A Phase 3b, 2-part, Randomized, Double-blind, Placebo-controlled Crossover Study With a Long-term Open-label Period to Investigate Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation
Phase: PHASE3
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated



3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

2 
PROTOCOL SYNOPSIS
Title
$3KDVHESDUW5DQGRPL]HG'RXEOHEOLQG3ODFHERFRQWUROOHG&URVVRYHU6WXG\
:LWKD/RQJWHUP2SHQODEHO3HULRGWR,QYHVWLJDWH,YDFDIWRULQ6XEMHFWV:LWK&\VWLF
)LEURVLV$JHG7KURXJK<HDUV:KR+DYHD6SHFLILHGCFTR*DWLQJ0XWDWLRQ

Brief Title
$6WXG\WR(YDOXDWH(IILFDF\DQG6DIHW\RI,YDFDIWRULQ6XEMHFWV:LWK&\VWLF)LEURVLV
$JHG7KURXJK<HDUV:KR+DYHD6SHFLILHGCFTR*DWLQJ0XWDWLRQ

Clinical Phase and 
Clinical Study Type 
3KDVHEHIILFDF\DQGVDIHW\

Objectives
3ULPDU\2EMHFWLYH
7RHYDOXDWHWKHHIILFDF\RILYDFDIWRUWUHDWPHQWDVPHDVXUHGE\OXQJFOHDUDQFHLQGH[
/&,LQVXEMHFWVZLWKF\VWLFILEURVLV&)ZKRKDYHDVSHFLILHG&)WUDQVPHPEUDQH
FRQGXFWDQFHUHJXODWRUCFTRJDWLQJPXWDWLRQDQGDUHWKURXJK\HDUVRIDJHDWWKH
VWDUWRIWKHVWXG\
6HFRQGDU\2EMHFWLYHV
7RHYDOXDWHWKHIROORZLQJLQVXEMHFWVZLWK&)ZKRKDYHDVSHFLILHGCFTRJDWLQJ
PXWDWLRQDQGDUHWKURXJK\HDUVRIDJHDWWKHVWDUWRIWKHVWXG\

x 'LVHDVHSURJUHVVLRQDVPHDVXUHGE\FKDQJHVLQSDQFUHDWLFIXQFWLRQ
x 7KHVDIHW\RILYDFDIWRUWUHDWPHQW

Endpoints
Part 1 Endpoints
3ULPDU\(QGSRLQW
$EVROXWHFKDQJHIURPEDVHOLQHLQ/&, WKURXJKZHHNVRIWUHDWPHQW
6HFRQGDU\(QGSRLQWV
x $EVROXWHFKDQJHIURPEDVHOLQHLQVHUXPOHYHOVRILPPXQRUHDFWLYHWU\SVLQRJHQDW
ZHHNVRIWUHDWPHQW
x $EVROXWHFKDQJHIURPEDVHOLQHLQIHFDOHODVWDVHDWZHHNVRIWUHDWPHQW
x $EVROXWHFKDQJHIURPEDVHOLQHLQZHLJKWDWZHHNVRIWUHDWPHQW
x $EVROXWHFKDQJHIURPEDVHOLQHLQERG\PDVVLQGH[%0,DWZHHNVRIWUHDWPHQW
x 6DIHW\DVGHWHUPLQHGE\$(VFOLQLFDOODERUDWRU\YDOXHVLQFOXGLQJ/)7V
RSKWKDOPRORJLFH[DPLQDWLRQV2(VSK\VLFDOH[DPLQDWLRQVDQGYLWDOVLJQV








Part 2 Endpoints


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

SULRUWRWKHLQLWLDODGPLQLVWUDWLRQRIVWXG\GUXJLQ7UHDWPHQW3HULRG
x 3HULRGEDVHOLQHLVGHILQHGDVWKHPRVWUHFHQWQRQPLVVLQJPHDVXUHPHQWFROOHFWHG
EHIRUHWKHLQLWLDODGPLQLVWUDWLRQRIVWXG\GUXJLQHDFK7UHDWPHQW3HULRG
,Q3DUWWKHSULPDU\HIILFDF\YDULDEOHLVWKHDEVROXWHFKDQJHIURPEDVHOLQHWKURXJK
ZHHNVRIWUHDWPHQWLQ/&,HQGSRLQW7KHDQDO\VLVZLOOEHEDVHGRQDPL[HGHIIHFWV
PRGHOIRUUHSHDWHGPHDVXUHVXWLOL]LQJWKH)XOO$QDO\VLV6HW7KHPRGHOZLOOLQFOXGH
WKHDEVROXWHFKDQJHIURPVWXG\EDVHOLQHLQHDFKSHULRGDVWKHGHSHQGHQWYDULDEOH
VHTXHQFHWUHDWPHQWSHULRGDQGYLVLWZLWKLQSHULRGDVIL[HGHIIHFWV/&,EDVHOLQHDQG
DJHDVFRYDULDWHVDQGVXEMHFWQHVWHGZLWKLQVHTXHQFHDVWKHUDQGRPHIIHFW
8QVWUXFWXUHGFRYDULDQFHPDWUL[LVIXUWKHUDVVXPHGIRUWKHUHSHDWHGPHDVXUHPHQWVRI
WKHVDPHVXEMHFWZLWKLQHDFKSHULRG
(IILFDF\DQDO\VHVZLOOEHEDVHGRQFKDQJHIURPVWXG\EDVHOLQHKRZHYHUHIILFDF\
DQDO\VHVEDVHGRQFKDQJHIURPSHULRGEDVHOLQHZLOODOVREHSUHVHQWHG
%HFDXVHRIWKHORZH[SHFWHGSRZHUD%D\HVLDQDQDO\VLVPD\EHSHUIRUPHG7KH
DQDO\VLVZLOOFRPSXWHWKHSRVWHULRUSUREDELOLW\WKDWWKHWUHDWPHQWGLIIHUHQFHLVJUHDWHU
WKDQEDVHGRQDQRQLQIRUPDWLYHSULRUGLVWULEXWLRQ7KHUHDUHQRVSHFLILFVXFFHVV
FULWHULDGXHWRWKHORZVXEMHFWQXPEHUVDYDLODEOHIRUDQDO\VLV
'DWDFROOHFWHGIURPVXEMHFWVLQ3DUWZLOOEHSUHVHQWHGLQVXEMHFWOLVWLQJV6XPPDU\
VWDWLVWLFVPD\DOVREHSURYLGHG

IDMC Reviews
$Q,QGHSHQGHQW'DWD0RQLWRULQJ&RPPLWWHH,'0&ZLOOEHIRUPHGIRUWKLVVWXG\
7KH,'0&ZLOOFRQGXFWUHJXODUSODQQHGUHYLHZVRIVWXG\GDWDGXULQJ3DUWZLWKWKH
SULPDU\JRDORIHYDOXDWLQJWKHVDIHW\RIWKHVWXG\GUXJUHJLPHQWRHQVXUHWKHVXEMHFWV

VDIHW\3URFHGXUDOGHWDLOVRIWKH,'0&
VVWUXFWXUHDQGIXQFWLRQIUHTXHQF\RI
PHHWLQJVDQGGDWDSODQQHGIRUUHYLHZZLOOEHLQFOXGHGLQWKH,'0&&KDUWHU7KH
,'0&&KDUWHUZDVILQDOL]HGEHIRUHWKHILUVWVXEMHFWZDVHQUROOHGLQWKHVWXG\7KH
,'0&&KDUWHUZLOOEHXSGDWHGIROORZLQJDSSURYDORIWKHSURWRFRODPHQGPHQWWR
UHIOHFWFKDQJHVLPSDFWHGE\WKHGHFLVLRQWRWHUPLQDWHWKHVWXG\HDUO\

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

3 
SCHEDULE OF ASSESSMENTS
Table 3-1 
Study VX15-770-123: Screening
Event/Assessment
Screening Period 
(Day -28 to Day -1)a
&OLQLFYLVLW
;
,QIRUPHGFRQVHQWDVVHQW
;
,QFOXVLRQH[FOXVLRQFULWHULDUHYLHZ
;
'HPRJUDSK\
;
CFTRJHQRW\SHE
;
0HGLFDOKLVWRU\
;
3ULRUDQGFRQFRPLWDQWPHGLFDWLRQV
;
+HLJKWDQGZHLJKW
;
3K\VLFDOH[DPLQDWLRQDQGYLWDOVLJQVF
;
0XOWLSOHEUHDWKZDVKRXWG
;
&RDJXODWLRQ
;
6HUXPFKHPLVWU\
;
+HPDWRORJ\
;
8ULQDO\VLV
;
2SKWKDOPRORJLFH[DPLQDWLRQVH
;
,PPXQRUHDFWLYHWU\SVLQRJHQI
;
)HFDOVDPSOHFROOHFWLRQJ
;
$GYHUVHHYHQWV
&RQWLQXRXVIURPVLJQLQJRI,&)WKURXJK
HQGRIVWXG\SDUWLFLSDWLRQ

D
$OO6FUHHQLQJDVVHVVPHQWVPXVWEHFRPSOHWHGEHIRUHWKH'D\9LVLW6XEMHFWVPD\EHUHVFUHHQHGDIWHU
GLVFXVVLRQZLWKDQGDSSURYDOIURPWKH9HUWH[PHGLFDOPRQLWRURUDXWKRUL]HGGHVLJQHHVHH6HFWLRQ
E
CFTRJHQRW\SLQJZLOOEHSHUIRUPHGWRFRQILUPWKDWWKHVXEMHFWKDVWKHG551D, G178R, S549N, S549R, G551S, 
G1244E, S1251N, S1255P, RUG1349DPXWDWLRQLQDWOHDVWCFTRDOOHOHWRPHHWLQFOXVLRQFULWHULD5HVXOWVRI
WKHJHQRW\SLQJVKRXOGEHFRQILUPHGGXULQJWKH6FUHHQLQJ3HULRG,IWKHCFTRVFUHHQLQJJHQRW\SHUHVXOWLVQRW
UHFHLYHGEHIRUHUDQGRPL]DWLRQDSUHYLRXVCFTRJHQRW\SHODEUHSRUWPD\EHXVHGWRHVWDEOLVKHOLJLELOLW\
Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be 
discontinued from the study
F
6HH6HFWLRQ
G
6XEMHFWVPXVWFRPSOHWHWKHPXOWLSOHEUHDWKZDVKRXW0%:DVVHVVPHQWDW6FUHHQLQJ7KHVXEMHFWZLOOEH
FRQVLGHUHGDVFUHHQIDLOXUHLIWKH0%:DVVHVVPHQWFDQQRWEHSHUIRUPHGLHLIWHFKQLFDOO\DFFHSWDEOH0%:
WHVWVDUHQRWDFKLHYHGDWWKH6FUHHQLQJ9LVLWRU5HVFUHHQLQJ9LVLWVHH6HFWLRQ$WOHDVW0%:WHVWV
ZLOOEHSHUIRUPHGVHH6HFWLRQDQGWKH6WXG\5HIHUHQFH0DQXDO
H
$Q2(ZLOOEHFRQGXFWHGE\DOLFHQVHGRSKWKDOPRORJLVWRURSWRPHWULVW6HFWLRQ7KHH[DPLQDWLRQGRHV
QRWQHHGWREHUHSHDWHGLIWKHUHLVGRFXPHQWDWLRQRIDQ2(PHHWLQJSURWRFROFULWHULDWKDWZDVFRQGXFWHGZLWKLQ
PRQWKVEHIRUHWKH6FUHHQLQJ9LVLW6XEMHFWVZLWKGRFXPHQWDWLRQRIELODWHUDOOHQVUHPRYDOGRQRWQHHGWKH2(
I
$EORRGVDPSOHIRULPPXQRUHDFWLYHWU\SVLQRJHQDVVHVVPHQWZLOOEHFROOHFWHG
J
$VWRROVDPSOHIRUIHFDOHODVWDVH
DQDO\VLVZLOOEHFROOHFWHGVHH6HFWLRQV

IRUGHWDLOV7KHVWRROVDPSOHWREHFROOHFWHGDW6FUHHQLQJPD\EHFROOHFWHGDWDQ\WLPH
IURP6FUHHQLQJXQWLOEHIRUHWKHILUVWGRVHDW'D\

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

Table 3-2 
Study VX15-770-123: Part 1 and Part 2 
Part 1 Placebo-controlled Crossover Perioda
Part 2 Open-label Perioda
(Wk 24 to Wk 144)
Treatment 
Period 1
(Day 1 to 
Wk 8)
Wash-
out
Treatment Period 2 
(Wk 16 to Wk 24)
Event/
Assessment
Day 1
Wk 4 
(r 3
days)
Wk 8 
(r 5
days)
8 Wks
(r 5
days)
Wk 16 
(r 3
days)
Wk 20
(r 3
days)
Wk 24
(r 5
days)
Wk 36
(r 2
wks)
Wk 48
(r 2
wks)
Wk 60
(r 2
wks)
Wk 72
(r 2
wks)
Wk 84
(r 2
wks)
Wk 96
(r 2
wks)
Wk 108
(r 2
wks)
Wk 120
(r 2
wks)
Wk 132
(r 2
wks)
Wk 144
(r 2
wks)
&OLQLFYLVLW
;
;
;

;
;
;
;
;
;
;
;
;
;
;
;
;
,QFOXVLRQH[FOXVLRQ
FULWHULDUHYLHZ
;
















5DQGRPL]DWLRQE
;
















&RQFRPLWDQW
PHGLFDWLRQV
;
;
;

;
;
;
;
;
;
;
;
;
;
;
;
;
&RQFRPLWDQW
WUHDWPHQWVDQG
SURFHGXUHV
;
;
;

;
;
;
;
;
;
;
;
;
;
;
;
;
+HLJKWDQGZHLJKW
;

;

;

;
;
;
;
;
;
;
;
;
;
;
0XOWLSOHEUHDWK
ZDVKRXWF
;
;
;

;
;
;

;



;



;

1RWHV6XEMHFWVPD\FRPSOHWHWKHLUDVVHVVPHQWVRYHUDSHULRGRIGD\VDWWKH'D\DQG:HHN9LVLWV2QWKH'D\:HHNDQG:HHN9LVLWVDOO
DVVHVVPHQWVPXVWEHFRPSOHWHGEHIRUHGRVLQJZLWKVWXG\GUXJ6\PSWRPGLUHFWHGSK\VLFDOH[DPLQDWLRQVDQGV\PSWRPGLUHFWHGYLWDOVLJQVFDQEHSHUIRUPHG
LIGHHPHGQHFHVVDU\E\WKHLQYHVWLJDWRURUKHDOWKFDUHSURYLGHUVHH6HFWLRQ

D
6XEMHFWVZKRSUHPDWXUHO\GLVFRQWLQXHVWXG\GUXJWUHDWPHQWIRUDQ\UHDVRQRWKHUWKDQHDUO\VWXG\WHUPLQDWLRQZLOOXQGHUJRWKHOLVWHGDVVHVVPHQWVDWWKHLU
(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWVHH7DEOHZKLFKLVWREHVFKHGXOHGDVVRRQDVSRVVLEOHDIWHUWKHVXEMHFWGHFLGHVWRWHUPLQDWHVWXG\GUXJ
WUHDWPHQW6XEMHFWVZKRSUHPDWXUHO\GLVFRQWLQXHWUHDWPHQWZLOODOVREHUHTXLUHGWRFRPSOHWHWKH6DIHW\)ROORZXS9LVLWDSSUR[LPDWHO\ZHHNVGD\V
DIWHUWKHLUODVWGRVHRIVWXG\GUXJ,IWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWRFFXUVZHHNVRUODWHUIROORZLQJWKHODVWGRVHRIVWXG\GUXJWKHQWKH(DUO\
7HUPLQDWLRQRI7UHDWPHQW9LVLWZLOOUHSODFHWKH6DIHW\)ROORZXS9LVLWDQGDVHSDUDWH6DIHW\)ROORZXS9LVLWZLOOQRWEHUHTXLUHGVHH6HFWLRQ
E
5DQGRPL]DWLRQZLOORFFXUDIWHUDOOLQFOXVLRQDQGH[FOXVLRQFULWHULDDUHPHW,IWKHVFUHHQLQJJHQRW\SHUHVXOWLVQRWUHFHLYHGEHIRUHUDQGRPL]DWLRQDSUHYLRXV
CFTRJHQRW\SHODEUHSRUWPD\EHXVHGWRHVWDEOLVKHOLJLELOLW\Subjects who have been randomized on the basis of a historical genotype lab report and 
whose screening genotype does not confirm study eligibility must be discontinued from the study
F
$WOHDVW0%:WHVWVZLOOEHSHUIRUPHGVHH6HFWLRQDQGWKH6WXG\5HIHUHQFH0DQXDO




3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

Table 3-2 
Study VX15-770-123: Part 1 and Part 2 
Part 1 Placebo-controlled Crossover Perioda
Part 2 Open-label Perioda
(Wk 24 to Wk 144)
Treatment 
Period 1
(Day 1 to 
Wk 8)
Wash-
out
Treatment Period 2 
(Wk 16 to Wk 24)
Event/
Assessment
Day 1
Wk 4 
(r 3
days)
Wk 8 
(r 5
days)
8 Wks
(r 5
days)
Wk 16 
(r 3
days)
Wk 20
(r 3
days)
Wk 24
(r 5
days)
Wk 36
(r 2
wks)
Wk 48
(r 2
wks)
Wk 60
(r 2
wks)
Wk 72
(r 2
wks)
Wk 84
(r 2
wks)
Wk 96
(r 2
wks)
Wk 108
(r 2
wks)
Wk 120
(r 2
wks)
Wk 132
(r 2
wks)
Wk 144
(r 2
wks)
0HDORUVQDFNDW
VWXG\FHQWHUL
;
;
;

;
;
;

;



;



;
6WXG\GUXJGRVLQJ
DWVWXG\YLVLWL
;
;
Xj

;
;
Xk

;



;



;
'LVSHQVHVWXG\
GUXJO
;
;


;
;
;
;
;
;
;
;
;
;
;
;

6WXG\GUXJFRXQW
;
;
;

;
;
;
;
;
;
;
;
;
;
;
;
;
$GYHUVHHYHQWV
&RQWLQXRXVIURPVLJQLQJRI,&)WKURXJKHQGRIVWXG\SDUWLFLSDWLRQ


L
6WXG\GUXJSODFHERRU.DO\GHFRZLOOEHDGPLQLVWHUHGIURP'D\WRWKHGRVHEHIRUHWKHSODQQHG:HHN9LVLW6WXG\GUXJVKRXOGEHDGPLQLVWHUHGHYHU\
KRXUVZLWKIDWFRQWDLQLQJIRRGVHH6HFWLRQ$WWKHVFKHGXOHGYLVLWVLQGLFDWHGWKLVPHDORUVQDFNZLOOEHSURYLGHGDWWKHFOLQLFWRVXEMHFWVDIWHUDOO
SUHGRVHDVVHVVPHQWVKDYHRFFXUUHG$OWKRXJKVXEMHFWVZLOOQRWEHGRVHGZLWKVWXG\GUXJDWWKH:HHNRU:HHN9LVLWVDPHDORUVQDFNZLOOEH
SURYLGHG$OOVXEMHFWVZLOOEHWUHDWHGZLWK.DO\GHFRGXULQJ3DUW
M
6WXG\GUXJZLOOQRWEHDGPLQLVWHUHGDWWKH:HHN9LVLWRI7UHDWPHQW3HULRG7KHODVWGRVHRIVWXG\GUXJLQ7UHDWPHQW3HULRGLVWKHGRVHRIVWXG\GUXJ
EHIRUHWKH:HHN9LVLW
N
7KHILUVWGRVHRI.DO\GHFRLQWKH2SHQODEHO3HULRGZLOOEHDGPLQLVWHUHGDWWKH:HHN9LVLW.DO\GHFRGRVLQJZLOOFRQWLQXHWRWKHGRVHEHIRUHWKHSODQQHG
:HHN9LVLW
O
6WXG\GUXJZLOOEHDVVLJQHGWKURXJKDQLQWHUDFWLYHYRLFHRUZHEUHVSRQVHV\VWHP

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

 ,QYHVWLJDWRU6LJQDWXUH3DJH 

List of Tables
7DEOH 
6WXG\9;6FUHHQLQJ 
7DEOH 
6WXG\9;3DUWDQG3DUW 
7DEOH 
6WXG\9;(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLW6DIHW\)ROORZXS
9LVLWDQG)ROORZXS7HOHSKRQH&RQWDFW 
7DEOH 
,GHQWLW\RI6WXG\'UXJV 
7DEOH 
6DIHW\/DERUDWRU\7HVW3DQHOV 
7DEOH 
6DPSOH6L]H&DOFXODWLRQ&RUUHVSRQGLQJWR'LIIHUHQW9DOXHVRI7UHDWPHQW(IIHFW
RQ/XQJ&OHDUDQFH,QGH[&KDQJH)URP3UHGRVH 
7DEOH 
*UDGLQJRI$(6HYHULW\ 
7DEOH 
&ODVVLILFDWLRQVIRU$(&DXVDOLW\ 
7DEOH 
&ODVVLILFDWLRQVIRU6WXG\'UXJ$FWLRQ7DNHQ:LWK5HJDUGWRDQ$( 
7DEOH 
&ODVVLILFDWLRQVIRU2XWFRPHRIDQ$( 
List of Figures
)LJXUH 
6FKHPDWLFRI6WXG\'HVLJQ9; 


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

5 
INTRODUCTION
5.1
Overview of Cystic Fibrosis 
&\VWLFILEURVLV&)LVDFKURQLFDOO\GHELOLWDWLQJDXWRVRPDOUHFHVVLYHGLVHDVHZLWKKLJKPRUELGLW\
DQGSUHPDWXUHPRUWDOLW\WKDWDIIHFWVDSSUR[LPDWHO\LQGLYLGXDOVLQWKH8QLWHG6WDWHVDQG
LQWKH(XURSHDQ8QLRQ(87KHGLVHDVHDIIHFWVSUHGRPLQDWHO\:KLWHVDQGLVFDXVHG
E\PXWDWLRQVLQWKH&)WUDQVPHPEUDQHFRQGXFWDQFHUHJXODWRUJHQHCFTRZKLFKUHVXOWVLQ
DEVHQWRUGHILFLHQWIXQFWLRQRIWKH&)75SURWHLQDWWKHFHOOVXUIDFH&)75LVDQHSLWKHOLDO
FKORULGHFKDQQHOUHVSRQVLEOHIRUDLGLQJLQWKHUHJXODWLRQRIVDOWDQGZDWHUDEVRUSWLRQDQG
VHFUHWLRQLQYDULRXVWLVVXHV7KHIDLOXUHWRUHJXODWHFKORULGHWUDQVSRUWLQWKHVHWLVVXHVUHVXOWVLQ
WKHPXOWLV\VWHPSDWKRORJ\DVVRFLDWHGZLWK&),QWKHOXQJVREVWUXFWLRQRIDLUZD\VZLWKWKLFN
PXFXVHVWDEOLVKPHQWRIDFKURQLFEDFWHULDOLQIHFWLRQLQWKHDLUZD\VDQGGDPDJLQJLQIODPPDWRU\
UHVSRQVHVDUHDOOWKRXJKWWRSOD\DUROHLQFDXVLQJLUUHYHUVLEOHVWUXFWXUDOFKDQJHVLQWKHOXQJVDQG
UHVSLUDWRU\IDLOXUH3URJUHVVLYHORVVRIOXQJIXQFWLRQLVWKHOHDGLQJFDXVHRIPRUWDOLW\
&XUUHQWO\WKHUHLVQRFXUHIRU&)DQGGHVSLWHDGMXQFWLYHWUHDWPHQWVZLWKQXWULWLRQDO
VXSSOHPHQWVDQWLELRWLFVDQGPXFRO\WLFVWKHPHGLDQSUHGLFWHGDJHRIVXUYLYDORILQGLYLGXDOV
ERUQWRGD\ZLWK&)LVDSSUR[LPDWHO\\HDUVRIDJH
0RUHWKDQPXWDWLRQVLQWKHCFTRJHQHKDYHEHHQLGHQWLILHG$QDO\VLVRICFTR JHQH
PXWDWLRQVVXJJHVWVWKDWLPSDLUHG&)75SURWHLQIXQFWLRQLQDLUZD\HSLWKHOLDLVKLJKO\FRUUHODWHG
ZLWKVHYHULW\RIOXQJGLVHDVHLQSDWLHQWVZLWK&)DQGVXSSRUWVWKHK\SRWKHVLVWKDWUHVWRUDWLRQRI
&)75SURWHLQDFWLYLW\ZRXOGVWRSRUVORZWKHGHFOLQHLQOXQJIXQFWLRQDQGH[WHQGOLIH
H[SHFWDQF\7KHPRVWSUHYDOHQWPXWDWLRQLVDQLQIUDPHGHOHWLRQUHVXOWLQJLQDORVVRI
SKHQ\ODODQLQHF508del-CFTR:KLOHWKHSUHGRPLQDQWHIIHFWRIWKHF508delJHQH
PXWDWLRQLVDVHYHUHGHFUHDVHLQWKHDPRXQWRI&)75WUDIILFNHGWRWKHFHOOVXUIDFHWKHPXWDWLRQ
DOVRUHVXOWVLQGHIHFWLYH&)75FKDQQHORSHQLQJ$GHIHFWLQFKDQQHORSHQLQJLVDOVRD
FKDUDFWHULVWLFRIG551D-CFTRDPLVVHQVHPXWDWLRQWKDWUHVXOWVLQWKHUHSODFHPHQWRIDJO\FLQH
UHVLGXHDWSRVLWLRQRI&)75ZLWKDQDVSDUWLFDFLGUHVLGXHEXWXQOLNH)GHO&)75
*'&)75LVGHOLYHUHGWRWKHFHOOVXUIDFHLQQRUPDODPRXQWVCFTRJHQHPXWDWLRQVOLNH
G551DLQZKLFKWKHSULPDU\GHIHFWLVUHGXFHGFKDQQHORSHQLQJDUHNQRZQDVCFTRJDWLQJ
PXWDWLRQVCFTRJDWLQJPXWDWLRQVFDQEHGHILQHGDVCFTRPXWDWLRQVWKDWUHVXOWLQWKH
SURGXFWLRQRID&)75SURWHLQIRUZKLFKWKHSUHGRPLQDQWGHIHFWLVDORZFKDQQHORSHQ
SUREDELOLW\FRPSDUHGWRQRUPDO&)75
2QHDSSURDFKWRLQFUHDVLQJWKHOHYHORIFKORULGHWUDQVSRUWWKURXJKWKH&)75FKDQQHOVLVWRWUHDW
ZLWKDSRWHQWLDWRUDFRPSRXQGWKDWLQFUHDVHVWKHFKDQQHOJDWLQJDFWLYLW\RI&)75SURWHLQ
ORFDWHGDWWKHFHOOVXUIDFHUHVXOWLQJLQLQFUHDVHGFKORULGHWUDQVSRUW3RWHQWLDWRUVUHSUHVHQWD
WKHUDSHXWLFVWUDWHJ\WRWUHDW&)$PRGHVWUHVWRUDWLRQRIFKORULGHVHFUHWLRQWKURXJKWKHDFWLRQRI
DSRWHQWLDWRUFRXOGSUHYHQWWKHK\SHUDEVRUSWLRQRIZDWHUDFURVVWKHDSLFDOVXUIDFHRIHSLWKHOLDO
FHOOVDOORZLQJIRUSURSHUPDLQWHQDQFHRIDLUZD\K\GUDWLRQ$GHTXDWHDLUZD\K\GUDWLRQFRXOG
DOOHYLDWHWKHF\FOHRIPXFXVSOXJJLQJLQIHFWLRQDQGLQIODPPDWLRQWKDWOHDGVWRLUUHYHUVLEOH
VWUXFWXUDOFKDQJHVLQWKHOXQJVDQGHYHQWXDOO\UHVSLUDWRU\IDLOXUHIRUSDWLHQWVZLWK&)
5.2
Overview of Ivacaftor
,YDFDIWRU.DO\GHFRLVDQRUDOO\DGPLQLVWHUHG&)75SRWHQWLDWRUWKDWLQFUHDVHVWKH
FKDQQHORSHQSUREDELOLW\RI&)75SURWHLQWRHQKDQFHFKORULGHWUDQVSRUWZKLFK\LHOGVFOLQLFDO
EHQHILWLQSDWLHQWVZLWK&)*OREDOO\.DO\GHFRLVLQGLFDWHGIRUWKHWUHDWPHQWRI&)LQSDWLHQWVDV

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

\RXQJDV\HDUVZKRKDYHWKHG551DDQGFHUWDLQRWKHUJDWLQJPXWDWLRQVDVZHOOWKHR117H
PXWDWLRQLQWKHCFTRJHQHGHSHQGLQJRQWKHFRXQWU\
5HVXOWVIURP3KDVHVWXGLHV9;>6WXG\@DQG9;>6WXG\@
VKRZHGWKDWLYDFDIWRULVHIIHFWLYHLQWKHWUHDWPHQWRIVXEMHFWVZLWK&)DQGWKH
G551D-CFTRPXWDWLRQDJHG\HDUVDQGROGHUDVHYLGHQFHGE\VXVWDLQHGLPSURYHPHQWVLQ
&)75FKDQQHOIXQFWLRQPHDVXUHGE\UHGXFWLRQLQVZHDWFKORULGHFRQFHQWUDWLRQDQG
FRUUHVSRQGLQJVXEVWDQWLDOGXUDEOHLPSURYHPHQWVLQOXQJIXQFWLRQSXOPRQDU\H[DFHUEDWLRQV
UHVSLUDWRU\V\PSWRPVDQGZHLJKWJDLQ,YDFDIWRUZDVDOVRZHOOWROHUDWHGDVHYLGHQFHGE\WKH
UDWHVDQGUHDVRQVIRUSUHPDWXUHGLVFRQWLQXDWLRQDQGUHVXOWVRIVDIHW\DVVHVVPHQWV6LPLODUUHVXOWV
ZHUHREVHUYHGLQ6WXG\9;6WXG\LQVXEMHFWVZLWK&)DJHG\HDUVDQGROGHU
ZLWKRQHRIWKHIROORZLQJCFTRJDWLQJPXWDWLRQVG1244E, G1349D, G178R, G551S, S1251N, 
S1255P, S549N, RUS549R. 5HVXOWVIURP6WXG\9;6WXG\GHPRQVWUDWHGWKDW
VXEMHFWVZLWK&)DJHG\HDUVDQGROGHUZKRZHUHWUHDWHGZLWKLYDFDIWRUFDQVKRZLPSURYHPHQWV
LQOXQJIXQFWLRQDVPHDVXUHGE\OXQJFOHDUDQFHLQGH[/&,
$3KDVHVWXG\9;>6WXG\@ZDVFRQGXFWHGWRHYDOXDWHWKHVDIHW\
SKDUPDFRNLQHWLFV3.DQGSKDUPDFRG\QDPLFVRILYDFDIWRUDQGPJGRVHVLQVXEMHFWV
ZLWK&)DJHGWKURXJK\HDUVZLWKDCFTRJDWLQJPXWDWLRQ7KHVDIHW\UHVXOWVGHPRQVWUDWHG
WKDWLYDFDIWRUZDVZHOOWROHUDWHGLQVXEMHFWVWKH3.SURILOHRIWKHDQGPJGRVHVRI
LYDFDIWRUZDVVLPLODUWRWKDWRIWKHPJGRVHRILYDFDIWRULQDGXOWVWKHUHE\GHPRQVWUDWLQJQR
VLJQLILFDQWGLIIHUHQFHVLQH[SRVXUHDQGWKHUHZHUHFOLQLFDOO\UHOHYDQWLPSURYHPHQWVLQVZHDW
FKORULGHSKDUPDFRG\QDPLFPHDVXUHQXWULWLRQDOVWDWXVDQGSDQFUHDWLFIXQFWLRQWKURXJKRXWD
ZHHNWUHDWPHQWSHULRG7KHVHSRVLWLYHVDIHW\3.DQGHIILFDF\UHVXOWVZHUHVXVWDLQHGRYHUDQ
DGGLWLRQDOZHHNVRIWUHDWPHQWZLWKLYDFDIWRULQRSHQODEHOUROORYHU6WXG\9;DQG
HIILFDF\PHDVXUHVUHPDLQHGDERYHWKH6WXG\EDVHOLQHWKURXJKRXWWKHGXUDWLRQRIWKDWVWXG\
7RJHWKHUWKHVHGDWDVXSSRUWWKHXVHRILYDFDIWRULQFKLOGUHQWKURXJK\HDUVRIDJHZLWK&)
5.3
Rationale for Present Study
7KHPDQLIHVWDWLRQVRI&)EHJLQDVHDUO\DVLQIDQF\LQFOXGLQJDLUZD\LQIODPPDWLRQJURZWK
LPSDLUPHQWDQGHYLGHQFHRIVWUXFWXUDOOXQJGDPDJHWKDWSUHFHGHVDORVVRISXOPRQDU\IXQFWLRQ
DVPHDVXUHGE\IRUFHGH[SLUDWRU\YROXPHLQVHFRQG)(9:LWKRXWHDUO\LQWHUYHQWLRQ&)LQ
\RXQJSDWLHQWVZLOOOHDGWRSURJUHVVLYHDQGLQVRPHFDVHVLUUHYHUVLEOHGHFOLQHLQQXWULWLRQDODQG
SXOPRQDU\VWDWXVLQFUHDVHGKRVSLWDODGPLVVLRQVDQGUHGXFHGOLIHH[SHFWDQF\6WXGLHVRIFKLOGUHQ
ZLWK&)PRQWKWKURXJK\HDUVRIDJHKDYHVKRZQWKHSUHVHQFHRIVWUXFWXUDOOXQJGLVHDVHRQ
FRPSXWHGWRPRJUDSK\&7VFDQVDWDQHDUO\DJH7KHUHDUHQRGDWDVSHFLILFDOO\GHVFULELQJ
OXQJGLVHDVHLQSDWLHQWV\RXQJHUWKDQ\HDUVRIDJHZKRKDYHDCFTRJDWLQJPXWDWLRQKRZHYHU
GDWDIURPVXEMHFWVZKRSDUWLFLSDWHGLQ6WXG\G551D-CFTRPXWDWLRQLQDWOHDVWDOOHOH
ZKRZHUH\HDUVRIDJHVXJJHVWWKDWVRPHVXEMHFWVKDGDOUHDG\GHYHORSHGOXQJGLVHDVHDQGKDG
QXWULWLRQDOFRPSOLFDWLRQVRI&)E\WKDWDJH:KLOHWKHSHUFHQWDJHRIDOOSDWLHQWVZLWK&)DQGWKH
G551D RURWKHUJDWLQJPXWDWLRQIRUVXEMHFWV\RXQJHUWKDQ\HDUVRIDJHVKDULQJWKHVH
FKDUDFWHULVWLFVZHUHXQNQRZQWKHVHGDWDGHPRQVWUDWHWKDWDWOHDVWDSURSRUWLRQRIVXEMHFWV
GHYHORSSXOPRQDU\DQGQXWULWLRQDOFRPSOLFDWLRQVRI&)EHIRUH\HDUVRIDJH
'DWDLQWKHOLWHUDWXUHVXJJHVWWKDWHDUO\WKHUDSHXWLFLQWHUYHQWLRQLVEHQHILFLDOWR\RXQJFKLOGUHQ
ZLWK&)$OWKRXJKIHZVWXGLHVKDYHEHHQGRQHWRHYDOXDWHWKHHIIHFWRIWKHUDSLHVLQFKLOGUHQ
ZLWK&)\RXQJHUWKDQ\HDUVRIDJHVWXGLHVKDYHGHPRQVWUDWHGEHQHILWVVXFKDVLPSURYHG
PHDVXUHVRIJURZWKQXWULWLRQDQGOXQJGLVHDVHWKURXJKHDUO\LQWHUYHQWLRQLQFKLOGUHQGLDJQRVHG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

E\QHZERUQVFUHHQLQJ&RPSRXQGVVXFKDV&)75PRGXODWRUVPD\KDYHWKHSRWHQWLDOWR
SUHVHUYHQRUPDOOXQJDQGSDQFUHDWLFH[RFULQHIXQFWLRQDQGWRPRGLI\WKHFRXUVHRIGLVHDVH
SURJUHVVLRQ)RUH[DPSOHUHVXOWVIURPORQJWHUPWUHDWPHQWZLWKLYDFDIWRULQSDWLHQWVZLWKWKH
G551DPXWDWLRQVKRZWKDWLQFUHDVLQJ&)75IXQFWLRQFDQVORZWKHUDWHRI)(9GHFOLQH
,YDFDIWRUUHGXFHGWKHVORSHRISHUFHQWSUHGLFWHG)(9E\DERXWFRPSDUHGWRDKRPR]\JRXV
F508delFRQWUROSRSXODWLRQIURPWKH86&))RXQGDWLRQUHJLVWU\GHPRQVWUDWLQJWKHVXVWDLQHG
EHQHILWVRILYDFDIWRUWUHDWPHQWDQGVXJJHVWLQJWKDWPRGXODWLQJ&)75IXQFWLRQFDQPRGLI\WKH
FRXUVHRIGLVHDVHLQSDWLHQWVZLWK&)
7KHUHVXOWVIURP6WXG\VKRZHGWKDWLYDFDIWRUDQGPJGRVHVZDVZHOOWROHUDWHGDQG
WKDWWKHUHZHUHFOLQLFDOO\UHOHYDQWLPSURYHPHQWVLQVZHDWFKORULGHQXWULWLRQDOVWDWXVDQG
SDQFUHDWLFIXQFWLRQWKURXJKRXWDZHHNWUHDWPHQWSHULRGLQ\RXQJVXEMHFWVZLWK&)ZLWKD
JDWLQJPXWDWLRQRQDWOHDVWDOOHOH6WXG\9;6WXG\ZLOOHYDOXDWHWKHHIILFDF\
RILYDFDIWRULQWKLVDJHUDQJHZLWKUHVSHFWWROXQJIXQFWLRQDVPHDVXUHGE\/&,

3DQFUHDWLFIXQFWLRQDVDVVHVVHGE\IHFDOHODVWDVHDQGLPPXQRUHDFWLYHWU\SVLQRJHQZLOODOVREH
HYDOXDWHG
6LQFHVSLURPHWU\LVFKDOOHQJLQJIRUFKLOGUHQ\RXQJHUWKDQ\HDUVRIDJHDQGUHVXOWVDUHYDULDEOH
WKHHIILFDF\RILYDFDIWRURQOXQJIXQFWLRQZLOOEHHYDOXDWHGE\XVLQJPHWKRGV/&,DPHDVXUH
RIYHQWLODWLRQLQKRPRJHQHLW\WKDWLVEDVHGRQWLGDOEUHDWKLQJWHFKQLTXHVWKDWKDYHEHHQHYDOXDWHG
LQSDWLHQWVDV\RXQJDVLQIDQWV
WRGHWHUPLQHVWUXFWXUDOOXQJ
DEQRUPDOLWLHVDQGWRPRQLWRUGLVHDVHSURJUHVVLRQ
7KHSUHVHQWVWXG\LVGHVLJQHGWRREWDLQORQJWHUPHIILFDF\DQGVDIHW\LQIRUPDWLRQLQWKLV\RXQJ
DJHJURXSWRIXUWKHUXQGHUVWDQGWKHLPSDFWRILYDFDIWRURQOXQJDQGSDQFUHDWLFIXQFWLRQ7KH
VWXG\ZLOODOVRH[DPLQHKRZORQJWHUPWUHDWPHQWZLWKLYDFDIWRULPSDFWVWKHFRXUVHRI&)GLVHDVH
SURJUHVVLRQ
6 
STUDY OBJECTIVES
6.1
Primary Objective  
7RHYDOXDWHWKHHIILFDF\RILYDFDIWRUWUHDWPHQWDVPHDVXUHGE\/&,LQVXEMHFWVZLWK&)ZKR
KDYHDVSHFLILHGCFTRJDWLQJPXWDWLRQDQGDUHWKURXJK\HDUVRIDJHDWWKHVWDUWRIWKHVWXG\
6.2
Secondary Objectives
7RHYDOXDWHWKHIROORZLQJLQVXEMHFWVZLWK&)KDYHDVSHFLILHGCFTRJDWLQJPXWDWLRQDQGDUH
WKURXJK\HDUVRIDJHDWWKHVWDUWRIWKHVWXG\

x
'LVHDVHSURJUHVVLRQDVPHDVXUHGE\FKDQJHVLQSDQFUHDWLFIXQFWLRQ
x
7KHVDIHW\RILYDFDIWRUWUHDWPHQW
7 
STUDY ENDPOINTS
7.1
Part 1
7.1.1
Primary Endpoint
x
$EVROXWHFKDQJHIURPEDVHOLQHLQ/&,WKURXJKZHHNVRIWUHDWPHQW

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG





8 
STUDY DESIGN
8.1
Overview of Study Design
7KLVLVD3KDVHESDUWUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGFURVVRYHUVWXG\ZLWKD
ORQJWHUPRSHQODEHOSHULRGRIRUDOO\DGPLQLVWHUHGLYDFDIWRULQVXEMHFWVZLWK&)DJHGWKURXJK
\HDUVDWWKHVWDUWRIWKHVWXG\ZKRKDYHRIWKHIROORZLQJVSHFLILHGCFTRJDWLQJPXWDWLRQVRQ
DWOHDVWDOOHOH G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, RUG1349D
$SSUR[LPDWHO\VXEMHFWVZLOOEHHQUROOHG
6XEMHFWVZLOOEHUDQGRPL]HGWRUHFHLYHRIWUHDWPHQWVHTXHQFHVGXULQJ3DUW
x
6HTXHQFHLYDFDIWRULQ7UHDWPHQW3HULRGÆZDVKRXWÆSODFHERLQ7UHDWPHQW3HULRG
x
6HTXHQFHSODFHERLQ7UHDWPHQW3HULRGÆZDVKRXWÆLYDFDIWRULQ7UHDWPHQW3HULRG
'XULQJ3DUWVXEMHFWVZLOOUHFHLYHPJRUPJLYDFDIWRUE\ZHLJKWVHH6HFWLRQRU
SODFHERHYHU\KRXUVTKIRUZHHNVRIWUHDWPHQW
'XULQJ7UHDWPHQW3HULRG'D\WKURXJK:HHNDSSUR[LPDWHO\VXEMHFWVZLOOEHGRVHG
ZLWKSODFHERDQGDSSUR[LPDWHO\VXEMHFWVZLOOEHGRVHGZLWKLYDFDIWRU'XULQJ7UHDWPHQW
3HULRG:HHNWKURXJK:HHNVXEMHFWVZKRZHUHGRVHGZLWKLYDFDIWRULQ7UHDWPHQW
3HULRGZLOOEHGRVHGZLWKSODFHERDQGVXEMHFWVZKRZHUHGRVHGZLWKSODFHERZLOOEHGRVHG
ZLWKLYDFDIWRU
3DUWZLOOEHRSHQODEHODQGZLOOFRQWLQXHWRXVHZHLJKWDSSURSULDWHGRVLQJVXEMHFWVPD\
WKHUHIRUHEHWUHDWHGZLWKPJLYDFDIWRUTK$IWHUFRPSOHWLRQRI3DUWVXEMHFWVZLOO
LPPHGLDWHO\EHJLQ3DUWWKHUHLVQRZDVKRXWSHULRGLQEHWZHHQ3DUWVDQG
7KHVWXG\GHVLJQLVGHSLFWHGLQ)LJXUH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
6DIHW\)ROORZXS9LVLWIRUVXEMHFWVZKRSUHPDWXUHO\GLVFRQWLQXHVWXG\GUXJWUHDWPHQW
DSSUR[LPDWHO\ZHHNVGD\VDIWHUWKHLUODVWGRVHRIVWXG\GUXJ
o
$6DIHW\)ROORZXS9LVLWZLOOQRWEHUHTXLUHGRIVXEMHFWVZLWKGUDZQIURPWKH
VWXG\GXHWRHDUO\VWXG\WHUPLQDWLRQ
6WXG\DVVHVVPHQWVDUHSUHVHQWHGLQ7DEOH7DEOHDQG7DEOH
Maintenance of Stable Medication Regimen for CF:
'XULQJ3DUWLWLVUHFRPPHQGHGWKDWVXEMHFWVUHPDLQRQVWDEOH&)PHGLFDWLRQUHJLPHQVIURP
ZHHNVEHIRUH'D\WKURXJKWKH:HHN9LVLW$VWDEOHPHGLFDWLRQUHJLPHQLVGHILQHGDVWKH
FXUUHQWPHGLFDWLRQUHJLPHQWKDWWKHVXEMHFWVKDYHEHHQIROORZLQJIRUDWOHDVWZHHNVEHIRUH
'D\
6SHFLILFUHTXLUHPHQWVDSSO\WRFHUWDLQ&)PHGLFDWLRQV
x
$WWKHWLPHRIVWXG\HQWU\VXEMHFWVZKRDUHRQDVWDEOHUHJLPHQRIDVLQJOHLQKDOHGDQWLELRWLF
WKDWLVFRQWLQXRXVO\DGPLQLVWHUHGVKRXOGUHPDLQRQWKLVDQWLELRWLFWKURXJKWKH6DIHW\
)ROORZXS9LVLW
x
$WWKHWLPHRIVWXG\HQWU\VXEMHFWVZKRDUHRQDVWDEOHUHJLPHQRIDVLQJOHLQKDOHGF\FOLQJ
DQWLELRWLFHJ7REUDP\FLQ,QKDODWLRQ6ROXWLRQ>72%,@UHJLPHQVKRXOGUHPDLQRQWKLV
DQWLELRWLFWKURXJKWKH6DIHW\)ROORZXS9LVLW,QKDOHGF\FOLQJDQWLELRWLFVVKRXOGEH
DGPLQLVWHUHGLQGD\RQGD\RIIF\FOHV6WXG\YLVLWVRQ'D\DQG:HHNRI7UHDWPHQW
3HULRGDQGRQ:HHNVDQGRI7UHDWPHQW3HULRGVKRXOGEHWLPHGWRRFFXUDWWKHHQG
RIDQRIIF\FOHEXWQRIHZHUWKDQGD\VDIWHUWKHODVWGRVHRILQKDOHGDQWLELRWLFVLQWKH
SUHYLRXVRQF\FOH
x
$WWKHWLPHRIVWXG\HQWU\VXEMHFWVZKRDUHRQDQDOWHUQDWLQJUHJLPHQRILQKDOHGF\FOLQJ
DQWLELRWLFVWKDWFRPSULVHFRQWLQXRXVDGPLQLVWUDWLRQRIDQWLELRWLFVHJ72%,DGPLQLVWUDWLRQ
DOWHUQDWLQJZLWK&D\VWRQVKRXOGUHPDLQRQWKHVHDQWLELRWLFVDFFRUGLQJWRWKHLUDOWHUQDWLQJ
UHJLPHQVWKURXJKWKH6DIHW\)ROORZXS9LVLW
,Q3DUWLWLVUHFRPPHQGHGWKDWVXEMHFWVPDLQWDLQVWDEOH&)PHGLFDWLRQUHJLPHQVWKURXJKWKH
HQGRIWKHVWXG\
8.1.1
Screening Period
6FUHHQLQJZLOORFFXUZLWKLQGD\VEHIRUHDGPLQLVWUDWLRQRIVWXG\GUXJ7KHLQYHVWLJDWRURUDQ
DSSURSULDWHDXWKRUL]HGGHVLJQHHDWWKHLQYHVWLJDWRUVLWHZLOOREWDLQLQIRUPHGFRQVHQWIURPWKH
VXEMHFW
VSDUHQWRUOHJDOJXDUGLDQDQGDVVHQWIURPHDFKVXEMHFWDVDSSOLFDEOH
6XEMHFWVPXVWFRPSOHWHWKH0%:DVVHVVPHQWDW6FUHHQLQJ7KHVXEMHFWZLOOEHFRQVLGHUHGD
VFUHHQIDLOXUHLIDQ0%:DVVHVVPHQWFDQQRWEHSHUIRUPHGLHWHFKQLFDOO\DFFHSWDEOH0%:
WHVWVDUHQRWDFKLHYHGDWWKH6FUHHQLQJ9LVLWRU5HVFUHHQLQJ9LVLWVHH6HFWLRQ
8.1.1.1
Repetition of Screening Period Assessments
5HSHWLWLRQRIVFUHHQLQJDVVHVVPHQWVWKDWGRQRWPHHWHOLJLELOLW\FULWHULDLVQRWSHUPLWWHGZLWK
WKHIROORZLQJH[FHSWLRQV
x
7KHUHLVFOHDUHYLGHQFHRIDODERUDWRU\HUURUHJKHPRO\]HGVDPSOHRUHTXLSPHQW
PDOIXQFWLRQ,QWKLVFDVHFROOHFWLRQRIDUHSHDWVDPSOHIRUWKHDSSURSULDWHODERUDWRU\WHVWPD\
EHSHUPLWWHGDIWHUGLVFXVVLRQZLWKWKH9HUWH[PHGLFDOPRQLWRURUDXWKRUL]HGGHVLJQHH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
,IDFRQYLQFLQJDOWHUQDWLYHHWLRORJ\LVLGHQWLILHGIRUHOHYDWHGWUDQVDPLQDVHVH[FOXVLRQDU\
OLYHUIXQFWLRQWHVW/)7OHYHOVPD\EHUHWHVWHGZLWKLQGD\VRIWKHRULJLQDO6FUHHQLQJ9LVLW
GDWH
x
7KH0%:DVVHVVPHQWFDQQRWEHSHUIRUPHG
,IUHSHDWYDOXHVDUHZLWKLQWKHHOLJLELOLW\FULWHULDDQGFRPSOHWHGZLWKLQWKH6FUHHQLQJ3HULRG
ZLQGRZWKHVXEMHFWLVHOLJLEOHIRUWKHVWXG\
8.1.1.2
Rescreening
6XEMHFWVPD\EHUHVFUHHQHGDIWHUGLVFXVVLRQZLWKDQGDSSURYDOIURPWKH9HUWH[PHGLFDO
PRQLWRURUDXWKRUL]HGGHVLJQHH,IDVXEMHFWLVUHVFUHHQHGDOO6FUHHQLQJ9LVLWDVVHVVPHQWVZLOOEH
UHSHDWHGH[FHSWIRU&)JHQRW\SLQJDQGWKH2(LIWKH2(ZDVSHUIRUPHGZLWKLQWKHODVWPRQWKV
EHIRUHWKH5HVFUHHQLQJ9LVLW,IDVXEMHFWLVUHVFUHHQHGWKHVFUHHQLQJZLQGRZZLOOEHJLQRQFH
WKHILUVWUHVFUHHQLQJDVVHVVPHQWKDVEHHQLQLWLDWHG
8.1.1.3
Extension of Screening Period Window
$VXEMHFWPD\KDYHWKH6FUHHQLQJ3HULRGZLQGRZH[WHQGHGE\ZHHNVIRUWKHIROORZLQJ
UHDVRQV
x
5HSHWLWLRQRI6FUHHQLQJ3HULRGDVVHVVPHQWV6HFWLRQ
x
8QH[SHFWHGRSHUDWLRQDORUORJLVWLFGHOD\VRUWRPHHWWKHHOLJLELOLW\FULWHULD
x
6FKHGXOLQJRIWKH2(6HFWLRQ
x
$YDLODELOLW\RIUHTXLUHGHTXLSPHQW
8.1.2
Part 1: Treatment Period 1 (8 Weeks)
7KHILUVWGRVHRIVWXG\GUXJZLOOEHDGPLQLVWHUHGLQ3DUWRQ'D\6WXG\GUXJVKRXOGEHWDNHQ
DFFRUGLQJWRLQVWUXFWLRQVSURYLGHG6WXG\YLVLWVZLOORFFXURQ'D\:HHNDQG:HHN7KH
ODVWGRVHRIVWXG\GUXJLQ7UHDWPHQW3HULRGLVWKHGRVHRIVWXG\GUXJEHIRUHWKHSODQQHG
:HHN9LVLW
8.1.3
Part 1: Washout Period (8 Weeks)
6XEMHFWVZLOOXQGHUJRD:DVKRXW3HULRGRIZHHNVrGD\V
8.1.4
Part 1: Treatment Period 2 (8 Weeks)
7KHILUVWGRVHRIVWXG\GUXJLQ7UHDWPHQW3HULRGZLOOEHDGPLQLVWHUHGDWWKH:HHN9LVLW
DIWHUFRPSOHWLQJWKH:HHNDVVHVVPHQWV6WXG\GUXJVKRXOGEHWDNHQDFFRUGLQJWRLQVWUXFWLRQV
SURYLGHG,QRUGHUWRFRQWLQXHLQWR7UHDWPHQW3HULRGVXEMHFWVPXVWQRWKDYHDQDFXWHXSSHURU
ORZHUUHVSLUDWRU\LQIHFWLRQSXOPRQDU\H[DFHUEDWLRQRUFKDQJHVLQWKHUDS\LQFOXGLQJ
DQWLELRWLFVIRUSXOPRQDU\GLVHDVHZLWKLQZHHNVEHIRUHWKH:HHN9LVLWILUVWGRVHRIVWXG\
GUXJLQ7UHDWPHQW3HULRGDQGPXVWQRWKDYHDQ\³QRQ&)UHODWHG´LOOQHVVZLWKLQZHHNV
EHIRUHWKH:HHN9LVLWILUVWGRVHRIVWXG\GUXJLQ7UHDWPHQW3HULRG³,OOQHVV´LVGHILQHGDV
DQDFXWHVHULRXVRUQRQVHULRXVFRQGLWLRQHJJDVWURHQWHULWLV,IWKHVXEMHFWGRHVQRWPHHW
WKHVHFULWHULDWKHQWKHFRQWLQXDWLRQRIWKHVXEMHFWLQWR7UHDWPHQW3HULRGVKRXOGEHGLVFXVVHG
ZLWKWKH9HUWH[PHGLFDOPRQLWRU7KHODVWGRVHRIVWXG\GUXJLQ7UHDWPHQW3HULRGLVWKHGRVHRI
VWXG\GUXJEHIRUHWKHSODQQHG:HHN9LVLW6WXG\YLVLWVZLOORFFXURQ:HHNVDQG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

)ROORZLQJDUHYLHZRIVWXG\HQUROOPHQWDQGDVVHVVPHQWRIWKHDYDLODEOHQXPEHURISRWHQWLDO
VXEMHFWVIRUWKLVVWXG\9HUWH[GHFLGHGWRFORVHHQUROOPHQWDQGWHUPLQDWHWKHVWXG\HDUO\$IWHU
WKHSURWRFRODPHQGPHQWKDVEHHQDSSURYHGDWDVLWHVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQIURP
WKHVWXG\DWWKHLU:HHN9LVLWVHH6HFWLRQ
8.1.5
Part 2: Open-label Period
7KHILUVWGRVHRIRSHQODEHOLYDFDIWRUZLOOEHDGPLQLVWHUHGDWWKH:HHN9LVLWDIWHUFRPSOHWLRQ
RIWKH:HHNDVVHVVPHQWV7KHODVWGRVHRILYDFDIWRUZLOOEHDGPLQLVWHUHGEHIRUHWKHSODQQHG
:HHN9LVLW7KHGRVHRILYDFDIWRUPJPJRUPJZLOOEHEDVHGRQWKHVXEMHFW¶V
ZHLJKWVHH6HFWLRQ6WXG\YLVLWVZLOORFFXURQ:HHNV
DQG
9HUWH[GHFLGHGWRFORVHHQUROOPHQWDQGWHUPLQDWHWKHVWXG\HDUO\$IWHUWKHSURWRFRODPHQGPHQW
KDVEHHQDSSURYHGDWDVLWHVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQIURPWKHVWXG\DQGUHTXHVWHGWR
FRPSOHWHWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWVHH6HFWLRQ
8.1.6
Follow-up Telephone Contact
$)ROORZXS7HOHSKRQH&RQWDFWLVVFKHGXOHGWRRFFXUZHHNVGD\VDIWHUWKH:HHN
9LVLWIRUVXEMHFWVZKRFRPSOHWHWKLVYLVLW$)ROORZXS7HOHSKRQH&RQWDFWLVQRWUHTXLUHGIRU
VXEMHFWVZKRKDYHDQ(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLW
8.1.7
Early Termination of Treatment
6XEMHFWVZKRSUHPDWXUHO\GLVFRQWLQXHVWXG\GUXJWUHDWPHQWLQ6WXG\IRUDQ\UHDVRQRWKHU
WKDQHDUO\VWXG\WHUPLQDWLRQZLOOEHUHTXLUHGWRFRPSOHWHWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW
9LVLWZKLFKLVWREHVFKHGXOHGDVVRRQDVSRVVLEOHDIWHULWLVGHFLGHGWKDWWKHVXEMHFWZLOO
WHUPLQDWHVWXG\GUXJWUHDWPHQW6XEMHFWVZKRSUHPDWXUHO\GLVFRQWLQXHVWXG\GUXJWUHDWPHQWZLOO
DOVREHUHTXLUHGWRFRPSOHWHWKH6DIHW\)ROORZXS9LVLWDSSUR[LPDWHO\ZHHNVGD\VDIWHU
WKHLUODVWGRVHRIVWXG\GUXJ7KHDVVHVVPHQWVSHUIRUPHGDWWKH6DIHW\)ROORZXS9LVLWDUHOLVWHG
LQ7DEOH
,IWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWRFFXUVZHHNVRUODWHUIROORZLQJWKHODVWGRVHRI
VWXG\GUXJWKHQWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWZLOOUHSODFHWKH6DIHW\)ROORZXS
9LVLWDQGDVHSDUDWH6DIHW\)ROORZXS9LVLWZLOOQRWEHUHTXLUHG
6XEMHFWVZLOOFRQWLQXHWRFRPSOHWHDOORWKHUVFKHGXOHGVWXG\YLVLWVIRUDVVHVVPHQWVRIHIILFDF\
DQGRWKHUHQGSRLQWVDVGHWDLOHGLQWKH6FKHGXOHRI$VVHVVPHQWVVHH6HFWLRQ
,IWKHVXEMHFWZLWKGUDZVFRQVHQWIRUWKHVWXG\QRIXUWKHUHYDOXDWLRQVVKRXOGEHSHUIRUPHGDQG
QRDGGLWLRQDOGDWDVKRXOGEHFROOHFWHG9HUWH[PD\UHWDLQDQGFRQWLQXHWRXVHDQ\GDWDFROOHFWHG
EHIRUHVXFKZLWKGUDZDORIFRQVHQW
6XEMHFWVZKRGLVFRQWLQXHVWXG\GUXJWUHDWPHQWGXULQJ3DUWZLOOQRWEHDOORZHGUHFHLYHVWXG\
GUXJWUHDWPHQWLQ3DUWRIWKHVWXG\EXWZLOOFRQWLQXHWRFRPSOHWHWKHDVVHVVPHQWVRIHIILFDF\DV
GHVFULEHGDERYH
$IWHUWKHSURWRFRODPHQGPHQWKDVEHHQDSSURYHGDWDVLWHVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQ
IURPWKHVWXG\DWWKHLU:HHN9LVLWDQGVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQIURPWKHVWXG\
DQGUHTXHVWHGWRFRPSOHWHWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWVHH6HFWLRQ

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

8.1.8
Safety Follow-up Visit
6XEMHFWVZKRSUHPDWXUHO\GLVFRQWLQXHVWXG\GUXJWUHDWPHQWIRUDQ\UHDVRQRWKHUWKDQHDUO\
VWXG\WHUPLQDWLRQZLOOKDYHD6DIHW\)ROORZXS9LVLWDSSUR[LPDWHO\ZHHNVGD\VDIWHU
WKHLUODVWGRVHRIVWXG\GUXJ,IWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWRFFXUVZHHNVRUODWHU
IROORZLQJWKHODVWGRVHRIVWXG\GUXJWKHQWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWZLOOUHSODFH
WKH6DIHW\)ROORZXS9LVLWDQGDVHSDUDWH6DIHW\)ROORZXS9LVLWZLOOQRWEHUHTXLUHG6DIHW\
)ROORZXSDVVHVVPHQWVDUHOLVWHGLQ7DEOH
8.1.9
Independent Data Monitoring Committee
$Q,QGHSHQGHQW'DWD0RQLWRULQJ&RPPLWWHH,'0&ZLOOEHIRUPHGIRUWKLVVWXG\7KH,'0&
ZLOOFRQGXFWUHJXODUSODQQHGUHYLHZVRIVWXG\GDWDGXULQJ3DUWZLWKWKHSULPDU\JRDORI
HYDOXDWLQJWKHVDIHW\RIWKHVWXG\GUXJUHJLPHQWRHQVXUHWKHVXEMHFWV
VDIHW\6HFWLRQ
3URFHGXUDOGHWDLOVRIWKH,'0&
VVWUXFWXUHDQGIXQFWLRQIUHTXHQF\RIPHHWLQJVDQGGDWDSODQQHG
IRUUHYLHZZLOOEHLQFOXGHGLQWKH,'0&&KDUWHU7KH,'0&&KDUWHUZDVILQDOL]HGEHIRUHWKH
ILUVWVXEMHFWZDVHQUROOHGLQWKHVWXG\7KH,'0&&KDUWHUZLOOEHXSGDWHGIROORZLQJDSSURYDORI
WKHSURWRFRODPHQGPHQWWRUHIOHFWFKDQJHVLPSDFWHGE\WKHGHFLVLRQWRWHUPLQDWHWKHVWXG\HDUO\
8.2
Rationale for Study Design and Study Drug Regimens
8.2.1
Study Design
7KLV3KDVHESDUWUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGFURVVRYHUVWXG\ZLWKD
ORQJWHUPRSHQODEHOIROORZRQSHULRGLVGHVLJQHGWRHYDOXDWHWKHHIILFDF\DQGVDIHW\RILYDFDIWRU
LQVXEMHFWVZLWK&)DJHGWKURXJK\HDUVDWWKHVWDUWRIVWXG\ZKRKDYHRIWKHIROORZLQJ
CFTRJDWLQJPXWDWLRQVRQDWOHDVWDOOHOH G551D, G178R, S549N, S549R, G551S, G1244E, 
S1251N, S1255P, RUG1349D.
&)SXOPRQDU\GLVHDVHSURJUHVVHVWKURXJKRXWOLIH+RZHYHULWLVQRWXQFRPPRQIRU\RXQJ
SDWLHQWVZLWK&)WRKDYHZHOOSUHVHUYHGRUHYHQQRUPDOOXQJIXQFWLRQDVPHDVXUHGE\
VSLURPHWU\ ,QVSLWHRIWKHSRWHQWLDOO\QRUPDOOXQJIXQFWLRQSDWLHQWVLQWKLVDJHJURXSZLWK
VHYHUH&)FDXVLQJPXWDWLRQVOLNHO\DOUHDG\KDYHSXOPRQDU\VWUXFWXUDODEHUUDWLRQV

 &RQVLVWHQWZLWKWKHVHREVHUYDWLRQVLPSDLUHG/&,ZKLFKPHDVXUHVWKH
GHJUHHRIVPDOODLUZD\GLVHDVHE\DVVHVVLQJYHQWLODWLRQLQKRPRJHQHLW\FDQEHREVHUYHGLQ
SHGLDWULFSDWLHQWVZLWKQRUPDOOXQJIXQFWLRQDVPHDVXUHGE\VSLURPHWU\7KHVHREVHUYDWLRQV
FRQILUPWKDWWKHGLVHDVHSURFHVVWKDWUHVXOWVIURPDODFNRI&)75DFWLYLW\EHJLQVHDUO\LQOLIHDQG
EHIRUHOXQJIXQFWLRQDVDVVHVVHGE\VSLURPHWU\LVDIIHFWHG
8QOLNHSUHYLRXVVWXGLHVZLWKLYDFDIWRULQWKLVDJHJURXSHJ6WXG\ZKLFKIRFXVHGRQWKH
VDIHW\DQG3.RILYDFDIWRU6WXG\ZLOOHYDOXDWHWKHHIILFDF\RILYDFDIWRUXVLQJHQGSRLQWVWKDW
DUHFRQVLVWHQWZLWKWKHQDWXUDOKLVWRU\RIGLVHDVHFRXUVHLQWKLVDJHJURXSWKHVHLQFOXGH/&,

DQGPHDVXUHVRISDQFUHDWLFIXQFWLRQ
x
&KDQJHVLQ/&,KDYHEHHQREVHUYHGLQDGYDQFHRIGHWHULRUDWLRQRIOXQJIXQFWLRQDVDVVHVVHG
E\VSLURPHWU\,Q6WXG\VXEMHFWVDJHG\HDUVDQGROGHUZLWK&)DQGWKHG551D 
PXWDWLRQZKRKDGZHOOSUHVHUYHGOXQJIXQFWLRQ)(9!SUHGLFWHGGHPRQVWUDWHG
VLJQLILFDQWLPSURYHPHQWVLQOXQJIXQFWLRQDVDVVHVVHGE\/&,GXULQJWUHDWPHQWZLWK
LYDFDIWRU,Q6WXG\/&,ZLOOEHHYDOXDWHGERWKGXULQJWKH3ODFHERFRQWUROOHG&URVVRYHU
3HULRGDQGGXULQJWKHORQJWHUP2SHQODEHO3HULRG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

9.2
Exclusion Criteria
 +LVWRU\RIDQ\LOOQHVVRUFRQGLWLRQWKDWLQWKHRSLQLRQRIWKHLQYHVWLJDWRUPLJKWFRQIRXQGWKH
UHVXOWVRIWKHVWXG\LPSDFWXVHRIWKH/&,RU&7VFDQDVDVVHVVPHQWVRUSRVHDQDGGLWLRQDO
ULVNLQDGPLQLVWHULQJVWXG\GUXJWRWKHVXEMHFW
 $QDFXWHXSSHURUORZHUUHVSLUDWRU\LQIHFWLRQSXOPRQDU\H[DFHUEDWLRQRUFKDQJHVLQWKHUDS\
LQFOXGLQJDQWLELRWLFVIRUSXOPRQDU\GLVHDVHZLWKLQZHHNVEHIRUH'D\
 $Q\FOLQLFDOO\VLJQLILFDQWODERUDWRU\DEQRUPDOLWLHVDWWKH6FUHHQLQJ9LVLWWKDWZRXOGLQWHUIHUH
ZLWKWKHVWXG\DVVHVVPHQWVRUSRVHDQXQGXHULVNIRUWKHVXEMHFWLQWKHRSLQLRQRIWKH
LQYHVWLJDWRU
 $EQRUPDOOLYHUIXQFWLRQDW6FUHHQLQJGHILQHGDVtîXSSHUOLPLWRIQRUPDO8/1RIDQ\
RUPRUHRIWKHIROORZLQJVHUXPDVSDUWDWHWUDQVDPLQDVH$67VHUXPDODQLQHWUDQVDPLQDVH
$/7JDPPDJOXWDP\OWUDQVSHSWLGDVH**7VHUXPDONDOLQHSKRVSKDWDVH$/3DQGWRWDO
ELOLUXELQ
 +LVWRU\RIVROLGRUJDQRUKHPDWRORJLFDOWUDQVSODQWDWLRQ
 $Q\FOLQLFDOO\VLJQLILFDQWQRQ&)UHODWHGLOOQHVVZLWKLQZHHNVEHIRUH'D\,OOQHVVLV
GHILQHGDVDQDFXWHVHULRXVRUQRQVHULRXVFRQGLWLRQHJJDVWURHQWHULWLV
 8VHRIDQ\PRGHUDWHRUVWURQJLQGXFHUVRULQKLELWRUVRIF\WRFKURPH3&<3$ZLWKLQ
ZHHNVEHIRUH'D\
 3DUWLFLSDWLRQLQDFOLQLFDOVWXG\LQYROYLQJDGPLQLVWUDWLRQRIHLWKHUDQLQYHVWLJDWLRQDORUD
PDUNHWHGGUXJZLWKLQGD\VRUWHUPLQDOKDOIOLYHVZKLFKHYHULVORQJHURUDVGHWHUPLQHG
E\WKHORFDOUHTXLUHPHQWVEHIRUH6FUHHQLQJ
9.3
Prior and Concomitant Medications
,QIRUPDWLRQUHJDUGLQJDOOSULRUDQGFRQFRPLWDQWPHGLFDWLRQVLQFOXGLQJWKHVXEMHFW
V&)
PHGLFDWLRQVRWKHUPHGLFDWLRQVDQGKHUEDODQGQDWXURSDWKLFUHPHGLHVLQFOXGLQJGUXJQDPH
GRVHDQGGRVHUHJLPHQDGPLQLVWHUHGIURP6FUHHQLQJWKURXJKWKHHQGRIVWXG\SDUWLFLSDWLRQZLOO
EHFROOHFWHG
,WLVUHFRPPHQGHGWKDWVXEMHFWVUHPDLQRQWKHLUPHGLFDWLRQUHJLPHQVIRUWKHLU&)IURP'D\
WKURXJKWKHHQGRIVWXG\SDUWLFLSDWLRQ
8VHRIVKRUWDFWLQJDQGORQJDFWLQJEURQFKRGLODWRUVZLOOEHUHFRUGHGLQWKHVRXUFHGRFXPHQWV
6XEMHFWVPXVWQRWXVHPRGHUDWHRUSRWHQW&<3$LQKLELWRUVDQGLQGXFHUVLQFOXGLQJFHUWDLQ
KHUEDOPHGLFDWLRQVDQGJUDSHIUXLWJUDSHIUXLWMXLFHWKURXJKWKHHQGRIVWXG\SDUWLFLSDWLRQ
6XEMHFWVPXVWQRWXVHFRPPHUFLDOO\DYDLODEOHLYDFDIWRU.DO\GHFRGXULQJWKHVWXG\
$PRUHFRPSUHKHQVLYHOLVWRIUHVWULFWHGPHGLFDWLRQVZLOOEHSURYLGHGLQWKH6WXG\0DQXDO
1RQFRPSOLDQFHZLWKWKHVHUHVWULFWLRQVZLOOEHDGGUHVVHGRQDFDVHE\FDVHEDVLVZLWKWKH9HUWH[
PHGLFDOPRQLWRU
9.4
Removal of Subjects in the Study
6XEMHFWVPD\ZLWKGUDZIURPWKHVWXG\DWDQ\WLPHDWWKHLURZQUHTXHVWRUDWWKHUHTXHVWRIWKH
SDUHQWRUOHJDOJXDUGLDQ6XEMHFWVPD\EHZLWKGUDZQIURPVWXG\GUXJWUHDWPHQWDWDQ\WLPHDWWKH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

GLVFUHWLRQRIWKHLQYHVWLJDWRURU9HUWH[IRUVDIHW\EHKDYLRUQRQFRPSOLDQFHZLWKVWXG\
SURFHGXUHVRUDGPLQLVWUDWLYHUHDVRQV
,IDVXEMHFWKDVEHHQZLWKGUDZQIURPVWXG\GUXJWUHDWPHQWWKHVXEMHFWZLOOFRQWLQXHWREH
IROORZHGSURYLGHGWKHVXEMHFWKDVQRWZLWKGUDZQFRQVHQW
6XEMHFWVZKRGLVFRQWLQXHVWXG\GUXJWUHDWPHQWHDUO\VKRXOGFRQWLQXHWRUHWXUQIRUVWXG\
DVVHVVPHQWVDVQRWHGLQ6HFWLRQ
,IDVXEMHFWGRHVQRWUHWXUQIRUDVFKHGXOHGYLVLWUHDVRQDEOHHIIRUWZLOOEHPDGHWRFRQWDFWWKH
VXEMHFW
VSDUHQWRUOHJDOJXDUGLDQ,QDQ\FLUFXPVWDQFHUHDVRQDEOHHIIRUWZLOOEHPDGHWR
GRFXPHQWVXEMHFWRXWFRPH7KHLQYHVWLJDWRUZLOOLQTXLUHDERXWWKHUHDVRQIRUZLWKGUDZDOUHTXHVW
WKDWWKHVXEMHFWUHWXUQDOOXQXVHGLQYHVWLJDWLRQDOSURGXFWVUHTXHVWWKDWWKHVXEMHFWUHWXUQIRUD
6DIHW\)ROORZXS9LVLWLIDSSOLFDEOHVHH6HFWLRQDQGIROORZXSZLWKWKHVXEMHFW
UHJDUGLQJDQ\XQUHVROYHG$(V
,IWKHVXEMHFWZLWKGUDZVFRQVHQWIRUWKHVWXG\QRIXUWKHUHYDOXDWLRQVZLOOEHSHUIRUPHGDQGQR
DGGLWLRQDOGDWDZLOOEHFROOHFWHG9HUWH[PD\UHWDLQDQGFRQWLQXHWRXVHDQ\GDWDFROOHFWHGEHIRUH
VXFKZLWKGUDZDORIFRQVHQW
$VXEMHFWwill beGLVFRQWLQXHGIURPWKHVWXG\IRUDQ\RIWKHIROORZLQJUHDVRQV
x
9HUWH[UHJXODWRU\DXWKRULWLHVRUWKHVLWH
V,QVWLWXWLRQDO5HYLHZ%RDUG,5%RU(WKLFV
&RPPLWWHH(&FORVHWKHVWXG\
x
$VXEMHFWEHJLQVWUHDWPHQWZLWKFRPPHUFLDOO\DYDLODEOHLYDFDIWRU.DO\GHFR
x
6XEMHFWVZKRDUHUDQGRPL]HGRQWKHEDVLVRIDKLVWRULFDOJHQRW\SLQJUHVXOWDQGZKRVH
VFUHHQLQJJHQRW\SHGRHVQRWFRQILUPHOLJLELOLW\
$VXEMHFWwill beGLVFRQWLQXHGIURPVWXG\GUXJGRVLQJIRUDQ\RIWKHIROORZLQJUHDVRQV
x
$VXEMHFWKDVRQHRIWKHIROORZLQJDQGQRDOWHUQDWLYHHWLRORJ\HJYLUDOKHSDWLWLVIRUWKH
HOHYDWHGWUDQVDPLQDVHLVLGHQWLILHGUHJDUGOHVVRIZKHWKHU$/7RU$67OHYHOVKDYHLPSURYHG
VHH6HFWLRQ
R
$QHOHYDWHG$/7RU$67RI!î8/1RU
R
$/7RU$67!î8/1IRUPRUHWKDQZHHNVRU
R
$QHOHYDWLRQRI$/7RU$67!î8/1LQDVVRFLDWLRQZLWKWRWDOELOLUXELQ!î8/1
DQGRUFOLQLFDOMDXQGLFH
x
$VXEMHFWLVQRQFRPSOLDQWZLWKVWXG\SURWRFROUHTXLUHPHQWVUHVWULFWLRQVDQGLQVWUXFWLRQV
x
$VXEMHFWSDUWLFLSDWHVLQDQRWKHUWKHUDSHXWLFFOLQLFDOVWXG\
$VXEMHFWmay beGLVFRQWLQXHGIURPWKHVWXG\DIWHUGLVFXVVLRQEHWZHHQWKHLQYHVWLJDWRUDQGWKH
9HUWH[PHGLFDOPRQLWRUIRUDQ\RIWKHIROORZLQJUHDVRQV
x
$VXEMHFWGHYHORSVDPHGLFDOFRQGLWLRQWKDWUHTXLUHVSURORQJHGFRQFRPLWDQWWKHUDS\ZLWKD
SURKLELWHGPHGLFDWLRQRUSURORQJHGLQWHUUXSWLRQRILYDFDIWRU
x
$VXEMHFWGHYHORSVDOLIHWKUHDWHQLQJ$(RUVHULRXV$(6$(WKDWSODFHVWKHPDWLPPHGLDWH
ULVN

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
$VXEMHFWKDVDQLQFUHDVHLQ/)7VHJ$67RU$/7OHYHOVWRî8/1LI/)7VDUHQRUPDO
DWEDVHOLQHRQ'D\RUDQLQFUHDVHWKDWH[FHHGVDQDEVROXWHYDOXHRIî8/1UHJDUGOHVVRI
ZKHWKHU/)7VDUHQRUPDODWEDVHOLQHRQ'D\
,IWKHVXEMHFWLVZLWKGUDZQIURPWKHVWXG\DQGWKHSDUHQWRUOHJDOJXDUGLDQDOVRZLWKGUDZV
FRQVHQWIRUGLVFORVXUHRIIXWXUHLQIRUPDWLRQQRIXUWKHUHYDOXDWLRQVVKRXOGEHSHUIRUPHGDQGQR
DGGLWLRQDOGDWDVKRXOGEHFROOHFWHG9HUWH[PD\UHWDLQDQGFRQWLQXHWRXVHDQ\GDWDFROOHFWHG
EHIRUHVXFKZLWKGUDZDORIFRQVHQW
)ROORZLQJDUHYLHZRIVWXG\HQUROOPHQWDQGDVVHVVPHQWRIWKHDYDLODEOHQXPEHURISRWHQWLDO
VXEMHFWVIRUWKLVVWXG\9HUWH[GHFLGHGWRFORVHHQUROOPHQWDQGWHUPLQDWHWKHVWXG\HDUO\$IWHU
WKHSURWRFRODPHQGPHQWKDVEHHQDSSURYHGDWDVLWHVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQIURP
WKHVWXG\DWWKHLU:HHN9LVLWDQGVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQIURPWKHVWXG\DQG
UHTXHVWHGWRFRPSOHWHWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWVHH6HFWLRQ
9.5
Replacement of Subjects
6XEMHFWVZKRZLWKGUDZRUDUHZLWKGUDZQGXULQJWKHVWXG\GUXJWUHDWPHQWSHULRGVZLOOQRWEH
UHSODFHG
10
STUDY DRUG ADMINISTRATION AND MANAGEMENT
10.1
Preparation and Dispensing
6WXG\GUXJPD\EHGLVSHQVHGRQO\XQGHUWKHVXSHUYLVLRQRIWKHLQYHVWLJDWRURUDQDXWKRUL]HG
GHVLJQHHDQGRQO\IRUDGPLQLVWUDWLRQWRWKHVWXG\VXEMHFWV
10.2
Administration
'XULQJ3DUWHDFKRUPJGRVHRILYDFDIWRUZLOOEHSURYLGHGDVJUDQXOHVLQDFDSVXOH
'XULQJ3DUWWKHVHGRVHVZLOOEHSURYLGHGDVJUDQXOHVLQDVDFKHW
7KHHQWLUHFRQWHQWVRIHDFKFDSVXOHRUVDFKHWRIJUDQXOHVVKRXOGEHPL[HGZLWKWHDVSRRQ
P/RIDJHDSSURSULDWHVRIWIRRGRUOLTXLGDQGFRPSOHWHO\FRQVXPHG(DFKGRVHVKRXOGEH
DGPLQLVWHUHGMXVWEHIRUHRUMXVWDIWHUIDWFRQWDLQLQJIRRG3DUHQWVZLOOEHLQVWUXFWHGRQKRZWR
HPSW\WKHFDSVXOHVRUVDFKHWVDQGDGPLQLVWHULYDFDIWRUZLWKIRRG'HWDLOVRIGRVHSUHSDUDWLRQDQG
GRVHDGPLQLVWUDWLRQZLOOEHSURYLGHGLQWKH6WXG\0DQXDO
7KHPJGRVHRILYDFDIWRUZLOOEHSURYLGHGDVWZRPJGRVHVRILYDFDIWRULQVDFKHWV7KH
PJGRVHPD\DOVREHSURYLGHGDVDWDEOHWDIWHUGLVFXVVLRQZLWKWKHPHGLFDOPRQLWRU,WLV
UHFRPPHQGHGWKDWVXEMHFWVWDNHPJGRVHRILYDFDIWRUZLWKIDWFRQWDLQLQJIRRG([DPSOHVRI
DSSURSULDWHIDWFRQWDLQLQJIRRGVZLOOEHGHVFULEHGLQWKH6WXG\0DQXDO
*XLGHOLQHVIRULYDFDIWRUDGPLQLVWUDWLRQDUHDVIROORZV
x
,YDFDIWRUVKRXOGEHDGPLQLVWHUHGTK
x
:KHQHYHUSRVVLEOHVXEMHFWVVKRXOGWDNHLYDFDIWRUDWWKHVDPHWLPHHDFKGD\)RUH[DPSOH
WKHPRUQLQJGRVHFRXOGEHWDNHQDW$0HYHU\PRUQLQJDQGWKHHYHQLQJGRVHFRXOGEH
WDNHQDW30HYHU\HYHQLQJWKURXJKRXWWKHVWXG\
x
,IVXEMHFWVIRUJHWWRWDNHDGRVHDQGUHPHPEHUZLWKLQWRKRXUVEHIRUHWKHKDOIZD\SRLQW
RIWKHGRVLQJLQWHUYDOWKH\VKRXOGWDNHWKHGRVHDWWKDWWLPHZLWKIDWFRQWDLQLQJIRRGDQG
UHVXPHWKHLUQRUPDOVFKHGXOHIRUWKHIROORZLQJGRVH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
,IVXEMHFWVIRUJHWWRWDNHDGRVHDQGUHPHPEHUZLWKLQWRKRXUVDIWHUWKHPLVVHGGRVH
WKH\VKRXOGVNLSWKDWGRVHDQGUHVXPHWKHLUQRUPDOVFKHGXOHIRUWKHIROORZLQJGRVH
10.3
Method of Assigning Subjects to Treatment Groups
Part 1
6XEMHFWVZLOOEHFRQVLGHUHGHQUROOHGZKHQWKH\DUHGHWHUPLQHGWRKDYHPHWDOOHOLJLELOLW\FULWHULD
DQGDUHUDQGRPL]HGWRDWUHDWPHQWVHTXHQFH6HTXHQFHRU6HTXHQFH6XEMHFWVZLOOEH
UDQGRPL]HGLQDUDWLR
$QLQWHUDFWLYHYRLFHUHVSRQVHV\VWHP,956LQWHUDFWLYHZHEUHVSRQVHV\VWHP,:56ZLOOEH
XVHGWRDVVLJQVXEMHFWVWRWUHDWPHQW'HWDLOHGLQVWUXFWLRQVIRUUDQGRPL]DWLRQDQGUDQGRPL]DWLRQ
FRGHJHQHUDWLRQZLOOEHSURYLGHGVHSDUDWHO\
Part 2
3DUWLVRSHQODEHO5DQGRPL]DWLRQLVQRWUHTXLUHGIRU3DUWEHFDXVHDOOVXEMHFWVZLOOUHFHLYH
LYDFDIWRU
10.4
Dose Modification for Toxicity
0RGLILFDWLRQVRIWKHLYDFDIWRUGRVHVDUHSURKLELWHG,QWHUUXSWLRQVRIVWXG\GUXJGRVLQJVKRXOGEH
GLVFXVVHGZLWKWKH9HUWH[PHGLFDOPRQLWRUDQGPD\EHFRQVLGHUHGRQDFDVHE\FDVHEDVLVDIWHU
GLVFXVVLRQZLWKWKH9HUWH[PHGLFDOPRQLWRU6SHFLILFLQVWUXFWLRQVIRULQWHUUXSWLRQIRUHOHYDWHG
/)7VDUHSURYLGHGLQ6HFWLRQ
10.5
Packaging and Labeling
)RU3DUWWKHPJRUPJGRVHVRILYDFDIWRURUSODFHERJUDQXOHVLQDFDSVXOHZLOOEH
VXSSOLHGE\9HUWH[LQERWWOHV)RU3DUWWKHVHGRVHVZLOOEHVXSSOLHGDVJUDQXOHVLQVDFKHWV7KH
ILOPFRDWHGLYDFDIWRUWDEOHWIRUPXODWLRQPJZLOOEHVXSSOLHGLQFKLOGUHVLVWDQWEOLVWHU
GRVLQJFDUGV6WXG\GUXJODEHOLQJZLOOEHLQFRPSOLDQFHZLWKDSSOLFDEOHORFDODQGQDWLRQDO
UHJXODWLRQV$GGLWLRQDOGHWDLOVUHJDUGLQJSDFNDJLQJODEHOLQJDQGGLVSHQVLQJIRULYDFDIWRUZLOOEH
LQFOXGHGLQWKHSKDUPDF\PDQXDO
10.6
Study Drug Supply, Storage, and Handling
7KHLQYHVWLJDWRURUDQDXWKRUL]HGGHVLJQHHHJDOLFHQVHGSKDUPDFLVWZLOOHQVXUHWKDWDOO
LQYHVWLJDWLRQDOSURGXFWLVVWRUHGLQDVHFXUHGDUHDXQGHUUHFRPPHQGHGVWRUDJHFRQGLWLRQVDQGLQ
DFFRUGDQFHZLWKDSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV6WRUDJHDQGKDQGOLQJFRQGLWLRQVZLOOEH
SURYLGHGLQWKHSKDUPDF\PDQXDO7KHLGHQWLW\RIVWXG\GUXJLVSUHVHQWHGLQ7DEOH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

Table 10-1 
Identity of Study Drugs
Dosage
Packaging
Formulation/
Route of Administration
Storage Condition
3ODFHER
6XSSOLHGDVPJRUPJ
FDSVXOHVLQERWWOHVFRQWDLQLQJ
JUDQXOHV
&DSVXOHVFRQWDLQLQJ
JUDQXOHVRUDO
6WRUHDW&ZLWK
H[FXUVLRQVWR&
PJLYDFDIWRU
6XSSOLHGDVPJFDSVXOHVLQ
ERWWOHVRUVDFKHWVDFRQWDLQLQJ
JUDQXOHV
&DSVXOHVRUVDFKHWVDFRQWDLQLQJ
JUDQXOHVRUDO
6WRUHDW&ZLWK
H[FXUVLRQVWR&
PJLYDFDIWRU
6XSSOLHGDVPJFDSVXOHVLQ
ERWWOHVRUVDFKHWVDFRQWDLQLQJ
JUDQXOHV
&DSVXOHVRUVDFKHWVDFRQWDLQLQJ
JUDQXOHVRUDO
6WRUHDW&ZLWK
H[FXUVLRQVWR&
PJLYDFDIWRU
x 6XSSOLHGDVWZRPJVDFKHWVD
x 6XSSOLHGDVPJWDEOHWVXSRQ
UHTXHVW
x 6DFKHWVDFRQWDLQLQJ
JUDQXOHVRUDO
x %OXHILOPFRDWHGWDEOHWZLWK
ZD[RUDO
6WRUHDW&ZLWK
H[FXUVLRQVWR&
D
7REHVSHFLILHGLQWKHSKDUPDF\PDQXDO
10.7
Drug Accountability
7KHSKDUPDFLVWRUGHVLJQDWHGVLWHVWDIIZLOOPDLQWDLQLQIRUPDWLRQUHJDUGLQJWKHGDWHVDQG
DPRXQWVRIVWXG\GUXJUHFHLYHGGUXJGLVSHQVHGWRWKHVXEMHFWVDQGGUXJUHWXUQHGE\
WKHVXEMHFWV6XEMHFWVZLOOEHLQVWUXFWHGWRUHWXUQDOOXVHGDQGXQXVHGPDWHULDOVDVVRFLDWHGZLWK
WKHVWXG\GUXJWRWKHVLWH7KHVHPDWHULDOVZLOOEHUHWDLQHGDWWKHVLWHDFFRUGLQJWRLQVWUXFWLRQV
SURYLGHGE\9HUWH[RULWVGHVLJQHHXQWLOLQYHQWRULHGE\WKHVWXG\PRQLWRU7KHVWXG\PRQLWRUZLOO
UHYLHZVWXG\GUXJUHFRUGVDQGLQYHQWRU\WKURXJKRXWWKHVWXG\
10.8
Disposal, Return, or Retention of Unused Drug
7KHVLWHVWDIIRUSKDUPDF\SHUVRQQHOZLOOUHWDLQDOOPDWHULDOVUHWXUQHGE\WKHVXEMHFWVXQWLOWKH
VWXG\PRQLWRUKDVSHUIRUPHGGUXJDFFRXQWDELOLW\$WWKHHQGRIWKHVWXG\WKHVWXG\PRQLWRUZLOO
SURYLGHLQVWUXFWLRQVDVWRWKHGLVSRVLWLRQRIDQ\XQXVHGLQYHVWLJDWLRQDOSURGXFW,IWKHVWXG\
PRQLWRUDXWKRUL]HVGHVWUXFWLRQDWWKHVWXG\VLWHWKHLQYHVWLJDWRUZLOOHQVXUHWKDWWKHPDWHULDOVDUH
GHVWUR\HGLQFRPSOLDQFHZLWKDSSOLFDEOHHQYLURQPHQWDOUHJXODWLRQVLQVWLWXWLRQDOSROLF\DQGDQ\
VSHFLDOLQVWUXFWLRQVSURYLGHGE\9HUWH['HVWUXFWLRQZLOOEHDGHTXDWHO\GRFXPHQWHG
10.9
Compliance 
6WXG\GUXJDFFRXQWDELOLW\VKRXOGEHDVVHVVHGDWHDFKYLVLWE\FRXQWLQJUHWXUQHGGRVDJHXQLWV
WDEOHWV>PJ@RUFDSVXOHVRUVDFKHWV>PJDQGPJ@'LVFUHSDQFLHVVKRXOGEHGLVFXVVHG
ZLWKWKHVXEMHFWDQGUHFRUGHGLQWKHFDVHUHSRUWIRUP&5)
,IVXEMHFWVGHPRQVWUDWHFRQWLQXHGQRQFRPSOLDQFHZLWKVWXG\UHTXLUHPHQWVUHVWULFWLRQV
LQVWUXFWLRQVDQGVWXG\GUXJGRVLQJGHVSLWHHGXFDWLRQDOHIIRUWVWKHLQYHVWLJDWRUVKRXOGFRQWDFW
WKH9HUWH[PHGLFDOPRQLWRUWRGLVFXVVQRQFRPSOLDQFHDQGGLVFRQWLQXDWLRQRIWKHVXEMHFWIURPWKH
VWXG\

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

10.10
Blinding and Unblinding
10.10.1
Blinding
3DUWLVDGRXEOHEOLQGVWXG\7KHVXEMHFWVDQGDOOVLWHSHUVRQQHOLQFOXGLQJWKHLQYHVWLJDWRUDQG
WKHVWXG\PRQLWRUZLOOUHPDLQEOLQGHGWRWUHDWPHQWDVVLJQPHQWVXQWLOGDWDEDVHORFN7KH9HUWH[
VWXG\WHDPZLOOUHPDLQEOLQGHGWRWUHDWPHQWDVVLJQPHQWVXQWLODOOVXEMHFWVKDYHFRPSOHWHG3DUW
RIWKHVWXG\
$OOVWXG\SHUVRQQHOZLOOEHEOLQGHGWRVXEMHFWWUHDWPHQWDVVLJQPHQWVH[FHSWIRUWKHIROORZLQJ
LQGLYLGXDOV
x
$Q\VLWHSHUVRQQHOIRUZKRPWKLVLQIRUPDWLRQLVLPSRUWDQWWRHQVXUHWKHVDIHW\RIWKHVXEMHFW
LQWKHHYHQWRIDOLIHWKUHDWHQLQJPHGLFDOHPHUJHQF\
x
9HUWH[*OREDO3DWLHQW6DIHW\*36DQG5HJXODWRU\$IIDLUVSHUVRQQHOWRVDWLVI\6$(
SURFHVVLQJDQGUHSRUWLQJUHJXODWLRQV
x
8QEOLQGHGVWDWLVWLFLDQSUHSDULQJWKHILQDOSURGXFWLRQUDQGRPL]DWLRQOLVWZKRLVQRWSDUWRI
WKHVWXG\WHDP
x
9HQGRUSUHSDULQJWKHXQEOLQGHGDQDO\VLVIRUWKH,'0&
x
9HUWH['DWD0DQDJHPHQW,:56PDQDJHPHQW
x
9HUWH[&OLQLFDO6XSSO\&KDLQ
/&,'DWD%OLQGLQJ
'HVSLWHWUHDWPHQWEOLQGLQJNQRZOHGJHRIWKH/&,UHVXOWVKDVWKHSRWHQWLDOWRVXJJHVWZKHWKHUD
VXEMHFWKDVEHHQDGPLQLVWHUHGDFWLYHVWXG\GUXJRUSODFHER7KHUHIRUHGXULQJ3DUWWKH9HUWH[
VWXG\WHDPZLOOKDYHQRDFFHVVWRWKHSRVWGRVH/&,GDWD
10.10.2
Unblinding
$WWKHLQLWLDWLRQRIWKHVWXG\WKHVWXG\VLWHZLOOEHLQVWUXFWHGRQWKHPHWKRGIRUEUHDNLQJWKH
EOLQG7KHXQEOLQGLQJPHWKRGZLOOEHHLWKHUDPDQXDORUHOHFWURQLFSURFHVV
8QEOLQGLQJRIWKHLQGLYLGXDOVXEMHFW
VWUHDWPHQWE\WKHLQYHVWLJDWRUZLOOEHOLPLWHGWRPHGLFDO
HPHUJHQFLHVRUXUJHQWFOLQLFDOVLWXDWLRQVLQZKLFKNQRZOHGJHRIWKHVXEMHFW
VVWXG\WUHDWPHQWLV
QHFHVVDU\IRUFOLQLFDOPDQDJHPHQW,QVXFKFDVHVLQYHVWLJDWRUVZLOOXVHWKHLUEHVWMXGJPHQWDVWR
ZKHWKHUWRXQEOLQGZLWKRXWILUVWDWWHPSWLQJWRFRQWDFWWKH9HUWH[PHGLFDOPRQLWRUWRGLVFXVVDQG
DJUHHWRWKHQHHGIRUXQEOLQGLQJ,ILQYHVWLJDWRUVGHHPLWQRWQHFHVVDU\WRXQEOLQGLPPHGLDWHO\
WKH\ZLOOILUVWDWWHPSWWRFRQWDFWWKHPHGLFDOPRQLWRUWRGLVFXVVDQGDJUHHWRWKHQHHGIRU
XQEOLQGLQJ,ILQYHVWLJDWRUVKDYHWULHGEXWDUHXQDEOHWRUHDFKWKHPHGLFDOPRQLWRUWKH\ZLOOXVH
WKHLUEHVWMXGJPHQWEDVHGRQWKHQDWXUHDQGXUJHQF\RIWKHFOLQLFDOVLWXDWLRQDQGPD\SURFHHG
ZLWKXQEOLQGLQJZLWKRXWKDYLQJVXFFHVVIXOO\UHDFKHGDQGGLVFXVVHGWKHVLWXDWLRQZLWKWKHPHGLFDO
PRQLWRU
&RQWDFWLQIRUPDWLRQIRUWKHPHGLFDOPRQLWRURUDSSURSULDWHEDFNXSZLOOEHSURYLGHGLQD
VHSDUDWHGRFXPHQW
,QDGGLWLRQWKH9HUWH[0HGLFDO,QIRUPDWLRQ&DOO&HQWHU
ZLOODQVZHUFDOOV
KRXUVDGD\GD\VDZHHNGD\VRIWKH\HDUDQGZLOOWULDJHWKHVHFDOOVWRWKHVWXG\
PHGLFDOPRQLWRURUDSSURSULDWHEDFNXS

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG






11.5
Safety
6DIHW\HYDOXDWLRQVZLOOLQFOXGHFOLQLFDOODERUDWRU\DVVHVVPHQWVLQFOXGLQJ/)7V2(VDQG
UHSRUWLQJRI$(V
11.5.1
Adverse Events
$OO$(VZLOOEHDVVHVVHGGRFXPHQWHGDQGUHSRUWHGLQDFFRUGDQFHZLWK,&+*&3JXLGHOLQHV
6HFWLRQRXWOLQHVWKHGHILQLWLRQVFROOHFWLRQSHULRGVFULWHULDDQGSURFHGXUHVIRU
GRFXPHQWLQJJUDGLQJDQGUHSRUWLQJ$(V$VHSDUDWHGRFXPHQWWKDWGHWDLOV$(&5)FRPSOHWLRQ
JXLGHOLQHVIRULQYHVWLJDWRUVDVZHOODVWUDLQLQJZLOOEHSURYLGHG
11.5.2
Clinical Laboratory Assessments
%ORRGVDPSOHVZLOOEHFROOHFWHGDWWLPHVVSHFLILHGLQ7DEOH7DEOHDQG7DEOHDQG
ZLOOEHDQDO\]HGDWDFHQWUDOODERUDWRU\1RWH,IXQGHUH[FHSWLRQDOFLUFXPVWDQFHVEORRG
VDPSOHVPXVWEHGUDZQDQGRUDQDO\]HGDWDORFDOODERUDWRU\DSSURYDOPXVWILUVWEHREWDLQHG
IURPWKHPHGLFDOPRQLWRU$OOEORRGVDPSOHVZLOOEHFROOHFWHGZKLOHVXEMHFWVDUHLQDVHDWHGRU
VXSLQHSRVLWLRQ6SHFLILFLQVWUXFWLRQVIRUWKHFROOHFWLRQSURFHVVLQJDQGVKLSPHQWRIVDPSOHVZLOO
EHSURYLGHGLQDVHSDUDWH/DERUDWRU\0DQXDO/DERUDWRU\WHVWUHVXOWVWKDWDUHDEQRUPDODQG
FRQVLGHUHGFOLQLFDOO\VLJQLILFDQWPXVWEHUHSRUWHGDV$(VVHH6HFWLRQ
7KHVDIHW\ODERUDWRU\WHVWSDQHOVDUHSUHVHQWHGLQ7DEOH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry
Hematology
Urinalysisa
*OXFRVH
%ORRGXUHDQLWURJHQ
&UHDWLQLQH
6RGLXP
3RWDVVLXP
&DOFLXP
,QRUJDQLFSKRVSKDWH
/DFWDWHGHK\GURJHQDVH
7RWDOSURWHLQ
$OEXPLQ
,QGLUHFWELOLUXELQ
$P\ODVH
/LSDVH
&UHDWLQHNLQDVHD
Liver Function Tests
$ONDOLQHSKRVSKDWDVH
$VSDUWDWHWUDQVDPLQDVH
$ODQLQHWUDQVDPLQDVH
*DPPDJOXWDP\OWUDQVIHUDVH
7RWDOELOLUXELQ
+HPRJORELQ
5HGEORRGFHOOFRXQW
3ODWHOHWFRXQW
:KLWHEORRGFHOOFRXQW
'LIIHUHQWLDODEVROXWHDQG
SHUFHQW
(RVLQRSKLOV
%DVRSKLOV
1HXWURSKLOV
/\PSKRF\WHV
0RQRF\WHV
Coagulation Studiesa
$FWLYDWHGSDUWLDOWKURPERSODVWLQ
WLPH
3URWKURPELQWLPH
3URWKURPELQWLPH,QWHUQDWLRQDO
1RUPDOL]HG5DWLR
/HXNRF\WHV
1LWULWH
8URELOLQRJHQ
3URWHLQ
S+
%ORRG
6SHFLILFJUDYLW\
.HWRQHV
%LOLUXELQ
*OXFRVH
D
7REHFRQGXFWHGDW6FUHHQLQJRQO\
CFTR Genotype
CFTRJHQRW\SLQJZLOOEHSHUIRUPHGWRFRQILUPWKHVXEMHFWKDVWKHG551D, G178R, S549N, 
S549R, G551S, G1244E, S1251N, S1255P, RUG1349DPXWDWLRQLQDWOHDVWCFTRDOOHOH.
6XEMHFWVZKRKDYHEHHQUDQGRPL]HGRQWKHEDVLVRIDKLVWRULFDOJHQRW\SHODEUHSRUWDQGZKRVH
VFUHHQLQJJHQRW\SHGRHVQRWFRQILUPVWXG\HOLJLELOLW\PXVWEHGLVFRQWLQXHGIURPWKHVWXG\
6SHFLILFLQVWUXFWLRQVZLOOEHSURYLGHGLQWKH/DERUDWRU\0DQXDO
Mandatory Liver Function Testing: 
/LYHUIXQFWLRQWHVWLQJ$/7$67**7$/3DQGWRWDOELOLUXELQPXVWEHSHUIRUPHGZKLOH
VXEMHFWVDUHUHFHLYLQJVWXG\GUXJWUHDWPHQWDFFRUGLQJWRWKHVFKHGXOHRIDVVHVVPHQWVZLWKWKH
H[FHSWLRQRIVXEMHFWVZKRPHHWSURWRFROGHILQHGFULWHULDIRUVWXG\GUXJLQWHUUXSWLRQRU
GLVFRQWLQXDWLRQEHORZ)RUWKHVHVXEMHFWV/)7VPXVWEHPRQLWRUHGDWOHDVWHYHU\ZHHNVDV
QRWHGLQ7DEOHDQGFDQUHWXUQWRPRQLWRULQJDWUHJXODUO\VFKHGXOHGVWXG\YLVLWVZKHQ/)7
UHVXOWVKDYHUHWXUQHGWRWKHVXEMHFW¶VEDVHOLQHDQGUHPDLQDWEDVHOLQHYDOXHVIRUZHHNV7KHVH
EORRGVDPSOHVVKRXOGEHSURFHVVHGDQGVKLSSHGLPPHGLDWHO\SHUWKH/DERUDWRU\0DQXDO
,IDVXEMHFWFDQQRWUHWXUQWRWKHVLWHIRUOLYHUIXQFWLRQWHVWLQJDORFDOODERUDWRU\PD\EHXVHG
(OHYDWLRQVLQ/)7Vtî8/1DWWKHORFDOODERUDWRU\PXVWEHUHSRUWHGLPPHGLDWHO\WRWKH9HUWH[
PHGLFDOPRQLWRU$1'WKHVXEMHFWPXVWKDYHWKHWHVWVUHSHDWHGDQGVHQWWRWKHFHQWUDOODERUDWRU\
DVVRRQDVSRVVLEOHLGHDOO\ZLWKLQWRKRXUV
,WLVVWURQJO\UHFRPPHQGHGWKDWVXEMHFWVZLWKQHZ$/7RU$67HOHYDWLRQVRI!î8/1DQG
FOLQLFDOV\PSWRPVEHIROORZHGFORVHO\LQFOXGLQJUHSHDWFRQILUPDWRU\WHVWLQJZLWKLQWR

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

KRXUVRIWKHLQLWLDOILQGLQJDQGVXEVHTXHQWFORVHPRQLWRULQJRI$/7DQG$67OHYHODV
FOLQLFDOO\LQGLFDWHG
$VGHVFULEHGLQ6HFWLRQLWLVUHFRPPHQGHGWKDWDQLQFUHDVHLQ/)7VWRî8/1LI/)7VDUH
QRUPDODWEDVHOLQHRUDQLQFUHDVHWKDWH[FHHGVDQDEVROXWHYDOXHRIî8/1UHJDUGOHVVRI
ZKHWKHU/)7VDUHQRUPDODWEDVHOLQHVKRXOGEHGLVFXVVHGZLWKWKH9HUWH[PHGLFDOPRQLWRU
Study Drug Interruption or Discontinuation Due to Elevated Liver Function Test 
Parameters:
6WXG\GUXJDGPLQLVWUDWLRQmust be interruptedLPPHGLDWHO\DQGWKH9HUWH[PHGLFDOPRQLWRU
PXVWEHQRWLILHGLIDQ\RIWKHIROORZLQJFULWHULDDUHPHW
x
$/7RU$67!î8/1RU
x
$/7RU$67!î8/1IRUPRUHWKDQZHHNVRU
x
$/7RU$67!î8/1LQDVVRFLDWLRQZLWKHOHYDWLRQRIWRWDOELOLUXELQ!î8/1DQGRU
FOLQLFDOMDXQGLFH
$WKRURXJKLQYHVWLJDWLRQRISRWHQWLDOFDXVHVVKRXOGEHFRQGXFWHGDQGWKHVXEMHFWVKRXOGEH
IROORZHGFORVHO\IRUFOLQLFDOSURJUHVVLRQ
,IQRFRQYLQFLQJDOWHUQDWLYHHWLRORJ\HJYLUDOKHSDWLWLVIRUWKHHOHYDWHGWUDQVDPLQDVHVLV
LGHQWLILHGUHJDUGOHVVRIZKHWKHU$/7RU$67OHYHOVKDYHLPSURYHGWKHsubject must be 
discontinued from the studyLQFRQVXOWDWLRQZLWKWKH9HUWH[PHGLFDOPRQLWRUVHH6HFWLRQ
6XEMHFWVGLVFRQWLQXHGIRUHOHYDWHGWUDQVDPLQDVHVVKRXOGEHIROORZHGXQWLOWKHLUWUDQVDPLQDVHV
QRUPDOL]HRUUHWXUQWREDVHOLQH
,IDFRQYLQFLQJDOWHUQDWLYHHWLRORJ\IRUWKHHOHYDWHGWUDQVDPLQDVHVLVLGHQWLILHGDQGWKHVXEMHFW
V
V\PSWRPVDQGODERUDWRU\ILQGLQJVKDYHLPSURYHGWKHLQYHVWLJDWRUPD\FRQVLGHUUHVXPLQJVWXG\
GUXJWUHDWPHQWLQFRQVXOWDWLRQZLWKWKH9HUWH[PHGLFDOPRQLWRU
Additional Evaluations: 
$GGLWLRQDOFOLQLFDOODERUDWRU\HYDOXDWLRQVZLOOEHSHUIRUPHGDWRWKHUWLPHVLIMXGJHGWREH
FOLQLFDOO\DSSURSULDWHRULIWKHRQJRLQJUHYLHZRIWKHGDWDVXJJHVWVWKDWDPRUHGHWDLOHG
DVVHVVPHQWRIFOLQLFDOODERUDWRU\VDIHW\HYDOXDWLRQVLVUHTXLUHG$Q\FKDQJHVWRWKHVFKHGXOHG
WLPHVRIFOLQLFDOODERUDWRU\GHWHUPLQDWLRQZLOOEHDJUHHGZLWK9HUWH[DQGGRFXPHQWHGLQWKH
VWXG\PDVWHUILOHV
11.5.3
Physical Examinations and Vital Signs
$SK\VLFDOH[DPLQDWLRQRIDOOERG\V\VWHPVDQGYLWDOVLJQVDVVHVVPHQWZLOOEHSHUIRUPHGDW
6FUHHQLQJVHH7DEOH$WRWKHUYLVLWVV\PSWRPGLUHFWHGSK\VLFDOH[DPLQDWLRQVDQG
V\PSWRPGLUHFWHGYLWDOVLJQDVVHVVPHQWVFDQEHSHUIRUPHGDWWKHGLVFUHWLRQRIWKHLQYHVWLJDWRURU
KHDOWKFDUHSURYLGHU
$SK\VLFDOH[DPLQDWLRQLQFOXGHVDUHYLHZRIWKHIROORZLQJV\VWHPVKHDGQHFNWK\URLG
H\HVHDUVQRVHWKURDW((17UHVSLUDWRU\FDUGLRYDVFXODUO\PSKQRGHVDEGRPHQVNLQ
PXVFXORVNHOHWDODQGQHXURORJLFDO%UHDVWDQRUHFWDODQGJHQLWDOH[DPLQDWLRQVZLOOEHSHUIRUPHG
ZKHQPHGLFDOO\LQGLFDWHG$IWHU6FUHHQLQJDQ\FOLQLFDOO\VLJQLILFDQWDEQRUPDOILQGLQJVLQ
SK\VLFDOH[DPLQDWLRQVZLOOEHUHSRUWHGDV$(V

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

9LWDOVLJQVLQFOXGHEORRGSUHVVXUHV\VWROLFDQGGLDVWROLFWHPSHUDWXUHKHDUWUDWHDQGUHVSLUDWLRQ
UDWH7KHVHZLOOEHDVVHVVHGIROORZLQJDWOHDVWDPLQXWHUHVW
11.5.4
Electrocardiograms
1RWDSSOLFDEOH
11.5.5
Contraception and Pregnancy
1RWDSSOLFDEOH
11.5.6
Ophthalmologic Examinations
6XEMHFWVZLOOXQGHUJRDQ2(DWDOOWLPHSRLQWVLQGLFDWHGLQ7DEOH7DEOHDQG7DEOH
7KH2(ZLOOEHFRQGXFWHGE\DOLFHQVHGRSKWKDOPRORJLVWRURSWRPHWULVWSUHIHUDEO\DSHGLDWULF
RSKWKDOPRORJLVW
7KH2(ZLOOLQFOXGHWKHIROORZLQJ
x
PHDVXUHPHQWRIEHVWFRUUHFWHGGLVWDQFHYLVXDODFXLW\RIHDFKH\H
x
PHDVXUHPHQWRIOHQVUHIUDFWLQJSRZHUDXWRUHIUDFWRURURSKWKDOPRVFRS\VWUHDNIROORZLQJ
F\FORSOHJLDDQG
x
H[DPLQDWLRQRIWKHOHQVZLWKDVOLWODPS
,QDGGLWLRQDW6FUHHQLQJUHOHYDQWPHGLFDOKLVWRU\ZLOOEHREWDLQHGIRUDOOVXEMHFWVLQFOXGLQJWKH
IROORZLQJ
x
KLVWRU\RIVWHURLGXVH
x
KLVWRU\RUSUHVHQFHRIGLDEHWHV
x
DQ\SULRURSKWKDOPRORJLFRURSWRPHWULFH[DPLQDWLRQV
x
KLVWRU\RIWUDXPDWRWKHH\H
x
DQ\IDPLO\KLVWRU\RIJODXFRPDFRQJHQLWDOFDWDUDFWVRUFDWDUDFWVDULVLQJODWHULQOLIH
x
XVHRIFRUUHFWLYHOHQVHVFRQWDFWOHQVHVRUH\HJODVVHV
x
KLVWRU\RISURORQJHGH[SRVXUHWRVXQOLJKWRUXOWUDYLROHWOLJKWDQGXVHRIVXQJODVVHV
x
KLVWRU\RIH[SRVXUHWRVHFRQGKDQGVPRNH
x
KLVWRU\RIUDGLDWLRQH[SRVXUHHJ;UD\DQG
x
KLVWRU\RIUHWLQRSDWK\RISUHPDWXULW\
,IDQDGHTXDWHVOLWODPSH[DPLQDWLRQFDQQRWEHFRQGXFWHGDWWKH6FUHHQLQJ2(WKHVXEMHFWZLOO
QRWEHHQUROOHGLQ3DUWXQWLODQDGHTXDWHUHSHDW2(LVFRPSOHWHGZLWKLQZHHNV7KH
6FUHHQLQJ2(GRHVQRWQHHGWREHUHSHDWHGLIWKHUHLVGRFXPHQWDWLRQRIDQH[DPLQDWLRQPHHWLQJ
SURWRFROFULWHULDWKDWZDVFRQGXFWHGZLWKLQPRQWKVEHIRUHWKH6FUHHQLQJ9LVLW6XEMHFWVZLWK
GRFXPHQWDWLRQRIELODWHUDOOHQVUHPRYDOGRQRWQHHGWKH2(
,IDYLVXDOO\VLJQLILFDQWOHQVRSDFLW\RUFDWDUDFWLVLGHQWLILHGDW6FUHHQLQJWKH9HUWH[PHGLFDO
PRQLWRUPXVWEHQRWLILHG$GGLWLRQDO2(VPD\EHUHTXLUHGLIDOHQVRSDFLW\RUFDWDUDFWLV
LGHQWLILHGDW6FUHHQLQJ

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

6XEMHFWVZKRGLVFRQWLQXHIURPVWXG\GUXJWUHDWPHQWZLOOKDYHDQ2(WKDWLVWRRFFXUEHWZHHQ
WKHLUODVWGRVHRIVWXG\GUXJDQGFRPSOHWLRQRIWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLW
12
STATISTICAL AND ANALYTICAL PLANS
$QDO\VLVRIDOOGDWDZLOOEHSHUIRUPHGE\9HUWH[RULWVGHVLJQHH$GHWDLOHGDQDO\VLVSODQIRU
WKHDQDO\VLVRIHIILFDF\DQGVDIHW\GDWDZLOOEHSUHVHQWHGLQWKHVWDWLVWLFDODQDO\VLVSODQ6$3
12.1
Sample Size and Power
,WLVSODQQHGWKDWDSSUR[LPDWHO\VXEMHFWVZLOOEHHQUROOHGLQWKLVVWXG\$VVKRZQLQ7DEOH
DVDPSOHVL]HRIVXEMHFWVZLOOSURYLGHDSSUR[LPDWHO\SRZHUWRGHWHFWDWUHDWPHQW
GLIIHUHQFHLQPHDQFKDQJHIURPVWXG\EDVHOLQHLQ/&,GLIIHUHQFHEHWZHHQLYDFDIWRUDQGSODFHER
LQWKHFKDQJHIURPVWXG\EDVHOLQHRISRLQWV7KHFDOFXODWLRQLVEDVHGRQDSDLUHGWWHVWZLWKD
VLGHGVLJQLILFDQFHOHYHORIDQGDVVXPHVWKDWWKHZLWKLQVXEMHFWVWDQGDUGGHYLDWLRQ6'
IRUWKHGLIIHUHQFHLQFKDQJHIURPVWXG\EDVHOLQHIRUWKHSHULRGVLVSRLQWVDQGWKDWWKH
GURSRXWUDWHLVDERXWIRU3DUW
'LIIHUHQWVFHQDULRVDUHSUHVHQWHGLQ7DEOHIRUWKHYDULDELOLW\DQGWKHPDJQLWXGHRIWKH
WUHDWPHQWHIIHFWEDVHGRQSRZHUDQGVLGHGVLJQLILFDQFHOHYHORI7KHPRVW
FRQVHUYDWLYHVFHQDULRVDUHSUHVHQWHGLQWKHODVWURZVRIWKHWDEOHLHWUHDWPHQWHIIHFWRI
DQGUHVSHFWLYHO\
Table 12-1 
Sample Size Calculation Corresponding to Different Values of Treatment 
Effect on Lung Clearance Index Change-From-Predose
Treatment Effect (points) on LCI
Change From Study Baseline
Standard Deviation of Paired 
Treatment Difference in LCI Change 
From Study Baseline
N 






















12.2
Analysis Sets
7KHFull Analysis Set)$6LVGHILQHGDVDOOUDQGRPL]HGVXEMHFWVZKRKDYHDG551D, G178R, 
S549N, S549R, G551S, G1244E, S1251N, S1255P, RUG1349DPXWDWLRQRQDWOHDVWDOOHOHDQG
ZKRUHFHLYHGDWOHDVWGRVHRIVWXG\GUXJLHLYDFDIWRURUSODFHERDQGKDGDWOHDVWSRVW
EDVHOLQHDVVHVVPHQW$OOQRQVDIHW\HJGHPRJUDSKLFVVXPPDULHVZLOOEHUHIHUHQFHGXVLQJWKH
)$6DVDSSURSULDWH,QWKH)$6VXEMHFWVZLOOEHDQDO\]HGDFFRUGLQJWRWKHWUHDWPHQWVHTXHQFH
WKH\ZHUHUDQGRPL]HGWR
7KHSafety SetLVGHILQHGDVDOOVXEMHFWVZKRUHFHLYHGDWOHDVWGRVHRIVWXG\GUXJ$OO
VXPPDULHVRIVDIHW\ZLOOEHUHIHUHQFHGXVLQJWKH6DIHW\6HWDQGZLOOEHSHUIRUPHGSHUWUHDWPHQW
UHFHLYHG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

$OOVXEMHFWGDWDZLOOEHSUHVHQWHGLQWKHVXEMHFWGDWDOLVWLQJV
12.3
Statistical Analysis
7KHSULPDU\REMHFWLYHRIWKHVWXG\LVWRHYDOXDWHWKHHIILFDF\RILYDFDIWRUWUHDWPHQWLQVXEMHFWV
ZLWK&)ZKRKDYHDVSHFLILHGCFTRJDWLQJPXWDWLRQDQGZKRDUHWKURXJK\HDUVRIDJHDWWKH
VWDUWRIWKHVWXG\DVPHDVXUHGE\/&,
7KLVVHFWLRQSUHVHQWVDVXPPDU\RIWKHSODQQHGVWDWLVWLFDODQDO\VHVRIHIILFDF\DQGVDIHW\IRUWKLV
VWXG\7KH9HUWH[%LRPHWULFVGHSDUWPHQWRUDGHVLJQDWHG&52ZLOODQDO\]HWKHGDWDGHULYHG
IURPWKLVVWXG\6$69HUVLRQRUKLJKHUZLOOEHXVHGWRJHQHUDWHDOOVWDWLVWLFDORXWSXWV
WDEOHVILJXUHVOLVWLQJVDQGGDWDVHWV
12.3.1
General Considerations
7KHIROORZLQJVXPPDULHVZLOOEHSHUIRUPHGIRU3DUW
x
Continuous variablesZLOOEHVXPPDUL]HGXVLQJWKHIROORZLQJGHVFULSWLYHVXPPDU\
VWDWLVWLFVWKHQXPEHURIVXEMHFWVQPHDQ6'VWDQGDUGHUURUPHGLDQPLQLPXPYDOXH
DQGPD[LPXPYDOXH
x
Categorical variablesZLOOEHVXPPDUL]HGXVLQJFRXQWVDQGSHUFHQWDJHV
Baseline:)RUWKLVFURVVRYHUVWXG\W\SHVRIEDVHOLQHVWXG\EDVHOLQHDQGSHULRGEDVHOLQHZLOO
EHGHILQHGIRU3DUWVDQG
)RU3DUW7KHVWXG\EDVHOLQHLVGHILQHGDVWKHPRVWUHFHQWQRQPLVVLQJPHDVXUHPHQWFROOHFWHG
SULRUWRWKHLQLWLDODGPLQLVWUDWLRQRIVWXG\GUXJLQ7UHDWPHQW3HULRG3HULRGEDVHOLQHLVGHILQHG
DVWKHPRVWUHFHQWQRQPLVVLQJPHDVXUHPHQWFROOHFWHGEHIRUHWKHLQLWLDODGPLQLVWUDWLRQRIVWXG\
GUXJLQHDFK7UHDWPHQW3HULRG)RU7UHDWPHQW3HULRGWKHSHULRGEDVHOLQHZLOOEHWKHVWXG\
EDVHOLQHIRU7UHDWPHQW3HULRGWKHSHULRGEDVHOLQHZLOOEHIURPDQDVVHVVPHQWPHDVXUHGDIWHU
WKH:DVKRXW3HULRG
)RU3DUW7KHVWXG\EDVHOLQHLVGHILQHGDVWKHPRVWUHFHQWQRQPLVVLQJPHDVXUHPHQWFROOHFWHG
SULRUWRWKHLQLWLDODGPLQLVWUDWLRQRIVWXG\GUXJRI7UHDWPHQW3HULRG3HULRGEDVHOLQHLVGHILQHG
DVIROORZV
x
)RU7UHDWPHQW6HTXHQFHLYDFDIWRUĺZDVKRXWĺSODFHERSHULRGEDVHOLQHZLOOEHGHILQHGDV
WKHPRVWUHFHQWQRQPLVVLQJPHDVXUHPHQWFROOHFWHGSULRUWRLQLWLDODGPLQLVWUDWLRQRILYDFDIWRU
LQWKH2SHQODEHO3HULRG3DUW
x
)RU7UHDWPHQW6HTXHQFHSODFHERĺZDVKRXWĺLYDFDIWRUSHULRGEDVHOLQHZLOOEHWKHVDPH
DVSHULRGEDVHOLQHIRU7UHDWPHQW3HULRGLQ3DUWLHWKH:HHN9LVLW
)RUDOOHIILFDF\DQDO\VHVWKHVWDWLVWLFDOLQIHUHQFHZLOOEHEDVHGRQFKDQJHIURPVWXG\EDVHOLQH
+RZHYHUHIILFDF\DQDO\VHVEDVHGRQFKDQJHIURPSHULRGEDVHOLQHZLOODOVREHSUHVHQWHG
6LPLODUO\VXPPDU\WDEOHVDVDSSOLFDEOHZLOOEHSUHVHQWHGEDVHGRQERWKEDVHOLQHV
'DWDFROOHFWHGIURPVXEMHFWVLQ3DUWZLOOEHSUHVHQWHGLQVXEMHFWOLVWLQJV6XPPDU\VWDWLVWLFV
PD\DOVREHSURYLGHG
12.3.2
Background Characteristics
6XEMHFWGLVSRVLWLRQGHPRJUDSKLFDQGEDVHOLQHFKDUDFWHULVWLFVSULRUDQGFRQFRPLWDQW
PHGLFDWLRQVVWXG\GUXJH[SRVXUHDQGFRPSOLDQFHDQGRWKHUEDFNJURXQGFKDUDFWHULVWLFVZLOOEH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

VXPPDUL]HG$OOVXPPDULHVZLOOEHEDVHGRQWKH)$6XQOHVVRWKHUZLVHVSHFLILHGLQWKH6$3DQG
ZLOOEHSHUIRUPHGVHSDUDWHO\E\GDWDLQ3DUWVDQG
12.3.2.1
Subject Disposition
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVLQHDFKGLVSRVLWLRQFDWHJRU\HJUDQGRPL]HGLQFOXGHG
LQ)$6FRPSOHWLQJWUHDWPHQWSHULRGFRPSOHWLQJWKH)ROORZXS7HOHSKRQH&RQWDFWDQG
GLVFRQWLQXLQJVWXG\ZLWKDEUHDNGRZQRIWKHUHDVRQVIRUGLVFRQWLQXDWLRQPD\EHVXPPDUL]HGE\
YDULRXVFDWHJRULHVLQFOXGLQJWUHDWPHQWVHTXHQFHDQGRYHUDOO
12.3.2.2
Demographics and Baseline Characteristics
'HPRJUDSKLFVDQGEDVHOLQHFKDUDFWHULVWLFVHJDJHVH[UDFHZHLJKWKHLJKWDQGJHQRW\SH
ZLOOEHVXPPDUL]HGE\WUHDWPHQWVHTXHQFHDQGRYHUDOO
12.3.2.3
Prior and Concomitant Medications
0HGLFDWLRQVXVHGLQWKLVVWXG\ZLOOEHFRGHGE\XVLQJWKH:RUOG+HDOWK2UJDQL]DWLRQ'UXJ
'LFWLRQDU\(QKDQFHGDQGZLOOEHGHILQHGDVIROORZV
x
3ULRUPHGLFDWLRQPHGLFDWLRQWDNHQEHIRUHLQLWLDOGRVLQJZLWKVWXG\GUXJUHJDUGOHVVRIZKHQ
LWHQGHG
x
&RQFRPLWDQWPHGLFDWLRQPHGLFDWLRQUHFHLYHGDWRUDIWHULQLWLDOGRVLQJRIVWXG\GUXJRUWKRVH
UHFHLYHGEHIRUHLQLWLDOGRVLQJZLWKVWXG\GUXJWKDWFRQWLQXHGDIWHULQLWLDOGRVLQJRIVWXG\
GUXJ
1RWHWKDWWKHPHGLFDWLRQWDNHQEHIRUHLQLWLDOGRVLQJRIVWXG\GUXJDQGFRQWLQXHGDIWHULQLWLDO
GRVLQJZLOOEHVXPPDUL]HGDVSULRUPHGLFDWLRQDQGVHSDUDWHO\DVFRQFRPLWDQWPHGLFDWLRQ
+DQGOLQJRIPLVVLQJGDWHVHJPLVVLQJVWDUWHQGGDWHZLOOEHGLVFXVVHGLQWKH6$3
3ULRUPHGLFDWLRQVZLOOEHVXPPDUL]HGE\WUHDWPHQWVHTXHQFHDQGFRQFRPLWDQWPHGLFDWLRQVZLOO
EHVXPPDUL]HGE\WUHDWPHQWJURXS
12.3.2.4
Study Drug Exposure and Compliance
([SRVXUHWRVWXG\GUXJDQGGRVLQJFRPSOLDQFHZLOOEHVXPPDUL]HGIRUWKH)$6E\PHDQVRI
VXPPDU\VWDWLVWLFVLQZD\V
x
H[SRVXUHGXULQJ3DUW
x
H[SRVXUHGXULQJ3DUWDQG
x
FXPXODWLYHLYDFDIWRUH[SRVXUH3DUWVDQG
'HWDLOVZLOOEHSURYLGHGLQWKH6$3
12.3.3
Part 1 Efficacy Analysis 
12.3.3.1
Analysis of Primary Variable
7KHSULPDU\HIILFDF\YDULDEOHLVWKHDEVROXWHFKDQJHIURPEDVHOLQHWKURXJKZHHNVRIWUHDWPHQW
LQ/&,HQGSRLQW7KHDQDO\VLVZLOOEHEDVHGRQDPL[HGHIIHFWVPRGHOIRUUHSHDWHGPHDVXUHV
0050XWLOL]LQJWKH)$6
7KHPRGHOZLOOLQFOXGHWKHDEVROXWHFKDQJHIURPVWXG\EDVHOLQHLQHDFKSHULRGDVWKHGHSHQGHQW
YDULDEOHVHTXHQFHWUHDWPHQWSHULRGDQGYLVLWZLWKLQSHULRGDVIL[HGHIIHFWV/&,EDVHOLQHDQG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

7KHLQFLGHQFHRI7($(VLVWKHNH\VDIHW\HQGSRLQWDQGZLOOEHVXPPDUL]HGE\WUHDWPHQWDQGE\
PHDQVRIFRQWLQJHQF\WDEOHVQSHUFHQWDJH$7($(ZLOOEHGHILQHGDVDQ\$(WKDWVWDUWHGDWRU
DIWHULQLWLDOGRVLQJRIVWXG\GUXJRULQFUHDVHGLQVHYHULW\DWRUDIWHULQLWLDOGRVLQJRIVWXG\GUXJ
)RURWKHUVDIHW\HQGSRLQWVHJYLWDOVLJQVWKHUDZYDOXHVDQGFKDQJHVIURPEDVHOLQHZLOOEH
VXPPDUL]HGE\WUHDWPHQWDVDSSURSULDWH$GGLWLRQDOO\DOOVXEMHFWVDIHW\GDWDZLOOEHSUHVHQWHG
LQVXEMHFWGDWDOLVWLQJV$OOVXPPDULHVZLOOEHEDVHGRQWKH6DIHW\6HWVHH6HFWLRQ
12.3.5.1
Adverse Events
7($(VGHILQHGDV$(VWKDWGHYHORSHGRUZRUVHQHGRQRUDIWHUWKHILUVWGRVHRIVWXG\GUXJZLOO
EHVXPPDUL]HG$(VZLOOEHDWWULEXWHGWRVWXG\GUXJGHSHQGLQJRQWKHGDWHRIRQVHWRIWKH$(
DQGWKHWUHDWPHQWWKDWWKHVXEMHFWLVUHFHLYLQJDWWKHWLPHRIRQVHWRIWKH$(V,IDVXEMHFW
GLVFRQWLQXHGWUHDWPHQWGXULQJDVSHFLILFSHULRGWKH6DIHW\)ROORZXS9LVLWZLOOEHFRQVLGHUHGDV
WKHHQGGDWH7($(VZLOOKHUHDIWHUEHUHIHUUHGWRDV$(V$(VXPPDU\WDEOHVZLOOLQFOXGHWKH
IROORZLQJ
x
$OO$(V
x
5HODWHGGHILQHGDVSRVVLEO\UHODWHGRUUHODWHG$(V
x
$(VOHDGLQJWRVWXG\GUXJWUHDWPHQWGLVFRQWLQXDWLRQ
x
6$(V
x
$(VE\VHYHULW\
x
$(VE\UHODWLRQVKLS
6XPPDULHVZLOOEHSUHVHQWHGE\0HG'5$V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUPXVLQJ
IUHTXHQF\FRXQWVDQGSHUFHQWDJHV$VXEMHFWZLWKPXOWLSOHRFFXUUHQFHVRIWKHVDPH$(RUD
FRQWLQXLQJ$(ZLOOEHFRXQWHGRQO\RQFHZLWKWKHKLJKHVWVHYHULW\RUUHODWLRQVKLS
,QDGGLWLRQDOLVWLQJFRQWDLQLQJLQGLYLGXDOVXEMHFW$(GDWDIRUDOOGHDWKVDQGRWKHUVHULRXVDQG
VLJQLILFDQW$(VZLOOEHSURYLGHG
12.3.5.2
Clinical Laboratory Assessments
$OOVWDWLVWLFDODQDO\VHVRIODERUDWRU\YDOXHVZLOOEHSHUIRUPHGXVLQJ6,XQLWV&RQWLQXRXV
FKHPLVWU\KHPDWRORJ\DQGFRDJXODWLRQUHVXOWVZLOOEHVXPPDUL]HGE\WUHDWPHQWDWHDFKYLVLW
&KDQJHVIURPEDVHOLQHZLOODOVREHVXPPDUL]HG7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWK
VKLIWFKDQJHVIURPEDVHOLQHEDVHGRQWKHODERUDWRU\QRUPDOUDQJHVZLOOEHWDEXODWHG7KH
PD[LPXPRQWUHDWPHQWUHVXOWVZLOOEHWDEXODWHGE\WUHDWPHQWDQGVWXG\SDUW
8ULQDO\VLVUHVXOWVZLOOEHOLVWHGEXWQRWVXPPDUL]HG,QDGGLWLRQDOLVWLQJFRQWDLQLQJLQGLYLGXDO
VXEMHFWKHPDWRORJ\FKHPLVWU\DQGFRDJXODWLRQYDOXHVRXWVLGHWKHUHIHUHQFHUDQJHVZLOOEH
SURYLGHG7KLVOLVWLQJZLOOLQFOXGHGDWDIURPVFKHGXOHGDQGXQVFKHGXOHGWLPHSRLQWV
&OLQLFDOO\VLJQLILFDQWDEQRUPDOILQGLQJVZLOOEHUHSRUWHGDV$(V
6XPPDU\DQGDQDO\VLVRIHOHYDWLRQRI/)7SDUDPHWHUVZLOOEHSURYLGHGLQGHWDLOLQWKH6$3
12.3.5.3
Vital Signs
9LWDOVLJQVZLOOEHSUHVHQWHGDVDGDWDOLVWLQJDVXPPDU\WDEOHE\WUHDWPHQWVHTXHQFHZLOODOVR
EHSURYLGHG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

12.3.5.4
Physical Examination
3K\VLFDOH[DPLQDWLRQILQGLQJVZLOOEHSUHVHQWHGDVDGDWDOLVWLQJRQO\&OLQLFDOO\UHOHYDQWUHVXOWV
LGHQWLILHGDIWHUVFUHHQLQJZLOOEHUHSRUWHGDV$(V
12.3.5.5
Other Safety Analysis
1RWDSSOLFDEOH
12.3.6
Interim and IDMC Analyses
)ROORZLQJDUHYLHZRIVWXG\HQUROOPHQWDQGDVVHVVPHQWRIWKHDYDLODEOHQXPEHURISRWHQWLDO
VXEMHFWVIRUWKLVVWXG\9HUWH[GHFLGHGWRFORVHHQUROOPHQWDVRI)HEUXDU\DQGZLWKGUDZ
VXEMHFWVLQRUGHUWRWHUPLQDWHWKHVWXG\$VDUHVXOWQRLQWHULPRU,'0&DQDO\VHVZLOOEH
FRQGXFWHG6HH6HFWLRQ7KH,'0&&KDUWHUZLOOEHXSGDWHGIROORZLQJDSSURYDORIWKH
SURWRFRODPHQGPHQWWRUHIOHFWFKDQJHVLPSDFWHGE\WKHGHFLVLRQWRWHUPLQDWHWKHVWXG\HDUO\
13
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
13.1
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting
13.1.1
Adverse Events
13.1.1.1
Definition of an Adverse Event
$Q$(LVGHILQHGDVDQ\XQWRZDUGPHGLFDORFFXUUHQFHLQDVXEMHFWGXULQJWKHVWXG\WKHHYHQW
GRHVQRWQHFHVVDULO\KDYHDFDXVDOUHODWLRQVKLSZLWKWKHWUHDWPHQW7KLVLQFOXGHVDQ\QHZO\
RFFXUULQJHYHQWRUZRUVHQLQJRIDSUHH[LVWLQJFRQGLWLRQHJLQFUHDVHLQLWVVHYHULW\RU
IUHTXHQF\DIWHUWKH,&)LVVLJQHG
$Q$(LVFRQVLGHUHGVHULRXVLILWPHHWVWKHGHILQLWLRQLQ6HFWLRQ
13.1.1.2
Clinically Significant Assessments
6WXG\DVVHVVPHQWVLQFOXGLQJODERUDWRU\WHVWVSK\VLFDOH[DPLQDWLRQVDQGYLWDOVLJQVZLOOEH
DVVHVVHGDQGWKRVHGHHPHGDVFOLQLFDOO\VLJQLILFDQWZRUVHQLQJIURPEDVHOLQHGRFXPHQWHGDVDQ
$(:KHQSRVVLEOHDFOLQLFDOGLDJQRVLVIRUWKHVWXG\DVVHVVPHQWZLOOEHSURYLGHGUDWKHUWKDQWKH
DEQRUPDOWHVWUHVXOWDORQHHJXULQDU\WUDFWLQIHFWLRQDQHPLD,QWKHDEVHQFHRIDGLDJQRVLV
WKHDEQRUPDOVWXG\DVVHVVPHQWLWVHOIZLOOEHOLVWHGDVWKH$(HJEDFWHULDLQXULQHRUGHFUHDVHG
KHPRJORELQ
$QDEQRUPDOVWXG\DVVHVVPHQWLVFRQVLGHUHGFOLQLFDOO\VLJQLILFDQWLIWKHVXEMHFWKDVRUPRUHRI
WKHIROORZLQJ
x
&RQFRPLWDQWVLJQVRUV\PSWRPVUHODWHGWRWKHDEQRUPDOVWXG\DVVHVVPHQW
x
)XUWKHUGLDJQRVWLFWHVWLQJRUPHGLFDOVXUJLFDOLQWHUYHQWLRQ
x
$FKDQJHLQWKHGRVHRIVWXG\GUXJRUGLVFRQWLQXDWLRQIURPWKHVWXG\
5HSHDWWHVWLQJWRGHWHUPLQHZKHWKHUWKHUHVXOWLVDEQRUPDOLQWKHDEVHQFHRIDQ\RIWKHDERYH
FULWHULDGRHVQRWQHFHVVDULO\PHHWFOLQLFDOO\VLJQLILFDQWFULWHULD7KHGHWHUPLQDWLRQRIZKHWKHUWKH
VWXG\DVVHVVPHQWUHVXOWVDUHFOLQLFDOO\VLJQLILFDQWZLOOEHPDGHE\WKHLQYHVWLJDWRU

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

$ODERUDWRU\YDOXHWKDWLV*UDGHZLOOQRWDXWRPDWLFDOO\EHDQ6$($*UDGHODERUDWRU\YDOXH
ZLOOEHDQ6$(LIWKHFOLQLFDOVWDWXVRIWKHVXEMHFWLQGLFDWHVDOLIHWKUHDWHQLQJ$(
13.1.1.3
Documentation of Adverse Events
$OO$(VZLOOEHFROOHFWHGIURPWKHWLPH,&)LVVLJQHGXQWLOWKHIROORZLQJWLPHSRLQWV
x
)RUVXEMHFWVZKRGRQRWHQUROOXQWLOWLPHRIVFUHHQIDLOXUHHJVFUHHQIDLOXUHZLWKGUDZDORI
FRQVHQW
x
)RUHQUROOHGVXEMHFWVZKRKDYHD6DIHW\)ROORZXS7HOHSKRQH&RQWDFWWKURXJKWKH6DIHW\
)ROORZXS7HOHSKRQH&RQWDFW
x
)RUHQUROOHGVXEMHFWVZKRGRQRWKDYHD6DIHW\)ROORZXS9LVLWWKHHDUOLHVWRI
R
GD\VDIWHUWKHODVWGRVHRIVWXG\GUXJRU
o
7KH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWLIWKDWYLVLWLVZHHNVRUODWHUIROORZLQJWKH
ODVWGRVHRIVWXG\GUXJVHH6HFWLRQ
$OOVXEMHFWVZLOOEHTXHULHGXVLQJQRQOHDGLQJTXHVWLRQVDERXWWKHRFFXUUHQFHRI$(VDWHDFK
VWXG\YLVLW:KHQSRVVLEOHDFRQVWHOODWLRQRIVLJQVDQGRUV\PSWRPVZLOOEHLGHQWLILHGDV
RYHUDOOHYHQWRUGLDJQRVLV$OO$(VIRUHQUROOHGVXEMHFWVZLOOEHUHFRUGHGLQWKH&5)DQG
VRXUFHGRFXPHQW$(VIRUVXEMHFWVZKRDUHVFUHHQHGEXWQRWVXEVHTXHQWO\HQUROOHGLQWKHVWXG\
ZLOOEHUHFRUGHGRQO\LQWKHVXEMHFW
VVRXUFHGRFXPHQWV7KHIROORZLQJGDWDZLOOEHGRFXPHQWHG
IRUHDFK$(
x
'HVFULSWLRQRIWKHHYHQW
x
&ODVVLILFDWLRQRI³VHULRXV´RU³QRQVHULRXV´
x
'DWHRIILUVWRFFXUUHQFHDQGGDWHRIUHVROXWLRQLIDSSOLFDEOH
x
6HYHULW\
x
&DXVDOUHODWLRQVKLSWRVWXG\GUXJV
x
$FWLRQWDNHQ
x
2XWFRPH
x
&RQFRPLWDQWPHGLFDWLRQRURWKHUWUHDWPHQWJLYHQ
13.1.1.4
Adverse Event Severity
7KHLQYHVWLJDWRUZLOOGHWHUPLQHDQGUHFRUGWKHVHYHULW\RIDOOVHULRXVDQGQRQVHULRXV$(V7KH
JXLGDQFHDYDLODEOHDWWKHIROORZLQJZHEVLWHZLOOEHFRQVXOWHG7R[LFLW\*UDGLQJ6FDOHIRU
+HDOWK\$GXOWDQG$GROHVFHQW9ROXQWHHUV(QUROOHGLQ3UHYHQWLYH9DFFLQH&OLQLFDO7ULDOV
6HSWHPEHU&HQWHUIRU%LRORJLFV(YDOXDWLRQDQG5HVHDUFK
KWWSZZZIGDJRY%LRORJLFV%ORRG9DFFLQHV*XLGDQFH&RPSOLDQFH5HJXODWRU\,QIRUPDWLRQ
*XLGDQFHV9DFFLQHVXFPKWP$FFHVVHG2FWREHU7KHVHYHULW\RIDQ$(WKDWGRHV
QRWDSSHDULQWKLVVFDOHZLOOEHGHWHUPLQHGDFFRUGLQJWRWKHGHILQLWLRQVLQ7DEOH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

Table 13-1 
Grading of AE Severity
Classification
Definition
Mild (Grade 1)
0LOGOHYHORIGLVFRPIRUWDQGGRHVQRWLQWHUIHUHZLWKUHJXODUDFWLYLWLHV
Moderate (Grade 2)
0RGHUDWHOHYHORIGLVFRPIRUWDQGVLJQLILFDQWO\LQWHUIHUHVZLWKUHJXODUDFWLYLWLHV
Severe (Grade 3)
6LJQLILFDQWOHYHORIGLVFRPIRUWDQGSUHYHQWVUHJXODUDFWLYLWLHV
Life-threatening (Grade 4)
$Q\DGYHUVHGUXJH[SHULHQFHWKDWSODFHVWKHVXEMHFWLQWKHYLHZRIWKHLQYHVWLJDWRU
DWLPPHGLDWHULVNRIGHDWK

13.1.1.5
Adverse Event Causality
(YHU\HIIRUWZLOOEHPDGHE\WKHLQYHVWLJDWRUWRDVVHVVWKHUHODWLRQVKLSRIWKH$(LIDQ\WRWKH
VWXG\GUXJV&DXVDOLW\ZLOOEHFODVVLILHGXVLQJWKHFDWHJRULHVSUHVHQWHGLQ7DEOH
Table 13-2 
Classifications for AE Causality
Classification
Definition
Related
7KHUHLVDQDVVRFLDWLRQEHWZHHQWKHHYHQWDQGWKHDGPLQLVWUDWLRQRILQYHVWLJDWLRQDO
VWXG\GUXJDSODXVLEOHPHFKDQLVPIRUWKHHYHQWWREHUHODWHGWRWKHLQYHVWLJDWLRQDO
VWXG\GUXJDQGFDXVHVRWKHUWKDQWKHLQYHVWLJDWLRQDOVWXG\GUXJKDYHEHHQUXOHGRXW
DQGRUWKHHYHQWUHDSSHDUHGRQUHH[SRVXUHWRWKHLQYHVWLJDWLRQDOVWXG\GUXJ
Possibly related
7KHUHLVDQDVVRFLDWLRQEHWZHHQWKHHYHQWDQGWKHDGPLQLVWUDWLRQRIWKH
LQYHVWLJDWLRQDOVWXG\GUXJDQGWKHUHLVDSODXVLEOHPHFKDQLVPIRUWKHHYHQWWREH
UHODWHGWRLQYHVWLJDWLRQDOVWXG\GUXJEXWWKHUHPD\DOVREHDOWHUQDWLYHHWLRORJ\VXFK
DVFKDUDFWHULVWLFVRIWKHVXEMHFW¶VFOLQLFDOVWDWXVRUXQGHUO\LQJGLVHDVH
Unlikely related
7KHHYHQWLVXQOLNHO\WREHUHODWHGWRWKHLQYHVWLJDWLRQDOVWXG\GUXJDQGOLNHO\WREH
UHODWHGWRIDFWRUVRWKHUWKDQLQYHVWLJDWLRQDOVWXG\GUXJ
Not related
7KHHYHQWLVUHODWHGWRDQHWLRORJ\RWKHUWKDQWKHLQYHVWLJDWLRQDOVWXG\GUXJWKH
DOWHUQDWLYHHWLRORJ\ZLOOEHGRFXPHQWHGLQWKHVWXG\VXEMHFW
VPHGLFDOUHFRUG

13.1.1.6
Study Drug Action Taken
7KHLQYHVWLJDWRUZLOOFODVVLI\WKHVWXG\GUXJDFWLRQWDNHQZLWKUHJDUGWRWKH$(7KHDFWLRQWDNHQ
ZLOOEHFODVVLILHGDFFRUGLQJWRWKHFDWHJRULHVVKRZQLQ7DEOH
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification
Definition
Dose not changed
6WXG\GUXJGRVHQRWFKDQJHGLQUHVSRQVHWRDQ$(
Dose reduced
6WXG\GUXJGRVHUHGXFHGLQUHVSRQVHWRDQ$(
Drug interrupted
6WXG\GUXJDGPLQLVWUDWLRQLQWHUUXSWHGLQUHVSRQVHWRDQ$(
Drug withdrawn
6WXG\GUXJDGPLQLVWUDWLRQSHUPDQHQWO\GLVFRQWLQXHGLQUHVSRQVHWRDQ$(
Not applicable
$FWLRQWDNHQUHJDUGLQJVWXG\GUXJDGPLQLVWUDWLRQGRHVQRWDSSO\
³1RWDSSOLFDEOH´ZLOOEHXVHGLQFLUFXPVWDQFHVVXFKDVZKHQWKHLQYHVWLJDWLRQDO
WUHDWPHQWKDGEHHQFRPSOHWHGEHIRUHWKH$(EHJDQDQGQRRSSRUWXQLW\WRGHFLGH
ZKHWKHUWRFRQWLQXHLQWHUUXSWRUZLWKGUDZWUHDWPHQWLVSRVVLEOH


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

13.1.1.7
Adverse Event Outcome
$Q$(ZLOOEHIROORZHGXQWLOWKHLQYHVWLJDWRUKDVGHWHUPLQHGDQGSURYLGHGWKHILQDORXWFRPH
7KHRXWFRPHZLOOEHFODVVLILHGDFFRUGLQJWRWKHFDWHJRULHVVKRZQLQ7DEOH
Table 13-4 
Classifications for Outcome of an AE 
Classification
Definition
Recovered/Resolved
5HVROXWLRQRIDQ$(ZLWKQRUHVLGXDOVLJQVRUV\PSWRPV
Recovered/ Resolved 
With Sequelae
5HVROXWLRQRIDQ$(ZLWKUHVLGXDOVLJQVRUV\PSWRPV
Not Recovered/Not 
Resolved (Continuing)
(LWKHULQFRPSOHWHLPSURYHPHQWRUQRLPSURYHPHQWRIDQ$(VXFKWKDWLWUHPDLQV
RQJRLQJ
Fatal
2XWFRPHRIDQ$(LVGHDWK³)DWDO´ZLOOEHXVHGZKHQGHDWKLVDWOHDVWSRVVLEO\
UHODWHGWRWKH$(
Unknown
2XWFRPHRIDQ$(LVQRWNQRZQHJDVXEMHFWORVWWRIROORZXS

13.1.1.8
Treatment Given
7KHLQYHVWLJDWRUHQVXUHVDGHTXDWHPHGLFDOFDUHLVSURYLGHGWRVXEMHFWVIRUDQ\$(VLQFOXGLQJ
FOLQLFDOO\VLJQLILFDQWODERUDWRU\YDOXHVUHODWHGWRVWXG\GUXJ,QDGGLWLRQWKHLQYHVWLJDWRUZLOO
GHVFULEHZKHWKHUDQ\WUHDWPHQWZDVJLYHQIRUWKH$(³<HV´LVXVHGLIDQ\WUHDWPHQWZDVJLYHQ
LQUHVSRQVHWRDQ$(DQGPD\LQFOXGHWUHDWPHQWVVXFKDVRWKHUPHGLFDWLRQVKRVSLWDOL]DWLRQ
VXUJHU\RUSK\VLFDOWKHUDS\³1R´LQGLFDWHVWKHDEVHQFHRIDQ\NLQGRIWUHDWPHQWIRUDQ$(
13.1.2
Serious Adverse Events
13.1.2.1
Definition of a Serious Adverse Event
$Q6$(LVDQ\$(WKDWPHHWVDQ\RIWKHIROORZLQJRXWFRPHV
x
)DWDOGHDWKUHJDUGOHVVRIFDXVHWKDWRFFXUVGXULQJSDUWLFLSDWLRQLQWKHVWXG\RURFFXUVDIWHU
SDUWLFLSDWLRQLQWKHVWXG\DQGLVVXVSHFWHGRIEHLQJDGHOD\HGWR[LFLW\GXHWRDGPLQLVWUDWLRQRI
WKHVWXG\GUXJ
x
/LIHWKUHDWHQLQJVXFKWKDWWKHVXEMHFWZDVDWLPPHGLDWHULVNRIGHDWKIURPWKHUHDFWLRQDVLW
RFFXUUHG
x
,QSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIKRVSLWDOL]DWLRQ
x
3HUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\GLVDELOLW\LVGHILQHGDVDVXEVWDQWLDOGLVUXSWLRQ
RIDSHUVRQ
VDELOLW\WRFRQGXFWQRUPDOOLIHIXQFWLRQV
x
&RQJHQLWDODQRPDO\RUELUWKGHIHFW
x
,PSRUWDQWPHGLFDOHYHQWWKDWEDVHGXSRQDSSURSULDWHPHGLFDOMXGJPHQWPD\MHRSDUGL]HWKH
VXEMHFWRUPD\UHTXLUHPHGLFDORUVXUJLFDOLQWHUYHQWLRQWRSUHYHQWRIWKHRXWFRPHVOLVWHG
DERYHHJDQDOOHUJLFEURQFKRVSDVPUHTXLULQJLQWHQVLYHWUHDWPHQWLQDQHPHUJHQF\URRPRU
DWKRPH
,IDVXEMHFWKDVDKRVSLWDOL]DWLRQRUSURFHGXUHHJVXUJHU\IRUDQHYHQWRUFRQGLWLRQWKDW
RFFXUUHGEHIRUHWKHVXEMHFWVLJQHGWKH,&)DQGWKHKRVSLWDOL]DWLRQRUSURFHGXUHZDVSODQQHG
EHIRUHWKHVXEMHFWVLJQHGWKH,&)WKHKRVSLWDOL]DWLRQRUSURFHGXUHVKRXOGQRWEHFRQVLGHUHGWR

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

,WLVWKHUHVSRQVLELOLW\RIWKHLQYHVWLJDWRURUGHVLJQHHWRSURPSWO\QRWLI\WKHORFDOLQVWLWXWLRQDO
UHYLHZERDUG,5%ORFDO,(&RIDOOXQH[SHFWHGVHULRXVDGYHUVHGUXJUHDFWLRQVLQYROYLQJULVNWR
KXPDQVXEMHFWV
13.2
Administrative Requirements
13.2.1
Ethical Considerations
7KHVWXG\ZLOOEHFRQGXFWHGLQDFFRUGDQFHZLWKWKHFXUUHQW,&+*&3*XLGHOLQHVZKLFKDUH
FRQVLVWHQWZLWKWKHHWKLFDOSULQFLSOHVIRXQGHGLQWKH'HFODUDWLRQRI+HOVLQNLDQGLQDFFRUGDQFH
ZLWKORFDODSSOLFDEOHODZVDQGUHJXODWLRQV7KH,5%,(&ZLOOUHYLHZDOODSSURSULDWHVWXG\
GRFXPHQWDWLRQWRVDIHJXDUGWKHULJKWVVDIHW\DQGZHOOEHLQJRIWKHVXEMHFWV7KHVWXG\ZLOORQO\
EHFRQGXFWHGDWVLWHVZKHUH,5%,(&DSSURYDOKDVEHHQREWDLQHG7KHSURWRFRO,QYHVWLJDWRU
V
%URFKXUHVDPSOH,&)DGYHUWLVHPHQWVLIDSSOLFDEOHZULWWHQLQIRUPDWLRQJLYHQWRWKHVXEMHFWV
LQFOXGLQJGLDU\FDUGVVDIHW\XSGDWHVDQQXDOSURJUHVVUHSRUWVDQGDQ\UHYLVLRQVWRWKHVH
GRFXPHQWVZLOOEHSURYLGHGWRWKH,5%,(&E\WKHLQYHVWLJDWRURU9HUWH[DVDOORZDEOHE\ORFDO
DSSOLFDEOHODZVDQGUHJXODWLRQV
13.2.2
Subject Information and Informed Consent
$IWHUWKHVWXG\KDVEHHQIXOO\H[SODLQHGZULWWHQLQIRUPHGFRQVHQWZLOOEHREWDLQHGIURPWKH
VXEMHFWRUOHJDOUHSUHVHQWDWLYHRUJXDUGLDQLIDSSOLFDEOHDQGDVVHQWZLOOEHREWDLQHGIURPWKH
VXEMHFWLIDSSOLFDEOHEHIRUHVWXG\SDUWLFLSDWLRQ7KHPHWKRGRIREWDLQLQJDQGGRFXPHQWLQJWKH
LQIRUPHGFRQVHQWDQGDVVHQWLIDSSOLFDEOHDQGWKHFRQWHQWVRIWKHFRQVHQWZLOOFRPSO\ZLWK
,&+*&3DQGDOODSSOLFDEOHODZVDQGUHJXODWLRQVDQGZLOOEHVXEMHFWWRDSSURYDOE\9HUWH[RULWV
GHVLJQHH
13.2.3
Investigator Compliance
1RPRGLILFDWLRQVWRWKHSURWRFROZLOOEHPDGHZLWKRXWWKHDSSURYDORIERWKWKHLQYHVWLJDWRUDQG
9HUWH[&KDQJHVWKDWVLJQLILFDQWO\DIIHFWWKHVDIHW\RIWKHVXEMHFWVWKHVFRSHRIWKHLQYHVWLJDWLRQ
RUWKHVFLHQWLILFTXDOLW\RIWKHVWXG\LHHIILFDF\DVVHVVPHQWVZLOOUHTXLUH,5%,(&QRWLILFDWLRQ
EHIRUHLPSOHPHQWDWLRQH[FHSWZKHUHWKHPRGLILFDWLRQLVQHFHVVDU\WRHOLPLQDWHDQDSSDUHQW
LPPHGLDWHKD]DUGWRKXPDQVXEMHFWV9HUWH[ZLOOVXEPLWDOOSURWRFROPRGLILFDWLRQVWRWKH
UHTXLUHGUHJXODWRU\DXWKRULWLHV
:KHQFLUFXPVWDQFHVUHTXLUHDQLPPHGLDWHGHSDUWXUHIURPSURFHGXUHVVHWIRUWKLQWKHSURWRFRO
WKHLQYHVWLJDWRUZLOOFRQWDFW9HUWH[WRGLVFXVVWKHSODQQHGFRXUVHRIDFWLRQ,ISRVVLEOHFRQWDFW
ZLOOEHPDGHEHIRUHWKHLPSOHPHQWDWLRQRIDQ\FKDQJHV$Q\GHSDUWXUHVIURPSURWRFROZLOOEH
IXOO\GRFXPHQWHGLQWKHVRXUFHGRFXPHQWDWLRQDQGLQDSURWRFROGHYLDWLRQORJ
13.2.4
Access to Records
7KHLQYHVWLJDWRUZLOOPDNHWKHRIILFHDQGRUKRVSLWDOUHFRUGVRIVXEMHFWVHQUROOHGLQWKLVVWXG\
DYDLODEOHIRULQVSHFWLRQE\9HUWH[RULWVUHSUHVHQWDWLYHDWWKHWLPHRIHDFKPRQLWRULQJYLVLWDQG
IRUDXGLWV7KHUHFRUGVZLOODOVREHDYDLODEOHIRUGLUHFWLQVSHFWLRQYHULILFDWLRQDQGFRS\LQJDV
UHTXLUHGE\DSSOLFDEOHODZVDQGUHJXODWLRQVE\RIILFLDOVRIWKHUHJXODWRU\KHDOWKDXWKRULWLHV
)'$DQGRWKHUV7KHLQYHVWLJDWRUZLOOFRPSO\ZLWKDSSOLFDEOHSULYDF\DQGVHFXULW\ODZVIRUXVH
DQGGLVFORVXUHRILQIRUPDWLRQUHODWHGWRWKHUHVHDUFKVHWIRUWKLQWKLVSURWRFRO

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

13.2.5
Subject Privacy
7RPDLQWDLQVXEMHFWFRQILGHQWLDOLW\DQGWRFRPSO\ZLWKDSSOLFDEOHGDWDSURWHFWLRQDQGSULYDF\
ODZVDQGUHJXODWLRQVDOO&5)VVWXG\UHSRUWVDQGFRPPXQLFDWLRQVUHODWLQJWRWKHVWXG\ZLOO
LGHQWLI\VXEMHFWVE\DVVLJQHGVXEMHFWQXPEHUVDQGDFFHVVWRVXEMHFWQDPHVOLQNHGWRVXFK
QXPEHUVVKDOOEHOLPLWHGWRWKHVLWHDQGWKHVWXG\GRFWRUDQGVKDOOQRWEHGLVFORVHGWR9HUWH[$V
UHTXLUHGE\DSSOLFDEOHODZVDQGUHJXODWLRQVLQWKHFRXQWULHVLQZKLFKWKHVWXG\LVEHLQJ
FRQGXFWHGWKHLQYHVWLJDWRUZLOODOORZ9HUWH[DQGRULWVUHSUHVHQWDWLYHVDFFHVVWRDOOSHUWLQHQW
PHGLFDOUHFRUGVWRDOORZIRUWKHYHULILFDWLRQRIGDWDJDWKHUHGLQWKH&5)V6$(IRUPVDQGWKH
UHYLHZRIWKHGDWDFROOHFWLRQSURFHVV7KH)'$DQGUHJXODWRU\DXWKRULWLHVLQRWKHUMXULVGLFWLRQV
LQFOXGLQJWKH,5%(&PD\DOVRUHTXHVWDFFHVVWRDOOVWXG\UHFRUGVLQFOXGLQJVRXUFH
GRFXPHQWDWLRQIRULQVSHFWLRQ
13.2.6
Record Retention
7KHLQYHVWLJDWRUZLOOPDLQWDLQDOOVWXG\UHFRUGVDFFRUGLQJWR,&+*&3JXLGHOLQHVDQGRU
DSSOLFDEOHORFDOUHJXODWRU\UHTXLUHPHQWVZKLFKHYHULVORQJHVWDVGHVFULEHGLQWKH&OLQLFDO
7ULDO$JUHHPHQW,IWKHLQYHVWLJDWRUZLWKGUDZVIURPWKHUHVSRQVLELOLW\RINHHSLQJWKHVWXG\
UHFRUGVFXVWRG\ZLOOEHWUDQVIHUUHGWRDSHUVRQZLOOLQJWRDFFHSWWKHUHVSRQVLELOLW\DQG9HUWH[
ZLOOEHQRWLILHG
13.2.7
Study Termination
$WDQ\WLPH9HUWH[PD\WHUPLQDWHWKLVVWXG\LQLWVHQWLUHW\RUPD\WHUPLQDWHWKLVVWXG\DWDQ\
SDUWLFXODUVLWH,QDGGLWLRQIRUUHDVRQDEOHFDXVHHLWKHUWKHLQYHVWLJDWRUVRUWKHLU,5%V,(&VPD\
WHUPLQDWHWKHVWXG\DWWKHLUFHQWHU
)ROORZLQJDUHYLHZRIVWXG\HQUROOPHQWDQGDVVHVVPHQWRIWKHDYDLODEOHQXPEHURISRWHQWLDO
VXEMHFWVIRUWKLVVWXG\9HUWH[GHFLGHGWRFORVHHQUROOPHQWDQGWHUPLQDWHWKHVWXG\$IWHUWKH
SURWRFRODPHQGPHQWKDVEHHQDSSURYHGDWDVLWHVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQIURPWKH
VWXG\DWWKHLU:HHN9LVLWDQGVXEMHFWVLQ3DUWZLOOEHZLWKGUDZQIURPWKHVWXG\DQG
UHTXHVWHGWRFRPSOHWHWKH(DUO\7HUPLQDWLRQRI7UHDWPHQW9LVLWVHH6HFWLRQ
&RQGLWLRQVWKDWPD\OHDGWRUHDVRQDEOHFDXVHDQGZDUUDQWWHUPLQDWLRQLQFOXGHEXWDUHQRWOLPLWHG
WR
x
6XEMHFWRULQYHVWLJDWRUQRQFRPSOLDQFH
x
8QVDWLVIDFWRU\VXEMHFWHQUROOPHQW
x
/DFNRIDGKHUHQFHWRSURWRFROSURFHGXUHV
x
/DFNRIHYDOXDEOHDQGRUFRPSOHWHGDWD
x
3RWHQWLDOO\XQDFFHSWDEOHULVNWRVWXG\VXEMHFWV
x
'HFLVLRQWRPRGLI\GUXJGHYHORSPHQWSODQ
x
'HFLVLRQE\WKH)'$RURWKHUUHJXODWRU\DXWKRULW\
:ULWWHQQRWLILFDWLRQWKDWLQFOXGHVWKHUHDVRQIRUWKHFOLQLFDOVWXG\WHUPLQDWLRQLVUHTXLUHG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

13.3
Data Quality Assurance
9HUWH[RULWVGHVLJQDWHGUHSUHVHQWDWLYHZLOOFRQGXFWDVWXG\VLWHYLVLWWRYHULI\WKHTXDOLILFDWLRQV
RIHDFKLQYHVWLJDWRULQVSHFWFOLQLFDOVWXG\VLWHIDFLOLWLHVDQGLQIRUPWKHLQYHVWLJDWRURI
UHVSRQVLELOLWLHVDQGSURFHGXUHVIRUHQVXULQJDGHTXDWHDQGFRUUHFWVWXG\GRFXPHQWDWLRQ
7KHLQYHVWLJDWRULVUHTXLUHGWRSUHSDUHDQGPDLQWDLQDGHTXDWHDQGDFFXUDWHFDVHKLVWRULHV
GHVLJQHGWRUHFRUGDOOREVHUYDWLRQVDQGRWKHUGDWDSHUWLQHQWWRWKHVWXG\IRUHDFKVWXG\
SDUWLFLSDQW6WXG\GDWDIRUHDFKHQUROOHGVXEMHFWZLOOEHHQWHUHGLQWRD&5)E\VWXG\VLWH
SHUVRQQHOXVLQJDVHFXUHYDOLGDWHGZHEEDVHGHOHFWURQLFGDWDFDSWXUH('&DSSOLFDWLRQ9HUWH[
ZLOOKDYHUHDGRQO\DFFHVVWRVLWHHQWHUHGFOLQLFDOGDWDLQWKH('&DSSOLFDWLRQ
,QVWDQFHVRIPLVVLQJGLVFUHSDQWRUXQLQWHUSUHWDEOHGDWDZLOOEHTXHULHGZLWKWKHLQYHVWLJDWRUIRU
UHVROXWLRQ$Q\FKDQJHVWRVWXG\GDWDZLOOEHPDGHWRWKH&5)DQGGRFXPHQWHGLQDQDXGLWWUDLO
ZKLFKZLOOEHPDLQWDLQHGZLWKLQWKHFOLQLFDOGDWDEDVH
13.4
Monitoring
0RQLWRULQJDQGDXGLWLQJSURFHGXUHVGHYHORSHGRUDSSURYHGE\9HUWH[ZLOOEHIROORZHGWR
FRPSO\ZLWK*&3JXLGHOLQHV2QVLWHFKHFNLQJRIWKH&5)V6$()RUPVIRUFRPSOHWHQHVVDQG
FODULW\FURVVFKHFNLQJZLWKVRXUFHGRFXPHQWVDQGFODULILFDWLRQRIDGPLQLVWUDWLYHPDWWHUVZLOOEH
SHUIRUPHG
7KHVWXG\ZLOOEHPRQLWRUHGE\9HUWH[RULWVGHVLJQHH0RQLWRULQJZLOOEHGRQHE\SHUVRQDO
YLVLWVIURPDUHSUHVHQWDWLYHRI9HUWH[RUGHVLJQHHVWXG\VLWHPRQLWRUZKRZLOOUHYLHZWKH
&5)V6$()RUPVDQGVRXUFHGRFXPHQWV7KHVWXG\VLWHPRQLWRUZLOOHQVXUHWKDWWKH
LQYHVWLJDWLRQLVFRQGXFWHGDFFRUGLQJWRWKHSURWRFROGHVLJQDQGUHJXODWRU\UHTXLUHPHQWV
13.5
Electronic Data Capture 
9HUWH[ZLOOSURYLGHWKHVWXG\VLWHVZLWKVHFXUHDFFHVVWRDQGWUDLQLQJRQWKH('&DSSOLFDWLRQ
VXIILFLHQWWRSHUPLWVWXG\VLWHSHUVRQQHOWRHQWHURUFRUUHFWLQIRUPDWLRQLQWKH&5)VRQWKH
VXEMHFWVIRUZKLFKWKH\DUHUHVSRQVLEOH
$&5)ZLOOEHFRPSOHWHGIRUHDFKHQUROOHGVWXG\VXEMHFW,WLVWKHLQYHVWLJDWRU
VUHVSRQVLELOLW\WR
HQVXUHWKHDFFXUDF\FRPSOHWHQHVVFODULW\DQGWLPHOLQHVVRIWKHGDWDUHSRUWHGLQWKHVXEMHFW
V
&5)6RXUFHGRFXPHQWDWLRQVXSSRUWLQJWKH&5)GDWDZLOOLQGLFDWHWKHVXEMHFW
VSDUWLFLSDWLRQLQ
WKHVWXG\DQGZLOOGRFXPHQWWKHGDWHVDQGGHWDLOVRIVWXG\SURFHGXUHV$(VRWKHUREVHUYDWLRQV
DQGVXEMHFWVWDWXV
7KHLQYHVWLJDWRURUGHVLJQDWHGUHSUHVHQWDWLYHZLOOFRPSOHWHWKH&5)DVVRRQDVSRVVLEOHDIWHU
LQIRUPDWLRQLVFROOHFWHG
7KHDXGLWWUDLOHQWU\ZLOOVKRZWKHXVHU
VLGHQWLILFDWLRQLQIRUPDWLRQDQGWKHGDWHDQGWLPHRIDQ\
FRUUHFWLRQ7KHLQYHVWLJDWRUZLOOSURYLGHIRUPDODSSURYDORIDOOWKHLQIRUPDWLRQLQWKH&5)V
LQFOXGLQJDQ\FKDQJHVPDGHWRWKH&5)VWRHQGRUVHWKHILQDOVXEPLWWHGGDWDIRUWKHVXEMHFWVIRU
ZKRPWKHLQYHVWLJDWRULVUHVSRQVLEOH
9HUWH[ZLOOUHWDLQWKH&5)GDWDDQGFRUUHVSRQGLQJDXGLWWUDLOV$FRS\RIWKHILQDODUFKLYDO&5)
LQWKHIRUPRID&'RURWKHUHOHFWURQLFPHGLDZLOOEHSODFHGLQWKHLQYHVWLJDWRU
VVWXG\ILOH

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

14
REFERENCES


&\VWLF)LEURVLV)RXQGDWLRQ3DWLHQW5HJLVWU\$QQXDO'DWD5HSRUW%HWKHVGD
0DU\ODQG&\VWLF)LEURVLV)RXQGDWLRQ

)DUUHOO307KHSUHYDOHQFHRIF\VWLFILEURVLVLQWKH(XURSHDQ8QLRQ-&\VW)LEURVLV


2¶6XOOLYDQ%3)UHHGPDQ6'&\VWLFILEURVLV/DQFHW

5RPPHQV-0,DQQX]]L0&.HUHP%'UXPP0/0HOPHU*'HDQ0HWDO
,GHQWLILFDWLRQRIWKHF\VWLFILEURVLVJHQHFKURPRVRPHZDONLQJDQGMXPSLQJ6FLHQFH


6KHSSDUG011LFKROVRQ$*7KHSDWKRORJ\RIF\VWLFILEURVLV&XUUHQW'LDJQRVWLF
3DWKRORJ\

.RQVWDQ0:9DQ'HYDQWHU'55DVRXOL\DQ/3DVWD'-<HJLQ$0RUJDQ:-HWDO
7UHQGVLQWKHXVHRIURXWLQHWKHUDSLHVLQF\VWLFILEURVLV3HGLDWU3XOPRQRO


8QLWHG.LQJGRP&\VWLF)LEURVLV5HJLVWU\$QQXDO'DWD5HSRUW/RQGRQ8QLWHG
.LQJGRP&\VWLF)LEURVLV7UXVW

&\VWLF)LEURVLV0XWDWLRQ'DWDEDVH&)75&\VWLF)LEURVLV&HQWUHDWWKH+RVSLWDOIRU
6LFN&KLOGUHQLQ7RURQWR:HEVLWH$YDLODEOH
DWKWWSZZZJHQHWVLFNNLGVRQFDFIWU6WDWLVWLFV3DJHKWPO$FFHVVHG2FWREHU

0F.RQH()*RVV&+$LWNHQ0/CFTRJHQRW\SHDVDSUHGLFWRURISURJQRVLVLQF\VWLF
ILEURVLV&KHVW

0F.RQH()(PHUVRQ66(GZDUGV./$LWNHQ0/(IIHFWRIJHQRW\SHRQSKHQRW\SH
DQGPRUWDOLW\LQF\VWLFILEURVLVDUHWURVSHFWLYHFRKRUWVWXG\7KH/DQFHW


'DOHPDQV:%DUEU\3&KDPSLJQ\*-DOODW6'RWW.'UH\HU'HWDO$OWHUHGFKORULGH
LRQFKDQQHONLQHWLFVDVVRFLDWHGZLWKWKHGHOWD)F\VWLFILEURVLVPXWDWLRQ1DWXUH


,OOHN%=KDQJ//HZLV1&0RVV5%'RQJ-<)LVFKHU+'HIHFWLYHIXQFWLRQRIWKH
F\VWLFILEURVLVFDXVLQJPLVVHQVHPXWDWLRQG551DLVUHFRYHUHGE\JHQLVWHLQ$P-
3K\VLRO&

9DQ*RRU)+DGLGD6*URRWHQKXLV33KDUPDFRORJLFDOUHVFXHRIPXWDQW&)75IXQFWLRQ
IRUWKHWUHDWPHQWRIF\VWLFILEURVLV7RS0HG&KHP

9HUNPDQ$6*DOLHWWD/-&KORULGHFKDQQHOVDVGUXJWDUJHWV1DW5HY'UXJ
'LVFRY


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG



6WLFN60%UHQQDQ60XUUD\&'RXJODV7YRQ8QJHUQ6WHUQEHUJ%6*DUUDWW/:HW
DO$XVWUDOLDQ5HVSLUDWRU\(DUO\6XUYHLOODQFH7HDPIRU&\VWLF)LEURVLV$5(67&)
%URQFKLHFWDVLVLQLQIDQWVDQGSUHVFKRROFKLOGUHQGLDJQRVHGZLWKF\VWLFILEURVLVDIWHU
QHZERUQVFUHHQLQJ-3HGLDWU

'|ULQJ*+RLE\1&RQVHQVXV6WXG\*URXS(DUO\LQWHUYHQWLRQDQGSUHYHQWLRQRIOXQJ
GLVHDVHLQF\VWLFILEURVLVD(XURSHDQFRQVHQVXV-&\VW)LEURV

)DUUHOO30.RVRURN055RFN0-/D[RYD$=HQJ//DL+&HWDO(DUO\GLDJQRVLVRI
F\VWLFILEURVLVWKURXJKQHRQDWDOVFUHHQLQJSUHYHQWVVHYHUHPDOQXWULWLRQDQGLPSURYHV
ORQJWHUPJURZWK:LVFRQVLQ&\VWLF)LEURVLV1HRQDWDO6FUHHQLQJ6WXG\*URXS
3HGLDWULFV

6DZLFNL*0F.RQH(3DVWD':DJHQHU--RKQVRQ&.RQVWDQ0:7KHHIIHFWRI
LYDFDIWRURQWKHUDWHRIOXQJIXQFWLRQGHFOLQHLQ&)SDWLHQWVZLWKDG551D-CFTR
PXWDWLRQ-&\VW)LEURV6XSSO6

+RUVOH\$/XQJFOHDUDQFHLQGH[LQWKHDVVHVVPHQWRIDLUZD\VGLVHDVH5HVSLU0HG


6LQKDO6*DODWL-%DOGZLQ'16WRFNV-3LOORZ--5HSURGXFLELOLW\RIPXOWLSOHEUHDWK
ZDVKRXWLQGLFHVLQXQVHGDWHGSUHWHUPQHRQDWH3HGLDWU3XOPRQRO

<DQNDVNDV-50DUVKDOO%&6XILDQ%6LPRQ5+5RGPDQ'&\VWLFILEURVLVDGXOWFDUH
&KHVW

&RUH\03RZHUFRQVLGHUDWLRQVIRUVWXGLHVRIOXQJIXQFWLRQLQF\VWLFILEURVLV3URF$P
7KRUDF6RF

0DFNOHP377KHSK\VLRORJ\RIVPDOODLUZD\V$P-5HVSLU&ULW&DUH0HG
6

7LGGHQV+$'HWHFWLQJHDUO\VWUXFWXUDOOXQJGDPDJHLQF\VWLFILEURVLV3HGLDWU3XOPRQDO


2ZHQV&0$XURUD36WDQRMHYLF6%XVK$:DGH$2OLYHU&HWDO/XQJ&OHDUDQFH
,QGH[DQG+5&7DUHFRPSOHPHQWDU\PDUNHUVRIOXQJDEQRUPDOLWLHVLQ\RXQJFKLOGUHQ
ZLWK&)7KRUD[

(OOHPXQWHU+)XFKV6,8QVLQQ.0)UHXQG0&:DOWQHU5RPHQ06WHLQNDPS*HW
DO6HQVLWLYLW\RI/XQJ&OHDUDQFH,QGH[DQGFKHVWFRPSXWHGWRPRJUDSK\LQHDUO\&)OXQJ
GLVHDVH5HVSLU0HG

*XVWDIVVRQ30'H-RQJ3$7LGGHQV+$/LQGEODG$0XOWLSOHEUHDWKLQHUWJDVZDVKRXW
DQGVSLURPHWU\YHUVXVVWUXFWXUDOOXQJGLVHDVHLQF\VWLFILEURVLV7KRUD[


GH-RQJ3$2WWLQN0'5REEHQ6*/HTXLQ0++RS:&+HQGULNV--HWDO
3XOPRQDU\GLVHDVHDVVHVVPHQWLQF\VWLFILEURVLVFRPSDULVRQRI&7VFRULQJV\VWHPVDQG
YDOXHRIEURQFKLDODQGDUWHULDOGLPHQVLRQPHDVXUHPHQWV5DGLRORJ\


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG



%URG\$67LGGHQV+$&DVWLOH5*&R[VRQ+2GH-RQJ3$*ROGLQ-HWDO&RPSXWHG
WRPRJUDSK\LQWKHHYDOXDWLRQRIF\VWLFILEURVLVOXQJGLVHDVH$P-5HVSLU&ULW&DUH0HG


-HQVHQ56WDQRMHYLF6*LEQH\.6DOD]DU-**XVWDIVVRQ36XEEDUDR3HWDO0XOWLSOH
EUHDWKQLWURJHQZDVKRXWDIHDVLEOHDOWHUQDWLYHWRPDVVVSHFWURPHWU\3/R62QH
HGRLMRXUQDOSRQH

/XP6*XVWDIVVRQ3/MXQJEHUJ++OVNDPS*%XVK$&DUU6%HWDO/RQGRQ&\VWLF
)LEURVLV&ROODERUDWLRQ(DUO\GHWHFWLRQRIF\VWLFILEURVLVOXQJGLVHDVHPXOWLSOHEUHDWK
ZDVKRXWYHUVXVUDLVHGYROXPHWHVWV7KRUD[

6KHLNK6,/RQJ)50F&R\.6-RKQVRQ75\DQ:HQJHU1$+D\HV'-U&RPSXWHG
WRPRJUDSK\FRUUHODWHVZLWKLPSURYHPHQWLQLYDFDIWRUWUHDWPHQWLQF\VWLFILEURVLVSDWLHQWV
ZLWK*'PXWDWLRQ-&\VW)LEURV

6WDQRMHYLF6-HQVHQ56XQGDUDOLQJDP'6DOD]DU-*<DPPLQH66LQJHU)HWDO
$OWHUQDWLYHRXWFRPHVIRUWKHPXOWLSOHEUHDWKZDVKRXWLQFKLOGUHQZLWK&)-&\VW)LEURV
$YDLODEOHIURPKWWSG[GRLRUJMMFI

7LGGHQV+$GH-RQJ3$,PDJLQJDQGFOLQLFDOWULDOVLQF\VWLFILEURVLV3URF$P7KRUDF
6RF

3HQFKDU]3%'XULH353DWKRJHQHVLVRIPDOQXWULWLRQLQF\VWLFILEURVLVDQGLWVWUHDWPHQW
&OLQ1XWU

6KDUPD5)ORUHD9*%ROJHU$3'RHKQHU:)ORUHD1'&RDWV$-6HWDO:DVWLQJDV
DQLQGHSHQGHQWSUHGLFWRURIPRUWDOLW\LQSDWLHQWVZLWKF\VWLFILEURVLV7KRUD[


.RQVWDQ0:0RUJDQ:-%XWOHU603DVWD'-&UDLE0/6LOYD6-HWDO5LVNIDFWRUV
IRUUDWHRIGHFOLQHLQIRUFHGH[SLUDWRU\YROXPHLQRQHVHFRQGLQFKLOGUHQDQGDGROHVFHQWV
ZLWKF\VWLFILEURVLV3HGLDWU3XOPRQRO

6DQGHUV'%%LWWQHU5&/5RVHQIHOG05HGGLQJ*-*RVV&+3XOPRQDU\H[DFHUEDWLRQ
DQGVXEVHTXHQW)(9GHFOLQHLQERWKDGXOWVDQGFKLOGUHQZLWKF\VWLFILEURVLV-3HGLDWU


0D\HU+DPEOHWW15DPVH\%:.URQPDO5$$GYDQFLQJRXWFRPHPHDVXUHVIRUWKH
QHZHUDRIGUXJGHYHORSPHQWLQF\VWLFILEURVLV3URF$P7KRUDF6RF

)XFKV+-%RURZLW]'6&KULVWLDQVHQ'+0RUULV(01DVK0/5DPVH\%:HWDO
(IIHFWRIDHURVROL]HGUHFRPELQDQWKXPDQ'1DVHRQH[DFHUEDWLRQVRIUHVSLUDWRU\
V\PSWRPVDQGRQSXOPRQDU\IXQFWLRQLQSDWLHQWVZLWKF\VWLFILEURVLV1(QJO-0HG


5DPVH\%:3HSH064XDQ-02WWR./0RQWJRPHU\$%:LOOLDPV:DUUHQ-HWDO
,QWHUPLWWHQWDGPLQLVWUDWLRQRILQKDOHGWREUDP\FLQLQSDWLHQWVZLWKF\VWLFILEURVLV&\VWLF
)LEURVLV,QKDOHG7REUDP\FLQ6WXG\*URXS1(QJ-0HG

5RVHQIHOG0(PHUVRQ-:LOOLDPV:DUUHQ-3HSH06PLWK$0RQWJRPHU\$%HWDO
'HILQLQJDSXOPRQDU\H[DFHUEDWLRQLQF\VWLFILEURVLV-3HGLDWU


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG



5DELQ+5%XWOHU60-RKQVRQ&$&ROLQ$$)LW]6LPPRQV6&*HOOHU'(HWDO
3XOPRQDU\H[DFHUEDWLRQVLQF\VWLFILEURVLV3HGLDWU3XOPRQRO

%OXPHU-/6DLPDQ/.RQVWDQ0:0HOQLFN'7KHHIILFDF\DQGVDIHW\RIPHURSHQHP
DQGWREUDP\FLQYVFHIWD]LGLPHDQGWREUDP\FLQLQWKHWUHDWPHQWRIDFXWHSXOPRQDU\
H[DFHUEDWLRQVLQSDWLHQWVZLWKF\VWLFILEURVLV&KHVW

'DYLV6'%URG\$6(PRQG0-%UXPEDFN/&5RVHQIHOG0(QGSRLQWVIRUFOLQLFDO
WULDOVLQ\RXQJFKLOGUHQZLWKF\VWLFILEURVLV3URF$P7KRUDF6RF

/LRX7*$GOHU)5)LW]VLPPRQV6&&DKLOO%&+LEEV-50DUVKDOO%&3UHGLFWLYH
\HDUVXUYLYRUVKLSPRGHORIF\VWLFILEURVLV$P-(SLGHPLRO

5RVHQIHOG0$QRYHUYLHZRIHQGSRLQWVIRUF\VWLFILEURVLVFOLQLFDOWULDOV3URF$P7KRUDF
6RF

+D\HV'-U.UDPDQ667KHSK\VLRORJLFEDVLVRIVSLURPHWU\5HVSLU&DUH


%RURZLW]'%DNHU66'XII\/%DNHU5')LW]SDWULFN/*\DPIL-HWDO8VHRIIHFDO
HODVWDVHWRFODVVLI\SDQFUHDWLFVWDWXVLQSDWLHQWVZLWKF\VWLFILEURVLV-3HGLD


'HPNR&$%\DUG3-'DYLV3%*HQGHUGLIIHUHQFHVLQF\VWLFILEURVLVPseudomonas 
aeruginosaLQIHFWLRQ-&OLQ(SLGHPLRO

/L=.RVRURN05)DUUHOO30/D[RYD$:HVW6(*UHHQ&*HWDO/RQJLWXGLQDO
GHYHORSPHQWRIPXFRLGPseudomonas aeruginosaLQIHFWLRQDQGOXQJGLVHDVHSURJUHVVLRQ
LQFKLOGUHQZLWKF\VWLFILEURVLV-$0$

.DOLVK/$:DOW]'$'RYH\03RWWHU%\QRH*0F$GDP$-/LSXPD--HWDO,PSDFW
RIBurkholderia dolosaRQOXQJIXQFWLRQDQGVXUYLYDOLQF\VWLFILEURVLV$P-5HVSLU&ULW
&DUH0HG

:HVW6(=HQJ//HH%/.RVRURN05/D[RYD$5RFN0-HWDO5HVSLUDWRU\
LQIHFWLRQVZLWKPseudomonas aeruginosaLQFKLOGUHQZLWKF\VWLFILEURVLVHDUO\GHWHFWLRQ
E\VHURORJ\DQGDVVHVVPHQWRIULVNIDFWRUV-$0$

:HLQWUDXE$%ODX+0XVVDIIL+3LFDUG(%HQWXU/.HUHP(HWDO([RFULQH
SDQFUHDWLFIXQFWLRQWHVWLQJLQSDWLHQWVZLWKF\VWLFILEURVLVDQGSDQFUHDWLFVXIILFLHQF\D
FRUUHODWLRQVWXG\, -3HGLDWU*DWURHQWHURO1XWU

%UX]]HVH(5DLD9*DXGLHOOR*3ROLWR*%XFFLJURVVL9)RUPLFROD9HWDO,QWHVWLQDO
LQIODPPDWLRQLVDIUHTXHQWIHDWXUHRIF\VWLFILEURVLVDQGLVUHGXFHGE\SURELRWLF
DGPLQLVWUDWLRQ$OLPHQW3KDUPDFRO7KHU

%DOWLHUL63LQDOL/%RUWROX]]L&9ROSL67ULGHOOR*7LGGHQV+$HWDO(YDOXDWLRQRI
OXQJGLVHDVHSURJUHVVLRQZLWK&7%URG\VFRUHLQSDWLHQWVZLWKF\VWLFILEURVLV
GRLHFU&

%URG\$6.OHLQ-60ROLQD3/4XDQ-%HDQ-$:LOPRWW5:+LJKUHVROXWLRQ
FRPSXWHGWRPRJUDSK\LQ\RXQJSDWLHQWVZLWKF\VWLFILEURVLVGLVWULEXWLRQRIDEQRUPDOLWLHV
DQGFRUUHODWLRQZLWKSXOPRQDU\IXQFWLRQWHVWV-3HGLDWU 


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG



/RHYH0*HUEUDQGV.+RS:&5RVHQIHOG0+DUWPDQQ,&7LGGHQV+$
%URQFKLHFWDVLVDQGSXOPRQDU\H[DFHUEDWLRQVLQFKLOGUHQDQG\RXQJDGXOWVZLWKF\VWLF
ILEURVLV&KHVW

5RELQVRQ7(/HXQJ$1&KHQ;0RVV5%(PRQG0-&\VWLFILEURVLV+5&7VFRUHV
FRUUHODWHVWURQJO\ZLWK3VHXGRPRQDVLQIHFWLRQ3HGLDWU3XOPRQRO 

5RVHQRZ72XGUDDG0&-0XUUD\&37XUNRYLF/.XR:GH%UXLMQH0HWDO
35$*0$&)DTXDQWLWDWLYHVWUXFWXUDOOXQJGLVHDVH&7RXWFRPHLQ\RXQJFKLOGUHQZLWK
F\VWLFILEURVLV$P-5HVSLU&ULW&DUH0HGGRLUFFP2&

6DLPDQ/$QVWHDG00D\HU+DPEOHWW1/DQGV/&.ORVWHU0+RFHYDU7UQND-HWDO
(IIHFWRID]LWKURP\FLQRQSXOPRQDU\IXQFWLRQLQSDWLHQWVZLWKF\VWLFILEURVLVXQLQIHFWHG
ZLWKPseudomonas aeruginosaDUDQGRPL]HGFRQWUROOHGWULDO-$0$

$PHULFDQ7KRUDFLF6RFLHW\6WDQGDUGL]DWLRQRIVSLURPHWU\XSGDWH$P-5HVSLU
&ULW&DUH0HG

3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

15.2
Investigator Signature Page
3URWRFRO
9;
9HUVLRQ

9HUVLRQ'DWH
$SULO
6WXG\7LWOH$3KDVHESDUW5DQGRPL]HG'RXEOHEOLQG3ODFHERFRQWUROOHG&URVVRYHU
6WXG\:LWKD/RQJWHUP2SHQODEHO3HULRGWR,QYHVWLJDWH,YDFDIWRULQ6XEMHFWV:LWK&\VWLF
)LEURVLV$JHG7KURXJK<HDUV:KR+DYHD6SHFLILHGCFTR*DWLQJ0XWDWLRQ

,KDYHUHDG3URWRFRO9;9HUVLRQDQGDJUHHWRFRQGXFWWKHVWXG\DFFRUGLQJWRLWV
WHUPV,XQGHUVWDQGWKDWDOOLQIRUPDWLRQFRQFHUQLQJLYDFDIWRUDQGWKLVSURWRFROVXSSOLHGWRPHE\
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG9HUWH[LVFRQILGHQWLDO

3ULQWHG1DPH


6LJQDWXUH

'DWH



