Clinical trial NCT02868229
Conditions: Anemia
Sponsor: Novo Nordisk A/S
Start date: 2016-09-12; Completion date: 2018-12-11
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled trial designed to evaluate the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of COR-001 or placebo

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: COR-001 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02868229 
Sponsor trial ID: 
NN6018-4791 
Official title of study: 
A PKDVH 1/2 RDQGRPLVHG, DRXEOH-EOLQG, PODFHER-FRQWUROOHG, 
CRKRUW DRVH-HVFDODWLRQ SWXG\ LQ HHPRGLDO\VLV PDWLHQWV WR 
AVVHVV WKH6DIHW\PKDUPDFRNLQHWLFV, DQGPKDUPDFRG\QDPLFV 
RI MXOWLSOH IV 'RVHVRICOR-001 
Document date: 
20 November 2017 


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

A PHASE 1/2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
COHORT DOSE-ESCALATION STUDY IN HEMODIALYSIS PATIENTS TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS
OF MULTIPLE IV DOSES OF COR-001 
DRUG NAME:
&25KXPDQPRQRFORQDODQWLERG\WR,/
PROTOCOL NUMBER:
&25
$PHQGPHQW
PHASE:


TRIAL SPONSOR:
&RUYLGLD7KHUDSHXWLFV
*DWHKRXVH'ULYH
:DOWKDP0$

MEDICAL MONITOR:

PROTOCOL DATE:
AMENDMENT DATE:
2ULJLQDO$SULO
$PHQGPHQW0D\
$PHQGPHQW6HSWHPEHU
$PHQGPHQW1RYHPEHU

Confidentiality Statement
This protocol is the property of Corvidia Therapeutics. It is a confidential communication. Acceptance implies an 
agreement not to disclose information contained herein that is not otherwise publicly available, with the exception that 
it may be disclosed to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the purpose of 
obtaining approval to conduct the study. The IRB/IEC is requested and expected to maintain confidentiality. This 
document may not be used or published without the consent of Corvidia Therapeutics.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

INVESTIGATOR’S AGREEMENT
,KDYHUHDGWKHDWWDFKHGSURWRFROHQWLWOHG³$3KDVHUDQGRPL]HGGRXEOHEOLQG
SODFHERFRQWUROOHGFRKRUWGRVHHVFDODWLRQVWXG\LQKHPRGLDO\VLVSDWLHQWVWRDVVHVVWKHVDIHW\
SKDUPDFRNLQHWLFVDQGSKDUPDFRG\QDPLFVRIPXOWLSOH,9GRVHVRI&25´DQGDJUHHWR
DELGHE\DOOSURYLVLRQVVHWIRUWKWKHUHLQ
,DJUHHWRFRPSO\ZLWKWKH,QWHUQDWLRQDO&RQIHUHQFHRQ+DUPRQLVDWLRQ,&+7ULSDUWLWH
*XLGHOLQHRQ*RRG&OLQLFDO3UDFWLFH*&3DQGDSSOLFDEOH)RRGDQG'UXJ$GPLQLVWUDWLRQ
)'$UHJXODWLRQVJXLGHOLQHVVHWIRUWKLQ&)53DUWVDQGDQGDOOORFDOO\
DSSOLFDEOHODZV
,DJUHHWRHQVXUHWKDWWKHFRQILGHQWLDOLQIRUPDWLRQFRQWDLQHGLQWKLVGRFXPHQWZLOOQRWEH
XVHGIRUDQ\SXUSRVHRWKHUWKDQWKHHYDOXDWLRQRUFRQGXFWRIWKHFOLQLFDOLQYHVWLJDWLRQZLWKRXW
WKHSULRUZULWWHQFRQVHQWRI&RUYLGLD7KHUDSHXWLFV





6LJQDWXUHRI3ULQFLSDO,QYHVWLJDWRU





1DPHRI3ULQFLSDO,QYHVWLJDWRU3ULQW

'DWH''0RQWK<<<<




&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Amendment 1 Summary of Changes
Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
6\QRSVLV
6HFWLRQ
6HFWLRQ
6HFWLRQ
6HFWLRQ
$GGLWLRQRIWH[W
1$
³,QDGGLWLRQ
SKDUPDFRNLQHWLF
DQG
SKDUPDFRG\QDPLF
UHVXOWVZLOOEH
UHYLHZHGWRDVVHVV
WKHDSSURSULDWHQHVV
RIWKHQH[WSODQQHG
GRVHDQGWRJXLGH
UHYLVLRQRIWKHQH[W
GRVHWREH
HYDOXDWHGLI
QHFHVVDU\´
8QGHUVFRUHWKDW
SULRUWRGRVH
HVFDODWLRQSODQQHG
GRVHVZLOOEHUH
HYDOXDWHGEDVHGRQ
HPHUJLQJ
SKDUPDFRNLQHWLF
DQG
SKDUPDFRG\QDPLF
GDWD
6\QRSVLV
6HFWLRQ
,QFOXVLRQ&ULWHULRQ

+HPRJORELQUDQJH
UHYLVHG

'XULQJWKHZHHNV
SULRUWR
UDQGRPL]DWLRQWKH
PHDQRIFRQVHFXWLYH
KHPRJORELQVEHWZHHQ
tDQGJG/
ZLWKWKHGLIIHUHQFH
EHWZHHQWKHILUVWDQG
ODVWPHDVXUHPHQWV
EHLQJJG/

'XULQJWKHZHHNV
SULRUWR
UDQGRPL]DWLRQWKH
PHDQRI
FRQVHFXWLYH
KHPRJORELQV
EHWZHHQtDQG
JG/ZLWKWKH
GLIIHUHQFHEHWZHHQ
WKHILUVWDQGODVW
PHDVXUHPHQWV
EHLQJJG/
%HWWHUDOLJQPHQW
ZLWK(6$
SUHVFULELQJ
LQIRUPDWLRQ
6\QRSVLV
6HFWLRQ
6HFWLRQ
6HFWLRQ
$SSHQGL[
'RVLQJVFKHGXOH
UHYLVHGIURPHYHU\
GD\VWRHYHU\
GD\V
&RUUHVSRQGLQJ
FKDQJHVWRDOOWDEOHV
DQGILJXUHV
3ODQQHGGRVLQJ
UHJLPHQVPJ4
GD\VPJ4GD\V
PJ4GD\VDQG
PJ4GD\V

3ODQQHGGRVLQJ
UHJLPHQVPJ
4GD\VPJ
4GD\VPJ
4GD\VDQG
PJ4GD\V

$OLJQ&25
GRVLQJIUHTXHQF\
ZLWKSULPDWH
WR[LFRORJ\VWXG\
GRVLQJIUHTXHQF\
6HFWLRQ
'/7WKUHVKROG
UDWLRQDOL]DWLRQ
1$
'RVH/LPLWLQJ
7R[LFLW\FULWHULD
DQGUXOHVIRU07'
ZLOOEHSUHGHILQHG
%HFDXVHRIWKHKLJK
EDFNJURXQG
IUHTXHQF\RI*UDGH
DQGDGYHUVH
HYHQWVLQ
KHPRGLDO\VLV
SDWLHQWVQRW
GLVVLPLODUIURP
FDQFHUSRSXODWLRQV
&ODULILFDWLRQDQG
UDWLRQDOL]DWLRQRI
'/7WKUHVKROGV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

WKH'/7WKUHVKROG
ZLOOEHGHILQHG
XVLQJDWKUHVKROGRI
t*UDGHHYHQWV 
6HFWLRQ
$GGLWLRQRIGRVH
HVFDODWLRQUXOH
1$
,QDGGLWLRQLIRI
&25WUHDWHG
SDWLHQWLQDFRKRUW
H[SHULHQFHVD*UDGH
RU'/7WKH
GRVHZLOOQRWEH
HVFDODWHG 
$YRLGVGRVH
HVFDODWLRQLID
VLQJOH*UDGHRU
'/7ZDVREVHUYHG
6HFWLRQ
6WRRORFFXOWEORRG
WHVWUHYLVLRQ
6WRROFDUGV
6WRROWHVWV
6WRROVDPSOHV
&HQWUDOODEVWRRO
WHVWLQJGRHVQRWXVH
FDUGV
6HFWLRQ
5HYLVLRQRIZHHNO\
VWXG\DFWLYLW\
GHVFULSWRUV
6WXG\DFWLYLWLHV
GHVFULEHGEDVHGRQ
ZHHNO\GRVLQJ
6WXG\DFWLYLWLHV
GHVFULEHGEDVHGRQ
HYHU\WZRZHHN
GRVLQJ
8SGDWHGVWXG\
DFWLYLW\WLPLQJWR
DOLJQZLWKHYHU\
WZRZHHNGRVLQJ
DQGDGGHG
DGGLWLRQDO3.3'
WLPHSRLQWV
6HFWLRQ
8SGDWHRIGUXJ
UHFRQVWLWXWLRQDQG
DGPLQLVWUDWLRQ
LQVWUXFWLRQVWDEOHV
DQGVFKHPDWLFV
1$
5HYLVHGWH[WWDEOHV
DQGVFKHPDWLFV
3URYLGHXSGDWHG
LQVWUXFWLRQVIRU
&25DQG
DVVRFLDWHG
DGPLQLVWUDWLRQ
PDWHULDOVKDQGOLQJ
EDVHGRQUHYLVHG
GRVLQJVFKHGXOH
6FKHGXOHRI(YHQWV
5HYLVHG3.DQG3'
VDPSOLQJ
3.3'VFKHGXOH
DSSURSULDWHWRZHHNO\
GRVLQJ
3.3'VFKHGXOH
DSSURSULDWHWRHYHU\
RWKHUZHHNGRVLQJ

$OLJQ3.3'
DVVHVVPHQWVZLWK
UHYLVHGGRVLQJ
VFKHGXOHDQGDGG
DGGLWLRQDO3.3'
WLPHSRLQWV
$VVHVVSRWHQWLDOIRU
GLDO\VLVFOHDUDQFH
RI&25
6FKHGXOHRI(YHQWV
$'$VDPSOLQJ
GXULQJ7UHDWPHQW
3HULRG
:HHNO\
(YHU\ZHHNVSULRU
WRGRVLQJ
$'$VDPSOLQJ
DGMXVWHGWRPDWFK
UHYLVHGGRVLQJ
VFKHGXOH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

6FKHGXOHRI(YHQWV
$GGLWLRQRI
IRRWQRWH
1$
9LVLWZLQGRZPD\
EHH[WHQGHGWR
GD\VRQO\LQ
LQVWDQFHVZKHQWKH
VWXG\GUXJZDV
PLVVHGRQWKH
WDUJHWHGYLVLWGD\
DQGDOVRFRXOGQRW
EHJLYHQGXULQJWKH
GLDO\VLVYLVLWDIWHU
WKHPLVVHGGRVH
3URSRUWLRQDO
LQFUHDVHLQYLVLW
ZLQGRZIRUGUXJ
GRVLQJLHIURP
GD\ZLQGRZIRU
TGD\GRVLQJWR
GD\ZLQGRZIRU
TGGRVLQJ
6\QRSVLV
6HFWLRQ
&RUUHFWLRQRI(5,
IRUPXOD
0XOWLSOLHURILQ
WKHGHQRPLQDWRU
UHVXOWH[SUHVVHGLQ
PFJNJSHUG/
0XOWLSOLHURILQ
WKHQXPHUDWRU
UHVXOWH[SUHVVHGLQ
XQLWVNJSHUG/
&RUUHFWHGHUURULQ
FRQYHUVLRQIRU
GDUEHSRHWLQDQG
PHWKR[\
SRO\HWK\OHQH
JO\FROHSRHWLQEHWD
WRHSRHWLQ
HTXLYDOHQWVIRU
FDOFXODWLRQRI(5,
6FKHGXOHRI(YHQWV
5HYLVHGWLPLQJRI
FDUGLDFPDUNHUV
SUR17%13DQG
WURSRQLQDWWHUPLQXV
RIWUHDWPHQWSHULRG
:HHNV
:HHN'D\
:HHN'D\
:HHN
0DLQWDLQWLPLQJRI
WKHVHPDUNHUVZLWK
WKHODVWYLVLWVRI
WKH7UHDWPHQW
3HULRG'D\
'D\DQG:HHN

7DEOHRI&RQWHQWV
8SGDWHG
1$
1$
8SGDWHGWRUHIOHFW
FKDQJHVOLVWHG
DERYH
7LWOHSDJHIRRWHUV
W\SRJUDSKLFDODQG
IRUPDWWLQJHUURUV
8SGDWHRISURWRFRO
GDWDDQGYHUVLRQ
QXPEHU
$SSHQGL[(
2ULJLQDO
$SULO
$PHQGPHQW
0D\
'RFXPHQWYHUVLRQ
PDQDJHPHQW
&RUUHFWLRQRI
W\SRJUDSKLFDODQG
IRUPDWWLQJHUURUV
$GGLWLRQRIPLVVLQJ
)$&,7)SDJH



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Amendment 2 Summary of Changes 
Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
6\QRSVLV
1XPEHURIVWXG\
VLWHVLQFUHDVHG
$SSUR[LPDWHO\
$SSUR[LPDWHO\
,QLWLDOVFUHHQLQJ
DFWLYLWLHV
VXJJHVWHGQHHG
IRUDGGLWLRQDO
VLWHVWRPHHW
HQUROOPHQWJRDOV
6\QRSVLV
6HFWLRQ

5HPRYDORIWRWDO
,/IURPWKH
SULPDU\3'
HQGSRLQW
³&KDQJHIURP
EDVHOLQHPHDQRI
6FUHHQLQJDQG'D\
LQWKHIUHHDQGWRWDO
,/WR:HHN
EHWZHHQWUHDWPHQW
JURXSV´
³&KDQJHIURP
EDVHOLQHPHDQRI
6FUHHQLQJDQG
'D\LQWKHIUHH
,/WR:HHN
EHWZHHQWUHDWPHQW
JURXSV´
7HFKQLFDO
OLPLWDWLRQVRI
DVVD\
6\QRSVLV
6HFWLRQ

5HYLVHGGHILQLWLRQ
RIWKHVWDUWRIWKH
,QLWLDODQG)XOO
6FUHHQLQJ3HULRGV
'HILQHGE\WKH
VLJQLQJRIWKH6KRUW
DQG/RQJ,&)V
UHVSHFWLYHO\
'HILQHGE\WKH
ILUVWVWXG\
SURFHGXUHLQWKH
,QLWLDO6FUHHQLQJ
3HULRGDQGWKH
:HHNGDWH
UHVSHFWLYHO\
7RDOORZ
DGGLWLRQDOWLPH
IRUWKHFRQVHQWLQJ
SURFHVV
6\QRSVLV
6HFWLRQ
,QFOXVLRQ
&ULWHULRQ
$JHUDQJHUHYLVHG
$JHWKURXJK
\HDUVLQFOXVLYHDW
WKHWLPHRIVLJQLQJ
RIWKH,&)
$JH!\HDUVDW
WKHWLPHRIVLJQLQJ
RIWKH,&)

)DFLOLWDWH
HQUROOPHQWRID
PRUH
UHSUHVHQWDWLYH
SRSXODWLRQRI
GLDO\VLVSDWLHQWV
E\DOORZLQJROGHU
SDWLHQWVZKR
RWKHUZLVHPHHW
HQWU\FULWHULD
LQFOXGLQJ
LQYHVWLJDWRUV
HYDOXDWLRQRI
LQGLYLGXDOULVN
([FOXVLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
6\QRSVLV
6HFWLRQ
,QFOXVLRQ
&ULWHULRQ
5HGXFWLRQRI,/
WKUHVKROGIRUHQWU\
LQWRWKHVWXG\
³7ZRVHUXP,/
OHYHOVtSJP/
PHDVXUHGDWOHDVW
ZHHNDSDUWGXULQJ
WKH6FUHHQLQJ
3HULRG´

³7ZRVHUXP,/
OHYHOVtSJP/
PHDVXUHGDWOHDVW
ZHHNDSDUW
GXULQJWKH
6FUHHQLQJ3HULRG´

,/!SJP/
RQFXUUHQW
SODWIRUPLVHTXDO
WR,/!
SJP/LQ
KLVWRULFDOFRKRUWV
XVHGWRSODQWKH
VWXG\
6\QRSVLV
6HFWLRQ
,QFOXVLRQ
&ULWHULRQ
5HPRYHG
UHTXLUHPHQWWKDW
SDWLHQWPXVWEH
DEOHWRUHDG
³7KHSDWLHQWLVDEOH
WRUHDGDQGJLYH
ZULWWHQLQIRUPHG
FRQVHQWDQGKDV
VLJQHGDFRQVHQW
IRUPDSSURYHGE\
WKH,QYHVWLJDWRU
V
,QVWLWXWLRQDO5HYLHZ
%RDUG,5%RU
,QGHSHQGHQW(WKLFV
&RPPLWWHH,(&´

³7KHSDWLHQWLV
DEOHWRJLYH
ZULWWHQLQIRUPHG
FRQVHQWDQGKDV
VLJQHGDFRQVHQW
IRUPDSSURYHGE\
WKH,QYHVWLJDWRU
V
,QVWLWXWLRQDO
5HYLHZ%RDUG
,5%RU
,QGHSHQGHQW
(WKLFV&RPPLWWHH
,(&´
7RDOORZSDWLHQWV
XQDEOHWRUHDGWR
SDUWLFLSDWHLQWKH
VWXG\
6\QRSVLV
6HFWLRQ
,QFOXVLRQ
&ULWHULRQ
$OORZDQFHRIXS
WRRQHPLVVHG
(SRJHQGRVHLQ
:HHNDQG
UHPRYDORIWKLV
UHTXLUHPHQWIURP
:HHNVDQG
³(SRHWLQDOIDPXVW
QRWKDYHKDGDQ\
GRVHVPLVVHGRUKHOG
GXULQJ:HHN
SULRUWR
5DQGRPL]DWLRQ´
³(SRHWLQDOID
PXVWQRWKDYHKDG
PRUHWKDQRQH
GRVHPLVVHGRU
KHOGGXULQJ
:HHNZHHNV
SULRUWR
5DQGRPL]DWLRQ´
%HFDXVHLWLVWRWDO
ZHHNO\GRVHWKDW
LVLQWHQGHGWREH
VWDEOHPLVVHGRU
KHOGGRVHVWKDWGR
QRWUHVXOWLQD
FKDQJHLQWRWDO
ZHHNO\GRVHSHU
,&DUH
DOORZDEOH
)DFLOLWDWH
HQUROOPHQW
ZLWKRXW
FRPSURPLVLQJ
RULJLQDOLQWHQWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
6\QRSVLV
6HFWLRQ
,QFOXVLRQ
&ULWHULRQ
&ODULILHGWKDW
³GRVH´UHIHUUHGWR
WRWDOZHHNO\GRVH
&ODULILHGFULWHULRQ
IRUSDWLHQWV
UHFHLYLQJDGRVH
RQERWK:HHN
DQG:HHN
“For ESAs dosed
less often than 
weekly: 
$Q\GRVHJLYHQ
GXULQJ)XOO
6FUHHQLQJ:HHN
DQG:HHNLV
XQFKDQJHGIURPWKH
LPPHGLDWHO\
SUHFHGLQJGRVH´

“For ESAs dosed
less often than 
weekly: 
$Q\GRVHJLYHQ
GXULQJ)XOO
6FUHHQLQJ
:HHNDQG
:HHNLV
XQFKDQJHGIURP
WKHLPPHGLDWHO\
SUHFHGLQJGRVH´
1RWH,IDGRVH
ZDVJLYHQRQERWK
:HHNDQG
:HHNWKHQ
ERWKGRVHVDUHWKH
VDPH7KHVH
GRVHVPD\EH
GLIIHUHQWWKDQ
HDUOLHUGRVHV´
&ODULILFDWLRQ
6\QRSVLV
6HFWLRQ
,QFOXVLRQ
&ULWHULRQ
&KDQJHRI³LH´
WR³HJ´DQG
DGGLWLRQRI
LQVWUXFWLRQIRUOHVV
IUHTXHQWWKDQ
ZHHNO\GRVLQJ
³+DVEHHQUHFHLYLQJ
LQWUDYHQRXV,9RU
GLDO\VDWHLURQ
UHJXODUO\DQG
FRQWLQXRXVO\LH
ZLWKHDFKGLDO\VLVRU
HDFKZHHNGXULQJ
WKHZHHNVSULRUWR
UDQGRPL]DWLRQ´

³UHJLPHQKDV
EHHQVWDEOHVDPH
HOHPHQWDOLURQGRVH
VDPHIUHTXHQF\DQG
VDPH
LURQSURGXFWZLWK
QRPRUHWKDQ
PLVVHGRUKHOGGRVHV
LIGRVHGZLWKHDFK
GLDO\VLV
DQGQRPLVVHGRU
KHOGGRVHVLIGRVHG
ZHHNO\GXULQJWKLV
WLPHIUDPH´
³+DVEHHQ
UHFHLYLQJ
LQWUDYHQRXV,9RU
GLDO\VDWHLURQ
UHJXODUO\DQG
FRQWLQXRXVO\HJ
ZLWKHDFKGLDO\VLV
RUHDFKZHHN
GXULQJWKHZHHNV
SULRUWR
UDQGRPL]DWLRQ´
³UHJLPHQKDV
EHHQVWDEOHVDPH
HOHPHQWDOLURQ
GRVHVDPH
IUHTXHQF\DQG
VDPH
LURQSURGXFWZLWK
QRPRUHWKDQ
PLVVHGRUKHOG
GRVHVLIGRVHG
ZLWKHDFKGLDO\VLV
DQGQRPLVVHGRU
KHOGGRVHVLI
GRVHGZHHNO\RU
OHVVIUHTXHQWO\
GXULQJWKLVWLPH
IUDPH´
&RUUHFWLRQRI
W\SRDQG
RPLVVLRQRI
LQVWUXFWLRQIRU
SDWLHQWVUHFHLYLQJ
,9LURQOHVVRIWHQ
WKDQZHHNO\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
6\QRSVLV
6HFWLRQ
,QFOXVLRQ
&ULWHULRQ
&ODULILFDWLRQWKDW
%DQGIRODWH
DERYHWKH
UHIHUHQFHUDQJH
DUHDOORZDEOH
³6HUXP9LWDPLQ
%DQGIRODWH
OHYHOVZLWKLQWKH
ODERUDWRU\QRUPDO
UDQJHGXULQJ)XOO
6FUHHQLQJ´
³6HUXP9LWDPLQ
%DQGIRODWH
OHYHOVDERYHWKH
ODERUDWRU\ORZHU
QRUPDOUDQJH
GXULQJ)XOO
6FUHHQLQJ´
&ODULILFDWLRQ
6\QRSVLV
6HFWLRQ
([FOXVLRQ
&ULWHULRQ
5HPRYDORI
H[FOXVLRQUHODWHG
WR33'LQIDYRURI
4XDQWLIHURQ7%
WHVWLQJRQO\
³3RVLWLYH
WXEHUFXORVLVEORRG
WHVWDW6FUHHQLQJRU
KLVWRU\RIDSRVLWLYH
33'RUSRVLWLYH
WXEHUFXORVLVWHVW´

³3RVLWLYH
WXEHUFXORVLVEORRG
WHVWDW6FUHHQLQJ´

&ODULILFDWLRQWKDW
WKHEORRG7%WHVW
DW6FUHHQLQJLVWR
EHXVHGWR
GHWHUPLQH7%
VWDWXVDVWKLVLV
PRUHWKHPRUH
VHQVLWLYHWHVW
6\QRSVLV
6HFWLRQ
([FOXVLRQ
&ULWHULRQ
5HYLVHGWR
PRQWKV
³0\RFDUGLDO
LQIDUFWLRQGXULQJWKH
PRQWKVSULRUWR
)XOO6FUHHQLQJRU
GXULQJ6FUHHQLQJ´

³0\RFDUGLDO
LQIDUFWLRQGXULQJ
WKHPRQWKVSULRU
WR)XOO6FUHHQLQJ
RUGXULQJ
6FUHHQLQJ´

$GHTXDWHFDUGLDF
UHFRYHU\
H[SHFWHGZLWKLQ
PRQWKV
6HFWLRQ
5HYLVHPDWUL[IRU
3.VDPSOH
3ODVPD&25
6HUXP&25
&RUUHFWLRQRIDQ
HUURU
6HFWLRQ
$OLJQWKH$(DQG
'/7VHFWLRQVE\
UHPRYLQJWKH
³GHILQLWHO\´
FDWHJRU\IURPWKH
'/7GHILQLWLRQ
:LWKWKHH[FHSWLRQ
RI*UDGHQRQ
KHPDWRORJLFHYHQWV
*UDGHRUKLJKHU
&7&$(WR[LFLW\RI
DERYHHYHQWVKDYLQJ
DQDVVHVVHG
UHODWLRQVKLSWRWKH
6WXG\'UXJRI
³GHILQLWHO\´
³SUREDEO\´
³SRVVLEO\´RU
³XQOLNHO\´ZLOOEH
FRQVLGHUHG'/7V
*UDGHQRQ
KHPDWRORJLF
WR[LFLWLHVKDYLQJDQ
DVVHVVHG
UHODWLRQVKLSWRWKH
6WXG\'UXJRI
³GHILQLWHO\´
³SUREDEO\´RU
:LWKWKH
H[FHSWLRQRI
*UDGHQRQ
KHPDWRORJLF
HYHQWV*UDGH
RUKLJKHU
&7&$(WR[LFLW\
RIDERYHHYHQWV
KDYLQJDQ
DVVHVVHG
UHODWLRQVKLSWRWKH
6WXG\'UXJRI
³SUREDEO\´
³SRVVLEO\´RU
³XQOLNHO\´ZLOOEH
FRQVLGHUHG'/7V
*UDGHQRQ
KHPDWRORJLF
WR[LFLWLHVKDYLQJ
DQDVVHVVHG
UHODWLRQVKLSWRWKH
6WXG\'UXJRI
,PSURYH
FRQVLVWHQF\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
³SRVVLEO\´ZLOOEH
FRQVLGHUHG'/7V
³SUREDEO\´RU
³SRVVLEO\´ZLOOEH
FRQVLGHUHG'/7V
6HFWLRQ
&ODULILHGZKLFK
'/7HYHQWVDUH
FRQVLGHUHG³QRQ
KHPDWRORJLF´
1RQH
1RWH³QRQ
KHPDWRORJLF
HYHQWV´UHIHUWR
'/7FULWHULD
DQGDERYH

&ODULILFDWLRQ
6HFWLRQ
6FUHHQLQJ05,
DOORZHGGXULQJ
:HHNZLWKRXW
PRQLWRUDSSURYDO
6FKHGXOH05,
GXULQJ:HHNRU
:HHNZLWK
PRQLWRUDSSURYDO
6FKHGXOH05,
GXULQJ)XOO
6FUHHQLQJ
$FFRPPRGDWH
VLWHORJLVWLFV
6HFWLRQ
6FUHHQLQJ
SURFHGXUHV¶
PRGLILFDWLRQ
DGGHGIRUSDWLHQWV
EHLQJUHVFUHHQHG
1RQH
*HQRW\SHWHVWLQJ
GRHVQRWQHHGWR
EHUHSHDWHG
&DUGLDF05,7%
WHVWLQJDQGVWRRO
RFFXOWEORRG
WHVWLQJGRHVQRW
QHHGWREH
UHSHDWHGLI
SHUIRUPHGZLWKLQ
ZHHNVRIUH
VFUHHQLQJ
:HHN
,QLWLDO6FUHHQLQJ
PHGLFDOKLVWRU\
QRWUHTXLUHGWREH
UHSHDWHG
&RQILUPDWLRQRI
HOLJLELOLW\UHPDLQV
DSURFHGXUH
GXULQJ)XOO
6FUHHQLQJ
6WUHDPOLQH
SURFHGXUHVIRUUH
VFUHHQHGSDWLHQWV
6HFWLRQ
$GGLWLRQRIDQHZ
DQDO\VLV
SRSXODWLRQ
1RQH
MTD analysis 
Population7KH
07'DQDO\VLV
SRSXODWLRQZLOOEH
GHILQHGDVD
VXEVHWRIVDIHW\
DQDO\VLV
SRSXODWLRQE\
H[FOXGLQJVXEMHFWV
UHSODFHGGXHWRD
QRQVDIHW\UHDVRQ
$GGUHVVHV
SRVVLEOHVLWXDWLRQ
WKDWDIIHFWVWKDW
GHQRPLQDWRUIRU
07'
GHWHUPLQDWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
7UHDWPHQW
FODVVLILFDWLRQZLOO
EHEDVHGRQWKH
DFWXDOWUHDWPHQW
UHFHLYHG7KLV
SRSXODWLRQZLOOEH
XVHGIRU07'DQG
'/7DQDO\VHV

6HFWLRQ
$GGFRQVWUDLQWV
RQLQIRUPDWLRQ
UHYHDOHGDWWKH
LQWHULPDQDO\VLV
7KH6SRQVRUZLOO
EHFRPHXQEOLQGHG
GXULQJWKHLQWHULP
DQDO\VLVEXWDOO
RWKHUEOLQGHGSDUWLHV
ZLOOUHPDLQEOLQGHG
7KH6SRQVRU
SHUVRQQHOZLOO
RQO\UHFHLYHWKH
WUHDWPHQWJURXS
OHYHOLQIRUPDWLRQ
DQGKDYHQR
DFFHVVWR
VXEMHFWOHYHO
WUHDWPHQW
LQIRUPDWLRQ
*UHDWHU
VSHFLILFLW\
6FKHGXOHRI(YHQWV
$GGLWLRQRI
KV&53WRWKH
,QLWLDO6FUHHQLQJ
3URFHGXUHV
1RQH
KV&53DGGHG
*DWKHUDGGLWLRQDO
GDWDLQFOXGLQJLQ
WKRVHIDLOLQJ
,QLWLDO6FUHHQLQJ
WRDVVHVV
FRUUHODWLRQ
EHWZHHQKV&53
DQG,/YDOXHV
6FKHGXOHRI(YHQWV
6\QRSVLV
6HFWLRQ
$OORZDQFHRI
UDQGRPL]DWLRQRQ
'D\
5DQGRPL]DWLRQWREH
SHUIRUPHGRQ'D\
RQO\
)RRWQRWH
³5DQGRPL]DWLRQ
PD\EH
SHUIRUPHGRQ
'D\LIQHHGHG
ZLWKDSSURYDORI
WKH0HGLFDO
0RQLWRU
$GPLQLVWUDWLRQRI
WKHILUVWGRVHRI
6WXG\'UXJZLOO
FRQWLQXHWRGHILQH
6WXG\'D\´
$FFRPPRGDWH
VLWHORJLVWLFDO
QHHGV
$SSHQGL['
$GGLWLRQRI
FDOFLXPDQG
SKRVSKDWHWRWKH
FKHPLVWU\
ODERUDWRU\SDQHO
1RQH
&DOFLXPDQG
SKRVSKDWHDGGHG
&RUUHFWLRQRIDQ
LQDGYHUWHQW
RPLVVLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Protocol Section 
Description of 
Change
Old
New
Rationale for 
Change
$SSHQGL['
5HYLVLRQRI
6SHFLDO5%&
LQGLFHV
UHGFHOOVL]HIDFWRU
DQGORZKHPRJORELQ
GHQVLW\SDUDPHWHUV
SUHVHQW
UHGFHOOVL]HIDFWRU
DQGORZ
KHPRJORELQ
GHQVLW\SDUDPHWHUV
UHPRYHG
&KDQJHWRD
GLIIHUHQW
ODERUDWRU\
DQDO\]HUSODWIRUP
ZKLFKGRHVQRW
PHDVXUHWKHVH
0XOWLSOH
&RUUHFWLRQRI
W\SRJUDSKLFDO
HUURUVXSGDWLQJRI
SURWRFROGDWHV
IRUPDWWLQJDQG
WDEOHRIFRQWHQWV


,PSURYH
UHDGDELOLW\



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Amendment 3 Summary of Changes 
3URWRFRO6HFWLRQ
Description of 
Change 
Old
New 
Rationale for 
Change 
6\QRSVLV6HFWLRQ
([FOXVLRQ
&ULWHULRQ
³1RWH8VHRIRWLF
RSKWKDOPLFLQKDOHG
DQGWRSLFDO
FRUWLFRVWHURLGVRU
ORFDOFRUWLFRVWHURLG
LQMHFWLRQVDUHQRW
H[FOXVLRQDU\´
³1RWH8VHRI
RWLFRSKWKDOPLF
LQKDOHGDQG
WRSLFDO
FRUWLFRVWHURLGVRU
ORFDO
FRUWLFRVWHURLG
LQMHFWLRQVDUHQRW
H[FOXVLRQDU\2UDO
SUHGQLVRQHXSWR
PJSHUGD\LVRU
HTXLYDOHQWLV
SHUPLWWHG´
7RFODULI\
ZRUNLQJ
GHILQLWLRQRI
DOORZDEOHXVHRI
JOXFRFRUWLFRLGV
6\QRSVLV6HFWLRQ
([FOXVLRQ
&ULWHULRQ
³,QDELOLW\WR
XQGHUJRDQRQ
FRQWUDVWPDJQHWLF
UHVRQDQFHLPDJLQJ
05,VFDQHJ
ZHLJKWRYHUWKH
OLPLWVIRU05,
PDFKLQH
FODXVWURSKRELDWKDW
FDQQRWEHPDQDJHG
FHUWDLQPHWDOOLF
LQGZHOOLQJIRUHLJQ
ERGLHV´
³,QDELOLW\WR
XQGHUJRDQRQ
FRQWUDVWPDJQHWLF
UHVRQDQFH
LPDJLQJ05,
VFDQHJZHLJKW
RYHUWKHOLPLWVIRU
05,PDFKLQH
FODXVWURSKRELD
WKDWFDQQRWEH
PDQDJHGFHUWDLQ
PHWDOOLF
LQGZHOOLQJIRUHLJQ
ERGLHV
5HTXLUHPHQWIRU
05,PD\
H[HPSWHGE\WKH
PHGLFDOPRQLWRU
GXHWRSUDFWLFDO
FRQVLGHUDWLRQV,Q
VXFKVLWXDWLRQV
SDWLHQWVPD\EH
HQUROOHGHYHQLI
WKH\DUHXQDEOHWR
XQGHUJR05,´
7RDOORZIRU
SUDFWLFDO
FRQVWUDLQWVZLWK
REWDLQLQJ05,VLQ
DOOSDWLHQWV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

6\QRSVLV6HFWLRQ
([FOXVLRQ
&ULWHULRQ
³$EVROXWH
QHXWURSKLOFRXQW
[/DW,QLWLDO
RU)XOO6FUHHQLQJ´

³$EVROXWH
QHXWURSKLO
FRXQW
[/DW,QLWLDO
DQG)XOO
6FUHHQLQJ´

7RDOORZIRU
HQUROOPHQWRI
SDWLHQWVZLWK
IOXFWXDWLRQVLQ
FRXQWVDWEDVHOLQH
6\QRSVLV6HFWLRQ
([FOXVLRQ
&ULWHULRQ
³3ODWHOHWFRXQW
[/DW
,QLWLDORU)XOO
6FUHHQLQJ´

³3ODWHOHWFRXQW
[/DW
,QLWLDODQG)XOO
6FUHHQLQJ´

7RDOORZIRU
HQUROOPHQWRI
SDWLHQWVZLWK
IOXFWXDWLRQVLQ
FRXQWVDWEDVHOLQH
6\QRSVLV6HFWLRQ
([FOXVLRQ
&ULWHULRQ
³L37+DW6FUHHQLQJ
!SJP/´
³L37+DW
6FUHHQLQJ!
SJP/´
7RLQFUHDVHFXW
RIIIRUSDWLHQWV
ZLWKRWKHUZLVH
JRRGHYLGHQFHRI
PDUURZIXQFWLRQ
EDVHGRQRWKHU
HOLJLELOLW\FULWHULD
6HFWLRQ$SSHQGL[$
IRRWQRWHV
'D\
UDQGRPL]DWLRQ
5DQGRPL]DWLRQPD\
EHSHUIRUPHGRQ
'D\ZLWK
PHGLFDOPRQLWRU
DSSURYDO
5DQGRPL]DWLRQ
PD\EHSHUIRUPHG
RQ'D\QR
PHGLFDOPRQLWRU
DSSURYDOQHHGHG
7RIDFLOLWDWHVLWH
ORJLVWLFV
6\QRSVLV6HFWLRQ
)UHH,/
3ULPDU\3'
HQGSRLQW
([SORUDWRU\3'
HQGSRLQW
7HFKQLFDO
OLPLWDWLRQVRI
DVVD\
$SSHQGL[$DQG$SSHQGL['
$GGLWLRQDOWLPH
SRLQWVIRUVHUXP
DOEXPLQDGGHG
SUHDOEXPLQ
UHPRYHGIURP
WKHVHVDPHWLPH
SRLQWV
:HHN'D\V

:HHN'D\V


7REHWWHUGHILQH
WKHWLPHFRXUVHRI
FKDQJHVLQ
DOEXPLQZLWKRXW
LQFUHDVLQJEORRG
YROXPHWDNHQ
IURPSDWLHQWV
$SSHQGL[$
6FUHHQLQJ3HULRG
ZLQGRZ

$OORZDQFHRIWKH
0HGLFDO0RQLWRU
WRDSSURYHDQ
LQFUHDVHLQWKH
6FUHHQLQJ3HULRG
ZLQGRZE\XSWR
GD\V
7RIDFLOLWDWHVLWH
ORJLVWLFVDQG
FHQWUDO05,
UHDGLQJV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

6\QRSVLVDQG6HFWLRQV
DQG
'HILQLWLRQRI
EDVHOLQHIRU
VHFRQGDU\
SKDUPDFRG\QDPLF
HQGSRLQWV
%DVHOLQHGHILQHGDV
WKHPHDQRI:HHN
DQG'D\IRU
76$7&+UDQG
KV&5SDQGDVPHDQ
RI6FUHHQLQJDQG
'D\IRU6$$DQG
DOEXPLQ
%DVHOLQHGHILQHG
DVWKHPHDQRI
6FUHHQLQJDQG
'D\IRU76$7
&+UKV&53
6$$DQGDOEXPLQ
0DNHXQLIRUPWKH
GHILQLWLRQRI
EDVHOLQHIRU
VHFRQGDU\
SKDUPDFRG\QDPLF
HQGSRLQWVODE
SDUDPHWHUV
6\QRSVLVDQG6HFWLRQV
DQG
3HUSURWRFRO
SRSXODWLRQ

3HUSURWRFRO
SRSXODWLRQDGGHG
7RDGGD
VHQVLWLYLW\
DQDO\VLV
6HFWLRQ
2EMHFWLYHV

$GGLWLRQRI
REMHFWLYHVUHODWHG
WRKDQGJULS
VWUHQJWKDQG
IDWLJXH
$OLJQPHQWRI
REMHFWLYHV
EHWZHHQV\QRSVLV
DQGSURWRFROERG\
6HFWLRQ
$GGLWLRQRI
UHODWHGQHVV
FDWHJRU\WR'/7
GHILQLWLRQ
³XQOLNHO\´
³SRVVLEO\´DQG
³SUREDEO\´
PHQWLRQHGDV
UHODWHGQHVV
FDWHJRULHV
³GHILQLWHO\´
UHODWHGDGGHGDVD
UHODWHGQHVV
FDWHJRU\
7RDOLJQ$(
UHODWHGQHVV
FDWHJRULHVZLWK
WKLVVHFWLRQ
6\QRSVLVDQG6HFWLRQ
$GGLWLRQRIDFWXDO
GRVHVXVHGIRU
FRPSOHWHGDQG
RQJRLQJFRKRUWV
3ODQQHGGRVHV
3ODQQHGGRVHVDQG
DFWXDOGRVHVIRU
&RKRUWV
7RXSGDWH
SURWRFRO
LQIRUPDWLRQEDVHG
RQDFWXDOFRKRUW
GRVHHVFDODWLRQ
6\QRSVLV(&DQG
6HFWLRQ



&ODULILFDWLRQWKDW
XSWRPJSHU
GD\RISUHGQLVRQH
LVDOORZDEOH
GXULQJWKHVWXG\
0XOWLSOH



&RUUHFWLRQRI
W\SRJUDSKLFDO
HUURUVPLQRU
LQFRQVLVWHQFLHV
DQGIRUPDWWLQJ
LVVXHV




&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

TABLE OF CONTENTS
,19(67,*$725¶6$*5((0(17 
&/,1,&$/678'<35272&2/$33529$/6,*1$785(3$*( 
7$%/(2)&217(176 
35272&2/6<1236,6 
/,672)$%%5(9,$7,216'(),1,7,216$1'7(506 
 
,1752'8&7,21 
 
%DFNJURXQG 
 
'HVFULSWLRQRI&25 
 
6XPPDU\RI5HOHYDQW1RQFOLQLFDO([SHULHQFHZLWK&25 
 
1RQ&OLQLFDO3KDUPDFRORJ\ 
 
3KDUPDFRNLQHWLFVLQDQLPDOV 
 
1RQ&OLQLFDO7R[LFRORJ\DQG6DIHW\ 
 
6XPPDU\RI5HOHYDQW&OLQLFDO([SHULHQFH 
 
3KDVH6WXG\RI&25LQ5KHXPDWRLG$UWKULWLV3DWLHQWV 
 
6XPPDU\RI6DIHW\IURP&OLQLFDO6WXGLHV'& 
 
678'<2%-(&7,9(6 
 
,19(67,*$7,21$/3/$1 
 
2YHUDOO6WXG\'HVLJQDQG3ODQ'HVFULSWLRQ 
 
3KDUPDFRNLQHWLFDQG3.3'0RGHOLQJ 
 
6DIHW\(QGSRLQWV 
 
3KDUPDFRG\QDPLF(QGSRLQWV 
 
6WXG\6FKHPDWLF 
 
%OLQGLQJDQG5DQGRPL]DWLRQ 
 
5DQGRPL]DWLRQ 
 
%OLQGLQJ 
 
8QEOLQGLQJ 
 
'XUDWLRQRIWKH6WXG\ 
 
'LVFXVVLRQRI6WXG\'HVLJQ,QFOXGLQJ&KRLFHRI&RQWURO$UP 
 
6WXG\3RSXODWLRQDQG&RQWURO$UP 
 
5DWLRQDOHIRU'RVLQJDQG/HQJWKRI6DIHW\(YDOXDWLRQ 
 
5DWLRQDOHIRUWKH3KDUPDFRG\QDPLF(QGSRLQWV 
 
5DWLRQDOHIRUWKH'RVH5HJLPHQV 
 
6DIHW\3ODQDQG0RQLWRULQJ 
 
%HQHILWDQG5LVN$VVHVVPHQW 
 
6(/(&7,212)678'<3238/$7,21$1'&5,7(5,$)25
:,7+'5$:$/ 
 
,QFOXVLRQ&ULWHULD 


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

 
([FOXVLRQ&ULWHULD 
 
&ULWHULDIRU'LVFRQWLQXDWLRQRI6WXG\'UXJ 
 
'RVH/LPLWLQJ7R[LFLWLHV0D[LPXP7ROHUDWHG'RVHDQG6WRSSLQJ5XOHV 
 
3DWLHQW5HSODFHPHQW 
 
6WXG\&RPSOHWLRQ 
 
(152//0(17$1'678'<352&('85(6 
 
3DWLHQW,GHQWLILFDWLRQ1XPEHUV 
 
6FUHHQLQJ9LVLW3URFHGXUHV8SWRZHHNV'D\VWR±,QLWLDO
6FUHHQLQJ 
 
6FUHHQLQJ9LVLW3URFHGXUHV'D\VWR±)XOO6FUHHQLQJ 
 
/DERUDWRU\5H7HVWLQJDQG5H6FUHHQLQJ 
 
7UHDWPHQW3HULRG6WXG\:HHNV 
 
:HHN'D\)LUVW'RVH 
 
:HHN'D\VDQG 
 
:HHN 
 
:HHN 
 
:HHN 
 
:HHN 
 
:HHN 
 
:HHN 
 
:HHN 
 
:HHN 
 
:HHN 
 
:HHN'D\ 
 
:HHN'D\ 
 
:HHN(7 
 
6DIHW\)ROORZ8S3HULRG3URFHGXUHV6WXG\:HHNV± 
 
:HHNVDQG 
 
:HHNVDQG(7 
 
([WHQGHG)ROORZ8S3URFHGXUHV6WXG\:HHN 
 
:HHN 
 
8QVFKHGXOHG9LVLW 
 
(DUO\7HUPLQDWLRQ9LVLW 
 
(DUO\:LWKGUDZDOIURPWKH6WXG\ 
 
'58*6833/,(6$1''26,1* 
 
'RVLQJDQG$GPLQLVWUDWLRQ 
 
6WRUDJH 
 
)RUPXODWLRQDQG3DFNDJLQJ 


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

 
'UXJ$FFRXQWDELOLW\DQG&RPSOLDQFH 
 
35,25$1'&21&20,7$170(',&$7,216$1'75($70(176 
 
3ULRU0HGLFDWLRQVDQG7UHDWPHQWV 
 
&RQFRPLWDQW0HGLFDWLRQVDQG7UHDWPHQWV 
 
0$1$*(0(172)63(&,),&$'9(56((9(176 
 
6HULRXV,QIHFWLRQV 
 
,QIXVLRQ5HODWHG5HDFWLRQV+\SHUVHQVLWLYLW\DQG$QDSK\OD[LV 
 
$'9(56((9(175(3257,1* 
 
$GYHUVH(YHQW'HILQLWLRQV 
 
6HULRXV$GYHUVH(YHQW'HILQLWLRQ 
 
$GYHUVH(YHQWVRI6SHFLDO,QWHUHVW 
 
$VVHVVPHQWRI&DXVDO5HODWLRQVKLS 
 
$VVHVVPHQWRI6HYHULW\ 
 
$GYHUVH(YHQW5HSRUWLQJ 
 
5HSRUWLQJRI6HULRXV$GYHUVH(YHQWVDQG$GYHUVH(YHQWVRI6SHFLDO
,QWHUHVW 
 
3UHJQDQF\5HSRUWLQJ 
 
678'<$66(660(176 
 
3KDUPDFRG\QDPLF$VVHVVPHQWV 
 
&DUGLDF0DJQHWLF5HVRQDQFH,PDJLQJIRU/90DVV,QGH[ 
 
+DQGJULS7HVW 
 
6DIHW\$VVHVVPHQWVRWKHUWKDQ$GYHUVH(YHQWV 
 
9LWDO6LJQV 
 
OHDG(&* 
 
3K\VLFDO([DPLQDWLRQ 
 
6WRRO2FFXOW%ORRG7HVWLQJ 
 
&OLQLFDO/DERUDWRU\7HVWLQJ 
 
67$7,67,&$/&216,'(5$7,216$1''$7$$1$/<6,6 
 
6DPSOH6L]H 
 
5DQGRPL]DWLRQ 
 
*HQHUDO6WDWLVWLFDO&RQVLGHUDWLRQVDQG'HILQLWLRQV 
 
*HQHUDO6WDWLVWLFDO0HWKRGV 
 
$QDO\VLV3RSXODWLRQV 
 
$QDO\VLV:LQGRZVDQG%DVHOLQH 
 
0LVVLQJ'DWD+DQGOLQJ 
 
6WDWLVWLFDO$QDO\VHV 
 
'HPRJUDSKLFDQG%DFNJURXQG&KDUDFWHULVWLFV 
 
6WXG\'UXJDQG&RQFRPLWDQW0HGLFDWLRQV 


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

 
(IILFDF\$QDO\VLV 
 
(IILFDF\9DULDEOHV 
 
6DIHW\$QDO\VLV 
 
$GYHUVH(YHQWV 
 
/DERUDWRU\7HVWV 
 
9LWDO6LJQV 
 
OHDG(&* 
 
3K\VLFDO([DPLQDWLRQ 
 
$QWLERGLHVWR&25 
 
3KDUPDFRNLQHWLF$QDO\VLVDQG3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF
$QDO\VLV 
 
3KDUPDFRNLQHWLF'DWD 
 
3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF$QDO\VLV 
 
,QWHULP$QDO\VHV 
 
678'<&200,77((6$1'&20081,&$7,216 
 
,19(67,*$725$1'$'0,1,675$7,9(5(48,5(0(176 
 
,QVWLWXWLRQDO5HYLHZ%RDUGRU,QGHSHQGHQW(WKLFV&RPPLWWHH 
 
,QIRUPHG&RQVHQW 
 
6XSSOHPHQWDU\'RFXPHQWDWLRQ 
 
'DWD5HSRUWLQJDQG&DVH5HSRUW)RUPV 
 
5HWHQWLRQRI'DWD 
 
'HYLDWLRQIURPWKH3URWRFRO 
 
6WXG\0RQLWRULQJ 
 
'UXJ$FFRXQWDELOLW\ 
 
'LVFORVXUHRI'DWD 
 
5()(5(1&(6 
 
$33(1',&(6 



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

LIST OF TABLES
7DEOH 
([SRVXUHVIRU3ODQQHG'RVHVDQG6DIHW\0DUJLQV5HODWLYHWR
7R[LFRORJ\6WXG\ 
7DEOH 
3ODQQHG&25'RVHV6HULDO'LOXWLRQVDQG$GPLQLVWHUHG9ROXPHV 
7DEOH 
&RPSRVLWLRQIRU&25IRU,QMHFWLRQPJ9LDO 
7DEOH 
&RPSRVLWLRQIRU3ODFHERIRU,QMHFWLRQP/YLDO 
7DEOH 
&RPSRVLWLRQ,9%DJ3URWHFWDQWDQG'LOXHQWP/YLDO 

LIST OF FIGURES
)LJXUH 
$PRGHOIRUWKHLQIOXHQFHRIJHQHWLFYDULDWLRQRQ,/±PHGLDWHG
FHOOXODULURQKDQGOLQJ 
)LJXUH 
'RVH(VFDODWLRQ6FKHPDWLF 
)LJXUH 
$DQG%5HFRQVWLWXWLRQDQG6HULDO'LOXWLRQRI&25IRU
$GPLQLVWUDWLRQ 

LIST OF APPENDICES
$SSHQGL[$ 
6FKHGXOHRI(YHQWV 
$SSHQGL[% 
([FOXVLRQDU\'UXJV 
$SSHQGL[& 
(6$DQG3DUHQWHUDO,URQ'RVH$GMXVWPHQWV 
$SSHQGL[' 
/DERUDWRU\0HDVXUHPHQWV 
$SSHQGL[( 
)$&,7) 
$SSHQGL[) 
*XLGDQFHRQ&RQWUDFHSWLRQ 



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

PROTOCOL SYNOPSIS
Title
$3KDVHUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGFRKRUWGRVHHVFDODWLRQVWXG\
LQKHPRGLDO\VLVSDWLHQWVWRDVVHVVWKHVDIHW\SKDUPDFRNLQHWLFVDQGSKDUPDFRG\QDPLFV
RIPXOWLSOH,9GRVHVRI&25

Study Number
&25
Study Phase

Objectives
,QDJHQRW\SHSRVLWLYHSRSXODWLRQRIPDLQWHQDQFHKHPRGLDO\VLVSDWLHQWVZLWKHOHYDWHG
,/OHYHOVWKHREMHFWLYHVDUHDVIROORZV

3ULPDU\REMHFWLYH
x
7RHYDOXDWHWKHVDIHW\RIPXOWLSOHGRVHVRI&25
6HFRQGDU\REMHFWLYHV

x
7RPRGHOWKHUHODWLRQVKLSRI&25SKDUPDFRNLQHWLFVDQGSULPDU\
SKDUPDFRG\QDPLFVDVDVVHVVHGE\IUHHDQGWRWDOVHUXP,/KLJKVHQVLWLYLW\
&UHDFWLYHSURWHLQKV&53DQGVHUXPDP\ORLG$6$$
x
7RHYDOXDWHWKHVHFRQGDU\SKDUPDFRG\QDPLFHIIHFWVRI&25DVDVVHVVHGE\
o
6\VWHPLFLURQDYDLODELOLW\WUDQVIHUULQVDWXUDWLRQ76$7UHWLFXORF\WH
KHPRJORELQ&+UDQGDEVROXWHUHWLFXORF\WHFRXQW
o
6\VWHPLFLURQVWRUHVVHUXP IHUULWLQDQGVXSSOHPHQWDOLURQGRVH
UHTXLUHPHQWV
o
(U\WKURSRLHVLVVWLPXODWLQJDJHQW(6$UHVLVWDQFHLQGH[(5,
o
0DOQXWULWLRQLQIODPPDWLRQSUHDOEXPLQDOEXPLQ
o
6HUXPFDUGLDFELRPDUNHUV7URSRQLQ7DQG1WHUPLQDOSUR%
QDWULXUHWLFSHSWLGH>17SUR%13@
o
/HIWYHQWULFXODUPDVVLQGH[/90,E\QRQFRQWUDVW05,
o
3K\VLFDOIXQFWLRQE\KDQGJULSVWUHQJWKDQGV\PSWRPVRIIDWLJXH

x
7RLQYHVWLJDWHWKHLPPXQRJHQLFLW\RI&25
Study Design
7KLVLVDUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGWULDOGHVLJQHGWRHYDOXDWHWKH
VDIHW\SKDUPDFRNLQHWLFVDQGSKDUPDFRG\QDPLFHIIHFWVRIPXOWLSOHGRVHVRI&25
RUSODFHERDGPLQLVWHUHGWRVHTXHQWLDOFRKRUWVRIKHPRGLDO\VLVSDWLHQWV
7HQKHPRGLDO\VLVSDWLHQWVZLOOEHUDQGRPL]HGWR&25RUSODFHERZLWKLQHDFK
GRVLQJFRKRUW:KHQDKLJKHUGRVHWKDQVWXGLHGLQDSULRUFRKRUWLVEHLQJLQLWLDWHG
WKHILUVWVHQWLQHOSDWLHQWVLQWKDWFRKRUWUDQGRPL]HGWR&25RUSODFHER
ZLOOEHUDQGRPL]HGILUVWDQGWKHUHPDLQLQJSDWLHQWVZLOOEHUDQGRPL]HGDWOHDVW
KRXUVODWHULQDUDWLRRI&25WRSODFHER7KHILQDOUDWLRRISDWLHQWVWUHDWHG
ZLWK&25YVSODFHERZLOOEHLQHDFKFRKRUWRISDWLHQWV

3ULRUWRGRVHHVFDODWLRQLHKLJKHUWRWDOGRVHWKDQVWXGLHGLQWKHSUHFHGLQJFRKRUWV
WKHUHZLOOEHDIRUPDOVDIHW\UHYLHZE\WKH6DIHW\5HYLHZ&RPPLWWHH65&ZKLFKZLOO
LQFOXGHDWOHDVWRQHQHSKURORJLVW7KH65&ZLOOVSHFLILFDOO\GHWHUPLQHZKHWKHUWKH
PD[LPXPWROHUDWHGGRVH07'KDVEHHQH[FHHGHGEDVHGRQSURWRFROGHILQHGGRVH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

OLPLWLQJWR[LFLWLHVRFFXUULQJWKURXJK6WXG\'D\LQWKHDFWLYHO\WUHDWHGSDWLHQWVLQ
WKHFXUUHQWFRKRUWVHH)LJXUH,QDGGLWLRQSKDUPDFRNLQHWLFDQGSKDUPDFRG\QDPLF
UHVXOWVZLOOEHUHYLHZHGWRDVVHVVWKHDSSURSULDWHQHVVRIWKHQH[WSODQQHGGRVHDQGWR
JXLGHUHYLVLRQRIWKHQH[WGRVHWREHHYDOXDWHGLIQHFHVVDU\

3DWLHQWVZLOOXQGHUJRDQXSWRZHHN6FUHHQLQJ3HULRGGXULQJZKLFKWKH(6$GRVHDQG
SDUHQWHUDOLURQGRVHVPXVWKDYHEHHQVWDEOHDVGHILQHGLQWKHLQFOXVLRQDQGH[FOXVLRQ
FULWHULD$OOSDWLHQWVUDQGRPL]HGZLOOEHFRQWLQXHGRQ(6$DQGSDUHQWHUDOLURQLIEHLQJ
JLYHQ

3DWLHQWVPHHWLQJWKHHQWU\FULWHULDZLOOJHQHUDOO\EHUDQGRPL]HGRQ'D\7KHILUVW
GRVHRI6WXG\'UXJZLOOEHDGPLQLVWHUHGGXULQJGLDO\VLV$GPLQLVWUDWLRQRIWKHILUVW
GRVHRI6WXG\'UXJZLOOGHILQH6WXG\'D\$GGLWLRQDOYLVLWVZLOOIROORZWKHVFKHGXOH
RIHYHQWVVHH$SSHQGL[$6FKHGXOHRI(YHQWV$OOVXEVHTXHQW6WXG\'UXJLQIXVLRQV
ZLOODOVREHDGPLQLVWHUHGGXULQJGLDO\VLVDQGVWXG\YLVLWVZLOOFRLQFLGHZLWKUHJXODUO\
VFKHGXOHGGLDO\VLVWUHDWPHQWV3DWLHQWVGURSSLQJRXWLHSUHPDWXUHO\GLVFRQWLQXLQJ
6WXG\'UXJWUHDWPHQWIRUUHDVRQVXQUHODWHGWRVDIHW\PD\EHUHSODFHGLQRUGHUWR
PDLQWDLQWKHUDQGRPL]DWLRQUDWLRZLWKLQHDFKFRKRUW
)ROORZLQJWKHZHHN7UHDWPHQW3HULRGSDWLHQWVZLOOEHIROORZHGIRUDQDGGLWLRQDO
ZHHNVIRUVDIHW\LQWKH6DIHW\)ROORZ8S3HULRG3DWLHQWVZLOOKDYHFRPSOHWHGWKHLU
SULPDU\VWXG\SDUWLFLSDWLRQDW:HHNHQGRIWKH6DIHW\)ROORZ8S3HULRG/LPLWHG
EORRGVDPSOLQJZLOORFFXURQ:HHNIRUDQWLGUXJDQWLERGLHVSKDUPDFRNLQHWLFVDQG
,/PHDVXUHPHQWVDVSDUWRIDQ([WHQGHG)ROORZ8S3HULRG
Study Periods:
7KHWRWDOVWXG\GXUDWLRQIRUDQLQGLYLGXDOSDWLHQWZLOOEHDSSUR[LPDWHO\PRQWKV
H[FOXGLQJWKH6FUHHQLQJ3HULRG
,QLWLDO6FUHHQLQJ3HULRGXSWRZHHNV>'D\VWR@
x6WDUWVZLWKWKHILUVWGDWHWKDW,QLWLDO6FUHHQLQJSURFHGXUHVZHUHSHUIRUPHG7KH
ILUVWSURFHGXUHDOVRGHILQHVWKHLQLWLDOVFUHHQLQJYLVLWGDWH
)XOO6FUHHQLQJ3HULRGXSWRZHHNV>'D\VWKURXJK'D\@
x6WDUWVZLWKWKHGDWHRIWKH:HHN9LVLW

7UHDWPHQW3HULRGZHHNV>:HHN'D\WKURXJK:HHN@
6DIHW\)ROORZ8S3HULRGZHHNV>:HHNVWKURXJK@
([WHQGHG)ROORZ8S3HULRGZHHNV>:HHNVWKURXJK@

Inclusion Criteria:
7REHHOLJLEOHSRWHQWLDOVWXG\SDWLHQWVPXVWPHHWDOORIWKHIROORZLQJFULWHULD


$JH!\HDUVDWWKHWLPHRIVLJQLQJRIWKH,&)

5HFHLYLQJFKURQLFKHPRGLDO\VLVIRUDWOHDVWWKUHHPRQWKVSULRUWR6FUHHQLQJYLD
DQDUWHULRYHQRXVILVWXODRUDUWHULRYHQRXVJUDIW
1RWH(YHU\HIIRUWZLOOEHPDGHWRUHFUXLWSDWLHQWVZKRKDYHDZHOOIXQFWLRQLQJ
DUWHULRYHQRXVILVWXODRUJUDIWWRPLQLPL]HWKHFKDQFHRIUHTXLULQJDFHQWUDOYHQRXV
FDWKHWHUGXULQJWKH7UHDWPHQW3HULRG

7KHSDWLHQWDJUHHVWRFRPSO\ZLWKWKHFRQWUDFHSWLRQDQGUHSURGXFWLRQUHVWULFWLRQVRI
WKHVWXG\
:RPHQRIFKLOGEHDULQJSRWHQWLDOPXVWEHXVLQJDPHWKRGRIFRQWUDFHSWLRQWKDWLV
³KLJKO\HIIHFWLYH´LHIDLOXUHUDWHVHH$SSHQGL[)


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

25
3RVWPHQRSDXVDOZRPHQPXVWKDYHKDGQRPHQVWUXDOEOHHGLQJIRUDWOHDVW\HDU
EHIRUHLQLWLDOGRVLQJDQGHLWKHUEHRYHUWKHDJHRI\HDUVRUKDYHDQHOHYDWHG
SODVPDIROOLFOHVWLPXODWLQJKRUPRQH)6+OHYHOLH!P,8P/DW6FUHHQLQJ
$1'
$OOIHPDOHSDWLHQWVRIFKLOGEHDULQJSRWHQWLDOPXVWKDYHDGRFXPHQWHGQHJDWLYH
SUHJQDQF\WHVWUHVXOWDW6FUHHQLQJ3DWLHQWVZLWKHOHYDWHGȕ+&*OHYHOVEHOLHYHGWR
EHGXHWRHQGVWDJHUHQDOGLVHDVHPD\EHHQUROOHGLIGRFXPHQWHGWRQRWEH
SUHJQDQW


7KHSDWLHQWLVDEOHWRJLYHZULWWHQLQIRUPHGFRQVHQWDQGKDVVLJQHGDFRQVHQWIRUP
DSSURYHGE\WKH,QYHVWLJDWRU
V,QVWLWXWLRQDO5HYLHZ%RDUG,5%RU,QGHSHQGHQW
(WKLFV&RPPLWWHH,(&

$WOHDVWRQHGRFXPHQWHGVS.W9!ZLWKLQZHHNVSULRUWRWKH)XOO6FUHHQLQJ
3HULRG

³*HQRW\SHSRVLWLYH´JHQRW\SH**RU$*DVGHILQHGE\WKH&HQWUDO/DEYLD
JHQHWLFWHVWLQJGHYHORSHGE\WKH6SRQVRUDW6FUHHQLQJ

7ZRVHUXP,/OHYHOVtSJP/PHDVXUHGDWOHDVWZHHNDSDUWGXULQJWKH
6FUHHQLQJ3HULRG

5HFHLYLQJRQHRIWKHIROORZLQJ,9RU6&(6$GUXJVFRQWLQXRXVO\SUHVFULEHGIRUD
PLQLPXPRIZHHNVSULRUWR)XOO6FUHHQLQJHSRHWLQDOIDGDUEHSRHWLQDOIDRU
PHWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWD
x
(SRHWLQDOIDPXVWQRWKDYHKDGPRUHWKDQRQHGRVHPLVVHGRUKHOGGXULQJ
:HHNSULRUWR5DQGRPL]DWLRQ
x
'DUEHSRHWLQDOIDPXVWQRWKDYHKDGDQ\GRVHVPLVVHGRUKHOGGXULQJWKH
ZHHNVSULRUWR5DQGRPL]DWLRQ
x
0HWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWDPXVWQRWKDYHKDGDQ\GRVHVPLVVHG
RUKHOGGXULQJWKHZHHNVSULRUWR5DQGRPL]DWLRQ


6WDEOH(6$GRVHVSULRUWRUDQGRPL]DWLRQGHILQHGDVIROORZV
For ESAs dosed weekly or more frequently
1RFKDQJHLQWKHWRWDOZHHNO\GRVHGXULQJ:HHNFRPSDUHGZLWK
:HHN
For ESAs dosed less often than weekly: 
$Q\GRVHJLYHQGXULQJ)XOO6FUHHQLQJ:HHNDQG:HHNLVXQFKDQJHG
IURPWKHLPPHGLDWHO\SUHFHGLQJGRVH
1RWH,IDGRVHZDVJLYHQRQERWK:HHNDQG:HHNWKHQERWKGRVHV
DUHWKHVDPH7KHVHGRVHVPD\EHGLIIHUHQWWKDQHDUOLHUGRVHV

 +DVEHHQUHFHLYLQJLQWUDYHQRXV,9RUGLDO\VDWHLURQUHJXODUO\DQGFRQWLQXRXVO\HJ
ZLWKHDFKGLDO\VLVRUHDFKZHHNGXULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQ25KDV
UHFHLYHGQR,9RUGLDO\VDWHLURQGXULQJWKLVWLPHIUDPHDQGXVHRI,9RUGLDO\VDWH
LURQLVQRWDQWLFLSDWHGWKURXJK6WXG\:HHN
,ISDUHQWHUDOLURQKDVEHHQDGPLQLVWHUHGGXULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

WKHUHJLPHQKDVEHHQVWDEOHVDPHHOHPHQWDOLURQGRVHVDPHIUHTXHQF\DQGVDPH
LURQSURGXFWZLWKQRPRUHWKDQPLVVHGRUKHOGGRVHVLIGRVHGZLWKHDFKGLDO\VLV
DQGQRPLVVHGRUKHOGGRVHVLIGRVHGZHHNO\RUOHVVIUHTXHQWO\GXULQJWKLVWLPH
IUDPH
 ,IUHFHLYLQJRUDOIHUULFFLWUDWHWKHSDWLHQWKDVEHHQSUHVFULEHGLWIRUDWOHDVWZHHNV
SULRUWR)XOO6FUHHQLQJDQGWKHGRVHLVQRWDQWLFLSDWHGWREHFKDQJHGWKURXJK6WXG\
:HHN
 $WOHDVWIHUULWLQYDOXHVGXULQJ6FUHHQLQJ!QJP/
 $WOHDVW76$7YDOXHVGXULQJ6FUHHQLQJEHWZHHQDQGLQFOXVLYH
 (6$UHVLVWDQFHLQGH[FRQILUPHGE\WKH6SRQVRUGXULQJWKHZHHNVSULRUWR
UDQGRPL]DWLRQ
For patient receiving epoetin alfa
7RWDOZHHNO\GRVHRIHSRHWLQDOIDXQLWV
!XQLWVNJSHUJG/
KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

For patients receiving darbepoetin alfa: 
7RWDOZHHNO\GRVHRIGDUEHSRHWLQDOIDPFJ
!XQLWVNJSHUJG/
KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

For patients receiving methoxy polyethylene glycol-epoetin beta
:HHNO\GRVHRIPHWKR[\SRO\HWK\OHQHJO\FROHSRHWLQ
EHWDPFJ
!XQLWVNJSHUJG/
KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

,IWKH(6$LVGRVHGOHVVRIWHQWKDQRQFHDZHHNGLYLGHWKHGRVHE\WKHGRVLQJ
LQWHUYDOWRGHWHUPLQHWKHZHHNO\GRVH)RUH[DPSOH:HHNO\GRVH GRVHJLYHQ
HYHU\WZRZHHNV·
7KHILUVWGD\RIHDFKZHHNXVHGIRUFDOFXODWLRQVLVGHILQHGDVWKHILUVWGLDO\VLVGD\
RIWKH:HHNLH0RQGD\RU7XHVGD\

 'XULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQWKHPHDQRIFRQVHFXWLYHKHPRJORELQV
EHWZHHQtDQGJG/ZLWKWKHGLIIHUHQFHEHWZHHQWKHILUVWDQGODVW
PHDVXUHPHQWVEHLQJJG/
1RWH4XDOLI\LQJKHPRJORELQVPXVWEHGUDZQRUPRUHGD\VDSDUWSUHGLDO\VLVZLWK
QRPRUHWKDQPHDVXUHPHQWVZLWKLQDFDOHQGDUZHHN7KHUHPXVWEHDWOHDVWGD\V
EHWZHHQWKHILUVWDQGODVWRIWKHTXDOLI\LQJKHPRJORELQYDOXHV
 ,QYHVWLJDWRUDQWLFLSDWHVQRFKDQJHWR(6$SDUHQWHUDORURUDOLURQSURGXFWVGRVHV
RUGRVLQJUHJLPHQGXULQJ6WXG\:HHNVWKURXJKDQGWKDWIROORZLQJWKHSURWRFRO
JXLGDQFHIRU(6$DQGLURQGRVHFKDQJHV$SSHQGL[&ZLOOEHFOLQLFDOO\
DSSURSULDWHIRUWKHSDWLHQW
 6HUXP9LWDPLQ%DQGIRODWHOHYHOVDERYHWKHODERUDWRU\ORZHUQRUPDOUDQJH
GXULQJ)XOO6FUHHQLQJ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Exclusion Criteria:
7REHHOLJLEOHIRUVWXG\HQUROOPHQWSRWHQWLDOVWXG\SDWLHQWVPXVWQRWPHHWDQ\RI
WKHIROORZLQJH[FOXVLRQFULWHULD


$Q\LQGZHOOLQJYDVFXODUFDWKHWHULQFOXGLQJWKDWXVHGIRUGLDO\VLVRUDQWLFLSDWHGRI
XVHRIDQLQGZHOOLQJFDWKHWHUDQ\WLPHGXULQJWKHVWXG\LQFOXGLQJWKH,QLWLDO
6FUHHQLQJDQG)XOO6FUHHQLQJ3HULRGV

3DWLHQWVIRUZKRPDFHQWUDOYHQRXVFDWKHWHULVXVHGZLWKLQZHHNVSULRUWR6WHSRI
WKH,QLWLDO6FUHHQLQJ3HULRGEORRGGUDZIRU,/VHH6HFWLRQZLOOEHDOVREH
FRQVLGHUHGVFUHHQLQJIDLOXUHV
8VHRIV\VWHPLFLPPXQRVXSSUHVVLYHGUXJVGXULQJWKH)XOO6FUHHQLQJ3HULRGRU
DQWLFLSDWHGXVHRIVXFKGUXJVDQ\WLPHGXULQJWKHVWXG\
1RWH8VHRIRWLFRSKWKDOPLFLQKDOHGDQGWRSLFDOFRUWLFRVWHURLGVRUORFDO
FRUWLFRVWHURLGLQMHFWLRQVDUHQRWH[FOXVLRQDU\2UDOSUHGQLVRQHXSWRPJSHUGD\LV
RUHTXLYDOHQWLVSHUPLWWHG


&OLQLFDOHYLGHQFHRUVXVSLFLRQRIDFWLYHRUVPROGHULQJLQIHFWLRQHJGLDEHWLF
IRRWXOFHURUXVHRIV\VWHPLFDQWLELRWLFVV\VWHPLFDQWLYLUDOVRUV\VWHPLF
DQWLIXQJDOVZLWKLQZHHNVSULRUWR6WHSRIWKH,QLWLDO6FUHHQLQJ3HULRGEORRG
GUDZIRU,/VHH6HFWLRQGXULQJWKH,QLWLDO6FUHHQLQJ3HULRGRUWKH)XOO
6FUHHQLQJ3HULRG
³6\VWHPLF´LVGHILQHGDVRUDORULQWUDYHQRXVGUXJVWKDWDUHDEVRUEHGLQWRWKH
FLUFXODWLRQ

+RVSLWDOL]DWLRQRURXWSDWLHQWSURFHGXUHVZLWKLQZHHNVSULRUWR6WHSRIWKH
,QLWLDO6FUHHQLQJ3HULRGEORRGGUDZIRU,/VHH6HFWLRQGXULQJWKH,QLWLDO
6FUHHQLQJ3HULRGRUWKH)XOO6FUHHQLQJ3HULRGXQOHVVDSSURYHGE\WKH0HGLFDO
0RQLWRU
1RWH3OHDVHFRQWDFWWKH0HGLFDO0RQLWRUIRUDSSURYDODQGGHWHUPLQDWLRQRIWLPLQJ
RI,/PHDVXUHPHQWVLIFRQVLGHULQJHQUROOLQJSDWLHQWVZLWKKRVSLWDOL]DWLRQVRU
RXWSDWLHQWSURFHGXUHVGXULQJWKLVWLPHIUDPH

,QDELOLW\WRXQGHUJRDQRQFRQWUDVWPDJQHWLFUHVRQDQFHLPDJLQJ05,VFDQHJ
ZHLJKWRYHUWKHOLPLWVIRU05,PDFKLQHFODXVWURSKRELDWKDWFDQQRWEHPDQDJHG
FHUWDLQPHWDOOLFLQGZHOOLQJIRUHLJQERGLHV5HTXLUHPHQWIRU05,PD\H[HPSWHGE\
WKHPHGLFDOPRQLWRUGXHWRSUDFWLFDOFRQVLGHUDWLRQV,QVXFKVLWXDWLRQVSDWLHQWVPD\
EHHQUROOHGHYHQLIWKH\DUHXQDEOHWRXQGHUJR05,

3RVLWLYHWXEHUFXORVLVEORRGWHVWDW6FUHHQLQJ

(YLGHQFHRI+,9RU+,9LQIHFWLRQE\VHURORJ\DW6FUHHQLQJ

+HSDWLWLV%RU&E\VHURORJ\LH+HSDWLWLV%6XUIDFH$QWLJHQRU+HSDWLWLV&
DQWLERG\SRVLWLYHDW6FUHHQLQJ

$67RU$/7![8/1DW6FUHHQLQJ
 +LVWRU\RIOLYHUFLUUKRVLVRUKRPHR[\JHQXVHRWKHUWKDQQRFWXUQDORQO\R[\JHQIRU
WKRVHZLWKVOHHSDSQHD
 +LVWRU\RIJDVWURLQWHVWLQDOXOFHUDWLRQRUDFWLYHGLYHUWLFXOLWLVLQWKH\HDUSULRUWR
,QLWLDO6FUHHQLQJ
 $EVROXWHQHXWURSKLOFRXQW[/DW,QLWLDODQG)XOO6FUHHQLQJ
 3ODWHOHWFRXQW[/DQG,QLWLDORU)XOO6FUHHQLQJ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

 ([SHFWHGWRUHFHLYHDQ\LQYHVWLJDWLRQDOGUXJRUDQ\RIWKHH[FOXVLRQDU\GUXJVOLVWHG
LQ$SSHQGL[%GXULQJWKH7UHDWPHQW3HULRGRU6DIHW\)ROORZ8S3HULRG
 5HFHLYHGDQLQYHVWLJDWLRQDOGUXJZLWKLQGD\VSULRUWRWKHVWDUWRIWKH)XOO
6FUHHQLQJ3HULRG
 .QRZQDOOHUJ\WRWKH6WXG\'UXJRUDQ\RILWVLQJUHGLHQWV
 &XUUHQWO\EUHDVWIHHGLQJ
 $Q\FRQGLWLRQWKDWFRXOGLQWHUIHUHZLWKRUIRUZKLFKWKHWUHDWPHQWPLJKWLQWHUIHUH
ZLWKWKHFRQGXFWRIWKHVWXG\RULQWHUSUHWDWLRQRIWKHVWXG\UHVXOWVRUWKDWZRXOGLQ
WKHRSLQLRQRIWKH,QYHVWLJDWRULQFUHDVHWKHULVNRIWKHSDWLHQW
VSDUWLFLSDWLRQLQWKH
VWXG\7KLVZRXOGLQFOXGHEXWLVQRWOLPLWHGWRDOFRKROLVPGUXJGHSHQGHQF\RU
DEXVHSV\FKLDWULFGLVHDVHHSLOHSV\DQHPLDDWWULEXWDEOHWRDSULPDU\KHPDWRORJLF
GLVHDVHHJVLFNOHFHOODQHPLDRUDQ\XQH[SODLQHGEODFNRXWV
 $FWLYHO\WUHDWHGRUDFWLYHPDOLJQDQF\RWKHUWKDQQRQPHODQRPDVNLQFDQFHUVRU
FHUYLFDOFDUFLQRPDLQVLWXFRQVLGHUHGFXUHGDWWKHWLPHRI)XOO6FUHHQLQJGXULQJWKH
\HDUSULRUWR)XOO6FUHHQLQJ
 0\RFDUGLDOLQIDUFWLRQGXULQJWKHPRQWKVSULRUWR)XOO6FUHHQLQJRUGXULQJ
6FUHHQLQJ
 .QRZQRUVXVSHFWHGRFFXOWRUDFWLYHEOHHGLQJRWKHUWKDQWKDWUHODWHGWRWKH
KHPRGLDO\VLVSURFHGXUH
 5HFHLYHGDUHGEORRGFHOORUZKROHEORRGWUDQVIXVLRQZLWKLQPRQWKVSULRUWR)XOO
6FUHHQLQJRUDQWLFLSDWHGWRUHFHLYHDEORRGWUDQVIXVLRQDWDQ\WLPHGXULQJWKHVWXG\
 +DYHLQIODPPDWRU\ERZHOGLVHDVHWKDWKDVEHHQFOLQLFDOO\DFWLYHGXULQJWKH
PRQWKVSULRUWR)XOO6FUHHQLQJRUERQHPDUURZRURUJDQWUDQVSODQW
1RWH3DWLHQWVZLWKDSUHYLRXVO\H[SODQWHGNLGQH\WUDQVSODQWDUHHOLJLEOHDVDUHWKRVH
ZKRKDYHDQLPSODQWHGNLGQH\WUDQVSODQWEXWKDYHQRWUHFHLYHGLPPXQRVXSSUHVVLRQIRU
DWOHDVWPRQWKVSULRUWR)XOO6FUHHQLQJ
 $QWLFLSDWHGWRUHFHLYHDQRUJDQWUDQVSODQWGXULQJWKHWLPHIUDPHRIWKHVWXG\
 L37+DW6FUHHQLQJ!SJP/

Test Product, Dose 
and Mode of 
Administration
&25ZLOOEHDGPLQLVWHUHGDVDQLQWUDYHQRXVLQIXVLRQVWDUWHGDQ\WLPHEHIRUHWKH
ODVWKRXURIWKHGLDO\VLVWUHDWPHQW
7KH&25GRVHUHJLPHQVSODQQHGDUHLWHPL]HGEHORZ7KHSODQQHGGRVHVPD\EH
VXEVWLWXWHGIRUORZHUGRVHVLQFOXGLQJSUHYLRXVO\VWXGLHGGRVHVEDVHGRQDFFUXLQJGDWD
7KHKLJKHVWGRVHWKDWZLOOEHVWXGLHGLVDFXPXODWLYHGRVHRIPJ
'RVH
&RKRUW
'RVH5HJLPHQ
1XPEHURI
'RVHV
7RWDO&XPXODWLYH
'RVH

PJHYHU\GD\V

PJ

PJHYHU\GD\V

PJ

PJHYHU\GD\V

PJ

PJHYHU\GD\V

PJ
$VRI$PHQGPHQWWKHDFWXDOGRVHVDOOJLYHQHYHU\GD\VZHUHPJ
&RKRUWVDQGPJ&RKRUWVDQGPJ&RKRUW

Reference Therapy, 
Dose, and Mode of 
Administration
7KHUHIHUHQFHGRVHUHJLPHQVWREHH[DPLQHGLQWKLVVWXG\DUH


0DWFKHGSODFHERLQWUDYHQRXVO\DGPLQLVWHUHGDWWKHVDPHIUHTXHQF\DVWKHDFWLYH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

WUHDWPHQWLQDJLYHQFRKRUW



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Pharmacokinetic and 
PK-PD Modeling: 
x
6HUXP&25FRQFHQWUDWLRQVZLOOEHVXEMHFWHGWR3.PRGHOLQJDQG
VHFRQGDU\3.SDUDPHWHUVVXFKDVPD[LPXPVHUXPGUXJFRQFHQWUDWLRQV&PD[
DUHDXQGHUWKHVHUXPGUXJFRQFHQWUDWLRQWLPHFXUYH$8&DQGWHUPLQDO
HOLPLQDWLRQKDOIOLIHWZLOOEHFDOFXODWHG
x
7KHIUHHXQERXQGWR&25DQGWRWDOIUHHERXQG,/$8&ZLOOEH
GHVFULEHG
x
7KHFKDQJHLQSODVPDFRQFHQWUDWLRQRI&25IURPSUHGLDO\VLVWR
SRVWGLDO\VLVZLOOEHGHVFULEHG
x
7KHUHODWLRQVKLSEHWZHHQ&25SKDUPDFRNLQHWLFVDQGSULPDU\
SKDUPDFRG\QDPLFHQGSRLQWVVSHFLILFDOO\IUHHDQGWRWDOVHUXP,/KLJK
VHQVLWLYLW\&UHDFWLYHSURWHLQKV&53DQGVHUXPDP\ORLG$6$$ZLOOEH
GHVFULEHG
Safety Endpoints:
Primary

&KDUDFWHUL]DWLRQRIWKH07'RUWRHVWDEOLVKWKDWWKHKLJKHVWGRVHH[DPLQHGGLG
QRWH[FHHGWKH07'
Secondary

'HVFULSWLRQRIWKHIUHTXHQF\RI'/7VGHILQHGLQ6HFWLRQE\WUHDWPHQW
JURXSDQGGRVH

'HVFULSWLRQRIWKHIUHTXHQF\RIWKHHYHQWVRILQWHUHVWE\WUHDWPHQWJURXSDQG
GRVHGHILQHGLQ6HFWLRQ

'HVFULSWLRQRIDGGLWLRQDOVDIHW\DVVHVVPHQWVE\WUHDWPHQWJURXSDQGGRVH
DGYHUVHHYHQWVYLWDOVLJQV(&*FOLQLFDOODERUDWRU\DQGDQWLGUXJDQWLERGLHV
ELQGLQJDQGQHXWUDOL]LQJ
Primary 
Pharmacodynamic 
Endpoints

x
&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\LQWKH6$$DQGKV&53
WR:HHNEHWZHHQWUHDWPHQWJURXSV

Secondary 
Pharmacodynamic 
Endpoints
0HDQGLIIHUHQFHVEHWZHHQSODFHERDQG&25WUHDWHGSDWLHQWVZLOOEH
GHWHUPLQHGIRUWKHIROORZLQJSDUDPHWHUV

x
&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQ76$7WR
:HHN
x
&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQWKH&+UWR
:HHN
x
&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQKV&53WRWKH
PHDQRI:HHNV
x
&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJ3HULRGDQG'D\YDOXHVLQ6$$WR
WKHWRWKHPHDQRI:HHNV
x
&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJ3HULRGDQG'D\YDOXHVLQVHUXP
SUHDOEXPLQWRWKHPHDQRI:HHNVDQGDOEXPLQWR:HHN
x
&KDQJHIURPEDVHOLQHZHHNO\PHDQRI6FUHHQLQJLQ(5,WR:HHN
x
&KDQJHIURPEDVHOLQHZHHNO\PHDQRI6FUHHQLQJLQ(5,WRWKHPHDQRI
:HHNV

([SORUDWRU\SKDUPDFRG\QDPLFVHQGSRLQWVDUHGHVFULEHGLQ6HFWLRQ

Sample Size
$SSUR[LPDWHO\LHXSWRFRKRUWVLQFOXGLQJH[SDQVLRQFRKRUWV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Study Centers
$SSUR[LPDWHO\VWXG\VLWHV
Statistical Methods 
Analysis
7KHIROORZLQJDQDO\VLV3RSXODWLRQVDUHGHILQHGIRUWKHGLIIHUHQWW\SHVRIGDWD
DQDO\VLV
x
,QWHQWWRWUHDW,77DQDO\VLVSRSXODWLRQWKHSULPDU\SRSXODWLRQIRUWKH
GLVSRVLWLRQDQGEDVHOLQHGDWDVXPPDULHV
x
3KDUPDFRG\QDPLFDQDO\VLVSRSXODWLRQWKHSRSXODWLRQIRUWKH
SKDUPDFRG\QDPLFDQDO\VHV
x
3KDUPDFRNLQHWLFVDQDO\VLVSRSXODWLRQIRU3.DQDO\VLV
x
3HUSURWRFRODQDO\VLVSRSXODWLRQIRUSKDUPDFRG\QDPLFVDQDO\VHV
x
6DIHW\DQDO\VLVSRSXODWLRQIRUWKHVDIHW\DQDO\VHV

$OOVWXG\FROOHFWHGGDWDZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSIRUWKHDSSURSULDWH
DQDO\VLVSRSXODWLRQXVLQJGHVFULSWLYHVWDWLVWLFV'HVFULSWLYHVWDWLVWLFVIRU
FRQWLQXRXVYDULDEOHVZLOOLQFOXGHQXPEHURISDWLHQWVQPHDQVWDQGDUGGHYLDWLRQ
6'PHGLDQTXDUWLOHV4DQG4PLQLPXPPLQDQGPD[LPXPPD[YDOXHV
$QDO\VLVRIFDWHJRULFDOYDULDEOHVZLOOLQFOXGHIUHTXHQF\DQGSHUFHQWDJHV
'DWDIURP&25WUHDWHGSDWLHQWVIURP&RKRUWVQRWH[FHHGLQJWKH07'ZLOOEH
SRROHGDQGGDWDIURPDOOSODFHERSDWLHQWVZLOOEHSRROHGIRUWKHSKDUPDFRG\QDPLF
HQGSRLQWDQDO\VHV
'HVFULSWLYHDQDO\VHVE\GRVHLQZKLFKDOOSODFHERSDWLHQWVDUHSRROHGZLOODOVREH
FRQGXFWHG



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

LIST OF ABBREVIATIONS, DEFINITIONS, AND TERMS
Term
Definition  
$(
$GYHUVHHYHQW
$/7
$ODQLQHDPLQRWUDQVIHUDVH

$67
$VSDUWDWHDPLQRWUDQVIHUDVH
$8&
$UHDXQGHUWKHFXUYH
ȕK&*
ȕ+XPDQFKRULRQLFJRQDGRWURSLQKRUPRQH
%03
%RQHPRUSKRJHQLFSURWHLQ
%035
%RQHPRUSKRJHQLFSURWHLQUHFHSWRU
%3
%ORRGSUHVVXUH
%81
%ORRGXUHDQLWURJHQ
&%&
&RPSOHWHEORRGFRXQW
&+U
5HWLFXORF\WHKHPRJORELQFRQFHQWUDWLRQ
&)5
&RGHRI)HGHUDO5HJXODWLRQV
&25
0RQRFORQDODQWLERG\WR,/
&PD[PLQ
0D[LPXPPLQLPXPREVHUYHGFRQFHQWUDWLRQ
&5)
&DVHUHSRUWIRUPV
&52
&RQWUDFWUHVHDUFKRUJDQL]DWLRQ
'/7
'RVH/LPLWLQJ7R[LFLW\
'LDO\VLV6WDUW7LPH
7KHVWDUWWLPHRIGLDO\VLVLVGHILQHGE\WKHHDUOLHVWWLPHSRLQWUHFRUGHG
RQWKHGLDO\VLVIORZVKHHWRUHTXLYDOHQWZLWKDEORRGIORZUDWH!
'LDO\VLV(QG7LPH
'LDO\VLVLVFRQVLGHUHGFRPSOHWHGZKHQWKHGLDO\VLVPDFKLQHVKRZV
PLQXWHVUHPDLQLQJIRUWKHWUHDWPHQW7KHHQGWLPHRIGLDO\VLVLV
GHILQHGE\WKHODWHVWWLPHSRLQWUHFRUGHGRQWKHGLDO\VLVIORZVKHHWRU
HTXLYDOHQWZLWKDEORRGIORZUDWH RUODVWUHFRUGHGEORRGIORZ
UDWHZKLFKHYHULVODWHU
(&*
(OHFWURFDUGLRJUDP
(5,
(6$UHVLVWDQFHLQGH[(6$ZHHNO\GRVHWDUJHWHGGU\ZHLJKWLQ
.JKHPRJORELQLQJG/
(6$
(U\WKURSRLHVLVVWLPXODWLQJDJHQW
)$&,7)
>TXHVWLRQQDLUH@
)XQFWLRQDO$VVHVVPHQWRI&KURQLF,OOQHVV7KHUDS\±)DWLJXH
)'$
)RRGDQG'UXJ$GPLQLVWUDWLRQ
)31
)HUURSRUWLQ
)6+
)ROOLFOHVWLPXODWLQJKRUPRQH
*&3
*RRG&OLQLFDO3UDFWLFH
*/3
*RRG/DERUDWRU\3UDFWLFHV
+$03
+HSFLGLQJHQH
+'/
+LJKGHQVLW\OLSRSURWHLQ
+JE
+HPRJORELQ
+,9
+XPDQ,PPXQRGHILFLHQF\9LUXV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Term
Definition  
+5
+HDUWUDWH
KV&53
+LJKVHQVLWLYLW\&5HDFWLYH3URWHLQ
,&)
,QIRUPHG&RQVHQW)RUP
,&+
,QWHUQDWLRQDO&RQIHUHQFHRQ+DUPRQLVDWLRQ
,(&
,QGHSHQGHQW(WKLFV&RPPLWWHH
,/
,QWHUOHXNLQ
,/5
,/UHFHSWRU
,1'
,QYHVWLJDWLRQDOQHZGUXJ
,15
,QWHUQDWLRQDOQRUPDOL]HGUDWLR
L37+
,QWDFWSDUDWK\URLGKRUPRQH
,5%
,QVWLWXWLRQDO5HYLHZ%RDUG
,9
,QWUDYHQRXV
,9%3
,9%DJ3URWHFWDQW
,:56
,QWHUDFWLYH:HE5HVSRQVH6\VWHP
NJ
.LORJUDP
.W9
0HDVXUHRIGLDO\VLVFOHDUDQFHDQGDGHTXDF\ZKHUH. GLDO\]HU
FOHDUDQFHRIXUHDW GLDO\VLVWLPHDQG9±YROXPHRIGLVWULEXWLRQRI
XUHD
/'/
/RZGHQVLW\/LSRSURWHLQ
/+'
/RZ+HPRJORELQGHQVLW\
//1
/RZHU/LPLWRI1RUPDO
/90,
/HIW9HQWULFXODU0DVV,QGH[
0&9
0HDQFRUSXVFXODUKHPRJORELQ
PJ
0LOOLJUDP
PLQ
0LQXWH
P/
0LOOLOLWHU
P,77
0RGLILHG,QWHQWWR7UHDW
05,
0\RFDUGLDO5HVRQDQFH,PDJLQJ
07'
0D[LPDOO\7ROHUDWHG'RVH
12$(/
1RREVHUYHGDGYHUVHHIIHFWOHYHO
17SUR%13
1WHUPLQDOSUR%QDWULXUHWLFSHSWLGH
3'
3KDUPDFRG\QDPLF
3.
3KDUPDFRNLQHWLF
3,
3ULQFLSDO,QYHVWLJDWRU
33'
3XULILHG3URWHLQ'HULYDWLYH
37
3URWKURPELQ7LPH
37+
3DUDWK\URLG+RUPRQH
5%&
5HG%ORRG&HOO
5':
5HGFHOOGLVWULEXWLRQZLGWK
56I
5HGFHOOVL]HIDFWRU


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Term
Definition  
55
5HVSLUDWRU\5DWH
6$$
6HUXPDP\ORLG$
6$(
6HULRXVDGYHUVHHYHQW
6$3
6WDWLVWLFDO$QDO\VLV3ODQ
65&
6DIHW\5HYLHZ&RPPLWWHH
623
6WDQGDUG2SHUDWLQJ3URFHGXUH
VS.79
6LQJOHSRRO.W9
686$5
6XVSHFWHG8QH[SHFWHG6HULRXV$GYHUVH5HDFWLRQ
Wò
+DOIOLIH
7%
WXEHUFXORVLV
7%'
7REHGHWHUPLQHG
7,%&
7RWDOLURQELQGLQJFDSDFLW\
703
7UDQVPHPEUDQH3UHVVXUH
76$7
7UDQVIHUULQVDWXUDWLRQ
8)5
8OWUDILOWUDWLRQ5DWH
8/1
8SSHUOLPLWRIQRUPDO
:%&
:KLWHEORRGFHOOV



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

1
INTRODUCTION
1.1
Background 
1HDUO\DOO!GLDO\VLVSDWLHQWVLQWKH8QLWHG6WDWHVDUHWUHDWHGZLWKHU\WKURSRLHVLV
VWLPXODWLQJDJHQWV(6$VDQGVXSSOHPHQWDOLURQIRUPDQDJHPHQWRIFKURQLFDQHPLDDQG
WUDQVIXVLRQDYRLGDQFH+RZHYHUWKHUHTXLUHPHQWIRUVXSUDSK\VLRORJLF(6$GRVHVWR
PDLQWDLQFOLQLFDOJXLGHOLQHDQG)'$VSHFLILHGWDUJHWKHPRJORELQOHYHOVVXJJHVWVVRPH
GHJUHHRIHU\WKURSRLHWLFLQHIILFLHQF\LQWKHVH³K\SRUHVSRQVLYH´SDWLHQWV0DF'RXJDOO
6XQ,QWKHKHDOWK\VWDWHVHUXPHU\WKURSRLHWLQOHYHOVDUHDSSUR[LPDWHO\8/
$IWHUDXQLWSKOHERWRP\DQGGHFOLQHLQKHPRJORELQIURPJG/WRJG/
HU\WKURSRLHWLQOHYHOVLQFUHDVHRYHUIROGWRDSSUR[LPDWHO\8/WUDQVLHQWO\,QFRQWUDVW
DPRGHUDWHIRUGLDO\VLVSDWLHQWLQWUDYHQRXVGRVHRIHU\WKURSRLHWLQRI8UHVXOWVLQDSHDN
HU\WKURSRLHWLQOHYHORIDSSUR[LPDWHO\8/OHYHOVQRWDFKLHYHGZLWKQDWLYH
HU\WKURSRLHWLQSURGXFWLRQXQWLOWKHKHPRJORELQOHYHOVUHDFKJG/)LVKEDQH
(U\WKURSRLHVLVVWLPXODWLQJDJHQWWULDOVUDQGRPL]LQJSDWLHQWVWRKLJKHUYVORZHUKHPRJORELQ
WDUJHWVKDYHVKRZQDQLQFUHDVHLQFDUGLRYDVFXODUHYHQWVDPRQJWKRVHWUHDWHGWRKLJKHU
KHPRJORELQWDUJHWVLQERWKGLDO\VLVGHSHQGHQWDQGQRQGLDO\VLVGHSHQGHQWFKURQLFNLGQH\
GLVHDVHSDWLHQWV%HVDUDEDQG6LQJK$QDO\VHVRIWKHVHWULDOVDQGRWKHUVKDYH
VKRZQWKDWSDWLHQWVDWJUHDWHVWULVNIRUFDUGLRYDVFXODUHYHQWVZHUHWKRVHUDQGRPL]HGWRWKH
KLJKHUKHPRJORELQWDUJHWZKRIDLOHGWRDFKLHYHVDLGWDUJHWLHK\SRUHVSRQGHUVDQGSHU
SURWRFROZHUHWUHDWHGZLWKKLJKHU(6$GRVHV)LVKEDQHDQG.LOSDWULFN
$QXPEHURISRWHQWLDOQRQPXWXDOO\H[FOXVLYHPHFKDQLVPVKDYHEHHQVXJJHVWHGWRH[SODLQ
WKHVHREVHUYDWLRQVHJSRWHQWLDOGLUHFWWR[LFHIIHFWVRIQRQELRORJLF(6$VDQGRULURQ
LQFUHDVHGSODWHOHWDFWLYLW\K\SHUYLVFRVLW\DQGHQGRWKHOLDOGDPDJHDQGDOORIWKHVH
PHFKDQLVPVDUHVXSHULPSRVHGXSRQLQGLYLGXDO(6$UHVSRQVLYHQHVV(6$
K\SRUHVSRQVLYHQHVVLVDOVRDPDQLIHVWDWLRQRIWKHPDOQXWULWLRQLQIODPPDWLRQFRPSOH[LQ
ZKLFKLQIODPPDWLRQLVDVVRFLDWHGZLWKUHGXFWLRQVLQSUHDOEXPLQDQGDOEXPLQ
.DODQWDU=DGHKDQGWUHDWPHQWRILQIODPPDWLRQKDVEHHQVKRZQWRLPSURYHQXWULWLRQDO
PDUNHUV+XQJ
3DWLHQWVZLWKWKHPRVWPDUNHG(6$K\SRUHVSRQVLYHQHVVDUHFKDUDFWHUL]HGE\ORZHU
KHPRJORELQOHYHOVORZHUWUDQVIHUULQVDWXUDWLRQOHYHOVDQGQRUPDORUKLJKIHUULWLQOHYHOV
.KDUDJMLWVLQJK7RJHWKHUWKHVHSDUDPHWHUVSRLQWWRDIXQFWLRQDOEORFNDGHLQUHOHDVH
RILURQIRUHU\WKURSRLHVLVIURPERGLO\VWRUHV2QHLPSRUWDQWPHFKDQLVPIRUWKLVEORFNDGHLV
LQIODPPDWLRQLQGXFHGH[SUHVVLRQRIWKH³PDVWHULURQUHJXODWRU´KHSFLGLQDSURWHLQZKLFK
SURKLELWVFHOOXODULURQWUDQVSRUWYLDGHJUDGDWLRQRIIHUURSRUWLQWKHRQO\NQRZQLURQH[SRUW
FKDQQHOLQKXPDQV+HQW]HHWDO+HQW]HHWDODQG6XQ8VHRIKLJKGRVHV
RILQWUDYHQRXVLURQFDQSDUWLDOO\RYHUFRPHWKLVEORFNDGHEXWKLJKHUGRVHV!PJPRQWK
DUHDVVRFLDWHGZLWKKLJKHUFDUGLRYDVFXODUPRUWDOLW\DQGDOOFDXVHPRUWDOLW\LQWKHFRQWH[WRI
LQIODPPDWLRQ.DODQWDU=DGHK&XUUHQWDQHPLDWUHDWPHQWVGRQRWUHGXFH
LQIODPPDWLRQDQGWKHUHIRUHIDLOWRDGGUHVVDQLPSRUWDQWPHFKDQLVPRIDQHPLDLQWKLV
SRSXODWLRQ
7KHVHREVHUYDWLRQVIRUPWKHEDVLVIRUWDUJHWLQJLQIODPPDWLRQDVDPHDQVWRWUHDWDQHPLDLQ
WKHGLDO\VLVSRSXODWLRQ,QKLELWLQJLQIODPPDWLRQDQGWKHUHE\LPSURYLQJIXQFWLRQDOLURQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

GHILFLHQF\ZRXOGEHH[SHFWHGWRUHGXFHWKHUHTXLUHG(6$DQGLURQVXSSOHPHQWDWLRQDWDQ\
OHYHORIWDUJHWHGKHPRJORELQDQGSRWHQWLDOO\DOOHYLDWHDVVRFLDWHGLDWURJHQLFFRPSOLFDWLRQV
1.2
Description of COR-001 
$GGLWLRQDOLQIRUPDWLRQDERXWWKHPHFKDQLVPDQGVWUXFWXUHRI&25FDQEHIRXQGLQWKH
&25,QYHVWLJDWRU¶V%URFKXUH
&25LVDKXPDQ,J*NDSSDDQWLERG\GLUHFWHGDJDLQVWLQWHUOHXNLQ,/FRQWDLQLQJD
³<7(´PXWDWLRQLQLWV)FUHJLRQZKLFKDIIRUGVWKHSRWHQWLDOIRUH[WHQGHGKDOIOLIH&25
LVEHLQJGHYHORSHGIRUWKHWUHDWPHQWRIDQHPLDLQJHQRW\SHSRVLWLYHSDWLHQWVZLWKFKURQLF
NLGQH\GLVHDVHRQKHPRGLDO\VLV
$OOHYLDWLRQRILQIODPPDWRU\DQHPLDZLWKDQWL,/WKHUDS\FRPHVIURPSXEOLVKHGZRUN
UHJDUGLQJWKHXVHRIVDLGWKHUDS\LQKXPDQVLQQRQUHQDOLQIODPPDWRU\FRQGLWLRQV
7RFLOL]XPDE5RFKHDQGFOD]DNL]XPDE$OGHU%LRSKDUPDFHXWLFDOVKDYHERWKVKRZQDELOLW\
WRUDLVHKHPRJORELQLQUKHXPDWRLGDUWKULWLV&DVWOHPDQ¶VGLVHDVHDQGDGYDQFHGPDOLJQDQF\
6RQJ6RQJHWDO%D\OLVV%\H[DPSOHWKHDGPLQLVWUDWLRQRIWRFLOL]XPDE
DQWL,/UHFHSWRUDQWLERG\UHYHUVHVVLJQVRILQIODPPDWLRQLPSURYHVLURQDYDLODELOLW\DQG
LQFUHDVHVKHPRJORELQLQ&DVWOHPDQ¶VSDWLHQWV
$OWKRXJKDQWL,/WKHUDSLHVKDYHQRWEHHQWHVWHGLQGLDO\VLVSDWLHQWVWRGDWHSXEOLVKHGDQG
6SRQVRU¶VXQSXEOLVKHGGDWDLQDODUJHSUHYDOHQWGLDO\VLVSRSXODWLRQGRFXPHQWVDFRUUHODWLRQ
EHWZHHQVHUXP,/OHYHOVDQGWKHGHJUHHRI(6$K\SRUHVSRQVLYHQHVVLHHU\WKURSRLHWLQ
GRVHUHTXLUHPHQWGLYLGHGE\DFKLHYHGVHUXPKHPRJORELQ:RQDQGVHH6HFWLRQRI
WKH&25,QYHVWLJDWRU¶V%URFKXUH
+RZHYHUWKHLQIOXHQFHRI,/LVQRWXQLYHUVDODQGDSSHDUVRYHUUHSUHVHQWHGLQDVSHFLILF
JHQRW\SLFDOO\GHILQHGGLDO\VLVVXESRSXODWLRQ%DVHGRQQRQFOLQLFDOVWXG\DQGUHWURVSHFWLYH
UHYLHZRIGLDO\VLVSRSXODWLRQV6SRQVRU¶VXQSXEOLVKHGGDWDLWDSSHDUVDJHQRW\SLFYDULDWLRQ
LQWKHLURQFRQWUROV\VWHPRIPDPPDOLDQFHOOVFDQUHQGHUWLVVXHVPRUHRUOHVVVXVFHSWLEOHWR
,/EDVHGLQIODPPDWLRQDQGGLFWDWHWKHLQIOXHQFHRIWKLVLQIODPPDWLRQRQFOLQLFDORXWFRPHV
VHH)LJXUHDQG6HFWLRQRIWKH&25,QYHVWLJDWRU¶V%URFKXUH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH
Figure 1 
A model for the influence of genetic variation on IL-6 –mediated 
cellular iron handling
%035 %03UHFHSWRU
,/5 ,/UHFHSWRU
+$03 KHSFLGLQJHQH
)31 IHUURSRUWLQ
)H LURQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

1.3
Summary of Relevant Nonclinical Experience with COR-001 
1.3.1
Non-Clinical Pharmacology 
,QYLWURVWXGLHVZHUHFRQGXFWHGWRGHWHUPLQHWKHDIILQLW\SRWHQF\DQGVSHFLILFLW\RI
&257KHVHVWXGLHVFRQILUP&25LVKLJKO\VXESLFRPRODUSRWHQWDQG
RXWFRPSHWHVFHOOERXQGRUVROXEOH,/UHFHSWRUVWKXVHIIHFWLYHO\SUHYHQWLQJFLUFXODWLQJ,/
IURPELQGLQJWRLWVUHFHSWRUVDQGHOLFLWLQJHIIHFWVYLDFODVVLFDORUWUDQVVLJQDOLQJ$SUHFOLQLFDO
SURRIRIFRQFHSWVWXG\LQDFDUGLRUHQDOURGHQWPRGHOZDVFRQGXFWHGWRH[SDQGRQSXEOLVKHG
GDWDDQGWKHUDWLRQDOHIRUWKHLQWHQGHGLQGLFDWLRQ)XUWKHUSUHFOLQLFDOVWXGLHVHOXFLGDWHGWKH
GLUHFWDQGLQGLUHFWPHFKDQLVPVRI,/PHGLDWHGLQIODPPDWRU\FDUGLDFLQMXU\
1.3.2
Pharmacokinetics in animals 
&\QRPROJXVPRQNH\ZDVVHOHFWHGDVWKHSKDUPDFRORJLFDOO\UHOHYDQWDQLPDOPRGHOWR
FKDUDFWHUL]HWKHSKDUPDFRNLQHWLFV3.DQGSKDUPDFRG\QDPLFV3'RI&25DQG
FRQGXFWQRQFOLQLFDOVDIHW\DVVHVVPHQWVWXGLHV2QHVLQJOHGRVHQRQ*/3VWXG\DQGRQH
PXOWLSOHGRVH*/3VWXG\ZDVFRQGXFWHG
7KHHOLPLQDWLRQKDOIOLIHRI&25ZDVH[WHQGHGE\DSSUR[LPDWHO\IROGDQGWKH
FOHDUDQFHZDVUHGXFHGE\DSSUR[LPDWHO\IROGFRPSDUHGWRWKHSDUHQWPROHFXOHODFNLQJWKH
<7()FUHJLRQPXWDWLRQV7KHDYHUDJHKDOIOLIHRI&25UDQJHGIURPWRGD\V
DQGFOHDUDQFHIURPWRP/GD\NJ
1.3.3
Non-Clinical Toxicology and Safety 
7KHQRQFOLQLFDOWR[LFRORJ\GDWDIRU&25LQFOXGHWZRVWXGLHVLQF\QRPROJXVPRQNH\VD
QRQ*/3VLQJOH,9RU6&GRVH3.DQGSKDUPDFRG\QDPLFVVWXG\DQGD*/3UHSHDW,9RU
6&DGPLQLVWUDWLRQWR[LFRORJ\VWXG\HYHU\RWKHUZHHNDGPLQLVWUDWLRQIRUZHHNVZLWKD
ZHHNUHFRYHU\,QWKHQRQ*/3VLQJOHGRVHVWXG\DOWKRXJKWKHUHZDVQRFRQWUROJURXS
FRPSDUDWRUWKHUHZHUHQRDGYHUVHILQGLQJVDWWULEXWHGWRVLQJOH&25DGPLQLVWUDWLRQRI
PJNJ,9RUPJNJ6&LQMHFWLRQVWKHKLJKHVWGRVHVWHVWHG
,QWKH*/3UHSHDWGRVHVWXG\WKH12$(/ZDVPJNJIRUDQLPDOVGRVHG,9DQG
PJNJIRUDQLPDOVGRVHG6&WKHKLJKHVWGRVHVWHVWHG,QDGGLWLRQ*/3WLVVXH
FURVVUHDFWLYLW\VWXGLHVLQDIXOOSDQHORIKXPDQDQGF\QRPROJXVPRQNH\WLVVXHVVKRZHG
VWDLQLQJMXGJHGDVH[SHFWHG
1.4
Summary of Relevant Clinical Experience
1.4.1
Phase 1 Study of COR-001 in Rheumatoid Arthritis Patients
7KHFOLQLFDOSURJUDPWRGDWHFRQVLVWVRIDVLQJOH3KDVHGRXEOHEOLQGSODFHERFRQWUROOHG
VLQJOHDVFHQGLQJGRVHVWXG\LQUKHXPDWRLGDUWKULWLVSDWLHQWV6WXG\'&FRQGXFWHG
E\0HG,PPXQHIURP0D\WR)HEUXDU\'RVHHVFDODWLRQZDVWREHJLQDW
PJZLWKSURYLVLRQDOGRVHVRIDQGPJWKHUHDIWHU$IWHUSDWLHQWVZHUH
HQUROOHGUHFHLYLQJ&25PJ,9VLQJOHGRVHDQGUHFHLYLQJSODFHERWKHVWXG\
ZDVWHUPLQDWHGGXHWRGLIILFXOWLHVZLWKUHFUXLWPHQW


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

1.4.2
Summary of Safety from Clinical Studies (D4430C00001) 
1RSDWLHQWVGLHGGXULQJWKHVWXG\1RSDWLHQWVUHSRUWHGDQ\VHULRXVDGYHUVHHYHQWV6$(VRU
GLVFRQWLQXHGLQYHVWLJDWLRQDOSURGXFWDGPLQLVWUDWLRQGXHWRDQ$($OORIWKH$(VZHUH
FRQVLGHUHGWREHRIPLOGWRPRGHUDWHLQWHQVLW\E\WKH,QYHVWLJDWRU7KHIROORZLQJ$(VZHUH
FRQVLGHUHGUHODWHGWRWKHLQYHVWLJDWLRQDOSURGXFWE\WKH,QYHVWLJDWRUDQGZHUHRIPRGHUDWH
LQWHQVLW\3URGXFWLYHFRXJKLQIOXHQ]D7KHIROORZLQJ$(VZHUHFRQVLGHUHGUHODWHGWRWKH
LQYHVWLJDWLRQDOSURGXFWE\WKH,QYHVWLJDWRUDQGZHUHRIPLOGLQWHQVLW\1DXVHDSODFHER
GLDUUKHDYRPLWLQJKHDGDFKHDQGQDVRSKDU\QJLWLV&25
1RVSHFLILFWUHQGVZHUHREVHUYHGLQODERUDWRU\YDOXHVZLWKWKHH[FHSWLRQRIFKDQJHVLQWKH
ZKLWHEORRGFHOO:%&DQGQHXWURSKLOFRXQWV:KHUHDVWKHSDWLHQWZKRUHFHLYHGSODFHER
KDGQRDEQRUPDO:%&RUQHXWURSKLOFRXQWVFKDQJHVZHUHREVHUYHGLQDOOSDWLHQWVZKR
UHFHLYHG&252QHSDWLHQWZKRUHFHLYHG&25KDGQRUPDO:%&DQGQHXWURSKLO
FRXQWVDWEDVHOLQHEXWQHXWURSKLOFRXQWVEHORZQRUPDOGXULQJ:HHNV WR $VHFRQG
SDWLHQWZKRUHFHLYHG&25KDGQRUPDO:%&DQGQHXWURSKLOFRXQWVDWEDVHOLQHZKLFK
GHFUHDVHGEHWZHHQ:HHN WR:HHN
UHDFKLQJDORZ:%&FRXQWRI
DQGDORZ
QHXWURSKLOFRXQWRI
7KHWKLUGSDWLHQWZKRUHFHLYHG&25KDGDQRUPDO
:%&DQGORZQHXWURSKLOFRXQW
DWEDVHOLQHZKLFKIXUWKHUGHFUHDVHGEHWZHHQ
'D\
DQG:HHN
UHDFKLQJDORZ:%&FRXQWRI
DQGDORZQHXWURSKLOFRXQWRI
)RUDOOWKUHHSDWLHQWVZKRUHFHLYHG&25:%&DQGQHXWURSKLOFRXQWV
UHWXUQHGWRQRUPDOE\WKHHQGRIWKHVWXG\
1RRWKHUQRWDEOHFKDQJHVLQODERUDWRU\SDUDPHWHUVLQFOXGLQJOLYHUIXQFWLRQYLWDOVLJQVRU
SK\VLFDODVVHVVPHQWVDVUHODWHGWRVDIHW\ZHUHQRWHG


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

2
STUDY OBJECTIVES
,QDJHQRW\SHSRVLWLYHSRSXODWLRQRIPDLQWHQDQFHKHPRGLDO\VLVSDWLHQWVZLWKHOHYDWHG,/
OHYHOVWKHREMHFWLYHVDUHDVIROORZV
3ULPDU\REMHFWLYH

7RHYDOXDWHWKHVDIHW\RIPXOWLSOHGRVHVRI&25
6HFRQGDU\REMHFWLYHV

7RPRGHOWKHUHODWLRQVKLSRI&25SKDUPDFRNLQHWLFVDQGSULPDU\SKDUPDFRG\QDPLFV
DVDVVHVVHGE\IUHHDQGWRWDOVHUXP,/KLJKVHQVLWLYLW\&UHDFWLYHSURWHLQKV&53DQG
VHUXPDP\ORLG$6$$

7RHYDOXDWHWKHVHFRQGDU\SKDUPDFRG\QDPLFHIIHFWVRI&25DVDVVHVVHGE\

6\VWHPLFLURQDYDLODELOLW\WUDQVIHUULQVDWXUDWLRQ76$7UHWLFXORF\WHKHPRJORELQ
&+UDQGUHWLFXORF\WHFRXQW

6\VWHPLFLURQVWRUHVVHUXPIHUULWLQDQGVXSSOHPHQWDOLURQGRVHUHTXLUHPHQWV

(U\WKURSRLHVLVVWLPXODWLQJDJHQWUHVLVWDQFHLQGH[(5,

0DOQXWULWLRQLQIODPPDWLRQSUHDOEXPLQDOEXPLQ

6HUXPFDUGLDFELRPDUNHUV7URSRQLQ7DQG1WHUPLQDOSUR%QDWULXUHWLFSHSWLGH
17SUR%13

/HIWYHQWULFXODUPDVVLQGH[/90,E\QRQFRQWUDVW05,

3K\VLFDOIXQFWLRQE\KDQGJULSVWUHQJWKDQGV\PSWRPVRIIDWLJXH

7RLQYHVWLJDWHWKHLPPXQRJHQLFLW\RI&25



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

3
INVESTIGATIONAL PLAN  
3.1
Overall Study Design and Plan: Description
7KLVLVDUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGWULDOGHVLJQHGWRHYDOXDWHWKHVDIHW\
SKDUPDFRNLQHWLFVDQGSKDUPDFRG\QDPLFHIIHFWVRIPXOWLSOHGRVHVRI&25RUSODFHER
DGPLQLVWHUHGWRVHTXHQWLDOFRKRUWVRIKHPRGLDO\VLVSDWLHQWV
7HQKHPRGLDO\VLVSDWLHQWVZLOOEHUDQGRPL]HGWR&25RUSODFHERZLWKLQHDFKGRVLQJ
FRKRUW:KHQDKLJKHUGRVHWKDQVWXGLHGLQDSULRUFRKRUWLVEHLQJLQLWLDWHGWKHILUVW
VHQWLQHOSDWLHQWVLQWKDWFRKRUWZLOOEHUDQGRPL]HGWR&25RUSODFHERWKH
UHPDLQLQJSDWLHQWVZLOOEHUDQGRPL]HGDWOHDVWKRXUVODWHULQDUDWLRRI&25WR
SODFHER
3ULRUWRGRVHHVFDODWLRQLHKLJKHUWRWDOGRVHWKDQVWXGLHGLQWKHSUHFHGLQJFRKRUWVWKHUH
ZLOOEHDIRUPDOVDIHW\UHYLHZE\WKH6DIHW\5HYLHZ&RPPLWWHH65&ZKLFKZLOOLQFOXGHDW
OHDVWRQHQHSKURORJLVW7KH65&ZLOOVSHFLILFDOO\GHWHUPLQHZKHWKHUWKHPD[LPXPWROHUDWHG
GRVH07'KDVEHHQH[FHHGHGEDVHGRQSURWRFROGHILQHGGRVHOLPLWLQJWR[LFLWLHVRFFXUULQJ
WKURXJK6WXG\'D\LQWKHDFWLYHO\WUHDWHGSDWLHQWVLQWKHFXUUHQWFRKRUWVHH)LJXUH,Q
DGGLWLRQ3.DQG3'UHVXOWVZLOOEHUHYLHZHGWRDVVHVVWKHDSSURSULDWHQHVVRIWKHQH[W
SODQQHGGRVHDQGWRJXLGHUHYLVLRQRIWKHQH[WGRVHWREHHYDOXDWHGLIQHFHVVDU\7KH
SODQQHGGRVHVDUHVKRZQLQ7DEOH7KHVHGRVHVPD\EHDGMXVWHGEDVHGRQDFFUXLQJGDWD
KRZHYHUWKHPD[LPXPGRVHWREHVWXGLHGZLOOQRWH[FHHGWKHSODQQHGWRWDOGRVHLQ&RKRUW
PJHYHU\GD\V>GRVHV@
$VLQJOHLQWHULPDQDO\VLVGHVFULEHGLQ6HFWLRQLVSODQQHGWRHQDEOHIXWXUHSURJUDP
SODQQLQJ
3DWLHQWVZLOOXQGHUJRD6FUHHQLQJ3HULRGGXULQJZKLFKWKH(6$GRVHDQGSDUHQWHUDOLURQ
GRVHVPXVWKDYHEHHQVWDEOHDVGHILQHGLQWKHLQFOXVLRQDQGH[FOXVLRQFULWHULD3DWLHQWV
UDQGRPL]HGWRERWK&25DQGSODFHERZLOOEHFRQWLQXHGRQ(6$DQGSDUHQWHUDOLURQ
LIEHLQJJLYHQ
3DWLHQWVPHHWLQJWKHHQWU\FULWHULDZLOOEHUDQGRPL]HGRQ'D\DGLDO\VLVGD\IROORZLQJ
ZKLFKWKH\ZLOOUHFHLYHWKHILUVWGRVHRI6WXG\'UXJGXULQJGLDO\VLV$GGLWLRQDOYLVLWVZLOO
IROORZWKHVFKHGXOHRIHYHQWV$SSHQGL[$$OOVXEVHTXHQW6WXG\'UXJLQIXVLRQVZLOODOVR
EHDGPLQLVWHUHGGXULQJGLDO\VLVDQGVWXG\YLVLWVZLOOFRLQFLGHZLWKUHJXODUO\VFKHGXOHG
GLDO\VLVWUHDWPHQWV3DWLHQWVGURSSLQJRXWLHSUHPDWXUHO\GLVFRQWLQXLQJ6WXG\'UXJ
WUHDWPHQWIRUUHDVRQVXQUHODWHGWRVDIHW\PD\EHUHSODFHG
)ROORZLQJWKHZHHN7UHDWPHQW3HULRGSDWLHQWVZLOOEHIROORZHGIRUDQDGGLWLRQDO
ZHHNVIRUVDIHW\LQWKH6DIHW\)ROORZ8S3HULRG7KHSDWLHQW¶VZLOOKDYHFRPSOHWHGWKHLU
SULPDU\VWXG\SDUWLFLSDWLRQDW:HHNHQGRIWKH6DIHW\)ROORZ8S3HULRG6SDUVHEORRG
VDPSOHVZLOOEHDGGLWLRQDOO\FROOHFWHGRQ:HHNIRUDQWLGUXJDQWLERGLHV
SKDUPDFRNLQHWLFVDQG,/PHDVXUHPHQWVDVSDUWRIDQ([WHQGHG)ROORZ8S3HULRG



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

3.1.1
Pharmacokinetic and PK-PD Modeling 

6HUXP&25FRQFHQWUDWLRQVZLOOEHVXEMHFWHGWR3.PRGHOLQJDQGVHFRQGDU\3.
SDUDPHWHUVVXFKDVPD[LPXPVHUXPGUXJFRQFHQWUDWLRQV&PD[DUHDXQGHUWKHVHUXP
GUXJFRQFHQWUDWLRQWLPHFXUYH$8&DQGWHUPLQDOHOLPLQDWLRQKDOIOLIHWZLOOEH
FDOFXODWHG

7KHIUHHXQERXQGWR&25DQGWRWDOIUHHERXQG,/$8&ZLOOEHGHVFULEHG

7KHFKDQJHLQVHUXPFRQFHQWUDWLRQRI&25IURPSUHGLDO\VLVWRSRVWGLDO\VLVZLOOEH
GHVFULEHG

7KHUHODWLRQVKLSEHWZHHQ&25SKDUPDFRNLQHWLFVDQGSULPDU\SKDUPDFRG\QDPLF
HQGSRLQWVVSHFLILFDOO\IUHHDQGWRWDOVHUXP,/KLJKVHQVLWLYLW\&UHDFWLYHSURWHLQ
KV&53DQGVHUXPDP\ORLG$6$$ZLOOEHGHVFULEHG

3.1.2
Safety Endpoints 
3ULPDU\

&KDUDFWHUL]DWLRQRIWKH07'RUWRHVWDEOLVKWKDWWKHKLJKHVWGRVHH[DPLQHGGLGQRW
H[FHHGWKH07'

6HFRQGDU\

'HVFULSWLRQRIWKHIUHTXHQF\RI'/7VGHILQHGLQ6HFWLRQE\WUHDWPHQWJURXSDQG
GRVH

'HVFULSWLRQRIWKHIUHTXHQF\RIWKHHYHQWVRILQWHUHVWE\WUHDWPHQWJURXSDQGGRVH
GHILQHGLQ6HFWLRQ

'HVFULSWLRQRIDGGLWLRQDOVDIHW\DVVHVVPHQWVE\WUHDWPHQWJURXSDQGGRVHDGYHUVHHYHQWV
YLWDOVLJQV(&*FOLQLFDOODERUDWRU\DQGDQWLGUXJDQWLERGLHVELQGLQJDQGQHXWUDOL]LQJ

3.1.3
Pharmacodynamic Endpoints 
'DWDIURP&25WUHDWHGSDWLHQWVIURP&RKRUWVQRWH[FHHGLQJWKH07'ZLOOEHSRROHG
DQGGDWDIURPDOOSODFHERSDWLHQWVZLOOEHSRROHGIRUWKHSKDUPDFRG\QDPLFHQGSRLQW
DQDO\VHV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

3ULPDU\

&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\LQWKH6$$DQGKV&53WR:HHN
EHWZHHQWUHDWPHQWJURXSV

6HFRQGDU\

0HDQGLIIHUHQFHVEHWZHHQSODFHERDQG&25WUHDWHGSDWLHQWVZLOOEHGHWHUPLQHGIRU
WKHIROORZLQJSDUDPHWHUV

&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQ76$7WR:HHN

&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQWKH&+UWR:HHN

&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQKV&53WRWKHPHDQRI
:HHNV±

&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQ6$$WRWKHPHDQRI
:HHNV±

&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQVHUXPSUHDOEXPLQWRWKH
PHDQRI:HHNV±DQGDOEXPLQWR:HHN

&KDQJHIURPEDVHOLQHZHHNO\PHDQRI6FUHHQLQJLQ(5,WR:HHNDPRQJSDWLHQWV

&KDQJHIURPEDVHOLQHZHHNO\PHDQRI6FUHHQLQJLQ(5,WRWKHPHDQRI:HHNV±

([SORUDWRU\

'HVFULSWLRQRIWKHV\VWHPLFLURQDYDLODELOLW\76$7DEVROXWHUHWLFXORF\WHFRXQW
KHPRJORELQ&+URYHUWLPH

'HVFULSWLRQRIPDUNHUVRIPDOQXWULWLRQLQIODPPDWLRQSUHDOEXPLQDQGDOEXPLQRYHU
WLPH

'HVFULSWLRQRIV\VWHPLFLURQVWRUHVVHUXPIHUULWLQKHSDWLFDQGVSOHQLFLURQFRQWHQWE\
05,DQGVXSSOHPHQWDOLURQGRVHUHTXLUHPHQWVRYHUWLPH

'HVFULSWLRQRI(5,FKDQJHIURPEDVHOLQHZHHNO\PHDQGXULQJWKH6FUHHQLQJ3HULRG
WKURXJK:HHN

'HVFULSWLRQRIFKDQJHV(6$DQGSDUHQWHUDOLURQGRVHUHTXLUHPHQWVIURPEDVHOLQHZHHNO\
PHDQGXULQJWKH6FUHHQLQJ3HULRGWR(YDOXDWLRQ3HULRG:HHNV±DQGWKURXJK
:HHN

'HVFULSWLRQRIFKDQJHVLQ/9PDVVLQGH[IURP6FUHHQLQJWR:HHN


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

'HVFULSWLRQRIFKDQJHVLQSUHGLDO\VLVSRVWGLDO\VLVDQGGHOWDVHUXP7URSRQLQDQG
17SUR%13GHILQHGDVWKHGLIIHUHQFHEHWZHHQWKHSUHDQGSRVWGLDO\VLVWURSRQLQIURP
EDVHOLQHPHDQRI6FUHHQLQJWR:HHNV±

'HVFULSWLRQRIKDQGJULSVWUHQJWK IURPEDVHOLQHGXULQJ6FUHHQLQJWR:HHN

'HVFULSWLRQRIWKH)$&,7IDWLJXHVFRUHIURPEDVHOLQHGXULQJ6FUHHQLQJWR:HHN
3.2
Study Schematic
Figure 2 
Dose Escalation Schematic 

,IWKH07'LVQRWH[FHHGHGGRVHHVFDODWLRQPD\FRQWLQXH

,IWKH07'LVH[FHHGHGDORZHUGRVHLQFOXGLQJSUHYLRXVO\VWXGLHGGRVHPD\EHVHOHFWHG
7KH07'DVVHVVPHQWZLOOEHEDVHGRQVDIHW\GDWDIURP:HHNVWR,IPRUHWKDQRI
DFWLYHSDWLHQWVLQDFRKRUWH[SHULHQFHD'/7WKH07'ZLOOEHFRQVLGHUHGWRKDYHEHHQ
H[FHHGHG
7KHSODQQHGGRVHVVKRZQKHUHPD\EHDGMXVWHGEDVHGRQDFFUXLQJ3.3'DQGVDIHW\GDWD
7KHKLJKHVWGRVHWKDWZLOOEHVWXGLHGLVDFXPXODWLYHGRVHRIPJ([SDQVLRQFRKRUWVWR
IXUWKHUHYDOXDWHGRVHVEHORZWKHGRVHWKDWH[FHHGHGWKH07'PD\EHLQLWLDWHGDWDQ\WLPH
7KHUDQGRPL]DWLRQUDWLRZLWKLQHDFKFRKRUWZLOOEH&25WRSODFHER


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

3.3
Blinding and Randomization 
3.3.1
Randomization 
5DQGRPL]HGWUHDWPHQWVZLOOEHDVVLJQHGYLDDQLQWHUDFWLYHZHEUHVSRQVHV\VWHP,:56
7HQKHPRGLDO\VLVSDWLHQWVZLOOEHUDQGRPL]HGWR&25RUSODFHERZLWKLQHDFKGRVLQJ
FRKRUW:KHQDKLJKHUGRVHWKDQVWXGLHGLQDSULRUFRKRUWLVEHLQJLQLWLDWHGWKHILUVW
VHQWLQHOSDWLHQWVLQWKDWFRKRUWUDQGRPL]HGWR&25RUSODFHERZLOOEHUDQGRPL]HG
ILUVWDQGWKHUHPDLQLQJSDWLHQWVZLOOEHUDQGRPL]HGDWOHDVWKRXUVODWHULQDUDWLRRI
&25WRSODFHER)RUFRKRUWVLQZKLFKGRVHVDUHOHVVWKDQWKHGRVHWKDWH[FHHGHGWKH
07'GHWHUPLQHGIURPHDUOLHUFRKRUWVUDQGRPL]DWLRQRIDOOSDWLHQWVZLOOSURFHHGLQ
SDUDOOHOWRDFKLHYHDQUDWLRRI&25WRSODFHER
3.3.2
Blinding
7KLVVWXG\LVGRXEOHEOLQG7KHSDWLHQWVLQYHVWLJDWRUVVLWHSHUVRQQHOQRWLQFOXGLQJVLWH
SHUVRQQHOUHVSRQVLEOHIRUGUXJYHUVXVSODFHERSUHSDUDWLRQVLWHPRQLWRUVDQG6SRQVRU
FOLQLFDORSHUDWLRQDOSHUVRQQHOZLOOEHEOLQGHGWRWKHWUHDWPHQWDVVLJQPHQW7KH6SRQVRU
UHSUHVHQWDWLYHVRQWKH65&ZLOOEHFRPHXQEOLQGHGIRUWKHVDIHW\UHYLHZVRIHDFKFRKRUWLQ
RUGHUWRVHOHFWGRVHVIRUWKHQH[WFRKRUW7KH65&ZLOOEHXQEOLQGHG,QDGGLWLRQFRQWUDFW
UHVHDUFKRUJDQL]DWLRQ&52SHUVRQQHODQDO\]LQJWKH3.VDPSOHVDQGSHUIRUPLQJWKH3.
WDUJHWHQJDJHPHQWDQGDQDO\VLVRI3.SKDUPDFRG\QDPLFUHODWLRQVKLSVDQGWKRVHUHVSRQVLEOH
IRULQWHUDFWLYHZHEUHVSRQVHV\VWHP,:56ZLOOKDYHDFFHVVWRWKHUDQGRPL]DWLRQOLVW7KH
UDQGRPL]DWLRQOLVWZLOOEHJHQHUDWHGE\D&52VWDWLVWLFLDQQRWRWKHUZLVHLQYROYHGLQWKHVWXG\
RUWKH65&XQEOLQGHGVWDWLVWLFLDQ
3.3.3
Unblinding
,QFDVHRIDPHGLFDOHPHUJHQF\RUPHGLFDOVLWXDWLRQLQZKLFKWKHWUHDWPHQWDVVLJQPHQWLV
QHFHVVDU\IRUSURSHUSDWLHQWPDQDJHPHQWWKH,QYHVWLJDWRUPD\REWDLQWKHWUHDWPHQW
DVVLJQPHQWIURPWKH,:567KH,QYHVWLJDWRUVKRXOGPDNHHYHU\UHDVRQDEOHDWWHPSWWR
FRQWDFWWKH0HGLFDO0RQLWRUEHIRUHXQEOLQGLQJDSDWLHQW,QDOOFDVHVWKH,QYHVWLJDWRUPXVW
VXEPLWDZULWWHQUHSRUWLQFOXGLQJDOOSHUWLQHQWGHWDLOVWRWKH0HGLFDO0RQLWRUZLWKLQ
KRXUVRIWKHXQEOLQGLQJ
3.4
Duration of the Study
7KHWRWDOVWXG\GXUDWLRQIRUDQLQGLYLGXDOSDWLHQWZLOOEHDSSUR[LPDWHO\PRQWKVH[FOXGLQJ
WKH6FUHHQLQJ3HULRG7KHVWXG\SHULRGVDUHDVIROORZV

,QLWLDO6FUHHQLQJ3HULRG8SWRZHHNV>'D\VWR@
–
6WDUWVZLWKWKHILUVWGDWHWKDW,QLWLDO6FUHHQLQJSURFHGXUHVZHUHSHUIRUPHG7KHILUVW
SURFHGXUHDOVRGHILQHVWKH,QLWLDO6FUHHQLQJYLVLWGDWH

)XOO6FUHHQLQJ3HULRGXSWRZHHNV>'D\VWKURXJK'D\@
–
6WDUWVZLWKWKHGDWHRIWKH:HHN9LVLW


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


7UHDWPHQW3HULRGZHHNV>:HHN'D\WKURXJK:HHN@
–
6DIHW\)ROORZ8S3HULRGZHHNV>:HHNVWKURXJK@

([WHQGHG)ROORZ8S3HULRGZHHNV>:HHNVWKURXJK@

3.5
Discussion of Study Design, Including Choice of Control Arm 
7KHVWXG\LVDUDQGRPL]HGZLWKLQFRKRUWGRXEOHEOLQGSODFHERFRQWUROOHGWULDO
5DQGRPL]DWLRQDQGGRXEOHEOLQGLQJDUHEHLQJXVHGWRPLQLPL]HELDV7KHWUHDWPHQWGXUDWLRQ
ZHHNVZDVFKRVHQDVWKHVKRUWHVWGXUDWLRQQHHGHGWRHYDOXDWHWKHSKDUPDFRG\QDPLF
HIIHFWRIVDLGGRVHVRQWKHSURSRVHGLQIODPPDWRU\KHPDWRORJLFDQGFDUGLRYDVFXODU
HQGSRLQWV6DPSOHVL]HFDOFXODWLRQVZHUHSHUIRUPHGIRUVHYHUDOSKDUPDFRG\QDPLFV
HQGSRLQWVDQGWKHVHDUHSUHVHQWHGLQ6HFWLRQ
3.5.1
Study Population and Control Arm
%HFDXVHWKH6WXG\'UXJLVEHLQJDGPLQLVWHUHGLQDGGLWLRQWRFXUUHQWWUHDWPHQWVIRUDQHPLDD
SODFHERFRQWUROLVMXVWLILDEOH$VWKHUHDUHQRFXUUHQWO\DSSURYHGWUHDWPHQWVWKDWLPSURYH
IXQFWLRQDOLURQGHILFLHQF\WKHUHDUHQRRSWLRQVIRUDQDFWLYHFRPSDUDWRU
7KHVWXG\LVEHLQJFRQGXFWHGLQWKHWDUJHWSRSXODWLRQEHFDXVHWKHSKDUPDFRG\QDPLF
HQGSRLQWVLQIODPPDWLRQIXQFWLRQDOLURQGHILFLHQF\DQGOHIWYHQWULFXODUK\SHUWURSK\DQG
VWUDLQFDQQRWEHHYDOXDWHGLQKHDOWK\YROXQWHHUV
)XUWKHUDVKXPDQSKDUPDFRNLQHWLFGDWDWRGDWHDUHDYDLODEOHRQO\IURPDQRQFKURQLFNLGQH\
GLVHDVHSRSXODWLRQLWLVRQHDLPRIWKHVWXG\WRREWDLQ3.GDWDLQWKHKHPRGLDO\VLV
SRSXODWLRQ
3.5.2
Rationale for Dosing and Length of Safety Evaluation 
,QKLELWLRQRIIUHH,/JUHDWHUWKDQLVQHHGHGWRDFKLHYHELRORJLFHIIHFWEHFDXVHJURZWK
IDFWRUVDQGVROXEOHF\WRNLQHVLQJHQHUDODUHDEOHWRHOLFLWVLJQDOLQJZLWKUHFHSWRURFFXSDQFLHV
RIOHVVWKDQ$EDVLFORJDULWKPLFGRVHHVFDODWLRQVFKHPHZDVXVHGDIWHUPRGHOLQJRI
,/ELQGLQJDQGWKH3.3'KV&53UHODWLRQVKLSIURPWKHFRQFOXGHG3KDVHWULDOLQ5$
SDWLHQWV6WXG\'&%DVHGRQWKHFOHDUDQFHRI&25GLFWDWHGE\WKH³<7(´
)FPXWDWLRQWKHGXUDWLRQRIVDIHW\PRQLWRULQJIRUZHHNVIROORZLQJWKHODVWGRVHDQG
H[WHQGHGIROORZXSIRU3.,/DQGDQWLERG\WHVWLQJWRZHHNVLVSODQQHG
3.5.3
Rationale for the Pharmacodynamic Endpoints 
7KHLQIODPPDWRU\SKDUPDFRG\QDPLFHQGSRLQWVRIKV&53DQG6HUXP$P\ORLG$UHGXFWLRQ
DUHFKRVHQDVWKH\DUHDGLUHFWPHDVXUHVRI,/IXQFWLRQVSHFLILFDOO\WKHLUJHQHVDUHLQGXFHG
E\,/$GGLWLRQDOO\KV&53LVDFOLQLFDOO\UHOHYDQWPHDVXUHRILQIODPPDWLRQWKDWPD\EH
XVHGLQIXWXUHWULDOV6HUXPDOEXPLQDQGSUHDOEXPLQDUHDOVRFORVHO\QHJDWLYHO\FRUUHODWHG
ZLWKLQIODPPDWLRQLQWKHGLDO\VLVSRSXODWLRQDVLVWKHUHIRUHDOVREHLQJDQDO\]HGDVDPDUNHU
RILQIODPPDWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

7KHKHPDWRORJLFSKDUPDFRG\QDPLFHQGSRLQWVFKRVHQDUHDVIROORZV76$7KHPRJORELQ
UHWLFXORF\WHFRXQW&+U(6$DQGLURQGRVHUHTXLUHPHQWVDQGHU\WKURSRLHWLQUHVLVWDQFH
LQGH[GHILQHGDVWKHHSRHWLQDOIDHTXLYDOHQWGRVHZHLJKWEDVHGSHUZHHNLQ8NJGLYLGHG
E\WKHVHUXPKHPRJORELQLQJG/7KHVHHQGSRLQWVDUHLQWHQGHGWRHYDOXDWHWKHHIIHFWVRI
UHGXFLQJLQIODPPDWLRQRQIXQFWLRQDOLURQGHILFLHQF\DQHPLDDVZHOODVRQ(6$DQGLURQ
UHTXLUHPHQWVWRPDLQWDLQKHPRJORELQDWDJLYHQJXLGHOLQHGULYHQOHYHO,WLVK\SRWKHVL]HG
WKDW&+UZLOOLQFUHDVHDVLURQLVUHOHDVHGIURPWLVVXHVWRUHVDQGWKDW(5,ZLOOGHFUHDVHDV
KHPRJORELQULVHVDQGRU(6$GRVHUHTXLUHPHQWVIDOODVVXPLQJDGPLQLVWHUHGLURQLV
PDLQWDLQHG7KHUHWLFXORF\WHFRXQWLVH[SHFWHGWRWUDQVLHQWO\LQFUHDVH76$7WRDOVR
H[SHFWHGWRLQFUHDVHRYHUWLPHDVPRUHLURQLVPRELOL]HGXQWLOLURQLVXWLOL]HGIRU
HU\WKURSRLHVLVUHIOHFWHGLQULVLQJKHPRJORELQDVVXPLQJ(6$DQGLURQGRVHVUHPDLQVWDEOH
6XSSRUWLYHFDUGLRYDVFXODUSKDUPDFRG\QDPLFHQGSRLQWVLQFOXGHVHUXPELRPDUNHUV7URSRQLQ
DQG17SUR%13DQGOHIWYHQWULFXODUPDVVLQGH[YLD05,7KHVHDUHFKRVHQEDVHGRQWKH
GRFXPHQWHGGHWULPHQWDOHIIHFWVRI,/DQGEHQHILFLDOHIIHFWVRIDQWL,/WKHUDSLHVRQ
FDUGLDFVWUXFWXUHDQGIXQFWLRQLQLQIODPPDWRU\FRQGLWLRQV
)LQDOO\LQIODPPDWLRQLVNQRZQWRDIIHFWV\VWHPLFV\PSWRPVQRWDEO\IDWLJXHDQGVNHOHWDO
PXVFOHVWUHQJWK
3.5.4
Rationale for the Dose Regimens 
7KHPDLQJRDORI&25GRVLQJLQWKHSODQQHG3KDVHKHPRGLDO\VLVSDWLHQWVWXG\LVWR
DWWDLQDQGPDLQWDLQVHUXP&25FRQFHQWUDWLRQVVXIILFLHQWIRU,/ELQGLQJRYHU
WKHPRQWK7UHDWPHQW3HULRGZLWKDVHFRQGDU\JRDORIUHGXFLQJKV&53WREHORZPJ/
ZKLOHNHHSLQJWKHKLJKHVWSODQQHGGRVHPRUHWKDQIROGEHORZWKHQRDGYHUVHHIIHFWOHYHO
12$(/REVHUYHGLQSULPDWHV
Effects on IL-6 and hsCRP
3KDUPDFRNLQHWLFDQG3'PRGHOVZHUHFUHDWHGEDVHGRQGDWDIURPWKH3KDVHWULDOLQ5$
SDWLHQWV6WXG\'&DQGXVHGWRVLPXODWHGRVLQJUHJLPHQVWKDWDFKLHYHWKHDERYH
JRDOV6HFWLRQ%DVHGRQWKHVHPRGHOVORZHUGRVHVZHUHQHHGHGWRPDLQWDLQVHUXP
&25FRQFHQWUDWLRQVDERYHWKHWDUJHWYDOXHLHWKDWYDOXHUHTXLUHGWRDFKLHYH!
,/ELQGLQJFRPSDUHGWRWKRVHQHHGHGWRQRUPDOL]HKV&53GHILQHGDVKV&53PJ/LQ
DK\SRWKHWLFDOKHPRGLDO\VLVSRSXODWLRQZKRVHEDVHOLQHKV&53LVDWPHGLDQDQGVHUXP,/
OHYHOLVDERYHWKHPHGLDQKV&53QRUPDOL]DWLRQLQDWOHDVWSDWLHQWVLVSUHGLFWHGIRU
FXPXODWLYH&25GRVHRIPJDQGLVQRWSUHGLFWHGIRUDOOSDWLHQWVXQWLOFXPXODWLYH
GRVHVRIPJRUJUHDWHUDUHDFKLHYHG7KH&25GRVHUHJLPHQVSODQQHGDUHLWHPL]HG
EHORZ/RZHUGRVHVLQFOXGLQJSUHYLRXVO\VWXGLHGGRVHVPD\EHVXEVWLWXWHGIRUWKHSODQQHG
GRVHVLQWKHWDEOHEHORZEDVHGRQDFFUXLQJGDWD,QDGGLWLRQ3.DQG3'UHVXOWVZLOOEH
UHYLHZHGWRDVVHVVWKHDSSURSULDWHQHVVRIWKHQH[WSODQQHGGRVHDQGWRJXLGHUHYLVLRQRIWKH
QH[WGRVHWREHHYDOXDWHGLIQHFHVVDU\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Dose Cohort
Dose Regimen
Number of Doses
Total Cumulative Dose

PJHYHU\GD\V

PJ

PJHYHU\GD\V

PJ

PJHYHU\GD\V

PJ

PJHYHU\GD\V

PJ

7KHSODQQHGGRVHVDOOSURYLGHSODVPD,/ELQGLQJLQH[FHVVRIIRUWKHGXUDWLRQRIWKH
VWXG\ZKLOHKV&53QRUPDOL]DWLRQLVH[SHFWHGWREHDWWDLQHGLQRISDWLHQWVDWWKHORZHVW
GRVHDQGLQSDWLHQWVDWWKHKLJKHVWGRVH)XOOVXSSUHVVLRQRIKV&53LVQRWEHOLHYHGWREH
UHTXLUHGIRUEHQHILFLDOHIIHFWRQKHPDWRORJLFRULURQSDUDPHWHUVJLYHQWKHOLQHDUFRUUHODWLRQ
EHWZHHQ&53DQGWKHGHJUHHRIHU\WKURSRLHWLFLQHIILFLHQF\%iUiQ\
$VRI$PHQGPHQWWKHDFWXDOGRVHVDOOJLYHQHYHU\GD\VZHUHPJ&RKRUWVDQG
PJ&RKRUWVDQGPJ&RKRUW
Safety Margins 
7KHSUHGLFWHGPD[LPXPVHUXP&25FRQFHQWUDWLRQZLWKLQDGRVLQJLQWHUYDO&PD[
PLQLPXPVHUXP&25FRQFHQWUDWLRQZLWKLQDGRVLQJLQWHUYDO&PLQDQGWKHFXPXODWLYH
DUHDXQGHUWKHFXUYHIURPWLPHWRLQILQLWHWLPH$8&IRUWKHSODQQHGGRVHVLQWKLVVWXG\
DUHVXPPDUL]HGLQ7DEOH7DEOHDOVRSURYLGHVWKHH[SRVXUHVREWDLQHGIRUWKHKLJKHVW
GRVHLQWKHF\QRPROJXVPRQNH\UHSHDWGRVHWR[LFRORJ\VWXG\6WXG\7KH
H[SRVXUHVIRUDOOFRKRUWVLQWKLVVWXG\KDYHVDIHW\PDUJLQVRItIROGEDVHGRQ$8&
UHODWLYHWRWKHQRREVHUYHGDGYHUVHHIIHFWOHYHO12$(/H[SRVXUHVLQF\QRPROJXVPRQNH\V


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Table 1 
Exposures for Planned Doses and Safety Margins Relative to 
Toxicology Study 
+XPDQ
&\QRPROJXV
0RQNH\
'RVLQJ6FKHGXOH
2 mg 
q14days 
6 mg 
q14days 
20 mg 
q14days 
60 mg 
q14days 
100 mg/kg
&PD[QJP/D

1st dose
712
2138
7126
21379
2420000
last dose
1640
4920
16399
49197
3230000
&PLQQJP/E
1st dose
268
803
2678
8032

last dose
1042
3125
10417
31251
&XPXODWLYH$8&
QJÂGD\P/F
167447
502372
1674472
5023416
111642743
6DIHW\0DUJLQV
&PD[QJP/D

1st dose
3399
1132
340
113
last dose
1970
657
197
66
&XPXODWLYH$8&
QJÂGD\P/F
667
222
67
22
D
'HILQHGDVWKHPHDQHQGRILQIXVLRQFRQFHQWUDWLRQIRUWKHVLPXODWHGVXEMHFWV
E
'HILQHGDVWKHPHDQFRQFHQWUDWLRQDWWKHHQGRIWKHGRVLQJLQWHUYDOIRUWKHVLPXODWHGVXEMHFWV
F
&DOFXODWHGEDVHGRQWKHPHDQFOHDUDQFHIRUWKHVLPXODWHGVXEMHFWV

3.6
Safety Plan and Monitoring
7KHVWXG\GHVLJQLQFOXGLQJHQWU\FULWHULDSODQQHGLQWHULPVDIHW\GDWDUHYLHZVDQGSODQQHG
FRQGXFWLQFOXGHVDQXPEHURIHOHPHQWVLQWHQGHGWRPLQLPL]HULVNLQWHQGHGWREHWWHUPRQLWRU
IRURUWRPLWLJDWHULVNWRVWXG\SDWLHQWV

$OO6WXG\'UXJGRVHVZLOOEHDGPLQLVWHUHGLQHLWKHUDKHPRGLDO\VLVXQLWRU3KDVH
UHVHDUFKXQLWZLWKKHPRGLDO\VLVFDSDELOLWLHVLQWKHSUHVHQFHRIWUDLQHGKHDOWKFDUH
SURIHVVLRQDOVDQGUHVXVFLWDWLYHHTXLSPHQW

3DWLHQWVZLOOEHLQFRQWDFWZLWKKHDOWKFDUHSURIHVVLRQDOVWKUHHWLPHVSHUZHHNGXULQJ
WKHLUKHPRGLDO\VLVWUHDWPHQWVDFWLYHO\REVHUYHGE\VWXG\VWDIIIRUDGYHUVHHYHQWVVXFKDV
LQIHFWLRQVDQGXQGHUJRUHJXODUVDIHW\PRQLWRULQJLHYLWDOVLJQV(&*SK\VLFDO
H[DPLQDWLRQODERUDWRU\HYDOXDWLRQV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


$OOSULQFLSDOLQYHVWLJDWRUVZLOOEHQHSKURORJLVWVDQGWKHUHIRUHVNLOOHGLQWKHPDQDJHPHQW
RIGLDO\VLVSDWLHQWV

'RVHHVFDODWLRQZLOORFFXUE\FRKRUWXSRQIRUPDOVDIHW\UHYLHZDVGHVFULEHGDERYH$Q
HYHU\RWKHUZHHNGRVHDGPLQLVWUDWLRQSDUDGLJPZDVFKRVHQEDVHGRQIRUPDO3.3'
PRGHOLQJWRDOORZIRUWLPHO\ZLWKGUDZDORILQYHVWLJDWLYHWKHUDS\LIUHTXLUHG7KHGRVH
HVFDODWLRQGHFLVLRQZLOODOVRWDNHLQWRDFFRXQWDFFUXHG3.3'GDWDIURPWKHVWXG\VRWKDW
WKHSODQQHGGRVHVFDQEHDGMXVWHGLIQHFHVVDU\

'RVH/LPLWLQJ7R[LFLW\FULWHULDDQGUXOHVIRU07'ZLOOEHSUHGHILQHG%HFDXVHRIWKH
KLJKEDFNJURXQGIUHTXHQF\RI*UDGHDQGDGYHUVHHYHQWVLQKHPRGLDO\VLVSDWLHQWVQRW
GLVVLPLODUIURPFDQFHUSRSXODWLRQVWKH'/7WKUHVKROGZLOOEHGHILQHGXVLQJDWKUHVKROG
RIt*UDGHHYHQWV

,QLWLDOGRVLQJLQHDFKFRKRUWH[DPLQLQJDKLJKHUGRVHWKDQVWXGLHGLQDSULRUFRKRUWZLOO
EHLQWZRVHQWLQHOSDWLHQWVZKRZLOOEHREVHUYHGIRUDWOHDVWKRXUVIRUHDUO\DGYHUVH
HIIHFWVEHIRUHDGGLWLRQDOSDWLHQWVDUHGRVHG

3DWLHQWVZLOOEHUHTXLUHGWRKDYHDQDEVROXWHQHXWURSKLOFRXQWRI![/GXULQJ
VFUHHQLQJDQGGHFUHDVHLQQHXWURSKLOFRXQWZLOOEHWUHDWHGDVDVDIHW\HYHQWRILQWHUHVW

3DWLHQWVDWKLJKULVNIRULQIHFWLRQVXFKDVWKRVHZLWKWHPSRUDU\KHPRGLDO\VLVFDWKHWHUV
UHFHQWRUFXUUHQWDFWLYHLQIHFWLRQVVPROGHULQJLQIHFWLRQVVHURORJLFHYLGHQFHRI+HSDWLWLV
%RU&RU+,9KLVWRU\RIWXEHUFXORVLVRUSRVLWLYHLQWHUIHURQJDPPDUHOHDVHWHVWLQJDQG
EDVHOLQHQHXWURSHQLDZLOOEHH[FOXGHG

3OHDVHVHHWKH*XLGDQFHWR,QYHVWLJDWRUVVHFWLRQRIWKH,QYHVWLJDWRU¶V%URFKXUHIRUD
GHVFULSWLRQRIVDIHW\ILQGLQJVIURPRWKHU,/PRQRFORQDODQWLERGLHVDQGJXLGDQFHIRU
FOLQLFDOPRQLWRULQJ
3.7
Benefit and Risk Assessment
,QIODPPDWRU\IXQFWLRQDOLURQGHILFLHQF\DQHPLDLVDFRPPRQFOLQLFDOIHDWXUHLQKHPRGLDO\VLV
SRSXODWLRQV7KLVFRQGLWLRQUHSUHVHQWVDQLQHIILFLHQF\RIHU\WKURSRLHVLVDVHYLGHQWE\WKH
QHHGIRUHOHYDWHGDQGHVFDODWLQJGRVHVRI(6$VRUSDUHQWHUDOLURQRUERWKLQRUGHUWR
PDLQWDLQVHUXPKHPRJORELQDWDQDFFHSWDEOHYDOXH7KHVHKLJKGRVHVRI(6$VDQGWKH
PDLQWHQDQFHRIDKLJKIHUULWLQOHYHODUHDVVRFLDWHGZLWKLQFUHDVHGULVNRIFDUGLRYDVFXODU
FRPSOLFDWLRQVWKHIRUPHURIZKLFKLVKLJKOLJKWHGE\WKH$JHQF\¶VER[HGZDUQLQJRQ(6$
SURGXFWODEHOLQJDGYLVLQJFRQVHUYDWLYHVHUXPKHPRJORELQWDUJHWVDQGDYRLGDQFHRIFRQWLQXHG
(6$GRVHHVFDODWLRQLQK\SRUHVSRQVLYHSDWLHQWV
'HVSLWHWKHIDFWWKDWWKHFRQFHSWRILQIODPPDWRU\ULVNLQUHQDOSDWLHQWVKDVEHHQLQWKHSXEOLF
GRPDLQIRUGHFDGHVZLWKDQDFWLYHEDVLFUHVHDUFKDQGFOLQLFDOLQYHVWLJDWLRQDOFRPPXQLW\
IRFXVHGRQLWVUHPHGLDWLRQQRWKHUDS\KDVEHHQVSHFLILFDOO\GHVLJQHGRUGHYHORSHGWRDGGUHVV
LW7KHDGYDQFHPHQWRIDQDQWLLQIODPPDWRU\WKHUDS\ZKLFKLPSURYHLURQXWLOL]DWLRQDQG
XOWLPDWHO\UHGXFHVWKHQHHGIRUHVFDODWLQJGRVHVRI(6$VDQGRUSDUHQWHUDOLURQZRXOGEHD
SDUDGLJPVKLIWLQWKHFDUHRIWKHVHSDWLHQWV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

$VIRUWKHULVNVDVVRFLDWHGZLWKDGPLQLVWUDWLRQRI&25QRQFOLQLFDOWR[LFRORJ\VWXGLHV
6HH,QYHVWLJDWRU¶V%URFKXUHHVWDEOLVKHGWKHQRREVHUYHGDGYHUVHHIIHFWOHYHOE\WKH
PD[LPDOGRVHDGPLQLVWHUHG%RWKLQWHUPVRIORFDODQGV\VWHPLFHIIHFWV&25ZDVZHOO
WROHUDWHGZLWKQRDSSDUHQWDGYHUVHILQGLQJV2IQRWHWKHKLJKHVW&25GRVHSODQQHGIRU
VWXG\DOORZVDQRYHUIROGPDUJLQWR12$(/LQWKHQRQFOLQLFDOWR[LFRORJ\SURJUDP
,Q6WXG\'&$VWUD=HQHFD,1'&25ZDVZHOOWROHUDWHGLQWKH
WKUHHSDWLHQWVZKRUHFHLYHGDVLQJOHPJGRVH1RSDWLHQWVGLHGQRSDWLHQWVUHSRUWHG
6$(VDQGQRSDWLHQWVGLVFRQWLQXHGWKHLQYHVWLJDWLRQDOSURGXFWRUIURPWKHVWXG\GXHWRDQ
$($OO$(VZHUHFRQVLGHUHGWREHPLOGWRPRGHUDWHLQLQWHQVLW\2YHUDOOWKHPRVW
FRPPRQO\UHSRUWHG$(ZDVYRPLWLQJIROORZHGE\GLDUUKHDUHSRUWHGE\SDWLHQWVRQ
&25RQO\$OWKRXJKKLJKDQGORZODERUDWRU\YDOXHVZHUHUHSRUWHGIRUDOOSDWLHQWVQR
VSHFLILFWUHQGVFRXOGEHREVHUYHGZLWKWKHH[FHSWLRQRIFKDQJHVLQWKH:%&DQGQHXWURSKLO
FRXQWV1RRWKHUQRWDEOHFKDQJHVLQODERUDWRU\SDUDPHWHUVLQFOXGLQJOLYHUIXQFWLRQYLWDO
VLJQVRUSK\VLFDODVVHVVPHQWVDVUHODWHGWRVDIHW\ZHUHQRWHG
$YDLODEOHGDWDIRUDQWL,/5WRFLOL]XPDEDQGDQWL,/VLOWX[LPDEWKHUDSLHVVXJJHVW
QHXWUDOL]DWLRQRI,/KDYHDFFHSWDEOHVDIHW\DQGWROHUDELOLW\SURILOHVIRUWKHLQGLFDWLRQV
VWXGLHG,QIXVLRQUHODWHGDQGOLIHWKUHDWHQLQJK\SHUVHQVLWLYLW\UHDFWLRQVDUHUDUHZLWKWKHVH
DJHQWV$QWLLQIODPPDWRU\WKHUDSLHVLQJHQHUDOUXQWKHULVNRILQGXFLQJLPPXQHVXSSUHVVLRQ
DQGSURPRWLQJWKHHPHUJHQFHRILQIHFWLRQVVRPHWLPHVVHULRXVLQQDWXUH$OWKRXJKDQWL,/
WKHUDSLHVORZHUQHXWURSKLOFRXQWVDQGPD\LQGXFHIUDQNQHXWURSHQLDWKHLUUDWHVRILQIHFWLRXV
FRPSOLFDWLRQVDSSHDUWREHVLPLODUWRRWKHULPPXQHPRGXODWRU\ELRORJLFDJHQWVZKHQ
DFFRXQWLQJIRUSDWLHQWVSHFLILFIDFWRUV6DNDL6DQRIL*DVWURLQWHVWLQDO
SHUIRUDWLRQKDVEHHQDVVRFLDWHGZLWKDQWL,/WKHUDS\KRZHYHUGDWDVXJJHVWVSURSHU
H[FOXVLRQFULWHULDPD\PLWLJDWHWKHVHULVNV7DQDND
7KHLQFOXVLRQDQGH[FOXVLRQFULWHULDDQGPRQLWRULQJVFKHPDHPSOR\HGLQWKHSODQQHGFOLQLFDO
VWXGLHVDUHGHVLJQHGWRPLQLPL]HDQGPDQDJHWKHSRWHQWLDOULVNVRI&25WKHUDS\DV
LQIHUUHGIURPRWKHUDQWL,/WKHUDSLHV7KHH[FOXVLRQRISDWLHQWVZLWKNQRZQLQIHFWLRQWKH
XVHRIDEVROXWHQHXWURSKLOFRXQWVWRSSLQJUXOHVSURKLELWLRQRIWKHXVHRIOLYHYDFFLQHVDQG
FHUWDLQFRQFRPLWDQWPHGLFDWLRQVZKLFKDUHPHWDEROL]HGE\WKH&<3V\VWHPDQGGLVSOD\
QDUURZWKHUDSHXWLFZLQGRZVH[FOXVLRQRISDWLHQWVZLWKDKLVWRU\RIGLYHUWLFXORVLVDVZHOODV
WKHXVHRIWKH&7&$(V\VWHPRIDGYHUVHHYHQWUHSRUWLQJDQGPD[LPXPWROHUDWHGGRVH
GHILQLWLRQDUHGHVLJQHGWRPLQLPL]HWKHGUXJDVVRFLDWHGULVNVWRVWXG\SDWLHQWV
&25ZLOOEHDGPLQLVWHUHGLQDPRQLWRUHGVHWWLQJWKHKHPRGLDO\VLVXQLWZKHUHIUHTXHQW
ODERUDWRU\PHDVXUHPHQWVWRDVFHUWDLQIRUHIIHFWVVXFKDVDOWHUHGOLYHUIXQFWLRQDQGHOHYDWLRQ
LQVHUXPFKROHVWHURODQGFORVHFRQWDFWZLWKGLDO\VLVVWDIIZLOODOORZIRUSUXGHQWPRQLWRULQJ
DQGHDUO\WUHDWPHQWRIFRPSOLFDWLRQVVKRXOGWKH\RFFXU
)LQDOO\WKHXVHRIDPHFKDQLVWLFDOO\GHULYHGJHQRW\SHSDWLHQWVHOHFWLRQVWUDWHJ\LVLQWHQGHG
WRHQULFKWKHHQUROOHGFRKRUWIRUSDWLHQWVZLWKWKHJUHDWHVWOLNHOLKRRGRIUHVSRQVHWRDQWL,/
WKHUDS\7KHUHIRUHWKHWUHDWPHQWLVSUHFLVHO\WDUJHWHGWRWKHSRSXODWLRQZKRPLJKWEHQHILW
WKHPRVW


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

2QEDODQFHWKHQWKH6SRQVRUSURSRVHVWKHSRWHQWLDOULVNVWRSDWLHQWVLQWKLVVWXG\DUH
MXVWLILDEOHDQGWKHEHQHILWWRULVNUDWLRSRVLWLYH3DWLHQWVZLOOEHFRQVHQWHGDVWRWKHSRWHQWLDO
ULVNVDQGZLOOEHUHTXLUHGWRVLJQDQ,&)GRFXPHQWLQJWKHLUXQGHUVWDQGLQJRIWKHVHULVNVDQG
ZLOOLQJQHVVWRSDUWLFLSDWHLQWKHVWXG\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

4
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL
4.1
Inclusion Criteria
7REHHOLJLEOHSRWHQWLDOVWXG\SDWLHQWVPXVWPHHWDOORIWKHIROORZLQJFULWHULD

$JH!\HDUVDWWKHWLPHRIVLJQLQJRIWKH,&)

5HFHLYLQJFKURQLFKHPRGLDO\VLVIRUDWOHDVWWKUHHPRQWKVSULRUWR6FUHHQLQJYLDDQ
DUWHULRYHQRXVILVWXODRUDUWHULRYHQRXVJUDIW
1RWH(YHU\HIIRUWZLOOEHPDGHWRUHFUXLWSDWLHQWVZKRKDYHDZHOOIXQFWLRQLQJ
DUWHULRYHQRXVILVWXODRUJUDIWWRPLQLPL]HWKHFKDQFHRIUHTXLULQJDFHQWUDOYHQRXV
FDWKHWHUGXULQJWKH7UHDWPHQW3HULRG

7KHSDWLHQWDJUHHVWRFRPSO\ZLWKWKHFRQWUDFHSWLRQDQGUHSURGXFWLRQUHVWULFWLRQVRIWKH
VWXG\
:RPHQRIFKLOGEHDULQJSRWHQWLDOPXVWEHXVLQJDPHWKRGRIFRQWUDFHSWLRQWKDWLV³KLJKO\
HIIHFWLYH´LHIDLOXUHUDWHVHH$SSHQGL[)
25
3RVWPHQRSDXVDOZRPHQPXVWKDYHKDGQRPHQVWUXDOEOHHGLQJIRUDWOHDVW\HDUEHIRUH
LQLWLDOGRVLQJDQGHLWKHUEHRYHUWKHDJHRI\HDUVRUKDYHDQHOHYDWHGSODVPDIROOLFOH
VWLPXODWLQJKRUPRQH)6+OHYHOLH!P,8P/DW6FUHHQLQJ
$1'
$OOIHPDOHSDWLHQWVRIFKLOGEHDULQJSRWHQWLDOPXVWKDYHDGRFXPHQWHGQHJDWLYHSUHJQDQF\
WHVWUHVXOWDW6FUHHQLQJ3DWLHQWVZLWKHOHYDWHGȕ+&*OHYHOVEHOLHYHGWREHGXHWRHQG
VWDJHUHQDOGLVHDVHPD\EHHQUROOHGLIGRFXPHQWHGWRQRWEHSUHJQDQW

7KHSDWLHQWLVDEOHWRJLYHZULWWHQLQIRUPHGFRQVHQWDQGKDVVLJQHGDFRQVHQWIRUP
DSSURYHGE\WKH,QYHVWLJDWRU
V,QVWLWXWLRQDO5HYLHZ%RDUG,5%RU,QGHSHQGHQW(WKLFV
&RPPLWWHH,(&

$WOHDVWRQHGRFXPHQWHGVS.W9!ZLWKLQZHHNVSULRUWRWKH)XOO6FUHHQLQJ3HULRG

³*HQRW\SHSRVLWLYH´JHQRW\SH**RU$*DVGHILQHGE\WKH&HQWUDO/DEYLDJHQHWLF
WHVWLQJGHYHORSHGE\WKH6SRQVRUDW6FUHHQLQJ

7ZRVHUXP,/OHYHOVtSJP/PHDVXUHGDWOHDVWZHHNDSDUWGXULQJWKH6FUHHQLQJ
3HULRG


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


5HFHLYLQJRQHRIWKHIROORZLQJ,9RU6&(6$GUXJVFRQWLQXRXVO\SUHVFULEHGIRUD
PLQLPXPRIZHHNVSULRUWR)XOO6FUHHQLQJHSRHWLQDOIDGDUEHSRHWLQDOIDRU
PHWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWD

(SRHWLQDOIDPXVWQRWKDYHKDGPRUHWKDQRQHGRVHPLVVHGRUKHOGGXULQJ:HHNZHHNV
SULRUWR5DQGRPL]DWLRQ

'DUEHSRHWLQDOIDPXVWQRWKDYHKDGDQ\GRVHVPLVVHGRUKHOGGXULQJWKHZHHNVSULRUWR
5DQGRPL]DWLRQ

0HWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWDPXVWQRWKDYHKDGDQ\GRVHVPLVVHGRUKHOG
GXULQJWKHZHHNVSULRUWR5DQGRPL]DWLRQ


6WDEOH(6$GRVHVSULRUWRUDQGRPL]DWLRQGHILQHGDVIROORZV
For ESAs dosed weekly or more frequently
1RFKDQJHLQWKHWRWDOZHHNO\GRVHGXULQJ:HHNFRPSDUHGZLWK:HHN
For ESAs dosed less often than weekly: 
$Q\GRVHJLYHQGXULQJ)XOO6FUHHQLQJ:HHNDQG:HHNLVXQFKDQJHGIURPWKH
LPPHGLDWHO\SUHFHGLQJGRVH
1RWH,IDGRVHZDVJLYHQRQERWK:HHNDQG:HHNWKHQERWKGRVHVDUHWKHVDPH
7KHVHGRVHVPD\EHGLIIHUHQWWKDQHDUOLHUGRVHV
 +DVEHHQUHFHLYLQJLQWUDYHQRXV,9RUGLDO\VDWHLURQUHJXODUO\DQGFRQWLQXRXVO\HJZLWK
HDFKGLDO\VLVRUHDFKZHHNGXULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQ25KDVUHFHLYHG
QR,9RUGLDO\VDWHLURQGXULQJWKLVWLPHIUDPHDQGXVHRI,9RUGLDO\VDWHLURQLVQRW
DQWLFLSDWHGWKURXJK6WXG\:HHN
,ISDUHQWHUDOLURQKDVEHHQDGPLQLVWHUHGGXULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQWKH
UHJLPHQKDVEHHQVWDEOHVDPHHOHPHQWDOLURQGRVHVDPHIUHTXHQF\DQGVDPHLURQ
SURGXFWZLWKQRPRUHWKDQPLVVHGRUKHOGGRVHVLIGRVHGZLWKHDFKGLDO\VLVDQGQR
PLVVHGRUKHOGGRVHVLIGRVHGZHHNO\RUOHVVIUHTXHQWO\GXULQJWKLVWLPHIUDPH
 ,IUHFHLYLQJRUDOIHUULFFLWUDWHWKHSDWLHQWKDVEHHQSUHVFULEHGLWIRUDWOHDVWZHHNVSULRU
WR)XOO6FUHHQLQJDQGWKHGRVHLVQRWDQWLFLSDWHGWREHFKDQJHGWKURXJK6WXG\:HHN
 $WOHDVWIHUULWLQYDOXHVGXULQJ6FUHHQLQJ!QJP/
 $WOHDVW76$7YDOXHVGXULQJ6FUHHQLQJEHWZHHQDQGLQFOXVLYH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

 (6$UHVLVWDQFHLQGH[FRQILUPHGE\WKH6SRQVRUGXULQJWKHZHHNVSULRUWR
UDQGRPL]DWLRQ
For patient receiving epoetin alfa
7RWDOZHHNO\GRVHRIHSRHWLQDOIDXQLWV
!XQLWVNJSHUJG/
KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

For patients receiving darbepoetin alfa: 
7RWDOZHHNO\GRVHRIGDUEHSRHWLQDOIDPFJ
!XQLWVNJSHUJG/

KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

For patients receiving methoxy polyethylene glycol-epoetin beta
:HHNO\GRVHRIPHWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWDPFJ
!XQLWVNJSHUJG/
KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

,IWKH(6$LVGRVHGOHVVRIWHQWKDQRQFHDZHHNGLYLGHWKHGRVHE\WKHGRVLQJLQWHUYDOWRGHWHUPLQHWKHZHHNO\
GRVH)RUH[DPSOH:HHNO\GRVH GRVHJLYHQHYHU\WZRZHHNV·
7KHILUVWGD\RIHDFKZHHNXVHGIRUFDOFXODWLRQVLVGHILQHGDVWKHILUVWGLDO\VLVGD\RIWKH:HHNLH0RQGD\RU
7XHVGD\
 'XULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQWKHPHDQRIFRQVHFXWLYHKHPRJORELQV
EHWZHHQtDQGJG/ZLWKWKHGLIIHUHQFHEHWZHHQWKHILUVWDQGODVW
PHDVXUHPHQWVEHLQJJG/
1RWH4XDOLI\LQJKHPRJORELQVPXVWEHGUDZQRUPRUHGD\VDSDUWSUHGLDO\VLVZLWKQR
PRUHWKDQPHDVXUHPHQWVZLWKLQDFDOHQGDUZHHN7KHUHPXVWEHDWOHDVWGD\V
EHWZHHQWKHILUVWDQGODVWRIWKHTXDOLI\LQJKHPRJORELQYDOXHV
 ,QYHVWLJDWRUDQWLFLSDWHVQRFKDQJHWR(6$SDUHQWHUDORURUDOLURQSURGXFWVGRVHVRU
GRVLQJUHJLPHQGXULQJ6WXG\:HHNVWKURXJKDQGWKDWIROORZLQJWKHSURWRFRO
JXLGDQFHIRU(6$DQGLURQGRVHFKDQJHV$SSHQGL[&ZLOOEHFOLQLFDOO\DSSURSULDWHIRU
WKHSDWLHQW
 6HUXP9LWDPLQ%DQGIRODWHOHYHOVDERYHWKHODERUDWRU\ORZHUQRUPDOUDQJHGXULQJ)XOO
6FUHHQLQJ



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

4.2
Exclusion Criteria
7REHHOLJLEOHIRUVWXG\HQUROOPHQWSRWHQWLDOVWXG\SDWLHQWVPXVWQRWPHHWDQ\RIWKH
IROORZLQJH[FOXVLRQFULWHULD

$Q\LQGZHOOLQJYDVFXODUFDWKHWHULQFOXGLQJWKDWXVHGIRUGLDO\VLVRUDQWLFLSDWHGRIXVHRI
DQLQGZHOOLQJFDWKHWHUDQ\WLPHGXULQJWKHVWXG\LQFOXGLQJWKH,QLWLDO6FUHHQLQJDQG)XOO
6FUHHQLQJ3HULRGV
3DWLHQWVIRUZKRPDFHQWUDOYHQRXVFDWKHWHULVXVHGZLWKLQZHHNVSULRUWR6WHSRIWKH
,QLWLDO6FUHHQLQJ3HULRGEORRGGUDZIRU,/VHH6HFWLRQZLOOEHDOVREHFRQVLGHUHG
VFUHHQLQJIDLOXUHV

8VHRIV\VWHPLFLPPXQRVXSSUHVVLYHGUXJVGXULQJWKH)XOO6FUHHQLQJ3HULRGRU
DQWLFLSDWHGXVHRIVXFKGUXJVDQ\WLPHGXULQJWKHVWXG\
1RWH8VHRIRWLFRSKWKDOPLFLQKDOHGDQGWRSLFDOFRUWLFRVWHURLGVRUORFDOFRUWLFRVWHURLG
LQMHFWLRQVDUHQRWH[FOXVLRQDU\2UDOSUHGQLVRQHXSWRPJSHUGD\RUHTXLYDOHQWLV
SHUPLWWHG

&OLQLFDOHYLGHQFHRUVXVSLFLRQRIDFWLYHRUVPROGHULQJLQIHFWLRQHJGLDEHWLFIRRWXOFHU
RUXVHRIV\VWHPLFDQWLELRWLFVV\VWHPLFDQWLYLUDOVRUV\VWHPLFDQWLIXQJDOVZLWKLQZHHNV
SULRUWR6WHSRIWKH,QLWLDO6FUHHQLQJ3HULRGEORRGGUDZIRU,/VHH6HFWLRQ
GXULQJWKH,QLWLDO6FUHHQLQJ3HULRGRUWKH)XOO6FUHHQLQJ3HULRG
³6\VWHPLF´LVGHILQHGDVRUDORULQWUDYHQRXVGUXJVWKDWDUHDEVRUEHGLQWRWKHFLUFXODWLRQ

+RVSLWDOL]DWLRQRURXWSDWLHQWSURFHGXUHVZLWKLQZHHNVSULRUWR6WHSRIWKH,QLWLDO
6FUHHQLQJ3HULRGEORRGGUDZIRU,/VHH6HFWLRQGXULQJWKH,QLWLDO6FUHHQLQJ
3HULRGRUWKH)XOO6FUHHQLQJ3HULRGXQOHVVDSSURYHGE\WKH0HGLFDO0RQLWRU
1RWH3OHDVHFRQWDFWWKH0HGLFDO0RQLWRUIRUDSSURYDODQGGHWHUPLQDWLRQRIWLPLQJRI
,/PHDVXUHPHQWVLIFRQVLGHULQJHQUROOLQJSDWLHQWVZLWKKRVSLWDOL]DWLRQVRURXWSDWLHQW
SURFHGXUHVGXULQJWKLVWLPHIUDPH

,QDELOLW\WRXQGHUJRDQRQFRQWUDVWPDJQHWLFUHVRQDQFHLPDJLQJ05,VFDQHJZHLJKW
RYHUWKHOLPLWVIRU05,PDFKLQHFODXVWURSKRELDWKDWFDQQRWEHPDQDJHGFHUWDLQPHWDOOLF
LQGZHOOLQJIRUHLJQERGLHV5HTXLUHPHQWIRU05,PD\H[HPSWHGE\WKHPHGLFDOPRQLWRU
GXHWRSUDFWLFDOFRQVLGHUDWLRQV,QVXFKVLWXDWLRQVSDWLHQWVPD\EHHQUROOHGHYHQLIWKH\
DUHXQDEOHWRXQGHUJR05,

3RVLWLYHWXEHUFXORVLVEORRGWHVWDW6FUHHQLQJ

(YLGHQFHRI+,9RU+,9LQIHFWLRQE\VHURORJ\DW6FUHHQLQJ

+HSDWLWLV%RU&E\VHURORJ\LH+HSDWLWLV%6XUIDFH$QWLJHQRU+HSDWLWLV&DQWLERG\
SRVLWLYHDW6FUHHQLQJ

$67RU$/7![8/1DW6FUHHQLQJ
 +LVWRU\RIOLYHUFLUUKRVLVRUKRPHR[\JHQXVHRWKHUWKDQQRFWXUQDORQO\R[\JHQIRUWKRVH
ZLWKVOHHSDSQHD
 +LVWRU\RIJDVWURLQWHVWLQDOXOFHUDWLRQRUDFWLYHGLYHUWLFXOLWLVLQWKH\HDUSULRUWR,QLWLDO
6FUHHQLQJ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

 $EVROXWHQHXWURSKLOFRXQW[/DW,QLWLDODQG)XOO6FUHHQLQJ
 3ODWHOHWFRXQW[/DW,QLWLDODQG)XOO6FUHHQLQJ
 ([SHFWHGWRUHFHLYHDQ\LQYHVWLJDWLRQDOGUXJRUDQ\RIWKHH[FOXVLRQDU\GUXJVOLVWHGLQ
$SSHQGL[%GXULQJWKH7UHDWPHQW3HULRGRU6DIHW\)ROORZ8S3HULRG
 5HFHLYHGDQLQYHVWLJDWLRQDOGUXJZLWKLQGD\VSULRUWRWKHVWDUWRIWKH)XOO6FUHHQLQJ
3HULRG
 .QRZQDOOHUJ\WRWKH6WXG\'UXJRUDQ\RILWVLQJUHGLHQWV
 &XUUHQWO\EUHDVWIHHGLQJ
 $Q\FRQGLWLRQWKDWFRXOGLQWHUIHUHZLWKRUIRUZKLFKWKHWUHDWPHQWPLJKWLQWHUIHUHZLWK
WKHFRQGXFWRIWKHVWXG\RULQWHUSUHWDWLRQRIWKHVWXG\UHVXOWVRUWKDWZRXOGLQWKHRSLQLRQ
RIWKH,QYHVWLJDWRULQFUHDVHWKHULVNRIWKHSDWLHQW
VSDUWLFLSDWLRQLQWKHVWXG\7KLVZRXOG
LQFOXGHEXWLVQRWOLPLWHGWRDOFRKROLVPGUXJGHSHQGHQF\RUDEXVHSV\FKLDWULFGLVHDVH
HSLOHSV\DQHPLDDWWULEXWDEOHWRDSULPDU\KHPDWRORJLFGLVHDVHHJVLFNOHFHOODQHPLD
RUDQ\XQH[SODLQHGEODFNRXWV
 $FWLYHO\WUHDWHGRUDFWLYHPDOLJQDQF\RWKHUWKDQQRQPHODQRPDVNLQFDQFHUVRUFHUYLFDO
FDUFLQRPDLQVLWXFRQVLGHUHGFXUHGDWWKHWLPHRI)XOO6FUHHQLQJGXULQJWKH\HDUSULRUWR
)XOO6FUHHQLQJ
 0\RFDUGLDOLQIDUFWLRQGXULQJWKHPRQWKVSULRUWR)XOO6FUHHQLQJRUGXULQJ6FUHHQLQJ
 .QRZQRUVXVSHFWHGRFFXOWRUDFWLYHEOHHGLQJRWKHUWKDQWKDWUHODWHGWRWKHKHPRGLDO\VLV
SURFHGXUH
 5HFHLYHGDUHGEORRGFHOORUZKROHEORRGWUDQVIXVLRQZLWKLQPRQWKVSULRUWR)XOO
6FUHHQLQJRUDQWLFLSDWHGWRUHFHLYHDEORRGWUDQVIXVLRQDWDQ\WLPHGXULQJWKHVWXG\
 +DYHLQIODPPDWRU\ERZHOGLVHDVHWKDWKDVEHHQFOLQLFDOO\DFWLYHGXULQJWKHPRQWKV
SULRUWR)XOO6FUHHQLQJRUERQHPDUURZRURUJDQWUDQVSODQW
1RWH3DWLHQWVZLWKDSUHYLRXVO\H[SODQWHGNLGQH\WUDQVSODQWDUHHOLJLEOHDVDUHWKRVHZKR
KDYHDQLPSODQWHGNLGQH\WUDQVSODQWEXWKDYHQRWUHFHLYHGLPPXQRVXSSUHVVLRQIRUDW
OHDVWPRQWKVSULRUWR)XOO6FUHHQLQJ
 $QWLFLSDWHGWRUHFHLYHDQRUJDQWUDQVSODQWGXULQJWKHWLPHIUDPHRIWKHVWXG\
 L37+DW6FUHHQLQJ!SJP/

4.3
Criteria for Discontinuation of Study Drug 
6WXG\'UXJPD\EHSUHPDWXUHO\GLVFRQWLQXHGIRUDQXPEHURIUHDVRQVLQFOXGLQJ

$QLQWHUFXUUHQWLOOQHVV

$Q\LQWROHUDEOH$(WKDWFDQQRWEHDPHOLRUDWHGE\DSSURSULDWHPHGLFDOLQWHUYHQWLRQRU
WKDWLQWKHRSLQLRQRIWKH0HGLFDO0RQLWRURU,QYHVWLJDWRUZRXOGOHDGWRXQGXHULVNLIWKH
SDWLHQWZHUHWRFRQWLQXHRQWUHDWPHQW


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


,PSOHPHQWDWLRQRIVWRSSLQJUXOHVVHH6HFWLRQ

3UHJQDQF\

2UJDQWUDQVSODQWDWLRQRUGHYHORSPHQWRIDQRWKHULQGLFDWLRQIRUFKURQLF
LPPXQRVXSSUHVVLRQ

:LWKGUDZDORIFRQVHQW$SDWLHQWPD\HOHFWWRZLWKGUDZFRQVHQWWRWUHDWPHQWDWDQ\WLPH
–
3DWLHQWVGLVFRQWLQXLQJ6WXG\'UXJWUHDWPHQWDIWHUUHFHLYLQJDQ\DPRXQWRI6WXG\
'UXJVKRXOGXQGHUJRDOOIROORZXSVWXG\SURFHGXUHVXQOHVVWKHSDWLHQWDOVRH[SOLFLWO\
ZLWKGUDZVFRQVHQWIRUWKHVHSURFHGXUHV7KH6WXG\'UXJKDVDORQJ
SKDUPDFRG\QDPLFHIIHFWWKHUHIRUHFRQWLQXHGPRQLWRULQJIRUSKDUPDFRG\QDPLF
HIIHFWVDQGVDIHW\LVSUXGHQW3DWLHQWVZLWKGUDZLQJWKHLUFRQVHQWIRUDOOVWXG\
SURFHGXUHVPXVWEHJLYHQWKHRSWLRQWRFRQWLQXHWRJLYHFRQVHQWIRUSDVVLYHIROORZXS
LHE\PHDQVRIFKDUWUHYLHZIRUDGYHUVHHYHQWVWKURXJK6WXG\:HHN

5HDVRQVIRUDOOZLWKGUDZDOVGLVFRQWLQXDWLRQVRI6WXG\'UXJZLOOEHUHFRUGHGDQGWKH
0HGLFDO0RQLWRUVKRXOGEHLQIRUPHGRIDOOVXFKFDVHVDVWKH\RFFXU
4.4
Dose-Limiting Toxicities, Maximum Tolerated Dose, and Stopping Rules
3ULRUWRGRVHHVFDODWLRQLHKLJKHUWRWDOGRVHWKDQVWXGLHGLQWKHSUHFHGLQJFRKRUWVWKHUH
ZLOOEHDIRUPDOVDIHW\UHYLHZE\WKH6DIHW\5HYLHZ&RPPLWWHH7KHVDIHW\UHYLHZUHTXLUHG
IRUGRVHHVFDODWLRQZLOOLQFOXGHGD\VRIWUHDWPHQWGDWDIURPWKHSUHFHGLQJFRKRUWV
'RVH/LPLWLQJ7R[LFLWLHVDUHGHILQHGDVIROORZV

&RQILUPHG*UDGHQHXWURSHQLDDQGUHSUHVHQWLQJDGHFOLQHRI!IURPEDVHOLQH

6HULRXVDGYHUVHHYHQWVRILQIHFWLRQLQWKHSUHVHQFHRIFRQILUPHG*UDGHRUKLJKHUQHZ
RQVHWO\PSKRSHQLDRUQHZRQVHWQHXWURSHQLD

t*UDGH$/7RU$67

t*UDGHKHPDWRORJLFWR[LFLW\

t*UDGHQRQKHPDWRORJLFWR[LFLW\

'/7ZLOOEHGHILQHGDVDQ\WR[LFLW\WKHUHODWLRQVKLSRIZKLFKWRWKHLQYHVWLJDWLRQDODJHQW
FDQQRWEHUXOHGRXWDVIROORZV

:LWKWKHH[FHSWLRQRI*UDGHQRQKHPDWRORJLFHYHQWV*UDGHRUKLJKHU&7&$(
WR[LFLW\RIDERYHHYHQWVKDYLQJDQDVVHVVHGUHODWLRQVKLSWRWKH6WXG\'UXJRI
³GHILQLWHO\´³SUREDEO\´³SRVVLEO\´RU³XQOLNHO\´ZLOOEHFRQVLGHUHG'/7V
1RWH³QRQKHPDWRORJLFHYHQWV´UHIHUWR'/7FULWHULDDQGDERYH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


*UDGHQRQKHPDWRORJLFWR[LFLWLHVKDYLQJDQDVVHVVHGUHODWLRQVKLSWRWKH6WXG\'UXJRI
³GHILQLWHO\´³SUREDEO\´RU³SRVVLEO\´ZLOOEHFRQVLGHUHG'/7V
,QDGGLWLRQGRVHHVFDODWLRQPD\EHKDOWHGIRUDQ\VDIHW\WUHQGEHOLHYHGWREHGRVHUHODWHG
WKDWZRXOGSRVHDQXQDFFHSWDEOHULVNLIGRVHZHUHHVFDODWHG
,IPRUHWKDQRI&25WUHDWHGSDWLHQWVLQDFRKRUWH[SHULHQFHD'/7WKH07'ZLOOEH
H[FHHGHGDQGVWRSSLQJFULWHULDIRUWKDWGRVHZLOOKDYHEHHQPHW
,QDGGLWLRQLIRI&25WUHDWHGSDWLHQWVLQDFRKRUWH[SHULHQFHVD*UDGHRU'/7
WKHGRVHZLOOQRWEHHVFDODWHG
Stopping Rules for Individual Patients 
6HYHUHLHt*UDGHLQIXVLRQUHODWHGUHDFWLRQVFDUGLRSXOPRQDU\LQIXVLRQUHDFWLRQV
DQDSK\OD[LVRUK\SHUVHQVLWLYLW\VHH6HFWLRQ
Stopping Rules for the Entire Study
,I!&25WUHDWHGSDWLHQWVGHYHORSDQDSK\OD[LVDWDQ\SRLQWGXULQJWKHHQWLUHVWXG\
HQUROOPHQWDQGIXUWKHUGRVLQJZLOOEHVWRSSHG
4.5
Patient Replacement
3DWLHQWVGURSSLQJRXWLHSUHPDWXUHO\GLVFRQWLQXLQJ6WXG\'UXJWUHDWPHQWIRUUHDVRQV
XQUHODWHGWRVDIHW\PD\EHUHSODFHGDWWKH6SRQVRU¶VGLVFUHWLRQ
4.6
Study Completion 
3ULPDU\VWXG\FRPSOHWLRQLVGHILQHGDVWKHFRPSOHWLRQRIWKH:HHNYLVLWHYHQLIRQHRU
PRUHLQWHULPYLVLWVRUSURFHGXUHVZDVZHUHPLVVHG
&RPSOHWLRQRIWKH([WHQGHG)ROORZ8SLVGHILQHGE\WKHFRPSOHWLRQRIWKH:HHNYLVLW
HYHQLIRQHRUPRUHLQWHULPYLVLWVRUSURFHGXUHVZDVZHUHPLVVHG


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

5
ENROLLMENT AND STUDY PROCEDURES
5.1
Patient Identification Numbers
$IWHUVLJQLQJWKH6KRUW,&)SDWLHQWVVKRXOGEHUHJLVWHUHGLQWRWKHHOHFWURQLFGDWDFDSWXUH
V\VWHPWRREWDLQDSDWLHQWLGHQWLILFDWLRQQXPEHUIRUWKHVWXG\
5.2
Screening Visit Procedures (Up to 2 weeks, Days -28 to -15) – Initial 
Screening
6FUHHQLQJZLOOEHFRQGXFWHGLQDVWHSZLVHPDQQHU
7KH,QLWLDO6FUHHQLQJSURFHGXUHVZLOOEHFRQGXFWHGXQGHUD6KRUW,&)WKDWZLOOLQFOXGHD
PHGLFDOFKDUWUHYLHZHJPHGLFDOKLVWRU\FRQFRPLWDQWPHGLFDWLRQODERUDWRU\GDWDIRU
HOLJLELOLW\FULWHULDWKDWFDQEHDVFHUWDLQHGLQWKLVPDQQHUStep 1,QDGGLWLRQWKH6KRUW,&)
ZLOOLQFOXGHFRQVHQWIRUDGMXVWLQJRUZDVKLQJRXWPHGLFDWLRQVDVQHHGHG8SRQGHWHUPLQLQJ
HOLJLELOLW\EDVHGRQPHGLFDOFKDUWUHYLHZ&HQWUDO/DERUDWRU\WHVWVLQFOXGLQJJHQRW\SLQJDQG
6FUHHQLQJ,/WHVWVVKRXOGEHVXEPLWWHGWRWKH&HQWUDO/DERUDWRU\VHH$SSHQGL[$
Step 2
'XULQJ,QLWLDO6FUHHQLQJSHULRGSDWLHQWVVKRXOGEHPRQLWRUHGIRUSURVSHFWLYHHOLJLELOLW\
EDVHGRQSDUDPHWHUVWREHDVVHVVHGGXULQJ)XOO6FUHHQLQJ6SHFLILFDOO\(5,KHPRJORELQ
VWDELOLW\DQGVWDELOLW\RI(6$DQGLURQGRVLQJVKRXOGEHREVHUYHGSHUWKH6FKHGXOHRI(YHQWV
DQGSDWLHQWVZKRLQWKHMXGJPHQWRIWKH,QYHVWLJDWRUDUHOLNHO\WRFOHDUWKHVHLQFOXVLRQFULWHULD
GXULQJ)XOO6FUHHQLQJVKRXOGEHDOORZHGWRHQWHUWKHZHHN)XOO6FUHHQLQJSHULRG
3DWLHQWVZKRDUHHOLJLEOHIROORZLQJ,QLWLDO6FUHHQLQJVKRXOGSURFHHGDVVRRQDVIHDVLEOHLQWR
WKHIXOO6FUHHQLQJ3HULRGWRHQVXUHWKDWWKHWLPHIURPWKHILUVW6FUHHQLQJ,/PHDVXUHPHQW
DQGUDQGRPL]DWLRQGRHVQRWH[FHHGZHHNV
7HQWDWLYHO\VFKHGXOHWKH&DUGLDF05,WRRFFXUGXULQJ)XOO6FUHHQLQJ
5.3
Screening Visit Procedures (Days -14 to -1) – Full Screening 
3ULRUWRFRQGXFWLQJDQ\SURFHGXUHVLQIRUPHGFRQVHQWIRUWKHIXOOVWXG\VKRXOGEHREWDLQHG
DQGWKH/RQJ,&)VLJQHG7KH/RQJ,&)LQFOXGHVFRQVHQWIRUDOOVWXG\SURFHGXUHV
VXEVHTXHQWWRWKH,QLWLDO6FUHHQLQJ
(YHU\HIIRUWVKRXOGEHPDGHWRREWDLQWKHEORRGWHVWVIRUHDFKYLVLWRQWKHVDPHGD\RIWKH
ZHHNHJRQ:HGQHVGD\V
Important3OHDVHQRWHWKDW(6$,9LURQDQGGLDO\VDWHLURQGRVLQJVKRXOGEHPRQLWRUHG
FDUHIXOO\GXULQJWKLVSHULRGDVLWLVUHTXLUHGWREHVWDEOHDVGHILQHGLQWKHLQFOXVLRQ
FULWHULDDQG6HFWLRQLQRUGHUIRUSDWLHQWVWREHHOLJLEOH8SGDWHVWDQGLQJRUGHUVIRU
WKHVHPHGLFDWLRQVDVQHHGHG
7KHIROORZLQJVHFWLRQVVXPPDUL]HWKHSURFHGXUHVIRU:HHNDQG:HHN3OHDVHVHH
$SSHQGL[$IRUIXOOGHWDLOV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Week -2
x
'LVSHQVHIHFDORFFXOWEORRGWHVWVFROOHFWLRQPDWHULDOVDQGUHYLHZLQVWUXFWLRQVIRU
VWRROFROOHFWLRQZLWKWKHSDWLHQWWRDYRLGIDOVHSRVLWLYHVVHH/DERUDWRU\0DQXDOIRU
LQVWUXFWLRQV5HTXHVWUHWXUQRIWKHVDPSOHVZLWKLQZHHNWRDOORZVXIILFLHQWWLPH
IRUDQDO\VHVRIWKHVHDWWKH&HQWUDO/DERUDWRU\,IQHFHVVDU\VWRRORFFXOWEORRG
WHVWLQJPD\EHSHUIRUPHGORFDOO\LIPDWHULDOVKDYHQRWEHHQUHWXUQHGLQDWLPHO\
PDQQHU

Week -2 and Week -1 

2QHDFKRIWKHVHZHHNVREWDLQEHIRUHDQGDIWHUDVLQJOHGLDO\VLVVHVVLRQSUHGLDO\VLVDQG
SRVWGLDO\VLV&HQWUDO/DERUDWRU\WHVWVSUHGLDO\VLVDQGSRVWGLDO\VLVYLWDOVLJQVDQG
ZHLJKWVDQGUHFRUGWKHQHWXOWUDILOWUDWLRQLHIOXLGUHPRYHGPLQXVIOXLGDGPLQLVWHUHG
GXULQJGLDO\VLVIURPWKHVDPHGLDO\VLVVHVVLRQDURXQGZKLFKDERYHSURFHGXUHVZHUH
SHUIRUPHG
–
$WDQ\WLPHGXULQJWKHVHZHHNVSHUIRUPDOLPLWHGSK\VLFDOH[DPLQDWLRQVHH
6HFWLRQREWDLQDOHDG(&*VHH6HFWLRQPHDVXUHWKHKDQGJULS
VWUHQJWKDQGKDYHWKHSDWLHQWFRPSOHWHWKH)$&,7)TXHVWLRQQDLUH
–
,QVWUXFWLRQVIRUSHUIRUPLQJWKHKDQGJULSVWUHQJWKDQGWKH)$&,7)TXHVWLRQQDLUHFDQ
EHIRXQGLQWKH6WXG\5HIHUHQFH0DQXDO

&ROOHFWDOOVWRRORFFXOWEORRGWHVWVIURPSDWLHQWVDQGVXEPLWWRWKH&HQWUDO/DERUDWRU\
/RFDOO\SHUIRUPHGVWRROWHVWLQJPD\EHVXEVWLWXWHGLI&HQWUDO/DERUDWRU\UHVXOWVDUHQRW
DYDLODEOHSULRUWRUDQGRPL]DWLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

$VFHUWDLQWKDWWKHSDWLHQWUHPDLQVHOLJLEOHEHIRUHSURFHHGLQJWRWKHQH[WYLVLW

6FKHGXOHWKH'D\YLVLWWRRFFXURQD0RQGD\7XHVGD\7KXUVGD\RU)ULGD\ZKHQHYHU
SRVVLEOH

2EWDLQDQRQFRQWUDVWFDUGLDF05,VHH05,7HFKQLFDO0DQXDOIRULQVWUXFWLRQVLQ
:HHNRU:HHN

5.3.1
Laboratory Re-Testing and Re-Screening
$QLQGLYLGXDOODERUDWRU\YDOXHPD\EHUHSHDWHGRQFHGXULQJ,QLWLDO6FUHHQLQJRU)XOO
6FUHHQLQJIRUDQ\UHDVRQHJ,QYHVWLJDWRUEHOLHYHVYDOXHWREHHUURQHRXV$Q\DGGLWLRQDO
ODERUDWRU\UHWHVWLQJPXVWEHDSSURYHGE\WKH0HGLFDO0RQLWRU
3DWLHQWVIDLOLQJ6FUHHQLQJPD\EHDOORZHGWRUHHQWHU6FUHHQLQJXQGHUVRPHFLUFXPVWDQFHV
ZLWKDSSURYDOIURPWKH0HGLFDO0RQLWRU


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

3DWLHQWVZKRDUHUHVFUHHQLQJPD\IROORZDQDEEUHYLDWHGPRGLILHGVHWRI6FUHHQLQJ
SURFHGXUHVDVIROORZV

*HQRW\SHWHVWLQJQRWUHTXLUHG

&DUGLDF05,QRWUHTXLUHGLISUHYLRXVO\SHUIRUPHGZLWKLQZHHNVSULRUWRWKH
UHVFUHHQLQJ:HHN9LVLWGDWH

,QLWLDO6FUHHQLQJPHGLFDOKLVWRU\QRWUHTXLUHG3OHDVHQRWHWKDWFRQILUPDWLRQRI
HOLJLELOLW\UHPDLQVDSURFHGXUHGXULQJ)XOO6FUHHQLQJ

7%WHVWLQJQRWUHTXLUHGLISUHYLRXVO\SHUIRUPHGZLWKLQZHHNVSULRUWRWKH
UHVFUHHQLQJ:HHN9LVLWGDWH

6WRRORFFXOWEORRGWHVWLQJQRWUHTXLUHGLISUHYLRXVO\SHUIRUPHGZLWKLQZHHNVSULRU
WRWKHUHVFUHHQLQJ:HHN9LVLWGDWH

6KRUW,&)DQG/RQJ,&)5HVLJQSULRUWRVWDUWLQJUHVFUHHQLQJSURFHGXUHV

7KHIROORZLQJVHFWLRQVVXPPDUL]HWKHSURFHGXUHVIRUWKH7UHDWPHQW3HULRG3OHDVHVHH
$SSHQGL[$IRUIXOOGHWDLOV
5.4
Treatment Period (Study Weeks 1 - 12) 
Important3OHDVHQRWHWKDW(6$DQG,9DQGGLDO\VDWHLURQGRVLQJVKRXOGEHFRQWUROOHG
FDUHIXOO\GXULQJWKLVSHULRGDVWKH\DUHUHTXLUHGWREHVWDEOHDVGHILQHGLQ$SSHQGL[&
(QVXUHSURFHVVHVDQGVWDIIWUDLQLQJDUHLQSODFHWRDYRLGLQDGYHUWHQWFKDQJHVLQWKHVH
PHGLFDWLRQ
6WXG\9LVLWVGXULQJZKLFK6WXG\'UXJLQIXVLRQVDUHUHTXLUHGVKRXOGEHSODQQHGIRUWKHVDPH
GD\RIWKHZHHNVRWKDW6WXG\'UXJDGPLQLVWUDWLRQFDQRFFXURQDVFKHGXOHRIHYHU\GD\V
6HH6HFWLRQIRUJXLGDQFHRQPLVVHGGRVHV
5.4.1
Week 1, Day 1 (First Dose) 

5DQGRPL]HWKHSDWLHQW

5DQGRPL]DWLRQPD\EHSHUIRUPHGRQ'D\LIQHHGHG$GPLQLVWUDWLRQRIWKHILUVW
GRVHRI6WXG\'UXJZLOOFRQWLQXHWRGHILQH6WXG\'D\

3UHSDUHWKH6WXG\'UXJSULRUWRWKHDQWLFLSDWHGWLPHRIDGPLQLVWUDWLRQVHH6HFWLRQ
DQG3KDUPDF\0DQXDO

3HUIRUPWKHKDQGJULSVWUHQJWKSULRUWRWKHVWDUWRIGLDO\VLVVHHLQVWUXFWLRQVLQWKH6WXG\
5HIHUHQFH0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQDQ(&*SULRUWRWKHVWDUWRIGLDO\VLVVHH6HFWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


+DYHSDWLHQWFRPSOHWHWKH)$&,7)TXHVWLRQQDLUHVHHLQVWUXFWLRQVLQ6WXG\5HIHUHQFH
0DQXDOSULRUWRGLDO\VLVRUGXULQJWKHILUVWKRXURIGLDO\VLV

$Q\WLPHSULRUWRWKHODVWRQHKRXURIGLDO\VLVVWDUWWKH6WXG\'UXJLQIXVLRQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
PLQXWHVIROORZLQJWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQGPLQXWHV
PLQXWHVDQGPLQXWHVIROORZLQJWKHHQGRIWKH6WXG\'UXJLQIXVLRQ

:LWKLQPLQXWHVDIWHUFRPSOHWLQJWKH6WXG\'UXJLQIXVLRQREWDLQEORRGVDPSOHV

:KHQHYHUIHDVLEOHHJILUVWVKLIWSDWLHQWVREWDLQ3.3'EORRGVDPSOHV>@KRXUV
DIWHUFRPSOHWLQJWKH6WXG\'UXJLQIXVLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

5.4.2
Week 1, Days 3 and 5 

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVDIWHUWKHHQGRIGLDO\VLV

5HFRUGDGYHUVHHYHQWDQGDQ\PHGLFDWLRQFKDQJHV

5.4.3
Week 2

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVDIWHUWKHHQGRIGLDO\VLV

5HFRUGDGYHUVHHYHQWDQGDQ\PHGLFDWLRQFKDQJHV

5.4.4
Week 3

3UHSDUHWKH6WXG\'UXJSULRUWRWKHDQWLFLSDWHGWLPHRIDGPLQLVWUDWLRQVHH6HFWLRQ
DQG3KDUPDF\0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

$Q\WLPHSULRUWRWKHODVWRQHKRXURIGLDO\VLVVWDUWWKH6WXG\'UXJLQIXVLRQ

:LWKLQPLQXWHVDIWHUFRPSOHWLQJWKH6WXG\'UXJLQIXVLRQREWDLQEORRGVDPSOHV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
DQGPLQXWHVIROORZLQJWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
PLQXWHVDQGPLQXWHVIROORZLQJWKHHQGRIWKH6WXG\'UXJLQIXVLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.4.5
Week 4

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

5HFRUGDGYHUVHHYHQWDQGDQ\PHGLFDWLRQFKDQJHV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

5.4.6
Week 5

3UHSDUHWKH6WXG\'UXJSULRUWRWKHDQWLFLSDWHGWLPHRIDGPLQLVWUDWLRQVHH6HFWLRQ
DQG3KDUPDF\0DQXDODQG3KDUPDF\0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

$Q\WLPHSULRUWRWKHODVWRQHKRXURIGLDO\VLVVWDUWWKH6WXG\'UXJLQIXVLRQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
DQGPLQXWHVIROORZLQJWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
PLQXWHVDQGPLQXWHVIROORZLQJWKHHQGRIWKH6WXG\'UXJLQIXVLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.4.7
Week 6 

3HUIRUPWKHKDQGJULSVWUHQJWKSULRUWRWKHVWDUWRIGLDO\VLVVHHLQVWUXFWLRQVLQWKH6WXG\
5HIHUHQFH0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQDQ(&*SULRUWRWKHVWDUWRIGLDO\VLVVHH6HFWLRQ

+DYHSDWLHQWFRPSOHWHWKH)$&,7)TXHVWLRQQDLUHVHHLQVWUXFWLRQVLQ6WXG\5HIHUHQFH
0DQXDOSULRUWRGLDO\VLVRUGXULQJWKHILUVWKRXURIGLDO\VLV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

3HUIRUPDOLPLWHGSK\VLFDOH[DPLQDWLRQVHH6HFWLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

,IQRWSUHYLRXVO\GRQH6FKHGXOH&DUGLDF05,WRRFFXURQ:HHN>ZHHNV@

5.4.8
Week 7 

3UHSDUHWKH6WXG\'UXJSULRUWRWKHDQWLFLSDWHGWLPHRIDGPLQLVWUDWLRQVHH6HFWLRQ
DQG3KDUPDF\0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

$Q\WLPHSULRUWRWKHODVWRQHKRXURIGLDO\VLVVWDUWWKH6WXG\'UXJLQIXVLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
DQGPLQXWHVIROORZLQJWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
PLQXWHVDQGPLQXWHVIROORZLQJWKHHQGRIWKH6WXG\'UXJLQIXVLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.4.9
Week 8 

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVDIWHUWKHHQGRIGLDO\VLV

5HFRUGDGYHUVHHYHQWDQGDQ\PHGLFDWLRQFKDQJHV

5.4.10
Week 9

3UHSDUHWKH6WXG\'UXJSULRUWRWKHDQWLFLSDWHGWLPHRIDGPLQLVWUDWLRQVHH6HFWLRQ
DQG3KDUPDF\0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

$Q\WLPHSULRUWRWKHODVWRQHKRXURIGLDO\VLVVWDUWWKH6WXG\'UXJLQIXVLRQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
DQGPLQXWHVIROORZLQJWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQG
PLQXWHVDQGPLQXWHVIROORZLQJWKHHQGRIWKH6WXG\'UXJLQIXVLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.4.11
Week 10

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

5HFRUGDGYHUVHHYHQWDQGDQ\PHGLFDWLRQFKDQJHV



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

5.4.12
Week 11, Day 71 

3UHSDUHWKH6WXG\'UXJSULRUWRWKHDQWLFLSDWHGWLPHRIDGPLQLVWUDWLRQVHH6HFWLRQ
DQG3KDUPDF\0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQZHLJKWZLWKLQPLQXWHVSULRUWRWKHVWDUWRIWKHGLDO\VLV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

$Q\WLPHSULRUWRWKHODVWRQHKRXURIGLDO\VLVVWDUWWKH6WXG\'UXJLQIXVLRQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHLQIXVLRQDQGPLQXWHV
IROORZLQJWKHVWDUWRIWKH6WXG\'UXJLQIXVLRQDQGPLQXWHVDQGPLQXWHV
IROORZLQJWKHHQGRIWKH6WXG\'UXJLQIXVLRQ

2EWDLQEORRGVDPSOHVZLWKLQPLQXWHVDIWHUFRPSOHWLQJLQIXVLRQ

2EWDLQEORRGVDPSOHVZLWKLQPLQXWHVDIWHUFRPSOHWLQJGLDO\VLV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVDIWHUGLDO\VLV

2EWDLQZHLJKWSRVWGLDO\VLVZLWKLQPLQXWHVDIWHUFRPSOHWLQJGLDO\VLV

:KHQHYHUIHDVLEOHHJILUVWVKLIWSDWLHQWVREWDLQ3.EORRGVDPSOHV>@KRXUVDIWHU
FRPSOHWLQJWKH6WXG\'UXJLQIXVLRQ

5HFRUGQHWXOWUDILOWUDWLRQIRUWKHGLDO\VLVVHVVLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.4.13
Week 11, Day 75 

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQZHLJKWZLWKLQPLQXWHVSULRUWRWKHVWDUWRIWKHGLDO\VLV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRVWDUWLQJGLDO\VLV

2EWDLQEORRGVDPSOHVZLWKLQPLQXWHVDIWHUFRPSOHWLQJGLDO\VLV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVDIWHUGLDO\VLV

2EWDLQZHLJKWSRVWGLDO\VLVZLWKLQPLQXWHVDIWHUFRPSOHWLQJGLDO\VLV

5HFRUGQHWXOWUDILOWUDWLRQIRUWKHGLDO\VLVVHVVLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

5.4.14
Week 12/ET-1 

3HUIRUPWKHKDQGJULSVWUHQJWKSULRUWRWKHVWDUWRIGLDO\VLVVHHLQVWUXFWLRQVLQWKH6WXG\
5HIHUHQFH0DQXDO

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQDZHLJKWZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQDQ(&*SULRUWRWKHVWDUWRIGLDO\VLVVHH6HFWLRQ

+DYHSDWLHQWFRPSOHWHWKH)$&,7)TXHVWLRQQDLUHVHHLQVWUXFWLRQVLQ6WXG\5HIHUHQFH
0DQXDOSULRUWRGLDO\VLVRUGXULQJWKHILUVWKRXURIGLDO\VLV

2EWDLQEORRGVDPSOHVZLWKLQPLQXWHVDIWHUFRPSOHWLQJGLDO\VLV

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVDIWHUGLDO\VLV

2EWDLQZHLJKWSRVWGLDO\VLVZLWKLQPLQXWHVDIWHUFRPSOHWLQJGLDO\VLV

5HFRUGQHWXOWUDILOWUDWLRQIRUWKHGLDO\VLVVHVVLRQ

3HUIRUPDOLPLWHGSK\VLFDOH[DPLQDWLRQVHH6HFWLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

2EWDLQDQRQFRQWUDVWFDUGLDF05,VHH05,7HFKQLFDO0DQXDOIRULQVWUXFWLRQV

5.5
Safety Follow-Up Period Procedures (Study Weeks 13 – 24) 
5.5.1
Weeks 14, 16, and 20 

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.5.2
Weeks 18 and 24/ET-2 

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

2EWDLQD/RFDO/DERUDWRU\RUSRLQWRIFDUH,15RQO\IRUSDWLHQWVRQZDUIDULQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


2EWDLQDQ(&*SULRUWRWKHVWDUWRIGLDO\VLVVHH6HFWLRQ

2EWDLQYLWDOVLJQVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

3HUIRUPDOLPLWHGSK\VLFDOH[DPLQDWLRQVHH6HFWLRQ

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.6
Extended Follow-Up Procedures (Study Week 35 ) 
5.6.1
Week 35 

2EWDLQ&HQWUDO/DERUDWRU\EORRGVDPSOHVZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV

5.7
Unscheduled Visit
$GGLWLRQDOFOLQLFDOYLVLWVPD\EHVFKHGXOHGDWWKH,QYHVWLJDWRUV¶GLVFUHWLRQLQRUGHUWRIROORZ
RUHYDOXDWH$(V7KHUHDVRQIRUDJLYHQXQVFKHGXOHGYLVLWZLOOEHUHFRUGHG
7KHIROORZLQJPXVWEHSHUIRUPHGDWDQ\XQVFKHGXOHGYLVLWRFFXUULQJSULRUWR:HHN

5HFRUGDGYHUVHHYHQWVDQGDQ\PHGLFDWLRQFKDQJHV

5.8
Early Termination Visit
7KHUHDUHWZRSRVVLEOHW\SHVRI(DUO\7HUPLQDWLRQYLVLWV
Early Termination Visit 1 (ET-1)5DQGRPL]HGSDWLHQWVWHUPLQDWLQJIURPWKHVWXG\
SUHPDWXUHO\SULRUWR6WXG\:HHNVKRXOGXQGHUJRDQ(DUO\7HUPLQDWLRQ9LVLWGXULQJZKLFK
:HHNSURFHGXUHVDUHSHUIRUPHG3DWLHQWVWHUPLQDWLQJWKHVWXG\SULRUWR:HHNVKRXOG
QRWXQGHUJRWKH:HHNFDUGLDF05,
Early Termination Visit 2 (ET-2)5DQGRPL]HGSDWLHQWVWHUPLQDWLQJIURPWKHVWXG\
SUHPDWXUHO\DIWHU6WXG\:HHNYLVLWEXWEHIRUH:HHNVKRXOGXQGHUJRDQHDUO\
WHUPLQDWLRQYLVLWGXULQJZKLFK:HHNSURFHGXUHVDUHSHUIRUPHG
5.8.1
Early Withdrawal from the Study 
&ULWHULDIRUGLVFRQWLQXDWLRQRI6WXG\'UXJFDQEHIRXQGLQ6HFWLRQ
3DWLHQWVPD\EHZLWKGUDZQIURPWKHVWXG\IRUDQXPEHURIUHDVRQVLQFOXGLQJWKRVHRXWOLQHG
EHORZ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


:LWKGUDZDORIFRQVHQWIRUDOOVWXG\SURFHGXUHV
–
3DWLHQWVZLWKGUDZLQJWKHLUFRQVHQWIRUDOOVWXG\SURFHGXUHVPXVWEHJLYHQWKHRSWLRQ
WRFRQWLQXHWRJLYHFRQVHQWIRUSDVVLYHIROORZXSLHE\PHDQVRIFKDUWUHYLHZIRU
DGYHUVHHYHQWVWKURXJK6WXG\:HHN

'LVFRQWLQXDWLRQRIWKHVWXG\E\WKH6SRQVRU



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

6
DRUG SUPPLIES AND DOSING
6.1.1
Dosing and Administration
7KHGRVHRI&25IRULQWUDYHQRXV,9DGPLQLVWUDWLRQPXVWEHSUHSDUHGXVLQJDVHSWLF
WHFKQLTXHV'UXJ3URGXFWLVSUHVHQWHGDVDVLQJOHXVHYLDODQGDQ\XQXVHGSRUWLRQPXVWEH
GLVFDUGHG
&25LVVXSSOLHGDVDO\RSKLOLVHGFDNH5HFRQVWLWXWLRQZLWKP/6WHULOH:DWHUIRU
,QMHFWLRQJLYHVDP/QRPLQDOYROXPHFRQWDLQLQJPJRI&25PJP/
&25VWRFNVROXWLRQLQP0/KLVWLGLQH/KLVWLGLQHK\GURFKORULGHPRQRK\GUDWH
P0>ZY@WUHKDORVHGLK\GUDWHZYSRO\VRUEDWHS+
7KHSODQQHGGRVHVIRUWKHVWXG\DUHGHVFULEHGLQ6HFWLRQDQGLQ7DEOH7KHDFWXDO
GRVHVZLOOEHEDVHGRQDUHYLHZRIVDIHW\DQGLQOLIHSKDUPDFRNLQHWLFGDWDWRWKHH[WHQW
DYDLODEOHGXULQJWKHVWXG\7KHUHFRQVWLWXWHG&25VWRFNVROXWLRQZLOOUHTXLUHVHULDO
GLOXWLRQLQ,9%DJ3URWHFWDQW,9%3WRREWDLQFRQFHQWUDWLRQVZKLFKSHUPLWPDQDJHDEOH
YROXPHVRIGUXJWREHKDQGOHG3OHDVHVHH7DEOHDQG)LJXUH3HUVRQQHOUHVSRQVLEOHIRU
VWXG\GUXJSUHSDUDWLRQVKRXOGKDYHDQDSSURSULDWHEDFNJURXQGLHSK\VLFLDQSKDUPDFLVW
SKDUPDF\WHFKQLFLDQQXUVHRURWKHUSHUVRQQHODSSURYHGE\WKH6SRQVRUDQGKDVEHHQ
DSSURSULDWHO\WUDLQHG3OHDVHVHH3KDUPDF\0DQXDOIRUIXOOGHWDLOV
7KHILQDOUHTXLUHGYROXPHRIGLOXWHG&25P/SOXV,9%DJ3URWHFWDQWP/
LVDGGHGWRP/VDOLQHIRU,9LQIXVLRQ)LJXUH
(DFKGRVHRI&25RUSODFHERZLOOEHDGPLQLVWHUHGYLD,9LQIXVLRQZLWKDPLFURQ
LQOLQHILOWHURYHUDSSUR[LPDWHO\PLQXWHVVWDUWLQJDQ\WLPHSULRUWRWKHODVWKRXURI
GLDO\VLV6WXG\9LVLWVGXULQJZKLFK6WXG\'UXJLQIXVLRQVDUHUHTXLUHGVKRXOGEHSODQQHGRQ
WKHVDPHGD\RIWKHZHHNVRWKDW6WXG\'UXJDGPLQLVWUDWLRQFDQRFFXURQDVFKHGXOHRIHYHU\
GD\V3OHDVHVHHWKH3KDUPDF\0DQXDOIRULQVWUXFWLRQVRQSUHSDULQJDQGDGPLQLVWHULQJ
WKH6WXG\'UXJDQGVWRUDJHRISUHSDUHG6WXG\'UXJ
6SHFLDO6LWXDWLRQV

,IWKHGLDO\VLVWUHDWPHQWLVHQGHGHDUOLHUWKDQSODQQHGFRQWLQXHWKH6WXG\'UXJLQIXVLRQ
XQWLOWKHLQIXVLRQLVFRPSOHWHG

,IWKHLQIXVLRQLVLQWHUUXSWHGRUIORZUDWHVORZHGHJGXHWRDQDGYHUVHHYHQWDQG
GLDO\VLVLVFRPSOHWHGEHIRUHWKH6WXG\'UXJLQIXVLRQKDVHQGHGFRQWLQXHWKH6WXG\'UXJ
LQIXVLRQXQWLOWKHLQIXVLRQLVFRPSOHWHG

3DWLHQWVZKRUHTXLUHVORZHUIORZUDWHVHJGXHWRSULRULQWROHUDQFHZLWKWKHQRUPDOIORZ
UDWHVWKH6WXG\'UXJDGPLQLVWUDWLRQPD\EHVWDUWHGHDUOLHULQWKHGLDO\VLVVHVVLRQWR
DOORZWKH6WXG\'UXJLQIXVLRQHQGWRFRLQFLGHZLWKWKHHQGRIGLDO\VLVRUSULRUWRWKHHQG
RIGLDO\VLV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


3DWLHQWVZKRPLVVDGRVHRI6WXG\'UXJHJGXHWRDPLVVHGGLDO\VLVYLVLWPD\UHFHLYH
WKHPLVVHG6WXG\'UXJXSWRKRXUVODWHURQDGLDO\VLVGD\,IWKHPLVVHGGRVHFDQQRW
EHDGPLQLVWHUHGZLWKLQWKLVWLPHIUDPHWKHGRVHVKRXOGEHFRQVLGHUHG³PLVVHG´DQGWKH
QH[WGRVHDGPLQLVWHUHGDWWKHQH[WVWXG\YLVLWDVSODQQHG

)RUSDWLHQWVIRUZKRPORJLVWLFDOFRQVLGHUDWLRQVUHTXLUHPLQRUDGMXVWPHQWVWRWKH6WXG\'UXJ
LQIXVLRQWLPLQJLQFOXGLQJDGPLQLVWUDWLRQRIWKH6WXG\'UXJSULRUWRRUDIWHUGLDO\VLVSOHDVH
FRQWDFWWKH0HGLFDO0RQLWRU
,QWKHDERYHVSHFLDOVLWXDWLRQVSOHDVHHQVXUHWKDWEORRGWHVWLQJWKDWLVWLPHGZLWKWKHVWDUWDQG
HQGRILQIXVLRQDUHDGKHUHGWR
Table 2 
Planned COR-001 Doses, Serial Dilutions and Administered Volumes
Dose 
Cohort
Dosing Regimen
Drug Stock 
Concentration
(mg/mL in 
sterile water)
# of serial 
dilutions
(1 ml drug 
stock added 
to 2 ml from 
dilution vial 
for final 
volume of 
3 ml)
Diluted Drug 
Volume to be 
Used
(mL)
IVBP volume 
to be added to 
saline 
infusion bag
(in 100 ml 
saline)
Total Volume 
to be added to 
100mL 0.9% 
saline

PJHYHU\GD\V






PJHYHU\GD\V






PJHYHU\GD\V






PJHYHU\GD\V



P/IURP
GUXJYLDOV




$VRI3URWRFRO$PHQGPHQWWKHDFWXDOGRVHVDOOJLYHQHYHU\GD\VZHUHPJ&RKRUWVDQGPJ
&RKRUWVDQGPJ&RKRUW


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH
Figure 3 
A and B: Reconstitution and Serial Dilution of COR-001 for 
Administration
7KHGDWHDQGWLPHRIDGPLQLVWUDWLRQRI6WXG\'UXJPXVWEHUHFRUGHGLQWKHDSSURSULDWH
VHFWLRQVRIWKH&5)V$Q\LQWHUUXSWLRQVLQWKHLQYHVWLJDWLRQDOSURGXFWLQIXVLRQGDWHDQG
WLPHLQIXVLRQZDVVWRSSHGDQGGDWHDQGWLPHLQIXVLRQZDVUHVWDUWHGDQGDQ\FKDQJHVLQIORZ
UDWHVKRXOGDOVREHGRFXPHQWHGLQWKH&5)ZLWKDQDSSURSULDWHH[SODQDWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

6.1.2
Storage 
&25SODFHERGLOXHQWDQGWKH,9EDJSURWHFWDQWPXVWEHVWRUHGDWWR&LQWKH
RULJLQDOFRQWDLQHUDQGPXVWQRWEHIUR]HQ
6.1.3
Formulation and Packaging 
Table 3 
Composition for COR-001 for Injection, 50 mg/Vial
Ingredients
Quantity per vial
&25
50 mg
/+LVWLGLQH
1.9 mg
/+LVWLGLQHK\GURFKORULGHPRQRK\GUDWH
2.6 mg
7UHKDORVHGHK\GUDWH
85.0 mg
3RO\VRUEDWH
0.5 mg
:DWHUIRU,QMHFWLRQ
1.2 mL reconstitution volume
Table 4 
Composition for Placebo for Injection (3 mL vial) 
Ingredients
Quantity per vial
/+LVWLGLQH
1.9 mg
/+LVWLGLQHK\GURFKORULGHPRQRK\GUDWH
2.6 mg
7UHKDORVHGHK\GUDWH
85.0 mg
3RO\VRUEDWH
0.5 mg

Table 5 
Composition IV Bag Protectant and Diluent (3 mL vial) 
Ingredients
Quantity per vial
6RGLXPFLWUDWH
11.3 mg
&LWULFDFLG
1.2 mg
3RO\VRUEDWH
139.1 mg

6.2
Drug Accountability and Compliance
7KHGLVSHQVLQJSKDUPDFLVWRUGHVLJQDWHGTXDOLILHGLQGLYLGXDOZLOOZULWHWKHGDWHGLVSHQVHG
GRVHGLVSHQVHGDQGWKHSDWLHQW¶VLGHQWLILFDWLRQQXPEHUDQGLQLWLDOVRQWKH'UXJ
$FFRXQWDELOLW\6RXUFH'RFXPHQWV$OOPHGLFDWLRQVXSSOLHGZLOOEHDFFRXQWHGIRURQWKH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

'UXJ$FFRXQWDELOLW\5HFRUG$OOSDUWLDOO\XVHGRUXQXVHGGUXJVXSSOLHVZLOOEHGHVWUR\HGDW
WKHVLWHLQDFFRUGDQFHZLWKDSSURYHGZULWWHQVLWHSURFHGXUHVRUUHWXUQHGWR&RUYLGLD
7KHUDSHXWLFVRQO\DIWHUZULWWHQDXWKRUL]DWLRQLVREWDLQHGIURP&RUYLGLD7KHUDSHXWLFV7KH
,QYHVWLJDWRUZLOOPDLQWDLQDUHFRUGRIWKHDPRXQWDQGGDWHVZKHQXQXVHGVXSSOLHVZHUHHLWKHU
GHVWUR\HGRUUHWXUQHGWR&RUYLGLD7KHUDSHXWLFV$OOUHFRUGVZLOOEHUHWDLQHGDVQRWHGLQ
6HFWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

7
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS
7.1
Prior Medications and Treatments
6HH6HFWLRQDQG6HFWLRQIRUUHVWULFWLRQVRQSULRUPHGLFDWLRQVDQGWUHDWPHQWV
7.2
Concomitant Medications and Treatments
3DWLHQWVPD\UHFHLYHFRQFRPLWDQWPHGLFDWLRQVDVFOLQLFDOO\LQGLFDWHGZLWKWKHIROORZLQJ
UHVWULFWLRQV

3DUHQWHUDOLURQ)RUSDWLHQWVUHFHLYLQJ,9RULQWUDGLDO\WLFLURQGRVHVDQGIUHTXHQF\PXVW
EHPDLQWDLQHGGXULQJ6WXG\:HHNVWKURXJKVHH$SSHQGL['

(6$V5HVWULFWLRQVRQGRVHDGMXVWPHQWGXULQJ6WXG\:HHNVDQGGRVHDGMXVWPHQWV
GXULQJ6WXG\:HHNVWKURXJKVKRXOGEHPDGHLQDJUHHPHQWZLWKWKHSURWRFRO
UHTXLUHPHQWVDQGJXLGHOLQHVVHH$SSHQGL['

2UDOIHUULFFLWUDWH)RUSDWLHQWVUHFHLYLQJWKLVGUXJGXULQJ6FUHHQLQJPDLQWDLQWKHGRVH
GXULQJ6WXG\:HHNVWKURXJK

6\VWHPLFLPPXQRVXSSUHVVLYHGUXJVLHVXFKDVF\FORVSRULQHWDFUROLPXVVLUROLPXV
P\FRSKHQRODWHRUDODQGLQWUDYHQRXVJOXFRFRUWLFRLGVRWKHUWKDQSUHGQLVRQH>RU
HTXLYDOHQW@XSWRDGRVHRIPJSHUGD\PD\QRWEHSUHVFULEHGDWDQ\WLPHGXULQJ6WXG\
:HHNV7RSLFDOXVHHJF\FORVSRULQHH\HGURSVLVQRWUHVWULFWHG
1RWH8VHRIRWLFRSKWKDOPLFLQKDOHGDQGWRSLFDOFRUWLFRVWHURLGVRUORFDO
FRUWLFRVWHURLGLQMHFWLRQVDUHQRWUHVWULFWHG6KRUWWHUPV\VWHPLFJOXFRFRUWLFRLGXVH
HJOHVVWKDQFRQVHFXWLYHGD\VIRUPDQDJLQJDFXWHLOOQHVVHVLVDOVRQRWUHVWULFWHG

1DUURZWKHUDSHXWLFZLQGRZPHGLFDWLRQVWKDWDUHLQIOXHQFHGE\&<3HQ]\PDWLFSDWKZD\V
6HHOLVWLQ$SSHQGL[%PD\QRWEHSUHVFULEHGDWDQ\WLPHGXULQJ6WXG\:HHNV
–
:DUIDULQLVSHUPLWWHGEXWWKH,15PXVWEHPRQLWRUHGFORVHO\DQGDWPLQLPXP
DFFRUGLQJWRWKHSURWRFRO6FKHGXOHRI(YHQWVVHH$SSHQGL[$



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

8
MANAGEMENT OF SPECIFIC ADVERSE EVENTS  
8.1
Serious Infections
6WXG\GUXJWUHDWPHQWVVKRXOGEHZLWKKHOGLISDWLHQWVH[SHULHQFHDVHULRXVLQIHFWLRQXQWLOWKH
LQIHFWLRQLVEHOLHYHGWRKDYHFRPSOHWHO\UHVROYHG7KH,QYHVWLJDWRUVKRXOGFRQWDFWWKH
0HGLFDO0RQLWRUWRGLVFXVVZKHWKHUWKHSDWLHQWVKRXOGUHWXUQWR6WXG\'UXJWUHDWPHQW
8.2
Infusion-Related Reactions, Hypersensitivity, and Anaphylaxis 
6LJQVRIDSRVVLEOHLQIXVLRQUHODWHGUHDFWLRQVLQFOXGHIHYHUFKLOOVSUXULWXVXUWLFDULD
&DUGLRSXOPRQDU\UHDFWLRQVLQFOXGLQJEXWQRWOLPLWHGWRFKHVWSDLQG\VSQHDK\SRWHQVLRQRU
K\SHUWHQVLRQPD\DOVREHLQGLFDWLYHRIDQLQIXVLRQUHDFWLRQEXWVRPHVXFKDVK\SRWHQVLRQ
PD\EHGLIILFXOWWRGLVWLQJXLVKIURPV\PSWRPVUHODWHGWRWKHGLDO\VLVSURFHGXUHUHODWHGVLJQV
DQGV\PSWRPV,QWKHVHVLWXDWLRQV,QYHVWLJDWRUVPXVWGHWHUPLQHZKHWKHURUQRWWKH
V\PSWRPVUHSUHVHQWDQLQIXVLRQUHODWHGUHDFWLRQHJE\FRQVLGHULQJV\PSWRPVDQG
V\PSWRPVHYHULW\DUHW\SLFDOIRUWKDWSDWLHQWHWF
$QDSK\OD[LVLVDVHYHUHSRWHQWLDOO\IDWDOV\VWHPLFDOOHUJLFUHDFWLRQWKDWRFFXUVVXGGHQO\
DIWHUFRQWDFWZLWKDQDOOHUJ\FDXVLQJVXEVWDQFHVXFKDVDQLQYHVWLJDWLRQDOSURGXFW
)RUWKHSXUSRVHVRIWKLVVWXG\DK\SHUVHQVLWLYLW\UHDFWLRQLVGHILQHGDVDQDFXWHRQVHWRIDQ
LOOQHVVZLWKLQYROYHPHQWRIWKHVNLQPXFRVDOWLVVXHRUERWKGXULQJLQIXVLRQRIWKH6WXG\
'UXJEXWGRHVQRWPHHWWKHGHILQLWLRQRIDQDSK\OD[LVGHVFULEHGDERYH
,IVLJQVDQGV\PSWRPVRILQIXVLRQUHODWHGUHDFWLRQVDUHREVHUYHGGXULQJWKHLQIXVLRQDQGWKH
SDWLHQW¶VFDUGLRYDVFXODUVWDWXVLVVWDEOH

5HGXFHWKHIORZUDWHRIWKHLQIXVLRQE\DWOHDVWKDOIDQGLQFUHDVHWKHLQIXVLRQWLPH

,IWKHSDWLHQWFRQWLQXHVWRVKRZVLJQVDQGV\PSWRPVRIK\SHUVHQVLWLYLW\DGPLQLVWHUDQ
,9GRVHRIDQWLKLVWDPLQHLIWKH,QYHVWLJDWRUEHOLHYHVWKLVLVDSSURSULDWH7KHLQIXVLRQ
PD\DOVREHLQWHUUXSWHGLIQHHGHGDQGUHVWDUWHGDWDIORZUDWHWKDWLVDWOHDVW
UHGXFHG

,QSDWLHQWVZKRKDYHH[SHULHQFHGPLOGRUPRGHUDWHLQIXVLRQUHDFWLRQVGXULQJSULRU6WXG\
'UXJDGPLQLVWUDWLRQVDQWLKLVWDPLQHVDQGRUDFHWDPLQRSKHQPD\EHDGPLQLVWHUHG
SURSK\ODFWLFDOO\SULRUWRVXEVHTXHQWLQIXVLRQVDWWKHGLVFUHWLRQRIWKH,QYHVWLJDWRU

,QSDWLHQWVZKRH[SHULHQFHVHYHUHLHt*UDGHLQIXVLRQUHODWHGUHDFWLRQV
FDUGLRSXOPRQDU\LQIXVLRQUHDFWLRQVDQDSK\OD[LVRUK\SHUVHQVLWLYLW\VHHGHILQLWLRQDQG
JUDGLQJEHORZ

3HUPDQHQWO\GLVFRQWLQXHWKH6WXG\'UXJ

7UHDWWKHSDWLHQWVDVIRUDQDQDSK\ODFWLFUHDFWLRQZLWK,9DQWLKLVWDPLQHVFRUWLFRVWHURLGV
HSLQHSKULQHLQKDOHGEURQFKRGLODWRUVDQGRWKHUPHDVXUHVDVQHFHVVDU\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


2EWDLQDEORRGVDPSOHIRUWKHSUHVHQFHRIDQWLGUXJDQWLERGLHV

7KHSDWLHQWVKRXOGUHPDLQLQWKHVWXG\IRUFRQWLQXHGIROORZXSEXWVKRXOGUHFHLYHQR
IXUWKHU6WXG\'UXJ

CTCAE Grading for Infusion-Related Reactions

*UDGH0LOGWUDQVLHQWUHDFWLRQLQIXVLRQLQWHUUXSWLRQQRWLQGLFDWHGLQWHUYHQWLRQQRW
LQGLFDWHG

*UDGH7KHUDS\RULQIXVLRQLQWHUUXSWLRQLQGLFDWHGEXWUHVSRQGVSURPSWO\WR
V\PSWRPDWLFWUHDWPHQWHJDQWLKLVWDPLQHQRQVWHURLGDODQWLLQIODPPDWRU\GUXJV
>16$,'6@QDUFRWLFV,9IOXLGVSURSK\ODFWLFPHGLFDWLRQVLQGLFDWHGIRUKRXUV

*UDGH3URORQJHGHJQRWUDSLGO\UHVSRQVLYHWRV\PSWRPDWLFPHGLFDWLRQDQGRUEULHI
LQWHUUXSWLRQRILQIXVLRQUHFXUUHQFHRIV\PSWRPVIROORZLQJLQLWLDOLPSURYHPHQW
KRVSLWDOL]DWLRQLQGLFDWHGIRUFOLQLFDOVHTXHODH

*UDGH/LIHWKUHDWHQLQJFRQVHTXHQFHVXUJHQWLQWHUYHQWLRQLQGLFDWHG

*UDGH'HDWK

CTCAE Grading for anaphylaxis  

*UDGH6\PSWRPDWLFEURQFKRVSDVPZLWKRUZLWKRXWXUWLFDULDOSDUHQWHUDOLQWHUYHQWLRQ
LQGLFDWHGDOOHUJ\UHODWHGHGHPDDQJLRHGHPDK\SRWHQVLRQ

*UDGH/LIHWKUHDWHQLQJFRQVHTXHQFHVXUJHQWLQWHUYHQWLRQLQGLFDWHG

*UDGH'HDWK



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

9
ADVERSE EVENT REPORTING
9.1
Adverse Event Definitions 
$Q$(LVDQ\XQGHVLUDEOHHYHQWRUDQ\XQWRZDUGPHGLFDORFFXUUHQFHWKDWRFFXUVWRD
SDUWLFLSDQWGXULQJWKHFRXUVHRIDVWXG\RUWKHSURWRFROGHILQHGWLPHDIWHUVWXG\WHUPLQDWLRQ
ZKHWKHURUQRWWKDWHYHQWLVFRQVLGHUHG6WXG\'UXJUHODWHG
([DPSOHVLQFOXGH

$Q\WUHDWPHQWHPHUJHQWVLJQVDQGV\PSWRPVHYHQWVWKDWDUHPDUNHGE\DFKDQJHIURP
WKHSDWLHQW¶VEDVHOLQHHQWU\VWDWXV>HJDQLQFUHDVHLQVHYHULW\RUIUHTXHQF\RISUH
H[LVWLQJDEQRUPDOLW\RUGLVRUGHU@

$OOUHDFWLRQVIURP6WXG\'UXJDEXVHRIGUXJZLWKGUDZDOSKHQRPHQDVHQVLWLYLW\RU
WR[LFLW\WR6WXG\'UXJ

$SSDUHQWO\XQUHODWHGLOOQHVVHV

,QMXULHVRUDFFLGHQWVHJIRUDIDOOVHFRQGDU\WRGL]]LQHVVUHFRUG³GL]]LQHVV´DVWKH
HYHQWDQGLQFOXGHWKHLQIRUPDWLRQDERXWWKHIDOOLQWKHFRPPHQWQDUUDWLYHVHFWLRQDQG
LQIRUPDWLRQDERXWDQ\LQMXU\VHFRQGDU\WRWKHIDOODVSDUWRIWKH³RXWFRPH´

([DFHUEDWLRQVLQFUHDVHLQIUHTXHQF\RUVHYHULW\RIV\PSWRPDWRORJ\VXEMHFWLYHSDWLHQW
UHSRUWHGHYHQWVQHZFOLQLFDOO\VLJQLILFDQWDEQRUPDOLWLHVLQFOLQLFDOODERUDWRU\
SK\VLRORJLFDOWHVWLQJRUSK\VLFDOH[DPLQDWLRQ

$EQRUPDOODERUDWRU\ILQGLQJVFRQVLGHUHGE\WKH,QYHVWLJDWRUWREHFOLQLFDOO\VLJQLILFDQW
,QJHQHUDODQDEQRUPDOODERUDWRU\YDOXHVKRXOGQRWEHUHFRUGHGDVDQDGYHUVHHYHQW
XQOHVV
–
,WLVDVVRFLDWHGZLWKFOLQLFDOVLJQVRUV\PSWRPV
–
5HTXLUHVDQLQWHUYHQWLRQUHVXOWVLQDVHULRXVDGYHUVHHYHQWRU
–
5HVXOWVLQVWXG\WHUPLQDWLRQRULQWHUUXSWLRQGLVFRQWLQXDWLRQRIVWXG\WUHDWPHQW

+RZHYHULIQRQHRIWKHDERYHDSSO\EXWWKHODERUDWRU\DEQRUPDOLW\LVFRQVLGHUHGFOLQLFDOO\
VLJQLILFDQWO\ZRUVHQHGLWVKRXOGEHUHSRUWHGDVDODERUDWRU\$(HJ³LQFUHDVHGZKLWHEORRG
FHOOFRXQW´:KHQUHFRUGLQJDQDGYHUVHHYHQWUHVXOWLQJIURPDODERUDWRU\DEQRUPDOLW\WKH
UHVXOWLQJPHGLFDOFRQGLWLRQUDWKHUWKDQWKHDEQRUPDOLW\LWVHOIVKRXOGEHUHFRUGHGHJUHFRUG
³DQHPLD´UDWKHUWKDQ³ORZKHPRJORELQ´


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

9.2
Serious Adverse Event Definition
$Q6$(LVDQ\$(RFFXUULQJDWDQ\GRVHDQGUHJDUGOHVVRIFDXVDOLW\WKDW

5HVXOWVLQGHDWK

,VOLIHWKUHDWHQLQJ/LIHWKUHDWHQLQJPHDQVWKDWLQWKHRSLQLRQRIWKH,QYHVWLJDWRURU6WXG\
6SRQVRUWKHSDWLHQWZDVDWLPPHGLDWHULVNRIGHDWKIURPWKHUHDFWLRQDVLWRFFXUUHGLH
LWGRHVQRWLQFOXGHDUHDFWLRQWKDWK\SRWKHWLFDOO\PLJKWKDYHFDXVHGGHDWKKDGLWRFFXUUHG
LQDPRUHVHYHUHIRUP

5HTXLUHVLQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ
+RVSLWDOL]DWLRQDGPLVVLRQVDQGRUVXUJLFDORSHUDWLRQVVFKHGXOHGWRRFFXUGXULQJWKHVWXG\
SHULRGEXWSODQQHGEHIRUHWKHVLJQLQJIRUWKH,&)DUHQRWFRQVLGHUHG$(VLIWKHLOOQHVVRU
GLVHDVHH[LVWHGEHIRUHWKHSDWLHQWZDVHQUROOHGLQWKHWULDOSURYLGHGWKDWLWGLGQRW
GHWHULRUDWHLQDQXQH[SHFWHGPDQQHUGXULQJWKHWULDOHJVXUJHU\SHUIRUPHGHDUOLHUWKDQ
SODQQHG

5HVXOWVLQSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\'LVDELOLW\LVGHILQHGDVD
VXEVWDQWLDOGLVUXSWLRQRIDSHUVRQ¶VDELOLW\WRFRQGXFWQRUPDOOLIHIXQFWLRQV

,VDFRQJHQLWDODQRPDO\ELUWKGHIHFW

,VDQLPSRUWDQWPHGLFDOHYHQW$QLPSRUWDQWPHGLFDOHYHQWLVDQHYHQWWKDWPD\QRW
UHVXOWLQGHDWKEHOLIHWKUHDWHQLQJRUUHTXLUHKRVSLWDOL]DWLRQEXWPD\EHFRQVLGHUHGDQ
6$(ZKHQEDVHGXSRQDSSURSULDWHPHGLFDOMXGJPHQWLWPD\MHRSDUGL]HWKHSDWLHQWDQG
PD\UHTXLUHPHGLFDORUVXUJLFDOLQWHUYHQWLRQWRSUHYHQWRQHRIWKHRXWFRPHVOLVWHGLQWKH
GHILQLWLRQVIRU6$(V([DPSOHVRIVXFKPHGLFDOHYHQWVLQFOXGHDOOHUJLFEURQFKRVSDVP
UHTXLULQJLQWHQVLYHWUHDWPHQWLQDQHPHUJHQF\URRPRUDWKRPHEORRGG\VFUDVLDVRU
FRQYXOVLRQVWKDWGRQRWUHVXOWLQLQSDWLHQWKRVSLWDOL]DWLRQRUWKHGHYHORSPHQWRIGUXJ
GHSHQGHQF\RUGUXJDEXVH

$GLVWLQFWLRQVKRXOGEHPDGHEHWZHHQWKHWHUPV³VHULRXV´DQG³VHYHUH´VLQFHWKH\are not
V\QRQ\PRXV7KHWHUP³VHYHUH´LVRIWHQXVHGWRGHVFULEHWKHLQWHQVLW\VHYHULW\RIDVSHFLILF
HYHQWDVLQPLOGPRGHUDWHRUVHYHUHP\RFDUGLDOLQIDUFWLRQWKHHYHQWLWVHOIKRZHYHUPD\
EHRIUHODWLYHO\PLQRUPHGLFDOVLJQLILFDQFHVXFKDVVHYHUHKHDGDFKH7KLVLVnotWKHVDPH
DV³VHULRXV´ZKLFKLVEDVHGRQSDWLHQWHYHQWRXWFRPHRUDFWLRQFULWHULDXVXDOO\DVVRFLDWHG
ZLWKHYHQWVWKDWSRVHDWKUHDWWRDSDWLHQW¶VOLIHRUIXQFWLRQLQJ$VHYHUHDGYHUVHHYHQWGRHV
QRWQHFHVVDULO\QHHGWREHFRQVLGHUHGVHULRXV)RUH[DPSOHSHUVLVWHQWQDXVHDRIVHYHUDO
KRXUVGXUDWLRQPD\EHFRQVLGHUHGVHYHUHQDXVHDEXWQRWDQ6$(LIWKHHYHQWGRHVQRWPHHW
WKHVHULRXVFULWHULD2QWKHRWKHUKDQGDVWURNHUHVXOWLQJLQRQO\DPLQRUGHJUHHRIGLVDELOLW\
PD\EHFRQVLGHUHGPLOGEXWZRXOGEHGHILQHGDVDQ6$(EDVHGRQWKHDERYHQRWHGVHULRXV
FULWHULD6HULRXVQHVVQRWVHYHULW\VHUYHVDVDJXLGHIRUGHILQLQJUHJXODWRU\UHSRUWLQJ
REOLJDWLRQV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

9.3
Adverse Events of Special Interest 
7KHIROORZLQJDGYHUVHHYHQWVRIVSHFLDOLQWHUHVWPXVWEHUHSRUWHGWRWKH6SRQVRUZLWKLQ
KRXUVRIWKH,QYHVWLJDWRU¶VDZDUHQHVVHYHQLIQRWPHHWLQJWKHGHILQLWLRQRIDVHULRXV
DGYHUVHHYHQW

6HYHUHLQIXVLRQUHODWHGUHDFWLRQVVHH6HFWLRQ

+\SHUVHQVLWLYLW\UHDFWLRQGXULQJWKH6WXG\'UXJLQIXVLRQVHH6HFWLRQ

$QDSK\OD[LVVHH6HFWLRQRFFXUULQJDWDQ\WLPHHYHQLIFRQVLGHUHGXQUHODWHGWRWKH
6WXG\'UXJ

$&5)IRUWKHFROOHFWLRQRIWKHGHWDLOVRIVXFKUHDFWLRQVZLOOEHDYDLODEOHLQWKH('&
1HXWURSHQLD*UDGHRUKLJKHU>LHDEVROXWHQHXWURSKLOFRXQWPPDQGGHFOLQHE\DW
OHDVWIURP%DVHOLQH@DUHDOVRHYHQWVRILQWHUHVWDQGWKHVHZLOOEHVHSDUDWHO\VXPPDUL]HG
E\WUHDWPHQWJURXSDQGGRVH
9.4
Assessment of Causal Relationship 
7KHFDXVDODVVRFLDWLRQRI$(VWR6WXG\'UXJDGPLQLVWUDWLRQVKRXOGEHGHWHUPLQHGDVIROORZV
7KHIROORZLQJFDWHJRULHVVKRXOGEHXVHGLQWKHFDXVDOLW\DVVHVVPHQWRIVXVSHFWHGDGYHUVH
UHDFWLRQV
3UREDEOH
7KH$(

IROORZVDUHDVRQDEOHWHPSRUDOVHTXHQFHIURPWKHWLPHRI6WXG\'UXJDGPLQLVWUDWLRQ
DQGRU

IROORZVDNQRZQUHVSRQVHSDWWHUQWRWKH6WXG\'UXJDQG

ZDVXQOLNHO\WRKDYHEHHQSURGXFHGE\RWKHUIDFWRUVVXFKDVWKHSDWLHQW¶VFOLQLFDOVWDWH
WKHUDSHXWLFLQWHUYHQWLRQRUFRQFRPLWDQWWKHUDS\

3RVVLEOH
7KH$(

IROORZVDUHDVRQDEOHWHPSRUDOVHTXHQFHIURPWKHWLPHRI6WXG\'UXJDGPLQLVWUDWLRQ
DQGRU

IROORZVDNQRZQUHVSRQVHSDWWHUQWRWKH6WXG\'UXJEXW

FRXOGKDYHEHHQSURGXFHGE\RWKHUIDFWRUVVXFKDVWKHSDWLHQW¶VFOLQLFDOVWDWHWKHUDSHXWLF
LQWHUYHQWLRQRUFRQFRPLWDQWWKHUDS\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

8QOLNHO\
7KH$(

GRHVQRWIROORZDUHDVRQDEOHWHPSRUDOVHTXHQFHIURPWKHWLPHRI6WXG\'UXJ
DGPLQLVWUDWLRQDQG

ZDVPRVWOLNHO\SURGXFHGE\RWKHUIDFWRUVVXFKDVWKHSDWLHQW¶VFOLQLFDOVWDWHWKHUDSHXWLF
LQWHUYHQWLRQRUFRQFRPLWDQWWKHUDS\
8QUHODWHG
7KLVFDWHJRU\LVDSSOLFDEOHWRWKRVH$(VWKDWDUHMXGJHGWREHFOHDUO\DQGLQFRQWURYHUWLEO\
GXHRQO\WRH[WUDQHRXVFDXVHVWKHSDWLHQW¶VFOLQLFDOVWDWHWKHUDSHXWLFLQWHUYHQWLRQRU
FRQFRPLWDQWWKHUDS\DQGGRQRWPHHWWKHFULWHULDIRU6WXG\'UXJUHODWLRQVKLSOLVWHGXQGHU
3UREDEOH3RVVLEOHRU8QOLNHO\
$Q$(ZLWKFDXVDOUHODWLRQVKLSQRWLQLWLDOO\GHWHUPLQHGZLOOUHTXLUHIROORZXSWRDVVLJQ
FDXVDOLW\
9.5
Assessment of Severity
7KH,QYHVWLJDWRUPXVWGHWHUPLQHWKHVHYHULW\RIWKHHYHQWDFFRUGLQJWR&7&$(YHUVLRQ
6HYHULW\GHVFULEHVWKHLQWHQVLW\RIWKHDGYHUVHHYHQW
)RUHYHQWVQRWFRYHUHGE\WKH&7&$(ZLOOEHTXDOLWDWLYHO\GHVFULEHGDVEHORZDQGPDSSHG
DV*UDGHWKURXJKDVVKRZQIRUDQDO\VLVSXUSRVHV
0LOG*UDGH
$ZDUHQHVVRIVLJQRUV\PSWRPEXWHDVLO\WROHUDWHG
0RGHUDWH*UDGH
'LVFRPIRUWHQRXJKWRFDXVHLQWHUIHUHQFHZLWKQRUPDOGDLO\
DFWLYLWLHV
6HYHUH*UDGH
,QDELOLW\WRSHUIRUPQRUPDOGDLO\DFWLYLWLHV
/LIH7KUHDWHQLQJ
*UDGH
,PPHGLDWHULVNRIGHDWKIURPWKHUHDFWLRQDVLWRFFXUUHG
)DWDO*UDGH
(YHQWUHVXOWHGLQGHDWK



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

9.6
Adverse Event Reporting
7KH$(UHSRUWLQJSHULRGVWDUWVZLWKWKHVLJQLQJRIWKH/RQJ,&)DQGFRQWLQXHVWKURXJKWKH
:HHNVWXG\YLVLWRWKHUWKDQIRU$(VEHOLHYHGWREHUHODWHGWRVWXG\SURFHGXUHVZKLFK
VKRXOGEHUHFRUGHGVWDUWLQJZLWKWKHVLJQLQJRIWKH6KRUW,&)3DWLHQWVLQWKLVVWXG\ZKR
H[SHULHQFHDGUXJUHODWHG$(RU6$(ZLOOEHIROORZHGXQWLOWKH$(RU6$(LVUHVROYHGRU
VWDELOL]HVSHUWKH,QYHVWLJDWRU¶VMXGJPHQWHYHQLIWKLVRFFXUVDIWHUWKHILQDOVWXG\YLVLW$OO
$(VVSRQWDQHRXVO\UHSRUWHGE\WKHSDWLHQWDQGRULQUHVSRQVHWRDQRSHQTXHVWLRQIURPVWXG\
SHUVRQQHORUUHYHDOHGE\REVHUYDWLRQSK\VLFDOH[DPLQDWLRQRURWKHUGLDJQRVWLFSURFHGXUHV
ZLOOEHUHFRUGHGDQGUHSRUWHGRQWKHDSSURSULDWH&5):KHQDXQLI\LQJGLDJQRVLVKDVEHHQ
PDGHWKDWDFFRXQWVIRUVHYHUDOSRVVLEOHVLJQVDQGRUV\PSWRPVWKHXQLI\LQJGLDJQRVLVVKRXOG
EHVHOHFWHGDVWKH$(WHUP)RUH[DPSOHWKHFRPELQDWLRQRIJHQHUDOPDODLVHPLOGIHYHU
KHDGDFKHDQGUKLQLWLVVKRXOGEHGHVFULEHGDV³XSSHUUHVSLUDWRU\V\QGURPH´LIWKLVGLDJQRVLV
KDVEHHQPDGHUDWKHUWKDQUHSRUWLQJWKHLQGLYLGXDOV\PSWRPVDVVHSDUDWHHYHQWV
,IDQ\ODERUDWRU\WHVWLVQHZO\DEQRUPDOGXULQJWKHFRXUVHRIWKHVWXG\LWZLOOEHIROORZHGDW
WKHGLVFUHWLRQRIWKH,QYHVWLJDWRU$EQRUPDOLWLHVRIODERUDWRU\WHVWVZKLFKDUHLQWKHRSLQLRQ
RIWKH,QYHVWLJDWRUFOLQLFDOO\VLJQLILFDQWO\ZRUVHFRPSDUHGWRSULRUWRWKHVLJQLQJRIWKH/RQJ
,&)RUIRUZKLFKDPHGLFDOLQWHUYHQWLRQLVLQLWLDWHGVKRXOGEHUHSRUWHGDV$(VRQWKH$(
&5)
9.7
Reporting of Serious Adverse Events and Adverse Events of Special 
Interest  
7KH6$(UHSRUWLQJSHULRGLVWKHVDPHDVWKH$(UHSRUWLQJSHULRG$OO6$(VWKDWRFFXU
GXULQJWKHUHSRUWLQJSHULRGDQGUHJDUGOHVVRIFDXVDOLW\PXVWEHUHSRUWHGE\WKH,QYHVWLJDWRU
WR
E\FRPSOHWLQJWKH6$()RUPLQWKHHOHFWURQLFGDWDFDSWXUH('&V\VWHP$Q\
SHUWLQHQWVRXUFHGRFXPHQWVVKRXOGDOVREHVXEPLWWHGDVVRRQDVWKH\DUHDYDLODEOH'RQRW
ZLWKKROGVXEPLVVLRQRIDQ6$(HYHQLIFRPSOHWHLQIRUPDWLRQDERXWWKHHYHQWLVQRWDYDLODEOH
DWWKHWLPHRIWKHLQLWLDOUHSRUW)ROORZXSLQIRUPDWLRQRQWKH6$(VKRXOGEHVHQWSURPSWO\
E\WKH,QYHVWLJDWRUZKHQDQ\DGGLWLRQDOUHOHYDQWLQIRUPDWLRQDERXWWKHHYHQWEHFRPHVNQRZQ
WRWKH,QYHVWLJDWRURUDVUHTXHVWHGE\
RU&RUYLGLD7KHUDSHXWLFV
SAE and Pregnancy Reporting Contact Information


+\SHUVHQVLWLYLW\UHDFWLRQVVHH6HFWLRQRFFXUULQJGXULQJWKH6WXG\'UXJLQIXVLRQDQG
DQDSK\OD[LVRFFXUULQJDQ\WLPHGXULQJ:HHNV±RIWKHVWXG\VKRXOGEHUHSRUWHGDV
DGYHUVHRUVHULRXVDGYHUVHHYHQWVZLWKLQWKH('&$(DQG6$(&5)VZLWKLQKRXUVRIWKH
VLWH¶VDZDUHQHVVRIWKHHYHQW$VXSSOHPHQWDO&5)ZLOODOVREHFRPSOHWHGIRUVXFKHYHQWV
3OHDVHVXEPLWDVPXFKLQIRUPDWLRQDVLVDYDLODEOHZLWKWKHLQLWLDOUHSRUW


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

&RUYLGLD7KHUDSHXWLFVZLOOLPPHGLDWHO\QRWLI\WKH,QYHVWLJDWRUDERXWLPSRUWDQWVDIHW\RU
WR[LFRORJ\LQIRUPDWLRQDVLWEHFRPHVDYDLODEOH,WLVWKHUHVSRQVLELOLW\RIWKH,QYHVWLJDWRUWR
SURPSWO\QRWLI\WKH,5%,(&DERXWQHZDQGUHOHYDQWVDIHW\LQIRUPDWLRQUHJDUGLQJWKH6WXG\
'UXJLQFOXGLQJVHULRXVDGYHUVHGUXJUHDFWLRQVLQYROYLQJULVNWRKXPDQVXEMHFWVLQ
DFFRUGDQFHZLWKWKHDSSOLFDEOHSROLFLHV$QXQH[SHFWHGHYHQWLVRQHWKDWLVQRWOLVWHGE\
QDWXUHRUVHYHULW\LQWKH,QYHVWLJDWRU¶V%URFKXUH
9.8
Pregnancy Reporting
,IDZRPDQZKRLVDVWXG\SDWLHQWEHFRPHVSUHJQDQWRUDZRPDQVXVSHFWVVKHLVSUHJQDQW
IURPDPDOHVWXG\SDWLHQWWKH,QYHVWLJDWRUVKRXOGEHLQIRUPHGLPPHGLDWHO\7KH6SRQVRU
PXVWLQWXUQDOVREHQRWLILHGE\WKH,QYHVWLJDWRULPPHGLDWHO\E\FRPSOHWLQJD3UHJQDQF\
)RUPDQGID[LQJRUHPDLOLQJLWWR
VHH6HFWLRQ7KHSUHJQDQF\PXVWEH
IROORZHGXSWKURXJKGHOLYHU\RURWKHUIHWDORXWFRPH)RUDQ\DEQRUPDOIHWDORXWFRPH
LQFOXGLQJFRQJHQLWDODQRPDO\RUELUWKGHIHFWVSRQWDQHRXVRUWKHUDSHXWLFDERUWLRQVWLOOELUWK
SUHPDWXUHELUWKRURWKHURXWFRPHRWKHUWKDQOLYHQRUPDOELUWKWKH,QYHVWLJDWRUVKRXOG
SURPSWO\UHSRUWWRWKH6SRQVRUWKHDEQRUPDOIHWDORXWFRPHRQDQ6$(IRUP


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

10
STUDY ASSESSMENTS
10.1
Pharmacodynamic Assessments
10.1.1
Cardiac Magnetic Resonance Imaging for LV Mass Index 
0DJQHWLFUHVRQDQFHLPDJLQJZLOOEHXVHGWRFKDUDFWHUL]HFDUGLDFOHIWYHQWULFXODUPDVVLQGH[
0HWKRGRORJ\IRUWKLVDVVHVVPHQWZLOOEHVSHFLILHGYLDDVHSDUDWHLPDJLQJSURWRFRODQG05,
7HFKQLFDO0DQXDO
10.1.2
Handgrip Test 
7KHKDQGJULSWHVWLVDPHDVXUHRIVWUHQJWK7KHPHWKRGRORJ\LVGHVFULEHGLQWKH6WXG\
5HIHUHQFH0DQXDO
10.2
Safety Assessments (other than Adverse Events)
10.2.1
Vital Signs
9LWDOVLJQVLQFOXGHWHPSHUDWXUHUHVSLUDWRU\UDWHKHDUWUDWHDQGEORRGSUHVVXUH:KHQHYHU
SRVVLEOHYLWDOVLJQVZLOOEHREWDLQHGDIWHUDWOHDVWPLQXWHVLQWKHVLWWLQJSRVLWLRQRUZKHQ
QHFHVVDU\LQDVHPLUHFXPEHQWSRVLWLRQ
10.2.2
12-lead ECG 
$WVSHFLILHGWLPHSRLQWVVWDQGDUGOHDG(&*ZLOOEHUHFRUGHGLQWKHVXSLQHSRVLWLRQ
RUZLWKWKHSDWLHQWDVIODWDVSRVVLEOH7KH(&*ZLOOEHORFDOO\UHDGE\WKH,QYHVWLJDWRU
10.2.3
Physical Examination 
6FKHGXOHGOLPLWHGSK\VLFDOH[DPVPXVWLQFOXGHDWDPLQLPXPDQH[DPLQDWLRQRIWKHVNLQ
RURSKDU\Q[OXQJVKHDUWDEGRPHQH[WUHPLWLHVLQFOXGLQJIHHWDQGDQ\DUHDVVXJJHVWHGE\
V\PSWRPVZLWKSDUWLFXODUDWWHQWLRQWRVLJQVRILQIHFWLRQ
10.2.4
Stool Occult Blood Testing
6WRROIHFDORFFXOWEORRGWHVWLQJZLOOEHSHUIRUPHGDW6FUHHQLQJDQGDQDO\]HGE\WKHFHQWUDO
ODE,IQHHGHGWRPHHW6FUHHQLQJWLPHOLQHVRQHRUPRUHVWRROWHVWVPD\EHSHUIRUPHGORFDOO\
10.2.5
Clinical Laboratory Testing 
'HWDLOVRQWKHFROOHFWLRQSURFHVVLQJVWRUDJHDQGVKLSPHQWRIFHQWUDOODEVDPSOHVDUH
FRQWDLQHGLQWKH/DERUDWRU\0DQXDO7KHOLVWRIODERUDWRU\SDUDPHWHUVFDQEHIRXQGLQ
$SSHQGL[(/RFDO/DERUDWRU\DVVHVVPHQWVDUHGHVFULEHGEHORZ
7KHIROORZLQJWHVWVZLOOEHSHUIRUPHGDWWKH/RFDO/DERUDWRU\

&RDJXODWLRQ,15RQO\IRUSDWLHQWVRQZDUIDULQ

6WRRORFFXOWEORRGLIQHHGHG



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

11
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS
7KHVWXG\GHVLJQDQGREMHFWLYHVDUHGHVFULEHGLQ6HFWLRQVDQGUHVSHFWLYHO\
11.1
Sample Size
7KHSULPDU\REMHFWLYHRIWKLVVWXG\LVWRGHWHUPLQHWKHPD[LPXPWROHUDWHGGRVH7KH07'
ZLOOEHH[FHHGHGDQGVWRSSLQJFULWHULDIRUWKDWGRVHZLOOKDYHEHHQPHWLIPRUHWKDQRI
&25WUHDWHGSDWLHQWVLQDFRKRUWH[SHULHQFHD'/7:LWKSDWLHQWVGRVHGLQ
HDFKFRKRUWDQGDWWKHH[SHFWHG'/7UDWHRIWKHSUREDELOLW\RIREVHUYLQJRUPRUH
SDWLHQWVZLWK'/7LVJUHDWHUWKDQDQGWKHSUREDELOLW\RIREVHUYLQJDWOHDVWSDWLHQWZLWK
'/7LV
6DPSOHVL]HFDOFXODWLRQVZHUHSHUIRUPHGIRUKV&5376$7DQG&+UEDVHGRQWKHOLWHUDWXUH
&R\QHDQG6LHSHU)RUSRZHUWRREVHUYHDQKV&53GLIIHUHQFHIURP
SODFHERRIPJG/ZLWKDFRPPRQVWDQGDUGGHYLDWLRQRIWKHVDPSOHVL]HUHTXLUHGLV
SDWLHQWVLQHDFKJURXS:LWKHIIHFWVL]HVUDQJLQJIURPWRWKHVDPSOHVL]H
UDQJHVIURPWRSDWLHQWV7KHVDPSOHVL]HZLWKSRZHUUHTXLUHGWRREVHUYHD76$7
GLIIHUHQFHRIZLWKDFRPPRQVWDQGDUGGHYLDWLRQRIHIIHFWVL]HRILVSDWLHQWV
ZLWKHIIHFWVL]HVUDQJLQJIURPWRUHTXLULQJWRSDWLHQWV7KHVDPSOHVL]HZLWK
SRZHUUHTXLUHGWRREVHUYHD&+UGLIIHUHQFHRISJZLWKDFRPPRQVWDQGDUGGHYLDWLRQ
RILVZLWKHIIHFWVL]HVUDQJLQJIURPWRUHTXLULQJVDPSOHVL]HIURPWR
SDWLHQWV$OOVDPSOHVL]HFDOFXODWLRQVZHUHGRQHZLWKWZRVLGHGWWHVWVDQGDVLJQLILFDQFH
OHYHORIĮ 
11.2
Randomization 
7RPD[LPL]HWKHFKDQFHRIDWOHDVWRQHSODFHERSDWLHQWLQDFRKRUWFRQVLGHULQJWKDWFRKRUW
PD\VWRSHQUROOPHQWHDUO\WKHILUVWVHQWLQHOSDWLHQWVLQWKDWFRKRUWZLOOEHUDQGRPL]HG
WR&25RUSODFHER7KHUHPDLQLQJSDWLHQWVZLOOEHUDQGRPL]HGDWOHDVWKRXUVODWHULQ
DUDWLRRI&25WRSODFHERZLWKDWRWDORISDWLHQWVSODQQHGIRUHDFKFRKRUW
11.3
General Statistical Considerations and Definitions
11.3.1
General Statistical Methods
$OOVWXG\FROOHFWHGGDWDZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSXVLQJGHVFULSWLYHVWDWLVWLFV
JUDSKVDQGRUUDZGDWDOLVWLQJV'HVFULSWLYHVWDWLVWLFVIRUFRQWLQXRXVYDULDEOHVZLOOLQFOXGH
QXPEHURISDWLHQWVQPHDQVWDQGDUGGHYLDWLRQ6'PHGLDQTXDUWLOHV4DQG4
PLQLPXPPLQDQGPD[LPXPPD[YDOXHV$QDO\VLVRIFDWHJRULFDOYDULDEOHVZLOOLQFOXGH
IUHTXHQF\DQGSHUFHQWDJH
11.3.2
Analysis Populations
Intent-to-treat (ITT) analysis population: 7KH,77SRSXODWLRQZLOOEHGHILQHGDVDOO
UDQGRPL]HGSDWLHQWV7UHDWPHQWFODVVLILFDWLRQZLOOEHEDVHGRQWKHUDQGRPL]HGWUHDWPHQW
7KLVZLOOEHWKHSULPDU\SRSXODWLRQIRUWKHDQDO\VHVRIGLVSRVLWLRQDQGEDVHOLQHGDWD


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Pharmacodynamic analysis population: 7KHSKDUPDFRG\QDPLFSRSXODWLRQZLOOEHGHILQHG
DVDOO,77SDWLHQWVZKRUHFHLYHGWKHLUDVVLJQHG6WXG\'UXJKDGDQ\SKDUPDFRG\QDPLF
DVVHVVPHQWVDQGGLGQRWKDYHPDMRUSURWRFROYLRODWLRQV7KLVZLOOEHWKHSRSXODWLRQIRUWKH
SKDUPDFRG\QDPLFDQDO\VHV
Per-protocol analysis population: 7KHVXEVHWRIWKHSKDUPDFRG\QDPLFVSRSXODWLRQWKDWGLG
QRWKDYHDPDMRUSURWRFROGHYLDWLRQDVGHILQHGLQWKH6$37KH3HU3URWRFRODQDO\VLV
SRSXODWLRQZLOOEHXVHGWRSHUIRUPWKHVHQVLWLYLW\DQDO\VLVIRUWKHSKDUPDFRG\QDPLFV
HQGSRLQWV
Pharmacokinetics analysis population: 7KH3.SRSXODWLRQZLOOEHGHILQHGDVDOOSDWLHQWV
ZKRKDYHDQ\YDOLGVDPSOHVPHDVXUHGIRU6WXG\'UXJOHYHOV7KLVZLOOEHXVHGIRU3.
DQDO\VLV
MTD analysis Population7KH07'DQDO\VLVSRSXODWLRQZLOOEHGHILQHGDVDVXEVHWRI
VDIHW\DQDO\VLVSRSXODWLRQE\H[FOXGLQJVXEMHFWVUHSODFHGGXHWRDQRQVDIHW\UHDVRQ
7UHDWPHQWFODVVLILFDWLRQZLOOEHEDVHGRQWKHDFWXDOWUHDWPHQWUHFHLYHG7KLVSRSXODWLRQZLOO
EHXVHGIRU07'DQG'/7DQDO\VHV
Safety analysis population: 7KHVDIHW\SRSXODWLRQZLOOFRQVLVWRIDOOSDWLHQWVUDQGRPL]HG
DQGWUHDWHGZLWKDQ\DPRXQWRIVWXG\PHGLFDWLRQ&25RUSODFHER7UHDWPHQW
FODVVLILFDWLRQZLOOEHEDVHGRQWKHDFWXDOWUHDWPHQWUHFHLYHG7KLVSRSXODWLRQZLOOEHXVHGIRU
WKHVDIHW\DQDO\VHV
11.3.3
Analysis Windows and Baseline 
,IGDWDDUHFROOHFWHGE\YLVLWWKHGDWDZLOOEHDQDO\]HGE\YLVLWEDVHGRQWKHSURWRFROSODQQHG
YLVLWV,IPXOWLSOHUHFRUGVDUHFROOHFWHGIRUDYLVLWWKHODWHVWUHFRUGZLOOEHXVHGIRUWKH
VXPPDU\IRUWKDWYLVLW
7KHREVHUYDWLRQDOSHULRGIRUWKHVWXG\ZLOOVWDUWIURPLQIRUPHGFRQVHQWDQGHQGZLWKVWXG\
FRPSOHWLRQVHH6HFWLRQIRUWKHGHILQLWLRQRIVWXG\FRPSOHWLRQ$Q\HYHQWRFFXUULQJ
DIWHUWKHGHILQHGREVHUYDWLRQDOSHULRGHYHQLIFROOHFWHGRQWKH&5)PD\QRWEHLQFOXGHGLQ
WKHSODQQHGVWDWLVWLFDODQDO\VLV+RZHYHUDOOGDWDLQFOXGLQJWKDWUHSRUWHGDIWHUWKHGHILQHG
REVHUYDWLRQDOSHULRGZLOOEHLQFOXGHGLQWKHSDWLHQWGDWDOLVWLQJV
)RUHYDOXDWLRQVWKDWDUHFROOHFWHGDWPXOWLSOHRFFDVLRQVSULRUWRLQLWLDWLRQRI6WXG\'UXJWKH
ODWHVWHYDOXDWLRQZLOOEHFRQVLGHUHGWKH%DVHOLQHHYDOXDWLRQIRUDQDO\VLVXQOHVVRWKHUZLVH
VSHFLILHG
11.3.4
Missing Data Handling
8QOHVVRWKHUZLVHVSHFLILHGPLVVLQJGDWDZLOOQRWEHLPSXWHGDQGZLOOEHH[FOXGHGIURPWKH
DVVRFLDWHGDQDO\VLV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

11.4
Statistical Analyses 
11.4.1
Demographic and Background Characteristics
3DWLHQWGHPRJUDSKLFVDQGEDVHOLQHFKDUDFWHULVWLFVZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXS
XVLQJWKHP,77SKDUPDFRG\QDPLFVSHUSURWRFRODQGVDIHW\SRSXODWLRQV
11.4.2
Study Drug and Concomitant Medications 
6XPPDULHVRISULRUSUHEDVHOLQHPHGLFDWLRQVDQGFRQFRPLWDQWEDVHOLQHRUODWHU
PHGLFDWLRQVZLOOEHSURYLGHGE\WUHDWPHQWJURXSXVLQJWKHVDIHW\SRSXODWLRQ0HGLFDWLRQV
ZLOOEHFRGHGZLWK:RUOG+HDOWK2UJDQL]DWLRQ:+2'UXJ'LFWLRQDU\3DWLHQWVZLOOEH
FRXQWHGRQO\RQFHE\PHGLFDWLRQFODVVRUQDPH
11.4.3
Efficacy Analysis
'DWDIURP&25WUHDWHGSDWLHQWVIURP&RKRUWVQRWH[FHHGLQJWKH07'ZLOOEHSRROHG
DQGGDWDIURPDOOSODFHERSDWLHQWVZLOOEHSRROHGIRUWKHSKDUPDFRG\QDPLFHQGSRLQW
DQDO\VHV
'HVFULSWLYHDQDO\VHVE\GRVHLQZKLFKDOOSODFHERSDWLHQWVDUHSRROHGZLOODOVREHFRQGXFWHG
11.4.4
Efficacy Variables
7KHSKDUPDFRG\QDPLFHIILFDF\RI&25FRPSDUHGWRSODFHERZLOOEHDVVHVVHGE\
HYDOXDWLQJWKHIROORZLQJ

FKDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQ76$7WR:HHN

FKDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQWKH&+UWR:HHN

FKDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQKV&53WRWKHPHDQRI
:HHNV

FKDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQ6$$WRWKHWRWKHPHDQRI
:HHNV

FKDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQVHUXPSUHDOEXPLQWRWKH
PHDQRI:HHNVDQGDOEXPLQWR:HHN

FKDQJHIURPEDVHOLQHZHHNO\PHDQRI6FUHHQLQJLQ(5,WR:HHN

FKDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJLQ(5,WRWKHPHDQRI:HHNV±

FKDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\LQWKHIUHH,/WR:HHNEHWZHHQ
WUHDWPHQWJURXSV




&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

$GGLWLRQDOVHFRQGDU\REMHFWLYHVLVWRH[SORUHWKHSKDUPDFRG\QDPLFHIIHFWVRI&25
FRPSDUHGWRSODFHERE\HYDOXDWLQJFKDQJHVLQ

V\VWHPLFLURQDYDLODELOLW\76$7DEVROXWHUHWLFXORF\WHFRXQWKHPRJORELQ&+U
K\SRFKURPLF5%&RYHUWLPH

PDUNHUVRIPDOQXWULWLRQLQIODPPDWLRQSUHDOEXPLQDQGDOEXPLQRYHUWLPH

V\VWHPLFLURQVWRUHVVHUXPIHUULWLQKHSDWLFDQGVSOHQLFLURQFRQWHQWDQGVXSSOHPHQWDO
LURQGRVHUHTXLUHPHQWVRYHUWLPH

(5,FKDQJHIURPEDVHOLQHZHHNO\PHDQGXULQJWKH6FUHHQLQJ3HULRGWKURXJK:HHN

(6$DQGSDUHQWHUDOLURQGRVHUHTXLUHPHQWVIURPEDVHOLQHZHHNO\PHDQGXULQJWKH
6FUHHQLQJ3HULRGWR(YDOXDWLRQ3HULRG:HHNV±DQGWKURXJK:HHN

/9PDVVLQGH[IURP6FUHHQLQJWR:HHN

'HVFULSWLRQRIFKDQJHVLQSUHGLDO\VLVSRVWGLDO\VLVDQGGHOWDVHUXP7URSRQLQDQG
17SUR%13GHILQHGDVWKHGLIIHUHQFHEHWZHHQWKHSUHDQGSRVWGLDO\VLVWURSRQLQIURP
EDVHOLQHPHDQRI6FUHHQLQJWR:HHNV±

+DQGJULSRYHUWLPH

)$&,7IDWLJXHVFRUHRYHUWLPH

)RUWKHDERYHHIILFDF\YDULDEOHVWKHREVHUYHGYDOXHVDQGFKDQJHVIURPEDVHOLQHZLOOEH
VXPPDUL]HGE\WUHDWPHQWJURXSXVLQJGHVFULSWLYHVWDWLVWLFVXVLQJP,77DQG33SRSXODWLRQV
11.4.5
Safety Analysis

$GYHUVH(YHQWV
7KH0HG'5$GLFWLRQDU\ZLOOEHXVHGIRUFRGLQJDGYHUVHHYHQWV$(V$Q$(FODVVLILHGDV
SUHIHUUHGWHUPRFFXUULQJGXULQJWKHGRXEOHEOLQGWUHDWPHQWSHULRGZLOOEHFRXQWHGDVD
WUHDWPHQWHPHUJHQW$(7($(LILWLVQRWSUHVHQWDWEDVHOLQH
7KHQXPEHUSHUFHQWDJHRISDWLHQWVUHSRUWLQJ7($(VIRUHDFKSUHIHUUHGWHUPZLOOEH
WDEXODWHGE\V\VWHPRUJDQFODVVE\V\VWHPRUJDQFODVVDQGVHYHULW\DQGE\V\VWHPRUJDQ
FODVVDQGUHODWLRQVKLSWR6WXG\'UXJ,IPRUHWKDQRQHHYHQWRFFXUUHGZLWKWKHVDPH
SUHIHUUHGWHUPIRUWKHVDPHSDWLHQWWKHSDWLHQWZLOOEHFRXQWHGRQO\RQFHIRUWKDWSUHIHUUHG
WHUPXVLQJWKHPRVWVHYHUHRUUHODWHGRFFXUUHQFHIRUWKHVXPPDU\E\VHYHULW\RUUHODWLRQVKLS
WR6WXG\'UXJUHVSHFWLYHO\
6DIHW\HYHQWVRIVSHFLDOLQWHUHVWZLOOEHVXPPDUL]HGE\GRVHJURXSDQGWUHDWPHQWDVVLJQPHQW


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


/DERUDWRU\7HVWV
/DERUDWRU\YDOXHVH[FOXGLQJHIILFDF\ODEZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSLQFOXGLQJ
FKDQJHVIURPEDVHOLQHDWHDFKYLVLW

9LWDO6LJQV
9LWDOVLJQVDQGFKDQJHIURPEDVHOLQHLQYLWDOVLJQVZLOOEHVXPPDUL]HGGHVFULSWLYHO\DWHDFK
YLVLWE\WUHDWPHQWJURXS7KHSHUFHQWDJHRISDWLHQWVH[FHHGLQJSUHGHILQHGDEVROXWHDQG
UHODWLYHWKUHVKROGYDOXHVZLOOEHVXPPDUL]HG

OHDG(&*
(&*LQWHUSUHWDWLRQQRUPDOYVDEQRUPDOZLOOEHVXPPDUL]HGXVLQJIUHTXHQF\DQG
SHUFHQWDJHDWHDFKYLVLWE\WUHDWPHQWJURXS(&*LQWHUYDOV3547+5DQG47F)ZLOOEH
VXPPDUL]HGGHVFULSWLYHO\DWHDFKYLVLW7KHSHUFHQWDJHRISDWLHQWVH[FHHGLQJSUHGHILQHG
DEVROXWHDQGUHODWLYHWKUHVKROGYDOXHVZLOOEHVXPPDUL]HG

3K\VLFDO([DPLQDWLRQ
3K\VLFDOH[DPLQDWLRQFOLQLFDOO\VLJQLILFDQWQHZRUZRUVHQLQJILQGLQJVZLOOEHUHSRUWHGDV
DGYHUVHHYHQWVDQGZLOOWKHUHIRUHEHVXPPDUL]HGDVGHVFULEHGIRUDGYHUVHHYHQWV

$QWLERGLHVWR&25
7KHLPPXQRJHQLFSRWHQWLDORI&25ZLOOEHDVVHVVHGE\VXPPDUL]LQJWKHQXPEHUDQG
SHUFHQWDJHRISDWLHQWVZKRGHYHORSGHWHFWDEOHDQWLGUXJDQWLERGLHV$'$$QWLGUXJ
DQWLERG\WLWHUVZLOOEHVXPPDUL]HGGHVFULSWLYHO\IRU$'$SRVLWLYHVDPSOHVDQGWKHLPSDFWRI
$'$RQ3.ZLOOEHDVVHVVHGLIGDWDDOORZV1HXWUDOL]LQJFDSDFLW\RIDQ\GHWHFWHG$'$ZLOO
EHVXPPDUL]HG
11.4.6
Pharmacokinetic Analysis and Pharmacokinetic/Pharmacodynamic 
Analysis

3KDUPDFRNLQHWLF'DWD
$OLVWLQJRI3.EORRGVDPSOHFROOHFWLRQWLPHVDVZHOODVGHULYHGVDPSOLQJWLPHGHYLDWLRQV
ZLOOEHSURYLGHG$SDWLHQWOLVWLQJRIDOOVHUXPFRQFHQWUDWLRQWLPHGDWDIRUHDFKGRVHJURXS
ZLOOEHSUHVHQWHG&25VHUXPFRQFHQWUDWLRQVZLOOEHVXPPDUL]HGE\GRVHJURXSDQG
QRPLQDOWLPHSRLQWXVLQJDSSURSULDWHGHVFULSWLYHVWDWLVWLFVHJQDULWKPHWLFPHDQVWDQGDUG
GHYLDWLRQ6'FRHIILFLHQWRIYDULDWLRQ&9PLQLPXPPHGLDQPD[LPXPJHRPHWULFPHDQ
DQGJHRPHWULF&9*&9
5HVXOWVRI3.SDUDPHWHUVVXFKDV&PD[$8&DQG7ZLOOEHVXPPDUL]HGE\GRVHJURXS
,QGLYLGXDODQGPHDQFRQFHQWUDWLRQWLPHSURILOHVZLOOEHSUHVHQWHGJUDSKLFDOO\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

7KHGDWDIURPWKLVVWXG\PD\EHXVHGLQFRPELQDWLRQZLWKGDWDIURPRWKHUVWXGLHVWRGHYHORS
DSRSXODWLRQ3.PRGHO,ISHUIRUPHGWKHSODQIRUDQGUHVXOWVRIVXFKDQDO\VLVZLOOEH
GRFXPHQWHGVHSDUDWHO\

3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF$QDO\VLV
3.3'PRGHOSDUDPHWHUVZLOOEHGHULYHGXVLQJSODVPD,/OHYHOVWRGHVFULEHWDUJHW
HQJDJHPHQWZLWKFOLQLFDOO\PHDQLQJIXO3'YDULDEOHVWKDWPD\LQFOXGHRQHRUPRUHRIWKH
IROORZLQJ&UHDFWLYHSURWHLQVHUXPDP\ORLG$WUDQVIHUULQVDWXUDWLRQKHPRJORELQ
UHWLFXORF\WHKHPRJORELQFRQWHQWRUUHWLFXORF\WHFRXQW7KHVSHFLILFPRGHOSDUDPHWHUVWREH
HVWLPDWHGZLOOEHGHWHUPLQHGEDVHGRQUHYLHZRIWKHREVHUYHGGDWD7KH3'HQGSRLQWVWREH
LQFOXGHGLQWKH3'DQDO\VLVZLOOEHGHWHUPLQHGIROORZLQJUHYLHZRIWKHVWXG\GDWD
$OLVWLQJRI3'EORRGVDPSOHFROOHFWLRQWLPHVDVZHOODVGHULYHGVDPSOLQJWLPHGHYLDWLRQV
ZLOOEHSURYLGHG$SDWLHQWOLVWLQJRIDOO3'UHVXOWVDQGWKHLUFRUUHVSRQGLQJFKDQJHIURP
EDVHOLQHYDOXHIRUHDFKGRVHJURXSZLOOEHSUHVHQWHG7KHREVHUYHGDQGFKDQJHIURP
EDVHOLQHVHUXPUHVXOWVZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFVE\GRVHJURXS
*UDSKLFDOSUHVHQWDWLRQVDVDSSURSULDWHIRU3'YDULDEOHVPD\LQFOXGHLQGLYLGXDOREVHUYHG
DQGSHUFHQWFKDQJHIURPEDVHOLQHVHUXPFRQFHQWUDWLRQWLPHFXUYHVIRUHDFKSDWLHQWRQOLQHDU
VFDOHDULWKPHWLFPHDQVHUXPFRQFHQWUDWLRQWLPHFXUYHVE\GRVHJURXSRQOLQHDUVFDOH
11.5
Interim Analyses
$VLQJOHLQWHULPDQDO\VLVZLOOEHFRQGXFWHGWKHSXUSRVHRIZKLFKLVWRJXLGHIXWXUH&25
FOLQLFDOSURJUDPDFWLYLWLHV7KHUHDUHQRVWRSSLQJUXOHVDVVRFLDWHGZLWKWKHLQWHULPDQDO\VLV
7KHLQWHULPDQDO\VLVZLOOEHFRQGXFWHGDWHDUOLHVWRQFHDOOFRKRUWVEHORZWKDWZKLFK
H[FHHGHGWKH07'H[FOXGLQJDQ\H[SDQVLRQFRKRUWVKDYHFRPSOHWHGWKHVWXG\WKURXJK
:HHNRUILQDOYLVLWLISUHPDWXUHO\GLVFRQWLQXHG7KH6SRQVRUSHUVRQQHOZLOORQO\UHFHLYH
WKHWUHDWPHQWJURXSOHYHOLQIRUPDWLRQDQGKDYHQRDFFHVVWRVXEMHFWOHYHOWUHDWPHQW
LQIRUPDWLRQ6SHFLILFVRILQWHULPDQDO\VLVZLOOEHGHVFULEHGLQWKHVWDWLVWLFDODQDO\VLVSODQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

12
STUDY COMMITTEES AND COMMUNICATIONS
$IWHUDOOSDWLHQWVLQDFRKRUWKDYHFRPSOHWHGGD\VRIWUHDWPHQWRUODVWYLVLWLISUHPDWXUHO\
GLVFRQWLQXHGWKH65&ZLOOHYDOXDWHWKHVDIHW\DQGWROHUDELOLW\RI&25DQGUHFRPPHQG
WKHQH[WGRVH7KH65&PD\QRWEHFRQYHQHGLIWKHQH[WFRKRUWLVH[SHFWHGWREHWKHODVW
FRKRUWLQWKHVWXG\3KDUPDFRNLQHWLFGDWDDVLWEHFRPHVDYDLODEOHZLOODOVREHPDGH
DYDLODEOHWRWKH65&7KH6DIHW\5HYLHZ&RPPLWWHHZLOODSSO\LWVMXGJPHQWWRWKHFRQGXFW
RIWKLVVWXG\LQRUGHUWRHQVXUHWKHVDIHW\RIVWXG\SDUWLFLSDQWV
7KH65&ZLOOFRQVLVWRIWKHIROORZLQJFRUHPHPEHUV

7ZRRUPRUHFOLQLFLDQVDWOHDVWRQHRIZKRPLVDQHSKURORJLVWZLWKH[SHUWLVHLQFOLQLFDO
WULDOVDIHW\GDWDUHYLHZ

$VWDWLVWLFLDQQRQYRWLQJPHPEHU

7KHIXOODFWLYLWLHVDQGUHVSRQVLELOLWLHVRIWKH65&DUHGHVFULEHGLQWKH65&FKDUWHU


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

13
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS
13.1
Institutional Review Board or Independent Ethics Committee
7KHSURWRFRODQGLQIRUPHGFRQVHQWIRUWKLVVWXG\PXVWEHUHYLHZHGDQGDSSURYHGE\DQ
DSSURSULDWH,5%RU,(&EHIRUHSDWLHQWVDUHHQUROOHGLQWKHVWXG\,WLVWKHUHVSRQVLELOLW\RIWKH
,QYHVWLJDWRUWRDVVXUHWKDWWKHVWXG\LVFRQGXFWHGLQDFFRUGDQFHZLWKFXUUHQWFRXQWU\DQG
/RFDO5HJXODWLRQV,QWHUQDWLRQDO&RQIHUHQFHRQ+DUPRQLVDWLRQ,&+*&3DQGWKH
'HFODUDWLRQRI+HOVLQNL$OHWWHUGRFXPHQWLQJWKHDSSURYDOWKDWVSHFLILFDOO\LGHQWLILHVWKH
SURWRFROE\QXPEHUDQGWLWOHDVZHOODVWKH,QYHVWLJDWRUPXVWEHUHFHLYHGE\&RUYLGLD
7KHUDSHXWLFVEHIRUHLQLWLDWLRQRIWKHVWXG\$PHQGPHQWVWRWKHSURWRFROZLOOEHSDWLHQWWRWKH
VDPHUHTXLUHPHQWVDVWKHRULJLQDOSURWRFRO
$IWHUWKHFRPSOHWLRQRUWHUPLQDWLRQRIWKHVWXG\WKH,QYHVWLJDWRUZLOOVXEPLWDUHSRUWWRWKH
,5%RU,(&
13.2
Informed Consent
(DFKSDWLHQWPXVWEHSURYLGHGZLWKRUDODQGZULWWHQLQIRUPDWLRQGHVFULELQJWKHQDWXUHDQG
GXUDWLRQRIWKHVWXG\DQGPXVWVLJQDZULWWHQ,&)LQDODQJXDJHLQZKLFKWKHSDWLHQWLVIOXHQW
EHIRUHVWXG\VSHFLILFSURFHGXUHVDUHFRQGXFWHG,QWKLVVWXG\SDWLHQWVZLOOVLJQERWKD6KRUW
DQG/RQJ,&)IRUSURFHGXUHVWREHFRPSOHWHGGXULQJWKH,QLWLDODQG)XOO6FUHHQLQJ3HULRGV
UHVSHFWLYHO\7KHVLJQHGDQGGDWHG,&)ZLOOEHUHWDLQHGZLWKWKHVWXG\UHFRUGV(DFKSDWLHQW
ZLOODOVREHJLYHQDFRS\RIWKHLUVLJQHG,&)
13.3
Supplementary Documentation
%HIRUHLQLWLDWLRQRIWKHVWXG\WKH,QYHVWLJDWRUPXVWSURYLGH&RUYLGLD7KHUDSHXWLFVZLWKWKH
IROORZLQJGRFXPHQWVFRSLHVRIZKLFKPXVWEHPDLQWDLQHGE\WKH,QYHVWLJDWRU

&XUULFXOXPYLWDHRIWKH,QYHVWLJDWRUDQGDQ\VXE,QYHVWLJDWRUVOLVWHGRQWKHIRUP

$VLJQHGFRS\RIWKH,5%RU,(&DSSURYDOQRWLFHIRUSURWRFRODQGLQIRUPHGFRQVHQW

$FRS\RIWKH,5%RU,(&DSSURYHG,&)

/DERUDWRU\FHUWLILFDWLRQZLWKDOLVWRIQRUPDOYDOXHVIRUODERUDWRU\WHVWVWKDWZLOOEH
FRQGXFWHGDWORFDOODERUDWRULHV

&RPSOHWHGILQDQFLDOGLVFORVXUHIRUPIRUWKH,QYHVWLJDWRUDQGDQ\VXE,QYHVWLJDWRUVOLVWHG
RQWKHIRUP

13.4
Data Reporting and Case Report Forms 
'DWDIRUHDFKSDWLHQWZLOOEHHQWHUHGLQWRWKH&5)DQGYHULILHGE\WKH,QYHVWLJDWRU,WLVWKH
,QYHVWLJDWRU¶VUHVSRQVLELOLW\WRHQVXUHWKHDFFXUDF\FRPSOHWHQHVVOHJLELOLW\DQGWLPHOLQHVV
RIWKHGDWDUHSRUWHGRQWKHSDWLHQW¶V&5)6RXUFHGRFXPHQWDWLRQVXSSRUWLQJWKH&5)GDWD
VKRXOGLQGLFDWHWKHSDWLHQW¶VSDUWLFLSDWLRQLQWKHVWXG\DQGVKRXOGGRFXPHQWWKHGDWHVDQG
GHWDLOVRIVWXG\SURFHGXUHV$(VDQGSDWLHQW¶VFOLQLFDOVWDWXV


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

7KH,QYHVWLJDWRURUGHVLJQDWHGUHSUHVHQWDWLYHVKRXOGFRPSOHWHWKH&5)DVVRRQDVSRVVLEOH
DIWHULQIRUPDWLRQLVFROOHFWHGSUHIHUDEO\RQWKHVDPHGD\WKDWDVWXG\SDWLHQWLVVHHQIRUDQ
H[DPLQDWLRQWUHDWPHQWRUDQ\RWKHUVWXG\SURFHGXUH$Q\RXWVWDQGLQJHQWULHVPXVWEH
FRPSOHWHGLPPHGLDWHO\DIWHUWKHILQDOH[DPLQDWLRQ&5)GDWDZLOOEHSURFHVVHGLQD86
&RGHRI)HGHUDO5HJXODWLRQV&)53DUWFRPSOLDQWV\VWHP
13.5
Retention of Data
86)HGHUDOUHJXODWLRQVUHTXLUHWKDWDFRS\RIUHFRUGVHJODERUDWRU\GDWDVOLSVVRXUFH
GRFXPHQWVWHVWDUWLFOHGLVEXUVHPHQWUHFRUGVZKLFKVXSSRUWFDVHUHFRUGVRIWKLVVWXG\PXVW
EHUHWDLQHGLQWKHILOHVRIWKHUHVSRQVLEOH,QYHVWLJDWRUIRUDPLQLPXPRI\HDUVDIWHU
QRWLILFDWLRQE\WKH6SRQVRUWKDWWKH)'$KDVDSSURYHGDPDUNHWLQJDSSOLFDWLRQIRUWKHGUXJ
DQGLQGLFDWLRQEHLQJLQYHVWLJDWHGRUWKHLQYHVWLJDWLRQKDVEHHQWHUPLQDWHG
13.6
Deviation from the Protocol 
7KH,QYHVWLJDWRUZLOOQRWGHYLDWHIURPWKHSURWRFRO,QPHGLFDOHPHUJHQFLHVWKH,QYHVWLJDWRU
ZLOOXVHPHGLFDOMXGJPHQWDQGZLOOUHPRYHWKHSDWLHQWIURPLPPHGLDWHKD]DUGDQGWKHQ
QRWLI\WKH&RUYLGLD7KHUDSHXWLFV0HGLFDO0RQLWRUDQGWKH,5%RU,(&LPPHGLDWHO\UHJDUGLQJ
WKHW\SHRIHPHUJHQF\DQGFRXUVHRIDFWLRQWDNHQ$Q\DFWLRQLQWKLVUHJDUGZLOOEHUHFRUGHG
RQWKHDSSURSULDWH&5)$Q\RWKHUFKDQJHVRUGHYLDWLRQVLQWKHSURWRFROZLOOEHPDGHDVDQ
DPHQGPHQWWRWKHSURWRFRODQGPXVWEHDSSURYHGE\&RUYLGLD7KHUDSHXWLFVDQGWKH,5%RU
,(&²EHIRUHWKHFKDQJHVRUGHYLDWLRQVDUHLPSOHPHQWHG&RUYLGLD7KHUDSHXWLFVZLOOQRW
DVVXPHDQ\UHVSRQVLELOLW\RUOLDELOLW\IRUDQ\GHYLDWLRQRUFKDQJH
13.7
Study Monitoring
7KH,QYHVWLJDWRUZLOODOORZUHSUHVHQWDWLYHVRI&RUYLGLD7KHUDSHXWLFVWRSHULRGLFDOO\DXGLW
DWPXWXDOO\FRQYHQLHQWWLPHVEHIRUHGXULQJDQGDIWHUWKHVWXG\KDVEHHQFRPSOHWHGDOO
&5)VDQGUHOHYDQWSRUWLRQVRIRIILFHFOLQLFDODQGODERUDWRU\UHFRUGVIRUHDFKSDWLHQW
$SSURSULDWHVRXUFHGRFXPHQWVVXFKDVDUHFRUGRIWKHSDWLHQW¶VPHGLFDOKLVWRU\DQG
FRQFRPLWDQWPHGLFDWLRQVIURPWKHSDWLHQW¶VSK\VLFLDQPXVWEHDYDLODEOHWRFRQILUPHOLJLELOLW\
IRUWKHVWXG\7KHPRQLWRULQJYLVLWVSURYLGH&RUYLGLD7KHUDSHXWLFVZLWKWKHRSSRUWXQLW\WR
HYDOXDWHWKHSURJUHVVRIWKHVWXG\YHULI\WKHDFFXUDF\DQGFRPSOHWHQHVVRI&5)VDVVXUHWKDW
DOOSURWRFROUHTXLUHPHQWVDSSOLFDEOHUHJXODWLRQVDQG,QYHVWLJDWRU
VREOLJDWLRQVDUHEHLQJ
IXOILOOHGDQGUHVROYHDQ\LQFRQVLVWHQFLHVLQWKHVWXG\UHFRUGV
13.8
Drug Accountability
7KH,QYHVWLJDWRUPXVWPDLQWDLQDFFXUDWHUHFRUGVRIWKHDPRXQWVDQGGDWHV6WXG\'UXJVZHUH
UHFHLYHGIURP&RUYLGLD7KHUDSHXWLFVDQGGLVSHQVHGWRWKHSDWLHQWVLQFOXGLQJWKHYROXPHDQG
FRQFHQWUDWLRQRIVWRFNVROXWLRQSUHSDUHGDQGUHPDLQLQJVWRFNVROXWLRQYROXPHDIWHUGRVH
SUHSDUDWLRQ$OOGUXJVXSSOLHVPXVWEHDFFRXQWHGIRUDWWKHWHUPLQDWLRQRIWKHVWXG\DQGD
ZULWWHQH[SODQDWLRQSURYLGHGIRUDQ\GLVFUHSDQFLHV$OOSDUWLDOO\XVHGRUXQXVHGGUXJ
VXSSOLHVZLOOEHGHVWUR\HGDWWKHVLWHLQDFFRUGDQFHZLWKDSSURYHGZULWWHQSURFHGXUHVRU
UHWXUQHGWR&RUYLGLD7KHUDSHXWLFVDIWHUZULWWHQDXWKRUL]DWLRQLVREWDLQHGIURP&RUYLGLD
7KHUDSHXWLFV7KH,QYHVWLJDWRUZLOOPDLQWDLQDUHFRUGRIWKHDPRXQWDQGGDWHVZKHQXQXVHG


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

VXSSOLHVZHUHHLWKHUGHVWUR\HGRUUHWXUQHG$OOUHFRUGVZLOOEHUHWDLQHGDVQRWHGLQ
6HFWLRQ
13.9
Disclosure of Data
,QGLYLGXDOSDWLHQWPHGLFDOLQIRUPDWLRQREWDLQHGDVDUHVXOWRIWKLVVWXG\LVFRQVLGHUHG
FRQILGHQWLDODQGGLVFORVXUHWRWKLUGSDUWLHVRWKHUWKDQWKRVHQRWHGEHORZLVSURKLELWHG3DWLHQW
FRQILGHQWLDOLW\ZLOOEHIXUWKHUDVVXUHGE\XWLOL]LQJSDWLHQWLGHQWLILFDWLRQFRGHQXPEHUVWR
FRUUHVSRQGWRWUHDWPHQWGDWDLQWKHFRPSXWHUILOHV7KHVWXG\SHUVRQQHOHPSOR\HHVRIWKH
UHJXODWRU\DJHQFLHVLQFOXGLQJWKH86)'$DQGWKHVWXG\VSRQVRU&RUYLGLD7KHUDSHXWLFV
DQGLWVDJHQWVZLOOQHHGWRUHYLHZSDWLHQWPHGLFDOUHFRUGVLQRUGHUWRDFFXUDWHO\UHFRUG
LQIRUPDWLRQIRUWKLVVWXG\,IUHVXOWVRIWKLVVWXG\DUHUHSRUWHGLQPHGLFDOMRXUQDOVRUDW
PHHWLQJVWKHSDWLHQW¶VLGHQWLW\ZLOOUHPDLQFRQILGHQWLDO


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

14
REFERENCES
%iUiQ\3'LYLQR)LOKR-&%HUJVWU|P-+LJK&UHDFWLYHSURWHLQLVDVWURQJSUHGLFWRURI
UHVLVWDQFHWRHU\WKURSRLHWLQLQKHPRGLDO\VLVSDWLHQWV$P-.LGQH\'LV
$SU
%D\OLVV7-6PLWK-76FKXVWHU0'UDJQHY.+5LJDV-5$KXPDQL]HGDQWL,/DQWLERG\
$/'LQQRQVPDOOFHOOOXQJFDQFHU([SHUW2SLQ%LRO7KHU'HF
%HVDUDE$%ROWRQ:.%URZQH-.(JULH-&1LVVHQVRQ$52NDPRWR'06FKZDE6-
*RRGNLQ'$7KHHIIHFWVRIQRUPDODVFRPSDUHGZLWKORZKHPDWRFULWYDOXHVLQSDWLHQWVZLWK
FDUGLDFGLVHDVHZKRDUHUHFHLYLQJKHPRGLDO\VLVDQGHSRHWLQ1(QJO-0HG

&R\QH':.DSRLDQ76XNL:6LQJK$.0RUDQ-('DKO195L]NDOD$5'5,9(6WXG\
*URXS)HUULFJOXFRQDWHLVKLJKO\HIILFDFLRXVLQDQHPLFKHPRGLDO\VLVSDWLHQWVZLWKKLJK
VHUXPIHUULWLQDQGORZWUDQVIHUULQVDWXUDWLRQUHVXOWVRIWKH'LDO\VLV3DWLHQWV
5HVSRQVHWR,9
,URQZLWK(OHYDWHG)HUULWLQ'5,9(6WXG\-$P6RF1HSKURO
)LVKEDQH6%HVDUDE$0HFKDQLVPRILQFUHDVHGPRUWDOLW\ULVNZLWKHU\WKURSRLHWLQWUHDWPHQW
WRKLJKHUKHPRJORELQWDUJHWV&OLQ-$P6RF1HSKURO±
+HQW]H0:0XFNHQWKDOHU0*DO\%&DPDVFKHOOD&7ZRWR7DQJR5HJXODWLRQRI
0DPPDOLDQ,URQ0HWDEROLVP&HOO±
+HQW]H0:0XFNHQWKDOHU08$QGUHZV1&%DODQFLQJDFWVPROHFXODUFRQWURORI
PDPPDOLDQLURQPHWDEROLVP&HOO±
+XQJ$+(OOLV&'6KLQWDQL$%RRNHU&,NL]OHU$,/%UHFHSWRUDQWDJRQLVWUHGXFHV
LQIODPPDWLRQLQKHPRGLDO\VLVSDWLHQWV-$P6RF1HSKURO
.DODQWDU=DGHK.0F$OOLVWHU&-/HKQ56/HH*+1LVVHQVRQ$5.RSSOH-'(IIHFWRI
PDOQXWULWLRQLQIODPPDWLRQFRPSOH[V\QGURPHRQ(32K\SRUHVSRQVLYHQHVVLQPDLQWHQDQFH
KHPRGLDO\VLVSDWLHQWV$P-.LGQH\'LV±
.DODQWDU=DGHK.5HJLGRU'/0F$OOLVWHU&-0LFKDHO%:DUQRFN'*7LPHGHSHQGHQW
DVVRFLDWLRQVEHWZHHQLURQDQGPRUWDOLW\LQKHPRGLDO\VLVSDWLHQWV-$P6RF1HSKURO
±
.KDUDJMLWVLQJK$9.RUHYDDU-&9DQGHQEURXFNH-3%RHVFKRWHQ(:.UHGLHW57'DKD
05'HNNHU):1(&26$'6WXG\*URXS,QFLGHQFHRIUHFRPELQDQWHU\WKURSRLHWLQ(32
K\SRUHVSRQVH(32DVVRFLDWHGDQWLERGLHVDQGSXUHUHGFHOODSODVLDLQGLDO\VLVSDWLHQWV
.LGQH\,QW
.LOSDWULFN5'&ULWFKORZ&:)LVKEDQH6HWDO*UHDWHUHSRHWLQDOIDUHVSRQVLYHQHVVLV
DVVRFLDWHGZLWKLPSURYHGVXUYLYDOLQKHPRGLDO\VLVSDWLHQWV&OLQ-$P6RF1HSKURO
±


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

0DFGRXJDOO,&&RRSHU$&+\SRUHVSRQVLYHQHVVWRHU\WKURSRLHWLFWKHUDS\GXHWRFKURQLF
LQIODPPDWLRQ(XU-&OLQ,QYHVW6XSSO
6DNDL5&KR6..1DQNL7:DWDQDEH.<DPD]DNL+7DQDND0HWDO+HDGWRKHDG
FRPSDULVRQRIWKHVDIHW\RIWRFLOL]XPDEDQGWXPRUQHFURVLVIDFWRULQKLELWRUVLQUKHXPDWRLG
DUWKULWLVSDWLHQWV5$LQFOLQLFDOSUDFWLFHUHVXOWVIURPWKHUHJLVWU\RI-DSDQHVH5$SDWLHQWVRQ
ELRORJLFVIRUORQJWHUPVDIHW\5($/UHJLVWU\$UWKULWLV5HV7KHU-DQ
6DQRIL5HJHQHURQ7RSOLQH5HVXOWVRI3KDVH0RQRWKHUDS\6WXG\'HPRQVWUDWLQJ6XSHULRULW\RI
6DULOXPDEYV$GDOLPXPDELQ3DWLHQWVZLWK$FWLYH5KHXPDWRLG$UWKULWLV0DU
6LHSHU-%UDXQ-.D\-%DGDODPHQWL65DGLQ$-LDR/)LRUH6HWDO6DULOXPDEIRU
WKHWUHDWPHQWRIDQN\ORVLQJVSRQG\OLWLVUHVXOWVRID3KDVH,,UDQGRPLVHGGRXEOHEOLQG
SODFHERFRQWUROOHGVWXG\$/,*1$QQ5KHXP'LV–
6LQJK$.6]F]HFK/7DQJ./HWDO&RUUHFWLRQRIDQHPLDZLWKHSRHWLQDOIDLQFKURQLF
NLGQH\GLVHDVH1(QJO-0HG±
6RQJ61,ZDKDVKL07RPRVXJL18QR.<DPDQD-<DPDQD6,VREH7,WR+.DZDEDWD
+<RVKL]DNL. &RPSDUDWLYHHYDOXDWLRQRIWKHHIIHFWVRIWUHDWPHQWZLWKWRFLOL]XPDEDQG
71)ĮLQKLELWRUVRQVHUXPKHSFLGLQDQHPLDUHVSRQVHDQGGLVHDVHDFWLYLW\LQUKHXPDWRLG
DUWKULWLVSDWLHQWV $UWKULWLV5HV7KHU2FW5
6RQJ617RPRVXJL1.DZDEDWD+,VKLNDZD71LVKLNDZD7<RVKL]DNL. 'RZQ
UHJXODWLRQRIKHSFLGLQUHVXOWLQJIURPORQJWHUPWUHDWPHQWZLWKDQDQWL,/UHFHSWRUDQWLERG\
WRFLOL]XPDELPSURYHVDQHPLDRILQIODPPDWLRQLQPXOWLFHQWULF&DVWOHPDQGLVHDVH %ORRG
1RY
6XQ&&9DMD9%DELWW-//LQ+<7DUJHWLQJWKHKHSFLGLQIHUURSRUWLQD[LVWRGHYHORSQHZ
WUHDWPHQWVWUDWHJLHVIRUDQHPLDRIFKURQLFGLVHDVHDQGDQHPLDRILQIODPPDWLRQ$P-
+HPDWRO
7DQDND<0DUWLQ0ROD(,/WDUJHWLQJFRPSDUHGWR71)WDUJHWLQJLQUKHXPDWRLGDUWKULWLV
VWXGLHVRIRORNL]XPDEVDULOXPDEDQGVLUXNXPDE$QQ5KHXP'LV6HS±
:RQ+6.LP+*<XQ<6-HRQ(..R<+.LP<6.LP<2<RRQ6$,/LVDQ
LQGHSHQGHQWULVNIDFWRUIRUUHVLVWDQFHWRHU\WKURSRLHVLVVWLPXODWLQJDJHQWVLQKHPRGLDO\VLV
SDWLHQWVZLWKRXWLURQGHILFLHQF\+HPRGLDO,QW-DQ



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

15
APPENDICES


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Appendix A 
Schedule of Events

Schedule of Events for the Screening Period 

Initial 
Screening
Full Screening 
6WXG\:HHNV



6WXG\'D\V>@
WR
WR
WR
Short,&)VLJQHG
;


0HGLFDO+LVWRU\
;


&RQFRPLWDQWDQG3ULRU0HGLFDWLRQV
;
*HQRW\SH
;


'HWHUPLQH&RQILUP(OLJLELOLW\
;

.HHS(6$DQG3DUHQWHUDO,URQ'RVHV6WDEOH>@
Long,&)VLJQHG

;

)HFDO2FFXOW%ORRG>@

;

/DE3DQHOV>,1)(&@DQG>%9,7@L37+

;>D@

6FUHHQLQJ,/WRWDOKV&53
;>D@
;>D@

6HUXP3UHJQDQF\)6+>@

;>D@

/DEHO3DQHO>&+(0@

;>D@

/DE3DQHO>,521@
;>D@
;>D@
;>D@
/DE3DQHO>+(0(@
;>D@
;>D@
;>D@
/DE3DQHO>635%&@


;>D@
/DE3DQHOV>,1)/@

;>D@
;>D@
/DE3DQHO>,1)/@SUHDOEXPLQKV&53

;>D@
;>D@
/DE3DQHO>&$5'@

;>DG@
;>DG@
9LWDO6LJQV>@

;
;
:HLJKWSUHGLDO\VLVDQGSRVWGLDO\VLV>@

;
;
5HFRUGQHWXOWUDILOWUDWLRQGXULQJGLDO\VLV>@

;
;
5HFRUGKHLJKW

;
OHDG(&*SUHGLDO\VLV

;
/LPLWHG3K\VLFDO([DPLQDWLRQ>@

;
&DUGLDF05,

;
+DQG*ULS6WUHQJWK>@

;
)$&,7)>@

;
$GYHUVH(YHQWV
;>@
;>@
/DERUDWRU\WHVWSDQHOVDUHGHILQHGLQ$SSHQGL['
(YHU\HIIRUWVKRXOGEHPDGHWRFRQGXFWWKHZHHNO\VWXG\YLVLWVRQWKHVDPHGD\RIWKHZHHNHJRQ
:HGQHVGD\V
)RUSDWLHQWVZKRDUHUHVFUHHQLQJSOHDVHUHIHUWR6HFWLRQIRUDOORZDEOHPRGLILFDWLRQVWR6FUHHQLQJ
3URFHGXUHV

0 0RQGD\: :HGQHVGD\7K 7KXUVGD\) )ULGD\
>D@>E@>F@>G@3OHDVHVHH)RRWQRWHL




&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

>@(YHU\HIIRUWVKRXOGEHPDGHWRREWDLQWKHEORRGWHVWVIRUHDFKYLVLWRQWKHVDPHGD\RIWKHZHHNHJRQ
:HGQHVGD\V7KH6FUHHQLQJ3HULRGPD\EHLQFUHDVHGE\XSWRGD\VZLWKDSSURYDOIURPWKH0HGLFDO
0RQLWRU
>@6HH,QFOXVLRQ&ULWHULDDQGIRUGHILQLWLRQRIVWDELOLW\6HFWLRQ
>@7KUHHVWRROWHVWVVKRXOGEHGLVWULEXWHGGXULQJ:HHNDQGVHQWWRWKH&HQWUDO/DERUDWRU\ZLWKLQD
WLPHIUDPHWKDWHQVXUHVUHVXOWVDUHUHWXUQHGSULRUWRUDQGRPL]DWLRQ/RFDOO\SHUIRUPHGVWRROWHVWLQJPD\EH
VXEVWLWXWHGLIQHHGHGLI&HQWUDO/DERUDWRU\UHVXOWVDUHQRWDYDLODEOHSULRUWRUDQGRPL]DWLRQ'D\
>@3UHJQDQF\LQZRPHQRIFKLOGEHDULQJSRWHQWLDORQO\)6+RQO\LQSRVWPHQRSDXVDOZRPHQEHORZ\HDUV
ZKRKDYHKDGQRPHQVHVIRU\HDU
>@2EWDLQEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUHZLWKLQPLQXWHVSULRUWRWKHVWDUWRI
GLDO\VLVDQGZLWKLQPLQXWHVDIWHUGLDO\VLV
>@2EWDLQZHLJKWZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLVDQGZLWKLQPLQXWHVDIWHUWKHHQGRIGLDO\VLV
IRUWKHsameGLDO\VLVVHVVLRQGXULQJZKLFK/DE3DQHO>&$5'@ZDVFROOHFWHG
>@1HWXOWUDILOWUDWLRQYROXPHVKRXOGEHUHFRUGHGIRUWKHsameGLDO\VLVVHVVLRQGXULQJZKLFK/DE3DQHO
>&$5'@GDWDZHUHFROOHFWHG
>@+DYHSDWLHQWFRPSOHWHWKH)$&,7)TXHVWLRQQDLUHVHHLQVWUXFWLRQVLQ6WXG\5HIHUHQFH0DQXDOSULRUWR
GLDO\VLVRUGXULQJWKHILUVWKRXURIGLDO\VLV
>@/LPLWHGSK\VLFDOH[DPWRLQFOXGHVNLQRURSKDU\Q[OXQJVKHDUWDEGRPHQH[WUHPLWLHVLQFOXGLQJIHHWDQG
DQ\DUHDVVXJJHVWHGE\V\PSWRPVZLWKSDUWLFXODUDWWHQWLRQWRVLJQVRILQIHFWLRQ0D\EHSHUIRUPHGE\D
SK\VLFLDQLQYHVWLJDWRURUPLGOHYHOSURYLGHU5HFRUGDEQRUPDOILQGLQJVLQWKHVRXUFHGRFXPHQWV
>@3HUIRUPDQ\WLPHSULRUWRVWDUWLQJGLDO\VLV
>@2QO\DGYHUVHHYHQWVFRQVLGHUHGUHODWHGWRVWXG\SURFHGXUHV
>@$OODGYHUVHHYHQWVDUHFROOHFWHGVWDUWLQJZLWKWKHVLJQLQJRIWKH/RQJ,&)



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Schedule of Events for the Treatment Period – Weeks 1 through 6 
Treatment Period
6WXG\:HHNV









9LVLW:LQGRZ







6WXG\'D\V


>07KLI
SRVVLEOH@













(6$DQGLURQGRVLQJSHU$SSHQGL[&
5DQGRPL]DWLRQ
;>@






6WXG\'UXJ
$GPLQLVWUDWLRQ>@

;


;

;

/DE3DQHO>&+(0@
;>D@





;>D@
/DE3DQHO>/,3@/SD
VHUXPSUHJQDQF\>@
;>D@





;>D@
/DE3DQHO>,1)/@
;>D@


;>D@
;>D@


3UH$OEXPLQKV&53
;>D@
;>DG@
;>DG@
;>DE@
;>D@
;>D@
;>D@
/DE3DQHO>635%&@
;>D@

;>D@
;>D@
;>D@
;>D@
;>D@
/DE3DQHO>+(0(@
;>D@

;>D@
;>D@
;>D@
;>D@
;>D@
/DE3DQHO>,521@
;>D@

;>D@
;>D@
;>D@
;>D@
;>D@
/DE3DQHO>3.@
;>DEF@
;>DG@
;>G@
;>DE@

;>D@

/DE3DQHO>&$5'@







/DE3DQHO>$'$@
;>D@


;>D@

;>D@

/DE3DQHO>,1)/@
;>DEF@
;>DG@
;>G@
;>DE@

;>D@

/DE3DQHO>%,2@
;>D@






6HUXPSUHJQDQF\>@
;>D@






Local Lab,15>@
;>D@

;>D@
;>D@
;>D@
;>D@
;>D@
OHDG(&*SUHGLDO\VLV
;





;
)$&,7)>@
;





;
/LPLWHG3K\VLFDO
([DPLQDWLRQ>@






;
9LWDO6LJQV
;>@

;>@
;>@
;>@
;>@
;>@
:HLJKWSUHGLDO\VLV







:HLJKWSRVWGLDO\VLV







5HFRUGQHWXOWUDILOWUDWLRQ
GXULQJGLDO\VLV






&DUGLDF05,







+DQGJULSVWUHQJWK
;>@





;>@
$GYHUVH(YHQWV
;
&RQFRPLWDQW
0HGLFDWLRQV
;



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Schedule of Events for the Treatment Period – Weeks 7 through 12/ET-1 
Treatment Period (continued)
6WXG\:HHNV







(7
9LVLW:LQGRZ







6WXG\'D\V
















(6$DQGLURQGRVLQJSHU$SSHQGL[&
6WXG\'UXJ
$GPLQLVWUDWLRQ>@

;

;


;


/DE3DQHO>&+(0@






;>D@
$OEXPLQ



;



/DE3DQHO>/,3@/SD






;>D@
/DE3DQHO>,1)/@
;>D@

;>D@
;>D@
;>D@

;>D@
KV&53
;>D@
;>G@
;>D@
;>D@
;>DEF@
;>DG@
;>D@
3UH$OEXPLQ
;>D@
;>G@
;>D@

;>DEF@
;>DG@
;>D@
/DE3DQHO>635%&@
;>D@
;>D@
;>D@
;>D@
;>D@

;>D@
/DE3DQHO>+(0(@
;>D@
;>D@
;>D@
;>D@
;>D@

;>D@
/DE3DQHO>,521@
;>D@
;>D@
;>D@
;>D@
;>D@

;>D@
/DE3DQHO>3.@
;>D@
;>G@
;>D@

;>DEF@
;>DG@

/DE3DQHO>&$5'@




;>DG@
;>DG@
;>DG@
/DE3DQHO>$'$@
;>D@

;>D@

;>D@


/DE3DQHO>,1)/@
;>D@
;>G@
;>D@

;>DEF@
;>DG@
;>D@
/DE3DQHO>%,2@






;>D@
6HUXPSUHJQDQF\>@






;>D@
Local Lab,15>@
;>D@
;>D@
;>D@
;>D@
;>D@

;>D@
OHDG(&*SUHGLDO\VLV






;
)$&,7)>@






;
/LPLWHG3K\VLFDO
([DPLQDWLRQ>@






;
9LWDO6LJQV
;>@
;>@
;>@
;>@
;>@
;>@
;>@
:HLJKWSUHGLDO\VLV




;>@
;>@
;>@
:HLJKWSRVWGLDO\VLV




;>@
;>@
;>@
5HFRUGQHWXOWUDILOWUDWLRQ
GXULQJGLDO\VLV




;>@

;>@
;>@
&DUGLDF05,






;>@
+DQGJULSVWUHQJWK






;>@
$GYHUVH(YHQWV
;
&RQFRPLWDQW
0HGLFDWLRQV
;
/DERUDWRU\WHVWSDQHOVDUHGHILQHGLQ$SSHQGL['
(YHU\HIIRUWVKRXOGEHPDGHWRFRQGXFWWKHZHHNO\VWXG\YLVLWVRQWKHVDPHGD\RIWKHZHHNHJRQ:HGQHVGD\V
(7 (DUO\7HUPLQDWLRQ9LVLWVHH6HFWLRQ
>D@>E@>F@>G@3OHDVHVHH)RRWQRWHL
>@7KH6WXG\'UXJLVWREHDGPLQLVWHUHGGXULQJGLDO\VLVRYHUDSSUR[LPDWHO\KRXUVWDUWLQJDQ\WLPHSULRUWR
WKHODVWKRXURIGLDO\VLVVHH6HFWLRQ
x
6WXG\9LVLWVGXULQJZKLFK6WXG\'UXJLQIXVLRQVDUHUHTXLUHGVKRXOGEHSODQQHGRQWKHVDPHGD\RIWKH
ZHHNVRWKDW6WXG\'UXJDGPLQLVWUDWLRQFDQRFFXURQDVFKHGXOHRIHYHU\GD\V


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

x
:KHQHYHUSRVVLEOHNHHSWKHWLPLQJRIWKHVWDUWRIVWXG\GUXJUHODWLYHWRWKHVWDUWRIGLDO\VLVFRQVWDQW
HJVWXG\GUXJLVDOZD\VVWDUWHGaPLQXWHVDIWHUGLDO\VLVLVVWDUWHG
x
3DWLHQWVZKRPLVVDGRVHRI6WXG\'UXJHJGXHWRDPLVVHGGLDO\VLVYLVLWPD\UHFHLYHWKHPLVVHG
6WXG\'UXJXSWRKRXUVRUGD\VODWHU,IWKHPLVVHGGRVHFDQQRWEHDGPLQLVWHUHGZLWKLQWKLVWLPH
IUDPHWKHGRVHVKRXOGEHFRQVLGHUHG³PLVVHG´DQGWKHQH[WGRVHDGPLQLVWHUHGDWWKHQH[WVWXG\YLVLWDV
SODQQHG
>@6HUXPSUHJQDQF\LQZRPHQRIFKLOGEHDULQJSRWHQWLDORQO\
>@3DWLHQWVUHFHLYLQJZDUIDULQRQO\0D\DOVREHGRQHXVLQJDSRLQWRIFDUHGHYLFH
>@2EWDLQZHLJKWZLWKLQPLQXWHVSULRUWRWKHVWDUWRIGLDO\VLV2Q:HHNVDQGVKRXOGEHUHFRUGHGIRU
WKHVDPHGLDO\VLVVHVVLRQGXULQJZKLFK/DE3DQHO>&$5'@GDWDZHUHFROOHFWHG
>@/LPLWHGSK\VLFDOH[DPWRLQFOXGHVNLQRURSKDU\Q[OXQJVKHDUWDEGRPHQH[WUHPLWLHVLQFOXGLQJIHHWDQG
DQ\DUHDVVXJJHVWHGE\V\PSWRPVZLWKSDUWLFXODUDWWHQWLRQWRVLJQVRILQIHFWLRQ0D\EHSHUIRUPHGE\D
SK\VLFLDQLQYHVWLJDWRURUPLGOHYHOSURYLGHU5HFRUGDEQRUPDOILQGLQJVLQWKHVRXUFHGRFXPHQWV
>@2EWDLQEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUHZLWKLQPLQXWHVSULRUWRVWDUWLQJ
GLDO\VLV
>@2Q'D\2EWDLQEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUHZLWKLQPLQXWHVSULRUWR
VWDUWLQJWKHLQIXVLRQDQGPLQXWHVIROORZLQJWKHVWDUWRIWKHLQIXVLRQDQGPLQXWHV
PLQXWHVDQGPLQXWHVIROORZLQJWKHHQGRIWKHLQIXVLRQ
$IWHU'D\2EWDLQEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUHZLWKLQPLQXWHVSULRUWR
VWDUWLQJWKHLQIXVLRQDQGPLQXWHVIROORZLQJWKHVWDUWRIWKHLQIXVLRQPLQXWHVDQG
PLQXWHVIROORZLQJWKHHQGRIWKHLQIXVLRQ
>@:LWKLQPLQXWHVDIWHUWKHHQGRIGLDO\VLV6KRXOGEHUHFRUGHGIRUWKHsameGLDO\VLVVHVVLRQGXULQJZKLFK
/DE3DQHO>&$5'@ZDVFROOHFWHG
>@1HWXOWUDILOWUDWLRQYROXPHVKRXOGEHUHFRUGHGIRUWKHsameGLDO\VLVVHVVLRQGXULQJZKLFK/DE3DQHO
>&$5'@GDWDZHUHFROOHFWHG
>@2EWDLQGXULQJ:HHNZHHNV
>@3HUIRUPKDQGJULSVWUHQJWKDQ\WLPHSULRUWRVWDUWLQJGLDO\VLV
>@2EWDLQEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUHZLWKLQPLQXWHVSULRUWRVWDUWLQJ
GLDO\VLVDQGZLWKLQPLQXWHVDIWHUGLDO\VLV
>@+DYHSDWLHQWFRPSOHWHWKH)$&,7)TXHVWLRQQDLUHVHHLQVWUXFWLRQVLQ6WXG\5HIHUHQFH0DQXDOSULRUWR
GLDO\VLVRUGXULQJWKHILUVWKRXURIGLDO\VLV2Q'D\PXVWEHFRPSOHWHGEHIRUHWKHVWDUWRIWKH6WXG\'UXJ
LQIXVLRQ
>@9LVLWZLQGRZPD\EHH[WHQGHGWRGD\VRQO\LQLQVWDQFHVZKHQWKHVWXG\GUXJZDVPLVVHGRQWKH
WDUJHWHGYLVLWGD\DQGDOVRFRXOGQRWEHJLYHQGXULQJWKHGLDO\VLVYLVLWDIWHUWKHPLVVHGGRVH
>@5DQGRPL]DWLRQPD\EHSHUIRUPHGRQ'D\LIQHHGHG$GPLQLVWUDWLRQRIWKHILUVWGRVHRI6WXG\'UXJ
ZLOOFRQWLQXHWRGHILQH6WXG\'D\


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Schedule of Events for the Safety Follow-Up and Extended Follow-Up Periods

Safety Follow-Up Period
Extended F/U
6WXG\:HHN




(7

9LVLW:LQGRZ







6WXG\'D\










(6$DQGLURQGRVLQJSHU$SSHQGL[&
/DE3DQHO>&+(0@





;>D@

$OEXPLQ
;

;



/DE3DQHO>/,3@/SD
VHUXPSUHJQDQF\>@




;>D@

/DE3DQHO>,1)/@
;>D@

;>D@

;>D@

KV&53
;>D@

;>D@

;>D@
;>D@
3UH$OEXPLQ




;>D@

/DE3DQHO>635%&@
;>D@
;>D@
;>D@
;>D@
;>D@

/DE3DQHO>+(0(@
;>D@
;>D@
;>D@
;>D@
;>D@

/DE3DQHO>,521@
;>D@
;>D@
;>D@
;>D@
;>D@

/DE3DQHO>3.@
;>D@

;>D@


;>D@
/DE3DQHO>$'$@




;>D@
;>D@
/DE3DQHO>,1)/@
;>D@

;>D@

;>D@
;>D@
Local Lab,15>@

;>D@
;>D@
;>D@
;>D@
;>D@

OHDG(&*SUHGLDO\VLV


;

;

/LPLWHG3K\VLFDO([DPLQDWLRQ>@


;

;

9LWDO6LJQVSUHGLDO\VLV>@
;
;
;
;
;

$GYHUVH(YHQWV
;

&RQFRPLWDQW0HGLFDWLRQV
;

>@6HUXPSUHJQDQF\LQZRPHQRIFKLOGEHDULQJSRWHQWLDORQO\
>@3DWLHQWVUHFHLYLQJZDUIDULQRQO\0D\DOVREHGRQHXVLQJDSRLQWRIFDUHGHYLFH
>@/LPLWHGSK\VLFDOH[DPWRLQFOXGHVNLQRURSKDU\Q[OXQJVKHDUWDEGRPHQH[WUHPLWLHVLQFOXGLQJIHHWDQG
DQ\DUHDVVXJJHVWHGE\V\PSWRPVZLWKSDUWLFXODUDWWHQWLRQWRVLJQVRILQIHFWLRQ0D\EHSHUIRUPHGE\D
SK\VLFLDQLQYHVWLJDWRURUPLGOHYHOSURYLGHU5HFRUGDEQRUPDOILQGLQJVLQWKHVRXUFHGRFXPHQWV
>@2EWDLQEORRGSUHVVXUHKHDUWUDWHUHVSLUDWRU\UDWHDQGWHPSHUDWXUHZLWKLQPLQXWHVSULRUWRGLDO\VLV
(YHU\HIIRUWVKRXOGEHPDGHWRFRQGXFWWKHVWXG\YLVLWVRQWKHVDPHGD\RIWKHZHHNHJRQ:HGQHVGD\V
/DERUDWRU\WHVWSDQHOVDUHGHILQHGLQ$SSHQGL['
(7 (DUO\7HUPLQDWLRQ9LVLWVHH6HFWLRQ


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

>D@>E@>F@>G@3OHDVHVHH)RRWQRWHL
Footnote i)RRWQRWHV Common to All Schedule of Events’ Tables
>D@:LWKLQPLQXWHVSULRUWRGLDO\VLV'UDZEORRGWKURXJKHLWKHUDSHULSKHUDOQHHGOHVWLFNRUWKHDUWHULDO
GLDO\VLVQHHGOHEHIRUHFRQQHFWLQJWKHDUWHULDOEORRGWXELQJRUIOXVKLQJWKHQHHGOH%HVXUHWKDWQRVDOLQHRU
KHSDULQLVLQWKHDUWHULDOQHHGOHRUWXELQJSULRUWRGUDZLQJWKHVDPSOH
>E@:LWKLQPLQXWHVDIWHUFRPSOHWLQJWKHLQIXVLRQ
,IGLDO\VLVKDVHQGHGGUDZWKHVDPSOHDIWHUWKHPDFKLQHKDVEHHQWXUQHGRIIHLWKHUWKURXJKDSHULSKHUDOQHHGOH
VWLFNRUIURPWKHDUWHULDOQHHGOHWXELQJSULRUWRWDNLQJRXWWKHQHHGOHRUDUWHULDOEORRGOLQHVDPSOHSRUW
,IGLDO\VLVLVVWLOORQJRLQJDQGWKHVDPSOHLVEHLQJGUDZQWKURXJKWKHDUWHULDOEORRGOLQHVDPSOHSRUWREWDLQWKH
VDPSOHLQDPDQQHUWKDWPLQLPL]HVSRVVLEOHUHFLUFXODWLRQLQWKHGLDO\VLVDFFHVV6HH6WXG\5HIHUHQFH0DQXDO
IRUUHFRPPHQGDWLRQV$OWHUQDWLYHO\WKHVDPSOHPD\EHGUDZQWKURXJKDSHULSKHUDOQHHGOHVWLFN
>F@>@KRXUVDIWHUFRPSOHWLQJWKHLQIXVLRQZKHQHYHUIHDVLEOHHJILUVWVKLIWSDWLHQWV
>G@:LWKLQPLQXWHVDIWHUFRPSOHWLQJGLDO\VLV3OHDVHVHHUHFRPPHQGDWLRQVIRUEORRGGUDZLQJLQVHFWLRQE
DERYH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Appendix B 
Exclusionary Drugs 
7KHIROORZLQJPHGLFDWLRQVDUHPHWDEROL]HGE\&<3HQ]\PDWLFSDWKZD\VDQGKDYHD
QDUURZWKHUDSHXWLFZLQGRZ7KHXVHRIWKHVHPHGLFDWLRQVIURPRQHGD\SULRUWR
5DQGRPL]DWLRQ'D\WKURXJK6WXG\:HHNLVSURKLELWHG

GLJR[LQ

WKHRSK\OOLQH

WHUIHQDGLQH

WL]DQLGLQH

TXLQLGLQH

SKHQ\WRLQDQGLWVGHULYDWLYHV

WD[DQHFKHPRWKHUDSHXWLFDJHQWV

F\FORVSRULQH

P725LQKLELWRUVVLUROLPXVWDFUROLPXV

HUJRWDONDORLGV

DQWLSV\FKRWLFPHGLFDWLRQVVSHFLILFDOO\SLPR]LGHWKLRULGD]LQH

IHQWDQ\ODQGGHULYDWLYHVHJDOIHQWDQLODQGVXIHQWDQLO



&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Appendix C 
ESA and Parenteral Iron Dose-Adjustments 
Weeks 1 - 4 

(6$GRVHVDUHQRWWREHDGMXVWHGRUKHOGGXULQJ:HHNVWKURXJKXQOHVVRQHRUPRUH
FRQILUPHGKHPRJORELQYDOXHVLHDWOHDVWFRQVHFXWLYHPHDVXUHPHQWVRUWKHSDWLHQW¶V
FOLQLFDOVWDWXVQHFHVVLWDWHVVXFKGXHWRDFOHDUDQGSUHVHQWVDIHW\ULVN

3DUHQWHUDOLURQGRVHVDUHQRWEHDGMXVWHGRUKHOGGXULQJ:HHNVWKURXJK

3DWLHQWVQRWUHFHLYLQJSDUHQWHUDOLURQSURGXFWVGXULQJ6FUHHQLQJPXVWQRWEHVWDUWHGRQ
WKHVHGXULQJ:HHNVWKURXJK

7KH0HGLFDO0RQLWRUPXVWEHFRQWDFWHGSULRUWRDQ\FRQWHPSODWHG(6$RUSDUHQWHUDOLURQ
GRVHFKDQJHV

Weeks 5 – 24 

&KDQJHVWR(6$GRVLQJPXVWEHEDVHGRQKHPRJORELQYDOXHVWKDWKDYHEHHQFRQILUPHG
LHDWOHDVWFRQVHFXWLYHPHDVXUHPHQWV

'RQRWLQFUHDVHWKHGRVHPRUHIUHTXHQWO\WKDQRQFHHYHU\ZHHNV7KHUHFRPPHQGHG
GRVHLQFUHDVHDWDQ\JLYHQWLPHLV

'HFUHDVHVLQGRVHPD\RFFXUPRUHIUHTXHQWO\WKDQRQFHHYHU\ZHHNV7KH
UHFRPPHQGHGPLQLPXPGXUDWLRQEHWZHHQGRVHUHGXFWLRQVLVZHHNV

,IWKHKHPRJORELQULVHVUDSLGO\HJPRUHWKDQJG/LQDQ\ZHHNSHULRGUHGXFHWKH
GRVHE\$JUHDWHUUHGXFWLRQPD\EHPDGHLIULVHLQKHPRJORELQLVXQDFFHSWDEO\
UDSLG

7KH0HGLFDO0RQLWRUPXVWEHFRQWDFWHGSULRUWRDQ\FRQWHPSODWHG(6$GRVHFKDQJHV
WKDWGHSDUWIURPWKHDERYHSURWRFROUHTXLUHPHQWVDQGUHFRPPHQGDWLRQVXQOHVVFOLQLFDO
XUJHQF\SUHFOXGHVWKLV,IWKH0HGLFDO0RQLWRULVQRWFRQWDFWHGLQDGYDQFHSOHDVHVHQGD
QRWLILFDWLRQZLWKLQKRXUVWKDWDQRIISURWRFRO(6$GRVHFKDQJHZDVPDGH

3DWLHQWVQRWUHFHLYLQJSDUHQWHUDOLURQSURGXFWVPXVWQRWEHVWDUWHGRQWKHVHGXULQJ:HHNV
WKURXJK

3DUHQWHUDOLURQGRVHVDUHQRWWREHDGMXVWHGRUKHOGGXULQJ:HHNVWKURXJKXQOHVV
DSSURYHGE\WKH0HGLFDO0RQLWRU





&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Appendix D 
Laboratory Measurements 
Laboratory
Panel Name
Tests Included
&HQWUDO
3DQHO&KHPLVWU\>&+(0@
6RGLXPSRWDVVLXPFKORULGHELFDUERQDWHRU&2
FDOFLXPSKRVSKDWHDODQLQHDPLQRWUDQVIHUDVH$/7
DVSDUWDWHDPLQRWUDQVIHUDVH$67EORRGXUHDQLWURJHQ
%81FUHDWLQLQHWRWDOELOLUXELQGLUHFWELOLUXELQ
DONDOLQHSKRVSKDWDVHDOEXPLQJOXFRVH
&HQWUDO
3DQHO/LSLGV>/,3@
7RWDOFKROHVWHUROORZGHQVLW\OLSRSURWHLQ/'/
FKROHVWHUROKLJKGHQVLW\OLSRSURWHLQ+'/WULJO\FHULGHV
&HQWUDO
3DQHO,QIODPPDWLRQ>,1)/@ VHUXPDP\ORLG$KHSFLGLQ
&HQWUDO
3DQHO6SHFLDO5%&,QGLFHV
>635%&@
UHWLFXORF\WHKHPRJORELQFRQFHQWUDWLRQ&+U
K\SRFKURPLFUHGFHOOV+5&
&HQWUDO
3DQHO+HPDWRORJ\>+(0(@
+HPRJORELQKHPDWRFULWUHWLFXORF\WHFRXQWUHGEORRG
FRXQW5%&LQGLFHVHJPHDQFRUSXVFXODUYROXPH
0&9UHGFHOOGLVWULEXWLRQZLGWK5':SODWHOHWV
ZKLWHEORRGFRXQW:%&:%&GLIIHUHQWLDO
&HQWUDO
3DQHO,URQ,QGLFHV>,521@
76$7IHUULWLQLURQWRWDOLURQELQGLQJFDSDFLW\7,%&
&HQWUDO
3DQHO3.>3.@
&25
&HQWUDO
3DQHO&DUGLDF0DUNHUV>&$5'@7URSRQLQ717SUR%13
&HQWUDO
3DQHO,QIHFWLRQ6FUHHQ>,1)(&@ +,9DQG+HSDWLWLV%VXUIDFHDQWLJHQ
+HSDWLWLV%VXUIDFHDQWLERG\+HSDWLWLV&DQWLERG\
P\FREDFWHULXPWXEHUFXORVLVEORRGWHVWLHLQWHUIHURQ
JDPPDUHOHDVHDVVD\
&HQWUDO
3DQHO$QWL'UXJ$QWLERGLHV
>$'$@
$QWL&25ELQGLQJDQWLERGLHVDQGQHXWUDOL]LQJ
DQWLERGLHVLIELQGLQJDQWLERGLHVDUHGHWHFWHG
&HQWUDO
3DQHO,QIODPPDWLRQ
>,1)/@
7RWDODQGIUHH,/

&HQWUDO
3DQHO)XWXUHELRPDUNHUV
>%,2@
)XWXUHFDUGLDFUHQDODQGKHPDWRORJLFPDUNHUVLQFOXGLQJ
JHQHYDULDWLRQVULERQXFOHLFDFLGRUSURWHLQPDUNHUV
&HQWUDO
3DQHO%9LWDPLQV>%9,7@
%IRODWH
&HQWUDO
2WKHULQGLYLGXDOWHVWV
6FUHHQLQJWRWDO,/JHQRW\SHLQWDFWSDUDWK\URLG
KRUPRQH>37+@OLSRSURWHLQD>/SD@SUHJQDQF\>ȕK&*
LQZRPHQRIFKLOGEHDULQJSRWHQWLDORQO\@IROOLFOH
VWLPXODWLQJKRUPRQH)6+VWRRORFFXOWEORRGSUH
DOEXPLQKV&53

/RFDO
&RDJXODWLRQ
,QWHUQDWLRQDOQRUPDOL]HGUDWLR,15ZDUIDULQWUHDWHG
SDWLHQWVRQO\





&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH
Appendix E 
FACIT-F 


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH


&25

&RUYLGLD7KHUDSHXWLFV
3URWRFRO&25$PHQGPHQW

3DJH

Appendix F 
Guidance on Contraception
)RUWKHSXUSRVHVRIWKHSURSRVHGVWXG\ “highly effective” contraceptive methodsDUH
GHILQHGDVWKRVHDORQHRULQFRPELQDWLRQWKDWUHVXOWLQDORZIDLOXUHUDWHLHOHVVWKDQ
SHUFHQWSHU\HDUZKHQXVHGFRQVLVWHQWO\DQGFRUUHFWO\DQGLQFOXGHWKHIROORZLQJ
x
6XUJLFDOVWHULOL]DWLRQDWOHDVWPRQWKVEHIRUH6WXG\'UXJDGPLQLVWUDWLRQ
x
,PSODQWV
x
/1*DQG&RSSHU7,8'V
x
6H[XDODEVWLQHQFH

3DWLHQWVZKRSUHIHUPHWKRGVZKLFKHYLGHQFHDKLJKHUIDLOXUHUDWHZLWKW\SLFDOXVHZLOO
EHUHTXLUHGWRHPSOR\DWOHDVWWZRPHWKRGVRIFRQWUDFHSWLRQFRQFXUUHQWO\7KHVHPHWKRGV
LQFOXGHWKHIROORZLQJ
x
,QMHFWDEOHKRUPRQHGHSRWV
x
2UDOFRQWUDFHSWLYHSLOO
x
+RUPRQHSDWFK
x
9DJLQDOULQJ

3HULRGLFDEVWLQHQFHHJFDOHQGDURYXODWLRQV\PSWRWKHUPDOSRVWRYXODWLRQPHWKRGVDQG
ZLWKGUDZDODUH127DFFHSWDEOHPHWKRGVRIFRQWUDFHSWLRQ
KWWSZZZFGFJRYUHSURGXFWLYHKHDOWKXQLQWHQGHGSUHJQDQF\SGIFRQWUDFHSWLYHBPHWKRGVB
SGIIRUDOLVWRIFRQWUDFHSWLYHPHWKRGVDQGHIIHFWLYHQHVV
,QYHVWLJDWRUVPD\FRQWDFWWKH0HGLFDO0RQLWRUWRGLVFXVVTXHVWLRQVUHJDUGLQJDSSURSULDWH
FRQWUDFHSWLRQ7KHJXLGDQFHZLOOIROORZWKDWGHVFULEHGLQWKHGRFXPHQW
KWWSZZZFRYDQFHFRPFRQWHQWGDPFRYDQFHDVVHW/LEUDU\SRVWHUV.DP$&&3SGIDQG
ZLOOFRPSO\ZLWK)'$05

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
6SRQVRUQDPH
1RYR1RUGLVN$6
1&7QXPEHU
1&7
6SRQVRUWULDO,'
11
2IILFLDOWLWOHRIVWXG\
'RFXPHQWGDWH
-XO\
$3KDVH5DQGRPLVHG'RXEOHEOLQG3ODFHERFRQWUROOHG
&RKRUW'RVHHVFDODWLRQ6WXG\LQ+HPRGLDO\VLV3DWLHQWVWR
$VVHVVWKH6DIHW\3KDUPDFRNLQHWLFVDQG3KDUPDFRG\QDPLFV
RI0XOWLSOH,9'RVHVRI&25


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI





6WDWLVWLFDO$QDO\VLV3ODQ

3URWRFRO1R&25


$3+$6(5$1'20,=(''28%/(%/,1'
3/$&(%2&21752//('
&2+257'26((6&$/$7,21678'<,1
+(02',$/<6,63$7,(17672
$66(667+(6$)(7<3+$50$&2.,1(7,&6$1'
3+$50$&2'<1$0,&6
2)08/7,3/(,9'26(62)&25






6SRQVRU
&RUYLGLD7KHUDSHXWLFV
9HUVLRQ

9HUVLRQ
,VVXH'DWH
-XO\




CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


67$7,67,&$/$1$/<6,63/$1$33529$/

Preparedby

BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB

'DWHBBBBBBBBBBBBBBBBBBB
Reviewed and approved by: 
BBBBBBBBBBBBBBBBBBBBBBB
'DWHBBBBBBBBBBBBBBBBBBB



6SRQVRU$SSURYDO
6LJQDWXUH
'DWH
1DPH



6LJQDWXUH
GG000\\\\




CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


7$%/(2)&217(176
$%%5(9,$7,216


,1752'8&7,21


678'<2%-(&7,9(6

 3ULPDU\2EMHFWLYH

 6HFRQGDU\2EMHFWLYHV


678'<(1'32,176

 3ULPDU\6DIHW\(QGSRLQW

 6HFRQGDU\6DIHW\(QGSRLQWV

 3KDUPDFRG\QDPLF(QGSRLQWV

 3ULPDU\3KDUPDFRG\QDPLF(QGSRLQWV

 6HFRQGDU\3KDUPDFRG\QDPLF(QGSRLQWV


6800$5<2)7+(678'<'(6,*1

 *HQHUDO6WXG\'HVLJQDQG3ODQ

 6DPSOH6L]HDQG6WDWLVWLFDO3RZHU&RQVLGHUDWLRQV


67$7,67,&$/0(7+2'6


*(1(5$/&216,'(5$7,216


'(),1,7,2162)$1$/<6,66(76


7,0(:,1'2:6)25$1$/<6,6


+$1'/,1*2)0,66,1*'$7$


35272&2/'(9,$7,216

 (6$DQG3DUHQWHUDO,URQ'RVH$GMXVWPHQWV

 2WKHU'HYLDWLRQV


$1$/<6,662)7:$5(


678'<68%-(&76


',6326,7,212)68%-(&76


'(02*5$3+,&6$1'%$6(/,1(&+$5$&7(5,67,&6


'(02*5$3+,&6$1'%$6(/,1(&+$5$&7(5,67,&6


',$/<6,66,*1$1'6<037206


0(',&$/+,6725<


678'<'58*$1'(;32685(


75($70(17&203/,$1&(


(;7(172)(;32685(


35,25$1'&21&20,7$177+(5$3<


(5<7+5232,(6,667,08/$7,1*$*(176$1'
3$5(17(5$/,521'26(6


3+$50$&2'<1$0,&$1$/<6(6


35,0$5<3+$50$&2'<1$0,&$1$/<6,6

CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



6(&21'$5<3+$50$&2'<1$0,&$1$/<6(6


27+(5()),&$&<$1$/<6(6


0$*1(7,&5(621$1&(,0$*,1*05,6&$1


6(16,7,9,7<$1$/<6(6


6$)(7<$1$/<6,6


35,0$5<6$)(7<$1$/<6,6


6(&21'$5<6$)(7<$1$/<6,6


$'9(56((9(176


&/,1,&$//$%25$725<3$5$0(7(56


,1)86,215(/$7('5($&7,216+<3(56(16,7,9,7<5($&7,216$1'
$1$3+</$;,6


,1)(&7,21'(7$,/6


',$/<6,6'(7$,/6


9,7$/6,*163+<6,&$/(;$0,1$7,21),1',1*6$1'(&*

 9LWDO6LJQV

 3K\VLFDO([DPLQDWLRQ

 /HDG(&*


$17,%2',(672&25


3+$50$&2.,1(7,&$1$/<6,6$1'
3+$50$&2.,1(7,&3+$50$&2'<1$0,&$1$/<6,6

 ,17(5,0$1$/<6(6$1'6$)(7<5(9,(:&200,77((
65&


6$)(7<5(9,(:&200,77((


,17(5,0$1$/<6,6


'$7$%$6(/2&.

 6800$5<2)0$-25&+$1*(6,17+(3/$11('
$1$/<6(6

 5()(5(1&(6

 02&.7$%/(6/,67,1*6$1'),*85(67/)6



CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


$%%5(9,$7,216
$EEUHYLDWLRQ
7HUP
$(
$GYHUVHHYHQW
$/7
$ODQLQHDPLQRWUDQVIHUDVH

$1&29$
$QDO\VLVRIFRYDULDQFH
$67
$VSDUWDWHDPLQRWUDQVIHUDVH
$8&
$UHDXQGHUWKHFXUYH
%3
%ORRGSUHVVXUH
&+U
5HWLFXORF\WHKHPRJORELQFRQWHQW
&PD[&PLQ
0D[LPXPPLQLPXPREVHUYHGFRQFHQWUDWLRQ
&5)
&DVHUHSRUWIRUPV
&52
&RQWUDFWUHVHDUFKRUJDQL]DWLRQ
'/7
'RVH/LPLWLQJ7R[LFLW\
(&*
(OHFWURFDUGLRJUDP
(5,
(6$UHVLVWDQFHLQGH[(6$ZHHNO\GRVH>WDUJHWHGGU\ZHLJKWLQ
.JKHPRJORELQLQJG/@
(6$
(U\WKURSRLHVLVVWLPXODWLQJDJHQW
)$&,7)
)XQFWLRQDO$VVHVVPHQWRI&KURQLF,OOQHVV7KHUDS\±)DWLJXH>TXHVWLRQQDLUH@
$1&29$
$QDO\VLVRI&RYDULDQFH
+5
+HDUWUDWH
KV&53
+LJKVHQVLWLYLW\&5HDFWLYH3URWHLQ
,&)
,QIRUPHGFRQVHQWIRUP
,/
,QWHUOHXNLQ
,9
,QWUDYHQRXV
,9%3
,9%DJ3URWHFWDQW
,:56
,QWHUDFWLYH:HE5HVSRQVH6\VWHP
NJ
.LORJUDP
/9(',
/HIWYHQWULFXODUHQGGLDVWROLFLQGH[
/9()
/HIWYHQWULFXODUHMHFWLRQIUDFWLRQ
/90,
/HIWYHQWULFXODUPDVVLQGH[
/9(60,
/HIWYHQWULFXODUHQGV\VWROLFYROXPHLQGH[
0&9
0HDQFRUSXVFXODUKHPRJORELQ
PJ
0LOOLJUDP
PLQ
0LQXWH
P/
0LOOLOLWHU
05,
0\RFDUGLDO5HVRQDQFH,PDJLQJ
07'
0D[LPDOO\7ROHUDWHG'RVH
17SUR%13
1WHUPLQDOSUR%QDWULXUHWLFSHSWLGH
3'
3KDUPDFRG\QDPLF
3.
3KDUPDFRNLQHWLF
6$$
6HUXPDP\ORLG$
6$(
6HULRXVDGYHUVHHYHQW
6$3
6WDWLVWLFDO$QDO\VLV3ODQ
6'
6WDQGDUG'HYLDWLRQ
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


$EEUHYLDWLRQ
7HUP
6(0
6WDQGDUG(UURURIWKH0HDQ
65&
6DIHW\5HYLHZ&RPPLWWHH
623
6WDQGDUGRSHUDWLQJSURFHGXUH
7ò
+DOIOLIH
76$7
7UDQVIHUULQVDWXUDWLRQ



CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



,1752'8&7,21
7KLV6WDWLVWLFDO$QDO\VLV3ODQ6$3GHVFULEHVWKHVWDWLVWLFDOPHWKRGVWKDWZLOOEHXVHGGXULQJWKH
DQDO\VLVDQGUHSRUWLQJRIGDWDFROOHFWHGXQGHU&RUYLGLD7KHUDSHXWLFV3URWRFRO&25
7KLV6$3VKRXOGEHUHDGLQFRQMXQFWLRQZLWKWKHVWXG\SURWRFRODQGHOHFWURQLFFDVHUHSRUWIRUPV
H&5)V7KLVYHUVLRQRIWKH6$3KDVEHHQGHYHORSHGXVLQJ3URWRFRODPHQGPHQWGDWHG6HS
DQGWKHILQDOH&5)VGDWHG-8/

3KDUPDFRNLQHWLFDQGSKDUPDFRNLQHWLFSKDUPDFRG\QDPLFPRGHOLQJDQDO\VHVDUHGHVFULEHGLQWKH
'DWD$QDO\VLV3ODQIRU3KDUPDFRNLQHWLFDQG3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF0RGHOLQJ

678'<2%-(&7,9(6

3ULPDU\2EMHFWLYH
7KHSULPDU\REMHFWLYHRIWKHVWXG\LVWRHYDOXDWHWKHVDIHW\RIPXOWLSOHGRVHVRI&25

6HFRQGDU\2EMHFWLYHV
7KHVHFRQGDU\REMHFWLYHVRIWKHVWXG\LQFOXGHWKHIROORZLQJ
x
7RPRGHOWKHUHODWLRQVKLSRI&25SKDUPDFRNLQHWLFVDQGSULPDU\SKDUPDFRG\QDPLFV
DVDVVHVVHGE\IUHHDQGWRWDOVHUXP,QWHUOHXNLQ,/KLJKVHQVLWLYLW\&UHDFWLYH
SURWHLQKV&53DQGVHUXPDP\ORLG$6$$

x
7RHYDOXDWHWKHVHFRQGDU\SKDUPDFRG\QDPLFHIIHFWVRI&25DVDVVHVVHGE\
o +HPRJORELQ
o (U\WKURSRLHVLVVWLPXODWLQJDJHQW(6$UHVLVWDQFHLQGH[(5,
o 6\VWHPLFLURQDYDLODELOLW\WUDQVIHUULQVDWXUDWLRQ76$7UHWLFXORF\WHKHPRJORELQ
FRQFHQWUDWLRQ&+UDQGDEVROXWHUHWLFXORF\WHFRXQW
o 6\VWHPLFLURQVWRUHVVHUXPIHUULWLQDQGVXSSOHPHQWDOLURQGRVHUHTXLUHPHQWV
o 0DOQXWULWLRQLQIODPPDWLRQSUHDOEXPLQDOEXPLQ
o 6HUXPFDUGLDFELRPDUNHUV7URSRQLQ7DQG1WHUPLQDOSUR%QDWULXUHWLFSHSWLGH
>17SUR%13@
o /HIWYHQWULFXODUPDVVLQGH[/90,E\QRQFRQWUDVW0\RFDUGLDO5HVRQDQFH
,PDJLQJ05,
o 3K\VLFDOIXQFWLRQE\KDQGJULSVWUHQJWKDQGV\PSWRPVRIIDWLJXH

x
7RLQYHVWLJDWHWKHLPPXQRJHQLFLW\RI&25

678'<(1'32,176

3ULPDU\6DIHW\(QGSRLQW
3ULPDU\VDIHW\HQGSRLQWLVFKDUDFWHUL]DWLRQRIWKH0D[LPDOO\7ROHUDWHG'RVH07'RUWRHVWDEOLVK
WKDWWKHKLJKHVWGRVHH[DPLQHGGLGQRWH[FHHGWKH07'07'ZLOOEHFKDUDFWHUL]HGEDVHGRQWKH
'RVH/LPLWLQJ 7R[LFLWLHV '/7V GHILQHG LQ6HFWLRQ  3RWHQWLDO '/7V ZLOO EH LGHQWLILHG
SURJUDPPDWLFDOO\DQGWKURXJKFOLQLFDOUHYLHZRIDGYHUVHHYHQWLQIRUPDWLRQDQGODELQIRUPDWLRQ
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



6HFRQGDU\6DIHW\(QGSRLQWV
͌ 'HVFULSWLRQRIWKHIUHTXHQF\RI'/7VE\WUHDWPHQWJURXS

͌ 'RVH/LPLWLQJ7R[LFLWLHVDUHLGHQWLILHGDVIROORZV
 &RQILUPHGLHDWOHDVWFRQVHFXWLYHPHDVXUHPHQWV*UDGHQHXWURSHQLDDQG
UHSUHVHQWLQJDGHFOLQHRI!IURPEDVHOLQH
 6HULRXVDGYHUVHHYHQWVRILQIHFWLRQLQWKHSUHVHQFHRIFRQILUPHGLHDWOHDVW
FRQVHFXWLYHPHDVXUHPHQWV*UDGHRUKLJKHUQHZRQVHWO\PSKRSHQLDRUQHZRQVHW
QHXWURSHQLD
 *UDGHDODQLQHDPLQRWUDQVIHUDVH$/7RUDVSDUWDWHDPLQRWUDQVIHUDVH$67
 *UDGHKHPDWRORJLFWR[LFLW\
 *UDGHQRQKHPDWRORJLFWR[LFLW\

'/7ZDVGHILQHGDVDQ\WR[LFLW\WKHUHODWLRQVKLSRIZKLFKWRWKHLQYHVWLJDWLRQDODJHQWFDQQRW
EHUXOHGRXWDVIROORZV


:LWKWKHH[FHSWLRQRI*UDGHQRQKHPDWRORJLFHYHQWV*UDGHRUKLJKHU&7&$(
WR[LFLW\RIDERYHHYHQWVKDYLQJDQDVVHVVHGUHODWLRQVKLSWRWKH6WXG\'UXJRI³GHILQLWHO\´
³SUREDEO\´³SRVVLEO\´RU³XQOLNHO\´ZLOOEHFRQVLGHUHG'/7V


*UDGHQRQKHPDWRORJLFWR[LFLWLHVKDYLQJDQDVVHVVHGUHODWLRQVKLSWRWKH6WXG\'UXJRI
³SUREDEO\´RU³SRVVLEO\´ZLOOEHFRQVLGHUHG'/7V

1RWH³QRQKHPDWRORJLFHYHQWV´UHIHUWR'/7FULWHULDDQGDERYH

 'HVFULSWLRQRIWKHIUHTXHQF\RIWKHHYHQWVRILQWHUHVWE\WUHDWPHQWJURXS7KHHYHQWVRI
LQWHUHVWLQFOXGHG
o 6HYHUHLQIXVLRQUHODWHGUHDFWLRQV
o +\SHUVHQVLWLYLW\UHDFWLRQGXULQJWKH6WXG\'UXJLQIXVLRQ
o $QDSK\OD[LVRFFXUULQJDWDQ\WLPHHYHQLIFRQVLGHUHGXQUHODWHGWRWKH6WXG\'UXJ

,QIXVLRQUHODWHGUHDFWLRQVK\SHUVHQVLWLYLW\UHDFWLRQVDQGDQDSK\OD[LVZLOOEHLGHQWLILDEOH
IURPDFKHFNER[RQWKH$(&5)DQGWKH&7&$(JUDGHRIWKHHYHQWDQGVXSSRUWHGE\
GDWDFROOHFWHGRQWKH,QIXVLRQUHODWHGUHDFWLRQ+\SHUVHQVLWLYLW\$QDSK\OD[LV&5)7KH
SURWRFROGHILQHVK\SHUVHQVLWLYLW\UHDFWLRQVDQGLQIXVLRQUHODWHGUHDFWLRQVE\WKHLU
WHPSRUDOUHODWLRQVKLSEDVHGRQWLPLQJRIRQVHWGXULQJWKHVWXG\GUXJLQIXVLRQ

 'HVFULSWLRQRIDGGLWLRQDOVDIHW\DVVHVVPHQWVE\WUHDWPHQWJURXSDGYHUVHHYHQWVYLWDOVLJQV
(&*FOLQLFDOODERUDWRU\DQGDQWLGUXJDQWLERGLHVELQGLQJDQGQHXWUDOL]LQJ
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



3KDUPDFRG\QDPLF(QGSRLQWV
'DWDIURP&25WUHDWHGSDWLHQWVIURP&RKRUWVQRWH[FHHGLQJWKH07'ZLOOEHSRROHGDQG
GDWDIURPDOOSODFHERSDWLHQWVZLOOEHSRROHGIRUWKHSKDUPDFRG\QDPLFHQGSRLQWDQDO\VHV'RVH
UHODWLRQVKLSVZLOOEHH[SORUHGE\DOVRSUHVHQWLQJGDWDE\GRVHUHJLPHQLHPJ4ZHHNV
PJ4ZHHNVPJ4ZHHNVDQGSRROHGSODFHER

3ULPDU\3KDUPDFRG\QDPLF(QGSRLQWV
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQKV&53WR:HHN
EHWZHHQWUHDWPHQWJURXSV
x &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ6$$WR:HHNEHWZHHQ
WUHDWPHQWJURXSV

6HFRQGDU\3KDUPDFRG\QDPLF(QGSRLQWV
x &KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQ76$7WR:HHN
x &KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQWKH&+UWR:HHN
x &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQKV&53WRWKHPHDQRI
:HHNV
x &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ6$$WRWKHPHDQRI
:HHNV
x &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQVHUXPSUHDOEXPLQWR
WKHPHDQRI:HHNVDQGDOEXPLQWR:HHN
x &KDQJHIURPEDVHOLQHZHHNO\PHDQRI6FUHHQLQJLQ(5,WR:HHN
x &KDQJHIURPEDVHOLQHZHHNO\PHDQRI6FUHHQLQJLQ(5,WRWKHPHDQRI:HHNV±
x &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ+HPRJORELQWR:HHN
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ+HPRJORELQWR:HHN

x &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ+HPRJORELQWR:HHN
H[FOXGLQJKHPRJORELQYDOXHVIROORZLQJDFKDQJHLQWKHWRWDOZHHNO\(6$GRVH$
FKDQJHLVGHILQHGDVWKHILUVWWLPHZKHQWKH(6$ZHHNO\GRVHJRHVXSE\!RUGRZQE\
!UHODWLYHWRWKHSUHYLRXVZHHN
VGRVH
x &KDQJHIURPEDVHOLQHZHHNO\PHDQRI)XOO6FUHHQLQJLQ(5,WRWKHPHDQRI:HHNV±
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ76$7WR:HHN

 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQWKH&+UWR:HHN
 
͌ &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQVHUXPDOEXPLQWR:HHN


([SORUDWRU\3KDUPDFRG\QDPLF(QGSRLQWV

x 'HVFULSWLRQRIWKHV\VWHPLFLURQDYDLODELOLW\76$7DEVROXWHUHWLFXORF\WHFRXQW
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


KHPRJORELQ&+URYHUWLPH

'HVFULSWLRQRIPDUNHUVRIPDOQXWULWLRQLQIODPPDWLRQSUHDOEXPLQDQGDOEXPLQRYHU
WLPH

'HVFULSWLRQRIV\VWHPLFLURQVWRUHVVHUXPIHUULWLQKHSDWLFDQGVSOHQLFLURQFRQWHQWE\
05,DQGVXSSOHPHQWDOLURQGRVHUHTXLUHPHQWVRYHUWLPH

'HVFULSWLRQRI(5,FKDQJHIURPEDVHOLQHZHHNO\PHDQGXULQJWKH6FUHHQLQJ3HULRG
WKURXJK:HHN

'HVFULSWLRQRIFKDQJHV(6$DQGSDUHQWHUDOLURQGRVHUHTXLUHPHQWVIURPEDVHOLQHZHHNO\
PHDQGXULQJWKH6FUHHQLQJ3HULRGWR(YDOXDWLRQ3HULRG:HHNV±DQGWKURXJK
:HHN

'HVFULSWLRQRIFKDQJHVLQ/9PDVVLQGH[IURP6FUHHQLQJWR:HHN
'HVFULSWLRQRIFKDQJHVLQSUHGLDO\VLVSRVWGLDO\VLVDQGGHOWDVHUXP7URSRQLQDQG
17SUR%13GHILQHGDVWKHGLIIHUHQFHEHWZHHQWKHSUHDQGSRVWGLDO\VLVWURSRQLQIURP
EDVHOLQHPHDQRI6FUHHQLQJWR:HHNV±

'HVFULSWLRQRIKDQGJULSVWUHQJWKIURPEDVHOLQHGXULQJ6FUHHQLQJWR:HHN

'HVFULSWLRQRIWKH)$&,7IDWLJXHVFRUHIURPEDVHOLQHGXULQJ6FUHHQLQJWR:HHN


6SHFLILFDOO\(5,LVFDOFXODWHGDVIROORZV

)RUSDWLHQWUHFHLYLQJHSRHWLQDOID
7RWDOZHHNO\GRVHRIHSRHWLQDOIDXQLWV

KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

)RUSDWLHQWVUHFHLYLQJGDUEHSRHWLQDOID
7RWDOZHHNO\GRVHRIGDUEHSRHWLQDOIDPFJ

KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

)RUSDWLHQWVUHFHLYLQJPHWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWD
:HHNO\GRVHRIPHWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWDPFJ 

KHPRJORELQ>JG/@WDUJHWGU\ERG\ZHLJKW>NJ@

6800$5<2)7+(678'<'(6,*1

*HQHUDO6WXG\'HVLJQDQG3ODQ
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


7KLVLVDUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGWULDOGHVLJQHGWRHYDOXDWHWKHVDIHW\
SKDUPDFRNLQHWLFVDQGSKDUPDFRG\QDPLFHIIHFWVRIPXOWLSOHGRVHVRI&25RUSODFHER
DGPLQLVWHUHGWRVHTXHQWLDOFRKRUWVRIKHPRGLDO\VLVSDWLHQWV

:LWKLQHDFKGRVLQJFRKRUWWHQKHPRGLDO\VLVSDWLHQWVZLOOEHUDQGRPL]HGWR&25RUSODFHER
DWUDWLRRIWR3ULRUWRGRVHHVFDODWLRQWKHUHZLOOEHDIRUPDOVDIHW\UHYLHZE\WKH6DIHW\
5HYLHZ&RPPLWWHH65&7KH65&ZLOOVSHFLILFDOO\GHWHUPLQHZKHWKHU07'KDVEHHQ
H[FHHGHGEDVHGRQSURWRFROGHILQHG'/7RFFXUULQJWKURXJK6WXG\'D\LQWKHDFWLYHO\
WUHDWHGSDWLHQWVLQWKHFXUUHQWFRKRUWVHH)LJXUH,QDGGLWLRQSKDUPDFRNLQHWLFDQG
SKDUPDFRG\QDPLFUHVXOWVZLOOEHUHYLHZHGWRDVVHVVWKHDSSURSULDWHQHVVRIWKHQH[WSODQQHGGRVH
DQGWRJXLGHUHYLVLRQRIWKHQH[WGRVHWREHHYDOXDWHGLIQHFHVVDU\7KHSODQQHGGRVHVDUHVKRZQ
LQ7DEOH7KHVHGRVHVPD\EHDGMXVWHGEDVHGRQDFFUXLQJGDWDKRZHYHUWKHPD[LPXPGRVHWR
EHVWXGLHGZLOOQRWH[FHHGWKHSODQQHGWRWDOGRVHLQ&RKRUWPJHYHU\GD\V>GRVHV@

$VLQJOHLQWHULPDQDO\VLVZDVSODQQHGWRHQDEOHIXWXUHSURJUDPSODQQLQJ

3DWLHQWVZLOOXQGHUJRDQXSWRZHHN6FUHHQLQJ3HULRG7KRVHZKRPHHWWKHHQWU\FULWHULDZLOO
EHUDQGRPL]HGRQ'D\DGLDO\VLVGD\RU'D\ZLWKDSSURYDODQGZLOOUHFHLYHWKHILUVWGRVH
RIVWXG\GUXJGXULQJGLDO\VLV$GGLWLRQDOYLVLWVZLOOIROORZWKHVFKHGXOHRIHYHQWV$SSHQGL[$
6HFWLRQRISURWRFRO$OOVXEVHTXHQWVWXG\GUXJLQIXVLRQVZLOODOVREHDGPLQLVWHUHGGXULQJ
GLDO\VLV DQG VWXG\ YLVLWV ZLOO FRLQFLGH ZLWK UHJXODUO\ VFKHGXOHG GLDO\VLV WUHDWPHQWV 3DWLHQWV
GURSSLQJRXWIRUUHDVRQVXQUHODWHGWRVDIHW\PD\EHUHSODFHG)ROORZLQJWKHZHHN7UHDWPHQW
3HULRGSDWLHQWVZLOOEHIROORZHGIRUDQDGGLWLRQDOZHHNVIRUVDIHW\7KHSDWLHQWVZLOOKDYH
FRPSOHWHGWKHLUSULPDU\VWXG\SDUWLFLSDWLRQDW:HHNHQGRIWKH6DIHW\)ROORZ8S3HULRG
6SDUVH EORRG VDPSOHV ZLOO EH DGGLWLRQDOO\ FROOHFWHG RQ :HHN  IRU DQWLGUXJ DQWLERGLHV
SKDUPDFRNLQHWLFVDQG,/PHDVXUHPHQWVDVSDUWRIDQ([WHQGHG)ROORZ8S3HULRG

)LJXUH'RVH(VFDODWLRQ6FKHPDWLF

&RKRUW6DIHW\)ROORZXS
&RKRUW6DIHW\)ROORZXS
&RKRUW6DIHW\)ROORZXS
&RKRUW6DIHW\)ROORZXS
([SDQVLRQ&RKRUW
6FUHHQLQJ
&RKRUW
6FUHHQLQJ
&RKRUW
6FUHHQLQJ
&RKRUW
6FUHHQLQJ
&RKRUW
6FUHHQLQJ
&RKRUWQ 
 PJ4GD\V[GRVHV
&RKRUWQ 
 PJ4GD\V[GRVHV
&RKRUWQ 
PJ4GD\V[GRVHV
&RKRUWQ 
PJ4GD\V[GRVHV
07'QRW
H[FHHGHG
07'H[FHHGHG
07'H[FHHGHG
07'H[FHHGHG
([SDQVLRQ&RKRUWQ 
'RVH7%'4G[GRVHV
([SDQVLRQ&RKRUWQ 
'RVH7%'4G[GRVHV
07'QRW
H[FHHGHG
07'QRW
H[FHHGHG
([SDQVLRQ&RKRUW
6DIHW\)ROORZXS
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



7KH07'DVVHVVPHQWZLOOEHEDVHGRQVDIHW\GDWDIURP:HHNVWR,IPRUHWKDQRIDFWLYHSDWLHQWVLQDFRKRUWH[SHULHQFHD
'/7WKH07'ZLOOEHFRQVLGHUHGWRKDYHEHHQH[FHHGHG
,IWKH07'LVQRWH[FHHGHGGRVHHVFDODWLRQPD\FRQWLQXH
,IWKH07'LVH[FHHGHGDORZHUGRVHLQFOXGLQJSUHYLRXVO\VWXGLHGGRVHPD\EHVHOHFWHG
7KHSODQQHGGRVHVVKRZQKHUHPD\EHDGMXVWHGEDVHGRQDFFUXLQJGDWD7KHKLJKHVWGRVHWKDWZLOOEHVWXGLHGLVDFXPXODWLYHGRVH
RIPJ([SDQVLRQFRKRUWVWRIXUWKHUHYDOXDWHGRVHVEHORZWKHGRVHWKDWH[FHHGHGWKH07'PD\EHLQLWLDWHGDWDQ\WLPH
7DEOH3ODQQHG&25'RVHV6HULDO'LOXWLRQVDQG$GPLQLVWHUHG9ROXPHV
'26(
&2+257
'26,1*
5(*,0(1
'58*672&.
&21&(175$7,21
0*0/,167(5,/(
:$7(5
2)6(5,$/
',/87,216
0/'58*
672&.$''('72
0/',/87,21
9,$/)25),1$/
92/80(2)0/
',/87('
'58*
92/80(72
%(86('
0/
,9%3
92/80(
72%(
$''('72
6$/,1(
,1)86,21
%$*
,10/
6$/,1(
727$/
92/80(72
%($''('
720/
6$/,1(

PJHYHU\GD\V






PJHYHU\GD\V






PJHYHU\
GD\V






PJHYHU\
GD\V



POIURP
GUXJYLDOV




6DPSOH6L]HDQG6WDWLVWLFDO3RZHU&RQVLGHUDWLRQV
7KHSULPDU\REMHFWLYHRIWKLVVWXG\LVWRGHWHUPLQHWKHPD[LPXPWROHUDWHGGRVH7KH07'ZLOO
EHH[FHHGHGDQGVWRSSLQJFULWHULDIRUWKDWGRVHZLOOKDYHEHHQPHWLIPRUHWKDQRI&25
WUHDWHGSDWLHQWVLQDFRKRUWH[SHULHQFHD'/7:LWKSDWLHQWVGRVHGLQHDFKFRKRUWDQG
DWWKHH[SHFWHG'/7UDWHRIWKHSUREDELOLW\RIREVHUYLQJRUPRUHSDWLHQWVZLWK'/7LV
JUHDWHUWKDQDQGWKHSUREDELOLW\RIREVHUYLQJDWOHDVWSDWLHQWZLWK'/7LV
6DPSOHVL]HFDOFXODWLRQVZHUHSHUIRUPHGIRUKV&5376$7DQG&+UEDVHGRQWKHOLWHUDWXUH
&R\QHDQG6LHSHU)RUSRZHUWRREVHUYHDQKV&53GLIIHUHQFHIURPSODFHERRI
PJG/ZLWKDFRPPRQVWDQGDUGGHYLDWLRQRIWKHVDPSOHVL]HUHTXLUHGLVSDWLHQWVLQ
HDFKJURXS:LWKHIIHFWVL]HVUDQJLQJIURPWRWKHVDPSOHVL]HUDQJHVIURPWR
SDWLHQWV7KHVDPSOHVL]HZLWKSRZHUUHTXLUHGWRREVHUYHD76$7GLIIHUHQFHRIZLWKD
FRPPRQVWDQGDUGGHYLDWLRQRIHIIHFWVL]HRILVSDWLHQWVZLWKHIIHFWVL]HVUDQJLQJ
IURPWRUHTXLULQJWRSDWLHQWV7KHVDPSOHVL]HZLWKSRZHUUHTXLUHGWR
REVHUYHD&+UGLIIHUHQFHRISJZLWKDFRPPRQVWDQGDUGGHYLDWLRQRILVZLWKHIIHFW
VL]HVUDQJLQJIURPWRUHTXLULQJVDPSOHVL]HIURPWRSDWLHQWV$OOVDPSOHVL]H
FDOFXODWLRQVZHUHGRQHZLWKWZRVLGHGWWHVWVDQGDVLJQLILFDQFHOHYHORIĮ 
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



67$7,67,&$/0(7+2'6

*(1(5$/&216,'(5$7,216
8QOHVVRWKHUZLVHVSHFLILHGDOOVWXG\FROOHFWHGGDWDZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSXVLQJ
GHVFULSWLYHVWDWLVWLFVJUDSKVDQGRUUDZGDWDOLVWLQJV'HVFULSWLYHVWDWLVWLFVIRUFRQWLQXRXV
YDULDEOHVZLOOLQFOXGHQXPEHURISDWLHQWVQPHDQVWDQGDUGGHYLDWLRQ6'PHGLDQTXDUWLOHV
4DQG4PLQLPXPPLQDQGPD[LPXPPD[YDOXHV$QDO\VLVRIFDWHJRULFDOYDULDEOHVZLOO
LQFOXGHIUHTXHQF\DQGSHUFHQWDJH

3YDOXHVZLOOEHURXQGHGWRWKUHHGHFLPDOSODFHV,IDSYDOXHLVOHVVWKDQLWZLOOEH
UHSRUWHGDV³´,IDSYDOXHLVJUHDWHUWKDQLWZLOOEHUHSRUWHGDV³!´
FRQILGHQFHLQWHUYDOVZLOOEHHVWLPDWHGIRUSKDUPDFRG\QDPLFHQGSRLQWV

)RUWKHDQDO\VHVWREHXVHGIRU65&WKHVXEMHFWVZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSZLWKLQ
HDFKFRKRUW7KHSODFHERJURXSZLOOQRWEHSRROHG

)RUWKHILQDO&65UHSRUWWKHVXEMHFWVZLOOEHVXPPDUL]HGDFFRUGLQJWRWKHLUWUHDWPHQWJURXS
7KHSODFHERVXEMHFWVDWHDFKFRKRUWZLOOEHSRROHGLQWRRQHJURXSDQGWKHVXEMHFWVWUHDWHGZLWK
&25ZLOOEHVXPPDUL]HGEDVHGRQWKHGRVLQJUHJLPHQ


'(),1,7,2162)$1$/<6,66(76
7KH QXPEHU RI VXEMHFWV HQWHUHG WKH QXPEHU DQG WKH SHUFHQWDJH RI VXEMHFWV LQFOXGHG LQ HDFK
DQDO\VLVVHWDQGWKHQXPEHUDQGWKHSHUFHQWDJHRIVXEMHFWVH[FOXGHGIURPHDFKDQDO\VLVVHWZLOO
EHSUHVHQWHGE\GRVHJURXSWUHDWPHQWDQGRYHUDOO
,QWHQWWRWUHDW,77DQDO\VLVSRSXODWLRQ7KH,77DQDO\VLVSRSXODWLRQZLOOEHGHILQHGDVDOO
UDQGRPL]HGSDWLHQWV7UHDWPHQWFODVVLILFDWLRQZLOOEHEDVHGRQWKHUDQGRPL]HGWUHDWPHQW
7KLVZLOOEHWKHSULPDU\SRSXODWLRQIRUWKHDQDO\VHVRIGLVSRVLWLRQDQGEDVHOLQHGDWD

3KDUPDFRG\QDPLFDQDO\VLVSRSXODWLRQ7KHSKDUPDFRG\QDPLFSRSXODWLRQZLOOEHGHILQHGDV
DOO,77SDWLHQWVZKRZHUHWUHDWHGZLWKWKHLUDVVLJQHGVWXG\GUXJWUHDWPHQWKDGDQ\
SKDUPDFRG\QDPLFDVVHVVPHQWVDQGGLGQRWKDYHFHUWDLQLPSRUWDQWSURWRFROGHYLDWLRQVGHVFULEHG
EHORZ7KLVZLOOEHWKHSRSXODWLRQIRUWKHSKDUPDFRG\QDPLFDQDO\VHV

x !0LVVHGGRVHVRU!LQFRUUHFWGRVHV
x ,PSRUWDQWSURWRFROGHYLDWLRQVWKDWDUHGHWHUPLQHGWRVLJQLILFDQWO\DIIHFWLQWHUSUHWDWLRQRI
3'HQGSRLQWVLGHQWLILHGSULRUWRXQEOLQGLQJRIWKHVWXG\
o 0LQRU GHSDUWXUHV IURP WKH (6$ GRVLQJ JXLGHOLQHV LQ WKH SURWRFRO ZLOO QRW EH
FRQVLGHUHGPDMRUGHYLDWLRQV

)RUVXEMHFWVZKRGRQRWUHFHLYHWKHDVVLJQHGGRVHDWDQ\WLPHGXULQJWUHDWPHQWWKHGRVHZLOOEH
GHILQHGDVWKHKLJKHVWGRVHUHFHLYHG

CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


3KDUPDFRNLQHWLFVDQDO\VLVSRSXODWLRQ7KH3.SRSXODWLRQZLOOEHGHILQHGDVDOOSDWLHQWVZKR
KDYHDQ\YDOLGVDPSOHVPHDVXUHGIRU6WXG\'UXJOHYHOV7KLVZLOOEHXVHGIRU3.DQDO\VLV

6DIHW\DQDO\VLVSRSXODWLRQ7KHVDIHW\DQDO\VLVSRSXODWLRQZLOOFRQVLVWRIDOOSDWLHQWV
UDQGRPL]HGDQGWUHDWHGZLWKDQ\DPRXQWRIVWXG\PHGLFDWLRQ&25RUSODFHER7UHDWPHQW
FODVVLILFDWLRQZLOOEHEDVHGRQWKHDFWXDOWUHDWPHQWUHFHLYHG7KLVSRSXODWLRQZLOOEHXVHGIRUWKH
VDIHW\DQDO\VHV

07'DQDO\VLV3RSXODWLRQ7KH07'DQDO\VLVSRSXODWLRQZLOOEHDVXEVHWRIVDIHW\DQDO\VLV
SRSXODWLRQE\H[FOXGLQJVXEMHFWVUHSODFHGGXHWRDQRQVDIHW\UHDVRQ7KLVSRSXODWLRQZLOOEH
XVHGIRU07'DQG'/7DQDO\VHV


7,0(:,1'2:6)25$1$/<6,6
,IGDWDDUHFROOHFWHGE\YLVLWWKHGDWDZLOOEHDQDO\]HGE\YLVLWEDVHGRQWKHSURWRFROSODQQHG
YLVLWV,IPXOWLSOHUHFRUGVDUHFROOHFWHGIRUDYLVLWWKHODWHVWUHFRUGZLOOEHXVHGIRUWKHVXPPDU\
IRUWKDWYLVLW8QOHVVRWKHUZLVHVSHFLILHGEDVHOLQHLVGHILQHGDVWKHODVWQRQPLVVLQJYDOXHSULRU
WRLQLWLDWLRQRIVWXG\GUXJ(DUO\WHUPLQDWLRQYLVLWZLOOEHPDSSHGWRWKHSRVWEDVHOLQHVFKHGXOHG
YLVLW$IWHUPDSSLQJLIWKHUHLVPRUHWKDQRQHYLVLWLQWKHVDPHZLQGRZWKHVFKHGXOHGYLVLWZLOO
EHXVHGLIDYDLODEOH,IWKHUHLVQRVFKHGXOHGYLVLWLQWKHVDPHZLQGRZWKHPDSSHGYLVLWFORVHUWR
WKHWDUJHWDVVHVVPHQWGD\ZLOOEHXVHG,IPRUHWKDQRQHYLVLWKDVWKHHTXDOGLVWDQFHWRWKHWDUJHW
GD\WKHQWKHODWHURQHZLOOEHXVHG7KHXQVFKHGXOHGYLVLWZLOOQRWEHLQFOXGHGLQWKHE\YLVLW
VXPPDU\EXWZLOOEHLQFOXGHGLQWKHRXWOLHUDQDO\VLV
7KHREVHUYDWLRQDOSHULRGIRUWKHVWXG\ZLOOVWDUWIURPLQIRUPHGFRQVHQWDQGHQGZLWKVWXG\
FRPSOHWLRQVHH6HFWLRQIRUWKHGHILQLWLRQRIVWXG\FRPSOHWLRQ$Q\HYHQWRFFXUULQJDIWHUWKH
GHILQHGREVHUYDWLRQDOSHULRGHYHQLIFROOHFWHGRQWKH&5)PD\QRWEHLQFOXGHGLQWKHVXPPDU\
VWDWLVWLFDODQDO\VLV+RZHYHUDOOGDWDLQFOXGLQJWKDWUHSRUWHGDIWHUWKHGHILQHGREVHUYDWLRQDO
SHULRGZLOOEHLQFOXGHGLQWKHSDWLHQWGDWDOLVWLQJV


+$1'/,1*2)0,66,1*'$7$
$V D JHQHUDO UXOH PLVVLQJ GDWD YDOXHV DUH QRW LPSXWHG XQOHVV RWKHUZLVH VSHFLILHG DQG LQ
SUHVHQWDWLRQRIFDWHJRULFDOYDULDEOHVXQNQRZQDQGPLVVLQJGDWDPD\EHSUHVHQWHGDVDVHSDUDWH
FDWHJRU\DQGWKHGHQRPLQDWRUZLOOLQFOXGHXQNQRZQRUPLVVLQJYDOXHVDVDSSURSULDWH

35272&2/'(9,$7,216

(6$DQG3DUHQWHUDO,URQ'RVH$GMXVWPHQWV
6HOHFWHG W\SHV RI (6$ GRVH DGMXVWPHQWV ZLOO EH VXPPDUL]HG E\ WUHDWPHQW XVLQJ GHVFULSWLYH
VWDWLVWLFVLQFOXGLQJ
x
&KDQJHLQWKHWRWDOZHHNO\GRVHRI(32*(1GXULQJ:HHNVFRPSDUHGZLWKWKH:HHN
RU:HHNGRVH
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


x
&KDQJHLQWKHWRWDOGRVHRI$5$1(63RU0,5&(5$GXULQJ:HHNVFRPSDUHGZLWKWKH
PHDQZHHNO\GRVHGXULQJVFUHHQLQJEDVHGRQWKHODVWGRVHVSULRUWRUDQGRPL]DWLRQ
PXOWLSOLHGE\
x
6WDUWRISDUHQWHUDORUGLDO\VDWHLURQGXULQJ:HHNVLQDSDWLHQWQRWUHFHLYLQJSDUHQWHUDO
RUGLDO\VDWHLURQGXULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQ
x
'LVFRQWLQXDWLRQRISDUHQWHUDOLURQGXULQJ:HHNVLQDSDWLHQWUHFHLYLQJSDUHQWHUDORU
GLDO\VDWHLURQGXULQJWKHZHHNVSULRUWRUDQGRPL]DWLRQ
x
&KDQJHLQWKHWRWDOGRVHRISDUHQWHUDOHOHPHQWDOLURQGXULQJ:HHNVFRPSDUHGZLWKWKH
PHDQZHHNO\GRVHGXULQJ:HHNVDQGPXOWLSOLHGE\
x
0RUHWKDQRQH(6$GRVHLQFUHDVHLQDQ\ZHHNSHULRGDIWHU:HHN
7KH(6$DQGSDUHQWHUDOLURQGRVLQJJXLGHOLQHVLQWKHSURWRFRODUHDVIROORZV
:HHNV
x (6$ GRVHV DUH QRW WR EH DGMXVWHG RU KHOG GXULQJ:HHNV  WKURXJK  XQOHVV RQH RU PRUH
FRQILUPHG KHPRJORELQ YDOXHV LH DW OHDVW  FRQVHFXWLYH PHDVXUHPHQWV RU WKH SDWLHQW¶V
FOLQLFDOVWDWXVQHFHVVLWDWHVVXFKGXHWRDFOHDUDQGSUHVHQWVDIHW\ULVN
x 3DUHQWHUDOLURQGRVHVDUHQRWEHDGMXVWHGRUKHOGGXULQJ:HHNVWKURXJK
x 3DWLHQWVQRWUHFHLYLQJSDUHQWHUDOLURQSURGXFWVGXULQJ6FUHHQLQJPXVWQRWEHVWDUWHGRQWKHVH
GXULQJ:HHNVWKURXJK
x 7KH0HGLFDO0RQLWRUPXVWEHFRQWDFWHGSULRUWRDQ\FRQWHPSODWHG(6$RUSDUHQWHUDOLURQGRVH
FKDQJHV
:HHNV±
x &KDQJHVWR(6$GRVLQJPXVWEHEDVHGRQKHPRJORELQYDOXHVWKDWKDYHEHHQFRQILUPHGLH
DWOHDVWFRQVHFXWLYHPHDVXUHPHQWV
x 'RQRWLQFUHDVHWKHGRVHPRUHIUHTXHQWO\WKDQRQFHHYHU\ZHHNV7KHUHFRPPHQGHGGRVH
LQFUHDVHDWDQ\JLYHQWLPHLV
x 'HFUHDVHVLQGRVHPD\RFFXUPRUHIUHTXHQWO\WKDQRQFHHYHU\ZHHNV7KHUHFRPPHQGHG
PLQLPXPGXUDWLRQEHWZHHQGRVHUHGXFWLRQVLVZHHNV
x ,IWKHKHPRJORELQULVHVUDSLGO\HJPRUHWKDQJG/LQDQ\ZHHNSHULRGUHGXFHWKHGRVH
E\$JUHDWHUUHGXFWLRQPD\EHPDGHLIULVHLQKHPRJORELQLVXQDFFHSWDEO\UDSLG
x 7KH0HGLFDO0RQLWRUPXVWEHFRQWDFWHGSULRUWRDQ\FRQWHPSODWHG(6$GRVHFKDQJHVWKDW
GHSDUWIURPWKHDERYHSURWRFROUHTXLUHPHQWVDQGUHFRPPHQGDWLRQVXQOHVVFOLQLFDOXUJHQF\
SUHFOXGHVWKLV,IWKH0HGLFDO0RQLWRULVQRWFRQWDFWHGLQDGYDQFHSOHDVHVHQGDQRWLILFDWLRQ
ZLWKLQKRXUVWKDWDQRIISURWRFRO(6$GRVHFKDQJHZDVPDGH
x 3DWLHQWVQRWUHFHLYLQJSDUHQWHUDOLURQSURGXFWVPXVWQRWEHVWDUWHGRQWKHVHGXULQJ:HHNV
WKURXJK
x 3DUHQWHUDOLURQGRVHVDUHQRWWREHDGMXVWHGRUKHOGGXULQJ:HHNVWKURXJKXQOHVVDSSURYHG
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


E\WKH0HGLFDO0RQLWRU

2WKHU'HYLDWLRQV
3URWRFRO GHYLDWLRQV RWKHU WKDQ WKRVH UHODWHG WR (6$ DQG LURQ GRVLQJ ZLOO EH LGHQWLILHG E\ D
FRPELQDWLRQ RI SURJUDPPDWLF TXHU\ RI WKH GDWDEDVH PDQXDO GDWD UHYLHZ DQG WKH FOLQLFDO
RSHUDWLRQVSURWRFROGHYLDWLRQWUDFNHU

$1$/<6,662)7:$5(
7KHSKDUPDFRNLQHWLF3.HYDOXDWLRQDQG3.3'PRGHOLQJZLOOEHSHUIRUPHGE\DQLQGHSHQGHQW
SKDUPDFRPHWULFLDQ
$OORWKHUVXPPDULHVDQGVWDWLVWLFDODQDO\VHVZLOOEH
JHQHUDWHG XVLQJ 6$6 YHUVLRQ  RU ODWHU 6HH 'DWD$QDO\VLV 3ODQ IRU 3KDUPDFRNLQHWLF DQG
3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF0RGHOLQJ


678'<68%-(&76

',6326,7,212)68%-(&76
7KHQXPEHURIVXEMHFWVVFUHHQHGDQGWKHQXPEHUSHUFHQWRIVXEMHFWVZKRIDLOHGVFUHHQLQJDQG
WKHUHDVRQVIRUVFUHHQIDLOXUHZLOOEHVXPPDUL]HGDVDYDLODEOHEDVHGRQGDWDUHSRUWHGRQWKH
6FUHHQLQJ)DLOXUH&5)7KHGLVWULEXWLRQRIWKHQXPEHURIUDQGRPL]HGVXEMHFWVHQUROOHGZLOOEH
VXPPDUL]HGIRUHDFKUDQGRPL]HGWUHDWPHQWJURXSLQHDFKGRVLQJUHJLPHQFRPELQLQJDOOSODFHER
SDWLHQWVDVRQHFRQWUROJURXSDQGRYHUDOOEDVHGRQWKH,77DQDO\VLVSRSXODWLRQ
7KH QXPEHU SHUFHQW RI UDQGRPL]HG DQG WUHDWHG VXEMHFWV ZKR FRPSOHWHG WUHDWPHQW ZLOO EH
VXPPDUL]HGE\WUHDWPHQWJURXSEDVHGRQWKH,77DQDO\VLVSRSXODWLRQ7KHVXEMHFWVGLVFRQWLQXHG
IURPVWXG\WUHDWPHQWZLOOEHVXPPDUL]HGDFFRUGLQJWRWKHUHDVRQVIRUGLVFRQWLQXDWLRQEDVHGRQ
GDWDUHSRUWHGRQWKH(QGRI6WXG\&5)
7KHQXPEHUSHUFHQWRIUDQGRPL]HGVXEMHFWVZKRFRPSOHWHGWKHVWXG\DQGZKRGLVFRQWLQXHGIURP
WKHVWXG\ZLOOEHVXPPDUL]HGDFFRUGLQJWRWKHUHDVRQVIRUGLVFRQWLQXDWLRQEDVHGRQGDWDUHSRUWHG
RQWKH(QGRI6WXG\&5)

'(02*5$3+,&6$1'%$6(/,1(&+$5$&7(5,67,&6

'(02*5$3+,&6$1'%$6(/,1(&+$5$&7(5,67,&6
'HPRJUDSKLFDQGEDVHOLQHFKDUDFWHULVWLFVZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSXVLQJ
GHVFULSWLYHVWDWLVWLFVIRUWKH,77SKDUPDFRG\QDPLFDQGVDIHW\DQDO\VLVSRSXODWLRQV&RQWLQXRXV
GHPRJUDSKLFDQGEDVHOLQHYDULDEOHVLQFOXGHDJHSUHGLDO\VLVZHLJKWDWZHHNSRVWGLDO\VLV
ZHLJKWDWZHHNKHLJKWERG\PDVVLQGH[%0,EDVHGRQSRVWGLDO\VLVZHLJKWDWZHHN
FDWHJRULFDOYDULDEOHVLQFOXGHVH[UDFHDQGHWKQLFLW\

',$/<6,66,*1$1'6<037206
7KHQXPEHUSHUFHQWRIVXEMHFWVZLWKHDFKVSHFLILFGLDO\VLVVLJQDQGV\PSWRPDVUHFRUGHGRQWKH
&5)ZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSDQGRYHUDOOIRUVDIHW\DQDO\VLVSRSXODWLRQ
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



0(',&$/+,6725<
x
.LGQH\'LVHDVH+LVWRU\
.LGQH\GLVHDVHKLVWRU\ZLOOEHVXPPDUL]HGVHSDUDWHO\IURPRWKHUPHGLFDOKLVWRULHV7KHGXUDWLRQ
RIHQGVWDJHUHQDOGLVHDVH(65'6LQJOHSRRO.W9VS.W9ZLWKLQZHHNVSULRUWRWKHIXOO
6FUHHQLQJ3HULRGQXPEHUSHUFHQWRIVXEMHFWVZLWKNLGQH\WUDQVSODQWVWDWXVRIWKHWUDQVSODQWHG
NLGQH\SULPDU\FDXVHRIFKURQLFNLGQH\GLVHDVHDQGGLDO\VLVDFFHVVXVHGGXULQJ:HHNZLOOEH
VXPPDUL]HGE\WUHDWPHQWJURXSDQGRYHUDOOIRUVDIHW\DQDO\VLVSRSXODWLRQ

x
6HOHFWHG0HGLFDO+LVWRU\

7KH QXPEHU SHUFHQW RI VXEMHFWV UHSRUWLQJ VHOHFWHG PHGLFDO KLVWRU\ LQFOXGLQJ FDUGLRYDVFXODU
KLVWRU\ LQIHFWLRQ KLVWRU\ DQG RWKHU KLVWRU\ DV UHFRUGHG RQ WKH &5) ZLOO EH VXPPDUL]HG E\
WUHDWPHQWJURXSDQGRYHUDOOIRUVDIHW\DQDO\VLVSRSXODWLRQ
x
2WKHU0HGLFDO+LVWRU\
7KH RWKHU PHGLFDO KLVWRU\ YHUEDWLP GHVFULSWLRQV LQYHVWLJDWRU WHUPV IURP WKH &5) ZLOO EH
FODVVLILHG LQWR PHGLFDO WHUPLQRORJ\ XVLQJ WKH 0HGLFDO 'LFWLRQDU\ IRU 5HJXODWRU\ $FWLYLWLHV
0HG'5$(YHQWVZLOOEHFRGHGWRSULPDU\6\VWHP2UJDQ&ODVV62&DQGSUHIHUUHGWHUP37
XVLQJ0HG'5$9HUVLRQ7KHSUHYDOHQFHRIPHGLFDOKLVWRU\HYHQWVZLOOEHUHSRUWHGDVWKH
QXPEHUSHUFHQWRIVXEMHFWVE\WUHDWPHQWJURXS62&DQG37IRUVDIHW\DQDO\VLVSRSXODWLRQ

678'<'58*$1'(;32685(

75($70(17&203/,$1&(
6LQFHWKHVWXG\GUXJZLOOEHDGPLQLVWHUHGDVDQLQWUDYHQRXVLQIXVLRQWKHWUHDWPHQWFRPSOLDQFH
ZLOOQRWEHSURYLGHG,QIRUPDWLRQUHJDUGLQJVWXG\GUXJDGPLQLVWUDWLRQZLOOEHSURYLGHGLQGDWD
OLVWLQJV

(;7(172)(;32685(
6WXG\GUXJZLOOEHDGPLQLVWHUHGE\LQIXVLRQRQFHHYHU\RWKHUZHHNIRUZHHNVGRVHVIRUWKH
SODQQHGWUHDWPHQWUHJLPHQVLQWKHSURWRFRO([SRVXUHZLOOEHVXPPDUL]HGXVLQJWKHFXPXODWLYH
IUHTXHQF\DQGSHUFHQWDJHRIVXEMHFWVUHFHLYLQJGRVHGRVHV«GRVHVDQGGRVHVE\
WUHDWPHQWJURXS'HVFULSWLYHVWDWLVWLFVQXPEHURIVXEMHFWVPHDQVWDQGDUGGHYLDWLRQPLQLPXP
PHGLDQTXDUWLOHVUDQJHDQGPD[LPXPIRUH[SRVXUHZLOOEHVXPPDUL]HG,QDGGLWLRQWKHH[SRVXUH
LQGD\VGHILQHGDVWKHGDWHRIWKHODVWGRVHRIVWXG\GUXJ±GDWHRIWKHILUVWGRVHRIVWXG\GUXJ
ZLOOEHVXPPDUL]HG([SRVXUHZLWKUHVSHFWWR&25EORRGOHYHOVZLOOEHGHVFULEHGLQWKH
3KDUPDFRNLQHWLFVDQG3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF0RGHOLQJ'DWD$QDO\VLV3ODQ

35,25$1'&21&20,7$177+(5$3<
(U\WKURSRLHVLVVWLPXODWLQJDJHQWVDQGSDUHQWHUDOLURQGRVHVZLOOEHVHSDUDWHO\VXPPDUL]HGVHH
6HFWLRQ
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


$OOLQYHVWLJDWRUWHUPVIRUPHGLFDWLRQVUHFRUGHGRQWKH&5)ZLOOEHFRGHGXVLQJWKH:RUOG
+HDOWK2UJDQL]DWLRQ:+2'UXJ'LFWLRQDU\7KHQXPEHUSHUFHQWRIVXEMHFWVZKRWRRNSULRU
DQGFRQFRPLWDQWPHGLFDWLRQVZLOOEHVXPPDUL]HGRQWKHVDIHW\DQDO\VLVSRSXODWLRQE\WUHDWPHQW
JURXSGRVHDQG$QDWRPLFDO7KHUDSHXWLF&KHPLFDO$7&&ODVVLILFDWLRQDQG:+2'UXJ
SUHIHUUHGWHUP


(5<7+5232,(6,667,08/$7,1*$*(176$1'3$5(17(5$/,521
'26(6
(6$GRVLQJZLOOEHVXPPDUL]HGVHSDUDWHO\IRU(32*(1HSRHWLQDOID$5$1(63GDUEHSRHWLQ
DOIDDQG0,5&(5$PHWKR[\SRO\HWK\OHQHJO\FROHSRHWLQEHWDUHVSHFWLYHO\+LVWRULF(6$GRVHV
SULRUWRUDQGRPL]DWLRQZLOOEHVXPPDUL]HGZHHNO\E\WUHDWPHQWJURXSIRUWKHSKDUPDFRG\QDPLF
DQDO\VLVSRSXODWLRQ7KHPHDQZHHNO\GRVHIURP:HHNWKURXJK:HHNZLOODOVREHFRPSXWHG
IRUDOO(6$V3HUFHQWFKDQJHIURPEDVHOLQHLQ(6$GRVHFKDQJHLQ(6$GRVHZLWK(6$QRUPDOL]HG
WR(32*(1XQLWVDQGFKDQJHLQ(6$WRDWKUHVKROGYDOXHZLOODOVREHFRPSXWHGZLWKDOO(6$V
SRROHG
7KHIROORZLQJDQDO\VHVZLOOEHSHUIRUPHG
x
&RPSDULVRQRIWKHPHDQZHHNO\(6$GRVHH[SUHVVHGLQ(32*(1XQLWVSULRUWR
UDQGRPL]DWLRQWRWKHSRVWUDQGRPL]DWLRQPHDQZHHNO\GRVHIRUHDFKZHHNLQWHUYDOLQ
WKH7UHDWPHQWDQG6DIHW\)ROORZXSSHULRGVHJ:HHNVHWF,QIHUHQWLDO
VWDWLVWLFVZLOOEHSHUIRUPHGIRUWKH:HHNDQGWKH:HHNSHULRGV

x &RQYHUVLRQ RI 0,5&(5$ DQG$5$1(63 GRVHV WR (32*(1 XQLWV ZLOO EH DV
IROORZV
0,5&(5$RU$5$1(63GRVHLQPFJ (32*(1XQLWHTXLYDOHQWGRVH
x
7KHSHUFHQWDJHFKDQJHIURPEDVHOLQHZLWKDOO(6$VFRPELQHGZLOOEHFDOFXODWHGIRU
HDFKZHHNLQWHUYDOLQWKH7UHDWPHQWDQG6DIHW\)ROORZXSSHULRGVHJ:HHNV
HWF,QIHUHQWLDOVWDWLVWLFVZLOOEHSHUIRUPHGIRUWKH:HHNDQGWKH:HHNSHULRGV

x
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWKGRVHFKDQJHE\DQG
ZLOOEHFRPSXWHGIRUHDFKZHHNLQWHUYDOLQWKH7UHDWPHQWDQG6DIHW\)ROORZXS
SHULRGVHJ:HHNVHWF
&DOFXODWLRQRIWKH%DVHOLQH(6$'RVH
7KHEDVHOLQHGRVHZLOOEHWKHEDVHOLQHPHDQZHHNO\GRVHIRUHDFK(6$DVGHILQHGEHORZPXOWLSOLHG
E\
x )RU (32*(1 WKH EDVHOLQH ZLOO EH WKH PHDQ ZHHNO\ GRVH EDVHG RQ WKH  ZHHNV
LPPHGLDWHO\SULRUWRUDQGRPL]DWLRQPXOWLSOLHGE\
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


x )RU$5$1(63DQG0,5&(5$WKHEDVHOLQHZLOOEHWKHPHDQZHHNO\GRVHEDVHGRQ
WKHGRVHVLPPHGLDWHO\SULRUWRUDQGRPL]DWLRQPXOWLSOLHGE\
x 7KHEDVHOLQHGRVHZLOOEHQRUPDOL]HGDVWKHDYHUDJHGRVHSHUZHHNGXULQJWKHWLPH
SHULRGRIWKHGRVHVXVHGWRGHILQHWKHEDVHOLQHPXOWLSOLHGE\

&DOFXODWLRQRIWKH3RVW%DVHOLQH(6$'RVH

x 7KHSRVWEDVHOLQHGRVHZLOOEHFDOFXODWHGEDVHGRQWKHVXPRIDOOGRVHVGXULQJDJLYHQ
WLPHLQWHUYDODQGZLOOEHH[SUHVVHGDVWKHDYHUDJHGRVHSHUZHHNGXULQJWKDWWLPH
SHULRGPXOWLSOLHGE\RUWKHQXPEHURIZHHNVLQWKHLQWHUYDO

x 7KHLQWHUYDOVWKDWZLOOEHGHVFULEHGDUH:HHNVHWFWKURXJK:HHN,Q
DGGLWLRQ:HHNVWKHHQGSRLQWDQG:HHNVZLOOEHGHVFULEHG

3DUHQWHUDOLURQGRVHVDUHJHQHUDOO\H[SHFWHGWREHDGPLQLVWHUHGZHHNO\HYHU\RWKHUZHHNRUZLWK
HDFKGLDO\VLV3DUHQWHUDOLURQGRVHVZLOOEHVXPPDUL]HGEDVHGRQHOHPHQWDOLURQFRQWDLQHGZLWKLQ
WKHLURQSURGXFWDGPLQLVWHUHG$OOSDUHQWHUDOLURQSURGXFWVZLOOEHFRPELQHGIRUWKHDQDO\VHV,I
GRVHXQLWVDUHUHSRUWHGLQP/WKHVHZLOOEHFRQYHUWHGWRPJRIHOHPHQWDOLURQDVIROORZV
,521352'8&7
(/(0(17$/,521
)HUULFJOXFRQDWHHJ)HUUOHFLW
PJSHUP/
)HUXPR[\WROHJ)HUDKHPH
PJSHUP/
)HUULFFDUER[\PDOWRVHHJ)HULQMHFW
PJSHUP/
)HUULFS\URSKRVSKDWHFLWUDWHHJ7ULIHULF
PJSHUP/
,URQVXFURVHHJ9HQRIHU
PJSHUP/

3RVWUDQGRPL]DWLRQSDUHQWHUDOLURQGRVHVZLOOEHVXPPDUL]HGLQDVLPLODUZD\WR(6$1RDQDO\VHV
ZLOOEHSHUIRUPHGXVLQJLQGLYLGXDOSDUHQWHUDOSURGXFWVKRZHYHU

3+$50$&2'<1$0,&$1$/<6(6
'DWDIURP&25WUHDWHGSDWLHQWVIURPFRKRUWVQRWH[FHHGLQJWKH07'ZLOOEHSRROHGDQG
GDWDIURPDOOSODFHERSDWLHQWVZLOOEHSRROHGIRUWKHSKDUPDFRG\QDPLFHQGSRLQWDQDO\VHV
'HVFULSWLYHDQDO\VHVE\GRVHLQZKLFKDOOSODFHERSDWLHQWVDUHSRROHGZLOODOVREHFRQGXFWHG 
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



35,0$5<3+$50$&2'<1$0,&$1$/<6,6
(QGSRLQWV
7KHSULPDU\SKDUPDFRG\QDPLFHIILFDF\RI&25FRPSDUHGWRSODFHERZLOOEHDVVHVVHGE\
HYDOXDWLQJWKHIROORZLQJ

 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQKV&53WR:HHN
EHWZHHQWUHDWPHQWJURXSV
x
7KH'D\YDOXHZLOOEHXVHGIRUWKLVDQDO\VLVUHIOHFWLQJDWOHDVWZHHNVRI
FRPSOHWHGWUHDWPHQW7RHQVXUHFRPSDUDELOLW\WRWKHSRVWEDVHOLQHYDOXHRQO\WKH
SUHGLDO\VLV6FUHHQLQJYDOXHVZLOOEHXVHGIRUWKHEDVHOLQH

$QDO\VLV6HW
3KDUPDFRG\QDPLFDQDO\VLVSRSXODWLRQ

0HWKRG
1XPEHURISDWLHQWVQPHDQVWDQGDUGGHYLDWLRQ6'PHGLDQTXDUWLOHV4DQG4PLQLPXP
PLQDQGPD[LPXPPD[YDOXHVIRUWKHREVHUYHGYDOXHDQGFKDQJHIURPEDVHOLQHZLOOEH
UHSRUWHG7KHGLIIHUHQFHLQFKDQJHV&253ODFHERZLOOEHSUHVHQWHG$QDQDO\VLVRI
FRYDULDQFH$1&29$PRGHOZLOOEHXVHGIRUWKLVSXUSRVHZLWKGRVHVSHFLILFDFWLYHGRVHRU
SODFHERSRROHGDVDIDFWRUDQGEDVHOLQHYDOXHDVDFRYDULDWH7KHOHDVWVTXDUHPHDQVIRUHDFK
GRVHWKHOHDVWVTXDUHPHDQGLIIHUHQFHVIURPSODFHERDORQJZLWKWKHDVVRFLDWHGFRQILGHQFH
LQWHUYDOV&,VDQGSYDOXHVZLOOEHSUHVHQWHG


6(&21'$5<3+$50$&2'<1$0,&$1$/<6(6
(QGSRLQWV
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQKV&53WRWKHPHDQ
RI:HHNV
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ6$$WR:HHN
EHWZHHQWUHDWPHQWJURXSV
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ6$$WRWKHPHDQRI
:HHNV
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQWKHIUHH,/WR:HHN
EHWZHHQWUHDWPHQWJURXSV
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ+HPRJORELQWR
:HHN
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ+HPRJORELQWR
:HHN
 &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ+HPRJORELQWR
:HHNH[FOXGLQJKHPRJORELQYDOXHVIROORZLQJDFKDQJHLQWKHWRWDOZHHNO\(6$
GRVH$FKDQJHLVGHILQHGDVWKHILUVWWLPHZKHQWKH(6$ZHHNO\GRVHJRHVXSE\!
RUGRZQE\!UHODWLYHWRWKHSUHYLRXVZHHN
VGRVH
 &KDQJHIURPEDVHOLQHZHHNO\PHDQRI)XOO6FUHHQLQJLQ(5,WRWKHPHDQRI:HHNV
DQG:HHNV±
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


D 7KH6FUHHQLQJ(5,LVGHILQHGDVWKH(5,XVHGWRTXDOLI\WKHSDWLHQWIRUWKHVWXG\
SHU,QFOXVLRQ&ULWHULRQ
 &KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQ76$7WR:HHN
&KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ76$7WR:HHNV

&KDQJHIURPEDVHOLQHPHDQRI6FUHHQLQJDQG'D\YDOXHVLQWKH&+UWR:HHN
&KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQWKH&+UWR:HHNV

&KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQVHUXPSUHDOEXPLQ
WRWKHPHDQRI:HHNV
&KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQVHUXPDOEXPLQWR
:HHN


$QDO\VLV6HW
3KDUPDFRG\QDPLFDQDO\VLVSRSXODWLRQ

0HWKRG
1XPEHURISDWLHQWVQPHDQVWDQGDUGGHYLDWLRQ6'PHGLDQTXDUWLOHV4DQG4PLQLPXP
PLQDQGPD[LPXPPD[YDOXHVIRUWKHREVHUYHGYDOXHDQGFKDQJHIURPEDVHOLQHZLOOEH
UHSRUWHG7KHGLIIHUHQFHLQFKDQJHV&253ODFHERZLOOEHSUHVHQWHG$Q$1&29$
PRGHOLQFOXGLQJGRVHDVDIDFWRUDQGEDVHOLQHYDOXHDVDFRYDULDWHZLOOEHXVHG7KHOHDVWVTXDUH
PHDQVIRUHDFKGRVHWKHOHDVWVTXDUHPHDQGLIIHUHQFHVIURPSODFHERDORQJZLWKWKHDVVRFLDWHG
&,VDQGSYDOXHVZLOOEHSUHVHQWHG,QDGGLWLRQIRUFKDQJHIURPEDVHOLQHLQ76$7WRZHHN
DVKLIWWDEOHDQDO\VLVZLWKWKHFDWHJRULHV!!ZLOOEH
SUHVHQWHG7KHZHHNO\PHDQRI(5,ZLOOEHFDOFXODWHGDQGSUHVHQWHGIRUDOO(6$VFRPELQHG
EDVHGRQWKHIRUPXODLQ6HFWLRQ


27+(5()),&$&<$1$/<6(6
$GGLWLRQDOVHFRQGDU\REMHFWLYHLVWRH[SORUHWKHSKDUPDFRG\QDPLFHIIHFWVRI&25
FRPSDUHGWRSODFHERE\HYDOXDWLQJFKDQJHVLQ

͌ &KDQJHLQKHPRJORELQIURPVFUHHQLQJWRSHDNKHPRJORELQGHILQHGDVSHUVXEMHFWDEVROXWH
PD[LPDOKHPRJORELQLQJG/
͌ (5,DQG+HPRJORELQIURPEDVHOLQHZHHNO\PHDQGXULQJWKH6FUHHQLQJ3HULRGIRU(5,DQG
PHDQRI)XOO6FUHHQLQJDQG'D\IRU+HPRJORELQWKURXJK:HHNDQG
͌ (5,DQG+HPRJORELQIURPEDVHOLQHZHHNO\PHDQGXULQJWKH6FUHHQLQJ3HULRGIRU(5,DQG
PHDQRI)XOO6FUHHQLQJDQG'D\IRU+HPRJORELQWKURXJK:HHNDQGVWUDWLILHGE\
EDVHOLQH(5,WHUWLOHV
͌ (6$DQGSDUHQWHUDOLURQGRVHUHTXLUHPHQWVIURPEDVHOLQHZHHNO\PHDQGXULQJWKH)XOO
6FUHHQLQJ3HULRGWR(YDOXDWLRQ3HULRG:HHNV±DQGWKURXJK:HHN
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


͌ 6\VWHPLFLURQVWRUHVVHUXPIHUULWLQKHSDWLFDQGVSOHQLFLURQFRQWHQWDQGVXSSOHPHQWDOLURQ
GRVHUHTXLUHPHQWVRYHUWLPH
x 0DUNHUVRIPDOQXWULWLRQLQIODPPDWLRQSUHDOEXPLQDQGDOEXPLQRYHUWLPH
x /9PDVVLQGH[IURP6FUHHQLQJWR:HHN
͌ 3UHGLDO\VLVSRVWGLDO\VLVDQGGHOWDVHUXP7URSRQLQDQG17SUR%13GHILQHGDVWKH
GLIIHUHQFHEHWZHHQWKHSUHDQGSRVWGLDO\VLVWURSRQLQIURPEDVHOLQHPHDQRI6FUHHQLQJWR
:HHNV±
͌ +DQGJULSVWUHQJWKIURPEDVHOLQHGXULQJVFUHHQLQJWR:HHN
)$&,7IDWLJXHVFRUHIURPEDVHOLQHGXULQJVFUHHQLQJWR:HHN
)RUWKHDERYHHIILFDF\YDULDEOHVWKHREVHUYHGYDOXHVDQGFKDQJHVIURPEDVHOLQHZLOOEH
VXPPDUL]HGE\WUHDWPHQWJURXSXVLQJGHVFULSWLYHVWDWLVWLFVIRU3KDUPDFRG\QDPLFDQDO\VLV
SRSXODWLRQ

6SHFLILFDOO\WKHZHHNO\PHDQRI(5,ZLOOEHFDOFXODWHGDQGSUHVHQWHGLQGLYLGXDOO\IRUHDFK(6$
EDVHGRQWKHIRUPXODLQ6HFWLRQ

7KHPHDQRIOHIWDQGULJKWKDQGJULSVWUHQJWKVZLOOEHXVHGIRUDQDO\VLVQRPDWWHUZKLFKKDQGLV
GRPLQDQW

7KH)$&,7)9HUVLRQLVDFRPSLODWLRQRIJHQHUDOTXHVWLRQVGLYLGHGLQWRILYHSULPDU\
GRPDLQV3K\VLFDO:HOO%HLQJ6RFLDO)DPLO\:HOO%HLQJ(PRWLRQDO:HOO%HLQJ)XQFWLRQDO
:HOO%HLQJDQG$GGLWLRQDO&RQFHUQV7KHGDWDLQ$GGLWLRQDO&RQFHUQGRPDLQZLOOEHOLVWHG
VHSDUDWHO\DQGFRQVLGHUHGWKHSULPDU\DQDO\VLVIRUWKH)$&,7)7KHWRWDOIDWLJXHVFRUHZLOOEH
FDOFXODWHGDVDVXPPDWLRQRIWKHVFRUHVLQWKHILYHSULPDU\GRPDLQV7KHREVHUYHGYDOXHDQG
FKDQJHIURPEDVHOLQHLQWRWDOIDWLJXHVFRUHZLOOEHVXPPDUL]HGE\WUHDWPHQW

0$*1(7,&5(621$1&(,0$*,1*05,6&$1
7KHDFWXDOYDOXHDQGSHUFHQWFKDQJHIURPEDVHOLQHRI05,PHDVXUHPHQWVVXFKDV/90,/9(69,
/9(',DQG/9()ZLOOEHVXPPDUL]HGE\YLVLWDQGWUHDWPHQWJURXSXVLQJGHVFULSWLYHVWDWLVWLFV
05,PHDVXUHPHQWVRWKHUWKDQWKHDERYHHJOLYHUDQGVSOHHQLURQFRQWHQW>PHDQKHSDWLF7@
DQG>PHDQVSOHQLF7@DQGFDUGLDF7PDSDUHH[SHFWHGIURPRQO\DVXEVHWRISDWLHQWV

6(16,7,9,7<$1$/<6(6
.H\DQHPLDUHODWHG3'HQGSRLQWVZLOOEHVXPPDUL]HGVHSDUDWHO\IRUSDWLHQWVZLWKDQGZLWKRXW
RIISURWRFRO(6$GRVLQJ3URWRFRO(6$GRVLQJLVGHILQHGLQ6HFWLRQ7KHVHFRQGDU\DQG
RWKHU3'HQGSRLQWVEDVHGRQPHDVXUHPHQWVRI76$7IHUULWLQ&+UK\SRFKURPLF5%&
UHWLFXORF\WHFRXQWDQGKHPRJORELQZLOOXQGHUJRWKHVHQVLWLYLW\DQDO\VHV7KHVHDQDO\VHVZLOO
H[FOXGHSDWLHQWVZKRKDYHRIISURWRFROGRVLQJRI(6$VRULURQGXULQJ:HHNV±DVGHILQHGLQ
6HFWLRQ

%HFDXVHKRVSLWDOL]DWLRQVDUHDVVRFLDWHGZLWKPXOWLIDFWRULDOUHGXFWLRQLQKHPRJORELQDQGPLVVHG
(6$GRVHVDVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHGRIWKHDERYHWZRDQDO\VHVLQZKLFKDQDO\VHV
RI(6$GRVHV(5,DQGKHPRJORELQDIWHUWKHVWDUWGDWHRIWKHILUVW6$(ZLOOEHH[FOXGHG
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



6$)(7<$1$/<6,6
$OOVDIHW\DQDO\VHVZLOOEHSHUIRUPHGRQWKHVDIHW\DQDO\VLVSRSXODWLRQ6DIHW\GDWDSUHVHQWHGE\
WUHDWPHQWJURXSZLOOEHVXPPDUL]HGRQDQµDVWUHDWHGWUHDWPHQWUHFHLYHG¶EDVLV

35,0$5<6$)(7<$1$/<6,6
7KHSULPDU\VDIHW\DQDO\VHVZLOOSURYLGHGDWDWKDWZLOOVXSSRUWWKHFKDUDFWHUL]DWLRQRIWKH07'RU
WRHVWDEOLVKWKDWWKHKLJKHVWGRVHH[DPLQHGGLGQRWH[FHHGWKH07'
1XPEHUSHUFHQWRIVXEMHFWVZKRSRWHQWLDOO\H[SHULHQFHG'/7VGHILQHGLQ6HFWLRQZLOO
EHUHSRUWHGE\WUHDWPHQWJURXS7KH$GYHUVH(YHQWVWKDWDUHXVHGWRLGHQWLI\'/7VZLOOEH
WDEXODWHG7KH$GYHUVH(YHQWVZLOOEHVXPPDUL]HGE\SUHIHUUHGWHUP&7&$(JUDGHDQG
UHODWLRQVKLSWRVWXG\GUXJ'HWHUPLQDWLRQRIWKH07'ZLOOEHPDGHE\WKH65&6SHFLILFDOO\
WKHVSRQVRUZLOOXVHODEOLVWLQJVWRLGHQWLI\SRVVLEOHODEEDVHG'/7V$Q\SRVVLEOH'/7VZLOOEH
TXHULHGWREHUHSRUWHGDV$(VE\WKHLQYHVWLJDWRUDQGWKHLQYHVWLJDWRU&7&$(JUDGHZKLFKZLOO
LQFOXGHWKHFOLQLFDOLQIRUPDWLRQQHHGHGIRUVRPHRIWKH&7&$(ODEGHILQLWLRQVHJLI
V\PSWRPDWLFRULIKRVSLWDOL]DWLRQQHHGHG´ZLOOEHXVHGIRU'/7GHWHUPLQDWLRQ


6(&21'$5<6$)(7<$1$/<6,6
1XPEHUSHUFHQWRIVXEMHFWVZKRH[SHULHQFHGWKHHYHQWVRILQWHUHVW6HYHUH!*UDGH
LQIXVLRQUHODWHGUHDFWLRQVK\SHUVHQVLWLYLW\UHDFWLRQVGXULQJWKH6WXG\'UXJLQIXVLRQDQGRU
DQDSK\OD[LVRFFXUULQJDWDQ\WLPHZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSSUHIHUUHGWHUP
&7&$(JUDGHUHODWHGQHVVWRWKHVWXG\GUXJDQGVHULRXVQHVV$OORIWKHVHHYHQWVZLOOEH
LGHQWLILHGIURPWKH,QIXVLRQ5HODWHG5HDFWLRQ+\SHUVHQVLWLYLW\DQG$QDSK\OD[LV&5)(YHQWV
RQWKLVOLVWWKDWDSSHDUWRPHHWWKHSURWRFROGHILQLWLRQRIK\SHUVHQVLWLYLW\DQGDQDSK\OD[LVEDVHG
RQWKH0HGLFDO0RQLWRU¶VUHYLHZZLOOEHTXHULHGLIWKH\KDYHQRWDOUHDG\EHHQUHSRUWHGRQWKH
,QIXVLRQ5HODWHG5HDFWLRQ+\SHUVHQVLWLYLW\DQG$QDSK\OD[LV&5)

'HVFULSWLYHVWDWLVWLFVZLOODOVREHUHSRUWHGIRUDGGLWLRQDOVDIHW\DVVHVVPHQWVE\WUHDWPHQWJURXS
LQFOXGLQJDGYHUVHHYHQWVSK\VLFDOH[DPLQDWLRQILQGLQJVRISRVVLEOHLQIHFWLRQYLWDOVLJQV(&*
FOLQLFDOODERUDWRU\DQGDQWLGUXJDQWLERGLHVELQGLQJDQGQHXWUDOL]LQJ


$'9(56((9(176
7KHDGYHUVHHYHQWYHUEDWLPGHVFULSWLRQVLQYHVWLJDWRUWHUPVIURPWKH&5)ZLOOEHFODVVLILHGLQWR
PHGLFDOWHUPLQRORJ\XVLQJWKH0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV0HG'5$$GYHUVH
HYHQWV ZLOO EH FRGHG WR SULPDU\ 6\VWHP 2UJDQ &ODVV 62& DQG SUHIHUUHG WHUP 37 XVLQJ
0HG'5$9HUVLRQ
$WUHDWPHQWHPHUJHQWDGYHUVHHYHQW7($(LVGHILQHGDVDQ$(WKDWLQLWLDWHGRUZRUVHQHGRQRU
DIWHUWKHGDWHRIILUVWGRVHRIVWXG\GUXJXSWRWKHHQGRIVDIHW\IROORZXS)RU$(VRFFXUULQJRQ
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


WKHILUVWGRVLQJGD\LIWKHVWDUWWLPHFDQQRWEHDVFHUWDLQHGWKHHYHQWZLOOEHFRXQWHGDVWUHDWPHQW
HPHUJHQW
2QO\WKRVH$(VDQG6$(VWKDWDUHWUHDWPHQWHPHUJHQWZLOOEHLQFOXGHGLQVXPPDU\WDEOHV$OO
$(VDQG6$(VWUHDWPHQWHPHUJHQWRURWKHUZLVHZLOOEHSUHVHQWHGLQVXEMHFWGDWDOLVWLQJV
7($(VDQG6$(VZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXS7KHLQFLGHQFHRI$(VZLOOEHUHSRUWHG
DVWKHQXPEHUSHUFHQWRIVXEMHFWVZLWK$(VZLWKLQ62&DQG377KHLQFLGHQFHRI$(VZLWKRQVHW
ZLWKLQ:HHNVDQG:HHNVZLOODOVREHVXPPDUL]HG6XEMHFWVZLOOEHFRXQWHGRQO\RQFH
ZLWKLQD62&DQG37HYHQLIWKHVXEMHFWH[SHULHQFHGPRUHWKDQRQHHYHQWZLWKLQDVSHFLILF62&
DQG377KHQXPEHUSHUFHQWRIVXEMHFWVZLWKHYHQWVZLOODOVREHVXPPDUL]HGE\KLJKHVW&7&
JUDGHDVZHOODVE\FORVHVWUHODWLRQVKLS,IPRUHWKDQRQHHYHQWRFFXUUHGZLWKWKHVDPHSUHIHUUHG
WHUPIRUWKHVDPHSDWLHQWWKHSDWLHQWZLOOEHFRXQWHGRQO\RQFHIRUWKDWSUHIHUUHGWHUPXVLQJWKH
PRVWVHYHUHRUUHODWHGRFFXUUHQFHIRUWKHVXPPDU\E\VHYHULW\RUUHODWLRQVKLSWR6WXG\'UXJ
UHVSHFWLYHO\
3DWLHQWFRXQWVDQGSHUFHQWDJHVZLOOEHSUHVHQWHGIRUWKHIROORZLQJVXPPDULHVE\WUHDWPHQWJURXS
DQGRYHUDOO

2YHUDOOVXPPDU\RI7($(¶V

$OO7($(VE\62&DQG37

7($(VUHODWHGWRVWXG\GUXJE\62&DQG37

7($(VE\UHODWLRQVKLSWRVWXG\GUXJE\62&DQG37

7($(VE\KLJKHVWVHYHULW\JUDGHE\62&DQG37

6XPPDU\RI7($(PHHWLQJ'RVH/LPLWLQJ7R[LFLW\&ULWHULD6WXG\'D\V±E\62&
DQG37

$OO7(6$(VE\62&DQG37

$OO$(VOHDGLQJWRGLVFRQWLQXDWLRQRIVWXG\GUXJE\62&DQG37
$VXEMHFWGDWDOLVWLQJRIDOO$(VOHDGLQJWRGHDWKLIDQ\ZLOOEHSURYLGHG
)ROORZLQJ 'DWDEDVH /RFN  DQG  DV GHVFULEHG LQ 6HFWLRQ  WZR YHUVLRQV RI WKH 2YHUDOO
VXPPDU\RI7($(¶VDQGDOO7($(¶VE\62&DQG37$(VOHDGLQJWRGLVFRQWLQXDWLRQRIVWXG\GUXJ
E\62&DQG37DQGDOO7(6$(VE\62&DQG37ZLOOEHFUHDWHG9HUVLRQZLOOLQFOXGHRQO\IUR]HQ
$(GDWD9HUVLRQZLOOLQFOXGHDOO$(V

&/,1,&$//$%25$725<3$5$0(7(56
)RUDOOTXDQWLWDWLYHSDUDPHWHUVOLVWHGLQ$SSHQGL['RIWKHSURWRFROH[FHSWIRUWKHODERUDWRU\
PHDVXUHPHQWVSHUIRUPHGIRUWKHSKDUPDFRG\QDPLFHQGSRLQWDQDO\VHVVHH6HFWLRQWKHDFWXDO
YDOXHDQGFKDQJHIURPEDVHOLQHZLOOEHVXPPDUL]HGE\YLVLWDQGWUHDWPHQWJURXSXVLQJGHVFULSWLYH
VWDWLVWLFV4XDOLWDWLYHSDUDPHWHUVOLVWHGLQ$SSHQGL['RIWKHSURWRFROZLOOEHVXPPDUL]HGXVLQJ
IUHTXHQFLHVQXPEHUDQGSHUFHQWRIVXEMHFWV3HUFHQWDJHVZLOOEHEDVHGRQWKHQXPEHURIVXEMHFWV
ZLWKQRQPLVVLQJUHVXOWV
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


)RUWKHODERUDWRU\SDUDPHWHUVWKDWDUHFROOHFWHGZLWK&7&$(JUDGHWKHQXPEHUDQGSHUFHQWRI
VXEMHFWVZLWKUHVXOWVWKDWDUHJUDGHIRUKHPDWRORJ\SDUDPHWHUVDVZHOODVWKHQXPEHUDQG
SHUFHQWRIVXEMHFWVZLWKUHVXOWVWKDWDUHJUDGHLQQRQKHPDWRORJ\SDUDPHWHUVZLOOEH
VXPPDUL]HG7KHVKLIWVXPPDU\RIKHPDWRORJ\DQGQRQKHPDWRORJ\ODERUDWRU\SDUDPHWHUVLQ
&7&JUDGHWRWKHZRUVWDEQRUPDOZLOODOVREHSUHVHQWHG1RWHWKDWWKH&7&JUDGHVDUHEDVHGRQ
WKHODERUDWRU\YDOXHVRQO\DQGGRQRWFRQVLGHUFOLQLFDOFRQVHTXHQFHVRULQWHUYHQWLRQVWKDWGHILQH
WKHJUDGH7KHUHIRUHWKH&7&JUDGHVWKURXJKZLOOEHFRQVLGHUHGWKHKLJKHVWSRWHQWLDO&7&
JUDGHIRUWKHODERUDWRU\YDOXHVIRUZKLFKWKHJUDGLQJGHILQLWLRQUHTXLUHVNQRZOHGJHRI
LQIRUPDWLRQRWKHUWKDQWKHODERUDWRU\YDOXH 

7KHODERUDWRU\PHDVXUHPHQWVIURP3URWRFRO$SSHQGL['SDQHO+HPDWRORJ\ZLOOEHXVHGIRUODE
EDVHGKHPDWRORJLFWR[LFLW\DVVHVVPHQW
7KHSHUFHQWDJHRISDWLHQWVH[FHHGLQJSUHGHILQHGDEVROXWHDQGUHODWLYHWKUHVKROGYDOXHVDFURVVWKH
HQWLUHWUHDWPHQWSHULRGDFURVVWKHHQWLUHVDIHW\IROORZXSSHULRGDQGDFURVVERWKRIWKHVHSHULRG
ZLOOEHVXPPDUL]HG6HH7DEOH
7DEOH3UHGHILQHG7KUHVKROG9DOXHIRU/DERUDWRU\3DUDPHWHUV
3DUDPHWHU
&ULWHULD
$/7
!;8/1
$67
!;8/1
$/7DQG$67
%RWK!;8/1
$/7$67DQG7RWDO%LOLUXELQ
$/7!;8/1DQG$67;8/1DQG7RWDO%LOLUXELQ
!8/1
+HPRJORELQ
,QFUHDVH!JG/LQZHHNV
+HPRJORELQ
!JG/LQZHHNV
+HPRJORELQ
!JG/RQFRQVHFXWLYHDVVHVVPHQWV
+HPRJORELQ
!JG/RQFRQVHFXWLYHDVVHVVPHQWV
+HPRJORELQ
JG/RQFRQVHFXWLYHDVVHVVPHQWV

%DVHOLQHIRUWKHODERUDWRU\SDUDPHWHUVZLOOEHGHILQHGDVPHDQRI:HHNDQG'D\YDOXHV

,1)86,215(/$7('5($&7,216+<3(56(16,7,9,7<5($&7,216$1'$1$3+</$;,6
7KH LQIXVLRQ UHODWHG UHDFWLRQV K\SHUVHQVLWLYLW\ UHDFWLRQV DQG DQDSK\OD[LV HYHQWV ZLOO EH
VXPPDUL]HGE\WUHDWPHQWJURXSXVLQJIUHTXHQFLHVQXPEHUDQGSHUFHQWRIVXEMHFWV

,1)(&7,21'(7$,/6
$ VXEMHFW OLVWLQJ IRU WKH LQIHFWLRQ GHWDLOV FDSWXUHG LQ &5) ZLOO EH SURYLGHG$GGLWLRQDOO\ D
VXPPDU\WDEOHZLOOEHJHQHUDWHGVXPPDUL]LQJW\SHVRILQIHFWLRQDQGW\SHRILQIHFWLRXVDJHQWLI
NQRZQHJEDFWHULDYLUXVIXQJXVHWF
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



',$/<6,6'(7$,/6
)RU HDFK GLDO\VLV WKH GXUDWLRQ LQ PLQXWHV WDUJHW GU\ ZHLJKW DQG IUHTXHQFLHV QXPEHU DQG
SHUFHQWDJH RI GLDO\VLV DFFHVV XVHG DQG QHW XOWUDILOWUDWLRQ YROXPH ZLOO EH VXPPDUL]HG
GHVFULSWLYHO\

9,7$/6,*163+<6,&$/(;$0,1$7,21),1',1*6$1'(&*

9LWDO6LJQV
$FFRUGLQJWRWKHFROOHFWLRQVFKHGXOHWKHREVHUYHGYDOXHRIYLWDOVLJQVSDUDPHWHUVGLDVWROLFDQG
V\VWROLFEORRGSUHVVXUHSXOVHUDWHUHVSLUDWLRQUDWHDQGWHPSHUDWXUHDQGFKDQJHIURPEDVHOLQHLQ
WKHVHSDUDPHWHUVZLOOEHVXPPDUL]HGLQWKUHHVHSDUDWHWDEOHV2QHIRUSUHGLDO\VLVE\YLVLWZLWK
EDVHOLQHEHLQJWKHSUHGLDO\VLVYDOXHVDWZHHN2QHIRUSRVWGLDO\VLVE\YLVLWZLWKEDVHOLQHEHLQJ
WKHSRVWGLDO\VLVYDOXHVDWZHHN$QGWKHWKLUGWDEOHIRUSUHDQGSRVWLQIXVLRQE\YLVLWZLWK
EDVHOLQHEHLQJWKHSUHLQIXVLRQYDOXHVDWWKDWYLVLWLQWKLVWDEOHFKDQJHIURPSUHWRSRVWLQIXVLRQ
ZLWKLQHDFKLQIXVLRQVHVVLRQZLOODOVREHSURYLGHG$VSUHGLDO\VLVZHLJKWLVFROOHFWHGLQDGLIIHUHQW
VFKHGXOHWKDQRWKHUYLWDOVLJQVWZRVHSDUDWHWDEOHVIRUSUHGLDO\VLVZHLJKWDQG%0,SRVWGLDO\VLV
ZHLJKWDQG%0,ZLOOEHSURYLGHGVHSDUDWHO\
,QDGGLWLRQWKHSHUFHQWDJHRISDWLHQWVH[FHHGLQJSUHGHILQHGDEVROXWHDQGUHODWLYHWKUHVKROGYDOXHV
DFURVVWKHHQWLUHWUHDWPHQWSHULRGDFURVVWKHHQWLUHVDIHW\IROORZXSSHULRGDQGDFURVVERWKRI
WKHVHSHULRGZLOOEHVXPPDUL]HGVHH
7DEOH:KHQFDOFXODWLQJWKHSHUFHQWDJHVQXPHUDWRUZLOOEHWKHQXPEHURIVXEMHFWVZLWKQRUPDO
EDVHOLQHZLWKUHVSHFWWRWKHVSHFLILFFULWHULRQDQGDWOHDVWSRVWEDVHOLQHRXWOLHUYDOXHZLWKLQWKH
DQDO\VLVSHULRGDQGGHQRPLQDWRUZLOOEHWKHQXPEHURIVXEMHFWVZLWKDEDVHOLQHDQGDWOHDVWSRVW
EDVHOLQHDVVHVVPHQWZLWKLQWKHDQDO\VLVSHULRG$VXEMHFWPD\EHFRXQWHGPRUHWKDQLQPXOWLSOH
FDWHJRULHVIRUDJLYHQSDUDPHWHU7KUHHWDEOHVZLOOEHSURYLGHGVHSDUDWHO\IRUSUHGLDO\VLVYDOXHV
SRVWGLDO\VLV YDOXHV DQG SUHSRVWLQIXVLRQ YDOXHV $OO UHVXOWV UHJDUGOHVV RI VFKHGXOHG RU
XQVFKHGXOHGZLOOEHFRQVLGHUHGLQWKLVVXPPDU\
7DEOH3UHGHILQHG7KUHVKROG9DOXHIRU9LWDO6LJQV
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


3DUDPHWHU
&ULWHULD
6\VWROLF%ORRG3UHVVXUH6%3
!PP+JLQFUHDVHGRUGHFUHDVHGIURPEDVHOLQH
6%3
!PP+JLQFUHDVHGRUGHFUHDVHGIURPEDVHOLQH
6%3
!PP+J
6%3
PP+J
+HDUW5DWH+5
!EHDWVSHUPLQXWH
+5
EHDWVSHUPLQXWH
5HVSLUDWLRQ5DWH
!EUHDWKVSHUPLQXWH
:HLJKWSUHGLDO\VLV
!NJLQFUHDVHGIURPEDVHOLQHSUHGLDO\VLVZHLJKW
:HLJKWSUHGLDO\VLV
!NJGHFUHDVHGIURPEDVHOLQHSUHGLDO\VLVZHLJKW
%0,
!LQFUHDVHGIURPEDVHOLQH
%0,
!GHFUHDVHGIURPEDVHOLQH


3K\VLFDO([DPLQDWLRQ
$VXEMHFWOLVWLQJRISK\VLFDOH[DPILQGLQJVRIVLJQVRILQIHFWLRQZLOOEHSURYLGHG

,QDGGLWLRQ3K\VLFDOH[DPLQDWLRQFOLQLFDOO\VLJQLILFDQWQHZRUZRUVHQLQJILQGLQJVZLOOEH
UHSRUWHGDVDGYHUVHHYHQWVDQGZLOOWKHUHIRUHEHVXPPDUL]HGDVGHVFULEHGIRUDGYHUVHHYHQWV


/HDG(&*
(&*LQWHUSUHWDWLRQQRUPDOYVDEQRUPDOZLOOEHVXPPDUL]HGXVLQJIUHTXHQF\DQGSHUFHQWDJHDW
HDFKYLVLWE\WUHDWPHQWJURXS2EVHUYHGYDOXHVDQGFKDQJHIURPEDVHOLQHLQ(&*LQWHUYDOV35
47+5DQG47F)UK\WKPDQGKHDUWUDWHZLOOEHVXPPDUL]HGGHVFULSWLYHO\DWHDFKYLVLWE\
WUHDWPHQWJURXS

7KHSHUFHQWDJHRISDWLHQWVH[FHHGLQJSUHGHILQHGDEVROXWHDQGUHODWLYHWKUHVKROGYDOXHVDFURVV
WKHHQWLUHWUHDWPHQWSHULRGDFURVVWKHHQWLUHVDIHW\IROORZXSSHULRGDQGDFURVVERWKRIWKHVH
SHULRGVZLOOEHVXPPDUL]HGVHH7DEOHB:KHQFDOFXODWLQJWKHSHUFHQWDJHVIRUWKHFULWHULRQ
UHODWHGWRDWKUHVKROGWKHQXPHUDWRUZLOOEHWKHQXPEHURIVXEMHFWVZLWKQRUPDOEDVHOLQHZLWK
UHVSHFWWRWKHVSHFLILFFULWHULRQDQGDWOHDVWSRVWEDVHOLQHRXWOLHUYDOXHZLWKLQWKHDQDO\VLV
SHULRGDQGGHQRPLQDWRUZLOOEHWKHQXPEHURIVXEMHFWVZLWKQRUPDOEDVHOLQHZLWKUHVSHFWWRWKH
VSHFLILFFULWHULRQDQGDWOHDVWSRVWEDVHOLQHDVVHVVPHQWZLWKLQWKHDQDO\VLVSHULRG:KHQ
FDOFXODWLQJWKHSHUFHQWDJHVIRUWKHFULWHULDUHODWHGWRFKDQJHIURPEDVHOLQHWKHQXPHUDWRUZLOOEH
WKHQXPEHURIVXEMHFWVPHHWLQJWKHFULWHULRQDQGGHQRPLQDWRUZLOOEHWKHQXPEHURIVXEMHFWV
ZLWKDEDVHOLQHDQGDWOHDVWSRVWEDVHOLQHDVVHVVPHQWZLWKLQWKHDQDO\VLVSHULRG$VXEMHFWPD\
EHFRXQWHGLQPXOWLSOHFDWHJRULHVIRUDJLYHQSDUDPHWHU$OOUHVXOWVUHJDUGOHVVRIVFKHGXOHGRU
XQVFKHGXOHGZLOOEHFRQVLGHUHGLQWKLVVXPPDU\


CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


7DEOH3UHGHILQHG7KUHVKROG9DOXHIRU(&*
3DUDPHWHU
&ULWHULD
35,QWHUYDO
!PVHF
47F)
!PVHF
47F)
!PVHF
47F)
!PVHF
47F)
,QFUHDVHIURPEDVHOLQH!PVHF
47F)
,QFUHDVHIURPEDVHOLQH!PVHF


$17,%2',(672&25
7KHLPPXQRJHQLFSRWHQWLDORI&25ZLOOEHDVVHVVHGE\VXPPDUL]LQJWKHQXPEHU
DQGSHUFHQWDJHRISDWLHQWVZKRGHYHORSGHWHFWDEOHDQWLGUXJDQWLERGLHV$'$E\GRVH
$QWLGUXJDQWLERG\WLWHUVZLOOEHVXPPDUL]HGGHVFULSWLYHO\IRU$'$SRVLWLYHVDPSOHVDQG
WKHLPSDFWRI$'$RQ3.ZLOOEHDVVHVVHGLIGDWDDOORZV1HXWUDOL]LQJFDSDFLW\RIDQ\
GHWHFWHG$'$ZLOOEHVXPPDUL]HG


3+$50$&2.,1(7,&$1$/<6,6$1'
3+$50$&2.,1(7,&3+$50$&2'<1$0,&$1$/<6,6

$SDWLHQWOLVWLQJRIDOOVHUXPFRQFHQWUDWLRQWLPHGDWDIRUHDFKGRVHJURXSZLOOEHSUHVHQWHG+LJK
VHQVLWLYLW\&53KV&53DQGVHUXP,/ZLOODOVREHSUHVHQWHGLQOLVWLQJV$QDO\VHVRI3.DQG
3.3' PRGHOLQJ DUH GHVFULEHG LQ WKH 'DWD $QDO\VLV 3ODQ IRU 3KDUPDFRNLQHWLFV DQG
3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF0RGHOLQJ


,17(5,0$1$/<6(6$1'6$)(7<5(9,(:&200,77((65&

6$)(7<5(9,(:&200,77((
$6DIHW\5HYLHZ&RPPLWWHH65&LVHVWDEOLVKHGDQGZLOODSSO\LWVMXGJPHQWWRWKHFRQGXFWRI
WKLVVWXG\LQRUGHUWRHQVXUHWKHVDIHW\RIVWXG\SDUWLFLSDQWV7KH65&ZLOOUHYLHZXQEOLQGHG
VDIHW\GDWDSULRUWRGRVHHVFDODWLRQLHKLJKHUWRWDOGRVHWKDQVWXGLHGLQWKHSUHFHGLQJFRKRUWV
7KHUHYLHZVZLOORFFXUDIWHUDOOSDWLHQWVLQDFRKRUWKDYHFRPSOHWHGGD\VRIWUHDWPHQWRUODVW
YLVLWLISUHPDWXUHO\GLVFRQWLQXHG7KH6SRQVRUZLOOFRQVLGHU65&UHFRPPHQGDWLRQVZKHQ
GHWHUPLQLQJWKHGRVHIRUWKHQH[WFRKRUW)ROORZLQJFRPSOHWLRQRIWKHGRVHHVFDODWLRQSKDVHRI
WKHVWXG\WKH65&ZLOOPHHWDSSUR[LPDWHO\HYHU\PRQWKVXQWLODOOVXEMHFWVKDYHFRPSOHWHG
VDIHW\IROORZXSSHULRGRUWHUPLQDWHGHDUO\WRUHYLHZDFFUXLQJVDIHW\GDWD

7KHIXOODFWLYLWLHVDQGUHVSRQVLELOLWLHVRIWKH65&DUHGHVFULEHGLQWKH65&FKDUWHU

CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



,17(5,0$1$/<6,6
$VLQJOHLQWHULPDQDO\VLVZLOOEHFRQGXFWHGIRUWKHSXUSRVHRIJXLGLQJIXWXUH&25FOLQLFDO
SURJUDPDFWLYLWLHV7KHUHDUHQRVWRSSLQJUXOHVDVVRFLDWHGZLWKWKHLQWHULPDQDO\VLVDQGWKHUHIRUH
QRVWDWLVWLFDODGMXVWPHQWIRUPXOWLSOLFLW\ZLOOEHPDGH7KHLQWHULPDQDO\VLVZLOOEHFRQGXFWHGDW
HDUOLHVWRQFHDOOFRKRUWVEHORZWKDWZKLFKH[FHHGWKH07'H[FOXGLQJDQ\H[SDQVLRQFRKRUWV
KDYHFRPSOHWHGWKHVWXG\WKURXJK:HHNRUILQDOYLVLWLISUHPDWXUHO\GLVFRQWLQXHG

7KHIROORZLQJHQGSRLQWVZLOOEHDVVHVVHGLQWKHLQWHULPDQDO\VLV

x 3'SDUDPHWHUVKV&536$$IUHHDQGRUWRWDOVHUXP,/DVZHOODVKHPRJORELQ
76$7&+USUHDOEXPLQDQGDOEXPLQ
x &KDQJHLQKHPRJORELQIURPVFUHHQLQJWRSHDNKHPRJORELQGHILQHGDVSHUVXEMHFW
DEVROXWHPD[LPDOKHPRJORELQLQJG/
x &KDQJHIURPEDVHOLQHPHDQRI)XOO6FUHHQLQJDQG'D\YDOXHVLQ+HPRJORELQWR
:HHNVH[FOXGLQJKHPRJORELQYDOXHVIROORZLQJDFKDQJHLQWKHWRWDOZHHNO\
(6$GRVH$FKDQJHLVGHILQHGDVWKHILUVWWLPHZKHQWKH(6$ZHHNO\GRVHJRHVXS
E\!RUGRZQE\!UHODWLYHWRWKHSUHYLRXVZHHN
VGRVH
x (5,
x +HPRJORELQDQG(5,VWUDWLILHGE\EDVHOLQH(5,PHGLDQRU! PHGLDQ
x &DUGLDFELRPDUNHUV3UR17%13DQGWURSRQLQ
x 05,RXWFRPH/90,/9(69,/9('9,DQG/9()
x +DQGJULSVWUHQJWK
x )$&,7IDWLJXHVFRUH

7KHVXPPDU\DSSURDFKIRUWKHVHOLVWHGHQGSRLQWVZLOOEHWKHVDPHDVGHVFULEHGLQWKH6$3DQG
ZLOOIROORZWKHVSHFLILFDWLRQVEHORZIRUSUHVHQWDWLRQLQRUGHUWRPDVNWKHWUHDWPHQWOHYHOGDWD

x %\ PDVNHG WUHDWPHQW JURXS HJ7UHDWPHQW$ 7UHDWPHQW % DQG HWF 6XEMHFWV
UHFHLYLQJSODFHERIURPDOOFRKRUWVZLOOEHFRPELQHGDVRQHRIWKHWUHDWPHQWJURXSV
o %RWK 3' DQDO\VLV SRSXODWLRQ  DQG 3HU3URWRFRO DQDO\VLV SRSXODWLRQ ZLOO EH
SHUIRUPHGRQPDVNHGGDWD
x 3RROHGWUHDWPHQWYVSRROHGSODFHER
x 3RROHGUHVSRQGHUDQDO\VLVGHILQHGDVFKDQJHIURPEDVHOLQHLQ3'SDUDPHWHUIRUDOO
SDWLHQWVUHJDUGOHVVRIDFWLYHYVSODFHERDVVLJQPHQWZKRDFKLHYHDUHGXFWLRQ
LQKV&53

7RDYRLGLGHQWLILFDWLRQRILQGLYLGXDOSDWLHQWVWKHQXPEHURIVXEMHFWVPLQLPXPPD[LPXP
YDOXHVDQGUDZQXPEHUVIRUWKHSHUFHQWDJHVLHQXPHUDWRUDQGGHQRPLQDWRUZLOOQRWEH
SUHVHQWHG2QO\WKHPHDQVVWDQGDUGGHYLDWLRQVDQGSHUFHQWDJHVZLOOEHSUHVHQWHG7KHVSRQVRU
SHUVRQQHOZLOORQO\UHFHLYHWKHPDVNHGWUHDWPHQWJURXSOHYHOLQIRUPDWLRQDQGKDYHQRDFFHVVWR
DFWXDOWUHDWPHQWOHYHOLQIRUPDWLRQQRUVXEMHFWOHYHOWUHDWPHQWLQIRUPDWLRQ

CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI



'$7$%$6(/2&.
7KHGDWDEDVHZLOOEHORFNHGVHTXHQWLDOO\WRHQDEOHSURJUDPSODQQLQJ
x 'DWDEDVH/RFNZLOORFFXUDIWHUWKHODVWSDWLHQWLQ&RKRUWFRPSOHWHVWKH:HHNYLVLW
RUHDUO\WHUPLQDWHVSULRUWR:HHN$OOYLVLWVSHFLILFFDVHUHSRUWIRUPVIRUDOOFRPSOHWHG
YLVLWVLQFOXGLQJXQVFKHGXOHGYLVLWVRFFXUULQJSULRUWRWKHGDWDEDVHFXWRIIGDWHZLOOEH
IUR]HQ IRU SDWLHQWV LQ DOO FRKRUWV %HFDXVH SDWLHQWV LQ &RKRUW  ZLOO DOUHDG\ KDYH
FRPSOHWHGWKHVWXG\WKHYDVWPDMRULW\RIGDWDZLOOEHORFNHGDWWKLVWLPH+DQGOLQJRQQRQ
YLVLW VSHFLILF &5)V LV GHVFULEHG EHORZ %HFDXVH WKH SULPDU\ DQG VHFRQGDU\
SKDUPDFRG\QDPLFHQGSRLQWVDUHEDVHGRQWLPHSRLQWVWKURXJK:HHNWKHUHIRUHWKHVH
GDWDZLOOEHORFNHGZLWK'DWDEDVH/RFNDQGEHXQDIIHFWHGE\VXEVHTXHQWGDWDEDVHORFNV
x 'DWDEDVH/RFNZLOORFFXUDIWHUWKHODVWSDWLHQWLQ&RKRUWFRPSOHWHVWKH:HHNYLVLW
RUHDUO\WHUPLQDWHVSULRUWR:HHN$OOYLVLWVSHFLILFFDVHUHSRUWIRUPVIRUDOOFRPSOHWHG
YLVLWVQRWDOUHDG\ORFNHGGXULQJ'DWDEDVH/RFNLQFOXGLQJXQVFKHGXOHGYLVLWVRFFXUULQJ
SULRUWRWKHGDWDEDVHFXWRIIGDWHZLOOEHORFNHGIRUSDWLHQWVLQDOOFRKRUWV+DQGOLQJRQQRQ
YLVLWVSHFLILF&5)VLVGHVFULEHGEHORZ
x 'DWDEDVH/RFNZLOORFFXUDIWHUWKHODVWSDWLHQWLQ&RKRUWFRPSOHWHVWKH:HHNYLVLW
RUHDUO\WHUPLQDWHVSULRUWR:HHN$OOYLVLWVSHFLILFFDVHUHSRUWIRUPVIRUDOOFRPSOHWHG
YLVLWVQRWDOUHDG\ORFNHGGXULQJ'DWDEDVH/RFNVDQGLQFOXGLQJXQVFKHGXOHGYLVLWVZLOO
EHORFNHGIRUSDWLHQWVLQDOOFRKRUWV$GYHUVHHYHQWVFRQFRPLWDQWPHGLFDWLRQVDQGRWKHU
ORJ&5)SDJHDQGHQGRIVWXG\&5)ZLOOEHKDQGOHGDVGHVFULEHGEHORZ
'DWDEDVH/RFNLQJ5XOHVIRU9LVLW1RQ6SHFLILF&5)V
͌ $GYHUVH HYHQWV ,QIHFWLRQ 'HWDLOV DQG ,QIXVLRQ5HODWHG 5HDFWLRQ &5)V ZLOO EH ORFNHG DW
'DWDEDVH/RFNVDQGLIHLWKHURIWKHEHORZDSSO\
͌ 7KH$(RUFRUUHVSRQGLQJ6$(RILQIHFWLRQRULQIXVLRQUHODWHGUHDFWLRQKDVDQHQGGDWH
,IWKHHYHQWLVDQ6$(WKH6$(FDVHPXVWDOVRKDYHEHHQFORVHG
͌ 7KHSDWLHQWFRPSOHWHGWKHVWXG\GLHGRUZDVZLWKGUDZQIURPWKHVWXG\
$OOUHPDLQLQJHYHQWVZLOOEHORFNHGDWWKHWLPHRI'DWDEDVH/RFN
͌ &RQFRPLWDQW0HGLFDWLRQVZLOOEHORFNHGDW'DWDEDVH/RFNVDQGLIDQ\RIWKHEHORZDSSO\
͌ 7KH FRQFRPLWDQW PHGLFDWLRQ LQGLFDWLRQ LV DQ$( DQG WKHUH LV DQ HQG GDWH IRU WKH
FRUUHVSRQGLQJ$(RUWKHSDWLHQWGLHGRUWKHSDWLHQWZDVZLWKGUDZQIURPWKHVWXG\,Q
FDVHRI6$(6$(FDVHPXVWDOVREHFORVHG
͌ 7KH FRQFRPLWDQW PHGLFDWLRQ LQGLFDWLRQ LV QRW$( DQG WKHUH LV DQ HQG GDWH IRU WKH
CONFIDENTIAL


&RUYLGLD&RUSRUDWLRQ

3URWRFRO1R&25
6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ-8/<
&RQILGHQWLDO
3DJHRI


FRQFRPLWDQWPHGLFDWLRQRUWKHSDWLHQWGLHGRUWKHSDWLHQWZDVZLWKGUDZQIURPWKHVWXG\
$OOUHPDLQLQJFRQFRPLWDQWPHGLFDWLRQVZLOOEHORFNHGDWWKHWLPHRI'DWDEDVH/RFN
͌ (QGRI6WXG\&5)
o 7KH(QGRI6WXG\&5)ZLOOEHIUR]HQDWWKHWLPHRI'DWDEDVH/RFNRU'DWDEDVH
/RFNLIWKH:HHNYLVLWKDVEHHQFRPSOHWHGRUWKHSDWLHQWGLHGRUZLWKSDWLHQW
ZDVZLWKGUDZQIURPWKHVWXG\DWWKHWLPHRIWKHORFN$Q\UHPDLQLQJ&5)VZLOOEH
ORFNHGDWWKHWLPHRI'DWDEDVH/RFN

6800$5<2)0$-25&+$1*(6,17+(3/$11('$1$/<6(6
7KHVWXG\SURWRFROZDVDPHQGHGRQ6HSWHPEHU$PHQGPHQW7KH6WDWLVWLFDO$QDO\VLV
3ODQLVGHYHORSHGEDVHGRQWKLVYHUVLRQRIWKHSURWRFRO$Q\IXUWKHUDQDO\VLVFKDQJHVPDGHDIWHU
WKLV6$3LVILQDOL]HGZLOOEHGRFXPHQWHGZLWKD6$3DPHQGPHQWRUGHVFULEHGLQWKHFOLQLFDOVWXG\
UHSRUW&65


5()(5(1&(6
 &R\QH':.DSRLDQ76XNL:6LQJK$.0RUDQ-('DKO195L]NDOD$5'5,9(
6WXG\*URXS)HUULFJOXFRQDWHLVKLJKO\HIILFDFLRXVLQDQHPLFKHPRGLDO\VLVSDWLHQWVZLWK
KLJKVHUXPIHUULWLQDQGORZWUDQVIHUULQVDWXUDWLRQUHVXOWVRIWKH'LDO\VLV3DWLHQWV

5HVSRQVHWR,9,URQZLWK(OHYDWHG)HUULWLQ'5,9(6WXG\-$P6RF1HSKURO
,&+JXLGDQFHIRULQGXVWU\(6WUXFWXUHDQG&RQWHQWRI&OLQLFDO6WXG\
5HSRUWV
 6LHSHU-%UDXQ-.D\-%DGDODPHQWL65DGLQ$-LDR/)LRUH6HWDO6DULOXPDEIRUWKH
WUHDWPHQWRIDQN\ORVLQJVSRQG\OLWLVUHVXOWVRID3KDVH,,UDQGRPLVHGGRXEOHEOLQG
SODFHERFRQWUROOHGVWXG\$/,*1$QQ5KHXP'LV±

02&.7$%/(6/,67,1*6$1'),*85(67/)6
7KHVWXG\7/)VKHOOVZLOOEHSURYLGHGLQDVHSDUDWHGRFXPHQWZKLFKZLOOVKRZWKHFRQWHQWDQG
IRUPDWRIDOOWDEOHVOLVWLQJVDQGILJXUHVLQGHWDLO
CONFIDENTIAL