an Adobe PDF file and as a Microsoft Word DOC file to NIDA's secure
Page 4 of 6
server (e.g., Livelink), and SRI will provide a comp lete set of all data tables as separate
files if requested by the COR. The data tab les shall be in a format such that the data can
be exported or copied (that is, not PDF or an image format) into other computer
programs, such as Microsoft Excel and GraphPad Prism, for possib le subsequent
analys is by NIDA. In addition, SR I will deliver to the NIDA COR the Final Study Report,
including all tables , figures, graphs and append ices, as an Adobe PDF file and as a
Microsoft Word DOC file, and the raw data tab les in a fo rmat can be exported or copied
(that is, not PDF or an image format ) into other computer programs , such as Microsoft
Excel and GraphPad Prism on electronic storage media such as an external hard drive
CD, DVD, USB flash drive or SD card a CD or DVD with the Final Study Report. A Final
Study Report will be issued fo r each of the 3 activ ities in this Task Orde r.
5. SRI will provide a Letter Report (not-to-exceed 1 page) summar izing the results of all
three activities in Task Order 1 at the end of the task order period .
SRI will ensure that all Study Reports are free from spe lling, typographica l, or
grammatica l errors. Study Reports containing such errors shall be deemed unacceptable
and returned to SRI. A revised report shall be submitted with the date of the revision.
C. KEY PERSONNEL AND JOB DESCRIPTIONS

jZedacted by agreement
Page 5 of 6
APPROVAL TO PROCEED: The Contractor shall not exceed the estimated T.O . amount or
change the T.O. leader without the prior written approval of the Project Officer and the
Contracting Officer. The following Accounting and Appropr iation Data are applicable to this
Task Order.
r
I. For the Contractor: ._______________
(Signature)
___, Date :september6. 2018
T yped name,
jRedactedby agreement I
'---.....,.. led,...act
_e__
d b-y -agr-eem
- ent________ ___,,------,
2. For the Government: Date: ------

(Contract ing Officer Representative)
ra cted by agreement
T yped name:I
Date : _____ _
.__ ______________ __,
T yped name rda cted bv agreement

,
Page 6 of 6
2
IMPORTANT : Mar k al l packages and pa pers w ith con tr ac t and/or order numbers. I 1 I
1. DATE OF ORDER 2. CO NTRACT NO. granyb 6 . SHIP TO:
HHSN271201 00 19 I
0 9/07/ 2 01 8
3. ORDER NO . 14. REQU ISITIO N/ REFERENCE NO.
6001 , NSC , Roc kvi lle
HHSN271 00001 5 122639
5. ISSUING OFFICE (Address correspondence to) b. STREET ADD RESS
Na ti on al I ns t it ut es o f Healt h Neu r os cie nce Ce nt e r
Na ti on al I ns t it ut e on Dr u g Abuse 6001 Ex e cutiv e Bl v d
Be t hesd a , MD 20 8 92 -7 511

Rockville MD 2 08 52
7. TO: f. SH IP VIA
a. NAME OF CONT RACTOR

SRI I NTERNATI ONAL : 11 10 101 8. TYPE O F ORDER
b. COMPANY NAME X
a . PURCHASE b. DELIV ERY
333 RAVENSWOODAVENUE Except for billing inst ructions on the
reverse , this delivery orde r is
subject to instructions containedon
this side only of th is form and is
Please furnish the followi ng on the terms issued subject to the terms and
and condit ions specified on both sides of conditions or the above -numbered
d. CITY
MENLO PARK
I e. STATE I f. Z IP CODE this order and on the attached sheet, if
contract.
CA 9402 53 4 93
9. ACCO UNTING AND APPROPR IATIO N DATA 10. REQU ISITIO NING OFFICE
See Sc he dul e Nat i ona l I n st it u t es o f Hea l th
11. BUS INESS CLASS IFICAT ION (Check appropriate box(es)) 12 . F.O.B . POINT
a. SMALL d b. OTHER THAN SMALL c. DISADVA NTAGED d. WOMEN -OW NED e. HUBZone
Desti n ation
f. SERV ICE-DISABLED g. WOME N-OWNED SMALL BUSINESS (WOS B)
h. EDWOSB
VETERAN -OW NED ELIG IBLE UNDER THE WOSB PROGRAM
13. PLAC E OF 14. GOVERNM ENT BIL NO. 15. DELIV ER TO F.O.B. POINT 16 . DISCOUN T TERMS
O N OR BEFORE fat e)
a. INSP ECTION I b. ACC EPTANCE 10/07/201
Des t inatio n Dest in at i on PROMPT PAY

IT EM NO. SUPPL IES OR SERV ICES ORDERED UN IT PR ICE AMOUNT ACCEPT ED
(a) (b) (C) (d) (el (/) (g)
PURPOSE: To awar d Tas k Order
No . HHSN27 100001 (Toxicologica l Eva l ua t io n s
o f Po t e nt ia l Med icat i ons ) und er ID/IQ
Co n trac t No . HHSN27120 1800 0 19I for wor k as
desc ri bed in t he a t tach e d NIDA Co n t ra ct
Tas k Or de r Pa rt I ' Se ct i on B . Tas k
Co n t in u ed ...
18. SHIPPING POINT 19. GROSS SHIPPING WE IG HT 20. INVOICE NO. 17(h)
TOTAL
(Cont.
pages)
•
a. NAM E $4 14, 444 . 00

Of fic e o f Fina nci al Man a g eme nt
SEE BILLING
INSTRU C TIONS b. STR EET AD DRESS 211 5 E J e ffer s on St
MSC 85 0 0 Su it e 4B 4 32 17(1)
GRA ND
•
TOTAL
c. CITY e. ZIP COD E

$4 14, 444 . 00
r .STATE
Be t hesda MD 20892 -85 00
22. UNIT ED STATES OF =acted by agreement
•
AM ERICA BY (Signature)
AUTHORIZED FOR LOCAL REPRODUCTION ONAL FORM 347 (Rev. 2/20 12)
PREVIOUS EDITION NOT USABLE scnbed by GSA/FAR48 CFFI:S3.:213{1)

IMPOR TANT: Mark all packages and papers with contract and/or order numbers .
DAT E OF ORD ER !CONTRAC T NO. ORDER NO.
09/07/2018 HHSN271201 800019I HHSN27100001
I
ITEM NO . SUPPLIES /SERV ICES QUA NTITY UNIT UNIT AMOUNT QUAN TITY
(a) (b) (c) (d) (e) (f) (g)
Admin Office :
Nationa l Inst it utes of Hea l th
Nationa l Instit ute on Drug Abuse
Be thes da , MD 20892 - 75 11
Period of Performance : 09/07/20 18 to
09/06/2023
1 FY 18 Task Order Award for HHSN271000 01 (TO 414 , 444 .0 0

1 ) Period of Performance : 09/07/18 to
09/06/2019 NIDA Ref . No . N0lDA-18-8939
Delivery To : Rm4 123
Product/Service Code : ANll
Product/Service Description : R&D-
MEDICAL: BIOMEDICAL (BASIC RESEARCH)
Project Data :
120500 . 1 .HN66 NIDA DTMC DIV I SION OF
THERAPEUTICS AND MEDICAL CONSEQU. 2555
RESEARCH AND DEVELOPMENT . 09/07/2018
Accou nt in g I n fo :
08029320181DA0 . 2018 . 01 . 6100 .HN61000000
C . E. 00182 . 406 . 9999 . 25 55 . 610001 . 9999 . 99
99 . 9999
Funded : $0 . 00
TOTA L CARR IED FORWARD TO 1ST PAGE (ITEM 17(H)) $414,444.00

AUTHOR IZED FOR LOCAL REPODUC TION OPTIONAL FORM 348 (Rev. 4/2006)

PREVIOUS EDITION NOT USAB LE
Prescnbedby GSAFAR(4$ CFR)53-213(1)
-o<:,-.
charles river
FINAL PROTOCOL
r
roprietary Info
Testing Facility Study~----~
.
Sponsor R ef erenc~..._ ___
J roprietary Info
__,
Evaluation of the Interaction BetweeJ roprietary info ~dministered Orally and

Cocain e Administered Intravenously to Conscious , Radiotelemetry-
Instrumented Beagle Dogs
GLP
SPONSOR :
SRI Biosciences
333 Ravenswood Avenue
Menlo Park, CA 94025
United States
TESTING FACILITY :
Charles River Laborato ries Ashland, LLC
1407 George Road
Ashland, OH 44805
United States
Page 1 of 34

TABLE OF CONTENTS
1. OBJECTIVE(S) .......................................................................................................................3
2. PROPOSED STUDY SCHEDULE ........................................................................................ 3
3. SPONSOR ............................................................................................................................... 3
4. RESPONSIBLE PERSONNEL ............................................................................................... 3
5. TEST MATERIALS ................................................................................................................4
6. DOSE FORMULATION AND ANALYSIS .......................................................................... 6
7. TEST SYSTEM ....................................................................................................................... 8
8. HUSBANDRY ...................................................................................................................... 10
9. EXPERIMENTAL DESIGN ................................................................................................. 12
10. IN-LIFE PROCEDURES, OBSERVATIONS, AND MEASUREMENTS ......................... 15
11. CLINICAL PATHOLOGY ................................................................................................... 19
12. DISPOSITION OF ANIMALS ............................................................................................. 20
13. STATIS TICAL ANALYSIS .................................................................................................21
14. COMPUTERIZED SYSTEMS .............................................................................................22
15. REGULATORY COMPLIANCE ......................................................................................... 24
16. QUALITY ASSURANCE ..................................................................................................... 24
17. AMENDMENTS AND DEVIATIONS ................................................................................24
18. RETENTION AND DISPOSITION OF RECORDS, SAMPLES, AND
SPECIMENS .........................................................................................................................24
19. REPORTING .........................................................................................................................25
20. JUSTIFICATIONS AND GUIDELINES ............................................................................. 26
21. ANIMAL WELFARE ........................................................................................................... 30
22. REFERENCES ......................................................................................................................31
TESTING FACILITY APPROV AL ..............................................................................................32
SPONSOR APPROVAL ............................................................................................................... 33
ATTACHMENT A ........................................................................................................................ 34
r roprietary Info
r roprietary Info
Page 2

1. OBJECTIVE(S)
The objecti ~OLUl)J.~:u.a~s...ri:l....e)laJ.JIJ.ale....IJJ..e.JD.ill:en.Jr.ta.1...filllYe.tse.....c..amtilllias.cJJJ..2u:....eill:crs~t
may
ropr
ietary
Info
resu lt when test
aiticle and cocaine (interaction article are administered to ether to male Bea le do
ropr
ietary
InfoS a fO rieta ropr ietaryInfo
ropr
ietary
Info
ropr
ietaryinfo NIDA is considering roprietaryinfoas a potential treatment for substance use disorders,
including cocaine disorder. The dogs will be implanted with telemetry transmitt rs an
subsequently dosed with combinations of orally (drug in capsule) administered ropr ietaryinfoand
intravenously administered cocaine to evaluate iffroprietaryinfopffects hemodynam1c an
effects of cocaine.
2. PROPOSED STUDY SCHEDULE

Proposed study dates are listed below. Actual dates will be included in the Final Report.
Animal Arrival: 06 May 202 1
Initiation of Dosing: 22 Jun 2021
Completion of In-life: 08 September 2021
(Release of animals from study)
Audited Draft Report: 17 November 2021
Final Report: 24 May 2022
(Expected date of Study Director signature of report)
Final SEND Dataset Package Based on Regulato1y Submission
Delive1y:
3. SPONSOR
IRole IName IContact Information
Redactedby agreement
4. RESPONSIBLE PERSONNEL
QAU
(Qua lity
Assurance
Role/Phase Unit) Name Contact Informat ion
rroprietary
Info rropr
ietaryInfo
Page 3

QAU
(Quality
Assura nce
Role/Phase Unit) Name Contact Info rmation
~edacted by agreement
Each IS is required to report any deviations or other circumstances that could affect the quality or
integrity of the study to the Study Director in a timely manner for
authorization/acknowledgement. Each IS will provide a report addressing their assigned phase of
the study, which will be included as an appendix to the Fina l Report .
The IS Phase Report will include the following:
• A listing of critical computerized systems used in the conduct and/or interpretation of the
assigned study phase
5. TEST MATERIALS
5.1. Test, Vehicle and Interaction Article Characteriza tion

The Sponsor w ill prov ide to the Test ing Facility documentat ion of the identity , strength, purity ,
composition, and stability for the test and interaction article(s). A Certificate of Analysis or
equivalent documentation will be provided for inclusion in the Final Report.
Vehicle and control article components will be characterized according to the product label
provided by the manufacturer.
The Sponsor has appropriate documentation on file concerning the method of synthesis ,
fabrication or derivation of the test article, and this information is available to the appropriate
regu latory agencies should it be requested .
r ropr ietary Info r ropr ietary Info
Page4

5.2. Test Article Identification
Test Article Ide ntificatio n
Test Article
fl'ropr ietary Info
Tdentifi n.,tinn• I
Proprietary Info
Retest Da te: Concomitant

Physical Description: To be documented
Purit y : 100%
Correction Factor: -
Stora2e Conditions: l8°C to 24°C
Provided by: Sponsor or Sponsor Desi1mee
- = not app licable
5.3. Interaction Article Identification
Interaction Article Identification

Interaction Article
Identifi cat ion: CocaineHC l
Alternate Identificat ion: (-)-Coca ine HCl
Ba tch/ Lot No.: To be documented
Expiration /Retest Date: To be documented
Phvsical Desc ription : To be documented
Purit y : To be documented
Co rrection Factor: -
Storaf!e Cond itions: l 8°C to 24°C
Provided by: Sponsor or Sponsor Designee
- = not app licable
Page 5

5.4. Vehicle Identification
Vehicle Identification (for Test Article Preparations)
Vehicle Article
Identification: Size # I I gelat in caps ules
Alterna te
-
Identification:
Stora2e Co ndition s: I 8°C to 24°C
Provided by: Tes tin_gFac ility
- = not applicable
Vehicle Identification (for Interaction Article Preparations)

Vehicle Article
0.9% sodium chloride for
Identification:
injection, USP
Alternate Identification: Saline
Stora2e Conditions: J8°C to 24°C
Provided by: T esting Facility
5.5. Reserve Samples

Reserve samples of the te st article will be taken in accorda nce with Charles Riv er Standard
Operating Procedures and stored in the Charles River Archives .
5.6. Test and Interaction Article Inventory and Disposition

Record s of the rece ipt, distribution , storag e, and disposition of test material s (includin g empty
containers of Sponsor-provided materials) will be maintained. All unused Sponsor-supplied bulk
test materials, with the exception of reserve samples, will be returned to the Sponsor at the
address prov ided in Attachment A.
5.7. Safety
A Safety Data Sheet (SDS), or equivalent documenta tion, will be provided by the Sponsor (if
available). It is the respon sibility of the Sponsor to notify the test facility of any special handling
requ irement s of the test article . Otherwise, routine safety prec autions wi ll be followed.
Appropri ate gloves, safety glasses and ann covers will be worn by individuals working with neat
test material or formulat ions .
6. DOSE FORMULATION AND ANALYSIS
6.1. Preparation of Formulations
Capsules will be dispen sed on each dosing occasion.
r roprietary Info r roprietary Info
Page 6

Preparation Details for Test Article
Dose Formu lation Frequency of Preparation Storage Conditions
Vehic le" At least week ly Set to maintain I 8°C to 24°C
Test Article Each day of dosing Set to maintain 18°C to 24 °C
• A sufficient number of empty gelatin capsules will be dispensed for oral vehicle administration
Dose formulations will be divided into aliquots where required to allow to be dispensed on each
dosing occasion .
Preparation Details for Interaction Article
Dose Formulation Frequency of Preparation Stora2e Conditions
Vehicle At least biweekly Set to maintain 5°C
Once , pr ior to the first interaction
Interaction Article Set to maintain l 8°C to 24 °C
dosing occasion
Frequency of preparation may be adjusted based on stabili ty results. Any residual volumes from
each dosing occasion will be discarded unless otherwise requested by the Study Director.
6.2. Preparation Details

Test Article:
The test substance for each animal will be weighed and placed into one or more gelatin
capsule(s) . Each capsule will be placed in an appropriate ly labeled and capped containers (study
number, animal number, group number , etc.) for dosing. In addition , animals will receive the
anticipated numb er of capsules to be administered to the high dose treatment (calculated based
on body weight at the tim e of the first control dosing sessio n). An adju stment for purity will not
be performed. Any procedures not covered by SOPs required for formulation will be approved
by the Study Director and included in the study records.
Interaction Article:
Dosing formulations will be prep ared at appropriat e concentrati ons to meet dose level
requirements. The prepared interaction article formu lations will not be adjusted for purity. Any
procedure s not covered by SOPs required for formulation w ill be approved by the Study Director
and included in the study records. Formulation pH will be within SOP range, if appl icable.
6.3. Sample Collection and Analysis

Test Article:
Analysis of the test article formulations will not be conducted for this study as the test article
suppli ed by the Sponsor will be administered neat in capsules, without any further modificati on.
Therefore, stability, homoge neity, and concentration assessment is not necessary .
Dose formu lation samples will be collected for analysis as indicated in the following table.
Additional samples may be collected and analyzed at the discretion of the Study Director.
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Page7
__.

Interaction Article Samp le Collection Schedule
Number of Samples Sample

Sampling per Concentration Volume
Sample Type Concentrations Stratum From Collected Analyzed Backup (mL) Intervals
Each
Preparation preparation
Concentration
All Treatments Middle container 4 2 2 0.5 and on each
Analyses
day of
dosing•
• = duplicate 0.5 mL samples to be collected from the residual interaction article dosing container following dosing.
One sample will be analyzed , and the alternate will be utilized as a backup sample.
Interaction article dose analysis results will be verifie d prior to the first interaction article do se
administration. If result s are deemed unacceptable, th e formulations will be prepared again and
analyzed.
Following preparation, and following eac h dose occasion, interac tion article samp les will be
tran sferred to the Ana lytical Chemistry Dep artment and stored refri gerate d until analyzed.
6.3.1. Analytical Method

Interaction article fo1mulations have been prev iously show n to be stab le over the range of
concentrations used on thi s study for at least 106 days at room temp erature (SRI study No.
M225-16 and M449 -20). Therefore, stabili ty of the interaction article will not be assessed on this
study .
Anal~ses described below will be : erfo rrned using a method validate d by C harles River t'"'"""""''
r ropnetary info lfor concentration. Any backup sampl es kept at
Char es River wi ll be discarded to owmg acce ptance of the analytica l results by the Study
Director.
6.3.1.1. Interaction Article Concentration Analysis
Sampl e Allocation: 2 for analysis, 2 for backup

Storage Con dition s: Temperature set to main tain 18-24°C
Acce ptance Criter ia: Solution:
Mean sample concentration wi thin 100% ± 10% of theore tical
concentra tion.
7. TEST SYSTEM
Spec ies: Dog
Strain : Beag le
Page 8

Cond ition: Purpose-bred, nai:ve
Source: Specific facility to be documented in study records.
Number and Sex: 7 males
Age at the Initiation of At least 6 months . Animals not utilized on study will be assigned to the
Dosing: Charles River animal colony.
Weight at the Initiation At least 5.0 kg
of Dosing:
The actual age and weight of the animals at the initiation of dosing will be listed in the Final
Report.
7.1. Animal Screening

Method: All animals used on study will have documentation of immuni zation for
parvovirus, distemper , adenovirus type 2, parainfluenza, Bordetella,
papilloma, and rabies.
Prior to surgery, all animals will have blood samples collected for
clinical pat hology screening to evaluate health status prior to the surgical
procedures. See Section 11 for parameters to be evaluated .
7.2. Animal Identification

Method: Tattoo or a subcutaneously implanted elech·onic identification chip.
7.3. Surgical Preparation of Animals

Method: Preane sthetics, surgica l preparatio n and implantation details (for the
telemetry implan t and VAPs) , and post-operative care and recover
rocedures will be performed as outlined i roprietary Info
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The transmitters have a fluid-filled catheter (coated with an

antithrombotic film to inhibit thrombus format ion) with the tip filled
with a patented gel for collection of blood pressure and 2 ECG leads
emulating a lead II configuration.
The V APs will be maintained per Charles River SOPs and will include
weekly assessments of patency until dosing. VAPs will be locked with
taurolidine citrate solution (TCS) between patency assessments.
7.4. Jacket Acclimation

Method: All animals will be acclimated to a tethered infusion system. Animals
w ill initially be conditioned to jackets and collars in a stepwise manner
until at least 24 hours of acclimat ion is achieved. Subsequently , animals
r ropr ietary Info r roprietary Info
Page9

w ill be accl imated to the tether and jackets for a period of 4 hours , and
for a period of at least 24 hours. Additio nal sess ions may be employed if
deemed necessary.
7.5. Environmental Acclimation

Method: Each animal will be inspected by a clinica l veter inarian upon receipt.
Animals judged to be in good health will be placed immediately in
accl imation for at least 6 days. See respect ive sections for parameters to
be evaluated . The anima ls will have been allowed at least 2 weeks to
recover following implantation of the telemetry device before the
administration of vehicle, test article and interaction articles.
7.6. Selection, Assignment, Replacement, and Disposition of Animals

Selection: Near the end of the acclimation period , animals judged to be suitable for
test ing (based on healt h and te lemetric assessment as indicated by
random ization approva l) will be assigned to groups arbitrar ily using a
computer program. A printout containing the animal numbers and
individual group assignments will be generated.
Replacement: Before the initiation of dosing , any assigned anima ls considered
unsuitable for use in the study will be replaced by alternate animals.
Afte r initiation of dosing, study animals may be replaced during the
replacement period with alternate animals in the event of accidental
injury, non-test article -related health issues, or simi lar circumstances.
Disposition: This study is non-terminal. Upo n completion of the study, the animals
will be maintained in the Charles River dog colony for future use or may
be euthanized (with intravenous sodium pentobarbital administration and
the radiote lemetry devices recove red, as applicable).
8. HUSBANDRY
8.1. Housing
Housing Single. Individual housing is necessary during periods of data collect ion
(Dosing Days): to prevent telemetry signal cross talk.
Following jacket remova l, animals will be returned to social housing .
Housing Gro up housed (up to 3 animals of the same sex)
(Non-Dos ing Days):
Animals will be separated in the afternoon on the day prior to dosing at
the time of fasting and will remain separated until following jacket
removal. This is to minimize variations in baseline data caused by
excitability and stress of animals from separation and placement into
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Page 10

te lemetry banks. Animals w ill have continua l access to water during
per iods of fasting.
Caging: Stainless steel cages with mesh floors.
Cage Identification: Will indicate animal/tattoo number(s), and sex.
Housing set-up is as specified in the USDA Animal We lfare Act (9 CFR, Parts 1, 2 and 3) and as
described in the Guide for the Care and Use of Laboratory Animals (National Research Counc il,
2011). Animals will be separated during designated procedures /activities or will be separated as
required for monitoring and/or health purposes, as deemed appropriate by Study Director and/or
Clinical Veteri narian.
8.2. Animal Enrichment

Method: For enrichment, animals will be provided w ith items such as chew toys,
except when interrupted by study procedures/activities. All anima ls will
be given regular opportunity for exercise and socialization and will have
enrichment through human interaction during the conduct of procedure
acclimation and daily study activities
8.3. Environmental Conditions

The targeted conditions for animal room environment will be as follows :
Temperature: 66°F to 76°F (19°C to 24°C)
Humidity: 30% to 70%
Light Cycle: 12 hours light and 12 hours dark (except during designated procedures)
8.4. Food
Diet: PMI Nutrition International, LLC Lab Diet Certified Canine Diet 5007
Type: Kibble (alternate diet may be provided on individual animal basis as
warranted as approved by the Study Director).
Frequency: Approx imately 300 g daily.
Animals will be fasted overnight prior to surgery. The daily ration of
food will be offered follow ing recovery from anesthesia. Anima ls will
be fasted overnight before dosing days. On dosing days, food will be
returned 4 hr after the cocaine dose (after 4 hr clinical observation post
dose). Animals will not be fasted for longer than 24 hours. Animals
will have contin ual access to water during periods of fasting.
Ana lys is: Results of analysis for nutritional components and environmenta l
contamina nts are provided by the suppl ier and are on file at the Testing
Page 11

Fac ility. It is cons idered that there are no known conta minants in the
fee d that wou ld interfe re with the obj ect ives of the study.
8.5. Water
Type : Municipal tap wate r, treated by reverse osmosis and ultraviolet
irradiation.
Freq uency/Ration: Freely availab le to eac h animal via an automat ic watering system
(except dur ing body weig ht measure ments, physical examin ations, and
during surgery).
Analys is: Periodic ana lysis of the water is performed , and resu lts of these ana lyses
are on file at the Testing Facility. It is considered that there are no
known contamina nt s in the water that wo uld interfere with the outcome
of the study.
8.6. Veterinary Care

Vete rina1y care will be ava ilable throughout the course of the study and ani mals will be
examined by the veterinary staff as warranted by clinical signs or other changes. In the event that
anima ls show signs of illness or distress, the responsible veterinarian may make initia l
recommendat ions about treatment of the an imal(s) and/or alterat ion of study procedures, wh ich
must be approved by the Study Director. Treatment of the anim al(s) for mino r injuries or
ailments may be approved without prior consultation with the Sponsor representative when such
treatment does not impact fulfillment of the study obj ectives. If the condition of the anima l(s)
warrants sig nificant therapeutic intervention or alte rations in study proced ures , the Spo nsor
representat ive will be contacted, when possible, to discuss approp riate act ion . If the condition of
the animal(s) is such that emergency measures must be taken, the Study Director and/or
attending veterinarian will attempt to consult with the Sponsor representative prior to responding
to the medical crisis, but the Study Director and/or veterinar ian has aut hority to act immediately
at his/her discret ion to alleviate suffe ring . The Sponsor representat ive will be fully informe d of
any such events.
If deemed necessary, dosing may be suspended for ind ividual animals upon recommendat ion of
the clinical veterinarian in consultation with the study director in order to provide appropriate
veterinary care.
9. EXPERIMENTAL DESIGN
The following tab le presents the treatment arrangement. Te st article aud iuterac tiau article dose
leve ls were selected based on data provided to NIDA byfropneraryinfo ~ee
Section 20.2) .
rropr
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Study Design
Interaction Interacti on
Test Artic le Interaction
!Proprietary Info Article Article
Treatment Article Dose No. of
Treatment (cocaine) Dose
No. uo se Level concentratio n Males<
Dose Level Volume
(mg/kg)• (mg/mL)
(mi?/k~)b (mL/k2)
0 (empty
I Vehicle+ Saline 0 (saline) 0 0.25 6
capsule)
Vehicle + Cocaine 0 (empty
2 0.56 2.24 0.25 6
(low) capsule)
Vehicle+ Cocaine 0 (empty
3 1.7 6.8 0.25 6
(high) capsule)
E ropr ietary Info t low)
4 250 0 (saline) 0 0.25 6
+ Saline
roprietary Info
llow)
5 250 0.56 2.24 0.25 6
+ Cocaine low)
roprietary Info ~low)
6 250 1.7 6.8 0.25 6
+Cocame 1high)
roprietary Info high)
7 750 0 (saline) 0 0.25 6
+ ~alme
Proprietary Info (high)
8 750 0.56 2.24 0.25 6
+ Cocame (low)
p ropr ietary Info igh)
9 750 1.7 6.8 0.25 6
+ Cocaine high)
NA = not applicabl ----~
• The test article ropr ietaryinfo will be administered orally as drug in capsule
b The interaction article , cocaine , will be adm inistered intravenously at the prescribed dose level at 2 hours(± 5
minutes) following test article dosing via ambulatory infusion
c The same 6 animals will be used for each treatment in an escalating design with 6 minimum days between
doses.
9.1. Administration of Test, Vehicle and Interaction Articles

Dose Route : Oral caps ule (test article) followed by intraveno us infusion (interact ion
article)
Frequency: Once daily; single administration for each Treatment
r roprietary Info r ropr ietary Info
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Method: Oral route: The vehicle (empty gelatin caps ules) or test article (in gelatin
capsu les) will be administered orally .
Intravenous route: The interaction article or its veh icle will be
admin istered at 2 hour s(± 5 minutes) following the oral dose via
intravenous infusion over an appro ximate 45 second infusion from an
infusion pump followed by a 5 mL saline flush administered at the same
rate. Doses will be delivered using a ca librat ed infusion pump w ith a
tethered infu sion system. Doses will be adm inistered in absence of
technical staff in the dosing room. Doses will be schedu led to initiate (at
least 90 minutes) following exiting of the room.
Doses will be delive red via the Cath-in -Cath sys tem to the indwelling
catheter appropriately placed. The infusion will be delivered to freely
mov ing animals. Indi vidual doses will be drawn into syringes labeled
with the anim al numb er, study numb er, and date, and documented
appropriately. The dosing syringes will be filled with the appropri ate
dosing volume (plus the additional vo lume of the dead space in the
extensio n line to the Y connector infusion syste m) of interact ion article
requir ed for dosing. Using a second infusion pump for each anima l, an
additional syringe will be filled with the approp riate vo lume of saline to
flush the extension lines to complete the prescribed dose. Anima ls wi ll be
dosed at approx imately the same t ime( ± 1 hour) each dose day . The
Sponsor will be notified in a timely manner in the eve nt of any issues
surrounding the dose administration (e.g., failed dose, incomplete dose,
emesis immediately following dosing, etc.).
9.2. Jacket and Tether System Procedures

Pretreatment Session:
Prior to Dose 1, a "sham" dos ing procedure imita tin g the dosing procedure for each treatment
session will be performed, including a telemetric recording (card iovascu lar, ECG, and body
temperature) obtained for at least 4 ho urs following the "sham" IV infusion (sal ine) . A ll animals
will undergo the p retreatment recordin g. An empty capsule will be used as the oral sham dosing
articl e, and saline will be uti lized as the intravenous sham dosing article. Doses will be
adm inis tered as outlined in section 9 .1. These data will be recorded but not reporte d. The
pretreatment session will includ e a minimum of 90 min recording period p rior to the target
"sham" oral dose w hile in telemetry cages, and then con tinu e for at least 4 hr follow ing the
"sham" IV infusion dose. The "s ham" IV infusion dose will be performed at 2 hours (±5
minutes) following the "sham" oral dose, as outlined in the section 9.1. Hemodynamic data
(systo lic, diastolic, mean arteria l press ure, pulse pre ssure and heart rate) and ECG intervals will
be measured and binned in appropriate interval s as desc ribed in Sect ion 10.2.
The ECG trac ings will be reviewed for rhythm distu rb ances (dy srhythmi as) for the six animals
participating in the study over the duration of recording pe riod . Data from the p retrea tment
Page 14

collection will be used to confirm acclimation to testing procedures of the animals placed on
study .
All animals will be placed into jackets prior to dosing. Patency check s will be performed prior to
introduction of the jacket system. All animals will be placed on a maintenance infusion of saline
(2 mL/hr ) in an effor t to maintain VAP patency during non-dosing periods. Animals will be
maintained in jackets for up to approximately 3 doses. Jackets will be removed for
approximately one week before subseque nt jacket placement.
10. IN-LIFE PROCEDURES, OBSERVATIONS , AND MEASUREMENTS
Genera l In-life Assessments

Frequency
Parameter Population(s) " (minimum required) Comments
Mo rtality All Animals" At least twice daily b Animals will be observed within
(morning and afternoon) their cage unless nece ssary for
beginning upon arrival identification or confirmatio n of
through term ination/release 1possible findings.
Cageside /Postdo se All Main Study Prior to oral dosing , and at Animals will be observed within
Observations c Anima ls approximately 4 hours their cage unless necessa ry for
postdosi ng (relative to identification or confirmation of
interact ion article possib le findings.
administration)
The absence or presence of findings
will be recorded for individual
animals.
Finding s noted outside the

above-specified observation periods
will also be recorded . Only the
presence of unscheduled
observations will be recorded; the
absence of findings will thus not be
recorded
Detailed Clinical All Main Study Following receipt Animals will be removed from the
Observations c Anima ls cage.
Weekly during the pretest
period The absence or presence of findings
will be recorded for individual
On the day of randomization animals.
On the day prior to each day

of dosi ng
Individual Body All Main Study Fo llowing receipt Body weights of potent ial
We ights Anima ls replacement animals may also be
Week ly during the prete st collected at any of these timepoints.
period These data will not be statistically
analyzed or included in study report.
On the day of randomization
Page 15

Frequency
Parameter Population(s)" (minimum required) Comments
On the day prior to each day

of dosi ng
a To include unused replacement animals until released from study.
b Except on days of receipt and study termination where frequency will be at least once daily.
c For observations that cannot be attributed to an individual anima l due to social housing, the observation will be
noted to each animal in the socialized group.
10.1. RADIOTELEMETRY
10.2. Radiotelemetry Data Acquisition and Analysis
10.2.1. Electrocardiograph y and Hemod ynamics

Frequency: Baseline arterial blood pressure (systolic, diastolic, and mean arterial
pressure), pulse pressure, hea1t rate, lead II electrocardiographic (ECG)
waveforms (PR, QRS, QT, QTcV and calculated individual QTc
intervals), and body temperature will be collected continuously for at
least 90 min prior to administration of the control or test article. If a
probe failure occurs prior to or during collection of baseline data, the
animal will be replaced with a reserve animal for this study, if available,
or repeated at a later date.
Following administration of the control or test article, the appropri ate
parameters will be collected continuously for at least 4 hour s following
intravenous dose of interaction article. Electrocardiograph y,
hemodynam ic parameters and body temperature data will be averaged to
appropriate time intervals for statistical analysis .
Population(s): All Main Study animals
System: The radiotelemetry system (Data Sciences International, St. Paul, MN)
will consist of large animal radiote lemetry transmitters (with capabi lities
to collect, at minim um, arteria l pressure, body temperature, and
electrocard iographi c wavefom1s), receivers (RMC-1), and 1 or more
data exchange matrices (DEM) that will relay informa tion from the
receivers to the computer . An ambient pressure reference monitor
(APR-1) will be coupled to the DEM to measure the baromeh·ic pressure
and provide a digital signal to the DSI PONEMAH system. The DSI
PONEMAH system uses the measurements provided by the APR-1 to
correct pressure measurements obtained from the implant for changes in
barometric pressure .
The hardware connected to the Dataquest™ OpenART™ Acquisition
Interface provides direct digital signals to the DSI PONEMAH software.
rrop rietary Info Lroprietary Info
Page 16

The ECG and arterial waveform and body temperature data will be
recorded and ana lyzed by the DSI PONEMAH data acquisition software,
version 5.0 or higher. ECG and arterial pressure waveforms will be
sampled at 500 Hz. Temperature data will be samp led at 50 Hz. Data
acquired continuously will be logged every 120 seconds . During data
processing the logging rate will be changed to 60 seco nds. The ECG
wavefonn data will be analyzed by the OSI PONEMAH ECG-PRO
Template Analysis software.
Procedure: Blood pressure (systolic , diastolic , and mean) , pulse pressure, heart rate,
electrocardiographic (ECG) wavefonns, and body temperature will be
collected continuously .
Evaluation: Cardiovascular parameters and body temperature data will be averaged
to appropriate time intervals for statistical analysis .
Quantitative ECG waveform analysis will be perfonned using the OSI
PONEMAH ECG -PRO Template Analysis software to determine the
PR, QRS, RR, and QT intervals. Heart rate-corrected QT (QTc) values
will be calculated with the Van de Water correction formula where
QTcV = QT- 0.087*(RR-1) (Spence, et al., 1988 and Van de Water , et
al., 1989). Additionally, individual QT rate-co rrections (P-values) will
be derived from treatment 1 dosing occasion for each animal's dosing
session. The heart rate-corrected QT intervals will be calculated using a
method based on Spence and modified by Miyazaki & Tagawa and
reported (Spence et al, 1998 and Miyazaki and Tagawa, 2002) .
For the purpose of data processing , Noise and Match derived parameters
will be collected. These parameters will not be reported or statistically
analyzed .
Qualitative assessment of ECG will be performed by trained personnel
for disturbances in rhythm and waveform morpho logy in I-minute
segments for every 30 minutes of data collected following test article or
con trol dosing (e.g., a start event or a dosing event) through 4 hours after
the interaction article or its vehicle dose . Abnormal rhythm results will
be reported in a table as frequency of events . Qualitative assessment of
blood pressure waveforms will not be performed. Abnormal waveforms
that are identified by Charles River personnel will be discussed with the
Study Director to detennine if these and additional waveforms should be
presented to a veterinary cardiology specia list for evaluation. In the
event that abnormal waveforms are identified and evaluated by a
veterinary cardiology specialist, a report with this evaluation will be
maintained in the raw data and included in the final report as an
appendix .
F roprietary Info r roprietary Info
Page 17

Within the process ing system used to average te lemetry data into
intervals for statist ical analysis and reporting, minimum and maximum
limits will be set per the table below. Following review of data, these
limits may be changed at the request of the Study Director which will be
documented along with reason for change.
Parameter Waveform Minimum Maximum
Type
Heart Rate Blood 0 beats per No limit
Pressure minute
Systolic Blood Pressure Blood 0mmHg 350mmHg
Pressure
Diastolic Blood Pressure Blood 0 mmHg No limit
Pressure
Mean Arterial Blood Blood 0mmHg No limit
Pressure Pressure
Pulse Pressure Blood 0 mmHg 150mmHg
Pressure
Body Temperature Temperature 30°c 4s c
0
PR Interval ECG 0 msec 10000 msec

QRS Complex ECG 0 msec 10000 msec
QT Interval ECG 0 msec 10000 msec
QTc Interval ECG 0 msec 10000 msec
RR Interval ECG 0 msec 10000 msec
For paramete rs indicated as conh·ol parameters , if the defined limits are
exceeded for a time point then all other parameters at this time point will
be omitted from analysis and reporting.
10.2.2. Video Monitoring

Frequency : On each day of telemetry collection, video data synchro nized with ECG
will be recorded to a secure workstat ion. Video data will be recorded
concurrently during periods of radio telemetry data collect ion.
Page 18

System: Axis cameras (or equivalent) will be used to collect time matched video
data synchroniz ed with the radiotelemetry system .
Procedure: Each camera will be configured to capture the video data for each subject.
During data review, video data will be viewed using an appropriate media
player.
Evaluation: Video data synchronized with ECG will be used to establish the
approx imate time of occu rrence of retching or emesis, if noted , beginning
from the time of test article admini stration thru the 4-hour period of post-
dosing observation after the interaction article dose. This time will be
recorded on an appropriate form and will be maintained in the study
records . The times may be entered into the appropriate LIMS at the
discretion of the study director. The video data will be maintained in the
study records but will not have any additional evaluations performed.
11. CLINICAL PATHOLOGY
11.1. Sample Collection
Clinical Pathology Sample Co llection
Group No(s). Time Point Hematolo!!v Clinical Chemistry

Prior to surgical
All Animals X X
implantation
at least 8 hours (no more than 24
Fasting: - hours)
Venipuncture
from a jugular
Venipuncture from a jugular vein
vein (saphenous
Method/Comments: (sap henou s or cephalic vein may
or cephalic vein
be used , if necessary)
may be used, if
necessary)
Tan?:et Volume (mL)": l 1.5
Anticoa2ulant: K2EDTA None
Special Requirements: - -
Processin2: None Serum
X = Sample to be collected ; - = Not applicable
a = Additional samples may be obtained (e.g., due to clotting ofnon-sernm samples) if
permissible sampling frequency and volume are not exceeded.
Page 19

11.2. Hematology
Hematolo gy Parameters
Red blood cell count White blood cell count''
Hemoglobin concentration Neutrophil count (absolute)
Hematocrit Lymphocyte count (absolute)
Mean corpuscular volume Monocyte count (absolute)
Red blood cell distribution width Eosinophil count (absolute)
Mean corpuscular hemoglobin concentration Basophil count (absolute)
Mean corpuscular hemoglobin Large unstained cells (absolute)
Reticulocyte count (absolute) Other cells (as appropriate)
Platelet co unt Mean platelet vo lume
a If performed manually, results of differe ntial counts will include p latelet estimates and RBC morpho logy
(individua l tables only) .
A blood smear will be prepared from each hematology sample . Blood smears will be labeled,
stained, and stored. If additional examination of blood smears is deemed necessa ry, the
smears may be subsequ ently evaluated and this evaluation will be descr ibed in a protocol
amendment.
11.3. Clinical Chemistry
Clinical Chemistry Parameter s

Tota l prote in
Alanine aminotransferase
Albumin
Aspartate aminotransferase
Globulin (calculated)
Alkal ine phosphatase
Albumin/globulin ratio
Gamma-g lutamyltransferase
Glucose
Creatine kinase
Cholesterol
Total bilirubin "
Trig lycerides
Urea nitrogen
Sodium
Creatinine
Potassium
Calcium
Chloride
Phosphorus
Sample quality b
a When total bilirubin is > 0. 5 mg/dL , direct bilirubin will also be measured and indirect bilirubin will be
calculated .
b Will include degree of hemolysis , lipemia, and icterus (individual tables only).
12. DISPOSITION OF ANIMALS
This study is non-terminal. Upo n completion of the study, the animals will be maintained in the
Charles River anima l colony for future use or may be euthanize d (with intravenous sodium
pentobarbital adm inistration and the radiotelemetry probes recovered, as applicable). Anima ls
not used on study will be returned to the Charles River animal colo ny.
Animals that experience severe or chronic pain or distress that cannot be relieved will be
euthanized via intraveno us sodium pentobarbital administration. All anima ls to be euthanized in
extremis will have a detailed physical examination and a body weight collected. The animal will
then be released for euthanasia and subsequent gross necropsy.
Page 20

13. STATISTICAL ANALYSIS
The following presents a propo sed statistical analysis plan. Statistical pl ans are data dependent ,
and this analysis plan may require modification if standard data assumptions are not met. Other
conceptua lly equivalent statistical testing routines may also be employ ed at the discretion of the
statistician. The actual analysis plan will be documented in the Final Report.
Each cardiovascular parameter (systo lic, diastolic, and mean arterial blood pressure; pulse
pressure , heart rate; PR, QRS, QT, and QTc intervals) and body temperature will be analyzed
using a SAS®System software. Cardiovascu lar data and body tempera ture will be exported to
and analyzed in accordance w ith GLP Reg ulat ions. These stati stical ana lyses and tables will be
incorporated into the report.
13.1. Statistical Comparisons

Control Treatment Comparison (Test Article) Treatments
1 2,3
1 4,7
2 5,8
3 6,9
13.2. Statistical Analysis
The data will be analy zed using the mixed model analysis procedure within the SAS/STAT
System (SAS) software. For statistical analysis, telemet ry data will be organized into the
following phases:
• Baseline: 90-min pre-ora l dose baseline
• Phase I: 8 subph ases of 15 min each post oral dose phase (prior to interac tion article)
• Phase II: 6 subph ases of 5 min each for hour O through 30 min (post interaction article)
• Phase III: 3 subph ases of 10 min each for 30 min through hour 1 (post interaction article)
• Pha se IV: 3 subph ases of 1 hour each for hour s 2 through 4 (post interaction article)
The analysis pha ses and post-dose time intervals will be the same for all study periods. A single
value (mean) will be calculated for each period' s pre-dose (baseline) and individual post-dose
time intervals.
Each cardiovascular parameter and body temperatur e will be analyze d, separate ly for each
analysis phase, with a repeated measure analysis of cova riance (RANCOV A). Fixed actors in
the model will include a covariate (BASE) (90 minute basel ine for each dosing occasion),
treatment group (TR T), time after dose (TIME) , and the two way interactions of each of the
factors (TRT*TIME , TRT*BASE and BASE*TIME). ANIMAL will be fit as a random effec t
for autoregress ive error structur es. The SAS® procedure PRO C GLIMMIX will be used for
analysis with TIME as the repeated effect and ANIMA L as the subject. The covarian ce structure
across time will be selec ted by evaluating corrected Akaike's Information Criterion (AICC).
Page 21

Summary statistics will be reported for each treatment at each time point and across all time
points for a given analys is phase. Summa ry grap hs (means with standard error) will be presented
for the averaged data for systo lic, diastolic, and mean arterial pressure, pulse pressure, heart rate,
body temperature and PR, QRS, QT, and calculated individual QTc. Individual data will not be
presented in the report but will be maintained in the study records . Mean values for each time
interval will be presented for individual animals. The statistical analysis summary report will be
presented as an appendix in the final report.
Following the initial data review, other data summa ry intervals and/o r segments may be used at
the discretion of the Study Director in order to optimize the interpretation of data from this study.
13.2.1. Descriptive Statistics

Endpoints: Body Temperature
Cardiovascula r Endpo ints
• Heart Rate
• Systo lic, Diastolic, and Mean Arteria l Blood Pressures
• Pulse Pressure
• ECG (RR, PR, QRS, QT, and QTc)
Description: The following statistica l analyses will be performed for each analysis
segment:
The data will be tabulated within each summary time interval and the
arithmet ic mean (Mean), number of subjects (N), least squares mean (LS
Mean), and standard error of the LS Mean (LSM s.e.) will be calcu lated
for each endpoint and treatment.
13.2.2. Repeated Measures Analysis of Covariance

Endpoints: Body Temperature
Cardiovascular Endpoints
• Heart Rate
• Systolic, Diastolic and Mean Arterial Blood Pressures
• Pulse Pressure
14. COMPUTERIZED SYSTEMS

The following computerized systems may be used in the study. The actua l comp uter ized systems
will be documented in the report.
As Char les River Ashland transitions between various computer systems, the study number may
appear a{'.ropr
ietary
Info ~nthe data records and report.
rropr
ietary
Info
r rop
rietaryInfo
Page 22

Critical Comp uterized Systems
Pro2ram /Sys tem Descriptio n
Advia 120 and/or ADVIA 2120 i Hemato loe:v
Adv ia 1800 Serum and Ur ine Chemistry Ana lysis
Bio Med ic Data Systems (BMDS) Implantable Micro
Animal identification.
Identification™ (IMI- 1000)
In-house developed system for use in conjunction with
Charl es River Fonnulations Dispense System
Provant is Dispense TMto ensure proper storage and use
(CR-FDS)
of fonnu lations .
Dionex Chromeleon ® software,
Varian MS Workstation ® software, Used for chromatographic data acquisition and
Agilent ChemStation ® software, or quantitation .
Molecular Devices SpectraMax ® software
OSI PONEMAH Physio logy Platfonn Model P3 Plus;
Computer-based systems (OSI) utilized for the
OSI PON EMAH ECG PRO Template Ana lysis
electronic collection and measurement of
software; DataquestTMOpenART™ Acquisition
cardiovascular , and body temperatu re data.
Interface
Deviation Information Library Deviation s
DocuSign 10 Collection of Part 11 compliant signature.
Controls and monitors animal room environmental
Metasys SMP
conditions.
Microsoft Office 20 l O or higher; Used in conjunction with the publishing software to
GraphPad Prism® 2008 or higher generate study reports.
In-house reporting software Nevis 2012 (using SAS) Reporting of in-life and postmortem data
Test material receipt, accountability, formulation
activities, in-life (e.g., clinical observations, body
Provant is® weig hts, food consumption) , clinical pathology
(clinica l chemistry , coag ulation , hematolo gy), and/or
postmort em (e.g, pathology)
SAS® Statist ical (non-WTDMS™) analyses
Share Docume nt Management System (SDMS) Report ing
In-house develop ed system used to record and report
WIL Meta sys
anima l room env ironmental condit ions .
WIL To xicology Data Management System™ In-house deve loped system used for collectio n and
(WTDMS TM) reporting of clinical patholo!!v and other data .
No te: Versio n number s ofWT DMS TMprograms used for the study are presented on the report data tables
(reportin g progr ams); vers ion number s and re lease dates are otherwise maintained in the study records and/or
facil ity records.
Data for parameters not required by protocol , which are automatically generated by analytical
devices used will be retain ed on file but not reported. Stati stica l ana lysis results that are
generated by the progr am but are not required by protoco l and/or are not scientifically releva nt
will be retained on file but will not be include d in the tabu lations.
Page 23

15. REGULATORY COMPLIANCE
The study will be performed in accordance with the U.S. Department of Health and Human
Services, Food and Drug Administration , United States Code of Federal Regulations, Title 21,
Pait 58: Good Laboratory Practice for No nclinical Laborato ry Studies and as accepted by
Regulatory Authori ties throughou t the European Union (OECD Principles of Good Laboratory
Practice), Japan (MHLW) , and other countries that are signatories to the OECD Mutual
Acceptance of Data Agreement.
16. QUALITY ASSURANCE

Study components performed at sites other than the test ing facility will be conduc ted according
to the protocol and that site's applicable SOPs.
Study components performed at sites other than the test ing facility will be audited by the QAU of
the applicable test site.
16.1. Testing Facility

The Testing Facility Quality Assura nce Unit (QAU) will monitor the study to assure the
facilities, equipment, personnel , methods , practices, records , and controls are in conformance
with GLP regulations. The QAU will review the protocol, conduct inspections at intervals
adequate to assure the integrity of the study, and audit the Final Report to ass ure that it
accurately describes the methods and standard operating procedures and that the reported results
accurately reflect the raw data of the study.
16.2. Test Site(s)/Subcontractor(s)

For all study phase(s) inspec ted by test site/subcontrac tor QAU(s) , copies of each periodic
inspection report will be made available to the Study Director, Testing Facility Management , and
the Testing Facility QAU.
17. AMENDMENTS AND DEVIATIONS

Changes to the approved protocol shall be made in the form of an amendm ent, which will be
signed and dated by the Study Director. Every reaso nable effort will be made to discuss any
necessary protocol changes in advance with the Sponsor. The Study Dire ctor will notify the
Sponsor of deviations that may result in a significant impac t on the study as soon as possible.
18. RETENTION AND DISPOSITION OF RECORDS, SAMPLES, AND SPECIMENS

All study-specific raw data, electronic data, documentation , protocol, retained samp les and
specimens, and final report s will be archived by no later than the date of final report issue. All
materials generated by Charles River Laboratorie s from thi s study will be transferred to a
Charles River Laboratories archive. At least 1 year after issue of the Draft Repo rt, the Sponsor
will be contacted.
Disposition of residual/retained analytical samples will be as described in the table below.
r roprietary Info
rro prietary Info
Page 24

Disposition of Resid ual/Retained Sam ples
Samp le Type Dispositio n Schedule
Clinical Patholoe:v Discard Prior to issuance of the Final Report .
Following acceptance of the
Do se Formula tion Analysis
Discard analytica l results by the Study
(including backups)
Director.
18.1. Study Classification

Study Category: Safety Pharmacology
Study Type: Cardiovascular Pharmacology
Study Design : Crossover
Primary Treatment CAS Not Avai lable
Regish·y Number:
Primary Treatment Unique Not Available
Ingredient ID:
Clas s of Compound: Not Avai lable
19. REPORTING
A comprehensive Draft Report will be prepared following comp letion of the study and will be
finalized following consultation with the Sponsor. The report will include all info1mation
necessary to provide a complete and accurate description of the experimental methods and
results and any circumstances that may have affected the quality or integrity of the study.
The Sponsor will receive an electronic version of the Draft and Final Report provided in Adobe
Acrobat PDF format (hyperlinked and searchable at final) along with a Microsoft Word version
of the text. The PDF document will be created from native electronic files to the extent poss ible,
including text and tables generated by the Testing Facility. Report components not available in
native electronic files and/or original signature pages will be scanned and converted to PDF
image files for incorporation .
A tabulated data summary following the appropriate format as outlined in the ICH Harmonized
Tripartite Guideline, The Common Technical Document for the Registration of Pharmaceuticals
for Human Use: Safety - M4S (R2), Nonclinical Overview and Nonclinical Summaries of
Module 2, Organisation of Module 4, will be provided at the same time as the Draft and Fina l
Reports as a separate Microsoft Word document.
Reports should be finali zed within 6 months of issue of the audited Draft Report.
19. 1. SEND Datasets
SEND dataset s will be generated and provided outside the context of the GLP Repo1t. The se
datasets will not be subject to QA Audit nor will they be used as the basis for the Study Director
interpretation of the study results. SEND datasets will be provided for the Report based on
regulatory submission date. The Sponsor is expected to provide submission dates.
r roprietary Info rropr ietary Info
Page 25

20. JUSTIFICATIONS AND GUIDELINES
20.1. Justification of Test System and Number of Animals

At this time, studies in laboratory animals provide the best available basis for extrapolation to
humans and are required to support regulatory submiss ions. Acceptab le models that do not use
live animals currently do not exist.
This species and breed of animal is recognized by regulatory agenc ies to be appropr iate for
safety pharmacology studies and it is a widely used breed for which significant historical contro l
data are available.
Only male dogs will be used because no sex differences in exposure are anticipated.
The total number of animals to be used in this study is cons idered to be the minimum required to
properly characterize the effects of the test article. This study has been designed such that it does
not require an unnecessary number of animals to accomplish its objectives.
20.2. Justification of Route and Dose Levels

Test Article:
The dose levels were selected by NIDA. The oral route of exposure was selected because this is
the intended route of human exposure.
rop rietary Info
ropr ietary Info

See below.
r ropri etary Info
Page 26

Page 50 of 97 to Page 52 of 97
Withhe ld pursuant to exemption
Proprietary Info
of the Freedom of Information and Privacy Act

The doses were selected by the NIDA. The intravenous route of exposure fort ,. ~ ...............
"""""' ~
.......
article was selected because this is a route used b individ uals that use cocaine.
ropr ietary Info
20.3. Guidelines for Study

The design of this study was based on the study objective(s) , the overa ll product development
strategy for the test article , and the following study design guidelines:
• ICH Harmonised Tripartite Guideline S7A. Guideline on Safety Pharmacology Studies for
Human Pharmaceuticals .
• ICH Harmonised Tripartite Guideline S7B. The Non-Clinical Evaluation of the Potential/or
Delayed Ventricular Repolari zation (QT Interval Prolongation) by Human Pharmaceuticals
21. ANIMAL WELFARE
This study will comply with all applicable sections of the Final Rules of the Animal Welfare Act
regulations (Code of Federa l Regu lations, Title 9), the Public Health Service Policy on Humane
Care and Use of Laborator y Animals from the Office of Laboratory Anima l Welfare (Office of
Laboratory Animal Welfare , 2015), and the Guide for the Care and Use of Laboratory Animals
from the National Research Council (2011). The protocol and any amendments or procedures
involving the care or use of anima ls in this study will be reviewed and approved by the Testing
Facility Institutional Animal Care and Use Committee before the initiation of such procedure s.
If an animal is determ ined to be in overt pain/distress or appea rs moribund and is beyond the
point where recovery appears reasonable, the animal will be euthanized for humane reasons in
accordance with the American Veterinary Medical Association (AVMA) Guidelines on
Euthanasia and with the procedure s outlined in the protocol (American Veterinary Medical
Assoc iation, 2020).
Page 30

By approving this protocol , the Sponsor affirms that there are no acceptable non-anima l
alternat ives for this study , that this study is required by a relevant government regulatory age ncy
and that it does not unnecessar ily dup licate any p revio us exper iments .
21.1. Institutional Anima l Care and Use Committee Appr oval

The protoco l and any amendment(s) or procedures invo lving the care and use of anima ls in this
study will be reviewed and approved by Charles River Ashland Institutional Animal Care and
Use Committee (IACUC) before cond uct. Dur ing the study, the care and use of animals will be
cond ucted w ith guidance fro m the guide lines of the USA Natio nal Resea rch Co uncil.
22. REFERENCES
Amer ican Veterinary Med ical Association . AVMA Guidelines on Euthanasia . Jan uary 2020.
Cochra n WG, Cox GM . P lans and Tab les of Random Perm utat ions. In: Exper imenta l De signs,
New York, NY: John Wiley and Sons; 1957;145:577-582.
Natio nal Resea rch Counc il. Gu ide for the Care and Use of Laboratory Anima ls, Comm ittee for
the Update of the Gu ide for the Care and Use of Laboratory Anima ls, Instit ute for Laboratory
Animal Research , Division on Earth and Life Sciences; The National Academies Press:
Washington , DC , 2011.
Office of Laboratory Animal We lfare. Publi c Health Services Policy on Humane Care and Use
of Laboratory Animals. Bethesda , MD: National Institutes of Health. March 2015.
SAS® Proprietary Software, Version 9.4; SAS Institute , Inc.: Cary, NC , 2002-2014 Spence S,
Soper K, Hoe C-M, Coleman J. The heart rate-corrected QT interva l of conscious Beagle dogs: a
form ula based on ana lys is of covariance. Toxicol Sci . 1998;45(2) :247-258 .
Spence S, Soper K, Hoe C-M, Coleman J. The heart rate-corrected QT interva l of conscious
Beag le dogs: a form ula based on ana lysis of covar iance . Toxicol Sci. 1998;45(2):24 7-258 .
Van de Water A, Verheyen J, Xhonneux R, Reneman RS. An improved method to correct the
QT interva l of the electrocard iogram for changes in heart rate. J Pharma col Met.
1989;22(3):207-217.
rropr ietaryInfo
r roprietary Info
Page 31

TESTING FACILI TY APPROVAL
The signature below indicates that Testing Facility Management approves the Study Director
identified in this protocol and management ' s responsibility to the study as defined by the
relevant GLP regu lations .
I - DocuSianed bv: I
The signature below indicate s that the Study Director approve s the study protoco l.
I - DocuSianed bv: I
Page 32

SPONSOR APPROVAL
r roprietaty Info r roprietaty Info
Page 33

ATTACHMENT A
Shipment of Samples and Study Reco rds
Day/
Week / Proposed Conditions for
Matri x• Purpose Aliquot Shipment Date Shipment Recipie nt/Address
~e dacted by agreement
Disposition of On b lue ice

To be
Test Article unused neat test - packs
doc umented
article
Disposition of
Interaction unused neat To be Ambient
Article interaction
- documented temperature
article
-- not applicable.
• Shipments performed via FedEx.
r roprietary Info r ropr ietary Info
Page 34

-o<:,-.
charles river
PROTOCOL AMENDMENT No. 6
roprietary Info
Testing Facility Study No
roprietary Info
Sponsor Reference No,_____r _.
Evaluation of the Interaction Between r roprietary info ~dministered Orally and

Cocaine Administered Intravenously to Conscious, Radiotelemetry-
Instrumented Beagle Dogs
GLP
SPONSOR:
SRI Biosciences
333 Raven swood Avenue
Menlo Park, CA 94025
United States
TESTING FACILITY:
Charles River Laborato ries Ash land, LLC
1407 George Road
Ashland, OH 44805
United States
Page 1 of 40

SUMMARY OF CHANGES AND JUSTIFICA TIO NS
Study Proto col effective date: 17 N ovem her 2020
Note : When applicab le, additions are indicated in bold underlined text and deletions are
indicated in bold strikethrough text in the affected sections of the document.
Item or Section(s) Justificat ion
Amendment l Effect ive Date: 04 Dece mber 2020
I 1.2 Bioanalytical Samp le Processi ng Storage co nditions changed to align with established stabi lity
conditions.
Attachment A Updated bioanalysis sample recipient information
Amendment 2 Effect ive Date: 11 February 2021
2. PROPOSED STUDY SCHEDULE Update d the initiation of dosing (CV Phase) date to reflect a
change in the study schedule.
8.4 Food Updated timing of food offering based on dose administration
time and post dose obsevat ions.
9. Experimental Design Update d minimum washout duration
9.1. Administration of Test, Vehicle Added the time following exit of the room to begin dose
and Interactio n Articles administration during the CV Phase. Exte nded duration to allow
for doses to be administered at the same time of the day to
account for potentia l dosing delays.
9.2. Jacket and Tethe r System Clarified sham administration articles. Added the time following
Procedures "s ham" oral dose to being administering the "s ham" IV dose.
11. I Bioanalytical Samp le Collection Removed the word approximate ly from the target volume in the
bioanalytical sample collection table.
Ame ndment 3 Effect ive Date: 16 Februa ry 2021
4. Respon sible Personnel Ph armacoki netic phase personnel updated.
6.1 Preparation of formu lations Updated frequency of preparation and storage conditions based on
ve hicle stability.
8.1 Housing Deletion of erroneous text. Deleted text represente d comments
during protocol review . Clarification animals will have continual
access to water durin g periods of fasting.
8.5 Wate r Clarification of when water will not be available
9. Expe rimental Design Dose levels updated following review ofphar macokinetic data .
Clarificatoin of treatment week designation for PK phase and CV
pha se.
9.1 Administration of Test, Vehic le Dose confirmation added to fina l report
and Interaction Articles
9.2 Jacket and Tether System Clarification of timing for jacket placement. Removal of
Procedure s requirement to place the jacket prior to each day of dosing.
14.2 Statistical Analysis Ph ase I subphases updated
20. Reporting Remova l of finalization by testing facility if no comments are
received by sponsor within 6 months
2 1.2 Justification of Dose Level Justification updated based on result of PK phase.

Selection
rrop netary Info r ropnetary Info
Protoco l Amendment No. 6 Page2

Item or Section(s) Justification
Amendment 4 Effective Date: 02 Mar 2021
6.1. Preparation of Formulations Correction of storage conditions in the Preparation Details table
for the test article based on the current analytical stabi lity results.
6.3. Sample Collection and Analysis Addition of footnote a to the Dose Formu lation Sample Collection
Schedule to indica t that homogeneity analysis will not be
con ducted on the vehicle treatment.
6.3. I Analytical Method Addtion of infonnation regarding storage conditions of the
interaction article and reference to the study number under which
stability was previous ly established.
9. Experimental Design Correct ion of previous erroneously labeled treatment week for CV
9. Corrected formatt ing errors from prev ious Amendment.
Amendme nt 5 Effec tive Date: 09 Mar 2021
6.3.1 Analytical Method Correction of the study references for the validated and qualified
methods for the test article and interaction article. Addition of
wording to differentiate and clarify the two analyses methods.
I 0.2.2 Video Monitoring Addition of section to descr ibe the procedures for collection and
evaluation of added video monitoring to aid in the evaluation of
potential time of occurrence of emesis during the telemetry
collection period.
14.2 Statistical Analysis Corrected the number of subphases and hours for analysis Phase
4.
Amendment 6 Effective Date: 28 Apr 2021
4. RESPONSIBLE PERSONNEL Addition of contact information for the PI performing the
pharmacokinetic analysis .
16. REGULATORY COMPLIANCE Addition of regulatory and agency comp liance for the
pharmacok inetic analysis portion of the study which will be
conducted in Japan.
Protocol Amendment No. 6 Page 3

TABLE OF CONTENTS
SUMMARY OF CHANGES AND JUSTIFICATIONS .................................................................2

1. OBJECTNE(S) ....................................................................................................................... 5
2. PROPOSED STUDY SCHEDULE ........................................................................................ 5
3. SPONSOR ............................................................................................................................... 5
4. RESPONSIBLE PERSONNEL ...............................................................................................5
5. TEST MATERIALS ................................................................................................................ 7
6. DOSE FORMULATION AND ANALYSIS .......................................................................... 9
7. TEST SYSTEM ..................................................................................................................... 11
8. HUSBANDRY ...................................................................................................................... 13
9. EXPERIMENTAL DESIGN ................................................................................................. 16
10. IN-LIFE PROCEDURES , OBSERVATIONS , AND MEASUREMENTS ......................... 19
11. BIO ANALYSIS AND PHARMACOKINETIC EVALUATION ........................................ 24
12. CLINICAL PATHOLOGY ...................................................................................................26
13. DISPOSITION OF ANIMALS .............................................................................................27
14. STATISTICAL ANALYSIS ................................................................................................. 27
15. COMPUTERIZED SYSTEMS ............................................................................................. 29
16. REGULATORY COMPLIANCE .........................................................................................30
17. QUALITY ASSURANCE .....................................................................................................31
18. AMENDMENTS AND DE VIA TIO NS ................................................................................ 32
19. RETENTION AND DISPOSITION OF RECORDS, SAMPLES, AND
SPECIMENS ......................................................................................................................... 32
20. REPORTING ......................................................................................................................... 32
21. JUSTIFICATIONS AND GUIDELINES ........................................................................ .....33
22. ANIMAL WELFARE ...........................................................................................................36
23. REFERENCES ...................................................................................................................... 37
AMENDMENT APPROVAL ....................................................................................................... 38
SPONSOR APPROVAL ...............................................................................................................39
ATTACHMENT A .................... ....................................................................................................40
Protocol Amendment No. 6 Page4

1. OBJECTIVE(S)
The objective of this study is to eva luate the potential adverse cardiovascular effects that may
result whenr ropr
ietaryinfob est article ) and cocaine (interaction article) are adminis tered together to
ma le Beag le dogs. The study will be conducted in two phases .
In the first phase (pharmacokinet ics, PK pha se), treatmen t-n aive Bea gle dogs will be exposed to
increas ing leve ls o rop
netaryinfoo dete1mine the p harmacokinet ics and its tolerabili ty .
In the second p hase (cardiovascu lar interaction , CV phase), the Beag le dogs will be implanted
with telemetr transmitters and subseque ntly dosed with combinations of orall ava e)
administere ropnetaryinfo nd intravenously administered cocaine to evaluate if ropr ietaryinfoffect the
hemodynamic and cardiac effects cocaine. ropr ietaryinfo ose levels in the cardiovascu ar
interact ion phase will be informed by the ou come o he pharmacokinetics phase.
2. PROPOSED STUDY SCHEDULE

Proposed study dates are listed below. Actua l dates will be included in the Fina l Report .
Animal Arrival: 17 Nov 2020
Initiation of Do sing (PK Pha se): 24 Nov 2020
Initiation of Do sing (CV Phase) : 16 Feb 2021
Complet ion of In-life: 14 Apr 2021
(Release of anima ls from study)
Audited Draft Report: 24 Jun 2021
Fina l Report: 06 De c 2021
(Expected date of Study Directo r signat ure of report)
Final SEND Dataset Package Based on Regu latory Submission
Delivery:
3. SPONSOR
IRole IName IContact Information
4. RESPONSIBLE PERSONNEL
QAU (Quality
Assurance
Role /Phase Unit) Name Contact Information
~edacted by agreement
rropr
ietaryInfo rropr
ietaryInfo
Protocol Amendmen t No. 6 Page 5

QAU (Quality
Assura nce
Role/Phase Unit) Name Contact Information
~edactedby agreement edacted by agreement
Charles River
Charles River
Charles River
Individual Scientist (IS)

!Redactedby agreement
Charles River
Princinal Invest i2ator (Pn

!Redacted by agreement
CMIC, Inc
CMIC
PhannaScience
Co., Ltd.
• Sponsor-designated Test Site
Each IS and PI is required to report any dev iations or other circumstances that cou ld affect the
quality or integrity of the study to the Study Director in a timely manner for
authorization/acknowledgement. Each IS and PI will provide a report addressing their assigned
phase of the study, which will be included as an append ix to the Final Report .
The IS Phase Report will include the following:
• A listing of critical computerized systems used in the conduct and/or interpretation of the
The PI Phase Report will include the following:
• A Statement of Comp liance
• A QA Statement (for Sponsor designated PI or for Testing Fac ility designated PI if audited by
a QAU other than that of the Testing Facility)
• The archive site for all records, samp les, specimens and reports generated from the phase or
segment (alternat ively, details regard ing the retent ion of the mater ials may be prov ided to the
Study Director for inclus ion in the Final Report)
r roprietary Info rrop rietary Info
Protoco l Amendment No. 6 Page 6

• A listing of critical computerized system s used in the conduct and/or interpr etation of the
5. TEST MATERIALS
5.1. Test, Vehicle and Interaction Article Characterization

The Spon sor will provide to the Testing Facility documentation of the identity, strength, purity,
composition, and stability for the test and interaction a1ticle(s). A Certificate of Analysis or
equivalent docum entation will be provided for inclusion in the Final Report.
Vehicle and control article components will be characterized according to the product label
provid ed by the manufacturer
The Sponsor has appropriate docum entation on file concerning the method of synthesis,
fabrication or derivation of the test article, and thi s information is available to the appropriate
regulatory agencies should it be requested.
5.2. Test Article Identification
Test Article Identification

lf'roprietary Info
Retest Date: Concomitant

Physical Description: To be docum ented
Purity: 100%
Correction Factor: -
Stora2e Conditions: 18°C to 24°C
Provided bv: Soonsor or Soonsor Designee
- = not app licable

5.3. Interaction Article Identification
Interaction Art icle Identification
Interaction Article
Identification: Cocaine HCI
Alternate Identification: (-)-Cocaine HC l
Batch/Lot No.: To be documented
Expiration/Retest Date: To be documented
Physical Description: To be documented
Purity: To be documented
Correction Fact or: -
Storal!:eConditions: 18°C to 24°C
Provided by: Sponsor or Sponsor Designee
- = not app licable
5.4. Vehicle Identification
Vehicle Identification (for Test Article Preparation s)

Vehicle Article Vehicle Component Vehicle Component
0.5% Methylcellulose (400
Identification: Meth ylcellulose (400 cps) Deionized (DI) water
cps)
Alternate Identification: - - -
Set to maintain a targ et

Storage Conditions: 18°C to 24°C l8 °C to 24°C
temperature of 5°C
Provided by: Testing Faci lity Testing Facility Testing Facility
- = not applicable.
Vehicle Identification (for Interaction Article Preparations)
Vehicle Article Vehicle Component Vehicle Component
0.9% sodium chloride for Reverse Osmosis (RO)
Identification: Sodium chloride
injection, USP water
Alternate Identification: - - -
Storal!:eConditions: l8°C to 24°C 18°C to 24°C l8 °C to 24 °C
Provided by: Test ing Facility Testing Faci lity Testing Facil ity
- = not applicable.
5.5. Reserve Samples

Reserve samples of the test article will be taken in accordance with Charles River Standard
Operating Procedures and stored in the Charles River Archives.
5.6. Test and Interaction Article Inventory and Disposition

Records of the receipt , distribution, storage, and disposition of test materials (including empty
containers of Sponsor -provided materials) will be mainta ined. All unused Sponsor-supplied bulk
test materia ls, with the except ion of reserve samp les, will be returned to the Sponsor at the
address provided in Attachment A.
Protocol Amendment No. 6 Pages

5.7. Safety
A Safety Data Sheet (SDS), or equivalent documentation, will be provided by the Sponsor (if
available). It is the responsibility of the Sponsor to notify the test facility of any special handling
requirement s of the test article. Othe1wise routine safety precautions will be followed.
Appropriate gloves, safety glasses and ann covers will be worn by individuals working with neat
test material or formulations.
6. DOSE FORMULATION AND ANALYSIS
6.1. Preparation of Formulations

Dose formulations will be divided into aliquots where required to allow to be dispensed on each
dosing occasion .
Preparation Details
Dose Formulation Frequency of Preparation Stora2e Conditions
Vehicle At least every 3 weeks Set to maintain 5°C
Once, prior to the first CV phase
Interaction Article Set to maintain l 8°C to 24 °C
dosing occasion
Test Article At least biweekly Set to maintain 5°C
Frequency of preparation may be adjusted based on stability results. Any residual volumes from
each dosing occasion will be discarded unle ss otherwise requested by the Study Director .
6.2. Preparation Details

Dosing formulations will be prepared at appropriate concentrations to meet dose level
requirement s. The prepared test article formulations will not be adjusted for purity . The prepared
interaction article formu lations will not be adjusted for purity. Any procedures not covered by
SOPs required for formulation will be approved by the Study Director and included in the study
records. Formulation pH will be within SOP range, if applicable.
6.3. Sample Collection and Analysis

Dose formulation samples will be collected for analysis as indicated in the following table.
Additional samples may be collected and analyzed at the discretion of the Study Director.
rrop rietary Info r roprietary Info

Dose Formulation Samp le Collection Schedule
Number of Samples Sample

Sampling per Concentrat ion Volume
Samp le Type Concentration s Stratum From Collected Analyzed Backup (mL) Intervals
Top 4 2 2 I
Homogeneity Preparation Each
AH Treatmentsa Middle 4 2 2 l
Analyses con ta iner preparat ion
Bottom 4 2 2 1
Preparation
Concentration container Each
All Tr eatments Midd le 4 2 2 1
Analyse s preparation
a= excluding the vehicle treatment.

Interaction Article Samp le Collection Sched ule
Number of Samp les Sample

Sampling per Concentration Volume
Sample Type Concentrations Stratum From Collected Analyzed Backup (mL) Intervals
Preparation Each
container preparation
Concentration
All Treatments Middle 4 2 2 0 .5 and on each
Analyse s
day of
dosing•
• = duplicate 0.5 mL samples to be collected from the residual interaction article dosing container follow ing dosing.
One sample will be analyzed and the alternate will be utilized as a backup sample.
Dose analysis results (formulated test article or initial interaction article formulation) will be
verified prior to dose adm ini stration at each sampling interval if available. If results are deeme d
unacceptable, the formulations will be prepared again and analyze d.
Interaction samples will be transferre d to the analytica l chemistry laboratory and stored
refrigerated until analyzed . Test article formulation samp les (including backups) will be
transferred at ambient temperature to the Analytica l Chemi stry Department at the Testing
Facility for same day analysis , where possible or stored for analysis within known formu lation
stability per iod.
6.3.1. Analytical Method

Test article formulations have been previously shown to be stable and homogeneous over the
ran e of conce ntration s used on this study for at least 15 days at room temperaturer roprietarylnfo
rop
netarylnfo Therefore, stability and resuspension homogeneity of test article formulations
will not be assessed on this study.
Analyses for
.
1,e
Jest Article described below will he performed usin g a method validated by
ropnetary
Info I,: .
Charles Rive ~------------------____. iror concentrat10n. Any
backup samples kept at Charles River will be discarded following acceptanc e of the analytica l
results by the Study Director.
r ropr
ietary
Info rropr
ietaryInfo

Interaction article formu lations have been previous ly shown to be stable over the ran e of
conce ntrations used on thi~ study for at least 106 days at room roprietaryinfo
r ropn etary Info jf herefore, stability of the interact ion._a_r_tJ._,.-
c...,...
le_w...,.
i1=1-n_o_t ..,...
b_e_a_s-se_s_s-ed-,.-o--'
n
this study.
Analyses for the Interaction Article described below will be erformed using a method qualified
by Charles River roprietaryinfo for concentration. Any
backup samples kept at ar es o owmg acceptance of the analyt ical
results by the Study Directo r.
6.3.1.1. Test Article Concentration and Homogeneity Analysis

Samp le Allocation: 2 for ana lysis, 2 for backup
Storage Condit ions : Temperatu re set to maintain 18-24°C
Acceptance Criteria: Suspension:
For concentrat ion : Mean samp le conce ntrat ion with in 100% ± 15% of
theoret ical concentrat ion .
For homogeneity: Relative standard deviation (RSD) of concentrations

of~ 10% for each group .
6.3.1.2. Interaction Article Concentration Analysis
Sample Allocation: 2 for analys is, 2 for backup

Storage Condit ions : Temperatu re set to maintain 18-24°C
Acceptance Criteria: Solution:
Mean sample concentrat ion within 100% ± 10% of theoret ical
conce ntrat ion.
7. TEST SYSTEM
Species: Dog
Strain: Beag le
Condition: Purpose-bred, nai:ve
Source: Specific facility to be documented in study records.
Number and Sex: 7 males
Age at the Initiation of At least 6 months . An imals not utilized on study will be assigned to the
Dos ing : Charles River an imal colony .

Weight at the At least 5.5 kg
Initiation of Dosing:
The actual age and weigh t of the animals at the initiation of dosing will be listed in the Final
Repo 1t.
7.1. Animal Screening

Method: All animals used on study will have documentat ion of immunizatio n for
parvovi rus, distemper, adenovirus type 2, parainfluenza, Bordetella ,
papilloma, and rabies.
Prior to surgery, all animals will have blood samp les collected for
clinical pathology screening to evaluate hea lth status prior to the surgica l
proced ures. See section 12 for paramete rs to be evaluated.
7.2. Animal Identification

Method: Tattoo or a subcutaneously implanted elech·onic identification chip.
7.3. Surgica l Preparation of Animals

Method:
Following the PK phase animals will be implanted with radiote lemetry
transm itters and vascu lar access ports 01APs) to allow for undisturbed
IV dosing as descr ibed in Charles River SOPs .
Preanesthet ics, surgica l preparatio n and implantation details (for the
telemetry implant and VAPs), and post-operative care and recove
rocedures will be performed as outlined in CRL SOP roprietary lnfo
roprietarylnfo ~-----~
The transmitters have a fluid-filled catheter (coated with an

antithrombotic film to inhibit thrombus formation) with the tip filled
with a patented gel for collection of blood pressure and 2 ECG leads
emulating a lead II configurat ion.
The V APs will be maintained per Charles River SOPs , and will include
weekly assess ments of patency until dosing. VAPs will be locked with
taurolidine citrate solution (TCS) between patency assessmen ts.
7.4. Jacket Acclimation

Method: Following the PK phase and prior to surgery for the cardiovasc ular
interaction phase , all animals will be acclimated to a tethered infusion
system. Animals will initially be conditioned to jackets and co llars in a
stepwise manner until at least 24 hours of acclimation is achieved .
Subsequently, animals will be acclimated to the tether and jackets for a

period of 4 hours, and for a period of at least 24 hours. Add itional
sessions may be employed if deemed necessary.
7.5. Environmental Acclimation

Method: Each animal will be inspected by a clinical veter inarian upon receipt.
Animals judged to be in good health will be placed immediately in
acclimation for at least 6 days. See respect ive sections for parameters to
be eva luated . The anima ls will have been allowed at least 2 weeks to
recover following imp lantat ion of the telemetry device before the
administration of test and interaction articles for the cardiovascular
phase.
7.6. Selection, Assignment, Replacement, and Disposition of Animals

Selection: Near the end of the acclimation period , animals judged to be suitable for
test ing (based on health as indicated by randomization approva l) will be
ass igned to groups at random based on body weig ht stratification into a
block design using a computer program. A printout containing the
animal numbers and individual group assignments will be generated. For
the CV phase, animals will be arbitrarily assigned to groups based on
health and telemetric assessment.
Rep lacement: Before the initiation of dosing, any assigned animals considered
unsuitable for use in the study will be replaced by alternate animals.
After initiation of dosing , study animals may be replaced during the
replacement period with alternate animals in the event of accidental
injury, non-test art icle-related health issues, or similar circumstances.
Disposition: This study is non-terminal. Upon comp letion of the study, the animals
will be maintained in the Charles River dog colony for future use or may
be euthanized (with intraveno us sodium pentoba rbital adm inistration and
the radiotelemetry devices recovered, as applicable).
8. HUSBANDRY
8.1. Housing
Housing Single. Individual housing is necessary during periods of data collection
(Dos ing Days): to prevent telemetry signal cross talk and to individually attribute any
clinical observations to individual animals to allow for a correlation to
the bioanalytical data.
PK Phase: the animals will be separated in the morning prior to dosing ,
on each day of dosing.

Following jacket remova l, or the final blood collection timepoint,
anima ls will be returned to social housing.
Housing Group housed (up to 3 animals of the same sex)
(Non-Dos ing Days):
CV Phase: Anima ls will be separated in the afternoon on the day prior to
dosing at the time of fasting and will remain separated until following
jacket removal. Subjects will have continual access to water during
periods of fasting. This is to minimi ze variations in baseline data caused
by excitability and stress of animals from separation and placement into
telemetry banks.
Caging: Stainless steel cages with mesh floors.
Cage Identification: Will indicate animal/tattoo number(s) , and sex.
Housing set-up is as specified in the USDA Anima l Welfare Act (9 CFR, Parts 1, 2 and 3) and as
described in the Guide for the Care and Use of Laboratory Animals (National Research Council ,
2011). Anima ls will be separated during designated procedures /activities or will be separated as
requ ired for monitoring and/or health purposes, as deemed approp riate by Study Director and/or
Clinical Veteri narian.
8.2. Animal Enrichment

Method: For enrichment , animals will be provided with items such as chew toys,
except when interrupted by study procedures /activities. All animals will
be given regular opportunity for exercise and socialization and will have
enrichme nt through human interaction during the conduct of procedure
acclimation and daily study activities
8.3. Environmental Conditions

The targeted conditions for animal room environment will be as follows :
Temperatu re: 66°F to 76°F (19°C to 24°C)
Humidity: 30% to 70%
Light Cycle: 12 hours light and 12 hours dark ( except during designated procedures)
8.4. Food
Diet: PMI Nutrition International , LLC Lab Diet Certified Canine Diet 5007
Type: Kibble (alternate diet may be provided on individual animal basis as
wan-anted as approved by the Study Director).
Frequency: Approx imately 300 g daily.
Animals will be fasted overnight prior to surgery. The daily ration of
food will be offered following recovery from anesthesia. Animals will

be fasted overnight before dosing days. On dosing days during the PK
phase, the daily ration of food will be provided after the 2 hr plasma
collection . On dosing days during the CV phase, food will be returned
4 hr after the cocaine dose (after 4 hr clinical observation post dose).
Anima ls will not be fasted for longer than 24 hours.
Analys is: Results of analysis for nutritional components and environmental
contaminants are provided by the supplier and are on file at the Testing
Facility. It is considered that there are no known contaminants in the
feed that would interfere with the objectives of the study.
8.5. Water
Type: Municipal tap water, treated by reverse osmosis and ultraviolet
irradiation.
Frequency /Ration: Freely available to each animal via an automatic watering system
(except during body weight measurements, physical examinations, and
during surgery) .
Analysis: Periodic analysis of the water is performed , and results of these analyses
are on file at the Testing Facility. It is cons idered that there are no
known contaminants in the water that would interfere with the outcome
of the study.
8.6. Veterinary Care

Veterinary care will be available throughout the course of the study and animals will be
examined by the veterinary staff as warranted by clinical signs or other changes. In the event that
animals show signs of illness or distress, the responsible veterinarian may make initial
recommendations about treatment of the animal(s) and/or alteration of study procedures, which
must be approved by the Study Director. Treatment of the animal(s) for minor injuries or
ailments may be approved without prior consultation with the Sponsor representative when such
treatment does not impact fulfillment of the study objectives. If the condition of the animal(s)
warrants significant therapeutic intervention or alterat ions in study proced ures, the Sponsor
representative will be contacted , when possible , to discuss appropriate action. If the condition of
the animal(s) is such that emergency measures must be taken, the Study Director and/or
attend ing veter inarian will attempt to consu lt with the Sponsor representative prior to responding
to the medical crisis, but the Study Director and/or veterinarian has authority to act immediately
at his/her discretion to alleviate suffering. The Sponsor representative will be fully informed of
any such events.
If deemed necessary , dosing may be suspended for individual animals upon recommendation of
the clinical veterinarian in consultation with the study director in order to provide appropriate
veterinary care .

9. EXPERIMENTAL DESIGN
The following tab le present s the treatment anangement. Frop
Prop
rietary
Info
riet
aryinfo I
rropr
ietary
Info Froprietary
Info

Stud y Design
Tes t
Test A rticle Interaction Int.e raction Interaction
Article Test Articl e
Treat ment Treatment Dose Article Article Dose Article Dose No. of
Treatm ent Dose Do se
No. W eek Concentration Do se Level concentration Volum e Males
Level Volum e
(mg/mL) (m g/kg)< (mg/mL) (rnL/kg)
(m!!/k2) (mL/k2)
Pharmacokinctic (PK) Phase•
roprietary Info
1 PK 1 1 0.1 10 NA NA NA 7
2 PK2 3 0.3 10 NA NA NA 7
3 PK3 10 1 10 NA NA NA 7
4 PK4 30 3 10 NA NA NA 7
Cardiovascular Interaction (CV) Phaseb
Vehicle+
5 CY I 0 0 10 0 0 0.25 (Saline) 6
Saline
Vehicle+
6 CY2 Cocaine 0 0 10 0.56 2.24 0.25 6
(low)
Vehicle+
7 CV3 Cocaine 0 0 10 1.7 6.8 0.25 6
(hi!!h)
r roprietary Info
8 CV4 (low)+ 3 0.3 10 0 0 0.25 (Saline) 6
Saline
f roprietary Info
(low)+
9 CY 5
Cocaine
3 0.3 10 0.56 2.24 0.25 6
now)
j"roprietary Info
(low)+
10 CV6 3 0.3 10 1.7 6.8 0.25 6
Cocaine
(hi!!h)
f roprietary Info
11 CV7 (high) + 10 0 0 0.25 (Saline) 6
30 3
Saline
Proprietary Info
llllgnJ -t-
12 CV8 10 0.56 2.24 0.25 6
Cocaine 30 3
now)
roprietary Info
(.,high)+
13 CV9
30 3
10 1.7 6.8 0.25 6
Coca ine
(h igh)
NA = not applicable
The same 7 animals will be used for each treatment in an escalating design with 6 minimum days between doses .
b 6 animals will be selected from the animals tested in the PK phase and the same 6 animals will be used for each treatment in ascending
treatment number order with 6 minimum days between dose s.
The interaction article will be adm inistered at the presc ribed dose leve l at 1 hour(± 5 mi nutes) following test article dosing via
ambulatory intravenous infus ion.
d Pendi ng outcome ofphannacokinetic phase.

9.1. Administration of Test, Vehicle and Interaction Articles
PK Phase:
Dose Route: Oral gavage (test article)
Method: The dose formulations will be stirred continuously at room temperature

during dosing . The doses will be given using a syringe with an attached
gavage tube. Each dose will be followed by 15-mL flush using deionized
water provided by the formulations department.
CV Phase:
Dose Route: Oral gavage (test article) followed by intravenous infusion (interaction
article)
Method: Oral route : The vehicle or test article will be stirred continuous ly at room
temperature during dosing. The doses will be given using a syringe with
an attached gavage tube. Each dose will be followed by 15-mL flush
using deioni zed water provided by the formulations department.
Intravenous route: The interaction article or its vehicle will be
administered at 1 hour(± 5 minutes) following the oral dose via
intravenous infusion over a 30 second infusion from an infusion pump
followed by a 5 mL saline flush administered at the same rate. Doses
will be delivered using a calibrated infusion pump with a tethered
infusion system. Doses will be administered in absence of technical staff
in the dosing room. Doses will be scheduled to initiate at least 30
minutes following exiting of the room.
Doses will be delivered via the Cath-in -Cath system to the indwelling
catheter appropriately placed. The infusion will be delivered to freely
moving animals. Individual doses will be drawn into syringes labeled
with the animal number, study number, and date, and documented
appropriately. The dosing syringes will be filled with the appropriate
dosing volume (plus the additional volume of the dead space in the
exten sion line to the Y connector infusion system) of interaction article
required for dosing. Using a second infusion pump for each animal , an
additional syringe will be filled with the appropriate volume of saline to
flush the extension lines to complete the prescribed dose. Animals will
be dosed at approximate ly the same time( ± 1 hour) each dose day. Dose
confirmation will be detennined by syringe verification and included in
the final repo1t.

9.2. Jacket and Tether System Procedures
Pretreatment Session:
Prior to Dose l of the Card iovascular Interaction Phase , a "sham" dosing procedure imitating the
dosing procedure for each treatment session will be performed, including a telemetric recording
(cardiovascular, ECG , and body temperature) obtained for at least 4 hours following the "sham"
IV infusion (saline). All an imals will undergo the pretreatment recording. Vehicle will be used as
the oral sham dosing article, and saline will be utilized as the intravenous sham dosing article .
Doses will be administered as outlined in section 9 .1. These data will be recorded but not
reported. The pretreatment session will include a minimum of 90 min recording period prior to
the target "sham" oral dose while in telemetry cages, and then continue for at least 4 hr following
the "sham" IV infusion dose. The "sham" IV infusion dose will be performed at l hr( ± 5
minutes) following the "sham" oral dose, as outlined in the CV interaction phase treatment
regimen. Hemodynamic data (systolic, diastolic, mean arterial pressure, pul se pressure and heart
rate) and ECG interval s will be measured and binned in appropriate interva ls as descr ibed in
Section 14.2.
The ECG tracings will be reviewed for rhythm disturbances (dysrhythmias) for the six animals
participating in the study over the duration of recording period. Data from the pretreatment
collection will be used to confirm acclimation to testing procedures of the animals placed on
study.
During the CV phase , all anima ls will be placed into jackets prior to dosing. Patency checks will
be performed prior to introduction of the jacket system. All animals will be placed on a
maintenance infusion of saline (2 mL/hr) in an effort to maintain V AP patency during non-
dosing per iods. Animals will be maintained in jackets for up to approx imately 3 doses. Jackets
will be removed for approximately one week before. subsequent jacket placement.
10. IN-LIFE PROCEDURES, OBSERVATIONS, AND MEASUREMENTS
Genera l In-life Assessme nts

Frequency
Parameter Population(s) " (minimum required) Comments
Mortality All Animals" At least twice daily b Animals will be observed within
(morning and afternoon) their cage unless necessary for
beginning upon arrival identification or confirmation of
through termination/release !possible findings.
Cageside / Postdose All Main Study During the PK phase Animals will be observed within
Observations c Animals observations will be their cage unless necessary for
conducted prior to dosing , identification or confirmation of
and at each PK time point. possible findings.
t roprietary Info r roprietary Info

Frequency
Parameter Popul ation(s) " (minimum required) Comments
Durin g the CY phase, The absence or presence of findings
observations will be will be recorded for individual
conducted, prior to oral animals.
dosing, and at approximately
4 hours postdosing (relative Find ings noted outside the
to intera ction article above -spec ified observation per iods
administration) will also be recorded. Only the
presence of unscheduled
observations will be recorded; the
absence of findings will thus not be
recorded
Detailed Clinical All Main Study Following receipt Animals will be removed from the
Observationsc Animals cage .
On the day of randomization
The absence or presence of findings
On the day prior to each day will be recorded for individual
of dosing (for both the PK animals.
and CV Phase)
Weekly between the end of

the PK phase and beginning
of the CY phase
Individual Body All Main Study Following receipt Body weights of potential
Weights Anima ls replacement animals may also be
On the day of randomization collected at any of these timepoints.
These data will not be statistically
On the day prior to each day analyzed or included in study report.
of dosing (for both the PK
and CV Phase)
Week ly between the end of

the PK phase and beginn ing
of the CV phase ; frequency
may increase to every other
day if ev idence of
deteriorat ion is noted (as
indicat ed by clinical
conditio n.)
• To include unused replacement animals until release d from study.
b Except on days of receipt and study tem1ination where frequency will be at least once daily.
c For observations that cannot be attributed to an individual animal due to soc ial housing, the observation will be
noted to each animal in the social ized group.

10.1. RADIOTELEMETRY
10.2. Radiotelemetry Data Acquisition and Analysis
10.2.1. Electrocardiography and Hemodynamics

Frequency: Base line arterial blood pre ssure (systolic, dia stolic , and mean arterial
pressur e), pulse pressure , heart rate, lead II electrocardiographic (ECG)
waveforms (PR , QRS , QT, and QTcV interva ls), and body temperature will
be co llected cont inuou sly for at least 90 min prior to adm inistration of
vehicle or test art icle. If a probe failure occurs prior to or during collection
of baseline data, the animal will be replaced with a reserve animal for this
study, if available , or repeated at a later date.
Follo wing administration of vehicle or test article , the appropriate
parameters will be collected continuously for at least 4 hours following
intr avenous dose of interact ion article. Electrocardiography , hemod ynam ic
paramete rs and body temperature data will be averaged to appropriate time
intervals for statistical analysis.
Population( s): All Main Study an imals
System : The rad iotelemet ry system (Data Sciences International, St. Paul , MN) will
cons ist of large animal radiotelemetry transmitters (with capabilities to
collect , at minimum, arterial pressure, bod y temperature, and
electrocardiographic waveforms), receiver s (RMC-1) , and I or more data
exchange matrice s (DEM) that will relay inform ation from the receivers to
the computer. An ambient pressure reference mon itor (APR- 1) will be
coup led to the DEM to measure the barometric pressur e and provide a digital
signal to the DSI PONEMAH system. The DSI PONEMAH system uses the
measurements provided by the APR-1 to con-ect pressure mea surements
obta ined from the implant for changes in barometric pressure.
The hardwar e connected to the Dataquest™ OpenART™ Acqu isition
Interface provide s direct digital sig nals to the DSI PONEMAH softwa re.
The ECG and arterial waveform and body temperature data will be recorded
and ana lyzed by the DSI PONEMAH data acquisition software, version 5.0
or higher. ECG and arterial pressure waveforms will be sampled at 500 Hz.
Temperature data will be sampl ed at 50 Hz. Data acqu ired cont inuou sly will
be logged every 120 seconds. During data processing the logging rate will be
changed to 60 seconds. The ECG waveform data will be analy zed by the
DSI PONEMAH ECG-PRO Template Analys is software.
Procedure: Blood pressure (systolic , diastolic , and mean) , pulse press ure , hea rt rate ,
electrocard iograph ic (ECG) waveforms, and body temperature will be
collected cont inuou sly.
r ropr ietary Info t ropr ietary Info

Evaluat ion : Cardio vascular parameters and body temperature data will be averaged to
appro priate time intervals for statistical analysis.
Quantitative ECG waveform analysis will be performed using the DSI
PONEMAH ECG-PRO Template Ana lysis software to determine the PR,
QRS , RR , and QT intervals. Heart rate-corrected QT (QTc) values will be
calculated with the Van de Water correction formula where QTcV = QT -
0.087*(RR-1) (Spence, et al., 1988 and Van de Wate r, et al., 1989).
Additi onally, QT will be corrected using an indiv idual correct ion facto r,
QTcH = 1010g(QT) - ~[tog(HR)-tog(HRm)J (Holzgrefe, 2007). The beta va lue for
QTcH will be collected from each anima ls' veh icle dosing data during the
CV ph ase (slope of QT to RR) .
For the purpose of data processing , Noise and Match derived parameters will
be collected . These parame ters will not be reported or statistically analyzed.
Qualitative assessment of ECG will be perfonned by trained personnel for
disturbances in rhythm and wavefo rm morphology in 1-minute segments for
every 30 minutes of data collected fo llowing test a1ticle or vehicle dosing
(e.g., a start event or a dosing event) through 4 hours after the interaction
arti cle or its vehicle dose. Abnormal rhythm results wi ll be reported in a
table as frequency of events. Qualitative assess ment of blood pressure
wavefo rms will not be pe rformed. Abnorma l wavefo rms that are identified
by Charles River personnel will be discussed with the Study Director to
detennine if these and additiona l waveforms shou ld be presented to a
veterinary cardio logy spec ialist for evaluation. In the event that abno1mal
wavefo 1ms are identified and evaluated by a veterinary card iology specialist,
a report wi th this evaluation will be maintained in the raw data and included
in the final report as an appendix.
Within the processing system used to average telemetry data into intervals
for statistical analysis and reporting , minimum and maximum limits will be
set per the table below . Following review of data, these limits may be
changed at the request of the Study Director which will be documented
along with reason for change.
Parameter Waveform Minimum Maximum
Type
Heart Rate Blood 0 beats per No lim it
Pressure minute
Systolic Blood Pressure Blood 0mmH g 350 mrnHg
Pressure
Proto col Amendment No. 6 Page 22

Diastolic Blood Pressure Blood 0mmHg No limit
Pressure
Mean Arterial Blood Blood 0mmHg No limit
Pressure Pressure
Pulse Pressure Blood 0mmHg 150 mmHg
Pressure
Body Temperature Temperature 30°c 4s 0 c
PR Interval ECG 0 msec 10000 msec

QRS Complex ECG 0 msec 10000 msec
QT Interval ECG 0 msec 10000 msec
QTc Interval ECG 0 msec 10000 msec
RR Interval ECG 0 msec 10000 msec
For parameters indicated as control parameters , if the defined limits are
exceeded for a time point then all other parameters at this time point will be
omitted from analysis and reporting.
10.2.2. Video Monitoring

Frequency: On each day of telemetry collection , video data synchronized with ECG
will be recorded to a secure workstation. Video data will be recorded
concurrently during periods of radiote lemetry data collect ion.

System: Axis cameras (or equivalent) will be used to collect time matched video
data synchronized with the radiotelemetry system.
Procedure: Each camera will be configured to capture the video data for each subject.
During data review, video data will be viewed using an appropriate media
player.
Evaluation: Video data synchronized with ECG will be used to establish the approximate
time of occurrence of retching or emesis, if noted, beginning from the time
of test article administration thru the 4-hour period of post-dosing
observation after the interact ion article dose . This time will be recorded on
an appropriate form and will be maintained in the study records. The times
rrop rietary Info r roprietary Info

may be entered into the appropr iate LIMS at the d iscretion of the study
director. The video data will be maintai ned in the study reco rds but will not
have any additional evaluations performed.
11. BIO ANALYSIS AND PHARMACOKINETIC EVALUATION
11.1. Bioanalytical Sample Collectio n
Bioanal ytical Sa mple Collect ion

Time Postdose on Davs 1, 8, 15 and 22
0 hr
Treatment No. 0.5 hr 1 hr 2 hr 4 hr 8 hr 12 hr 24 hr
(pre dose)
1 X X X X X X X X
2 X X X X X X X X
3 X X X X X X X X
4 X X X X X X X X
Venipuncture from a jugular vein (saphenous or cephalic vein may be used, if
Method /Comments :
necessary) .
Tan:?et Vo lume (mL): I mL/time point co llected without anesthes ia .
Anticoa2 ulant: Sodium Heparin
Speci al Requirements: Keep samp les chilled during collection and processing.
Processin2: Plasma
X = sample to be collected; hr = hour
11.2. Bioanalytical Sample Processing
Samp les will be mixed gently and centrifuged as soon as pract ical.
The samples will be centrifuged and the result ant plasma wi ll be separated , transferred to
duplicate uni quely labeled polyprop ylene tube s, and frozen immedi ately ove r dry ice until
tran sferred to storage. Samples wi ll be stored in a freezer set to main ta in a target of -20°C .
Samp les will be shipp ed by overnight courier to the address provided in Attachment A.
The samples will be shipped in 2 batches (each with l set of aliquots). The recipient , Sponsor
Rep resen tativ e, and Study Dir ector will be contacted prio r to shipment to ensure that the
shipment wi ll be handl ed appropriate ly upon rece ipt. Upon rece ipt at the analyt ical laboratory ,
the sample s will be stored in a freeze r set to maintain a target of -20°C.
11.3. Bioanalytical Sample Analysis

Bioanalvtical samoles will be analvzed for concentration otf ropr
!Prop
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Protocol Amendm ent No. 6 Page 24

Analysis will be perfom1ed according to the va lidated method and SOPs of the performing
laboratory. Appropr iate comp uter software will be used for the collection and analysis of data ;
specific software versions will be noted in the bioanalytical repo rt. Statistical analy ses, including
regression analysis, and descriptive statistics, including arithmet ic means and standard
deviation s, accuracy and prec ision will be performed.
11.4. Pharmacokinetic Evaluation

Pharmacokinetic paramete rs will be estimated using Phoenix pharmacokine tic software. A
non-compa rtmenta l approac h cons istent with the oral route of admini stration will be used for
parameter estimation. All parameters will be generated from rroprietarylnfo
~ndividual concentrat ions
in plasma from Day s 1, 8, 15, and 22 whenever practica l. Parameters will be estimated using
sampling time s made relative to the start of each dose admini stration.
Parameters to be Estimated
Parameter Description of Paramet er
trnax The time after dosing at which the maximum concentration was observed .
Crnax The maximum observed concentration measu red after dosing.
Cma,/ Do se The Cmax divided by the dose administered.
The area under the concentration versus time curve from the start of dose admin istration to
AUC,1as1
the last observed quantifiable concentration calculated using the linear trapezoidal metho d.
AUC11as1/Dose The AUC.1as1divided by the dose administered.
t1as
1 The time after dosing at which the last quantifiable concentration was observed
Parti al AUCs (between two defined sampl e times), and correspo nding dose-norm alized values,
may be derived and reported to aid interpretation . Descriptive statistics (e.g., number , arithme tic
mean , median , standa rd deviation, standard error, coeffic ient of va riation) will be report ed as
deemed approp riate, as well as ratio s for appro pri ate grouping and sorting variables (e.g., AUC)
may be generated. Pharmacokinetic table s and graphs will also be generated.
Ana lysis will be performed acco rding to SOPs of the performing laborato ry.
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Protoco l Amendmen t No. 6 Page 25

12. CLINICAL PATHOLOGY
12.1. Sample Collection
Clinical Patholo gy Sam ple Collection
Group No(s). Time Point Hematoloe:v Clinical Chemistry

Prior to PK p hase
All Anima ls and after surg ical X X
implantation
Fasting: - at least 8 hours (no more than 24 hours)
Yenipuncture from a jugular
Yenipuncture from a jugular vein
vein (saphenous or cephalic
Method/Comments: (saphenous or cepha lic vein may be used,
vein may be used, if
if necessary)
necessa ry)
Tan zet Volume (mL)•: I 1.5
Anticoagulant : K2EDTA No ne
Special Requirements: - -
Process ing: None Serum
X = Sample to be collected; - = Not applicable
a= Additional samples may be obtained (e.g., due to c lotting of non-serum samp les) if permissible
samp ling frequency and volume are not exceeded.
12.2. Hematology
Hemato logy Parameters

Red blood cell count Whit e blood cell count'
Hemoglobin concentration Neutrophil count (absol ute)
Hematocrit Lymphocyt e count (absolute)
Mean corpuscu lar volume Monocyte count (absolute)
Red blood cell distribution width Eosinophil count (absolute)
Mean corpuscular hemoglobin concentration Basophil count (absolute)
Mean corpuscular hemoglobin Large unstained cells (abso lute)
Reticulocyte count (absolute) Other cells (as appropriate)
Platelet count Mean platelet volume
a If performed manually, results of differential counts will include platelet estimates and RBC morphology
(individual tables only).
A blood smear will be prepared from each hemato logy sample . Blood smea rs will be
labe led,sta ined, and stored. If add itiona l exam inatio n of blood smear s is deemed necessary,
the smears may be subsequently evaluated and this evaluation will be described in a protocol
amendment.
12.3. Clinical Chemistry
Clinica l Chemistry Parameters
Protocol Amendm ent No. 6 Page 26

Total protein
Alanine aminotransferase
Albumin
Aspartate aminotransferase
Globulin (calculated)
Alkaline phosphatase
Albumin /globulin ratio
Gamma -glutamyltran sferase
Glucose
Creatine kinase
Cholesterol
Total bilirubin"
Trig lycerides
Urea nitrogen
Sodium
Crea tinine
Potass ium
Calcium
Chloride
Phosphorus
Sampl e quality b
a When total bilirubin is > 0. 5 mg/dL, direct bilirubin will also be measured and indir ect bilirubin will be
calculated.
b Will include degree ofhemolysis, lipem ia, and icterus (individual tables only).
13. DISPOSITION OF ANIMALS

This study is non-terminal. Upon completion of the study, the animals will be maintained in the
Charles River animal colony for future use or may be euthanized (with intravenous sodium
pentobarbital adm inistration and the radiotelemetry probes recovered, as applicab le). Animals
not used on study will be returned to the Charles River animal colony.
Animals that experience severe or chronic pain or distress that cannot be relieved will be
euthanized via intravenous sodium pentobarbital administration. All animals to be euthanized in
extremis will have a detailed physical examination and a body weight collected. The anima l will
then be released for euthanasia and subsequent gross necropsy.
14. STATISTICAL ANALYSIS

The following presents a proposed statistical analysis plan. Statistical plans are data dependent,
and this analysis plan may require modification if standard data assumptions are not met. Other
conceptually equivalent statistical testing routines may also be employed at the discretion of the
statistician. The actual analysis plan will be documented in the Final Report.
Each cardiovascular parameter (systolic, diastolic , and mean arterial blood pressure; pulse
pressure , heart rate; PR, QRS , QT, and QTc intervals) and body temperature will be analyzed
using a SAS®System software. Cardiovascular data and body temperature will be exported to
and analyzed in accordance with GLP Regulations. These statistical analyses and tables will be
incorporated into the report.
rropr ietary Info r ropr ietary Info

14.1. Statistical Comparisons
Control Treatment Comparison (Test Article) Treatments
5 6,7
5 8,11
6 9,12
7 10, 13
14.2. Statistical Analysis
The data will be analyzed using the mixed model analysis procedure within the SAS/STAT
System (SAS) software. For statistical analysis, telemetry data will be organized into the
following phases:
• Baseline: 90-min pre-oral dose baseline
• Phase I: 4 subphases of 15 min each post oral dose phase (prior to interaction article)
• Phase II: 6 subphases of 5 min each for hour O through 30 min (post interaction article)
• Phase III: 3 subphases of 10 min each for 30 min through hour 1 (post interaction a1ticle)
• Phase IV: 3 subphases of 1 h each for hours 2 through 4 (post interaction article)
The analysis phases and post-dose time intervals will be the same for all study periods. A single
value (mean) will be calculated for each period's pre-dose (baseline) and individual post-dose
time intervals.
Each cardiovascular parameter and body temperature will be analyzed, separately for each
analysis phase, with a repeated measure analysis of covariance (RANCOV A). Fixed actors in
the model will include baseline (BASE) as a covariate , treatment group (TRT), time after dose
(TIME), and the two way interactions of each of the factors (TRT*TIME , TRT*BASE and
BASE*TIME). ANIMAL will be fit as a random effect for autoregres sive error structures . The
SAS®procedure PROC GLIMMIX will be used for ana lysis with TIME as the repeated effect
and ANIMAL as the subject. The covariance structure across time will be selected by evaluating
corrected Akaike's Information Criterion (AICC).
Summary statistics will be reported for each treatment at each time point and across all time
points for a given analysis pha se. Summary graphs (means with standard error) will be presented
for the averaged data for systolic , diastolic , and mean arterial pressure, pulse pressure, heart rate,
body temperature and PR, QRS, QT, and QTcV. Individual data will not be presented in the
report but will be maintained in the study records. Mean values for each time interval will be
presented for individual animals. The statistical analysis summary report will be presented as an
appendix in the final report.
Following the initial data review, other data summary intervals and/or segments may be used at
the discretion of the Study Director in order to optimize the interpretat ion of data from this study.
rropr ietary Info rrop rietary Info

14.2.1. Descriptive Statistics
Endpoin ts: Body Temperature
Cardiovascular Endpoints
• Heart Rate
• Systolic, Diastolic, and Mean Arteria l Blood Pressures
• Pulse Pressure
Description: The following statistical ana lyses will be perfo1med for each analysis
segment:
The data wi ll be tabulated within each summary time interval and the
arithmetic mean (Mean) , number of subjects (N), least squares mean (LS
Mean) , and standard error of the LS Mean (LSM s.e.) will be calculated
for each endpoint and treatment.
14.2.2. Repeated Measures Analysis of Covariance

Endpoints: Body Temp erature
Cardiovascular Endpoint s
• Heart Rate
• Systolic, Diastolic and Mean Arte rial Blood Pressures
• Pulse Pressure
15. COMPUTERIZED SYSTEMS

The following computerized systems may be used in the study. The actua l computerized systems
will be documented in the report.
As Charles River Ashland tran sitions between vario us com
appear a ,__ _______________________
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_.
F ropr ietary Info F ropr ietary Info

Critical Comp uterized Systems
Pro2ram/System Descriptio n
Advia 120 Hematoloe:v
Adv ia 1800 Serum and Urine Chemistry Ana lysis
Bio Medic Data Systems (BMDS) Implantable Micro
Animal identification.
Identification TM(IMI -500 or IMI- 1000)
In-house dev eloped system for use in conjunction with
Charl es River Formulations Dispense System
Provantis Dispense TMto ensure proper storage and use
(CR-FDS)
of fonnulations.
Dionex Chromeleon ® software,
Varian MS Workstation ® software, Used for chromatographic data acquisition and
Agilent ChemStation ® software, or quantitation .
Molecular Devices SpectraMax ® software
DSI PONEMAH Physio logy Platfonn Model P3 Plus;
Computer-based systems (DSI) utilized for the
DSI PONE MAH ECG PRO Template Analysis
electronic collection and measurement of
software; DataquestTMOpenART™ Acquisition
cardiovascular, and body temperature data.
Interface
Deviation Information Library Deviations
DocuSign 10 Collection of Part 11 compliant signature.
Controls and monitors animal room environmental
Metasys SMP
conditions.
Microsoft Office 20 l O or higher ; Used in conjunction with the publishing software to
GraphPad Prism® 2008 or higher generate study reports.
In-house reporting software Nevis 2012 (using SAS) Report ing of in- life and postmortem data
Test material receipt, accountability, formulation
activities, in-life (e.g.,. clinical observations , body
Provantis ® weights, food consumption) , clinical pathology
(clinica l chemistry , coagulation, hematology) , and/or
postmo11em (e.g.,. pathology , ovarian contents)
SAS® Statistical (non-WTDMSTM)analy ses
Share Document Management System (SDMS) Reporting
In-house developed system used to record and report
WIL Metasys
animal room env ironmental condition s.
WIL Tox icology Data Management System™ In-house developed system used for collection and
(WTDMSTM) reporting of clinical pathology and other data.
Note: Version numbers ofWTDMSTM programs used for the study are presented on the report data tables
(reporting programs) ; version numbers and release dates are otherwise maintained in the study records and/or
facility records.
Data for parameters not required by protocol , which are automatically generated by analytica l
devices used will be retained on file but not reported. Statist ical ana lys is results that are
generated by the program but are not required by protoco l and/o r are not scientifically relevant
will be retained on file but will not be included in the tabulations.
16. REGULAT ORY COMPLIANCE

The study will be performed in accordance with the U.S. Department of Health and Human
Services, Food and Drug Administration, United States Code of Federal Regulations , Title 21,
Pait 58: Good Laboratory Practice for Nonclin ica l Laboratory Studies and as accepted by

Regulatory Authorities throughout the European Union (OECD Principle s of Good Laboratory
Practice), Japan (MHLW), and other countrie s that are signatories to the OECD Mutual
Acceptance of Data Agreement.
Any portion of this study conducted in Japan will be performed in accordance with
MHW Ordinance No. 21: Good Laboratory Practice Standards for Non-Clinical Safety
Studies on Drugs, 1997 and the Partial Revision {Ordinance No. 114, 2008) and as accepted
by Regulatory Authorities throughout the European Union, United States of America
(FDA), and other countries that are signatories to the OECD Mutual Acceptance of Data
Agreement.
Exceptions to GLPs include the following study elements:
• Characterization of the test and interaction articles will be/were performed by the Sponsor or
Sponsor subcontractor at a laboratory that follows FDA Good Manufactur ing Practice (GMP)
regulations.
• Characterization of the test and interaction articles will be/were performed by the Sponsor or
Sponsor subcontractor according to established SOPs, controls, and approved test
methodologies to ensure integrity and validity of the results generated; these analyses will
not be/were not conducted in compliance with the GLP or GMP regulations.
17. QUALITY ASSURANCE

Study components performed at sites other than the testing facility will be conducted according
to the protocol and that site's applicable SOPs.
Study components performed at sites other than the testing facility will be audited by the QAU of
the applicable test site.
17.1. Testing Facility

The Testing Facility Quality Assurance Unit (QAU) will monitor the study to assure the
facilities, equipment, personnel, method s, practice s, records, and controls are in conformance
with GLP regulations. The QAU will review the protocol, conduct inspections at interval s
adequate to assure the integrity of the study, and audit the Final Report to assure that it
accurately describes the methods and standard operating procedures and that the reported results
accurately reflect the raw data of the study.
17.2. Test Site(s)/Subcontractor(s)

For all study phase(s) inspected by test site/subcontractor QAU(s), copies of each periodic
inspection report will be made available to the Study Director , Testing Facility Man agement, and
the Testing Facility QAU.

18. AMENDMENTS AND DEVIATIONS
Changes to the approved protocol shall be made in the form of an amendment , which will be
signed and dated by the Study Director. Every reasonable effort will be made to discuss any
necessary protoco l cha nges in advance with the Sponsor . The Study Director will notify the
Sponsor of deviations that may result in a significant impact on the study as soon as possible.
19. RETENTION AND DISPOSITION OF RECORDS, SAMPLES, AND SPECIMENS

All study-specific raw data, electronic data, documentation, protocol, retained samples and
specimens, and final reports will be archived by no later than the date of final report issue. All
materials generated by Charles River Laborato ries from this study will be transferred to a
Charles River Laboratories archive. At least 1 year after issue of the Draft Report, the Sponsor
will be contacted.
Disposition ofresidual/retained ana lytical samples will be as described in the tab le below .
Disposition of Residual/Retained Samples

Samp le Type Disposition Schedule
Following acceptance of the
Dose Formulation Analysis
Discard analytical results by the Study
(including backups)
Director.
19.1. Study Classific ation

Study Category: Safety Pharmacology
Study Type: Cardiovascular Pharmaco logy; Pharmacokinetics
Study Design: Crossove r
Primary Treatment CAS Not Available
Regish·y Number:
Primary Treatment Un ique Not Avai lable
Ingredient ID:
Class of Compound: No t Available
20. REPORTING
A comprehensive Draft Report will be prepared following completion of the study and will be
finalized following consultation with the Sponsor. The report will include all info1mation
necessary to provide a comp lete and accurate description of the experimenta l methods and
results and any circumstances that may have affected the quality or integrity of the study.
The Sponsor will receive an electronic version of the Draft and Final Report provided in Adobe
Acrobat PDF format (hyperlinked and searchable at final) along with a Microsoft Word version
of the text. The PDF document will be created from native elec tronic files to the extent possible,
including text and tables generated by the Testing Facility. Report components not available in

native electronic files and/or original signature pages will be scanned and conve rted to PDF
image files for incorporati on.
A tabu lated data summar y following the appropriate format as outlined in the ICH Harmoni zed
Tripaitite Guid eline , The Common Technical Document for the Registration of Pharmaceuticals
for Human Use: Safety- M4S (R2), Nonclinical Overview and Nonclinical Summaries of
Modul e 2, Organisation of Module 4, will be provided at the same time as the Draft and Final
Reports as a separa te Microsoft Word docum ent.
Report s shou ld be finalized within 6 months of issue of the audited Draft Report .
20.1. SEND Datasets
SEND datasets will be ge nerated and provid ed outside th e context of the GLP Report . These
datasets will not be subject to QA Audit nor will they be used as the basis for the Study Director
interpreta tion of the study results. SEND data sets will be provided for the Report based on
regulatory submi ssion date. The Sponsor is expected to provide submi ssion date s.
21. JUSTIFICATIONS AND GUIDELINES
21.1. Justification of Test System and Number of Animals

At this tim e, studies in laboratory animals provide the best avai lable basis for extrapolation to
humans and are required to support regulatory submissions. Acceptable models that do no t use
live animals currently do not exist.
This species and breed of animal is recogni zed by regulatory agencies to be appropriate for
safety phannacolo gy studie s and it is a wide ly used breed for which significan t historical con trol
data are available .
Only male dogs wi ll be used because no sex differences in expo sure are anticipa ted.
The total number of animals to be used in this study is considered to be the minim um required to
prop erly characteri ze the effects of the test article. This study has been designe d such that it do es
not require an unn ecessary numb er of animals to accomplish its objectives .
21.2. Justification of Route and Dose Levels

Test Articl e:
PK Phase:
The doses were selec ted by the NIDA. The oral route of exposure for the test article was
selected because this is the intende d route of human exposure. The exposur e levels of the test
aiticle for a substance abuse indication in hum an subjects isfroprietary info
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Dose leve ls of te._s_t_a-1t..,.ic
_,,
l_e _w_,i~ll,-.,
b,-e- se-,,l-ec_t_e..,.
d-to___ ___,
correspond with human plasma leve ls at intentio n to treat a 3x multiple of that do se to pro vide a
safety margin in the even t of increased exposure in patients attributable to individual differences
in metabolism or excess drug takin g.
rropr
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Page 91 of 97 to Page 92 of 97
Withhe ld pursuant to exemption
Proprietary Info
of the Freedom of Information and Privacy Act

Interac tion Article:
The doses were selected by the NIDA. The intraveno us route of exposure for the interact ion
article was selected because this is a route used bv individuals that use cocaine. r roprietaryinfo
fropr ietary Info
I
21.3. Guidelines for Study

The design of this study was based on the study obj ective(s), the overa ll product development
strategy for the test article, and the following study design guide lines:
• OECD Guidel ine 4 17. Toxicokinetics.
• ICH Harmon ised Tripartite Guideline S3A. Note for Guidance on Toxicokinetics: The
Assessment of Systemic Exposure in Toxicity Studies.
• ICH Harmonised Tripartite Guideline S7A. Guideline on Safety Pharmacology Studies for
Human Pharmaceuticals .
• ICH Harmonised Tripartite Guideline S7B . The Non-Clinical Evaluation of the Potentialfor
Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals
22. ANIMAL WELFARE

This study will comply with all app licable sections of the Final Rules of the Animal Welfare Act
regu lations (Code of Federal Regu lations, Title 9), the Public Health Service Policy on Humane
Care and Use of Laboratory Animals from the Office of Laboratory Anima l Welfare (Office of
Laboratory Animal Welfa re, 2015), and the Guide for the Care and Use of Laboratory Anima ls
from the National Resea rch Council (201 1). The protoco l and any amendments or procedures
involving the care or use of animals in this study will be reviewed and approve d by the Testing
Facility Institutiona l An imal Care and Use Commi ttee before the initia tion of such procedures.
If an animal is determined to be in overt pain/distress or appea rs moribund and is beyond the
point where recovery appears reasonable, the anima l will be euthanized for humane reasons in
accordance with the American Veterinary Medical Association (AVMA) Guidelines on
Euthanasia and with the procedu res outlined in the protoco l (American Vete rinary Medical
Assoc iation, 2020).

By approving this protocol , the Sponsor affirms that there are no acceptable non-animal
alternat ives for this study, that this study is required by a relevant government regulatory age ncy
and that it does not unnecessarily duplicate any previous exper iments .
22.1. Institutional Animal Care and Use Committee Approval

The protocol and any amendment(s) or procedures involving the care and use of anima ls in this
study will be reviewed and approved by Charles River Ashland Institutional Animal Care and
Use Committee (IACUC) before cond uct. During the study, the care and use of animals will be
conducted with guid ance from the guidelines of the USA Natio nal Research Council.
23. REFERENCES
Amer ican Veterinary Med ical Association . AVMA Guidelines on Euthanasia . January 2020.
Cochran WG, Cox GM. Plans and Tables of Random Permutations. In: Exper imenta l De signs,
New York , NY: John Wiley and Sons; 1957;145:577-582.
National Research Council. Guide for the Care and Use of Laboratory Anima ls, Committee for
the Update of the Guide for the Care and Use of Laboratory Anima ls, Institute for Laboratory
Animal Research , Division on Earth and Life Sciences; The National Academies Press:
Washington , DC , 2011.
Office of Laboratory Animal Welfare. Publi c Health Services Policy on Humane Care and Use
of Laboratory Animals. Bethesda , MD: National Institutes of Health. March 2015.
SAS® Proprietary Software, Version 9.4; SAS Institute , Inc.: Cary, NC , 2002-2014 Spence S,
Soper K, Hoe C-M, Coleman J. The heart rate-corrected QT interva l of conscious Beagle dogs: a
formula based on analysis of covariance. Toxicol Sci . 1998;45(2):247-258.
Spence S, Soper K, Hoe C-M, Coleman J. The heart rate-corrected QT interval of conscious
Beagle dogs: a formula based on ana lysis of covar iance . Toxicol Sci. 1998;45(2):24 7-258 .
Van de Water A, Verheyen J, Xhonneux R, Reneman RS. An improved method to correct the
QT interva l of the electrocard iogram for changes in heart rate. J Pharma col Met.
1989;22(3):207-217.

AMENDMENT
APPROVAL

SPONSOR APPROVAL
The signature below indicates that the Sponsor Representative approves the study protocol
amendment.
rropr ietary Info froprietary Info

ATTACHMENT A
Shipment of Samples and Study Reco rds
Day/
Week / Proposed Conditions for
Matri x• Purpose Aliquot Shipment Date Shipment Recipie nt/Address
Disposition of On b lue ice

To be
Test Article unused neat test - packs
doc umented
article
Disposition of
Interaction unused neat To be Ambient
Article interaction
- documented temperature
article
Shipment of
specimens for To be Frozen, on dry
Plasma
Bioanalytical
- documented !Ce
Ana lysis
- - not applicable.
• Shipments perfor med via FedEx.

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ORDER FOR SUPPLIES OR SERVICES I PAGE OF PAGES

IMPORTANT : Ma rk al l packages and pa pers w ith con tr ac t and/or order numbers. I 1 I 7

c. CITY I d. STATE I e. Z IP CODE

QUANTI TY UNIT QUANT ITY

a. NAM E $1 , 256 , 044 . 00

Obtained via FOIA by White Coat Waste Project

Task Or de r Amou nt : $1 , 256 , 044

FY20 , Period o f Performance 09/14 /202 0 to

Overt im e (pr emi um) pay for ju nior a nd

1 FY20 . Task Order No . 75N95020F00002 . Period 1, 2 5 6 , 044 . 00

Obtained via FOIA by White Coat Waste Project

TASK ORDER (TO)

Contractor: SRI International T.0.Titlef''"'""'""

T.O. Type : Cost Reimbursement (Completion)

PART I. INITIATOR'S REQUEST

A. Period of Performance: 12 months from effective date of award.

Obtained via FOIA by White Coat Waste Project

be revised multiple times before it is acceptable to the NIDA.

Propr ietary Info

Obtained via FOIA by White Coat Waste Project

Obtained via FOIA by White Coat Waste Project

Obtained via FOIA by White Coat Waste Project

TASK ORDER PROPOSAL RESPONSE

Contract No: HHSN271201800019I T.O Order No: 75N95020F00002 Modification No: 1

T.O. Originator: NIDA DPMCDAr~ e-da-cte_d-by-agr

Statement of Work Task Area{s}: 1 Date Prepared: July 17, 2020

PART II. SRI INTERNATIONAL'S RESPONSE TO TASK ORDER REQUEST FOR

A. Estimated Cost and Effort:

For the Government

Obtained via FOIA by White Coat Waste Project

IMPORTANT : Ma rk al l packages and pa pers w ith con tr ac t and/or order numbers. I 1 I 8

c. CITY I d. STATE I e. Z IP CODE

QUANTI TY UNIT QUANT ITY

a. NAM E $1 , ll3 , 092 . 00

AUTHOR IZED FOR LOCA L REPRODUCTION

Task Or de r Amou nt : $1 , 11 3 , 092

FY20 , Period o f Performance : 03/25 / 2020 to

Overt im e (pr emium) pay for ju nior a nd

1 FY20 . Task Order No . 75N95020F0000 1 . Per i od 1, 113 , 092 . 00

TOTA L CARR IED FORWA RD TO 1ST PAGE (ITEM 17(H)) $1 ,113,092.00

Obtained via FOIA by White Coat Waste Project

TASK ORDER (TO)

Contractor: SRI International T.O. Title: Interaction Safety Studies in Rats

Contract No: HHSN271201800019I T.O. No.: 75N95020F00001

T .O . O ngIna . NIDA DTMC

T.O. Type : Cost reimbursement (Completion)

PART I. INITIATOR'S REQUEST

A. Period of Performance: 12 Months from Award Date

1. Activity Description: Cocaine Interaction Study in Rats (Activity A)

Obtained via FOIA by White Coat Waste Project

1. Activity Description: Cardiovascular Safety Interaction Study in Dogs (Act ivity B)

Obtained via FOIA by White Coat Waste Project

Obtained via FOIA by White Coat Waste Project

Obtained via FOIA by White Coat Waste Project

TASK ORDER PROPOSAL RESPONSE