A Phase 3b, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Switching From Regimens Consisting of Abacavir/Lamivudine (ABC/3TC) Plus a Third Antiretroviral Agent to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination (FDC) in Virologically-Suppressed HIV 1 Infected Adult Subjects
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Gilead Sciences



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TABLE OF CONTENTS
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
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IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
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Study Centers Planned:
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Study Design:
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1.3.
Rationale for This Study
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1.4.
Risk/Benefit Assessment for the Study
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1.5.
Compliance
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2.
OBJECTIVES
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3.
STUDY DESIGN
3.1.
Endpoints
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3.2.
Study Design
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HIILFDF\RIVZLWFKLQJIURP$%&7&SOXV DWKLUGDQWLUHWURYLUDO DJHQWDVSUHVFULEHGE\
WKH ,QYHVWLJDWRU WR(&)7$))'&WDEOHWFRPSDUHGWRVWD\LQJRQWKHLUFXUUHQWUHJLPHQLQ +,9
LQIHFWHGDGXOWVXEMHFWV ZKRDUHYLURORJLFDOO\VXSSUHVVHG+,9 51$FRSLHVP/RQD
VWDEOHUHJLPHQFRQWDLQLQJ$%&7&IRUFRQVHFXWLYHPRQWKVSULRUWRVFUHHQLQJ
3.3.
Study Treatments
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IURP$%&7&WR(&)7$))'&WUHDWPHQW7UHDWPHQW*URXS RUFRQWLQXLQJRQWKHLU
H[LVWLQJUHJLPHQIRUZHHNVIROORZHGE\DGHOD\HGVZLWFK WR(&)7$) )'&
7UHDWPHQW *URXS5DQGRPL]DWLRQZLOOEHVWUDWLILHGE\DJH\HDUVRU\HDUV

Treatment Group 1: ,PPHGLDWHVZLWFK IURP$%&7&SOXVDWKLUGDQWLUHWURYLUDODJHQWWR
(&)7$) )'&Q 

Treatment Group 2: &RQWLQXH RQWKHFXUUHQW UHJLPHQRI$%&7&SOXVD
WKLUG DQWLUHWURYLUDODJHQW IRUZHHNVIROORZHGE\DGHOD\HGVZLWFKWR(&)7$) )'&
Q  
$OORZHGWKLUGDQWLUHWURYLUDO DJHQWVLQFOXGH
Antiretroviral Class
Agents
%RRVWHG3,
$79&2%,RU$79&2%,)'&'59&2%,RU'59&2%,)'&
'59579 /39U $79579
1157,
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,167,
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
$SSUR[LPDWHO\VXEMHFWVZKRPHHWWKHHOLJLELOLW\FULWHULDZLOOEHHQUROOHG
4.2.
Inclusion Criteria
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VWXG\
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SULRUWRLQLWLDWLRQRIVWXG\SURFHGXUHV
 $JH\HDUV
 &XUUHQWO\UHFHLYLQJ$%&7& SOXV DWKLUGDQWLUHWURYLUDO $59 DJHQWIRU
  FRQVHFXWLYH PRQWKVSULRUWRWKHVFUHHQLQJ YLVLW 6XEMHFWVPXVWEHRQWKHLU
ILUVW RU VHFRQG $59UHJLPHQ 5HIHUWR7DEOH  IRUDOORZHGWKLUGDJHQWVRIWKH
FXUUHQW UHJLPHQ
 'RFXPHQWHGSODVPD+,951$OHYHOVFRSLHVP/IRUPRQWKVSUHFHGLQJWKH
VFUHHQLQJYLVLWPHDVXUHGDWOHDVWWZLFHXVLQJWKHVDPHDVVD\
D ,QWKHSUHFHGLQJPRQWKVSULRUWRVFUHHQLQJRQHHSLVRGHRI³EOLS´
+,9 51$ !  DQGFRSLHVP/LVDFFHSWDEOHRQO\LI+,951$LV
  FRSLHVP/LPPHGLDWHO\EHIRUHDQGDIWHUWKH³EOLS´
E 7RGHWHUPLQHYLURORJLFVXSSUHVVLRQLQWKHSUHFHGLQJPRQWKVSULRUWRVFUHHQLQJWKH
ORZHUOLPLWRITXDQWLILFDWLRQ//24E\WKHORFDO+,951$DVVD\PD\EHXVHGRQO\LI
LWV//24LVJUHDWHUWKDQFRSLHVP/HJ //24RIFRSLHVP/
 3ODVPD+,951$OHYHOFRSLHVP/DWVFUHHQLQJYLVLW
 'RFXPHQWHGKLVWRULFDOJHQRW\SHSULRUWRVWDUWLQJLQLWLDO$59WKHUDS\$57VKRZLQJQR
NQRZQUHVLVWDQFHWR7')RU )7&LQFOXGLQJEXWQRWOLPLWHGWRWKHSUHVHQFHRIUHYHUVH
WUDQVFULSWDVHUHVLVWDQFHPXWDQWV.509,RUWK\PLGLQHDQDORJDVVRFLDWHGPXWDWLRQV
7$0V 7$0VDUH 0/ '1.5/: 7<) .4(15 ,ID KLVWRULFDO
JHQRW\SHLVQRWDYDLODEOHVXEMHFWZLOOKDYHSURYLUDOJHQRW\SHDQDO\VLVIRUDUFKLYHGUHVLVWDQFH
DWVFUHHQLQJYLVLW
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 î VHUXPFUHDWLQLQHLQ PJG/
 +HSDWLFWUDQVDPLQDVHV$67DQG$/7î XSSHUOLPLWRIQRUPDO8/1
 7RWDOELOLUXELQPJG/RUQRUPDOGLUHFWELOLUXELQVXEMHFWVZLWKGRFXPHQWHG
*LOEHUW¶V V\QGURPHRUZLWKDWD]DQDYLUDVVRFLDWHGK\SHUELOLUXELQHPLDPD\KDYHWRWDOELOLUXELQ
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3ODWHOHWV PP
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+HPRJORELQJG/
 $IHPDOHVXEMHFWLVHOLJLEOHWRHQWHUWKHVWXG\LILWLVFRQILUPHGWKDWVKHLV
D 1RWSUHJQDQWFRQILUPHGE\DQHJDWLYHVHUXPSUHJQDQF\WHVWZKLFKLVUHTXLUHGIRUIHPDOH
VXEMHFWVXQOHVVSHUPDQHQWO\ VWHULOHRUJUHDWHUWKDQWZR\HDUVSRVWPHQRSDXVDO
E 1RW QXUVLQJ/DFWDWLQJIHPDOHVPXVWDJUHHWRGLVFRQWLQXHQXUVLQJEHIRUHWKHVWXG\GUXJ LV
DGPLQLVWHUHG
F 2IQRQFKLOGEHDULQJSRWHQWLDOHJZRPHQ ZKRKDYHKDGDK\VWHUHFWRP\KDYHKDGERWK
RYDULHVUHPRYHGRUPHGLFDOO\GRFXPHQWHGRYDULDQIDLOXUHRUDUHSRVWPHQRSDXVDOZRPHQ
! \HDUVRIDJHZLWKFHVVDWLRQIRU PRQWKVRISUHYLRXVO\RFFXUULQJPHQVHV
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VSHFLILHGPHWKRGRIFRQWUDFHSWLRQ RUEHQRQKHWHURVH[XDOO\DFWLYHRUSUDFWLFHVH[XDO
DEVWLQHQFHDV GHILQHGLQ$SSHQGL[ IURPVFUHHQLQJWKURXJKRXWWKHGXUDWLRQRIVWXG\
WUHDWPHQWDQGIRUGD\VIROORZLQJGLVFRQWLQXDWLRQRIVWXG\GUXJV
H )HPDOHVXEMHFWVZKRXWLOL]HKRUPRQDOFRQWUDFHSWLYHDVRQHRIWKHLUELUWKFRQWUROPHWKRGV
PXVWKDYHXVHGWKHVDPHPHWKRGIRUDWOHDVWWKUHHPRQWKVSULRUWRVWXG\GRVLQJ
 0DOH VXEMHFWVPXVWDJUHHWRVSHFLILHGKLJKO\HIIHFWLYHPHWKRG RIFRQWUDFHSWLRQDVGHILQHG
LQ $SSHQGL[  GXULQJKHWHURVH[XDOLQWHUFRXUVHRUEHQRQKHWHURVH[XDOO\DFWLYHRUSUDFWLFH
VH[XDODEVWLQHQFHIURPILUVWGRVHWKURXJKRXWWKHVWXG\SHULRGDQGIRUGD\VIROORZLQJWKH
ODVWVWXG\GUXJGRVH

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Table 4-1.
Allowable Antiretroviral Agents of Pre-Existing Regimen
Antiretroviral Class
Agents
%RRVWHG3,
$79&2%,RU$79&2%,)'&'59&2%,RU'59&2%,)'&
'59579 /39U $79579
1157,
()9(75193539
,167,
'7*5$/
4.3.
Exclusion Criteria
6XEMHFWVZKRPHHWany RIWKHIROORZLQJH[FOXVLRQFULWHULDDUHQRWWREHHQUROOHGLQWKLVVWXG\
 3UHYLRXVXVHRIDQ\DSSURYHGRUH[SHULPHQWDOLQWHJUDVHVWUDQGWUDQVIHULQKLELWRU,167,
IRU DQ\OHQJWKRIWLPHLIWKHFXUUHQWUHJLPHQFRQWDLQVD3,U
 6XEMHFWVZLOOKDYHQRHYLGHQFHRISUHYLRXVYLURORJLFIDLOXUHRQD3,URU,167,EDVHG
UHJLPHQZLWKRUZLWKRXWUHVLVWDQFHWRHLWKHUFODVVRI$59
 $QHZ$,'6GHILQLQJFRQGLWLRQGLDJQRVHGZLWKLQWKHGD\VSULRUWRVFUHHQLQJ
H[FHSW &' FHOOFRXQWDQGRUSHUFHQWDJHFULWHULDUHIHUWR $SSHQGL[ 
 +HSDWLWLV&YLUXVWKDWZRXOGUHTXLUH WKHUDS\GXULQJWKHVWXG\
 3RVLWLYH+HSDWLWLV%VXUIDFHDQWLJHQ+%V$J
 6XEMHFWVZLWKFOLQLFDOHYLGHQFHRIGHFRPSHQVDWHGFLUUKRVLVDVFLWHVHQFHSKDORSDWK\
YDULFHDO EOHHGLQJ
 )HPDOHVZKRDUHEUHDVWIHHGLQJ
 3RVLWLYHVHUXPSUHJQDQF\WHVW
 +DYHDQLPSODQWHGGHILEULOODWRURUSDFHPDNHU
 &XUUHQWDOFRKRORUVXEVWDQFHXVHMXGJHGE\WKH,QYHVWLJDWRUWRSRWHQWLDOO\LQWHUIHUHZLWK
VXEMHFWVWXG\FRPSOLDQFH
 $KLVWRU\RIPDOLJQDQF\ZLWKLQWKHSDVW\HDUVSULRUWRVFUHHQLQJRURQJRLQJPDOLJQDQF\
RWKHUWKDQFXWDQHRXV.DSRVL
VVDUFRPD.6EDVDOFHOOFDUFLQRPDRUUHVHFWHGQRQLQYDVLYH
FXWDQHRXVVTXDPRXVFDUFLQRPD6XEMHFWVZLWKFXWDQHRXV.6DUHHOLJLEOHEXWPXVWQRWKDYH
UHFHLYHGDQ\V\VWHPLFWKHUDS\IRU.6ZLWKLQGD\VRI'D\YLVLW DQGPXVWQRWEH
DQWLFLSDWHGWRUHTXLUHV\VWHPLFWKHUDS\GXULQJWKHVWXG\
 $FWLYHVHULRXVLQIHFWLRQVRWKHUWKDQ+,9LQIHFWLRQUHTXLULQJSDUHQWHUDODQWLELRWLFRU
DQWLIXQJDOWKHUDS\ZLWKLQGD\VSULRUWR'D\

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PDNHWKHVXEMHFWXQVXLWDEOHIRUWKHVWXG\RUXQDEOHWRFRPSO\ZLWKGRVLQJUHTXLUHPHQWV
 3DUWLFLSDWLRQLQDQ\RWKHUFOLQLFDOWULDOLQFOXGLQJREVHUYDWLRQDOWULDOVZLWKRXWSULRUDSSURYDO
IURPWKHVSRQVRULVSURKLELWHGZKLOHSDUWLFLSDWLQJLQWKLVWULDO
 .QRZQK\SHUVHQVLWLYLW\WRWKH VWXG\GUXJWKH PHWDEROLWHVRUIRUPXODWLRQH[FLSLHQWV
 6XEMHFWVUHFHLYLQJRQJRLQJWKHUDS\ZLWKDQ\RIWKHPHGLFDWLRQVLQ7DEOH LQFOXGLQJGUXJV
QRWWREHXVHGGXHWRWKHSRWHQWLDOIRULQWHUDFWLRQZLWK 7&&2%, (9*)7&RU7$)
IRU 7&&2%,(9* RU )7&UHIHUWRWKHLQGLYLGXDODJHQWV¶3UHVFULELQJ,QIRUPDWLRQIRU
7$)UHIHUWRWKH(&)7$))'&,QYHVWLJDWRU¶V%URFKXUHRUVXEMHFWVZLWKDQ\NQRZQ
DOOHUJLHVWRWKHH[FLSLHQWVRI(&)7$))'&WDEOHWV
Table 4-2.
Disallowed Agents
Drug Class
Agents Disallowed*
$OSKD$GUHQHUJLF5HFHSWRU$QWDJRQLVWV
$OIX]RVLQ
&DOFLXP&KDQQHO%ORFNHUV
%HSULGLO
$QWLFRQYXOVDQWV
3KHQREDUELWDO3KHQ\WRLQ&DUEDPD]HSLQH
2[FDUED]HSLQH
$QWLKLVWDPLQHV
$VWHPL]ROH7HUIHQDGLQH
$QWLP\FREDFWHULDOV
5LIDPSLQ5LIDSHQWLQH5LIDEXWLQ
(UJRW'HULYDWLYHV
(UJRWDPLQH(UJRQRYLQH
'LK\GURHUJRWDPLQH
0HWK\OHUJRQRYLQH
(UJRPHWULQH
*,0RWLOLW\$JHQWV
&LVDSULGH
+HUEDO1DWXUDO6XSSOHPHQWV
6W-RKQ¶V:RUW(FKLQDFHD
+0*&R$5HGXFWDVH,QKLELWRUV
6LPYDVWDWLQ/RYDVWDWLQ
,QKDOHG%HWD$JRQLVW
6DOPHWHURO
1HXUROHSWLFV
3LPR]LGH
3KRVSKRGLHVWHUDVH,QKLELWRUV
6LOGHQDILOIRU3$+
6HGDWLYHV+\SQRWLFV
2UDOO\DGPLQLVWHUHG0LGD]RODP7ULD]RODP
*
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GXUDWLRQRIWKHVWXG\

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
6XEMHFWVZLOOEHUDQGRPL]HGLQDUDWLRWR7UHDWPHQW*URXS RU7UHDWPHQW*URXS 
5DQGRPL]DWLRQZLOOEHVWUDWLILHGE\DJH \HDUV RU\HDUV

Treatment Group 1: ,PPHGLDWHVZLWFKIURP$%&7&SOXVDWKLUGDQWLUHWURYLUDODJHQWWR
(&)7$) )'&Q DSSUR[LPDWHO\

Treatment Group 2: &RQWLQXH RQWKHFXUUHQW UHJLPHQ RI$%&7&SOXVD
WKLUG DQWLUHWURYLUDODJHQW IRUZHHNVIROORZHGE\DGHOD\HGVZLWFKWRIL[HGGRVHUHJLPHQ
FRQVLVWLQJRI(&)7$) )'& Q DSSUR[LPDWHO\
7KLVLVDQRSHQODEHOVWXG\
6XEMHFWVZLOOEHDVVLJQHGDVFUHHQLQJQXPEHUDWWKHWLPHRIFRQVHQW
2QFHHOLJLELOLW\KDVEHHQFRQILUPHGHDFKVXEMHFWZLOOEHDVVLJQHGDXQLTXHVXEMHFWQXPEHUXVLQJ
,QWHUDFWLYH:HE5HVSRQVH6\VWHP,:562QFHDVXEMHFWQXPEHUKDVEHHQDVVLJQHGLWZLOOQRW
EHUHDVVLJQHGWRDQ\RWKHUVXEMHFW7KHVXEMHFWQXPEHUDVVLJQPHQWDQG UDQGRPL]DWLRQPD\EH
SHUIRUPHGXSWR GD\VSULRUWRWKHLQFOLQLF'D\ YLVLWSURYLGHGWKDWDOO VFUHHQLQJSURFHGXUHV
KDYHEHHQFRPSOHWHGDQGVXEMHFWHOLJLELOLW\KDVEHHQFRQILUPHG
Randomization and baseline visit cannot occur until subject eligibility has been confirmed.
,:56ZLOODVVLJQRSHQODEHO VWXG\GUXJERWWOHQXPEHUVDWHDFKVWXG\YLVLW IRUVXEMHFWVLQ
7UHDWPHQW*URXS DQGDW:HHNDQGRQZDUGVIRUVXEMHFWVLQ7UHDWPHQW *URXS All Day 1
visit tests and procedures must be completed prior to the administration of the first dose of 
the study drug ,QLWLDWLRQRIWUHDWPHQWZLWKWKHVWXG\GUXJPXVWWDNHSODFHZLWKLQKRXUVDIWHU
WKH'D\ YLVLWIRU VXEMHFWVLQ 7UHDWPHQW*URXSDQGZLWKLQKRXUVDIWHUWKH:HHNYLVLWIRU
7UHDWPHQW*URXS
5.2.
Description and Handling of E/C/F/TAF FDC
5.2.1.
Formulation
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³*6,´RQRQHVLGHRIWKHWDEOHWDQG³´RQWKHRWKHUVLGHRIWKHWDEOHW(&)7$))'&WDEOHWV
FRQWDLQPJRI(9*PJRI&2%,PJRI)7&DQGPJRI7$)DVPJRI
7$)IXPDUDWH
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Treatment Assessments
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6.5.
Post-treatment Assessments
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit
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6.6.
Assessments for Premature Discontinuation from Study
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6.7.
Criteria for Discontinuation of Study Treatment
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6.8.
Other Evaluations
6.8.1.
Blood and Urine Storage
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Bone Safety and Inflammation
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Markers of Platelet Function and Coagulation
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Markers of Renal Tubular Function
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6.9.
End of Study
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Post Study Care
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6.11.
Virologic Failure
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6.11.1.
Management of Virologic Failure
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events
7.1.1.
Adverse Events
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Serious Adverse Events
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Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
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Assessment of Adverse Events and Serious Adverse Events
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Assessment of Severity
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7.3.
Investigator Requirements and Instructions for Reporting Adverse Events
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Serious Adverse Events
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Electronic Serious Adverse Event (eSAE) Reporting Process
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Gilead Reporting Requirements
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Special Situations Reports
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
7KHSULPDU\REMHFWLYHRIWKLVVWXG\LV
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UHJLPHQFRQVLVWLQJRI$%&7&SOXV DWKLUGDQWLUHWURYLUDODJHQW LQPDLQWDLQLQJ+,951$
 FRSLHVP/DW:HHNXVLQJ)'$VQDSVKRWDOJRULWKPLQYLURORJLFDOO\VXSSUHVVHG
+,9LQIHFWHGDGXOWVXEMHFWV
7KHVHFRQGDU\REMHFWLYHVRIWKLVVWXG\DUH

7RHYDOXDWH WKHSURSRUWLRQRIVXEMHFWVPDLQWDLQLQJ YLURORJLFDOUHVSRQVHGHILQHGDV
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
7RHYDOXDWHFKDQJHVIURPEDVHOLQHLQ&' FHOOFRXQWVDW:HHNVDQG

7RHYDOXDWHWKHVDIHW\DQGWROHUDELOLW\RIWKHWZRWUHDWPHQWJURXSV RYHUDQGZHHNV
8.1.2.
Primary Endpoint
7KHSULPDU\HQGSRLQWLVWKHSURSRUWLRQRIVXEMHFWVZLWK+,951$FRSLHVP/ DW:HHN
DVGHILQHGE\WKH)'$VQDSVKRWDOJRULWKP
8.1.3.
Secondary Endpoint
6HFRQGDU\HIILFDF\HQGSRLQWVDUH
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3URSRUWLRQRIVXEMHFWVZLWK+,951$FRSLHVP/ DW:HHNV  DQG DVGHILQHGE\
WKH)'$VQDSVKRWDOJRULWKP

7KHFKDQJHIURPEDVHOLQHLQ&' FHOOFRXQWVDW:HHNVDQG
8.2.
Analysis Conventions
8.2.1.
Analysis Sets

(IILFDF\
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RQHGRVHRIVWXG\GUXJ7KH)$6ZLOOH[FOXGHVXEMHFWVZLWKPDMRUSURWRFROYLRODWLRQV
HJ QRW RQWKHFRUUHFWEDVHOLQHUHJLPHQ UHJLPHQ6XEMHFWVZLOOEHJURXSHGDFFRUGLQJWRWKH
WUHDWPHQWWRZKLFKWKH\ ZHUHUDQGRPL]HG7KH)$6DQDO\VLVVHWLVWKHSULPDU\DQDO\VLVVHWIRU
WKHHIILFDF\ EDVHGDQDO\VHV

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VWXG\DQGUHFHLYHGDWOHDVW RQHGRVHRIVWXG\PHGLFDWLRQ6XEMHFWVZLOOEHJURXSHGDFFRUGLQJWR
WKHWUHDWPHQWWKH\DFWXDOO\UHFHLYHG
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8.3.
Demographic Data and Baseline Characteristics
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'HPRJUDSKLFVXPPDULHVZLOOLQFOXGHVH[UDFHHWKQLFLW\ DQGDJH
%DVHOLQHGDWDZLOOLQFOXGHDVXPPDU\RIERG\ZHLJKWKHLJKWERG\PDVVLQGH[ULVNIDFWRUVIRU
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WHVWZLOOEHXVHGWRFRPSDUHWUHDWPHQWJURXSV)RUFRQWLQXRXVGHPRJUDSKLFDQGEDVHOLQH
FKDUDFWHULVWLFVD:LOFR[RQUDQNVXPWHVWZLOOEHXVHGWRFRPSDUHWUHDWPHQWJURXSV
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
7KHQXOOK\SRWKHVLVLVWKDWWKHSURSRUWLRQRIVXEMHFWVPDLQWDLQLQJ +,951$FRSLHVP/
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6ZLWFKLVDWOHDVW ZRUVHWKDQWKHUHVSRQVHUDWHLQWKH7UHDWPHQW*URXS  'HOD\HG6ZLWFK
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WKDQWKDWLQ7UHDWPHQW*URXS 
7KHSULPDU\HYDOXDWLRQRIQRQLQIHULRULW\DW:HHNZLOOEHGRQHE\FRQVWUXFWLQJDWZRVLGHG
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WUHDWPHQW UHJLPHQXVLQJLQYHUWHGWZRRQHVLGHGWHVWVZLWKWKHVWDQGDUGL]HGVWDWLVWLF
2QFHQRQLQIHULRULW\RI7UHDWPHQW*URXS(&)7$) )'& WUHDWPHQWUHJLPHQ WR7UHDWPHQW
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8.4.2.
Secondary Analyses
7KHPHWKRGVWRDVVHVVSURSRUWLRQ RI+,951$FRSLHVP/DW:HHNV  DQG XVLQJ
)'$VQDSVKRWDQDO\VLVZLOOEHYHU\VLPLODUWRWKHSULPDU\HQGSRLQWDQDO\VLVH[FHSWWKHDQDO\VLV
ZLQGRZZLOOGLIIHUDQGWKHVHDQDO\VLVZLQGRZVZLOOEHGHILQHGLQWKH6WDWLVWLFDO$QDO\VLV3ODQ
7KHFKDQJHVIURPEDVHOLQHLQ&' FRXQWDW:HHNVDQGZLOOEHVXPPDUL]HG XVLQJ
GHVFULSWLYHVWDWLVWLFV7KHGLIIHUHQFHVLQFKDQJHVIURPEDVHOLQHEHWZHHQWKHWZRWUHDWPHQWJURXSV
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8.5.
Safety Analysis
$OOVDIHW\DQDO\VHVZLOOEHSHUIRUPHGXVLQJWKHVDIHW\DQDO\VLVVHW
$OOVDIHW\GDWDFROOHFWHGRQRUDIWHUWKHGDWHVWXG\GUXJ ZDVILUVWGLVSHQVHGXSWRWKHGDWHRIODVW
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LQFOXGHGLQGDWDOLVWLQJV
8.5.1.
Extent of Exposure
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8.5.2.
Adverse Events
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
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8.5.3.
Laboratory Evaluations
6HOHFWHGODERUDWRU\GDWD ZLOOEHVXPPDUL]HGXVLQJRQO\REVHUYHGGDWD$EVROXWH YDOXHVDQG
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RQHWR[LFLW\JUDGHIURPEDVHOLQHDWDQ\WLPHSRVWEDVHOLQHXSWRWKHGDWHRIODVWGRVHRI VWXG\
GUXJSOXVGD\VZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXS,IEDVHOLQHGDWDDUHPLVVLQJ WKHQDQ\
JUDGHGDEQRUPDOLW\LHDWOHDVWD*UDGHZLOOEHFRQVLGHUHGWUHDWPHQWHPHUJHQW
7KH PD[LPXPWR[LFLW\JUDGHZLOOEHVXPPDUL]HGE\ODERUDWRU\SDUDPHWHU
/DERUDWRU\DEQRUPDOLWLHVWKDWRFFXUEHIRUHWKHILUVWGRVHRIVWXG\GUXJRUDIWHUWKHVXEMHFWKDV
EHHQGLVFRQWLQXHGIURPWUHDWPHQWSOXVGD\VZLOOEHLQFOXGHGLQDGDWDOLVWLQJ
8.5.4.
Other Safety Evaluations
:HLJKWZLOOEHVXPPDUL]HGE\YLVLW
6DIHW\(&*VZLOOEHOLVWHGDQGVXPPDUL]HGIRUVXEMHFWVLQWKH6DIHW\$QDO\VLV6HW 7KHQXPEHU
DQGSHUFHQWRIVXEMHFWVZLWKDEQRUPDOVDIHW\(&*ZLOOEHVXPPDUL]HGE\YLVLW
8.6.
Biomarker Analysis
7KH UHQDO YDVFXODUDQGLQIODPPDWRU\PDUNHUV ZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSDQGYLVLW
XVLQJ GHVFULSWLYHVWDWLVWLFV7KHGLIIHUHQFHLQFKDQJHIURPEDVHOLQHLQWKHVHELRPDUNHUVEHWZHHQ
WZR WUHDWPHQWJURXSV ZLOOEHWHVWHGXVLQJ:LOFR[RQUDQNVXPWHVW
8.7.
Sample Size
:LWKVXEMHFWVUDQGRPL]HGWRVZLWFKWRWKH(&)7$))'&DW'D\DQGVXEMHFWV
UDQGRPL]HGWRWKHGHOD\HGVZLWFKJURXSDW:HHNWKHORZHUOLPLWRIWKHREVHUYHGRQHVLGHG
FRQILGHQFHLQWHUYDOZLOOEHH[SHFWHGWREHJUHDWHUWKDQLHQRQLQIHULRULW\PDUJLQ
RIZLWK!SRZHUZKHQWKHSHUFHQWDJHRIUHVSRQGHUVLQERWKWUHDWPHQWJURXSVIRUWKH
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
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Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
Review and Approval
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Informed Consent
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Confidentiality
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9.1.5.
Study Files and Retention of Records
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9.1.6.
Case Report Forms
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9.1.7.
Inspections
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9.1.8.
Protocol Compliance
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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
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9.2.2.
Study Report and Publications
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Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
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Access to Information for Monitoring
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Access to Information for Auditing or Inspections
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9.3.4.
Study Discontinuation
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10.
REFERENCES
13
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DGROHVFHQWVDQGDGXOWV00:555
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11.
APPENDICES
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Appendix 2.
Study Procedures Table
Study Procedure
Screeninga
Day 1b
End of Weekc
30 Day 
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Study Procedure
Screeninga
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Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
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WRPP
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3ODWHOHWV
WR PP
 WR *,/
WRPP
 WR*,/
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PP WRPP
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 WR *,/
WR *,/
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 WR  PJG/
WR PJG/
 WR PJG/
 PJG/
 WR  J/
 WR J/
WR J/
 J/
+\SHUILEULQRJHQHPLD
8/1WR PJG/
 PJG/
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WR ȝJP/
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WR PJ/
WR PJ/
WR PJ/
 PJ/
3URWKURPELQ7LPH37
WR 8/1
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WR[8/1
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 WR 8/1
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 WR 
 WR 
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3DJH 
-XO\
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
+\SRQDWUHPLD
WR//1 P(T/
WR  P(T/
WR  P(T/
P(T/
WR //1 PPRO/
WR  PPRO/
WR  PPRO/
PPRO/
+\SHUQDWUHPLD
!8/1WRP(T/
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WRP(T/
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!8/1WRPPRO/
WRPPRO/
WRPPRO/
PPRO/
+\SRNDOHPLD
Adult and Pediatric
1 Year
WR//1 P(T/
WR  P(T/
WR  P(T/
P(T/
WR //1 PPRO/
WR  PPRO/
WR  PPRO/
PPRO/
Infant <1 Year 
WRP(T/
WRPPRO/
WR  P(T/
WRPPRO/
WR  P(T/
WRPPRO/
P(T/
PPRO/
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Adult and Pediatric
1 Year
WRP(T/
WRPPRO/
WR P(T/
WR PPRO/
WR P(T/
WR PPRO/
P(T/
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Infant <1 Year
!8/1WRP(T/
!8/1WRPPRO/
!WRP(T/
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WR P(T/
WR PPRO/
P(T/
PPRO/
+\SRJO\FHPLD
Adult and Pediatric
1 Month
 WR PJG/
WR PPRO/
WR  PJG/
WR  PPRO/
WR  PJG/
WR  PPRO/
PJG/
PPRO/
Infant, 1 Month
WR PJG/
WR PPRO/
WR PJG/
WR PPRO/
WR PJG/
WR PPRO/
PJG/
PPRO/
+\SHUJO\FHPLD1RQIDVWLQJ
 WR PJG/
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WR PPRO/
WR PPRO/
WR PPRO/
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WRPJG/
WRPPRO/
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!WRPJG/
!WRPPRO/
!PJG/
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(9*&2%,)7&7$)
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-XO\
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
+\SRFDOFHPLD
FRUUHFWHGIRUDOEXPLQ LI
DSSURSULDWH
Adult and Pediatric
2 Years
//1PJG/
WR//1 PPRO/
WR PJG/
WR PPRO/
WR  PJG/
WR PPRO/
 PJG/
 PPRO/
Pediatric ≥7 days -2 Years
WRPJG/
WRPPRO/
WRPJG/
WRPPRO/
WRPJG/
WRPPRO/
PJG/
PPRO/
Infant, 7 Days
WRPJG/
WRPPRO/
WRPJG/
WRPPRO/
WRPJG/
WRPPRO/
PJG/
PPRO/
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Adult and Pediatric 7 Days
!8/1 WRPJG/
WRPJG/
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!8/1WRPPRO/
WRPPRO/
WRPPRO/
PPRO/
Infant, 7 Days
WRPJG/
WRPPRO/
WRPJG/
!WRPPRO/
WRPJG/
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+\SRFDOFHPLDLRQL]HG
PJG/WR //1
WRPJG/
WR PJG/
PJG/
PPRO/WR //1
WR PPRO/
WR PPRO/
PPRO/
+\SHUFDOFHPLDLRQL]HG
8/1WRPJG/
WRPJG/
WRPJG/
PJG/
8/1WRPPRO/
WRPPRO/
WRPPRO/
PPRO/
+\SRPDJQHVHPLD
WR //1PJG/
WR//1 P(T/
WR PJG/
WRP(T/
WR PJG/
WRP(T/
PJG/
P(T/
WR //1 PPRO/
WR PPRO/
WR PPRO/
PPRO/

(9*&2%,)7&7$)
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3DJH 
-XO\
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
+\SRSKRVSKDWHPLD
Adult and Pediatric
14 Years
WR//1PJG/
WR//1PPRO/
WR PJG/
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WR PPRO/
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Pediatric 1 Year–14 Years 
WR//1 PJG/
WR//1 PPRO/
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WR  PPRO/
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Pediatric 1 Year
WR//1 PJG/
WR//1 PPRO/
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 WR  PPRO/
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WRPPRO/
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Adult and Pediatric > 14 Days
WR8/1
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Infant, 14 Days
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Infant, 14 Days
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!8/1 WRPJG/
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!8/1 WRȝPRO/
WRȝPRO/
WRȝPRO/
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(9*&2%,)7&7$)
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3DJH 
-XO\
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
+\SRXULFHPLD
Adult and Pediatric           
≥ 1 year
Infant  < 1 Year
PJG/WR //1
ȝPRO/WR //1
WR PJG/
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WR PJG/
WR ȝPRO/
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 WRPJG/
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 WR ȝPRO/
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Adult and Pediatric 
≥ 4 Years
 P(T/WR //1
WR P(T/
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WR PPRO/
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Pediatric < 4 Years
1$
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PPRO/WR//1
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7ULJO\FHULGHV
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3HGLDWULF!WR\HDUV
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
+\SHUFKROHVWHUROHPLD
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WRPJG/
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WRPPRO/
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Pediatric 18 Years
WRPJG/
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WRPJG/
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PPRO/
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
$676*27
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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
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2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
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b) Contraception Requirements for Female Subjects of Childbearing Potential
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3) Contraception Requirements for Male Subjects
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4) Unacceptable Birth Control Methods
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