A Randomized, Double-Blind, Two Treatment, Two Period, Chronic Dosing (2 Weeks), Cross-Over, Single-Center Study to Evaluate the Effects of PT003 and Placebo MDI on Specific Image Based Airway Volumes and Resistance in Subjects With Moderate to Severe COPD
Phase: PHASE3
Conditions: COPD
Sponsor: Pearl Therapeutics, Inc.

 
 
Revised Clinical Study Protocol 
Study Code 
PT003018 / FLUI-2015-139 
NCT #  
NCT02643082 
Date submitted: 
   02 MAY 2016 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Two Treatment, Two Period, Chronic 
Dosing (2 Weeks), Cross-Over, Single-Center Study to Evaluate the Effects 
of PT003 and Placebo MDI on Specific Image Based Airway Volumes and 
Resistance in Subjects With Moderate to Severe COPD 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
The following Amendment(s) are included in this revised protocol: 
  
Amendment No.        
Date of Amendment           
Version 1 
15SEP2015 
Version 2,  Amendment 1 
16FEB2016 
Version 3,  Amendment 2  
02MAY2016 
 
 
 

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&OLQLFDO7ULDO3URWRFRO37)/8,
Title:
$ 5DQGRPL]HG 'RXEOH%OLQG 7ZR 7UHDWPHQW 7ZR 3HULRG
&KURQLF'RVLQJ:HHNV&URVV2YHU6LQJOH&HQWHU6WXG\WR
(YDOXDWH WKH (IIHFWV RI 37 DQG 3ODFHER 0', RQ 6SHFLILF
,PDJH%DVHG$LUZD\9ROXPHVDQG5HVLVWDQFHLQ6XEMHFWV:LWK
0RGHUDWHWR6HYHUH&23'
Study Number:
37)/8,
Study Phase:
,,,E
Product Name:
*O\FRS\UURQLXP DQG )RUPRWHURO )XPDUDWH ,QKDODWLRQ $HURVRO
37 *O\FRS\UURQLXP DQG )RUPRWHURO )XPDUDWH *))
0HWHUHG'RVH,QKDOHU0',
3ODFHER 0HWHUHG 'RVH ,QKDOHU 0', IRU *O\FRS\UURQLXP DQG
)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
EudraCT 
Number:
Indication:



&23'
Investigators: 
6LQJOHFHQWHU
Sponsor:
Sponsor Contact: 

Version Number
Date
Original 
Protocol:
9HUVLRQ
6HSWHPEHU
Amended 
Protocol #1 
9HUVLRQ
)HEUXDU\
Amended 
Protocol #2 
9HUVLRQ
0D\
Confidentiality Statement
3URSHUW\RI3HDUO7KHUDSHXWLFV,QF
7KLVGRFXPHQWLVFRQILGHQWLDODQGPD\QRWEHXVHGGLYXOJHGSXEOLVKHGRURWKHUZLVH
GLVFORVHGZLWKRXWFRQVHQWRI3HDUO7KHUDSHXWLFV,QF

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
6800$5<2)&+$1*(67235272&2/9(56,21'$7('
)(%58$5<)259(56,21

7KHDPHQGHGVWXG\SURWRFRO37)/8,9HUVLRQLQFOXGHVWKH
IROORZLQJHGLWV1HZO\DGGHGWH[WLVVKRZQLQbold fontDQGGHOHWHGWH[WLVVKRZQDV
VWULNHWKURXJKIRQW
1R
'HVFULSWLRQRI&KDQJH
5DWLRQDOH

6HFWLRQ2YHUDOO6WXG\'HVLJQDQG3ODQ

3URYLGLQJWKHVXEMHFWPHHWVWKHHOLJLELOLW\FULWHULD
WKH ,QYHVWLJDWRU RU GHVLJQHH ZLOO UHYLHZ FXUUHQW
&23' PHGLFDWLRQV DQG LI QHFHVVDU\ ZLOO PDNH
DUUDQJHPHQWV WR DGMXVW WKH SURKLELWHG &23'
WKHUDS\WRSURWRFRODOORZDEOH&23'WKHUDS\At 
Visit 1 (Screening), eligible VXEMHFWVZKRDUHQRW
XVLQJ D SURKLELWHG COPD PHGLFDWLRQ UHIHU WR
7DEOH  DQG PHHW DOO RWKHU HQWU\FULWHULD ZLOO
UHWXUQWRWKHFOLQLFDIWHUXSand WR21GD\V
DIWHU6FUHHQLQJIRU9LVLW5DQGRPL]DWLRQ9LVLW
)RU PRUH GHWDLOV RQ 9LVLW  SURFHGXUHV UHIHU WR
6HFWLRQ8
7RSURYLGHFODULILFDWLRQRIZDVK
RXWRISURKLELWHG&23'
PHGLFDWLRQVSULRUWR9LVLW
5DQGRPL]DWLRQ

6HFWLRQ2YHUDOO6WXG\'HVLJQDQG3ODQ

7KHEDVHOLQH&7VFDQV7/&DQG)5&VFDQZLOO
EHWDNHQDWOHDVWPLQXWHVSULRUWRGRVLQJ
'XULQJWKHSUHGRVHDVVHVVHPHQWVDQDGGLWLRQDO
assessments aVFDQRIWKHXSSHUDLUZD\8$ZLOO
EHWDNHQ$IWHUWKH&7VFDQVDUHWDNHQ
spirometry and body plethysmography will be 
performed;WKHLQKDODWLRQSURILOHZLOOEH
PHDVXUHGZLWKWKHERG\SOHWK\VPRJUDSKDQG
UHVSLUDWLRQEHOWVDQGERG\SOHWK\VPRJUDSK\ZLOO
EHSHUIRUPHG7KHVXEMHFW
VLQKDODWLRQSURILOH
ZLOOEHPHDVXUHGLQRUGHUWRGUDZDQDLUIORZ
YHUVXVWLPHFXUYH$WWKHPRPHQWRIWKLV
PHDVXUHPHQWWKHVLJQDOIURPWKHUHVSLUDWLRQEHOW
XVHGIRUWKHPHDVXUHPHQWRIWKHLQKDODWLRQSURILOH
GXULQJWKHVWXG\GUXJDGPLQLVWUDWLRQZLOODOVREH
ORJJHG
7RSURYLGHFODULILFDWLRQWKDWWKH
&7VFDQZLOOEHREWDLQHGDIWHUWKH
PLQXWH)(9DQGSULRUWRWKH
PLQXWHV)(9DW9LVLW
5DQGRPL]DWLRQ

6HFWLRQ2YHUDOO6WXG\'HVLJQDQG3ODQ

7RSURYLGHFODULILFDWLRQRQZKLFK
)(9YDOXHVDW9LVLWZLOOEH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

$W 9LVLW 'D\ RI 73 LW LV LPSRUWDQW WR
HQVXUH WKDW WKH EDVHOLQH )(9 LV VWDEOH DQG
UHIOHFWLYHRIWKHVXEMHFW¶V&23'VHYHULW\SULRUWR
FRQWLQXLQJ WR WKH VHFRQG WUHDWPHQW SHULRG $V
VXFK WKH EDVHOLQH VWDELOLW\ FULWHULD ZLOO EH
HYDOXDWHG VHH VHFWLRQ  To ensure baseline 
FEV1 stability at Visit 4 the -60 minute FEV1
value obtained at Visit 4 will be compared to 
the average predose (-60 and -30 minute) FEV1
values obtained at Visit 2.  6XEMHFWV PHHWLQJ
EDVHOLQH VWDELOLW\ FULWHULD ZLOO EH GLVSHQVHG
WUHDWPHQWSHULRGVWXG\GUXJDFFRUGLQJWRWKHLU
DVVLJQHG WUHDWPHQW VHTXHQFH DQG ZLOO DGPLQLVWHU
WKHLUILUVWGRVHLQWKHFOLQLFXQGHUVLWHSHUVRQQHO
VXSHUYLVLRQ
6XEMHFWV
ZLOO
XQGHUJR
DOO
SURWRFROGHILQHG DVVHVVPHQWV VHH 7DEOH DQG
7DEOH  ZLOO EH GLVFKDUJHG IURP WKH FOLQLF
DQG ZLOO EH LQVWUXFWHG WR FRQWLQXH VWXG\ GUXJ
DGPLQLVWUDWLRQ IRU DSSUR[LPDWHO\  ZHHNV 
GD\VGD\VXQWLO9LVLW)RUPRUHGHWDLOVRQ
9LVLW  SURFHGXUHV UHIHU WR 6HFWLRQ  DQG
7DEOH
XVHGWRDVVHVVVWDELOLW\FULWHULD

6HFWLRQ*HQHUDO&RQVLGHUDWLRQVIRU
7UHDWPHQW9LVLWWKURXJK9LVLWLQFOLQLF


$WWKHVWDUWRIHDFKWUHDWPHQWSHULRG9LVLW
DQG 9LVLW  SULRU WR DQ\ VWXG\ SURFHGXUHV
EHLQJSHUIRUPHGVLWHSHUVRQQHOPXVWFRQILUP
WKH VXEMHFW ZLWKKHOG DOO QRQVWXG\ inhaled
&23' PHGLFDWLRQV
(including ICS and 
rescue medication, eg, Ventolin HFA),
H[FHSW VSRQVRUSURYLGHG $WURYHQW +)$ IRU
DWOHDVWKRXUVE\FRQILUPLQJWKHODVWWLPHRI
GRVLQJIRUDOO&23'PHGLFDWLRQV
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQWKHUHTXLUHGZDVKRXWRIWKH
LQKDOHG&23'PHGLFDWLRQVDWWKH
VWDUWRIHDFK7UHDWPHQW3HULRG

6HFWLRQ*HQHUDO&RQVLGHUDWLRQVIRU
7UHDWPHQW9LVLWWKURXJK9LVLWLQFOLQLF

Note6XEMHFWVZKRLQDGYHUWHQWO\WRRNinhaled 
&23'PHGLFDWLRQVH[FHSWIRUVSRQVRU
SURYLGHG$WURYHQW+)$ZLWKLQKRXUVRIWKH
VWDUWRIVWXG\SURFHGXUHVPXVWEHUHVFKHGXOHGDV
VRRQDVLVSUDFWLFDOEXWZLWKLQWKHVSHFLILHGYLVLW
³H[FHSWIRUVSRQVRUSURYLGHG
$WURYHQW+)$´GHOHWHGWR
SURYLGHFODULILFDWLRQRQWKH
UHTXLUHGZDVKRXWRISURKLELWHG
LQKDOHG&23'PHGLFDWLRQVDWWKH
HQGRIHDFK7UHDWPHQW3HULRG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
ZLQGRZ


6HFWLRQ,QFOXVLRQ&ULWHULD

6WDELOLW\FULWHULD

$W9LVLWLIWKHSUHGRVH-60 minute )(9YDOXH
LV RXWVLGH RI WKH  UDQJH FRPSDUHG WR WKH
average (-30 and -60 minute) SUHGRVH )(9
YDOXHRI9LVLWWKHYLVLWPD\EHUHVFKHGXOHGDW
WKH ,QYHVWLJDWRU¶V GLVFUHWLRQ RU WKH VXEMHFW PD\
EHGLVFRQWLQXHG
(GLWHGWRSURYLGHFODULILFDWLRQRQ
ZKLFK)(9YDOXHVDW9LVLWZLOO
EHXVHGWRDVVHVVVWDELOLW\FULWHULD

6HFWLRQ3URKLELWHG&23'0HGLFDWLRQV

7KHIROORZLQJPHGLFDWLRQVXVHGIRUWKHWUHDWPHQW
RI &23' DUH QRW SHUPLWWHG GXULQJ WKLV VWXG\
7KHVH PHGLFDWLRQV PXVW EH GLVFRQWLQXHG DW 6
hours to 24 hours prior to9LVLW6FUHHQLQJ
DQG DUH QRW SHUPLWWHG GXULQJ WKH UXQLQ SHULRG
7KHPLQLPXPZDVKRXWSHULRGbefore Visit 1 and
EHWZHHQ 9LVLW  DQG 9LVLW LV are VKRZQ LQ
7DEOH  The only COPD medications 
permitted during the study are sponsor-
provided 
Atrovent 
HFA®
for 
COPD 
maintainance during the run-in and wash-out 
period and sponsor-provided Ventolin HFA®
for rescue of COPD symptoms during the 
study
$GGLWLRQRISURKLELWHG&23'
PHGLFDWLRQZDVKRXWUHTXLUHPHQWV
SULRUWR9LVLW6FUHHQLQJ

7DEOH 3URKLELWHG&23'0HGLFDWLRQVDQG
5HTXLUHG:DVKRXW3HULRGV3ULRUWR9LVLW

3URKLELWHG&23'0HGLFDWLRQVDQG5HTXLUHG
:DVKRXW3HULRGV3ULRUWRVisit 1 and9LVLW
7DEOHWLWOHHGLWHGWRLQFOXGH9LVLW
DQGSURKLELWHG&23'
PHGLFDWLRQVUHTXLULQJZDVKRXW
SULRUWR9LVLW6FUHHQLQJDGGHG

7DEOH 3URKLELWHG&23'0HGLFDWLRQVDQG
5HTXLUHG:DVKRXW3HULRGV3ULRUWR9LVLW

(GLWHGWRSURYLGHFODULILFDWLRQRI
WKHSURKLELWHG&23'PHGLFDWLRQV
DQGWKHZDVKRXWUHTXLUHPHQWVRI
SURKLELWHG&23'PHGLFDWLRQV
SULRUWR9LVLW6FUHHQLQJ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


6HFWLRQ3URKLELWHG&23'0HGLFDWLRQV


6XEMHFWV
WDNLQJ
prohibited
&23'
PHGLFDWLRQV OLVWHG SUHYLRXVO\ DW 9LVLW 
6FUHHQLQJ
ZLOO
GLVFRQWLQXH
WKHVH
PHGLFDWLRQV6 to 24 hours before Visit 1IRU
WKHGXUDWLRQRIWKHWULDO.  At Visit 1 subjects 
will DQG EH VZLWFKHG WR VSRQVRUSURYLGHG
$WURYHQW +)$ 0', DGPLQLVWHUHG 4,' DQG
VSRQVRUSURYLGHG
9HQWROLQ+)$
WR
EH
DGPLQLVWHUHG XS WR IRXU WLPHV SHU GD\ DV
QHHGHG351IRUFRQWURORIV\PSWRPVGXULQJ
WKHUXQLQSHULRG


5HYLVHGWRSURYLGHFODULILFDWLRQRI
WKHZDVKRXWUHTXLUHPHQWVRI
SURKLELWHG&23'PHGLFDWLRQV
SULRUWR9LVLW6FUHHQLQJ

6HFWLRQ3URKLELWHG&23'0HGLFDWLRQV


At Visit 1, subjects who meet all entry 
criteria and are taking prohibited COPD 
medications in Table 5-1 will start with 
sponsor-provided Atrovent HFA MDI 
administered QID for COPD maintenance, 
and sponsor-provided Ventolin HFA to be 
administered up to four times per day, as 
needed (PRN) for control of symptoms 
during the run-in period 
%XOOHWDGGHGWRSURYLGH
FODULILFDWLRQWKDWVXEMHFWVZKR
PHHWDOOHQWU\FULWHULDDQGDUH
XVLQJRQHRUPRUHRIWKH
SURKLELWHG&23'PHGLFDWLRQV
ZLOOVWDUWZLWKVSRQVRUSURYLGHG
$WURYHQW+)$DQGVSRQVRU
SURYLGHG9HQWROLQ+)$DW9LVLW
6FUHHQLQJ

6HFWLRQ5HDVRQVDQG3URFHGXUHVIRU(DUO\
7HUPLQDWLRQ

5HYLVHGWRSURYLGHFODULILFDWLRQRI
WKHGHILQLWLRQRIEDVHOLQH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

)ROORZLQJ GRVLQJ D KHDUW UDWH LQFUHDVH RI
JUHDWHUWKDQESPIURPWKHSUHGRVHYDOXH
REWDLQHGRQ'D\RIHDFK7UHDWPHQW3HULRG
1 9LVLW  DQG 7UHDWPHQW 3HULRG  2 9LVLW
3HULRG DQG WKH PHDVXUHG YDOXH LV DOVR
!ESP

6HFWLRQ5HDVRQVDQG3URFHGXUHVIRU(DUO\
7HUPLQDWLRQ


)ROORZLQJ GRVLQJ D V\VWROLF EORRG SUHVVXUH
6%3LQFUHDVHRIPRUHWKDQPP+JIURP
WKH SUHGRVH YDOXH REWDLQHG RQ 'D\  RI
HDFK7UHDWPHQW 3HULRG  1 9LVLW  DQG
7UHDWPHQW 3HULRG  2 9LVLW   DQG WKH
PHDVXUHGYDOXHLVDOVR!PP+J
5HYLVHGWRSURYLGHFODULILFDWLRQRI
WKHGHILQLWLRQRIEDVHOLQH

6HFWLRQ5HDVRQVDQG3URFHGXUHVIRU(DUO\
7HUPLQDWLRQ


Initiation of corticosteroids/antibiotics for 
the treatment of exacerbation 
%XOOHWDGGHGWRSURYLGH
FODULILFDWLRQWKDWWKHLQLWLDWLRQRI
FRUWLFRVWHURLGVDQWLELRWLFVIRUWKH
WUHDWPHQWRIDQH[DFHUEDWLRQZLOO
EHDUHDVRQIRUHDUO\WHUPLQDWLRQ

6HFWLRQ6SLURPHWU\

$W9LVLWDQG9LVLWVSLURPHWU\ZLOOEHREWDLQHG
DWWKHEHJLQQLQJRIWKHYLVLW$VHFRQGVSLURPHWU\
ZLOO
EH
REWDLQHG
EHIRUH
WKH
VWXG\
GUXJ
DGPLQLVWUDWLRQ DIWHU WKH SUHGRVH &7VFDQV DUH
WDNHQ 7KH DYHUDJH RI WKH -60 minute )(9
YDOXHV value REWDLQHG DW 9LVLW  SULRU WR VWXG\
GUXJ DGPLQLVWUDWLRQ ZLOO EH XVHG WR FKHFN WKH
VWDELOLW\FULWHULD$W9LVLWDQG9LVLWVSLURPHWU\
ZLOO
EH
REWDLQHG
EHIRUH
WKH
VWXG\
GUXJ
DGPLQLVWUDWLRQ DQG SRVWGRVLQJ RI VWXG\ GUXJ
3RVWGRVH VSLURPHWU\ DVVHVVPHQWV ZLOO QRW EH
FRQGXFWHGEHIRUHWKH&7VFDQLVWDNHQ$W9LVLWV
 DQG  QRQH RI WKH SRVW GRVH DVVHVVPHQWV ZLOO
VWDUWEHIRUHKRXUDIWHUWKHDGPLQLVWUDWLRQRIWKH
VWXG\GUXJ$OODVVHVVPHQWVVKRXOGEHFRPSOHWHG
ZLWKLQKRXUVDIWHUGRVLQJ
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQZKLFK)(9YDOXHVDW9LVLW
ZLOOEHXVHGWRDVVHVVWKHVWDELOLW\
FULWHULD

6HFWLRQ6WDELOLW\&ULWHULD

$W 9LVLW  VSLURPHWU\ ZLOO EH REWDLQHG DW WKH
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQZKLFK)(9YDOXHVDW9LVLW
ZLOOEHXVHGWRDVVHVVWKHVWDELOLW\
FULWHULD

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
EHJLQQLQJRIWKHYLVLW$VHFRQGVSLURPHWU\ZLOO
EHREWDLQHGEHIRUHWKHVWXG\GUXJDGPLQLVWUDWLRQ
DIWHU WKH SUHGRVH &7 VFDQV DUH WDNHQ 7KH
DYHUDJH RI WKH )(9 YDOXHV REWDLQHG SULRU WR
VWXG\GUXJDGPLQLVWUDWLRQPLQDQGPLQ
at Visit 2 ZLOO EH WKH EDVHOLQH YDOXH XVHG WR
FRPSDUH ZLWK WKH DYHUDJH RI -60 minute )(9
YDOXHREWDLQHGDW9LVLW

7DEOH6FKHGXOHRIHYHQWV

$GGLWLRQRIVWXG\GUXJGLVSHQVLQJFROOHFWLRQDQG
UHYLHZUHFRUG9HQWROLQ+)$GRVHLQGLFDWRU
UHDGLQJDW9LVLWDQGUHYLHZRI'LDU\DW9LVLW
5HYLVHGWRSURYLGHFODULILFDWLRQ
WKDWVWXG\GUXJGLVSHQVLQJ
FROOHFWLRQDQGUHYLHZUHFRUG
9HQWROLQ+)$GRVHLQGLFDWRU
UHDGLQJDW9LVLWDQG'LDU\ZLOO
EHUHYLHZHGDW9LVLW

7DEOH6FKHGXOHRIHYHQWV

D
6FKHGXOLQJYLVLWV7KHPD[LPXPUXQLQ
SHULRGLVGD\V7KHHDUOLHVWDVXEMHFWFDQEH
UDQGRPL]HGIURPWKH9LVLWGDWHLVGD\V
GD\VIRU/$%$ZDVKRXWRUGD\VIRU
IOH[LELOLW\RUGD\VIRUIOH[LELOLW\7KHVLWH
VKRXOGPDNHHYHU\HIIRUWWRPDLQWDLQVXEMHFWV
ZLWKLQWKHVFKHGXOHGYLVLWZLQGRZ
5HPRYDORI³RUGD\VIRU
IOH[LELOLW\´IRUFODULILFDWLRQ
SXUSRVHV

7DEOH6FKHGXOHRIHYHQWV

L$IWHUREWDLQLQJLQIRUPHGFRQVHQWRUDW9LVLW
6FUHHQLQJ VWRS SURKLELWHG &23' PHGLFDWLRQV
DQGFKDQJH&23'PHGLFDWLRQVsubjects will be 
instructed to withhold prohibited
COPD 
medications 6 hours to 24 hours before Visit 1 
(Screening). At Visit 1 (Screening), subjects 
will be given Sponsor-provided Atrovent HFA 
with or without ICS, rescue Ventolin HFA 
only after a subject is determined to be eligible 
to proceed to Visit 2 (Day 1) (i.e., only if a 
subject meets the definition of COPD following 
spirometry assessments at Screening)
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQZDVKRXWLQVWUXFWLRQDIWHU
REWDLQLQJLQIRUPHGFRQVHQWDQG
ZKHQVXEMHFWVZLOOEHSURYLGHG
6SRQVRUSURYLGHG$WURYHQW+)$
ZLWKRUZLWKRXW,&6UHVFXH
9HQWROLQ+)$

7DEOH6FKHGXOHRIHYHQWV

M
At Visit 1COPD medications will be 
changed DVVSHFLILHGLQWKHSURWRFROLH
6SRQVRUSURYLGHG$WURYHQW+)$ZLWKRUZLWKRXW
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQWKHZDVKRXWUHTXLUHPHQWVRI
SURKLELWHG&23'PHGLFDWLRQV
SULRUWR9LVLW6FUHHQLQJ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
,&6$WWKHHQGRI9LVLWUHWXUQVXEMHFWWRSUH
VWXG\RURWKHUDSSURSULDWHLQKDOHGPDLQWHQDQFH
&23'PHGLFDWLRQV

7DEOH6FKHGXOHRIHYHQWV

N
6SRQVRUSURYLGHG$WURYHQW+)$RU9HQWROLQ
+)$LVGLVSHQVHGRQO\DIWHUDVXEMHFWLV
GHWHUPLQHGWREHHOLJLEOHWRSURFHHGWR9LVLW
'D\LHRQO\LIDVXEMHFWPHHWVWKHGHILQLWLRQ
RI&23'IROORZLQJVSLURPHWU\DVVHVVPHQWVDW
6FUHHQLQJ
'HOHWHGDVSUHYLRXVO\VWDWHGLQ
IRRWQRWH³L´

7DEOH6FKHGXOHRIHYHQWV

Note:6LWHVKRXOGSODQWRSHUIRUPWKHVHDFWLYLWLHV
VR DV QRW WR LQWHUIHUH ZLWK FROOHFWLRQ RI WLPHG
DVVHVVPHQWV VXFK DV VSLURPHWU\ :KHUH GDWD
FROOHFWLRQ WLPHSRLQWV DUH FRQFXUUHQW YDULDEOHV
PXVWEHFROOHFWHGLQWKHIROORZLQJRUGHU2Q'D\
 RI HDFK WUHDWPHQW SHULRG Predose: 8ULQH
SUHJQDQF\ WHVW 6SLURPHWU\ REWDLQ )(9 WR
HYDOXWDWH evaluate VWDELOLW\ FULWHULD YLWDO VLJQV
(&* FOLQLFDO ODERUDWRU\ DVVHVVPHQWV LQ FDVH D
UHWHVW LV QHHGHG GXULQJ eGFR at 9LVLW  1
(screening) must be repeated prior to Visit 2 
and have the results available at Visit 2 to 
confirmHOLJLELOLW\WKLVFDQEHSHUIRUPHGHDUOLHU
3UHGRVH
&7
VFDQV
6SLURPHWU\
%RG\
3OHWK\VPRJUDSK\ ,QKDODWLRQ 3URILOH Postdose:
YLWDOVLJQV(&*2Q'D\GD\VRIHDFK
73 Predose: 8ULQH SUHJQDQF\ WHVW YLWDO VLJQV
(&* FOLQLFDO ODERUDWRU\ DVVHVVPHQWV Postdose:
9LWDO
VLJQV
(&*
SRVWGRVH
&7
6FDQ
6SLURPHWU\%RG\3OHWK\VPRJUDSK\
5HYLVHGWRSURYLGHFODULILFDWLRQ
WKDWVXEMHFWVQRWPHHWLQJH*)5
FULWHULRQDWYLVLWPXVWPHHWWKH
FULWHULRQRQUHSHDWWHVWLQJSULRUWR
9LVLWWRFRQILUPHOLJLELOLW\

7DEOH7LPHG$VVHVVPHQWVDW9LVLWDQG
9LVLW

F$WWKHVWDUWRIHDFKWUHDWPHQWYLVLWVXEMHFW
PXVWZLWKKROGDOO&23'PHGLFDWLRQVLQFOXGLQJ
VWXG\PHGLFDWLRQUHVFXH9HQWROLQ+)$DQG,&6
IRUDWOHDVWKRXUVSULRUWRVWDUWRIWHVWGD\
SURFHGXUHVH[FHSWIRUVSRQVRUSURYLGHG
$WURYHQW+)$DW9LVLWDQG9LVLWG7KLVLV
QRWDWLPHGDVVHVVPHQW6LWHVVKRXOGSODQWR
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQZKLFKDFWLYLWLHVDUHQRWWLPHG
DVVHVVPHQWV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
SHUIRUPWKHVHDFWLYLWLHVVRDVQRWWRLQWHUIHUHZLWK
FROOHFWLRQRIWLPHGDVVHVVPHQWVVXFKDV
VSLURPHWU\
Note:6XEMHFWVZLWKDFDOFXODWHGFUHDWLQLQH
FOHDUDQFHPOPLQPA0'5'DW9LVLW
PXVWKDYHDH*)50'5'!POPLQPA
RQWKHUHSHDWWHVWLQJSULRUWR9LVLWWREH
UDQGRPL]HGLQWKLVVWXG\

7DEOH7LPHG$VVHVVPHQWVDW9LVLWDQG
9LVLW

L:LOOEHSHUIRUPHGDWWKHEHJLQQLQJRIWKHYLVLW
7KHAt Visit 4 theREWDLQHG -60 minute )(9
YDOXHZLOOEHXVHGWRFKHFNWKHVWDELOLW\FULWHULD
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQZKLFK)(9YDOXHVDW9LVLW
ZLOOEHXVHGWRDVVHVVWKHVWDELOLW\
FULWHULD

7DEOH7LPHG$VVHVVPHQWVDW9LVLWDQG
9LVLW

)RRWQRWHV³E´DQG³F´UHDOLJQHG
5HYLVHGWRSURYLGHFODULILFDWLRQ
RQZKLFKDFWLYLWLHVDUHQRWWLPHG
DFWLYLWLHVDW9LVLWDQG9LVLW

7DEOH7LPHG$VVHVVPHQWVDW9LVLWDQG
9LVLW

Note6LWHVKRXOGSODQWRSHUIRUPWKHVHDFWLYLWLHV
VRDVQRWWRLQWHUIHUHZLWKFROOHFWLRQRIWLPHG
DVVHVVPHQWVVXFKDVVSLURPHWU\:KHUHGDWD
FROOHFWLRQWLPHSRLQWVDUHFRQFXUUHQWYDULDEOHV
PXVWEHFROOHFWHGLQWKHIROORZLQJRUGHU3UHGRVH
8ULQHSUHJQDQF\WHVWspirometry,YLWDOVLJQV
(&*FOLQLFDOODERUDWRU\DVVHVVPHQWV3RVWGRVH
9LWDOVLJQV(&*SRVWGRVH&7VFDQVSLURPHWU\
ERG\SOHWK\VPRJUDSK\
$GGLWLRQRIVSLURPHWU\
DVVHVVPHQWWRWKHSUHGRVH
DVVHVVPHQWVFRQGXFWHGDW9LVLW

6HFWLRQ9LVLW6FUHHQLQJ


2EWDLQ LQIRUPHG FRQVHQW prior to or at the 
beginning of Visit 1 prior to conducting 
any study related procedures
5HYLVHGWRSURYLGHFODULILFDWLRQ
WKDWLQIRUPHGFRQVHQWFDQEH
REWDLQHGSULRUWRRUDWWKH
EHJLQQLQJRI9LVLWSULRUWR
FRQGXFWLQJDQ\VWXG\UHODWHG
SURFHGXUHV

6HFWLRQ9LVLW6FUHHQLQJ


Determine time of last dose of prohibited 
COPD medication as defined in table 5-1  
5HYLVHGWRSURYLGHFODULILFDWLRQ
WKDWWKHWLPHRIODVWGRVHRI
SURKLELWHG&23'PHGLFDWLRQDV
GHILQHGLQ7DEOHPXVWEH
GHWHUPLQHG

6HFWLRQ9LVLW6FUHHQLQJ

5HYLVHGWRRSURYLGHFODULILFDWLRQ
RQZKHQVXEMHFWVZLOOEH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

6WRSSURKLELWHG&23'PHGLFDWLRQVDQG
FKDQJHChangeFRQFXUUHQW&23'
PHGLFDWLRQVDVVSHFLILHGLQSURWRFROUHIHUWR
6HFWLRQ6SRQVRUZLOOSURYLGH
$WURYHQW+)$4,'IRU&23'PDLQWHQDQFH
DQG9HQWROLQ+)$DVQHHGHGIRUV\PSWRPDWLF
UHOLHI
LQVWUXFWHGVXEMHFWVWREHJLQZDVK
RXWRIWKHLUFRQFXUUHQW&23'
PHGLFDWLRQVDVSHU7DEOH

6HFWLRQ9LVLW5DQGRPL]DWLRQ'D\RI73


Note:5HYLHZLQFOXVLRQH[FOXVLRQFULWHULDUHSHDW
WHVWLQJRIWKHFUHDWLQLQHFOHDUDQFHprior to Visit 
2, if necessary. Creatnine clearance eligibility
PXVW EH NQRZQ EHIRUH WKH +5&7 VFDQ FDQ EH
WDNHQ
5HYLVHGWRSURYLGHFODULILFDWLRQ
WKDWWKHUHVXOWVRIUHSHDWWHVWLQJRI
WKHFUHDWLQLQHFOHDUDQFHZKLFK
KDVWREHSHUIRUPHGSULRUWR9LVLW
PXVWEHNQRZQEHIRUHWKH
+5&7VFDQFDQEHWDNHQ

6HFWLRQ9LVLW'D\RI73

Note: Confirm if patient meets stability 
requirements, if not
the visit may be 
rescheduled within the allowed visit window, 
at the Investigator’s discretion, or the subject 
may be discontinued
1RWHZDVDGGHGWRFODULI\LID
VXEMHFWGRHVQRWPHHWVWDELOLW\
FULWHULDDW9LVLWWKHYLVLWPD\EH
UHVFKHGXOHGRUWKHVXEMHFWPD\EH
GLVFRQWLQXHG

6HFWLRQ9LVLW'D\RI73


6XEMHFWVZLOOEHLQVWUXFWHGWREULQJDOOVWXG\
PHGLFDWLRQ LQFOXGLQJ XVHG VWXG\ GUXJ
UHSODFHPHQW 0', NLW VSRQVRU SURYLGHG
$WURYHQW+)$DQGUHVFXH9HQWROLQ+)$DQG
WKH'LDU\WRWKHQH[WVFKHGXOHGFOLQLFYLVLW
5HYLVHGWRSURYLGHFODULILFDWLRQ
WKDWVXEMHFWVZLOOEHLQVWUXFWHGDW
9LVLWWREULQJVWXG\GUXJ
UHSODFHPHQW0',NLWDQGUHVFXH
9HQWROLQ+)$WRWKHLUQH[W
VFKHGXOHGYLVLW

0LQRUW\SRJUDSKLFDOHUURUVZHUHDGGUHVVHGEXW
QRWFDSWXUHGDVLQGLYLGXDOLWHPVLQWKHVXPPDU\
RIFKDQJHV
7RLPSURYHUHDGDELOLW\



*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

SYNOPSIS
Sponsor:
3HDUO7KHUDSHXWLFV,QF³3HDUO´



Names of Finished Products:
*O\FRS\UURQLXP DQG )RUPRWHURO )XPDUDWH ,QKDODWLRQ $HURVRO 37 *O\FRS\UURQLXP DQG
)RUPRWHURO)XPDUDWH0HWHUHG'RVH,QKDOHU*))0',
3ODFHER0HWHUHG'RVH,QKDOHU0',IRU*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH
,QKDODWLRQ$HURVRO
Name of Active Ingredients:
*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH
Study Title:
$5DQGRPL]HG'RXEOH%OLQG7ZR7UHDWPHQW7ZR3HULRG&KURQLF'RVLQJ:HHNV&URVV
2YHU6LQJOH&HQWHU6WXG\WR(YDOXDWHWKH(IIHFWVRI37DQG3ODFHER0',RQ6SHFLILF,PDJH
%DVHG$LUZD\9ROXPHVDQG5HVLVWDQFHLQ6XEMHFWV:LWK0RGHUDWHWR6HYHUH&23'
Study Number:  37)/8,
Study Phase:,,,E
Study Objectives:
Primary Objectives:
x
7RDVVHVVWKHHIIHFWRIWUHDWPHQWZLWK*))0',WZLFHGDLO\%,'FRPSDUHGZLWK3ODFHER
0',RQ VSHFLILF LPDJHEDVHG DLUZD\ YROXPHVDQGUHVLVWDQFHLQVXEMHFWVZLWKPRGHUDWHWR
VHYHUH FKURQLF REVWUXFWLYH SXOPRQDU\ GLVHDVH &23' IROORZLQJ FKURQLF GRVLQJ DIWHU
DSSUR[LPDWHO\WZRZHHNVWUHDWPHQW
Secondary Objectives:

7R FRPSDUH WKH HIIHFWV RI *)) 0', RQ YDULRXV )XQFWLRQDO 5HVSLUDWRU\ ,PDJLQJ )5,
SDUDPHWHUV

7RFRPSDUHWKHHIIHFWV RI*))0',DQG3ODFHER0',RQSXOPRQDU\IXQFWLRQWHVW3)7
SDUDPHWHUV
Safety Objective:
7RDVVHVVWKHVDIHW\RI*))0',LQVXEMHFWVZLWKPRGHUDWHWRVHYHUH&23'EDVHGRQDGYHUVH
HYHQWV $(V DQG DQ\ FOLQLFDOO\ UHOHYDQW ILQGLQJV IURP YLWDO VLJQ PHDVXUHPHQWV
HOHFWURFDUGLRJUDPV(&*VSK\VLFDOH[DPLQDWLRQILQGLQJVDQGFOLQLFDOODERUDWRU\HYDOXDWLRQV
Study Design:
7KLVLVDVLQJOHFHQWHUGRXEOHEOLQGWZRWUHDWPHQWWZRSHULRGIXOOFURVVRYHUFKURQLFGRVLQJ
ZHHNVVWXG\WRDVVHVVWKHHIIHFWVRI*))0',J%,'FRPSDUHGZLWK3ODFHER0',
RQ VSHFLILF LPDJHEDVHG DLUZD\ YROXPHV DQG UHVLVWDQFH LQ VXEMHFWV ZLWK PRGHUDWH WR VHYHUH
&23'7KHVHQVLWLYLW\RIWKHVWXG\LQFUHDVHVZLWKWKHFURVVRYHUGHVLJQZKHUHHDFKVXEMHFWDFWVDV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
KLVKHURZQFRQWURO,QWKLVVWXG\WKHFDOFXODWLRQRIDLUZD\GLPHQVLRQSDUDPHWHUVEHWZHHQWKH
DFWLYH FRPSRXQG DQG WKH SODFHER ZLOO EH FRPSDUHG ZLWKLQ WKH VDPH VXEMHFW DIWHU WKH
DGPLQLVWUDWLRQRIERWKWKHDFWLYHFRPSRXQGDVZHOODVWKHSODFHER
,WLVSODQQHGWRFRQGXFWWKLVVLQJOHFHQWHUVWXG\DWRQHVLWHLQ%HOJLXPZLWKWKHVLWHFRQWULEXWLQJ
DSSUR[LPDWHO\UDQGRPL]HGVXEMHFWVZLWKPRGHUDWHWRVHYHUH&23'
Study design chart



Computed Tomography (CT)-scans during study:2Q'D\RI HDFK7UHDWPHQW3HULRG73
>9LVLWDQG9LVLW@EDVHOLQHPHDVXUHPHQWLQVSLUDWRU\VFDQWRWDOOXQJFDSDFLW\>7/&@VFDQDQG
H[SLUDWRU\VFDQIXQFWLRQDOUHVLGXDOFDSDFLW\>)5&@VFDQZLOOEHFRQGXFWHG'XULQJ9LVLWDQ
DGGLWLRQDOVFDQRIWKHXSSHUDLUZD\8$ZLOOEHWDNHQ3RVWGRVHPHDVXUHPHQWLQVSLUDWRU\VFDQ
WRWDOOXQJFDSDFLW\>7/&@VFDQZLOOEHWDNHQDIWHUDSSUR[LPDWHO\ZHHNVRIWUHDWPHQWZLWKHLWKHU
*))0',RU3ODFHER0',RQ'D\GD\V9LVLWDQG9LVLW3RVWGRVHDFWLYLWLHVVKRXOG
EHVWDUWHGKRXUDIWHUGRVLQJRQ9LVLWDQG9LVLWDQGVKRXOGEHFRQFOXGHGZLWKLQKRXUVDIWHU
GRVLQJ%HWZHHQWKH7UHDWPHQW3HULRGVWKHUHZLOOEHDZDVKRXWSHULRGRIGD\V
Study Duration: 
7KHHQWLUHVWXG\SHULRGLVVFKHGXOHGWRWDNHDSSUR[LPDWHO\ZHHNVIRUHDFKLQGLYLGXDOVXEMHFW
Study Population:
$SSUR[LPDWHO\VXEMHFWVZLWKPRGHUDWHWRVHYHUH&23'ZLOOEHUDQGRPL]HGLQWRWKHVWXG\


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Test Product, Dose, and Mode of Administration:
,QYHVWLJDWLRQDOPDWHULDOVZLOOEHSURYLGHGE\3HDUODVVXPPDUL]HG
Investigational materials 
Product Name and 
Dosage 
Product Strength
Dose Form/Fill 
Count
Administration
Study Medications
*))0',37
JH[DFWXDWRU
*))0',JSHU
DFWXDWLRQ
0',
LQKDODWLRQV
7DNHQDVWZRLQKDODWLRQV
%,'
Open-label Products
9HQWROLQDOEXWHUROVXOIDWH
+)$LQKDODWLRQDHURVRO
JH[DFWXDWRU
9HQWROLQDOEXWHUROVXOIDWH
+)$LQKDODWLRQDHURVROZLOO
EHWKHVXSSOLHGSURGXFW
(DFKLQKDODWLRQFRQWDLQV
ȝJFRUUHVSRQGLQJWR
JDOEXWHUROEDVHSHU
DFWXDWLRQ
0',
RUDFWXDWLRQV
7DNHQDVQHHGHG351

$WURYHQWLSUDWURSLXP
EURPLGH+)$LQKDODWLRQ
DHURVROȝJH[DFWXDWRU
$WURYHQWLSUDWURSLXP
EURPLGH+)$ZLOOEHWKH
VXSSOLHGSURGXFW
(DFKLQKDODWLRQFRQWDLQV
ȝJH[DFWXDWRUSHU
DFWXDWLRQ
0',
DFWXDWLRQV
7DNHQDVWZRLQKDODWLRQV
4,'GXULQJUXQLQSHULRG
DQGZDVKRXWSHULRG

Placebo
3ODFHER0',
)RUPXODWLRQGRHVQRW
FRQWDLQDFWLYHLQJUHGLHQW
0',
LQKDODWLRQV
7DNHQDVWZRLQKDODWLRQV
%,'
$EEUHYLDWLRQV %,' WZLFH GDLO\ &23' FKURQLF REVWUXFWLYH SXOPRQDU\ GLVHDVH *))
0', *O\FRS\UURQLXP DQG )RUPRWHURO )XPDUDWH ,QKDODWLRQ $HURVRO 0', 0HWHUHG 'RVH
,QKDOHU351 DVQHHGHG4,' IRXUWLPHVGDLO\
Note:$OOVWXG\GUXJVZLOOEHDGPLQLVWHUHGE\RUDOLQKDODWLRQ
Note*O\FRS\UURQLXPJLQ*))0',LVHTXLYDOHQWWRJRIJO\FRS\UURQLXPEURPLGH
Duration of Treatment:
(DFKVXEMHFWZLOOUHFHLYHLQWRWDOVWXG\WUHDWPHQWIRUDSSUR[LPDWHO\ZHHNVWZRVHSDUDWH73VRI
DSSUR[LPDWHO\ WZR ZHHNV 7KH HQWLUH VWXG\ LV VFKHGXOHG WR WDNH DSSUR[LPDWHO\ ZHHNV IRU
HDFKLQGLYLGXDOVXEMHFWIURPWKHWLPHRIVFUHHQLQJWKURXJKIROORZXS

Primary Efficacy Endpoints: 
FRI Parameters:

6SHFLILFDLUZD\YROXPHVL9DZ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

6SHFLILFDLUZD\UHVLVWDQFHVL5DZ
 Secondary Efficacy Endpoints: 
FRI Parameters:

$LUZD\YROXPHL9DZ

$LUZD\UHVLVWDQFHL5DZ
Spirometry Parameters:

)RUFHGH[SLUDWRU\YROXPHLQRQHVHFRQG)(9
Body Plethysmography Parameters: 

)5&
Other Efficacy Endpoints:
FRI Parameters:

/REHYROXPHVL9OREHV

$LUWUDSSLQJ

,QWHUQDOOREDUDLUIORZGLVWULEXWLRQ

/RZDWWHQXDWLRQRUHPSK\VHPDVFRUH

%ORRGYHVVHOGHQVLW\RUILEURVLVVFRUH

$LUZD\ZDOOWKLFNQHVV

0DVVRIGHSRVLWHGSDUWLFOHVSHUGHILQHGDLUZD\VHFWLRQ
Spirometry Parameters:

)RUFHGYLWDOFDSDFLW\)9&

7LIIHQHDXLQGH[)(9)9&UDWLR

)RUFHGH[SLUDWRU\IORZ)()

,QVSLUDWRU\FDSDFLW\,&

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
 Body Plethysmography Parameters: 

5HVLGXDOYROXPH59

7/&

$LUZD\UHVLVWDQFH5DZ

6SHFLILFDLUZD\UHVLVWDQFHV5DZ

6SHFLILFDLUZD\FRQGXFWDQFHV*DZ

Safety Endpoints:

$(V
Statistical Methods:
$OOVWDWLVWLFDODQDO\VLVZLOOEHFRQGXFWHGXVLQJ


)RUWKHHIILFDF\DQDO\VHVWKHQXOOK\SRWKHVLVIRUHDFKSDLUZLVHFRPSDULVRQZLOOEHWKDWWKHPHDQ
*))0',WUHDWPHQWHIIHFWLVHTXDOWRWKDWRI3ODFHER0',WKHDOWHUQDWLYHK\SRWKHVLVLVWKHQWKDW
WKH *)) 0', WUHDWPHQW HIIHFW DQG WKDW RI 3ODFHER 0', RUDQLQGLYLGXDO FRPSRQHQW DUH QRW
HTXDO3YDOXHVZLOOWKXVEHUHSRUWHGDVWZRVLGHG7KHHIIHFWLVGHILQHGDVWKHGLIIHUHQFHEHWZHHQ
WKHYDOXHDW'D\GD\VDQGWKHYDOXHDW'D\RIDFHUWDLQ73(IIHFWLVWKXVGHILQHGDVWKH
FKDQJHIURPEDVHOLQHWRSODFHERIRUDSODFHERWUHDWPHQWDQGDVWKHFKDQJHIURPEDVHOLQHWR*))
0', IRU D *)) 0', WUHDWPHQW 7KHQXOO + DQG DOWHUQDWLYH + K\SRWKHVHV ZLWK 
UHSUHVHQWLQJWKHPHDQDUH
+*)) SODFHER
+*))SODFHER
)RU HDFK SDUDPHWHU LQ HDFK JURXS SULPDU\ HIILFDF\ HQGSRLQWV )5, VHFRQGDU\ HIILFDF\
HQGSRLQWV )5, VSLURPHWU\ DQG ERG\ SOHWK\VPRJUDSK\ RWKHU HIILFDF\ HQGSRLQWV DOO )5,
SDUDPHWHUVH[FHSWWKHPDVVRIGHSRVLWHGSDUWLFOHVVSLURPHWU\DQGERG\SOHWK\VPRJUDSK\WKLV
QXOOK\SRWKHVLVZLOOEHWHVWHG$OLQHDUPL[HGPRGHODSSURDFKZLOOEHFKRVHQDQGVSHFLILHGIXOO\
LQWKHVWDWLVWLFDODQDO\VLVSODQ
)RUWKHSULPDU\HIILFDF\HQGSRLQWV+RFKEHUJ
VVWHSXSSURFHGXUHZLOOEHXVHGDVPXOWLSOLFLW\
DGMXVWPHQW1RFRUUHFWLRQZLOOEHSHUIRUPHGIRUWKHVHFRQGDU\DQGWKHRWKHUHIILFDF\HQGSRLQWV

,Q RUGHU WR JDLQ H[WUD LQVLJKW LQWR WKH PRGH RI DFWLRQ RI WKH SURGXFW DGGLWLRQDO H[SORUDWRU\
DQDO\VHVFDQEHH[HFXWHGXVLQJUREXVWOLQHDUUHJUHVVLRQRUPL[HGPRGHOV

7KH ,QWHQWWR7UHDW ,77 3RSXODWLRQ ZLOO EH FRQVLGHUHG WKH SULPDU\ DQDO\VLV SRSXODWLRQ IRU
HIILFDF\
Date of Approved Protocol:6HSWHPEHU

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Date of Protocol Amendment 1 (Version 2.0)HEUXDU\
Date of Protocol Amendment 2 (Version 3.00D\

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

7$%/(2)&217(176
6800$5<2)&+$1*(67235272&2/9(56,21'$7('$35,/
)259(56,21 
6<1236,6 
7$%/(2)&217(176 
/,672),17(;77$%/(6 
/,672),17(;7),*85(6 
/,672)$33(1',&(6 
/,672)$%%5(9,$7,216$1''(),1,7,2162)7(506 
75$'(0$5.,1)250$7,21 
 
,1752'8&7,21$1'678'<5$7,21$/( 
 
6WXG\5DWLRQDOH 
 
678'<2%-(&7,9(6 
 
3ULPDU\2EMHFWLYH 
 
6HFRQGDU\2EMHFWLYHV 
 
6DIHW\2EMHFWLYHV 
 
678'<(1'32,176 
 
(IILFDF\(QGSRLQWV 
 
3ULPDU\(IILFDF\(QGSRLQWV 
 
6HFRQGDU\(IILFDF\(QGSRLQWV 
 
2WKHU(IILFDF\(QGSRLQWV 
 
6DIHW\(QGSRLQWV 
 
,19(67,*$7,21$/3/$1 
 
2YHUDOO6WXG\'HVLJQDQG3ODQ 
 
*HQHUDO&RQVLGHUDWLRQVIRU7UHDWPHQW9LVLWWKURXJK9LVLWLQFOLQLF 
 
5DWLRQDOHRI6WXG\'HVLJQ 
 
5DWLRQDOHRI'RVH5HJLPHQ'XUDWLRQRI7UHDWPHQWDQG3ODFHER$UP 
 
678'<3238/$7,216(/(&7,21$1':,7+'5$:$/&5,7(5,$ 
 
,QFOXVLRQ&ULWHULD 
 
([FOXVLRQ&ULWHULD 
 
6XEMHFW,GHQWLILFDWLRQ 
 
3ULRU&RQFRPLWDQWDQG3URKLELWHG0HGLFDWLRQV 
 
3URKLELWHG&23'0HGLFDWLRQV 
 
2WKHU3URKLELWHG0HGLFDWLRQV 
 
2WKHU5HVWULFWLRQV,OOLFLW'UXJVRU'UXJVRI$EXVH 
 
,OOLFLW'UXJVDQGRU'UXJVRI$EXVH 

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
 
'LHWDU\5HVWULFWLRQV 
 
6PRNLQJ6WDWXV 
 
5HDVRQVDQG3URFHGXUHVIRU(DUO\7HUPLQDWLRQ 
 
/$%(/,1*3$&.$*,1*6725$*(',63(16,1*$1'5(78512)
&/,1,&$/6833/,(6 
 
6XEMHFW,QIRUPDWLRQ 
 
3URGXFW'HVFULSWLRQV 
 
3ULPDU\3DFNDJLQJDQG/DEHOLQJ,QIRUPDWLRQ 
 
6HFRQGDU\3DFNDJLQJDQG/DEHOLQJ,QIRUPDWLRQ%R[ 
 
(PHUJHQF\8QEOLQGLQJRI7UHDWPHQW$VVLJQPHQW 
 
6WRUDJH5HTXLUHPHQWV 
 
,QVWUXFWLRQVIRU3UHSDUDWLRQRI7UHDWPHQWVIRU$GPLQLVWUDWLRQDQG'LVSHQVLQJ 
 
*))0',DQG3ODFHER0', 
 
$WURYHQW+)$,SUDWURSLXP%URPLGH 
 
9HQWROLQ+)$$OEXWHURO6XOIDWH 
 
'UXJ$FFRXQWDELOLW\5HWXUQRI&OLQLFDO6XSSOLHV 
 
678'<352&('85(6 
 
(IILFDF\$VVHVVPHQWV 
 
+5&7VFDQV 
 
6SLURPHWU\ 
 
&KDUDFWHUL]DWLRQRI5HYHUVLELOLW\ 
 
6WDELOLW\&ULWHULD 
 
,QVSLUDWRU\&DSDFLW\ 
 
6WDQGDUGL]DWLRQRI,&DQG6SLURPHWU\&ROOHFWLRQV 
 
%RG\SOHWK\VPRJUDSK\ 
 
'LIIXVLRQFDSDFLW\ 
 
,QKDODWLRQ3URILOHZLWK%RG\3OHWK\VPRJUDSK\ 
 
,QKDODWLRQ3URILOHGXULQJDGPLQLVWUDWLRQ 
 
6XEMHFW'LDU\'DWD&ROOHFWLRQ 
 
5HVFXH9HQWROLQ+)$8VH 
 
5HFRUGLQJRI'RVH,QGLFDWRU5HDGLQJ 
 
6XEMHFW4XHVWLRQQDLUHV 
 
&23'$VVHVVPHQW7HVW 
 
0RGLILHG0HGLFDO5HVHDUFK&RXQFLO'\VSQHD6FDOH 
 
&23'([DFHUEDWLRQV 
 
6DIHW\$VVHVVPHQWV 
 
0HGLFDO6XUJLFDO+LVWRU\DQG3K\VLFDO([DPLQDWLRQ 
 
9LWDO6LJQ0HDVXUHPHQWV 
 
/HDG(OHFWURFDUGLRJUDP 

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
 
&OLQLFDO/DERUDWRU\7HVWV 
 
+HPDWRORJ\ 
 
&OLQLFDO&KHPLVWU\ 
 
8ULQDO\VLV 
 
3UHJQDQF\7HVW 
 
$GYHUVH(YHQWV 
 
3HUIRUPLQJ$GYHUVH(YHQWV$VVHVVPHQWV 
 
$GYHUVH(YHQW'HILQLWLRQV 
 
3UH5DQGRPL]DWLRQ$GYHUVH(YHQWV 
 
6HYHULW\ 
 
5HODWLRQVKLS 
 
&OLQLFDO/DERUDWRU\$GYHUVH(YHQWV 
 
6HULRXV$GYHUVH(YHQWV 
 
5HSRUWLQJ6HULRXV$GYHUVH(YHQWV 
 
6XSSOHPHQWDO,QYHVWLJDWLRQVRI6$(V 
 
3RVW6WXG\)ROORZ8SRI$GYHUVH(YHQWV 
 
1RWLILFDWLRQRI3RVW6WXG\6HULRXV$GYHUVH(YHQWV 
 
,5%,(&1RWLILFDWLRQRI6HULRXV$GYHUVH(YHQWV 
 
+HDOWK$XWKRULW\6DIHW\5HSRUWV 
 
2YHUGRVH 
 
3UHJQDQF\ 
 
7HUPLQDWLRQRIWKH6WXG\ 
 
678'<$&7,9,7,(6 
 
9LVLW6FUHHQLQJ 
 
9LVLW5DQGRPL]DWLRQ'D\RI73 
 
9LVLW'D\GD\VRI73 
 
9LVLW'D\RI73 
 
9LVLW'D\GD\VRI73 
 
8QVFKHGXOHG9LVLW3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW 
 
)ROORZ8S7HOHSKRQH&DOO 
 
&RPSOHWLRQRIWKH6WXG\ 
 
3/$11('67$7,67,&$/0(7+2'6 
 
,QWURGXFWLRQ 
 
3URWRFRO9DULDEOHV 
 
(IILFDF\(QGSRLQWV 
 
3ULPDU\(IILFDF\(QGSRLQWVRQ'D\DQG'D\H[FHSWDV
RWKHUZLVHQRWHG 
 
6HFRQGDU\(IILFDF\(QGSRLQWVPHDVXUHGRQ'D\DQG'D\
H[FHSWDVRWKHUZLVHQRWHG 
 
2WKHU(IILFDF\(QGSRLQWVPHDVXUHGRQ'D\DQG'D\H[FHSWDV
RWKHUZLVHQRWHG 

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
 
6DIHW\(QGSRLQWV 
 
(IILFDF\$QDO\VHV 
 
(IILFDF\$QDO\VLV 
 
&RQWURORI7\SH,HUURU 
 
6DIHW\$QDO\VLV 
 
$GYHUVH(YHQWV 
 
5DQGRPL]DWLRQ 
 
([SHULPHQWDOGHVLJQ 
 
6DPSOH6L]H&RQVLGHUDWLRQ 
 
'DWD9DOLGDWLRQDQG7UDQVIRUPDWLRQ 
 
$QDO\VLV3ODQ 
 
6WXG\3RSXODWLRQV 
 
+DQGOLQJRI0LVVLQJ'DWD 
 
6WDWLVWLFDO6RIWZDUH 
 $'0,1,675$7,9(&216,'(5$7,216 
 
5HJXODWRU\$XWKRULW\$SSURYDO 
 
(WKLFDO&RQGXFWRIWKH6WXG\DQG,QVWLWXWLRQDO5HYLHZ%RDUG,5%RU
,QGHSHQGHQW(WKLFV&RPPLWWHH,(&$SSURYDO 
 
6XEMHFW,QIRUPDWLRQDQG&RQVHQW 
 
/DERUDWRU\$FFUHGLWDWLRQ 
 
&RQILGHQWLDOLW\ 
 
&RQILGHQWLDOLW\RI'DWD 
 
&RQILGHQWLDOLW\RI6XEMHFW6XEMHFW5HFRUGV 
 
4XDOLW\&RQWURODQG$VVXUDQFH 
 
'DWD0DQDJHPHQW 
 
6WXG\0RQLWRULQJ 
 
5HWHQWLRQRI'DWD 
 )LQDQFLDO'LVFORVXUH 
 ,QYHVWLJDWRU
V)LQDO5HSRUW 
 3XEOLFDWLRQ3ROLF\ 
 5()(5(1&(/,67 
 $33(1',&(6 

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

/,672),17(;77$%/(6
7DEOH 
3URKLELWHG&23'0HGLFDWLRQVDQG5HTXLUHG:DVKRXW3HULRGV3ULRUWR9LVLW
7LWOHZDVUHYLVHG 
7DEOH 
3URKLELWHG&23'0HGLFDWLRQVDQG5HTXLUHG:DVKRXW3HULRGV3ULRUWR9LVLW
DQG9LVLW 
7DEOH 
2WKHU5HVSLUDWRU\1DVDO0HGLFDWLRQV5HTXLUHG:DVKRXW3HULRGV 
7DEOH 
1RQ&23'0HGLFDWLRQV$OORZHG8QGHU&HUWDLQ&RQGLWLRQ 
7DEOH 
3URKLELWHG0HGLFDWLRQV 
7DEOH 
6WXG\3URGXFW3DFNDJLQJ'HVFULSWLRQV 
7DEOH 
'HVFULSWLRQRI%R[HV 
7DEOH 
005&'\VSQHD6FDOH 
7DEOH 
/DE3DUDPHWHUV 
7DEOH 
7LPHG$VVHVVPHQWVDW9LVLWDQG9LVLW 
7DEOH 
7LPHG$VVHVVPHQWVDW9LVLWDQG9LVLW 
7DEOH 
5DQGRPL]DWLRQ6FKHGXOH 

/,672),17(;7),*85(6
)LJXUH 
6WXG\'HVLJQ&KDUW 
)LJXUH$ ,QGLFDWRUDW7RSRI&DQLVWHU 
)LJXUH$ :DVK$FWXDWRUWKURXJK7RSRI$FWXDWRU 
)LJXUH$ :DVK$FWXDWRUWKURXJK0RXWKSLHFH 
)LJXUH$ 0HWHUHG'RVH,QKDOHU3DUWV 

/,672)$33(1',&(6
$SSHQGL[ 
6XEMHFW,QVWUXFWLRQVIRU8VHRI*))DQG3ODFHER0', 
$SSHQGL[ 
,QVWUXFWLRQVIRU8VHRI$WURYHQW+)$,QKDODWLRQ$HURVRO'HYLFH 
$SSHQGL[ 
,QVWUXFWLRQVIRU8VHRI9HQWROLQ+)$,QKDOHU 
$SSHQGL[ 
&23'$VVHVVPHQW7HVW 
$SSHQGL[ 
0RGLILHG0HGLFDO5HVHDUFK&RXQFLO'\VSQHD6FDOH$VVHVVPHQW 
$SSHQGL[ 
'RVH,QGLFDWRU'LVSOD\5HDGLQJ,QVWUXFWLRQV 
$SSHQGL[ 
3URWRFRORI+5&7VFDQDQG&)'PHWKRG 
$SSHQGL[ 
6SRQVRU6LJQDWRU\ 
$SSHQGL[ 
,QYHVWLJDWRU¶V$JUHHPHQWDQG6LJQDWXUH3DJH 


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

/,672)$%%5(9,$7,216$1''(),1,7,2162)7(506
$(
$GYHUVHHYHQW
$/7
$ODQLQHDPLQRWUDQVIHUDVH
$67
$VSDUWDWHDPLQRWUDQVIHUDVH
$76
$PHULFDQ7KRUDFLF6RFLHW\
$9
$WULRYHQWULFXODUEORFN
%,'
ELVLQGLH7ZLFH'DLO\
%L3$3
%LOHYHO3RVLWLYH$LUZD\3UHVVXUH
%SP
%HDWVSHUPLQXWH
%81
%ORRGXUHDQLWURJHQ
&$7
&23'$VVHVVPHQW7HVW
&)'
&RPSXWDWLRQDOIOXLGG\QDPLFV
&)5
&RGHRI)HGHUDO5HJXODWLRQV
&+)
&RQJHVWLYH+HDUW)DLOXUH
&+03
&RPPLWWHHIRU0HGLFLQDO3URGXFWVIRU+XPDQ8VH
&216257
&RQVROLGDWHG6WDQGDUGVRI5HSRUWLQJ7ULDOV
&23'
&KURQLF2EVWUXFWLYH3XOPRQDU\'LVHDVH
&3$3
&RQWLQXRXV3RVLWLYH$LUZD\3UHVVXUH
&7
&RPSXWHG7RPRJUDSK\
'%3
'LDVWROLFEORRGSUHVVXUH
(&*
(OHFWURFDUGLRJUDP
H&5)
(OHFWURQLF&DVH5HSRUW)RUP
(J
([HPSOLJUDWLDIRUH[DPSOH
(5
(PHUJHQF\5RRP
(56
(XURSHDQ5HVSLUDWRU\6RFLHW\
(8
(XURSHDQ8QLRQ
H[DFWXDWRU
'RVH'HOLYHUHG)URP7KH$FWXDWRULHPRXWKSLHFH2I7KH0',
)'$
)RRGDQG'UXJ$GPLQLVWUDWLRQ
)()
)RUFHG([SLUDWRU\)ORZEHWZHHQWRRI)9&
)(9
)RUFHG([SLUDWRU\9ROXPH,Q6HFRQG
))0',
)RUPRWHURO)XPDUDWH0',

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
)5&
)XQFWLRQDO5HVLGXDO&DSDFLW\
)5,
)XQFWLRQDO5HVSLUDWRU\,PDJLQJ
)9&
)RUFHG9LWDO&DSDFLW\
*&3
*RRG&OLQLFDO3UDFWLFH
*))0',
*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH0',
*)50'5'
*ORPHUXODU)LOWUDWLRQ5DWHHVWLPDWHGXVLQJWKH0RGLILFDWLRQRI'LHWLQ5HQDO'LVHDVH
HTXDWLRQ
*2/'
*OREDO,QLWLDWLYHIRU&KURQLF2EVWUXFWLYH/XQJ'LVHDVH
*30',
*O\FRS\UURQLXP0',
+
1XOO+\SRWKHVLV
+
$OWHUQDWLYH+\SRWKHVLV
+&*
+XPDQ&KRULRQLF*RQDGRWURSLQ
+)$
+\GURIOXRURDONDQH
+5&7
+LJK5HVROXWLRQ&RPSXWHG7RPRJUDSK\
,%
,QYHVWLJDWRU¶V%URFKXUH
,&
,QVSLUDWRU\&DSDFLW\
,&)
,QIRUPHG&RQVHQW)RUP
,&+
,QWHUQDWLRQDO&RQIHUHQFHRQ+DUPRQL]DWLRQ
,&0-(
,QWHUQDWLRQDO&RPPLWWHHRI0HGLFDO-RXUQDO(GLWRUV
,&6
,QKDOHG&RUWLFRVWHURLG
,'
,GHQWLILFDWLRQ
LH
,GHVWWKDWLV
,(&
,QGHSHQGHQW(WKLFV&RPPLWWHH
,3)
,QWHUVWLWLDO3XOPRQDU\)LEURVLV
L5DZ
,PDJHEDVHG$LUZD\UHVLVWDQFH
,5%
,QVWLWXWLRQDO5HYLHZ%RDUG
,77
,QWHQWLRQWRWUHDW
,8'
,QWUDXWHULQHGHYLFH
L9DZ
,PDJHEDVHG$LUZD\YROXPH
L9DZZ
$LUZD\ZDOOYROXPH
L9OREHV
,PDJHEDVHG/REHYROXPHV
/
/LWHU
/$%$
/RQJDFWLQJ%HWD$JRQLVW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
/$0$
/RQJDFWLQJ0XVFDULQLF$QWDJRQLVW
/727
/RQJ7HUP2[\JHQ7KHUDS\
0&+
0HDQ&RUSXVFXODU+HPRJORELQ
0&+&
0HDQ&RUSXVFXODU+HPRJORELQ&RQFHQWUDWLRQ
0&9
0HDQ&RUSXVFXODU9ROXPH
0',
0HWHUHG'RVH,QKDOHU
P,77
0RGLILHG,QWHQWWR7UHDW
PO
0LOOLOLWHU
005&
0RGLILHG0HGLFDO5HVHDUFK&RXQFLO
0VHFPV
0LOOLVHFRQG
1+$1(6,,,
7KLUG1DWLRQDO+HDOWKDQG1XWULWLRQ([DPLQDWLRQ6XUYH\
1,339
1RQLQYDVLYH3RVLWLYH3UHVVXUH9HQWLODWLRQ'HYLFH
1<+$
7KH1HZ<RUN+HDUW$VVRFLDWLRQ
27&
2YHUWKHFRXQWHU
3)7
3XOPRQDU\)XQFWLRQ7HVW
351
SURUHQDWD$V1HHGHG
4'
TXDTXHGLH2QFH'DLO\
4,'
TXDWHULQGLH)RXU7LPHV'DLO\
47F)
47XVLQJ)ULGHULFLD¶VFRUUHFWLRQIDFWRU
5$16
5H\QROGVDYHUDJHG1DYLHU6WRNHV
5DZ
$LUZD\UHVLVWDQFH
59
5HVLGXDO9ROXPH
6$%$
6KRUWDFWLQJ%HWD$JRQLVW
6$(
6HULRXV$GYHUVH(YHQW
6$3
6WDWLVWLFDO$QDO\VLV3ODQ
6%3
6\VWROLFEORRGSUHVVXUH
V*DZ
6SHFLILFDLUZD\FRQGXFWDQFH
VL5DZ
,PDJHEDVHG6SHFLILFDLUZD\UHVLVWDQFH
VL9DZ
,PDJHEDVHG6SHFLILFDLUZD\YROXPH
615,
6HURWRQLQQRUHSLQHSKULQHUHXSWDNHLQKLELWRUV
6'
6WDQGDUG'HYLDWLRQ
623
6WDQGDUG2SHUDWLQJ3URFHGXUH
V5DZ
6SHFLILFDLUZD\UHVLVWDQFH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
665,
6HOHFWLYH6HURWRQLQ5HXSWDNH,QKLELWRUV
7&
7HOHSKRQH&DOO
7&2
7KHVLQJOHEUHDWKGLIIXVLQJFDSDFLW\RIWKHOXQJVIRUFDUERQPRQR[LGH
7($(
7UHDWPHQW(PHUJHQW$GYHUVH(YHQW
7/&
7RWDO/XQJ&DSDFLW\
71)Į
$QWLWXPRU1HFURVLV)DFWRUĮ
73
7UHDWPHQW3HULRG
7853
7UDQVXUHWKUDO5HVHFWLRQRI3URVWDWH
8$
8SSHU$LUZD\
86
8QLWHG6WDWHV
9$
$OYHRODUYROXPH
9EY
%ORRGYHVVHOYROXPH


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

75$'(0$5.,1)250$7,21
Trademarks Not Owned By Pearl Therapeutics, Inc.
$HUROL]HU
0RQWHOXNDVW
$QRUR(OOLSWD
6HHEUL%UHH]KDOHU
$WURYHQW
6SLULYD+DQGLKDOHU
%UHWDULV*HQXDLU
6SLROWR5HVSLPDW
&RPELYHQW
7XGRU]D3UHVVDLU
'D[DV
8OWLEUR%UHH]KDOHU
'XDNOLU*HQXDLU
9HQWROLQ
)RUDGLO
=DILUOXNDVW
,QFUXVH(OOLSWD


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


INTRODUCTION AND STUDY RATIONALE
&KURQLFREVWUXFWLYHSXOPRQDU\GLVHDVH&23'LVDOHDGLQJFDXVHRIPRUELGLW\DQGPRUWDOLW\DW
DJOREDOOHYHODQGUHFHQWVWDWLVWLFVVXJJHVWLWZLOOEHFRPHPRUHSUHYDOHQWDVVPRNLQJIUHTXHQFLHV
ULVH DQG WKH SRSXODWLRQ DJHV &DOYHUOH\  )HHQVWUD  )HUUHU  0XUUD\ 
6XOOLYDQ  ,Q D V\VWHPDWLF UHYLHZ DQG PHWDDQDO\VLV E\ +DOEHUW DQG FROOHDJXHV WKH
SUHYDOHQFHRISK\VLRORJLFDOO\GHILQHG&23'LQDGXOWVDJHG\HDUVZDVREVHUYHGWREH
+DOEHUWDQG+DOEHUW7KHFDXVHVEHKLQG&23'DUHPXOWLIDFWRULDOZKHUHYDULRXVULVN
IDFWRUVDQGHQYLURQPHQWDOVWLPXOLKDYHEHHQLGHQWLILHGDQGLQFOXGHVPRNLQJDLUSROOXWLRQDQG
RFFXSDWLRQDOKD]DUGV+HQFH&23'LVQRWRQO\DVPRNHU¶VGLVHDVHZLWKIDPLOLDORULJLQVEXWRQH
WKDWZRUVHQVZLWKDJH
&23'LVDGLVHDVHRIWKHOXQJVFKDUDFWHUL]HGE\DLUIORZOLPLWDWLRQWKDWLVQRWIXOO\UHYHUVLEOH
7KHFKURQLFDLUIORZOLPLWDWLRQFKDUDFWHULVWLFRI&23'LVFDXVHGE\DPL[WXUHRIVPDOODLUZD\V
GLVHDVH REVWUXFWLYH EURQFKLROLWLV DQG SDUHQFK\PDO GHVWUXFWLRQ HPSK\VHPD WKH UHODWLYH
FRQWULEXWLRQV RI ZKLFK YDU\ IURP SHUVRQ WR SHUVRQ 7KH DLUIORZ OLPLWDWLRQ LV SURJUHVVLYH LQ
QDWXUHDQGDVVRFLDWHGZLWKDQDEQRUPDOLQIODPPDWRU\UHVSRQVHRIWKHOXQJWRQR[LRXVSDUWLFOHVRU
JDVHV7KLVGLVHDVHLVFKDUDFWHUL]HGE\SUHPDWXUHORVVRIYHQWLODWRUIXQFWLRQDVGHWHUPLQHGE\D
GHFOLQH LQ IRUFHG H[SLUDWRU\ YROXPH LQ WKH ILUVW VHFRQG RI H[KDODWLRQ )(9 3DWKRORJLFDO
LQIODPPDWRU\ FKDQJHV DUH FKDUDFWHUL]HG E\ HOHYDWLRQV LQ DFWLYDWHG PDFURSKDJHV QHXWURSKLOV
HODVWDVHVDQG&'O\PSKRF\WHV7KHVHPROHFXODUDQGFHOOXODUFKDQJHVFDXVHGWKHGHVWUXFWLRQRI
VPDOO DLUZD\V DQG VXUURXQGLQJ DOYHROL $V H[SLUDWRU\ DLUIORZ )(9 RU IRUFHG YLWDO FDSDFLW\
)9&LVDIXQFWLRQRISUHVVXUHDJDLQVWUHVLVWDQFHDLUIORZLQ&23'LVGLPLQLVKHGGXHWRDORVV
RIHODVWLFUHFRLODQGDLUZD\FRQVWULFWLRQ
3KDUPDFRORJLFWKHUDS\IRU&23'LVXVHGWRUHGXFHV\PSWRPVUHGXFHWKHIUHTXHQF\DQGVHYHULW\
RI H[DFHUEDWLRQV DQG LPSURYH KHDOWK VWDWXV DQG H[HUFLVH WROHUDQFH %URQFKRGLODWRUV DUH WKH
PDLQVWD\ RI SKDUPDFRORJLF WUHDWPHQW RI &23' 7KH SULQFLSDO EURQFKRGLODWRU WUHDWPHQWV DUH
VKRUWDFWLQJEHWDDJRQLVWV6$%$VORQJDFWLQJEHWDDJRQLVWV/$%$VVKRUWDFWLQJPXVFDULQLF
DQWDJRQLVWV ORQJDFWLQJ PXVFDULQLF DQWDJRQLVWV /$0$V DQG PHWK\O[DQWKLQHV XVHG DV
PRQRWKHUDS\ RU LQ FRPELQDWLRQ ,Q VXEMHFWV ZLWK VLJQLILFDQW V\PSWRPV EXW ORZ ULVN RI
H[DFHUEDWLRQV UHJXODU WUHDWPHQW ZLWK /$%$V LV PRUH HIIHFWLYH LQ WKH PDQDJHPHQW RI &23'
WKDQ 6$%$V ,Q VXEMHFWV ZLWK D KLJK ULVN RI H[DFHUEDWLRQV UHJDUGOHVV RI WKH QXPEHU RI
V\PSWRPV D IL[HG FRPELQDWLRQ RI DQ LQKDOHG FRUWLFRVWHURLG ,&6/$%$ RU D /$0$ LV
UHFRPPHQGHG*2/'
&XUUHQWO\IRXUIL[HGGRVHFRPELQDWLRQVRI/$%$DQGD/$0$DUHFRPPHUFLDOO\DYDLODEOHLQ
(XURSH 'XDNOLU *HQXDLU >DFOLGLQLXP DQG IRUPRWHURO@ IURP $VWUD =HQHFD $QRUR (OOLSWD
>XPHFOLGLQLXP DQG YLODQWHURO@
 8OWLEUR %UHH]KDOHU >LQGDFDWHURO DQG
JO\FRS\UURQLXP@ IURP
 DQG 6SLROWR  5HVSLPDW >WLRWURSLXP DQG RORGDWHURO@ IURP
 &RPELYHQW >VDOEXWDPRO VXOIDWH DQG LSUDWURSLXP EURPLGH@ LV D VKRUW
DFWLQJIL[HGGRVHFRPELQDWLRQRID6$%$DQGVKRUWDFWLQJPXVFDULQLFDQWDJRQLVWLQGLFDWHGIRU
WKHWUHDWPHQWRI&23'DQGLVDGPLQLVWHUHGDVWZRLQKDODWLRQVIRXUWLPHVGDLO\3XEOLVKHGVWXGLHV
YDQ 1RRUG  YDQ 1RRUG  9RJHOPHLHU  KDYH VKRZQ WKDW WKH FRPSOHPHQWDU\

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
PHFKDQLVPV RI DFWLRQ RI /$%$ IRUPRWHURO IXPDUDWH DQG D /$0$ WLRWURSLXP EURPLGH
VLJQLILFDQWO\LPSURYHGEURQFKRGLODWLRQLQ&23'VXEMHFWVFRPSDUHGWRWKHLQGLYLGXDODJHQWV
3HDUO 7KHUDSHXWLFV ,QF KHUHDIWHU UHIHUUHG WR DV 3HDUO LV GHYHORSLQJ D FRPELQDWLRQ SURGXFW
*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO37KHUHDIWHUUHIHUUHGWRDV
*))PHWHUHGGRVHLQKDOHU>0',@DVDPDLQWHQDQFHEURQFKRGLODWRUWUHDWPHQWLQVXEMHFWVZLWK
&23',QWKLVVWXG\*))0',JFRQWDLQVJRIJO\FRS\UURQLXPDQGJRI
IRUPRWHUROIXPDUDWH*))0',LVDGPLQLVWHUHGWZLFHGDLO\%,'7KHGRVHRIJO\FRS\UURQLXP
JLQ*))0',LVHTXLYDOHQWWRJRIJO\FRS\UURODWHJO\FRS\UURQLXPEURPLGH
*O\FRS\UURQLXPLVD/$0$ZKLFKH[HUWVEURQFKRGLODWRUHIIHFWYLDPXVFDULQLFUHFHSWRUVORFDWHG
RQVPRRWKPXVFOHFHOOVZLWKLQWKHWUDFKHDDQGEURQFKL*O\FRS\UURQLXPLVDSSURYHGLQPDQ\
FRXQWULHVLQPXOWLSOHIRUPXODWLRQVIRUGLIIHUHQWLQGLFDWLRQVLQFOXGLQJ&23'
$Q LQKDOHG IRUPXODWLRQ RI JO\FRS\UURQLXP 6HHEUL %UHH]KDOHU ,QKDODWLRQ 3RZGHU
JO\FRS\UURQLXP EURPLGH ZDV UHFHQWO\ DSSURYHG WKURXJKRXW WKH (XURSHDQ 8QLRQ (8
$XVWUDOLD &DQDGD DQG -DSDQ IRU WKH PDQDJHPHQW RI DGXOW VXEMHFWV ZLWK &23' 7KH
UHFRPPHQGHGGRVHLVJGHOLYHUHGGRVHRIJRIJO\FRS\UURQLXPEURPLGHHTXLYDOHQWWR
JRIJO\FRS\UURQLXPDGPLQLVWHUHGRQFHGDLO\4'XVLQJWKH6HHEUL%UHH]KDOHULQKDOHU7KH
FOLQLFDOGHYHORSPHQW SURJUDP IRU 6HHEUL %UHH]KDOHU LQFOXGHG FOLQLFDOVWXGLHVILYH3KDVH ,
VWXGLHVIRXU3KDVH ,, FOLQLFDOVWXGLHVDQGWKUHH3KDVH ,,,FOLQLFDOVWXGLHV2YHUDOOWKHFOLQLFDO
GHYHORSPHQWSURJUDPLQFOXGHGDWRWDORIVXEMHFWVZLWK&23'H[SRVHGWR6HHEUL%UHH]KDOHU
J4'ZLWKDWRWDORIDQGVXEMHFWVZLWK&23'H[SRVHGWR6HHEUL%UHH]KDOHUJ
4'IRUZHHNVDQGZHHNVUHVSHFWLYHO\>&RPPLWWHHIRU0HGLFLQDO3URGXFWVIRU+XPDQ
8VH&+03$VVHVVPHQW5HSRUWIRU6HHEUL%UHH]KDOHU@,QDGGLWLRQWRWKHSXEOLVKHGGDWD
ZLWK6HHEUL%UHH]KDOHUDOVRUHIHUUHGWRDV19$WKHUHLVDOVRODUJHERG\RISXEOLVKHGGDWD
HYDOXDWLQJWKHVDIHW\DQGHIILFDF\RILQKDOHGJO\FRS\UURQLXPLQKHDOWK\YROXQWHHUVVXEMHFWVZLWK
&23'DQGVXEMHFWVZLWKDVWKPD
)RUPRWHUROIXPDUDWHLVDSRWHQWDQGVHOHFWLYH/$%$DSSURYHGLQPDQ\FRXQWULHVZRUOGZLGHIRU
XVH LQ DVWKPD DQG &23' :KHQ LQKDOHG IRUPRWHURO IXPDUDWH DFWV ORFDOO\ LQ WKH OXQJ DV D
EURQFKRGLODWRU )RUPRWHURO IXPDUDWH VWLPXODWHV ȕ DGUHQRUHFHSWRUV LQ WKH DLUZD\V LQGXFLQJ
DLUZD\VPRRWKPXVFOHUHOD[DWLRQDQGUHGXFLQJRUSUHYHQWLQJEURQFKRFRQVWULFWLRQ
5HFHQWO\3HDUOKDVFRPSOHWHGSLYRWDO3KDVH,,,VWXGLHVVWXG\37VWXG\37DQG
VWXG\ 37 RQ *))0', DQG LWV FRPSRQHQWV *O\FRS\UURQLXP 0', *3 0', DQG
)RUPRWHURO)XPDUDWH0',))0',$QLQWHQGHGWKHUDSHXWLFGRVHRI*))ȝJ%,'ZDV
FKRVHQIRUWKHVHVWXGLHV3ULRUWRWKHVH3KDVH,,,VWXGLHV3HDUOFRQGXFWHGDQXPEHURI3KDVH,
DQG 3KDVH ,, VWXGLHV WR VXSSRUW WKH GRVH VHOHFWLRQ RI WKHVH 3KDVH ,,, VWXGLHV ,Q DGGLWLRQ D
WKRURXJK47VWXG\DQGDFDUGLRYDVFXODUVDIHW\VWXG\ZHUHFRQGXFWHGWRVXSSRUWWKHVH3KDVH,,,
VWXGLHV
6WXG\ 37 DQG VWXG\ 37 ZHUH PXOWLFHQWHU VWXGLHV 6WXG\ 37 ZDV D
UDQGRPL]HGGRXEOHEOLQGVWXG\GUXJDFWLYHFRQWURODQGSODFHERFKURQLFGRVLQJZHHNV
SODFHERFRQWUROOHG SDUDOOHO JURXS PXOWLFHQWHU VWXG\ WR DVVHVV WKH HIILFDF\ DQG VDIHW\ RI
*))0',))0',DQG*30',LQVXEMHFWVZLWKPRGHUDWHWRYHU\VHYHUH&23'FRPSDUHG
ZLWKSODFHERDQG6SLULYD+DQGLKDOHU7LRWURSLXP%URPLGHȝJ2SHQ/DEHODVDQDFWLYH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
FRQWUROZLWKVLWHVLQ8QLWHG6WDWHV86$XVWUDOLDDQG1HZ=HDODQG6WXG\37ZDVD
UHSOLFDWHGVWXG\RIVWXG\37ZLWKRXWRSHQODEHO6SLULYDDVDQDFWLYHFRQWUROZLWKVLWHVLQ
WKH 8QLWHG 6WDWHV 86 &RPELQHG WRWDO RI 37 DQG 37 VWXGLHV LQFOXGH 
VXEMHFWV  VXEMHFWV IURP 37DQGVXEMHFWVIURP37 ,QWKHVHVWXGLHV
*))0',ȝJ))0',ȝJDQG*30',ȝJZHUHVDIHZHOOWROHUDWHGZLWKQR
XQH[SHFWHGVDIHW\ILQGLQJVDQGKDYHGHPRQVWUDWHGLPSURYHPHQWVFRPSDUHGWR3ODFHER0',LQ
OXQJ IXQFWLRQ &23' V\PSWRPV DQG TXDOLW\ RI OLIH DV ZHOO DV &23' H[DFHUEDWLRQV 6WXG\
37ZDVDZHHNVDIHW\H[WHQVLRQVWXG\RI6WXGLHV37DQG37WRHYDOXDWH
ORQJWHUPVDIHW\DQGWROHUDELOLW\RI*))0',*30',DQG))0',LQVXEMHFWVZLWKPRGHUDWH
WRYHU\VHYHUH&23'RYHUDWRWDOREVHUYDWLRQSHULRGRIZHHNVDQGVXEMHFWV2SHQODEHO
6SLULYDZDVLQFOXGHGDVDQDFWLYHFRQWURO7KHVXEMHFWVFRQWLQXHGWRUHPDLQRQWKHLURULJLQDOO\
DVVLJQHGWUHDWPHQWVIURPVWXGLHV37DQG376XEMHFWVLQ6WXGLHV37DQG
37DVVLJQHGWR3ODFHER0',ZHUHQRWLQYLWHGWRSDUWLFLSDWHLQWKLVH[WHQVLRQVWXG\,QWKLV
VWXG\*))0',JGHPRQVWUDWHGLPSURYHPHQWVFRPSDUHGWR*30',JDQG))
0',JLQOXQJIXQFWLRQHYDOXDWHGRYHUWKHZHHNWUHDWPHQWSHULRGWKHLPSURYHPHQWVLQ
OXQJIXQFWLRQREVHUYHGRYHUWKHILUVWZHHNVRIWKHOHDGLQVWXGLHV37RU37
ZHUHJHQHUDOO\FRQVLVWHQWWKURXJK:HHN2YHUDOOWKHVDIHW\SURILOHVRI*))0',J
))0',JRU*30',JZHUHVLPLODUWRWKRVHREVHUYHGIRURWKHUDSSURYHG/$0$V
DQG/$%$VHJWLRWURSLXPDFOLGLQLXPXPHFOLGLQLXPYLODQWHURORORGDWHURODQGLQGDFDWHURO
1RVLJQLILFDQWDGGLWLRQDOVDIHW\ULVNVZHUHREVHUYHGZLWKWKHFRPELQDWLRQ*))0',J
RYHUWKHLQGLYLGXDOFRPSRQHQWV))0',JDQG*30',JRURYHU6SLULYDJ
$ PRUH GHWDLOHG GHVFULSWLRQ RI WKH FRQGXFWHG VWXGLHV DQG UHVXOWV FDQ EH REWDLQHG LQ WKH
,QYHVWLJDWRU%URFKXUH,%
1.1
6WXG\5DWLRQDOH
7KHGXDODFWLRQEURQFKRGLODWRU*))0',RIIHUVUDSLGRQVHWRIDFWLRQZLWKWKHHIIHFWSHUVLVWLQJ
RYHUKRXUV37PD\RIIHUDVLJQLILFDQWDGYDQWDJHWRVXEMHFWVLQWHUPVRIVXVWDLQHGHIILFDF\
RYHUKRXUVFRPSOHWHDLUZD\FRYHUDJHYLD3HDUO¶VSRURXVSDUWLFOHVDORQJZLWKWKHUHOLDELOLW\
RI3HDUO
V0',GRVDJHIRUPZLWKQRFRIRUPXODWLRQHIIHFWGXULQJVWRUDJHRUVXEMHFWXVH
,QWKLVVWXG\WKHHIIHFWVRIWUHDWPHQWZLWK*))0',FRPSDUHGZLWK3ODFHER0',RQVSHFLILF
LPDJHEDVHGDLUZD\YROXPHVDQGUHVLVWDQFHLQVXEMHFWVZLWKPRGHUDWHWRVHYHUH&23'ZLOOEH
DVVHVVHG7KLVLPDJLQJPHWKRGRORJ\ZLOODOORZDQDVVHVVPHQWRIWKHH[WHQWRIDLUZD\FKDQJHV
XVLQJ D ORQJ DFWLQJ EURQFKRGLODWRU FRPELQDWLRQ 3UHYLRXV VWXGLHV GHPRQVWUDWHG WKDW ORRNLQJ
GLUHFWO\DWDLUZD\YROXPHVDQGUHVLVWDQFHLVDPRUHVHQVLWLYHPHDVXUHDV)(9WRHYDOXDWHWKH
DFXWH EURQFKRGLODWLQJ HIIHFW RI LQKDOHG /$%$ DQGRU /$0$ 'H %DFNHU  'H %DFNHU
9RV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


STUDY OBJECTIVES 

7RDVVHVVWKHHIILFDF\DQGVDIHW\RIWUHDWPHQWZLWK*))0',ȝJ%,'DQG
3ODFHER0',LQVXEMHFWVZLWKPRGHUDWHWRYHU\VHYHUH&23'

2.1
3ULPDU\2EMHFWLYH
x
7RDVVHVVWKHHIIHFWRIWUHDWPHQWZLWK*))0',WZLFHGDLO\%,'FRPSDUHGZLWK3ODFHER
0',RQVSHFLILFLPDJHEDVHGDLUZD\YROXPHVDQGUHVLVWDQFHLQVXEMHFWVZLWKPRGHUDWHWR
VHYHUH FKURQLF REVWUXFWLYH SXOPRQDU\ GLVHDVH &23' IROORZLQJ FKURQLF GRVLQJ DIWHU
DSSUR[LPDWHO\WZRZHHNVWUHDWPHQW
2.2
6HFRQGDU\2EMHFWLYHV

7R FRPSDUH WKH HIIHFWV RI *)) 0', RQ YDULRXV )XQFWLRQDO 5HVSLUDWRU\ ,PDJLQJ )5,
SDUDPHWHUV

7RFRPSDUHWKHHIIHFWVRI*))0',DQG3ODFHER0',RQSXOPRQDU\IXQFWLRQWHVW3)7
SDUDPHWHUV

2.3
6DIHW\2EMHFWLYHV

7R DVVHVV WKH VDIHW\ RI *)) 0',LQ VXEMHFWV ZLWK PRGHUDWH WR VHYHUH &23' EDVHG RQ
$GYHUVH(YHQWV$(VDQGDQ\FOLQLFDOO\UHOHYDQWILQGLQJVIURPYLWDOVLJQPHDVXUHPHQWV
HOHFWURFDUGLRJUDPV (&*V SK\VLFDO H[DPLQDWLRQ ILQGLQJV DQG FOLQLFDO ODERUDWRU\
HYDOXDWLRQV













*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


STUDY ENDPOINTS
3.1
(IILFDF\(QGSRLQWV
7KHILUVWGD\RIWUHDWPHQWLQHDFK7UHDWPHQW3HULRG73LV'D\9LVLWVDQG2Q'D\RI
HDFK73EDVHOLQHPHDVXUHPHQWVLQFOXGLQJDQLQVSLUDWRU\VFDQ7RWDO/XQJ&DSDFLW\>7/&@VFDQ
DQG DQ H[SLUDWRU\ VFDQ )XQFWLRQDO 5HVLGXDO&DSDFLW\>)5&@VFDQZLOOEHFRQGXFWHG'XULQJ
9LVLWDQDGGLWLRQDOVFDQRIWKHXSSHUDLUZD\8$ZLOOEHWDNHQ(DFK73LVSODQQHGWRFRQWDLQ
DSSUR[LPDWHO\ZHHNVEHWZHHQWKHILUVWDQGODVWGRVHFRUUHVSRQGLQJWRDVSDQRIFDOHQGDU
GD\VGD\V7KHUHIRUHSRVWGRVHDVVHVVPHQWVFROOHFWHGRQ'D\GD\V9LVLWVDQG
ZLOORFFXUIROORZLQJDSSUR[LPDWHO\ZHHNVRIWUHDWPHQWZLWK*))0',RU3ODFHER0',3RVW
GRVH&RPSXWHG7RPRJUDSK\&7VFDQ7/&VFDQZLOOEHWDNHQRQ'D\GD\V9LVLW
DQG9LVLW

/XQJIXQFWLRQPHDVXUHPHQWVDQGV\PSWRPEDVHGHQGSRLQWVZLOOEHHYDOXDWHGRQ'D\DQG'D\
GD\VRI7UHDWPHQW3HULRGDQG9LVLWVDQG

3.1.1
3ULPDU\(IILFDF\(QGSRLQWV
FRI Parameters:

6SHFLILFDLUZD\YROXPHVL9DZ

6SHFLILFDLUZD\UHVLVWDQFHVL5DZ

3.1.2
6HFRQGDU\(IILFDF\(QGSRLQWV
FRI Parameters:

$LUZD\YROXPHL9DZ

$LUZD\UHVLVWDQFHL5DZ
Spirometry Parameters:

)RUFHGH[SLUDWRU\YROXPHLQRQHVHFRQG)(9
Body Plethysmography Parameters: 

)5&


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
3.1.3
2WKHU(IILFDF\(QGSRLQWV
FRI Parameters:

/REHYROXPHVL9OREHV

$LUWUDSSLQJ

,QWHUQDOOREDUDLUIORZGLVWULEXWLRQ

/RZDWWHQXDWLRQRUHPSK\VHPDVFRUH

%ORRGYHVVHOGHQVLW\RUILEURVLVVFRUH

$LUZD\ZDOOWKLFNQHVV

0DVVRIGHSRVLWHGSDUWLFOHVSHUGHILQHGDLUZD\VHFWLRQ

Spirometry Parameters:

)RUFHGYLWDOFDSDFLW\)9&

7LIIHQHDXLQGH[)(9)9&UDWLR

)RUFHGH[SLUDWRU\IORZ)()

,QVSLUDWRU\FDSDFLW\,&

Body Plethysmography Parameters: 

5HVLGXDOYROXPH59

7/&

$LUZD\UHVLVWDQFH5DZ

6SHFLILFDLUZD\UHVLVWDQFHV5DZ

6SHFLILFDLUZD\FRQGXFWDQFHV*DZ


3.2
6DIHW\(QGSRLQWV

$(V




*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

INVESTIGATIONAL PLAN
4.1
2YHUDOO6WXG\'HVLJQDQG3ODQ
7KLVLVDVLQJOHFHQWHUFKURQLFGRVLQJZHHNVVWXG\WRDVVHVVWKHHIIHFWVRI*))0',
J%,'FRPSDUHGZLWK3ODFHER0',LQVXEMHFWVZLWKPRGHUDWHWRVHYHUH&23'RQVSHFLILF
LPDJHEDVHGDLUZD\YROXPHVDQGUHVLVWDQFH
,Q WKLV VWXG\  VXEMHFWV ZLOO EH LQFOXGHG ZLWK PRGHUDWH WR VHYHUH &23' 6XEMHFWV ZLOO EH
UDQGRPL]HGLQWZRWUHDWPHQWVHTXHQFHV6XEMHFWVLQVHTXHQFHZLOOUHFHLYH*))0',LQ73
IROORZHGE\3ODFHER0',LQ736XEMHFWVLQVHTXHQFHZLOOUHFHLYH3ODFHER0',LQ73
IROORZHGE\*))0',LQ73
6XEMHFWV ZLOO UHFHLYH DSSUR[LPDWHO\  ZHHNV RI VWXG\ WUHDWPHQW ZLWK HDFK RI WKHLU DVVLJQHG
WUHDWPHQWVIRUDWRWDORIWZRVHSDUDWH73V$ZDVKRXWSHULRGRIGD\VZLOORFFXUEHWZHHQ
HDFK7UHDWPHQW3HULRG7KHHQWLUHVWXG\SHULRGLVVFKHGXOHGWRWDNHDSSUR[LPDWHO\ZHHNVIRU
HDFKLQGLYLGXDOVXEMHFWIURPWKHWLPHRI6FUHHQLQJ
3ULRU WR RUDW 9LVLW  6FUHHQLQJ DOO VXEMHFWV DUH WR VLJQ DQ LQIRUPHGFRQVHQW IRUP SULRU WR WKH
FRQGXFW RI DQ\ VFUHHQLQJ DVVHVVPHQWV 7KH ,QYHVWLJDWRU RU GHVLJQHH ZLOOREWDLQ D PHGLFDO KLVWRU\
LQFOXGLQJ VSHFLILF FDUGLRYDVFXODU KLVWRU\ &23' H[DFHUEDWLRQV ZLWKLQ WKH ODVW \HDU FOLQLFDO
ODERUDWRU\WHVWVSK\VLFDOH[DPLQDWLRQSUHJQDQF\WHVWDQGDQ\UHTXLUHGGRFXPHQWDWLRQLQRUGHUWR
GHWHUPLQH HOLJLELOLW\ IRU SDUWLFLSDWLRQ LH LQFOXVLRQH[FOXVLRQ FULWHULD 6XEMHFWV PXVW PHHW
VSLURPHWU\FULWHULDIRU&23')(9SUHGLFWHGDQG)(9)9&UDWLRDW9LVLWWR
TXDOLI\ IRU VWXG\ HQUROOPHQW 5HYHUVLELOLW\ RI )(9 DSSUR[LPDWHO\ PLQXWHV IROORZLQJ
IRXUSXIIVRI9HQWROLQ+)$ZLOOEHDVVHVVHGDQGDYHQWLODWLRQSHUIXVLRQUHODWLRQVKLSPHDVXUHPHQW
GLIIXVLRQFDSDFLW\ZLOOEHSHUIRUPHGDW6FUHHQLQJ9LVLWWRFKDUDFWHUL]HWKHVXEMHFWSRSXODWLRQ
5HVFUHHQLQJLVQRWDOORZHGIRUVXEMHFWVZKRGRQRWPHHWWKHVSLURPHWU\FULWHULDDW9LVLW
3URYLGLQJ WKH VXEMHFW PHHWV WKH HOLJLELOLW\ FULWHULD WKH ,QYHVWLJDWRU RU GHVLJQHH ZLOO UHYLHZ
FXUUHQW&23'PHGLFDWLRQVDQGLIQHFHVVDU\ZLOOPDNHDUUDQJHPHQWVWRDGMXVWWKHSURKLELWHG
&23' WKHUDS\ WR SURWRFRODOORZDEOH &23' WKHUDS\ $W 9LVLW  6FUHHQLQJ HOLJLEOH VXEMHFWV
ZKR DUH  XVLQJ D SURKLELWHG &23' PHGLFDWLRQ UHIHU WR 7DEOH  DQG PHHW DOO RWKHU HQWU\
FULWHULDZLOOUHWXUQWRWKHFOLQLFDQGWRGD\VIRU9LVLW5DQGRPL]DWLRQ9LVLW)RUPRUH
GHWDLOVRQ9LVLWSURFHGXUHVUHIHUWR6HFWLRQ
6XEMHFWVZKRPHHWDOOHQWU\FULWHULDEXWDUHXVLQJFHUWDLQSURKLELWHG&23'PHGLFDWLRQVHJRUDO
ȕDJRQLVWV /$%$V /$0$V /$%$/$0$ FRUWLFRVWHURLG/$%$ FRPELQDWLRQ SURGXFWV
FURPRJO\FDWHRUQHGRFURPLOLQKDOHUVOHXNRWULHQHDQWDJRQLVWV>HJ]DILUOXNDVWPRQWHOXNDVW@RU
WLRWURSLXP
>6SLULYD@
JO\FRS\UURQLXP
>HJ6HHEUL@
DQG
DFOLGLQLXP
>HJ7XGRU]D
3UHVVDLU%UHWDULV *HQXDLU@ XPHFOLGLQLXP >,QFUXVH (OOLSWD@ DQG IL[HG GRVH /$0$/$%$
FRPELQDWLRQV 'XDNOLU *HQXDLU DFOLGLQLXP DQG IRUPRWHURO $QRUR XPHFOLGLQLXP DQG
YLODQWHURO 8OWLEUR %UHH]KDOHU LQGDFDWHURO DQG JO\FRS\UURQLXP DQG 6SLROWR 5HVSLPDW
WLRWURSLXP DQG RORGDWHURO ZLOO GLVFRQWLQXH WKHVH PHGLFDWLRQV IRU WKH GXUDWLRQ RI WKH VWXG\
6XEMHFWVWDNLQJDIL[HGGRVHFRPELQDWLRQWUHDWPHQWZLWKDQ,&6SOXVD/$%$PXVWGLVFRQWLQXH
WKHFRPELQHGPHGLFDWLRQDQGLQVWHDGEHSUHVFULEHGDQ,&6PRQRWKHUDS\DWDQHTXLYDOHQWGRVH
DQGUHJLPHQIRUWKHGXUDWLRQRIWKHVWXG\'XULQJWKH5XQLQSHULRGDQGEHWZHHQ9LVLWVDQG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
VXEMHFWV ZLOO XVH 6SRQVRUSURYLGHG $WURYHQW+)$ >$WURYHQW @ DGPLQLVWHUHG IRXU WLPHV
GDLO\4,'VHH6HFWLRQDQGVSRQVRUSURYLGHGUHVFXH9HQWROLQ+)$DOEXWHUROVXOIDWH
LQKDODWLRQ DHURVRO
 DV QHHGHG 351 WR FRQWURO V\PSWRPV VHH
6HFWLRQ 6XEMHFWV SUHYLRXVO\ XVLQJ DQ ,&6 DQGRU SKRVSKRGLHVWHUDVH LQKLELWRU PD\
FRQWLQXHXVLQJWKHPHGLFDWLRQVDWWKHVDPHGRVHDVSUHYLRXVO\GHVFULEHG

$W9LVLWVHYHUDONH\DVVHVVPHQWVUHIHUWR7DEOHVKDOOEHREWDLQHG$GGLWLRQDOO\G\VSQHD
ZLOOEHHYDOXDWHGWKURXJKWKH0RGLILHG0HGLFDO5HVHDUFK&RXQFLO005&TXHVWLRQQDLUHDQGWKH
EXUGHQ RI GLVHDVH ZLOO EH DVVHVVHG WKURXJK WKH &23' $VVHVVPHQW 7HVW &$7 WKHUHIRUH LW LV
QHFHVVDU\IRUDOOVXEMHFWVWREHDSSURSULDWHO\ZDVKHGRXWRIWKHLULQKDOHG&23'PHGLFDWLRQVSULRUWR
9LVLWUHIHUWR6HFWLRQ
$W9LVLW5DQGRPL]DWLRQ9LVLW'D\RI73VXEMHFWVZLOOUHWXUQWRWKHFOLQLF6LWHVWDIIPXVW
FRQILUP WKH VXEMHFW PHHWV DOO SURWRFROVSHFLILF UHTXLUHPHQWV DQG HQVXUH DGHTXDWH ZDVKRXW
KRXUVRUORQJHURIDOOLQKDOHGPHGLFDWLRQVLQFOXGLQJ,&6DQGUHVFXHPHGLFDWLRQH[FHSWIRU
VSRQVRUSURYLGHG $WURYHQW +)$ 6XEMHFWV ZKR FRQWLQXH WR PHHW HQWU\ LQFOXVLRQH[FOXVLRQ
FULWHULD DQG UHPDLQ HOLJLEOH IRU SDUWLFLSDWLRQ LQ WKH VWXG\ ZLOOEH UDQGRPL]HGLQWRRQHRIWZR
SUHGHILQHG WUHDWPHQW VHTXHQFHV SRVVLEOH WUHDWPHQW VHTXHQFHV WR ZKLFK D VXEMHFW FDQ EH
UDQGRPL]HGDUHVKRZQLQ6HFWLRQ$W'D\RI7UHDWPHQW3HULRG5DQGRPL]DWLRQ9LVLW
HDFKVXEMHFWZLOOEHDVVLJQHGWRHLWKHU*))0',RU3ODFHER0',$W'D\RI7UHDWPHQW3HULRG
HDFKVXEMHFWZLOOEHDVVLJQHGWRWKHRSSRVLWHWUHDWPHQWWRZKLFKWKH\ZHUHDVVLJQHGGXULQJ
7UHDPHQW3HULRG7KH:DVKRXW3HULRGEHWZHHQ7UHDPHQW3HULRGDQGLVWRGD\VLQ
GXUDWLRQ
$W9LVLWVXEMHFWVZLOOFRPSOHWHDOOSUHGRVHWLPHGDVVHVVPHQWVDQGLQWKHEHJLQQLQJRIWKHYLVLW
WKHEDVHOLQH)(9YDOXHZLOOEHREWDLQHGUHIHUWR7DEOHSULRUWRUHFHLYLQJWKHLUILUVWGRVHRI
*))0',RU3ODFHER0',LQWKHFOLQLFXQGHUVLWHSHUVRQQHOVXSHUYLVLRQ'XULQJWKHSUHGRVH
DVVHVVPHQWV D VFDQ RI WKH XSSHU DLUZD\ 8$ ZLOO EH WDNHQ $IWHU WKH &7VFDQV DUH WDNHQ
VSLURPHWU\DQGERG\SOHWK\VPRJUDSK\ZLOOEHSHUIRUPHGWKHLQKDODWLRQSURILOHZLOOEHPHDVXUHG
ZLWK WKH ERG\ SOHWK\VPRJUDSK DQG UHVSLUDWLRQ EHOWV 7KH VXEMHFW
V LQKDODWLRQ SURILOH ZLOO EH
PHDVXUHGLQRUGHUWRGUDZDQDLUIORZYHUVXVWLPHFXUYH$WWKHPRPHQWRIWKLVPHDVXUHPHQWWKH
VLJQDOIURPWKHUHVSLUDWLRQEHOWXVHGIRUWKHPHDVXUHPHQWRIWKHLQKDODWLRQSURILOHGXULQJWKH
VWXG\GUXJDGPLQLVWUDWLRQZLOODOVREHORJJHG
3ULRU WR 0', DGPLQLVWUDWLRQ RQ 'D\  RI WUHDWPHQW SHULRG  DQG  WKH 0', GHYLFH ZLOO EH
SULPHGIRXUDFWXDWLRQVWRZDVWHDWWKHVWXG\VLWHE\WKHVWXG\WHDPLQDURRPVHSDUDWHGIURPWKH
SDWLHQW  $IWHU DGPLQLVWUDWLRQ RI WKH VXEMHFW¶V ILUVW GRVH DOO SRVWGRVH DVVHVVPHQWV ZLOO EH
SHUIRUPHG UHIHU WR 7DEOH  )ROORZLQJ FRPSOHWLRQ RI DOO DVVHVVPHQWV VXEMHFWV ZLOO EH
GLVFKDUJHGIURPWKHFOLQLFDQGZLOOEHLQVWUXFWHGWRFRQWLQXHWRDGPLQLVWHU7UHDWPHQWSHULRG
VWXG\GUXJIRUDSSUR[LPDWHO\ZHHNVDWKRPHXQWLO9LVLW
)RUPRUHGHWDLOVRQ9LVLWSURFHGXUHVUHIHUWR6HFWLRQ
7KHVXEMHFWFOLQLFDOVLWHSHUVRQQHODQG3HDUOZLOOEHXQDZDUHRIWKHWUHDWPHQWVHTXHQFHDVVLJQHG
WRDVXEMHFWLWZLOOQRWEHSRVVLEOHWRGLIIHUHQWLDWHEHWZHHQ*))DQG3ODFHER0',VVLQFHWKH\
ZLOOEHLGHQWLFDOLQDOODVSHFWV7KH*))DQG3ODFHER0',VZLOOEHDGPLQLVWHUHG%,'

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
6XEMHFWVZLOOEHWUDLQHGRQKRZWRUHDGWKHGRVHLQGLFDWRU6HH6HFWLRQDQG$SSHQGL[IRU
LQVWUXFWLRQVRQKRZDQGZKHQWRUHDGWKHGRVHLQGLFDWRU
2Q9LVLW'D\RI73VXEMHFWVZLOOSHUIRUPDVSLURPHWU\WHVWDQGZLOOXQGHUJR9LVLW
SURWRFROGHILQHGSUHGRVHDVVHVVPHQWVUHIHUWR7DEOHDQG7DEOH7KHVLWHSHUVRQQHOZLOO
ZDLWKRXUDIWHUWKHDGPLQLVWUDWLRQRIVWXG\GUXJEHIRUHLQLWLDWLQJSRVWGRVHDVVHVVPHQWV3RVW
GRVHDVVHVVPHQWVQHHGWREHFRPSOHWHGZLWKLQKRXUVDIWHUGRVLQJWKHVXEMHFW6WXG\GUXJZLOO
EHFROOHFWHG3ULRUWRGLVFKDUJHIURPWKHVWXG\FOLQLFVXEMHFWVZLOOEHLQVWUXFWHGWRXQGHUJRD
ZDVKRXWSHULRGRIWRGD\VZKLOHRQ6SRQVRUSURYLGHG$WURYHQW+)$0',DGPLQLVWHUHG
4,'DQG9HQWROLQ+)$IRUUHVFXHXVHDVQHHGHG351SULRUWRLQLWLDWLQJWKHQH[WWUHDWPHQWLQ
WKHLUDVVLJQHGWUHDWPHQWVHTXHQFH)RUPRUHGHWDLOVRQ9LVLWSURFHGXUHVUHIHUWR6HFWLRQ
DQG7DEOH
$W9LVLW'D\RI73LWLVLPSRUWDQWWRHQVXUHWKDWWKHEDVHOLQH)(9LVVWDEOHDQGUHIOHFWLYH
RIWKHVXEMHFW¶V&23'VHYHULW\SULRUWRFRQWLQXLQJWRWKHVHFRQGWUHDWPHQWSHULRG$VVXFKWKH
EDVHOLQHVWDELOLW\FULWHULDZLOOEHHYDOXDWHGVHHVHFWLRQ7RHQVXUHEDVHOLQH)(9VWDELOLW\DW
9LVLWWKHPLQXWH)(9YDOXHREWDLQHGDW9LVLWZLOOEHFRPSDUHGWRWKHDYHUDJHSUHGRVH
DQGPLQXWH)(9YDOXHVREWDLQHGDW9LVLW6XEMHFWVPHHWLQJEDVHOLQHVWDELOLW\FULWHULD
ZLOOEHGLVSHQVHGWUHDWPHQWSHULRGVWXG\GUXJDFFRUGLQJWRWKHLUDVVLJQHGWUHDWPHQWVHTXHQFH
DQGZLOODGPLQLVWHUWKHLUILUVWGRVHLQWKHFOLQLFXQGHUVLWHSHUVRQQHOVXSHUYLVLRQ6XEMHFWVZLOO
XQGHUJRDOOSURWRFROGHILQHGDVVHVVPHQWVVHH7DEOHDQG7DEOHZLOOEHGLVFKDUJHGIURP
WKH FOLQLF DQG ZLOO EH LQVWUXFWHG WR FRQWLQXH VWXG\ GUXJ DGPLQLVWUDWLRQ IRU DSSUR[LPDWHO\ 
ZHHNVGD\VGD\VXQWLO9LVLW)RUPRUHGHWDLOVRQ9LVLWSURFHGXUHVUHIHUWR6HFWLRQ
DQG7DEOH
$W9LVLW'D\GD\VRI73VXEMHFWVZLOODJDLQUHWXUQWRWKHFOLQLFIRUDGPLQLVWUDWLRQRI
WKHILQDOGRVHRI73VWXG\GUXJXQGHUVLWHSHUVRQQHOVXSHUYLVLRQ9LVLWZLOOVHUYHDVWKHILQDO
FOLQLFYLVLW3ULRUWRWKHDGPLQLVWUDWLRQRIWKHILQDOGRVHRIVWXG\GUXJVXEMHFWVZLOOSHUIRUPD
VSLURPHWU\ WHVW DQG ZLOO XQGHUJR 9LVLW  SURWRFROGHILQHG SUHGRVH DVVHVVPHQWV VHH
7DEOHDQG7DEOH7KHVLWHSHUVRQQHOZLOOZDLWKRXUDIWHUWKHDGPLQLVWUDWLRQRIVWXG\GUXJ
EHIRUHLQLWLDWLQJSRVWGRVHDVVHVVPHQWV3RVWGRVHDVVHVVPHQWVQHHGWR EHFRPSOHWHG ZLWKLQ
KRXUV DIWHUGRVLQJ WKH VXEMHFW 6WXG\ GUXJ ZLOO EH FROOHFWHG VXEMHFWV UHWXUQHG WR SUHVWXG\ RU
DSSURSULDWHPDLQWHQDQFH&23'PHGLFDWLRQVDQGVXEMHFWVZLOOEHGLVFKDUJHGIURPWKHVWXG\$
WHOHSKRQHIROORZXSZLOOEHSHUIRUPHGZLWKLQWRGD\VIROORZLQJ9LVLW)RUPRUHGHWDLOVRQ
9LVLWSURFHGXUHVUHIHUWR6HFWLRQDQG7DEOH
5HIHUWR7DEOHIRUWKHRYHUYLHZRIWKHVWXG\SURFHGXUHVDQGDVVHVVPHQWVWREHSHUIRUPHGDW
WKHVWXG\YLVLWV
4.1.1
*HQHUDO&RQVLGHUDWLRQVIRU7UHDWPHQW9LVLWWKURXJK9LVLWLQFOLQLF

$WWKHVWDUWRIHDFKWUHDWPHQWSHULRG9LVLWDQG9LVLWSULRUWRDQ\VWXG\SURFHGXUHV
EHLQJSHUIRUPHGVLWHSHUVRQQHOPXVWFRQILUPWKHVXEMHFWZLWKKHOGDOOLQKDOHG&23'
PHGLFDWLRQVLQFOXGLQJ,&6DQGUHVFXHPHGLFDWLRQHJ9HQWROLQ+)$H[FHSWVSRQVRU
SURYLGHG$WURYHQW+)$IRUDWOHDVWKRXUVE\FRQILUPLQJWKHODVWWLPHRIGRVLQJIRUDOO
&23'PHGLFDWLRQV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Note  6XEMHFWV ZKR LQDGYHUWHQWO\ WRRN &23' PHGLFDWLRQV H[FHSW IRU VSRQVRU
SURYLGHG $WURYHQW+)$ZLWKLQ  KRXUV RI WKH VWDUW RI VWXG\ SURFHGXUHV PXVWEH
UHVFKHGXOHGDVVRRQDVLVSUDFWLFDOEXWZLWKLQWKHVSHFLILHGYLVLWZLQGRZ
Note:  %HIRUH WKH LQFOLQLF GRVH LV DGPLQLVWHUHG WKH VLWH PXVW FRQILUPWKH VXEMHFW
PHHWVDOORWKHUSURWRFROVSHFLILHGUHTXLUHPHQWV
Note: 6XEMHFWVZLOOEHLQVWUXFWHGWRDGPLQLVWHUVSRQVRUSURYLGHG$WURYHQW+)$WKH
PRUQLQJRI9LVLWDQG9LVLWKRXUVSULRUWRWKHDQWLFLSDWHGWLPHRIWKHSRVWGRVH
&7VFDQ

$WWKHHQGRIHDFKWUHDWPHQWSHULRG9LVLWDQG9LVLWSULRUWRDQ\VWXG\SURFHGXUHVEHLQJ
SHUIRUPHG VLWH SHUVRQQHO PXVW FRQILUP WKH VXEMHFW ZLWKKHOG DOO LQKDOHG &23' PHGLFDWLRQV
LQFOXGLQJUDQGRPL]HGVWXG\PHGLFDWLRQ,&6DQGUHVFXHPHGLFDWLRQHJ9HQWROLQ+)$IRUDW
OHDVWKRXUVE\FRQILUPLQJWKHODVWWLPHRIGRVLQJIRUDOO&23'PHGLFDWLRQV
Note6XEMHFWVZKRLQDGYHUWHQWO\WRRNLQKDOHG&23'PHGLFDWLRQVZLWKLQKRXUV
RIWKHVWDUWRIVWXG\SURFHGXUHVPXVWEHUHVFKHGXOHGDVVRRQDVLVSUDFWLFDOEXWZLWKLQ
WKHVSHFLILHGYLVLWZLQGRZ
Note:  %HIRUH WKH LQFOLQLF GRVH LV DGPLQLVWHUHG WKH VLWH PXVW FRQILUP WKH VXEMHFW
PHHWVDOORWKHUSURWRFROVSHFLILHGUHTXLUHPHQWV

6XEMHFWVPXVWQRWLQJHVW[DQWKLQHFRQWDLQLQJIRRGVDQGEHYHUDJHVIRUDWOHDVWKRXUVSULRUWR
HDFKVWXG\YLVLWDQGIRUWKHGXUDWLRQRIHDFKVWXG\YLVLWVHH6HFWLRQ

6XEMHFWVZLOOEHUHTXLUHGWRUHIUDLQIURPVPRNLQJQLFRWLQHJXPVDQGSDWFKHVDUHDOORZHG
IRUDWOHDVWKRXUVSULRUWRHDFKVWXG\YLVLWDQGWKURXJKRXWWKHGXUDWLRQRIHDFKVWXG\YLVLW

7RHQVXUHVWDQGDUGL]DWLRQRIGRVLQJWLPHVLWLVUHFRPPHQGHGWKHVLWHHQFRXUDJHVXEMHFWVWR
PDLQWDLQDGRVLQJVFKHGXOHDWKRPHFRQVLVWHQWZLWKWKHLULQFOLQLFGRVLQJWLPH
6XEMHFWVZLOOEHUHTXLUHGWRWDNHWKHLUVWXG\GUXJ%,'LQWKHPRUQLQJEHWZHHQ
DQG DP EUHDNIDVW WLPH DQG LQ WKH HYHQLQJ EHWZHHQ  DQG SP
GLQQHUWLPH

,QRUGHUWRPLQLPL]HGLXUQDOYDULDQFHVLWHVVKRXOGGLVFXVVWKHLPSRUWDQFHZLWKWKHVXEMHFWRI
GRVLQJLQDWLPHO\PDQQHUHYHU\KRXUVIRUEOLQGHGVWXG\PHGLFDWLRQ

,QRUGHUWRPLQLPL]HGLXUQDOYDULDQFHVLWHVVKRXOGPDNHHYHU\HIIRUWWRDVVHVVVXEMHFWVDWWKH
VDPHWLPHWKURXJKRXWWKHVWXG\
6XEMHFWVZLOOEHUHTXLUHGWRUHWXUQWRWKHFOLQLFDWDSSUR[LPDWHO\WKHVDPHWLPHIRUDOO
WUHDWPHQWYLVLWVDQGZLOOEHUHTXLUHGWRUHPDLQDWWKHFOLQLFXQWLOFRPSOHWLRQRIDOO
SURWRFROGHILQHGDVVHVVPHQWV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

7KHVLWHVKRXOGPDNHHYHU\HIIRUWWRHQVXUHWKDWWKHLQFOLQLFGRVLQJWLPHIRU%,'WUHDWPHQW
RFFXUVDURXQGDPDQGZLWKLQKRXUVRIWKHSULRUDWKRPHHYHQLQJGRVLQJWLPH6LWHV
DUHHQFRXUDJHGWRFDOOWKHVXEMHFWRQWKHGD\EHIRUHDVFKHGXOHGYLVLWWRUHPLQGWKHVXEMHFWRIWKH
IROORZLQJ
7RWDNHWKHLUODVWGRVHRI%,'WUHDWPHQWVWKHHYHQLQJEHIRUHWKHVFKHGXOHGYLVLWDW
DSSUR[LPDWHO\SP
7R EULQJ WKHLU VWXG\ GUXJ VSRQVRUSURYLGHG $WURYHQW +)$ DQG VSRQVRUSURYLGHG
9HQWROLQ+)$ZLWKWKHPWRWKHFOLQLF
7RDGPLQLVWHUVSRQVRUSURYLGHG$WURYHQW+)$WKHPRUQLQJRI9LVLWDQG9LVLW
KRXUVSULRUWRWKHDQWLFLSDWHGWLPHRIWKHSRVWGRVH&7VFDQ
7RZLWKKROGDOOLQKDOHG&23'PHGLFDWLRQVLQFOXGLQJUDQGRPL]HGVWXG\GUXJ,&6
DQG UHVFXH PHGLFDWLRQ IRU DW OHDVW KRXUV SULRU WR VWXG\ DVVHVVPHQWV ZLWK WKH
H[FHSWLRQRIVSRQVRUSURYLGHG$WURYHQW+)$DW9LVLWDQG9LVLW
7RUHIUDLQIURPLQJHVWLQJ[DQWKLQHFRQWDLQLQJIRRGVDQGEHYHUDJHVIRUDWOHDVWKRXUV
SULRUWRHDFKVWXG\YLVLWDQGIRUWKHGXUDWLRQRIHDFKVWXG\YLVLW
7RUHIUDLQIURPVPRNLQJIRUDWOHDVWKRXUVSULRUWRWKHVWXG\YLVLWDQGWKURXJKRXWWKH
GXUDWLRQRIHDFKVWXG\YLVLW

7KHLQFOLQLFGRVLQJWLPHZLOOEHUHFRUGHGDVWKHWLPHRIDGPLQLVWUDWLRQRIWKHVHFRQGSXIIRI
VWXG\GUXJ

6LWHSHUVRQQHOZLOOLQVWUXFWVXEMHFWVQRWWRWDNHDQ\QRQVWXG\&23'PHGLFDWLRQVZLWKRXW
VLWHSHUVRQQHOSHUPLVVLRQGXULQJDYLVLWXQWLODOOVWXG\SURFHGXUHVKDYHEHHQFRPSOHWHGDQGWKH
VXEMHFWLVGLVFKDUJHGIURPWKHFOLQLF6LWHSHUVRQQHOVKRXOGWDNHHYHU\SUHFDXWLRQWRSUHYHQWXVH
RI QRQVWXG\ LQKDOHG &23' PHGLFDWLRQV GXULQJ D WHVW GD\ 6LWH SHUVRQQHO PD\ UHTXHVW WKH
VXEMHFW WR VXUUHQGHU DOO QRQVWXG\ &23' PHGLFDWLRQV SULRU WR WKH VWDUW RI WKH YLVLW EHIRUH
SHUIRUPLQJDQ\VWXG\SURFHGXUHVDQGUHWXUQWKHPHGLFDWLRQVWRWKHVXEMHFWDWWKHHQGRIWKHYLVLW
ZKHQDOOVWXG\SURFHGXUHVDUHFRPSOHWHGLIWKH,QYHVWLJDWRULVRIWKHRSLQLRQWKLVLVQHHGHG

,IDVXEMHFWLVH[SHULHQFLQJVHYHUHV\PSWRPVDQGUHTXLUHV9HQWROLQ+)$IRUUHOLHIRI&23'
V\PSWRPVDWDQ\WLPHGXULQJDWHVWGD\VLWHSHUVRQQHOPXVWQRWHWKHWLPHDQGMXVWLILFDWLRQIRU
XVH LQ WKH VXEMHFW¶V ZRUNVKHHW DQG DOO VXEVHTXHQW VSLURPHWU\ DVVHVVPHQWV VKRXOG EH VWRSSHG
+RZHYHUVDIHW\DVVHVVPHQWVVKRXOGEHFRQWLQXHGDWWKHGLVFUHWLRQRIWKH,QYHVWLJDWRU

(YHU\HIIRUWPXVWEHPDGHWRHQVXUHWKDWVXEMHFWVUHWXUQWRWKHFOLQLFRQ'D\IROORZLQJ
WKHLQLWLDWLRQRIHDFKWUHDWPHQWSHULRG7RDFFRPPRGDWHVFKHGXOLQJFRQIOLFWVDZLQGRZRI
GD\V LV SHUPLWWHG LH'D\ SURFHGXUHV PXVW EH GRQH ZLWKLQ D PLQLPXP RI GD\V DQG D
PD[LPXPRIGD\VIURP'D\
'XULQJ HDFK 73 9LVLWV WR  DQG 9LVLWV WR  VXEMHFWV ZLOO EH SHUPLWWHG WR XVH
6SRQVRUSURYLGHG9HQWROLQ+)$RQDQDVQHHGHGEDVLVIRUUHOLHIRI&23'V\PSWRPV
'XULQJWKHUXQLQSHULRGDQGZDVKRXWSHULRGZKHQVXEMHFWVDUHQRWWDNLQJVWXG\GUXJ9LVLWVWR
 DQG 9LVLWV WR  VXEMHFWV ZLOO XVH WKH 6SRQVRUSURYLGHG VKRUWDFWLQJ EURQFKRGLODWRU
$WURYHQW+)$DGPLQLVWHUHG4,'DQGPD\XVH9HQWROLQ+)$RQDQDVQHHGHGEDVLV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
3URWRFRODGMXVWHG ,&6 WKHUDS\ GHILQHG DW 6FUHHQLQJ LI DQ\ VKRXOG EH FRQWLQXHG DQG UHPDLQ
VWDEOH IRU WKH GXUDWLRQ RI WKH VWXG\ VHH 6HFWLRQ IRU IXUWKHU JXLGDQFH UHODWHG WR
SKRVSKRGLHVWHUDVHLQKLELWRUV
$6WXG\)ORZ'LDJUDPLVGLVSOD\HGLQ)LJXUH


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

Figure 1
Study Design Chart


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
4.2
5DWLRQDOHRI6WXG\'HVLJQ
7KLVVWXG\ZLOODVVHVVWKHHIIHFWVRI*))0',JDGPLQLVWHUHG%,'FRPSDUHGWR
3ODFHER0',RQVSHFLILFLPDJHEDVHGDLUZD\YROXPHVDQGUHVLVWDQFH
$UDQGRPL]HGGRXEOHEOLQGFURVVRYHUGHVLJQZDVDGRSWHGLQRUGHUWRLQFUHDVHWKHSUHFLVLRQ
RIFRPSDULVRQVEHWZHHQWUHDWPHQWJURXSV
4.3
5DWLRQDOHRI'RVH5HJLPHQ'XUDWLRQRI7UHDWPHQWDQG3ODFHER
$UP
7KHVHOHFWLRQRIWKH*))0',ȝJ%,'GRVHLQWKLVVWXG\ZDVEDVHGRQGDWDIURP
WKH ILQGLQJV RI WKUHH SUHYLRXV GRVHUDQJLQJ VWXGLHV ZLWK *3 0', 6WXGLHV37
37
DQG
37
WZR
GRVHUDQJLQJ
FOLQLFDO
VWXGLHV
ZLWK
))
0',
6WXGLHV37DQG37DQGIRXUVWXGLHVZLWK*))0',6WXGLHV37
3737DQG37
7KHVHSURJUDPVLGHQWLILHGWKHRSWLPDOGRVHVDVȝJ%,'IRU))0',DQGȝJ%,'
IRU*30',7KHDIRUHPHQWLRQHGVWXGLHVDOVRVKRZHGWKDW*O\FRS\UURQLXPJZKHQ
DGGHG WR IRUPRWHURO IXPDUDWH J SURYLGHV D UHDVRQDEOH EHQHILW DFURVV DOO SDUDPHWHUV
*))0',  J ZDV VDIH DQG ZHOO WROHUDWHG ZLWK DQ $( SURILOH VLPLODU WR LWV
FRPSRQHQWV DQG RWKHU DSSURYHG SURGXFWV IRUWKH PDQDJHPHQW RI &23' LH 6SLULYD
$WURYHQWDQG)RUDGLO$HUROL]HU
7KHVWXG\ZLOOHYDOXDWHWKHHIIHFWVRI*))0',DQG3ODFHER0',RQVSHFLILFLPDJHEDVHG
DLUZD\ YROXPHV DQG UHVLVWDQFH RWKHU YDULRXV )5, SDUDPHWHUV OXQJ IXQFWLRQ WHVWV
RYHUZHHNV
$3ODFHER0',DUPZLOOEHLQFOXGHGLQWKHWULDO7KH3ODFHER0',DUPGRHVQRWLPSO\WKDW
WKLV FRKRUW LV XQWUHDWHG 6XEMHFWV ZLOO EH SHUPLWWHG WR UHFHLYH PDLQWHQDQFH ,&6 DQGRU
SKRVSKRGLHVWHUDVH LQKLELWRUV LI WKH\ ZHUH RQ D VWDEOH GRVH RI WKHVH PHGLFDWLRQV SULRU WR
HQUROOLQJLQWKHVWXG\DQG9HQWROLQ+)$0',ZLOOEHSURYLGHGDVUHVFXHPHGLFDWLRQ1R
FXUUHQWO\ DSSURYHG WUHDWPHQW SUHYHQWV GHDWK RU LUUHYHUVLEOH PRUELGLW\ E\ LQIOXHQFLQJ WKH
FRXUVHRIGLVHDVH
:LWKUHVSHFWWRH[DFHUEDWLRQVFKDQJLQJDQ,&6/$%$WRDQ,&6DQG3519HQWROLQ+)$
0', RU FKDQJLQJ 6SLULYD 6HHEUL WR 351 9HQWROLQ+)$ LVXQOLNHO\WR FDXVH VLJQLILFDQW
VKRUWWHUP KDUP 7KHUH DUH WKUHH IXUWKHU VDIHJXDUGV WR HQVXUHVXEMHFW VDIHW\ LQ WKLV VWXG\
)LUVW5RIOXPLODVW'D[DVDUHFHQWO\DSSURYHGGUXJWRSUHYHQW&23'H[DFHUEDWLRQVLVD
SHUPLVVLEOH PHGLFDWLRQ WKURXJKRXW WKH FRXUVH RI WKH VWXG\ SURYLGHG WKH VXEMHFW ZDV RQ D
VWDEOH GRVH SULRU WR HQUROOPHQW 6HFRQG VXEMHFWV H[SHULHQFLQJ H[DFHUEDWLRQ WKDW UHTXLUHV
WUHDWPHQWZLWKRUDOFRUWLFRVWHURLGVRUDQWLELRWLFVZLWKLQZHHNVSULRUWR9LVLW6FUHHQLQJ
RU GXULQJWKHUXQLQSHULRG9LVLWWR9LVLWZLOOEHGLVFRQWLQXHGIURPWKHWULDO7KLUG
VXEMHFWVH[SHULHQFLQJD&23'H[DFHUEDWLRQGXULQJWKHWUHDWPHQWSHULRGVRUGXULQJWKHZDVK
RXW EHWZHHQ WUHDWPHQW SHULRGV UHTXLULQJ RUDO LQWUDPXVFXODU RU LQWUDYHQRXV FRUWLFRVWHURLGV
DQGRUDQWLELRWLFVVKRXOGEHSUHPDWXUHO\GLVFRQWLQXHGIURPWKHVWXG\

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA 
5.1
,QFOXVLRQ&ULWHULD
6XEMHFWVHOLJLEOHIRUHQUROPHQWLQWKHVWXG\PXVWPHHWDOORIWKHIROORZLQJFULWHULD

 *LYHWKHLUVLJQHGZULWWHQLQIRUPHGFRQVHQWWRSDUWLFLSDWH
 $UHDWOHDVW\HDUVRIDJHDQGQRROGHUWKDQDW9LVLW
 $IHPDOHLVHOLJLEOHWRHQWHUDQGSDUWLFLSDWHLQWKHVWXG\LIVKHLVRI

1RQFKLOGEHDULQJSRWHQWLDOLHSK\VLRORJLFDOO\LQFDSDEOHRIEHFRPLQJSUHJQDQW
LQFOXGLQJDQ\IHPDOHZKRLV\HDUVSRVWPHQRSDXVDORU

&KLOGEHDULQJSRWHQWLDOKDVDQHJDWLYHXULQHSUHJQDQF\WHVWDW9LVLWDQGDJUHHV
WR RQH RI WKH IROORZLQJ DFFHSWDEOH FRQWUDFHSWLYH PHWKRGV XVHG FRQVLVWHQWO\ DQG
FRUUHFWO\DVRXWOLQHGEHORZLHLQDFFRUGDQFHZLWKWKHDSSURYHGSURGXFWODEHODQG
WKH LQVWUXFWLRQV RI WKH SK\VLFLDQ IRU WKH GXUDWLRQ RI WKH VWXG\ IURP 9LVLW 
6FUHHQLQJXQWLOGD\VDIWHU9LVLW

&RPSOHWHDEVWLQHQFHIURPLQWHUFRXUVHRU

,PSODQWVRIOHYRQRUJHVWUHOLQVHUWHGIRUDWOHDVWPRQWKSULRUWRWKHVWXG\GUXJ
DGPLQLVWUDWLRQEXWQRWEH\RQGWKHWKLUGVXFFHVVLYH\HDUIROORZLQJLQVHUWLRQRU

,QMHFWDEOHSURJHVWRJHQDGPLQLVWHUHGIRUDWOHDVWPRQWKSULRUWRVWXG\GUXJ
DGPLQLVWUDWLRQRU

2UDOFRQWUDFHSWLYHFRPELQHGRUSURJHVWRJHQRQO\DGPLQLVWHUHGIRUDWOHDVW
RQHPRQWKO\F\FOHSULRUWRVWXG\GUXJDGPLQLVWUDWLRQRU

'RXEOHEDUULHUPHWKRGFRQGRPRURFFOXVLYHFDSGLDSKUDJPRUFHUYLFDOYDXOW
FDSVSOXVVSHUPLFLGDODJHQWIRDPJHOILOPFUHDPVXSSRVLWRU\RU

$Q LQWUDXWHULQH GHYLFH ,8' LQVHUWHG E\ D TXDOLILHG SK\VLFLDQ ZLWK
SXEOLVKHGGDWDVKRZLQJWKDWWKHKLJKHVWH[SHFWHGIDLOXUHUDWHLVOHVVWKDQ
SHU\HDURU

(VWURJHQLFYDJLQDOULQJRU

3HUFXWDQHRXVFRQWUDFHSWLYHSDWFKHV
 $0DOHLVHOLJLEOHWRHQWHUDQGSDUWLFLSDWHLQWKHVWXG\LIKHLVZLOOLQJQRWWRIDWKHUD
FKLOGGXULQJWKHVWXG\
 &23''LDJQRVLV6XEMHFWVZLWKDQHVWDEOLVKHGFOLQLFDOKLVWRU\RI&23'DVGHILQHGE\
WKH $PHULFDQ 7KRUDFLF 6RFLHW\ $76(XURSHDQ 5HVSLUDWRU\ 6RFLHW\ (56
&HOOLFKDUDFWHUL]HGE\

$LUIORZ OLPLWDWLRQ WKDW LV QRW IXOO\ UHYHUVLEOH 3URJUHVVLYH DLUIORZ OLPLWDWLRQ
DVVRFLDWHG ZLWK DQ DEQRUPDO LQIODPPDWRU\ UHVSRQVH RI WKH OXQJV WR QR[LRXV
SDUWLFOHVRUJDVHVSULPDULO\FDXVHGE\FLJDUHWWHVPRNLQJ
 7REDFFR8VH&XUUHQWRUIRUPHUVPRNHUVZLWKDKLVWRU\RIDWOHDVWSDFN\HDUVRI
FLJDUHWWHVPRNLQJ>1XPEHURISDFN\HDUV QXPEHURIFLJDUHWWHVSHUGD\[
QXPEHURI\HDUVVPRNHGHJFLJDUHWWHVSHUGD\IRU\HDUVRUFLJDUHWWHVSHU
GD\IRU\HDUVUHSUHVHQWSDFN\HDUV@

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
 6HYHULW\ RI 'LVHDVH 6XEMHFWV ZLWK DQ HVWDEOLVKHG FOLQLFDO KLVWRU\ RI &23' DQG
VHYHULW\GHILQHGDV

$W9LVLWSUHEURQFKRGLODWRU)(9)9&UDWLRRI

$W9LVLWSRVWEURQFKRGLODWRU)(9PXVWEH!DQGSUHGLFWHGQRUPDO
YDOXH FDOFXODWHG XVLQJ 7KH 7KLUG 1DWLRQDO +HDOWK DQG 1XWULWLRQ ([DPLQDWLRQ
6XUYH\1+$1(6,,,UHIHUHQFHHTXDWLRQV
 6WDELOLW\FULWHULD
$W 9LVLW  LI WKH SUHGRVH  PLQXWH )(9 YDOXH LV RXWVLGH RI WKH  UDQJH
FRPSDUHGWRWKHDYHUDJHDQGPLQXWHSUHGRVH)(9YDOXHRI9LVLWWKHYLVLW
PD\ EH UHVFKHGXOHG DW WKH ,QYHVWLJDWRU¶V GLVFUHWLRQ RU WKH VXEMHFW PD\ EH
GLVFRQWLQXHG
 6XEMHFWLVZLOOLQJDQGLQWKHRSLQLRQRIWKH,QYHVWLJDWRUDEOHWRDGMXVWFXUUHQW&23'
WKHUDS\DVUHTXLUHGE\WKHSURWRFRO
 6FUHHQLQJFOLQLFDOODERUDWRU\WHVWVPXVWEHDFFHSWDEOHWRWKH,QYHVWLJDWRU
 6FUHHQLQJ(&*PXVWEHDFFHSWDEOHWRWKH,QYHVWLJDWRU
 &KHVW;UD\RU&7VFDQRIWKHFKHVWOXQJVZLWKLQPRQWKVSULRUWR9LVLWPXVWEH
DFFHSWDEOH WR WKH ,QYHVWLJDWRU 6XEMHFWV ZKR KDYH D FKHVW ;UD\ RU &7 VFDQ WKDW
UHYHDOVFOLQLFDOO\VLJQLILFDQWDEQRUPDOLWLHVQRWEHOLHYHGWREHGXHWRWKHSUHVHQFHRI
&23'VKRXOGQRWEHLQFOXGHG$FKHVW;UD\PXVWEHFRQGXFWHGDW9LVLWLIWKHPRVW
UHFHQWFKHVW;UD\RU&7VFDQLVPRUHWKDQPRQWKVROGDWWKHWLPHRI9LVLW
 &RPSOLDQFH6XEMHFWVPXVWEHZLOOLQJWRUHPDLQDWWKHVWXG\FHQWHUDVUHTXLUHGSHU
SURWRFROWRFRPSOHWHDOOYLVLWDVVHVVPHQWV
5.2
([FOXVLRQ&ULWHULD
6XEMHFWVPHHWLQJDQ\RIWKHIROORZLQJFULWHULDDUHWREHH[FOXGHG
 6LJQLILFDQWGLVHDVHVRWKHUWKDQ&23'LHGLVHDVHRUFRQGLWLRQZKLFKLQWKHRSLQLRQ
RIWKH,QYHVWLJDWRUPD\SXWWKHVXEMHFWDWULVNEHFDXVHRISDUWLFLSDWLRQLQWKHVWXG\RU
PD\LQIOXHQFHHLWKHUWKHUHVXOWVRIWKHVWXG\RUWKHVXEMHFW¶VDELOLW\WRSDUWLFLSDWHLQWKH
VWXG\
 3UHJQDQF\:RPHQZKRDUHSUHJQDQWRUODFWDWLQJ
 0DOHVZKRLQWHQGWRIDWKHUDFKLOGGXULQJWKHVWXG\
 5HVSLUDWRU\
D $VWKPD6XEMHFWVZKRLQWKHRSLQLRQRIWKH,QYHVWLJDWRUKDYHDFXUUHQWGLDJQRVLV
RIDVWKPD
E $OSKD$QWLWU\SVLQ'HILFLHQF\6XEMHFWVZKRKDYHDOSKDDQWLWU\SVLQGHILFLHQF\
DVWKHFDXVHRI&23'
F 2WKHU5HVSLUDWRU\'LVRUGHUV6XEMHFWVZKRKDYHRWKHUDFWLYHSXOPRQDU\GLVHDVH
VXFK DV DFWLYH WXEHUFXORVLV OXQJ FDQFHU EURQFKLHFWDVLV +LJK 5HVROXWLRQ
&RPSXWHG7RPRJUDSK\+5&7HYLGHQFHRIEURQFKLHFWDVLVWKDWFDXVHVUHSHDWHG
DFXWHH[DFHUEDWLRQVVDUFRLGRVLVLGLRSDWKLFLQWHUVWLWLDOSXOPRQDU\ILEURVLV,3)

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
SULPDU\SXOPRQDU\K\SHUWHQVLRQRUXQFRQWUROOHGVOHHSDSQHDLHLQWKHRSLQLRQ
RIWKH,QYHVWLJDWRUVHYHULW\RIWKHGLVRUGHUZRXOGLPSDFWWKHFRQGXFWRIWKHVWXG\
Note:$OOHUJLFUKLQLWLVLVQRWH[FOXVLRQDU\
G /XQJ9ROXPH5HGXFWLRQ6XEMHFWVZKRKDYHXQGHUJRQHOXQJYROXPHUHGXFWLRQ
VXUJHU\ OREHFWRP\ RU EURQFKRVFRSLF OXQJ YROXPH UHGXFWLRQ HQGREURQFKLDO
EORFNHUVDLUZD\E\SDVVHQGREURQFKLDOYDOYHVWKHUPDOYDSRUDEODWLRQELRORJLFDO
VHDODQWVDQGDLUZD\LPSODQWVZLWKLQ\HDURI9LVLW
H +RVSLWDOL]DWLRQ 6XEMHFWV ZKR KDYH EHHQ KRVSLWDOL]HG GXH WR SRRUO\ FRQWUROOHG
&23'ZLWKLQPRQWKVSULRUWR9LVLW6FUHHQLQJRUGXULQJWKHUXQLQSHULRG
9LVLWWR9LVLW
I
3RRUO\&RQWUROOHG&23'6XEMHFWVZKRKDYHSRRUO\FRQWUROOHG&23'GHILQHGDV
DFXWH ZRUVHQLQJ RI &23' WKDW UHTXLUHV WUHDWPHQW ZLWK RUDO FRUWLFRVWHURLGV RU
DQWLELRWLFVZLWKLQZHHNVSULRUWR9LVLW6FUHHQLQJRUGXULQJWKHUXQLQSHULRG
9LVLWWR9LVLW
Note:6XEMHFWVZKRDUHVWHURLGGHSHQGHQWDQGPDLQWDLQHGRQDQHTXLYDOHQWRI
PJSUHGQLVRQHSHUGD\RUPJHYHU\RWKHUGD\IRUDWOHDVWPRQWKVSULRUWR
9LVLW  DUH HOLJLEOH IRU HQUROOPHQW SURYLGLQJ WKH GRVH RI RUDO VWHURLGV UHPDLQV
VWDEOHGXULQJWKHUXQLQSHULRG9LVLWWKURXJK9LVLW
J /RZHU 5HVSLUDWRU\ 7UDFW ,QIHFWLRQ 6XEMHFWV ZKR KDG ORZHU UHVSLUDWRU\ WUDFW
LQIHFWLRQV WKDW UHTXLUHG DQWLELRWLFV DQGRU RUDO VWHURLGV ZLWKLQ  ZHHNV SULRU WR
9LVLW6FUHHQLQJRUGXULQJWKHUXQLQSHULRG9LVLWWR9LVLW
K 6SLURPHWU\3HUIRUPDQFH
 $FFHSWDELOLW\ 6XEMHFWV ZKR FDQQRW SHUIRUP DFFHSWDEOH VSLURPHWU\ LH
PHHW$76(56DFFHSWDELOLW\FULWHULD
 5HSHDWDELOLW\ 6XEMHFWV ZKR FDQQRW SHUIRUP WHFKQLFDOO\ DFFHSWDEOH
VSLURPHWU\ZLWKDWOHDVWWKUHHDFFHSWDEOH IORZYROXPHFXUYHVZLWKWZRRU
PRUH PHHWLQJ $76 UHSHDWDELOLW\ FULWHULD IRU )(9 GXULQJ WKH SUH
EURQFKRGLODWRU DVVHVVPHQWV DW 9LVLW  DQG DW WKH SRVWEURQFKRGLODWRU
DVVHVVPHQWDW9LVLW
L
2[\JHQ 6XEMHFWV UHFHLYLQJ ORQJWHUPR[\JHQ WKHUDS\ /727 RU QRFWXUQDO
R[\JHQWKHUDS\UHTXLUHGIRUJUHDWHUWKDQKRXUVDGD\
Note:351R[\JHQXVHLVQRWH[FOXVLRQDU\
M
6XEMHFWXVHRIDQ\QRQLQYDVLYHSRVLWLYHSUHVVXUHYHQWLODWLRQGHYLFH1,339
Note: 6XEMHFWV XVLQJ FRQWLQXRXV SRVLWLYH DLUZD\ SUHVVXUH &3$3 RU ELOHYHO
SRVLWLYHDLUZD\SUHVVXUH%L3$3IRU6OHHS$SQHD6\QGURPHDUHDOORZHGLQWKH
VWXG\
N &KDQJHLQVPRNLQJVWDWXVLHVWDUWRUVWRSVPRNLQJRULQLWLDWLRQRIDVPRNLQJ
FHVVDWLRQ SURJUDP ZLWKLQ  ZHHNV RI 9LVLW  DQG WKURXJKRXW WKH UXQLQ SHULRG
9LVLWWR9LVLW
O
3XOPRQDU\5HKDELOLWDWLRQ6XEMHFWVZKRKDYHSDUWLFLSDWHGLQWKHDFXWHSKDVHRID
SXOPRQDU\UHKDELOLWDWLRQSURJUDPZLWKLQZHHNVSULRUWR9LVLW6FUHHQLQJRU
ZKRZLOOHQWHUWKHDFXWHSKDVHRIDSXOPRQDU\UHKDELOLWDWLRQSURJUDPGXULQJWKH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
VWXG\6XEMHFWVZKRDUHLQWKHPDLQWHQDQFHSKDVHRIDSXOPRQDU\UHKDELOLWDWLRQ
SURJUDPDUHQRWWREHH[FOXGHG
P 6XEMHFWV ZKR KDYH LQLWLDWHG RU DOWHUHG WKH GRVH UHJLPHQ RI LQWUDQDVDO
FRUWLFRVWHURLGVLQWUDQDVDODQWLKLVWDPLQHVRUDFRPELQDWLRQWKHUHRIZLWKLQGD\V
SULRUWR9LVLWRUGXULQJWKHUXQLQSHULRG9LVLWWR9LVLW
 &DUGLDFGLVHDVH
D 6XEMHFWV ZKR KDYH XQVWDEOH LVFKHPLF KHDUW GLVHDVH OHIW YHQWULFXODU IDLOXUH RU
GRFXPHQWHG P\RFDUGLDO LQIDUFWLRQ ZLWKLQ  PRQWKV RI 6FUHHQLQJ 9LVLW 
6XEMHFWV ZLWK D UHFHQW KLVWRU\ RI DFXWH FRURQDU\ V\QGURPH RU ZKR KDYH
XQGHUJRQH SHUFXWDQHRXV FRURQDU\ LQWHUYHQWLRQ RU FRURQDU\ DUWHU\ E\SDVV JUDIW
ZLWKLQWKHSDVWPRQWKVDUHWREHH[FOXGHG
E 6XEMHFWVZLWKFRQJHVWLYHKHDUWIDLOXUH&+)7KH1HZ<RUN+HDUW$VVRFLDWLRQ
1<+$&ODVV,,,,9
F &OLQLFDOO\ VLJQLILFDQW DEQRUPDO (&* $ FOLQLFDOO\ VLJQLILFDQW DEQRUPDO (&* LV
GHILQHGDVEXWQRWOLPLWHGWRDQ\RIWKHIROORZLQJ
 &OLQLFDOO\ VLJQLILFDQW FRQGXFWLRQ DEQRUPDOLWLHV >HJ OHIW EXQGOH EUDQFK
EORFN :ROII3DUNLQVRQ:KLWH V\QGURPH RU HYLGHQFH RI VHFRQG GHJUHH
0RELW]7\SH,,RUWKLUGGHJUHHDWULRYHQWULFXODU$9EORFN@
 &OLQLFDOO\ VLJQLILFDQW DUUK\WKPLDV HJ DWULDO ILEULOODWLRQ ZLWK LUUHJXODU
YHQWULFXODUUHVSRQVHDWULDOIOXWWHUYHQWULFXODUWDFK\FDUGLD
Note:$WULDOILEULOODWLRQWKDWKDVEHHQFOLQLFDOO\VWDEOHIRUDWOHDVWPRQWKV
LV DSSURSULDWHO\ WUHDWHG ZLWK DQWLFRDJXODWLRQ DQG FRQWUROOHG ZLWK D UDWH
FRQWUROVWUDWHJ\LHVHOHFWLYHEHWDEORFNHUFDOFLXPFKDQQHOEORFNHUGLJR[LQ
RUDEODWLRQWKHUDS\IRUDWOHDVWPRQWKVLVDOORZHGIRULQFOXVLRQ,QVXFK
VXEMHFWVDWULDOILEULOODWLRQPXVWEHSUHVHQWDWSUHUDQGRPL]DWLRQYLVLWVZLWK
D UHVWLQJ YHQWULFXODU UDWH  EHDWV SHU PLQXWH ESP $W VFUHHQLQJ WKH
DWULDOILEULOODWLRQPXVWEHFRQILUPHGE\FHQWUDOUHDGLQJ
 $ PHDQ FRUUHFWHG 47 LQWHUYDO XVLQJ )ULGHULFLD¶V FRUUHFWLRQ IDFWRU 47F)
YDOXHDWVFUHHQLQJ!PVHFIRUPDOHVDQG!PVHFIRUIHPDOHVRUDQ
(&* WKDW LV QRW VXLWDEOH IRU 47 PHDVXUHPHQWV HJ SRRUO\ GHILQHG
WHUPLQDWLRQRIWKH7ZDYHDW9LVLWWKDWUHPDLQVHOHYDWHGRQUHSHDWWHVWLQJ
SULRUWR9LVLW
 9HQWULFXODUUDWHESP
 3DWKRORJLFDO4ZDYHVRI\HDU
 67 7 ZDYH DEQRUPDOLWLHV GHHPHG WR EH FOLQLFDOO\ VLJQLILFDQW E\ WKH
,QYHVWLJDWRU
Note: 6XEMHFWV ZLWK QRQVSHFLILF 677 ZDYH DEQRUPDOLWLHV WKDW DUH QRW
GHHPHGFOLQLFDOO\VLJQLILFDQWSHU,QYHVWLJDWRUDUHDOORZHG
 $Q\ RWKHU (&* DEQRUPDOLWLHV QRW OLVWHG DERYH WKDW LQ WKH RSLQLRQ RI WKH
,QYHVWLJDWRUDUHFOLQLFDOO\VLJQLILFDQW
 &OLQLFDOO\ 8QFRQWUROOHG +\SHUWHQVLRQ 6XEMHFWV ZKR KDYH FOLQLFDOO\
VLJQLILFDQWXQFRQWUROOHGK\SHUWHQVLRQ


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

 1HXURORJLFDO
D 6XEMHFWVZLWKVHL]XUHVUHTXLULQJDQWLFRQYXOVDQWVZLWKLQPRQWKVSULRUWR9LVLW
6FUHHQLQJ
Note: 6XEMHFWV WUHDWHG ZLWK DQWLFRQYXOVDQW PHGLFDWLRQ IRU  PRQWKV RU PRUH
ZLWKQRVHL]XUHHYHQWVDUHHOLJLEOH
E 6XEMHFWV WDNLQJ VHOHFWLYH VHURWRQLQ UHXSWDNH LQKLELWRUV 665,V RU VHURWRQLQ
QRUHSLQHSKULQHUHXSWDNHLQKLELWRUV615,VZKRVHGRVHKDVQRWEHHQVWDEOHIRUDW
OHDVW IRXU ZHHNV SULRU WR 9LVLW  RU LV DOWHUHG DW DQ\ SRLQW GXULQJ WKH 5XQLQ
3HULRG9LVLWWR9LVLWRUH[FHHGVWKHPD[LPXPUHFRPPHQGHGGRVH
 5HQDO
D 6XEMHFWVZLWKV\PSWRPDWLFSURVWDWLFK\SHUWURSK\WKDWLVFOLQLFDOO\VLJQLILFDQWLQ
WKH RSLQLRQ RI WKH ,QYHVWLJDWRU 6XEMHFWV ZLWK D WUDQVXUHWKUDO UHVHFWLRQ RI
SURVWDWH7853RUIXOOUHVHFWLRQRIWKHSURVWDWHZLWKLQPRQWKVSULRUWR9LVLW
DUHH[FOXGHGIURPWKHVWXG\
E 6XEMHFWV ZLWK EODGGHU QHFN REVWUXFWLRQ RU XULQDU\ UHWHQWLRQ WKDW LV FOLQLFDOO\
VLJQLILFDQWLQWKHRSLQLRQRIWKH,QYHVWLJDWRU
F 6XEMHFWVZLWKDFDOFXODWHGFUHDWLQLQHFOHDUDQFHPOPLQPAHVWLPDWHG
XVLQJWKH0RGLILFDWLRQRI'LHWLQ5HQDO'LVHDVH(TXDWLRQH*)50'5'DW9LVLW
DQGRQUHSHDWWHVWLQJSULRUWR9LVLW
Note:  6XEMHFWV ZLWK D FRQILUPHG FDOFXODWHG FUHDWLQLQH FOHDUDQFH  
POPLQ PA HVWLPDWHG XVLQJ WKH 0RGLILFDWLRQ RI 'LHW LQ 5HQDO 'LVHDVH
(TXDWLRQ H*)50'5' UHSHDWHG SULRU WR 9LVLW  ZLOO QRW EH UDQGRPL]HG LQ WKH
VWXG\
Note:6XEMHFWVZLWKRYHUDFWLYHEODGGHUV\QGURPHWUHDWHGZLWKRUDODQWLFKROLQHUJLFV
WKDWKDYHEHHQRQWUHDWPHQWIRUDWOHDVWRQHPRQWKDUHDOORZHGLQWKH6WXG\

 (QGRFULQH
D 6XEMHFWV ZKR LQ WKH RSLQLRQ RI WKH ,QYHVWLJDWRU KDYH XQFRQWUROOHG K\SRRU
K\SHUWK\URLGLVPK\SRNDOHPLDRUK\SHUDGUHQHUJLFVWDWH
E 6XEMHFWVZKRLQWKHRSLQLRQRIWKH,QYHVWLJDWRUKDYHXQFRQWUROOHG7\SH,RU,,
GLDEHWHV
 /LYHU6XEMHFWVZLWKDEQRUPDOOLYHUIXQFWLRQWHVWVGHILQHGDV$ODQLQHDPLQRWUDQVIHUDVH
$67$VSDUWDWHDPLQRWUDQVIHUDVH$/7RUWRWDOELOLUXELQWLPHVXSSHUOLPLWRI
QRUPDODW9LVLWDQGRQUHSHDWWHVWLQJSULRUWR9LVLW
 &DQFHU6XEMHFWVZKRKDYHFDQFHUWKDWKDVQRWEHHQLQFRPSOHWHUHPLVVLRQIRUDWOHDVW
ILYH\HDUV
Note:6XEMHFWVZLWKVTXDPRXVFHOOFDUFLQRPDRIWKHVNLQEDVDOFHOOFDUFLQRPDRIWKH
VNLQRUORFDOL]HGSURVWDWHFDQFHUDUHHOLJLEOHLILQWKHRSLQLRQRIWKH,QYHVWLJDWRUWKH
FRQGLWLRQ KDV EHHQ DGHTXDWHO\ HYDOXDWHG LV FOLQLFDOO\ FRQWUROOHG DQG WKH VXEMHFW¶V
SDUWLFLSDWLRQLQWKHVWXG\ZRXOGQRWUHSUHVHQWDVDIHW\FRQFHUQ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
 *ODXFRPD 6XEMHFWV ZLWK D GLDJQRVLV RI DQJOH FORVXUH JODXFRPD ZLOO EH H[FOXGHG
UHJDUGOHVVRIZKHWKHURUQRWWKH\KDYHEHHQWUHDWHG6XEMHFWVZLWKDGLDJQRVLVRIRSHQ
DQJOH JODXFRPD ZKR KDYH LQWUDRFXODU SUHVVXUH FRQWUROOHG ZLWK PHGLFDWLRQV DUH
HOLJLEOH $OO PHGLFDWLRQV DSSURYHG IRU FRQWURO RI LQWUDRFXODU SUHVVXUHV DUH DOORZHG
LQFOXGLQJ WRSLFDO RSKWKDOPLF QRQVHOHFWLYH ȕEORFNHUV VXFK DV EHWD[RORO FDUWHRORO
OHYREXQROROPHWLSUDQRORORUWLPRORO
 'UXJ $OOHUJ\ 6XEMHFWV ZKR KDYH D KLVWRU\ RI K\SHUVHQVLWLYLW\ WR ȕDJRQLVWV
JO\FRS\UURQLXPRURWKHUPXVFDULQLFDQWLFKROLQHUJLFVRUDQ\FRPSRQHQWRIWKH0',
 6XEVWDQFH$EXVH6XEMHFWVZKRLQWKHRSLQLRQRIWKH,QYHVWLJDWRUVLJQLILFDQWO\DEXVH
DOFRKRORUGUXJVUHIHUWR([FOXVLRQ&ULWHULRQ
 0HGLFDWLRQSULRUWRVSLURPHWU\6XEMHFWVZKRDUHPHGLFDOO\XQDEOHWRZLWKKROGWKHLU
VKRUWDFWLQJEURQFKRGLODWRUVIRUWKHKRXUSHULRGUHTXLUHGSULRUWRVSLURPHWU\WHVWLQJ
DWHDFKVWXG\YLVLWZLOOEHH[FOXGHG
 3URKLELWHG0HGLFDWLRQV6XEMHFWVZKRLQWKHRSLQLRQRIWKH,QYHVWLJDWRUZRXOGEH
XQDEOHWRDEVWDLQIURPSURWRFROGHILQHGSURKLELWHGPHGLFDWLRQVGXULQJWKH6FUHHQLQJ
3HULRGDQGWUHDWPHQWSKDVHVRIWKLVVWXG\UHIHUWR6HFWLRQ
 9DFFLQDWLRQV6XEMHFWVZKRUHFHLYHGDOLYHDWWHQXDWHGYDFFLQDWLRQZLWKLQGD\VSULRU
WR9LVLW6FUHHQLQJRUGXULQJWKH5XQLQ3HULRGEHWZHHQ9LVLWDQG9LVLW
Note: ,QDFWLYDWHG LQIOXHQ]D YDFFLQDWLRQ SQHXPRFRFFDO YDFFLQDWLRQ RU DQ\ RWKHU
LQDFWLYDWHGYDFFLQHLVDFFHSWDEOHSURYLGHGLWLVQRWDGPLQLVWHUHGZLWKLQKRXUVSULRU
WR9LVLW6FUHHQLQJRU9LVLW5DQGRPL]DWLRQ
 1RQFRPSOLDQFH6XEMHFWVXQDEOHWRFRPSO\ZLWKVWXG\SURFHGXUHV
 $IILOLDWLRQV ZLWK ,QYHVWLJDWRU VLWH 6WXG\ ,QYHVWLJDWRUV VXE,QYHVWLJDWRUV VWXG\
FRRUGLQDWRUVHPSOR\HHVRIDSDUWLFLSDWLQJ,QYHVWLJDWRURULPPHGLDWHIDPLO\PHPEHUV
RIWKHDIRUHPHQWLRQHGDUHH[FOXGHGIURPSDUWLFLSDWLRQLQWKLVVWXG\
 4XHVWLRQDEOH 9DOLGLW\ RI &RQVHQW 6XEMHFWV ZLWK D KLVWRU\ RI SV\FKLDWULF GLVHDVH
LQWHOOHFWXDOGHILFLHQF\SRRUPRWLYDWLRQVXEVWDQFHDEXVHLQFOXGLQJGUXJDQGDOFRKRO
RURWKHUFRQGLWLRQVWKDWZLOOOLPLWWKHYDOLGLW\RILQIRUPHGFRQVHQWWRSDUWLFLSDWHLQWKH
VWXG\
 ,QYHVWLJDWLRQDO'UXJVRU'HYLFHV7UHDWPHQWZLWKLQYHVWLJDWLRQDOVWXG\GUXJRUGHYLFH
LQ DQRWKHU FOLQLFDO WULDO ZLWKLQ WKH ODVW  GD\V RU ILYH KDOIOLYHV SULRU WR 9LVLW 
6FUHHQLQJZKLFKHYHULVORQJHU
Note: 6XEMHFW SDUWLFLSDWLRQ LQ REVHUYDWLRQDO VWXGLHV LH VWXGLHV WKDW GR QRW UHTXLUH
FKDQJHWRPHGLFDWLRQRUDQDGGLWLRQDOLQWHUYHQWLRQLVQRWH[FOXVLRQDU\
 +DQGWR%UHDWK &RRUGLQDWLRQ  6XEMHFWV ZKR UHTXLUHV WKH XVH RI D VSDFHU GHYLFH WR
FRPSHQVDWHIRUSRRUKDQGWREUHDWKFRRUGLQDWLRQZLWKD0',
Note:8VHRIDQHEXOL]HUWRGHOLYHU&23'PHGLFDWLRQVLVSURKLELWHGWKURXJKRXWWKH
WULDO
 3UHYLRXV3DUWLFLSDWLRQ6XEMHFWVZKRZHUHSUHYLRXVO\HQUROOHGLQDQ\WULDOFRQGXFWHG
RUVSRQVRUHGE\3HDUO


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
5.3
6XEMHFW,GHQWLILFDWLRQ
$OO VXEMHFWV ZKR XQGHUJR VFUHHQLQJ ZLOO EH DVVLJQHG D XQLTXH VFUHHQLQJ LGHQWLILFDWLRQ
QXPEHUDWWKH6FUHHQLQJ9LVLW2QO\VXEMHFWVFRQWLQXLQJWRPHHWHQWU\LQFOXVLRQH[FOXVLRQ
FULWHULDDW9LVLWZLOOEHDVVLJQHGDXQLTXHVXEMHFWUDQGRPL]DWLRQQXPEHU
5.4
3ULRU&RQFRPLWDQWDQG3URKLELWHG0HGLFDWLRQV
$OO SUHVFULSWLRQ DQG RYHUWKHFRXQWHU 27& PHGLFDWLRQV WDNHQ E\ WKH VXEMHFW ZLWKLQ
GD\VEHIRUH 9LVLW  6FUHHQLQJ ZLOO EH UHFRUGHG RQ WKH SULRUFRQFRPLWDQW PHGLFDWLRQV
HOHFWURQLF &DVH 5HSRUW )RUP H&5) $Q\DGGLWLRQV GHOHWLRQV RU FKDQJHV LQ WKH GRVH RI
WKHVHPHGLFDWLRQVZKLOHLQWKHVWXG\VKRXOGEHHQWHUHGRQWKHH&5)$Q\FXUUHQWRQJRLQJ
PHGLFDWLRQVLQFOXGLQJ27&GUXJVDQGKHUEDOVXSSOHPHQWVZLOOEHDOORZHGSURYLGHGWKH\DUH
QRWSURKLELWHGE\WKHSURWRFROUHIHUWR6HFWLRQDQGDUHDSSURYHGE\WKH,QYHVWLJDWRU
6XEMHFWVVKRXOGDOVREHLQVWUXFWHGWRFRQWDFWWKH,QYHVWLJDWRULIWKH\GHYHORSDQ\LOOQHVVHV
$OO FRQFRPLWDQW PHGLFDWLRQV WDNHQ GXULQJ WKH VWXG\ ZLOO EH UHFRUGHG RQ WKH &RQFRPLWDQW
0HGLFDWLRQVH&5)ZLWKLQGLFDWLRQGRVHGRVHUHJLPHQDQGGDWHVRIGUXJDGPLQLVWUDWLRQ
5.4.1
3URKLELWHG&23'0HGLFDWLRQV
7KH IROORZLQJ PHGLFDWLRQV XVHG IRU WKH WUHDWPHQW RI &23' DUH QRW SHUPLWWHG GXULQJ WKLV
VWXG\ 7KHVH PHGLFDWLRQV PXVW EH GLVFRQWLQXHG  KRXUV WR  KRXUV SULRU WR  9LVLW 
6FUHHQLQJ DQGDUHQRWSHUPLWWHGGXULQJWKH UXQLQSHULRG7KHPLQLPXPZDVKRXWSHULRG
EHIRUH9LVLW  DQG EHWZHHQ 9LVLWDQG 9LVLWDUHVKRZQLQ7DEOH  7KH RQO\ &23'
PHGLFDWLRQV SHUPLWWHG GXULQJ WKH VWXG\ DUH VSRQVRUSURYLGHG $WURYHQW +)$ IRU &23'
PDLQWDLQDQFHGXULQJWKHUXQLQDQGZDVKRXWSHULRGDQGVSRQVRUSURYLGHG9HQWROLQ+)$
IRUUHVFXHRI&23'V\PSWRPVGXULQJWKHVWXG\

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7DEOH
3URKLELWHG&23'0HGLFDWLRQVDQG5HTXLUHG:DVKRXW3HULRGV
3ULRUWR9LVLWDQG9LVLW

Minimum Washout Period Prior to: 
Class of Medication 
Visit 1
Visit 2 
/$0$V
KRXUV
7LRWURSLXPGD\V
$FOLGLQLXPGD\V
*O\FRS\UURQLXPGD\V
8PHFOLGLQLXPGD\V
6KRUWDFWLQJPXVFDULQLFDQWDJRQLVWV
6$0$D
KRXUV
KRXUV
/$%$VLQKDOHG
KRXUV
KRXUV,QGDFDWHUROGD\V

)L[HGFRPELQDWLRQVRI/$%$/$0$
KRXUV
GD\VGD\VIRU
LQGDFDWHUROJO\FRS\UURQLXP
DQGRORGDWHUROWLRWURSLXP
)L[HGFRPELQDWLRQVRI/$%$,&6
KRXUV
GD\V
)L[HGFRPELQDWLRQVRI6$%$VDQG6$0$V KRXUV
KRXUV
6$%$VE
KRXUV
KRXUV
2UDOȕDJRQLVWV

GD\V
7KHRSK\OOLQHWRWDOGDLO\GRVH
!PJGD\F

GD\V
0RQRWKHUDS\RI,&6

KRXUV
$EEUHYLDWLRQV&23' FKURQLFREVWUXFWLYHSXOPRQDU\GLVHDVH+)$ K\GURIOXRURDONDQH,&6 LQKDOHG
FRUWLFRVWHURLG/$%$ ORQJDFWLQJȕDJRQLVW/$0$ ORQJDFWLQJPXVFDULQLFDQWDJRQLVW6$%$ VKRUWDFWLQJ
ȕDJRQLVW
1RWH6XEMHFWVWDNLQJURIOXPLODVWDUHDOORZHGSURYLGHGWKH\KDYHEHHQRQVWDEOHGRVHRIWKHUDS\IRUDWOHDVW
PRQWKVSULRUWR5DQGRPL]DWLRQ
D 'LVFRQWLQXHDQGXVHRQO\VSRQVRUSURYLGHG$WURYHQW+)$GXULQJVFUHHQLQJ
E 'LVFRQWLQXHDQGXVHRQO\VSRQVRUSURYLGHGUHVFXH9HQWROLQ+)$WKURXJKRXWWKHVWXG\
F 7KHRSK\OOLQHPJGD\LVSHUPLWWHGSURYLGHGWKHVXEMHFWKDVEHHQRQDVWDEOHGRVHRIWKHUDS\IRUDW
OHDVWZHHNVSULRUWR5DQGRPL]DWLRQ

6XEMHFWV WKDW KDYH UHFHLYHG GHSRW FRUWLFRVWHURLGV LQFOXGLQJ LQWUDDUWLFXODU RU LQWUDRFXODU
FRUWLFRVWHURLGVUHTXLUHDPRQWKZDVKRXWSULRUWR9LVLW6XEMHFWVWKDWKDYHUHFHLYHGRUDO
LQWUDYHQRXVRULQWUDPXVFXODUFRUWLFRVWHURLGVIRUDQ\UHDVRQUHTXLUHDZHHNZDVKRXWSULRU
WR9LVLW$Q\VXEMHFWWKDWUHTXLUHVXVHRIV\VWHPLFFRUWLFRVWHURLGVGXULQJWKHUXQLQSHULRG
9LVLWWR9LVLWZLOOEHVFUHHQIDLOHG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Note:

6XEMHFWV ZKR DUH VWHURLG GHSHQGHQW DQG PDLQWDLQHG RQ DQ HTXLYDOHQW RI PJ RUDO
SUHGQLVRQH SHU GD\ RU  PJ RUDO SUHGQLVRQH HYHU\ RWKHU GD\ IRU DW OHDVW PRQWKV
SULRUWR 9LVLW DUH HOLJLEOH SURYLGLQJ WKH GRVH RI RUDO VWHURLGV UHPDLQV VWDEOH GXULQJ
WKHUXQLQSHULRG9LVLW9LVLW

'XULQJWKHWUHDWPHQWSHULRGV9LVLWWR9LVLWDQG9LVLWWR9LVLWVXEMHFWVWUHDWHG
ZLWKRUDOFRUWLFRVWHURLGVDQGRUDQWLELRWLFVIRUH[DFHUEDWLRQVKRXOGEHGLVFRQWLQXHGIURP
WKHVWXG\
6XEMHFWV ZKR PHHW DOO HQWU\ FULWHULD EXW DUH XVLQJ RQH RU PRUH RI WKH SURKLELWHG &23'
PHGLFDWLRQVSUHYLRXVO\OLVWHGZLOOKDYHWKHLUPDLQWHQDQFHWKHUDS\IRU&23'DGMXVWHGDV
IROORZV

6XEMHFWVWDNLQJSURKLELWHG&23'PHGLFDWLRQVOLVWHGSUHYLRXVO\DW9LVLW6FUHHQLQJ
ZLOOGLVFRQWLQXHWKHVHPHGLFDWLRQVWRKRXUVEHIRUH9LVLWIRUWKHGXUDWLRQRIWKH
WULDO$W9LVLWVXEMHFWVZLOODQGEHVZLWFKHGWRVSRQVRUSURYLGHG$WURYHQW+)$0',
DGPLQLVWHUHG 4,' DQG VSRQVRUSURYLGHG 9HQWROLQ+)$ WR EH DGPLQLVWHUHG XS WR IRXU
WLPHVSHUGD\DVQHHGHG351IRUFRQWURORIV\PSWRPVGXULQJWKHUXQLQSHULRG

6XEMHFWV UHFHLYLQJDPDLQWHQDQFHGRVHRIDQ ,&6 DV SDUW RIDIL[HG GRVHFRPELQDWLRQ
WKHUDS\FRQWDLQLQJIOXWLFDVRQHDQGVDOPHWHUROPRPHWDVRQHDQGIRUPRWHUROEXGHVRQLGH
DQGIRUPRWHURORUIOXWLFDVRQHDQGIRUPRWHUROPXVWKDYHEHHQRQWKH,&6FRPSRQHQWDQG
RQDVWDEOHGRVHIRUDWOHDVWZHHNVSULRUWR9LVLW  6FUHHQLQJ DQGPDLQWDLQHGRQD
VWDEOHGRVHIRUDWOHDVWZHHNVSULRUWR9LVLW6FUHHQLQJ$W9LVLWWKHVHVXEMHFWVZLOO
EH VZLWFKHG WR WKH FRUUHVSRQGLQJ GRVH RI IOXWLFDVRQH PRPHWDVRQH RU EXGHVRQLGH
DGPLQLVWHUHG DV D VLQJOH DJHQW %,' ZLWK VSRQVRUSURYLGHG $WURYHQW +)$ 0',
DGPLQLVWHUHG 4,' DQG VSRQVRUSURYLGHG9HQWROLQ+)$WREHDGPLQLVWHUHGXSWR IRXU
WLPHVSHUGD\DVQHHGHG351IRUFRQWURORIV\PSWRPVGXULQJWKHUXQLQSHULRG

6XEMHFWVUHFHLYLQJDPDLQWHQDQFHGRVHRIDQ,&6WKDWLVQRWDGPLQLVWHUHGDVDIL[HGGRVH
FRPELQDWLRQWRJHWKHUZLWKD/$%$ZLOOEHSHUPLWWHGWRFRQWLQXHWKH,&6SURYLGHGWKH\
KDYHEHHQPDLQWDLQHGRQDVWDEOHGRVHIRUDWOHDVWZHHNVSULRUWR9LVLW6FUHHQLQJ

$OOVXEMHFWVWUHDWHGZLWKHLWKHUD/$%$VDOPHWHUROIRUPRWHUROLQGDFDWHURORUFXUUHQWO\
PDUNHWHG /$0$ WLRWURSLXP DFOLGLQLXP JO\FRS\UURQLXP >HJ 6HHEUL@ DGPLQLVWHUHG
DORQHRUDVDORRVHFRPELQDWLRQZLOOKDYHWKHVHPHGLFDWLRQVGLVFRQWLQXHGDQGUHSODFHG
ZLWK VSRQVRUSURYLGHG $WURYHQW+)$0', DGPLQLVWHUHG 4,' DQG VSRQVRUSURYLGHG
9HQWROLQ+)$WREHDGPLQLVWHUHGXSWRIRXUWLPHVSHUGD\DVQHHGHG351IRUFRQWURO
RIV\PSWRPVGXULQJWKHUXQLQSHULRG

$W9LVLWVXEMHFWVZKRPHHWDOOHQWU\FULWHULDDQGDUHWDNLQJSURKLELWHG&23'
PHGLFDWLRQVLQ7DEOHZLOOVWDUWZLWKVSRQVRUSURYLGHG$WURYHQW+)$0',
DGPLQLVWHUHG4,'IRU&23'PDLQWHQDQFHDQGVSRQVRUSURYLGHG9HQWROLQ+)$WREH
DGPLQLVWHUHGXSWRIRXUWLPHVSHUGD\DVQHHGHG351IRUFRQWURORIV\PSWRPVGXULQJ
WKHUXQLQSHULRG
7KHIROORZLQJUHVSLUDWRU\PHGLFDWLRQVDUHQRWSHUPLWWHGGXULQJWKLVVWXG\7DEOH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

Table 5-2:  Other Respiratory/Nasal Medications: Required Washout Periods
Required washout periods prior to Visit 2:
Class of medication
Minimum cessation period prior to Visit 2 
/HXNRWULHQH
DQWDJRQLVWV
HJ
]DILUOXNDVW
PRQWHOXNDVW
GD\V
&URPRJO\FDWH
GD\V
1HGRFURPLO
GD\V
.HWRWLIHQ
GD\V
.HWRWLIHQH\HGURSVDUHDOORZHG

5.4.2
2WKHU3URKLELWHG0HGLFDWLRQV
7KH IROORZLQJ PHGLFDWLRQV VKRXOG EH XVHG XQGHU WKH VWDWHG FRQGLWLRQV GXULQJ WKLV VWXG\
7DEOH  (DFK FRQFRPLWDQW GUXJ PXVW EH LQGLYLGXDOO\ DVVHVVHG DJDLQVW DOO H[FOXVLRQ
FULWHULD,ILQGRXEWWKH,QYHVWLJDWRUVKRXOGFRQWDFWWKHVSRQVRUEHIRUHUDQGRPL]LQJDVXEMHFW
RUDOORZLQJDQHZPHGLFDWLRQWREHVWDUWHG
Table 5-3:
Non-COPD Medications Allowed Under Certain Condition
Medications allowed under 
certain conditions 
Condition 
665,VRU615,V

7UHDWPHQWUHJLPHQKDVEHHQVWDEOHIRUDWOHDVW
IRXU ZHHNV SULRU WR 9LVLW  DQG QRW DOWHUHG
GXULQJWKHUXQLQSHULRGDQGGRHVQRWH[FHHG
WKHPD[LPXPUHFRPPHQGHGGRVH
,QWUDQDVDOFRUWLFRVWHURLGVLQWUDQDVDO
DQWLKLVWDPLQHVRUFRPELQDWLRQWKHUHRI

$GPLQLVWHUHG DW FRQVWDQW GRVH DQG GRVLQJ
UHJLPHQ IRU DW OHDVW  GD\V SULRU WR 9LVLW 
6FUHHQLQJDQGGXULQJWKHUXQLQSHULRG

6XEMHFWV UHTXLULQJ WKH IROORZLQJ PHGLFDWLRQV DUH SURKLELWHG IURP WKLV VWXG\ 7DEOH 
6XEMHFWVZKRUHFHQWO\GLVFRQWLQXHGXVHRIWKHVHPHGLFDWLRQVPD\EHFRQVLGHUHGIRUVWXG\
HQUROOPHQW SURYLGLQJ WKH\ KDYH PHW WKH PLQLPXP ZDVKRXW SHULRG SULRU WR 9LVLW 
6FUHHQLQJ7KHVHPHGLFDWLRQVDUHSURKLELWHGWKURXJKRXWWKHFRXUVHRIWKHVWXG\DQGVKRXOG
DVXEMHFWUHTXLUHXVHRIDQ\RIWKHOLVWHGPHGLFDWLRQVWKH\VKRXOGEHGLVFRQWLQXHG


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

Table 5-4:  Prohibited Medications
Prohibited medications
Minimum cessation period prior to Visit 1 
(Screening)
$Q\GUXJZLWKSRWHQWLDOWRVLJQLILFDQWO\SURORQJWKH
47LQWHUYDO
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
2WKHULQYHVWLJDWLRQDOGUXJV
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
1RQVHOHFWLYHEHWDEORFNLQJDJHQWV
GD\V
&DUGLDFDQWLDUUK\WKPLFV&ODVV,D,,,
GD\VDPLRGDURQHPRQWKV
$QWLFRQYXOVDQWVIRUVHL]XUHGLVRUGHU
$OORZHG LI VWDEOH GRVH IRU  PRQWKV DQG IUHH RI
VHL]XUHVIRU\HDU
$QWLFRQYXOVDQWVIRURWKHULQGLFDWLRQV
$OORZHGLIVWDEOHGRVHIRUDWOHDVWPRQWKVDQGWKH
,QYHVWLJDWRU FRQILUPV WKHUH KDYH EHHQ QR VHL]XUHV
ZLWKLQWKHSDVWPRQWKV
7ULF\FOLFDQWLGHSUHVVDQWV
GD\V
0RQRDPLQHR[LGDVHLQKLELWRUV
GD\V
$QWLWXPRUQHFURVLVIDFWRUĮ71)ĮDQWLERGLHVHJ
LQIOL[LPDE DQG DQ\ RWKHU PHPEHUV RI WKLV FODVV RI
GUXJV
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
0RQRFORQDODQWLERGLHV
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
$QWLSV\FKRWLFGUXJVD
GD\V
6\VWHPLF FDOFLQHXULQ LQKLELWRUV V\VWHPLF DQWLIXQJDO
DJHQWVSURWHDVHLQKLELWRUVDQGFLPHWLGLQH
GD\V
6\VWHPLFDQWLFKROLQHUJLFVE
GD\V
G
$QWLSV\FKRWLFDJHQWVXVHGIRURWKHULQGLFDWLRQVPD\EHDOORZHGDIWHUFRQVXOWDWLRQZLWKWKH0HGLFDO0RQLWRURU
GHVLJQHHRIWKHWULDO
H
,IV\VWHPLFDQWLFKROLQHUJLFVDUHXVHGIRUWUHDWPHQWRIRYHUDFWLYHEODGGHUDQGWKHWUHDWPHQWKDVEHHQFRQVWDQWIRUDWOHDVW
PRQWKWKH\DUHDOORZHG
Note:%HQ]RGLD]HSLQHVDUHQRWH[FOXVLRQDU\

5.5
2WKHU5HVWULFWLRQV,OOLFLW'UXJVRU'UXJVRI$EXVH
5.5.1
,OOLFLW'UXJVDQGRU'UXJVRI$EXVH
,OOLFLWGUXJVRUGUXJVRIDEXVHZLOOQRWEHDOORZHGIURPWKHVWDUWRI6FUHHQLQJ9LVLWWRWKH
HQGRI9LVLWRUWRZKHQHYHUWKHVXEMHFWGLVFRQWLQXHVWKHVWXG\,IDQ\LOOLFLWGUXJVRUGUXJV
RIDEXVHDUHXVHGE\WKHVXEMHFWGXULQJWKHVWXG\WKHGDWHVRIXVHDQGWKHDPRXQWZLOOEH
GRFXPHQWHGDQGWKHVXEMHFWZLOOEHGLVFRQWLQXHG0HGLFDOPDULMXDQDLVQRWDQH[FOXVLRQDU\
GUXJ LI XVHG IRU PHGLFDO SXUSRVHV DQG WKHUH LV QR FKDQJH LQ WKH GRVH RU IUHTXHQF\ RI
FRQVXPSWLRQ
5.5.2
'LHWDU\5HVWULFWLRQV
6XEMHFWVDUHHQFRXUDJHGWRUHIUDLQIURPFRQVXPLQJJUDSHIUXLWVRUJUDSHIUXLWMXLFHWKURXJKRXW
WKHVWXG\6XEMHFWVPXVWQRWLQJHVW[DQWKLQHLHFDIIHLQHFRQWDLQLQJIRRGVDQGEHYHUDJHVIRU
DWOHDVWKRXUVSULRUWRHDFKVWXG\YLVLWDQGIRUWKHGXUDWLRQRIHDFKVWXG\YLVLW([DPSOHVRI

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
VXFK SURGXFWV LQFOXGH FRIIHH WHD FKRFRODWH DQG FROD 'HFDIIHLQDWHG EHYHUDJHV DUH
DFFHSWDEOH
5.6
6PRNLQJ6WDWXV
&KDQJHV LQ D VXEMHFW¶V VPRNLQJ VWDWXV LH VWRSSLQJ RU UHVWDUWLQJ VPRNLQJ PD\ KDYH DQ
LPSDFWRQWKHHIILFDF\RXWFRPHPHDVXUHV$WDOOYLVLWVWKHVXEMHFWZLOOEHDVNHGDERXWDQ\
UHFHQWFKDQJHLQWKHLUVPRNLQJVWDWXVLHZKHWKHUDVXEMHFW¶VVWDWXVKDVFKDQJHGIURPVPRNHU
WRQRQVPRNHURUYLFHYHUVD$Q\FKDQJHLQVPRNLQJVWDWXVGXULQJWKHUXQLQSHULRG9LVLW
WR9LVLWZLOOUHVXOWLQDVFUHHQIDLOXUH6PRNLQJVWDWXVFKDQJHVGXULQJWKHZHHN73VZLOO
EHFDSWXUHGLQWKHH&5)EXWWKHVXEMHFWZLOOEHSHUPLWWHGWRFRQWLQXHLQWKHVWXG\6XEMHFWV
ZLOO EH UHTXLUHG WR UHIUDLQ IURP VPRNLQJ LQFOXGLQJ PHGLFDO PDULMXDQD DQG HOHFWURQLF
FLJDUHWWHVIRUDWOHDVWKRXUVSULRUWRHDFKVWXG\YLVLWDQGWKURXJKRXWWKHGXUDWLRQRIHDFK
VWXG\YLVLW6WXG\SDUWLFLSDQWVPD\XWLOL]HYDULRXVQLFRWLQHUHSODFHPHQWWUHDWPHQWVVXFKDV
FKHZLQJJXPDQGSDWFKHV351LQDFFRUGDQFHZLWKUHFRPPHQGDWLRQVIURPWKH,QYHVWLJDWRU
GXULQJWKHHQWLUHVWXG\YLVLW
Note: )RUWKLVVWXG\WKHXVHRI HOHFWURQLFFLJDUHWWHVZLOOEHWUHDWHGLQWKHVDPHPDQQHUDV
VPRNLQJH[FHSWIRUWKHFDOFXODWLRQRISDFN\HDUVWRGHWHUPLQHFLJDUHWWHVPRNLQJKLVWRU\
5.7
5HDVRQVDQG3URFHGXUHVIRU(DUO\7HUPLQDWLRQ
6XEMHFWVPD\EHZLWKGUDZQIURPWKHVWXG\DWDQ\WLPHDWWKHLURZQUHTXHVWXSRQUHTXHVWRI
WKH,QYHVWLJDWRURUE\3HDUODWDQ\WLPHRUIRUDQ\UHDVRQ$OOVXEMHFWVZKRGLVFRQWLQXHWKH
VWXG\EHFDXVHRI$(VZLOOEHIROORZHGXSDWVXLWDEOHLQWHUYDOVLQRUGHUWRHYDOXDWHWKHFRXUVH
RIWKH$(DQGWRHQVXUHWKHUHYHUVLELOLW\RUVWDELOL]DWLRQRIWKHDEQRUPDOLW\$OOVXEMHFWVZKR
SUHPDWXUHO\ GLVFRQWLQXH WKH VWXG\DIWHUEHLQJ UDQGRPL]HGUHJDUGOHVVRIWKHFDXVHVKRXOG
XQGHUJRWKHDVVHVVPHQWVRXWOLQHGLQ6HFWLRQRQWKHGDWHRIGLVFRQWLQXDWLRQ,IDVXEMHFW
H[SHULHQFHV DQ\ RI WKH FKDQJHV RI FRQFHUQ OLVWHG EHORZ D UHSHDW DVVHVVPHQW VKRXOG EH
REWDLQHGDQGLIFRQILUPHGWKH,QYHVWLJDWRURUGHVLJQHHQHHGVWRPDNHDGHWHUPLQDWLRQDVWR
WKHVXLWDELOLW\RIFRQWLQXLQJWKHVXEMHFWLQWKHVWXG\7KHFKDQJHVRIFRQFHUQLQFOXGH

)ROORZLQJGRVLQJDKHDUWUDWHLQFUHDVHRIJUHDWHUWKDQESPIURPWKHSUHGRVHYDOXH
REWDLQHGRQ'D\RI7UHDWPHQW3HULRG9LVLWDQG7UHDWPHQW3HULRG9LVLWDQG
WKHPHDVXUHGYDOXHLVDOVR!ESP

)ROORZLQJGRVLQJDV\VWROLFEORRGSUHVVXUH6%3LQFUHDVHRIPRUHWKDQPP+JIURP
WKH SUHGRVH YDOXH REWDLQHG RQ 'D\  RI 7UHDWPHQW 3HULRG  9LVLW  DQG 7UHDWPHQW
3HULRG9LVLWDQGWKHPHDVXUHGYDOXHLVDOVR!PP+J

'HFUHDVH LQ FUHDWLQLQH FOHDUDQFH WR D YDOXH EHORZ POPLQXWHP XVLQJ 0'5'
HTXDWLRQRUDFOLQLFDOO\UHOHYDQWFKDQJHIURPEDVHOLQHDVGHWHUPLQHGE\WKH,QYHVWLJDWRU

+HSDWLF LPSDLUPHQW GHILQHG DV DEQRUPDO OLYHU IXQFWLRQ WHVW RI $67 $/7 RU WRWDO
ELOLUXELQWLPHVXSSHUOLPLWRIQRUPDORQUHSHDWWHVWLQJ

&DOFXODWHG47F)LQWHUYDOV!PLOOLVHFRQGPVHFDQGKDYHLQFUHDVHGE\PVHFRU
PRUHRYHUEDVHOLQHYDOXHREWDLQHGDW'D\RI7UHDWPHQW3HULRG9LVLWDQG
7UHDWPHQW3HULRG9LVLW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

6XEMHFWVZKRVXIIHUDPLOGH[DFHUEDWLRQZLOOUHPDLQLQWKHVWXG\DQGFRQWLQXHWRWDNH
WKHLUDVVLJQHGVWXG\GUXJXQOHVVWKH,QYHVWLJDWRUGHFLGHVWKDWLWLVLQWKHEHVWLQWHUHVWRI
WKHVXEMHFWWRGLVFRQWLQXHHDUO\IURPWKHVWXG\$Q\VXEMHFWZKRVXIIHUVDPRGHUDWHRU
VHYHUHH[DFHUEDWLRQZLOOEHGLVFRQWLQXHG
$QH[DFHUEDWLRQZLOOEHGHILQHGDVDFKDQJHLQWKHVXEMHFW¶VEDVHOLQHG\VSQHDFRXJKDQGRU
VSXWXPLQFUHDVHLQYROXPHRUFKDQJHLQFRORUWRZDUGVSXUXOHQFHWKDWODVWVRUPRUHGD\V
LVEH\RQGQRUPDOGD\WRGD\YDULDWLRQVLVDFXWHLQRQVHWDQGPD\ZDUUDQWDFKDQJHLQUHJXODU
PHGLFDWLRQ7KHVHYHULW\RIH[DFHUEDWLRQVZLOOEHFODVVLILHGDVIROORZV

0LOGH[DFHUEDWLRQVWKDWGRQRWUHTXLUHV\VWHPLFVWHURLGVRUDQWLELRWLFVDQGGRQRWUHVXOW
LQKRVSLWDOL]DWLRQRUGHDWK

0RGHUDWHH[DFHUEDWLRQVWKDWUHTXLUHVWUHDWPHQWZLWKV\VWHPLFVWHURLGVDQGRUDQWLELRWLFV
DQGGRQRWUHVXOWLQKRVSLWDOL]DWLRQRUGHDWK

6HYHUHH[DFHUEDWLRQVWKDWUHVXOWLQKRVSLWDOL]DWLRQRUGHDWK
,IDVXEMHFWUHTXLUHVWKHIROORZLQJSURKLELWHGPHGLFDWLRQVWKH\VKRXOGEHGLVFRQWLQXHGIURP
WKHVWXG\

,QLWLDWLRQRIPDLQWHQDQFHWKHUDS\ZLWKDQ\SURKLELWHGPHGLFDWLRQVDVOLVWHGLQ7DEOH

,QLWLDWLRQRIPDLQWHQDQFHWKHUDS\ZLWKDPDUNHWHG/$%$HJVDOPHWHUROIRUPRWHURO
LQGDFDWHURODGPLQLVWHUHGDORQHRULQFRPELQDWLRQZLWKDQ,&6RUDPDUNHWHG/$0$
HJWLRWURSLXPDFOLGLQLXPRUJO\FRS\UURQLXPEURPLGH>6HHEUL@

,QLWLDWLRQRIFRUWLFRVWHURLGVDQWLELRWLFVIRUWKHWUHDWPHQWRIH[DFHUEDWLRQ

,I D IHPDOH VXEMHFW EHFRPHV SUHJQDQW GXULQJ WKH FRXUVH RI WKH VWXG\ WKH VXEMHFW ZLOO EH
GLVFRQWLQXHGDQGWKHSUHJQDQF\ZLOOEHIROORZHGIXOOWHUPWKURXJKGHOLYHU\RUILQDORXWFRPH
UHIHUWR6HFWLRQ





*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES
6.1
6XEMHFW,QIRUPDWLRQ
&OLQLFDOVXSSOLHVZLOOEHSDFNDJHGWRVXSSRUWHQUROOPHQWRIWKHVWXG\&OLQLFDOVXSSOLHVZLOO
EHSDFNDJHGDFFRUGLQJWRDFRPSRQHQWVFKHGXOHJHQHUDWHGE\DVSHFLDOL]HGFRPSDQ\7KH
XQEOLQGHG VWXG\ SKDUPDFLVW ZLOO DVVLJQ WKH VWXG\ GUXJ WR VXEMHFWV DFFRUGLQJWRDVHSDUDWH
UDQGRPL]DWLRQVFKHGXOHDQGZLOOPDQDJHWKHGLVWULEXWLRQRIFOLQLFDOVXSSOLHV$OORWKHUVWXG\
SHUVRQQHOZLOOUHPDLQEOLQGHG
6.2
3URGXFW'HVFULSWLRQV
,QYHVWLJDWLRQDOPDWHULDOVZLOOEHSURYLGHGE\3HDUODVVXPPDUL]HGLQ7DEOH
7UHDWPHQWV ZLOO EH EOLQGHG LQ WHUPV RI *)) 0', RU 3ODFHER 0', DGPLQLVWHUHG WKHVH
SURGXFWVDUHLGHQWLFDOLQIRUPDQGIXQFWLRQDQGLQGLVWLQJXLVKDEOHIURPHDFKRWKHU9HQWROLQ
DQG$WURYHQWDUHRSHQODEHOSURGXFWV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Table 6-5.  
Study Product Packaging Descriptions
Product name and 
dosage 
Product strength
Dose form/fill 
count
Administration
Study medications
*))0',37
JH[DFWXDWRU
*))0',JSHU
DFWXDWLRQ
0',
LQKDODWLRQV
7DNHQDVWZRLQKDODWLRQV
%,'
Open-label products
9HQWROLQDOEXWHUROVXOIDWH
+)$LQKDODWLRQDHURVRO
JH[DFWXDWRU
9HQWROLQDOEXWHUROVXOIDWH
+)$LQKDODWLRQDHURVROZLOO
EHWKHVXSSOLHGSURGXFW
(DFKLQKDODWLRQFRQWDLQV
ȝJFRUUHVSRQGLQJWR
JDOEXWHUROEDVHSHU
DFWXDWLRQ
0',
RUDFWXDWLRQV
7DNHQ351

$WURYHQWLSUDWURSLXP
EURPLGH+)$LQKDODWLRQ
DHURVROȝJH[DFWXDWRU
$WURYHQWLSUDWURSLXP
EURPLGH+)$ZLOOEHWKH
VXSSOLHGSURGXFW
(DFKLQKDODWLRQFRQWDLQV
ȝJH[DFWXDWRUSHU
DFWXDWLRQ
0',
DFWXDWLRQV
7DNHQDVWZRLQKDODWLRQV
4,'GXULQJUXQLQ
SHULRGDQGZDVKRXW
SHULRG

Placebo
3ODFHER0',
)RUPXODWLRQGRHVQRWFRQWDLQ
DFWLYHLQJUHGLHQW
0',
LQKDODWLRQV
7DNHQDVWZRLQKDODWLRQV
%,'
$EEUHYLDWLRQV%,' WZLFHGDLO\&23' FKURQLFREVWUXFWLYHSXOPRQDU\GLVHDVH*))0', *O\FRS\UURQLXP
DQG )RUPRWHURO )XPDUDWH ,QKDODWLRQ $HURVRO +)$ +\GURIOXRURDONDQH 0', 0HWHUHG 'RVH ,QKDOHU
351 DVQHHGHG4,' IRXUWLPHVGDLO\
Note:$OOVWXG\GUXJVZLOOEHDGPLQLVWHUHGE\RUDOLQKDODWLRQ
Note:*O\FRS\UURQLXPJLQ*))0',LVHTXLYDOHQWWRJRIJO\FRS\UURQLXPEURPLGH
2SHQODEHO$WURYHQW+)$0',VZLOOEHSURYLGHGIURPFRPPHUFLDOVXSSOLHV0DQXIDFWXUHU¶V
LQVWUXFWLRQVIRUVWXG\GUXJDGPLQLVWUDWLRQZLOOEHSURYLGHG
2SHQODEHO 9HQWROLQ +)$ 0',V ZLWK GRVH FRXQWHUV ZLOO EH SURYLGHG IURP FRPPHUFLDO
VXSSOLHV 0DQXIDFWXUHU¶VLQVWUXFWLRQVIRUVWXG\GUXJDGPLQLVWUDWLRQZLOOEHSURYLGHG
6.3
3ULPDU\3DFNDJLQJDQG/DEHOLQJ,QIRUPDWLRQ
,QYHVWLJDWLRQDO PDWHULDOV ZLOO EH SDFNDJHG E\ 3HDUO  $WURYHQW +)$ DQG 9HQWROLQ +)$
VXSSOLHVZLOOEHVXSSOLHGDVRSHQODEHO0',V

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Blinded Supplies(DFK0',ZLOOEHODEHOHGZLWKDVLQJOHODEHO7KH0',DFWXDWRUZLOOEH
ODEHOHGZLWKDVLQJOHODEHO7KHIRLOSRXFKZLOOEHODEHOHGZLWKDVLQJOHODEHO
Open-label Supplies 2SHQODEHO $WURYHQW +)$ DQG 9HQWROLQ +)$ ZLOO EH SURYLGHG DV
LQGLYLGXDOO\ODEHOHG0',V(DFK0',ZLOOFRQWDLQDVLQJOHODEHO7KH0',DFWXDWRUZLOOEH
ODEHOHGZLWKDVLQJOHODEHO7KHIRLOSRXFKZLOOEHODEHOHGZLWKDVLQJOHODEHO
%RWKVLQJOHDQGWZRSDUWODEHOVZLOOEHSULQWHGZLWKEODFNLQNDQGPD\LQFOXGHWKHIROORZLQJ
WH[W
3DFNDJLQJ/RW7UDFH,'
6SDFHIRUHQWU\RIVFUHHQLQJ
&RPSRQHQW,'
6SDFHIRUHQWU\RIUDQGRPL]DWLRQ
)LOO&RXQW	'RVDJH)RUP
6SDFHIRUHQWU\RI,QWHUYDO,'9LVLWRQO\
5HHYDOXDWLRQ([SLUDWLRQGDWHLIDSSOLFDEOH
'RVLQJ,QVWUXFWLRQV
6WRUDJH&RQGLWLRQV
&RPSRXQG,'3URWRFRO
&RXQWU\UHJXODWRU\UHTXLUHPHQWV
6SRQVRUDGGUHVV,IDSSOLFDEOH
7UDQVODWLRQ.H\,IDSSOLFDEOH
$EEUHYLDWLRQ,' LGHQWLILFDWLRQ
6.4
6HFRQGDU\3DFNDJLQJDQG/DEHOLQJ,QIRUPDWLRQ%R[
%OLQGHGLQYHVWLJDWLRQDOGUXJDQGRSHQODEHO$WURYHQW+)$DQG9HQWROLQ+)$VXSSOLHVZLOO
EHSDFNDJHG LQ LQGLYLGXDO ER[HV DV RXWOLQHG LQ7DEOH %R[ FRQILJXUDWLRQ LV VXEMHFW WR
FKDQJHDVDUHVXOWRISDFNDJLQJFRQVWUDLQWV
Table 6-6. Description of Boxes
Drug supplies
Individual box contents 
%OLQGHG
$WURYHQW+)$
9HQWROLQ+)$
0',
0',
0',


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
(DFKER[ZLOOEHODEHOHGZLWKDWZRSDUWODEHOSULQWHGZLWKEODFNLQNDQGPD\LQFOXGHWKH
IROORZLQJWH[W
3DFNDJLQJ/RW,'
6SDFHIRUHQWU\RIVFUHHQLQJ
&RPSRQHQW,'
6SDFHIRUHQWU\RIUDQGRPL]DWLRQ
.LW&RQWHQWV0',
6SDFHIRUHQWU\RI,QWHUYDO,'
5HHYDOXDWLRQ([SLUDWLRQGDWHLIDSSOLFDEOH
'RVLQJ,QVWUXFWLRQVLIDSSOLFDEOH
6WRUDJH&RQGLWLRQV
&RPSRXQG,'3URWRFRO
&RXQWU\UHJXODWRU\UHTXLUHPHQWV
6SRQVRUDGGUHVV,IDSSOLFDEOH
7UDQVODWLRQ.H\,IDSSOLFDEOH
$EEUHYLDWLRQ,' LGHQWLILFDWLRQ
6.5
(PHUJHQF\8QEOLQGLQJRI7UHDWPHQW$VVLJQPHQW
7KHLQGLYLGXDOVXEMHFWHPHUJHQF\FRGHEUHDNVHDOHGHQYHORSHVVKRXOGEHXVHGLQRUGHUWR
XQEOLQG VXEMHFWV DQG WR XQPDVN GUXJ LGHQWLW\ :KHQ WKH ,QYHVWLJDWRU QHHGV WR XQEOLQG D
VXEMHFWKHVKHPXVWFRQILUPWKHQHFHVVLW\WRXQEOLQGWKHVXEMHFW7KH,QYHVWLJDWRURUWUHDWLQJ
SK\VLFLDQPD\XQEOLQGDVXEMHFW¶VWUHDWPHQWDVVLJQPHQWRQO\LQWKHFDVHRIDQHPHUJHQF\
ZKHQNQRZOHGJHRIWKHVWXG\WUHDWPHQWLVHVVHQWLDOIRUWKHDSSURSULDWHFOLQLFDOPDQDJHPHQW
RUZHOIDUHRIWKHVXEMHFW:KHQHYHUSRVVLEOHWKH,QYHVWLJDWRUPXVWILUVWGLVFXVVRSWLRQVZLWK
WKH 6SRQVRU RU DSSURSULDWH VWXG\ SHUVRQQHO EHIRUH XQEOLQGLQJ WKH VXEMHFW¶V WUHDWPHQW
DVVLJQPHQW,IWKLVLVLPSUDFWLFDOWKH,QYHVWLJDWRUPXVWQRWLI\3HDUODVVRRQDVSRVVLEOHEXW
ZLWKRXWUHYHDOLQJWKHWUHDWPHQWDVVLJQPHQWRIWKHXQEOLQGHGVXEMHFWXQOHVVWKDWLQIRUPDWLRQ
LVLPSRUWDQW IRU WKH VDIHW\ RI VXEMHFWVFXUUHQWO\ LQWKHVWXG\ 7KH GDWH DQG UHDVRQ IRUWKH
XQEOLQGLQJPXVWEHUHFRUGHGLQWKHDSSURSULDWHGDWDFROOHFWLRQWRRO
6.6
6WRUDJH5HTXLUHPHQWV
Blinded supplies6WRUHEHORZ&)LQDGU\SODFH([FXUVLRQVSHUPLWWHGXSWR&
)
Ventolin HFA supplies: 6WRUHEHWZHHQDQG&DQG)6WRUHWKHLQKDOHUZLWK
WKHPRXWKSLHFHGRZQ)RUEHVWUHVXOWVWKHLQKDOHUVKRXOGEHDWURRPWHPSHUDWXUHEHIRUHXVH
'RQRWXVHRUVWRUHQHDUKHDWRURSHQIODPH([SRVXUHWRWHPSHUDWXUHVDERYH)&
PD\FDXVHEXUVWLQJ1HYHUWKURZLQWRDILUHRULQFLQHUDWRU
Atrovent HFA supplies: 6WRUH DW & ) H[FXUVLRQV SHUPLWWHG WR &
))RURSWLPDOUHVXOWVWKHFDQLVWHUVKRXOGEHDWURRPWHPSHUDWXUHEHIRUHXVH'R
QRWSXQFWXUH'RQRWXVHRUVWRUHQHDUKHDWRURSHQIODPH([SRVXUHWRWHPSHUDWXUHVDERYH
)PD\FDXVHEXUVWLQJ1HYHUWKURZWKHLQKDOHULQWRDILUHRULQFLQHUDWRU
7KH FOLQLFDO VXSSOLHV VWRUDJH DUHD DW WKH VLWH PXVW EH PRQLWRUHG E\ WKH VLWH VWDII IRU
WHPSHUDWXUH FRQVLVWHQF\ ZLWK WKH DFFHSWDEOH VWRUDJH WHPSHUDWXUH UDQJH VSHFLILHG LQ WKLV
SURWRFRO RU LQ WKH SURGXFW ODEHO 'RFXPHQWDWLRQ RI WHPSHUDWXUH PRQLWRULQJ VKRXOG EH
PDLQWDLQHG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
6.7
,QVWUXFWLRQVIRU3UHSDUDWLRQRI7UHDWPHQWVIRU$GPLQLVWUDWLRQDQG
'LVSHQVLQJ
6.7.1
*))0',DQG3ODFHER0',
,QGLYLGXDO*))0',DQG3ODFHER0',ZLOOEHSDFNDJHGLQDIRLOSRXFKDQGFRQWDLQHGLQDQ
LQGLYLGXDOYLVLWWUHDWPHQWER[%RWKWKHYLVLWWUHDWPHQWER[DQGWKHIRLORYHUZUDSZLOOKDYHD
ODEHO ZLWK D FRPSRQHQW LGHQWLILFDWLRQ QXPEHU &RQILUP WKDW WKH LGHQWLILHU JLYHQ E\ WKH
UDQGRPL]DWLRQ OLVWV DQG WKH FRPSRQHQW LGHQWLILFDWLRQ QXPEHU ZULWWHQ RQ WKH ODEHO DUH WKH
VDPH7KHYLVLWWUHDWPHQWER[LVODEHOHGZLWKDWZRSDUWODEHO:ULWHWKHVXEMHFWQXPEHUDQG
WUHDWPHQWYLVLWQXPEHURQHDFKRIWKHWZRSDUWODEHOV7KHµWHDURII¶SDUWRIWKHODEHOLVWREH
SODFHGRQWRWKHVXEMHFWVZRUNVKHHWV
$OO0',VPXVWEHSULPHGEHIRUHWKHILUVWXVH3ULPLQJLQYROYHVUHOHDVLQJDFHUWDLQQXPEHURI
VSUD\VLQWRWKHDLUEHIRUHWKHILUVWXVHRIWKHLQKDOHU6KDNLQJDQGSULPLQJWKHLQKDOHUILOOV
DFKDPEHULQVLGHWKHFDQLVWHUZLWKWKHFRUUHFWGRVHDQGPL[RIPHGLFDWLRQVRWKDWWKHLQKDOHU
LVUHDG\WRXVH
7KH0',PXVWEHSULPHGLQDVHSDUDWHURRPIURPWKHVXEMHFWWUHDWPHQWDUHD(DFKGRVHZLOO
FRQVLVW RI SXIIV IURP WKH 0', 6XEMHFWV ZLOO EH GLVSHQVHG WKH 0', DQG LQVWUXFWHG WR
FRQWLQXH WDNLQJ VWXG\ PHGLFDWLRQ WZLFH GDLO\  SXIIV LQ WKH PRUQLQJ DQG SXIIV LQ WKH
HYHQLQJDSSUR[LPDWHO\KRXUVDSDUWXQWLOVXEMHFWUHWXUQVWRWKHFOLQLF7KH0',VKRXOGEH
VWRUHG XSULJKW DW URRP WHPSHUDWXUH E\ WKH VXEMHFW DYRLGLQJ WHPSHUDWXUH H[WUHPHV DQG
VWRUDJHLQGLUHFWVXQOLJKW5HIHUWR$SSHQGL[IRULQVWUXFWLRQVRQWKHDGPLQLVWUDWLRQRI*))
0',DQG3ODFHER0',&OHDQLQJLQVWUXFWLRQVDUHSURYLGHGLQ$SSHQGL[
6.7.2
$WURYHQW+)$,SUDWURSLXP%URPLGH
2SHQODEHO$WURYHQW+)$ZLOOEHSURYLGHGE\3HDUODQGVWRUHGLQDVHFXUHGORFDWLRQZLWKLQ
WKHFOLQLFRUSKDUPDF\IDFLOLWLHV
$WURYHQW+)$LVDVROXWLRQDHURVROWKDWGRHVQRWUHTXLUHVKDNLQJ+RZHYHUDVZLWKDQ\RWKHU
0', VRPH FRRUGLQDWLRQ LV UHTXLUHG EHWZHHQ DFWXDWLQJ WKH FDQLVWHU DQG LQKDOLQJ WKH
PHGLFDWLRQ $WURYHQW +)$ VKRXOG EH SULPHG SHU PDQXIDFWXUHU¶V LQVWUXFWLRQV SULRU WR
GLVSHQVLQJWRVXEMHFWLHSULPHRUDFWXDWH$WURYHQW+)$EHIRUHXVLQJIRUWKHILUVWWLPHE\
UHOHDVLQJWHVWVSUD\VLQWRWKHDLUDZD\IURPWKHIDFH,QFDVHVZKHUHWKHLQKDOHUKDVQRW
EHHQXVHGIRUPRUHWKDQGD\VSULPHWKHLQKDOHUDJDLQE\UHOHDVLQJWHVWVSUD\VLQWRWKHDLU
DZD\IURPWKHIDFH6XEMHFWVVKRXOGDYRLGVSUD\LQJ$WURYHQW+)$LQWRWKHLUH\HV
6XEMHFWVZLOOEHGLVSHQVHGWKH$WURYHQW+)$IRU&23'PDLQWHQDQFHWKHUDS\GXULQJWKHUXQ
LQSHULRGEHWZHHQ9LVLWDQGDQGGXULQJWKHZDVKRXWSHULRGEHWZHHQ9LVLWDQGSHU
WKH PDQXIDFWXUHU¶V LQVWUXFWLRQ SXIIV ZLWK HDFK DGPLQLVWUDWLRQ IRXU WLPHV D GD\ GLYLGHG
RYHUWKHGD\WLPH7KH0',VKRXOGEHVWRUHGDWURRPWHPSHUDWXUHE\WKHVXEMHFWDYRLGLQJ
WHPSHUDWXUH H[WUHPHV DQG VWRUDJH LQ GLUHFW VXQOLJKW 5HIHU WR $SSHQGL[  IRU WKH
PDQXIDFWXUHU¶VLQVWUXFWLRQVRQWKHDGPLQLVWUDWLRQRI$WURYHQW+)$

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
6.7.3
9HQWROLQ+)$$OEXWHURO6XOIDWH
2SHQODEHO9HQWROLQ+)$ZLOOEHSURYLGHGE\3HDUODQGVWRUHGLQDVHFXUHGORFDWLRQZLWKLQ
WKHFOLQLFRUSKDUPDF\IDFLOLWLHV9HQWROLQ+)$VKRXOGEHVWRUHGDWURRPWHPSHUDWXUHE\WKH
VXEMHFW9HQWROLQ+)$VKRXOGEHSULPHGSHUPDQXIDFWXUHU¶VLQVWUXFWLRQVSULRUWRGLVSHQVLQJ
WRVXEMHFW5HIHUWR$SSHQGL[IRUWKHPDQXIDFWXUHU¶VLQVWUXFWLRQVRQWKHDGPLQLVWUDWLRQRI
9HQWROLQ +)$ 6WXG\ SHUVRQQHO ZLOO UHFRUG QXPEHU RQ WKH GRVH FRXQWHU DW WKH WLPH RI
GLVSHQVLQJIROORZLQJSULPLQJDQGFKDUDFWHUL]DWLRQRIUHYHUVLELOLW\DQGXSRQUHWXUQ
6.8
'UXJ$FFRXQWDELOLW\5HWXUQRI&OLQLFDO6XSSOLHV
Under no circumstances will the Investigator(s) allow the study drug to be used other 
than as directed by this protocol.
,QYHVWLJDWLRQDOFOLQLFDOVXSSOLHVPXVWEHUHFHLYHGE\DGHVLJQDWHGSHUVRQDWWKHVWXG\VLWH
KDQGOHG DQG VWRUHG VDIHO\ DQG SURSHUO\ DQG NHSW LQ D VHFXUH ORFDWLRQ WR ZKLFK RQO\ WKH
,QYHVWLJDWRU DQG GHVLJQDWHG DVVLVWDQWV KDYH DFFHVV 6WRUDJH FRQGLWLRQV IRU WKH FOLQLFDO
VXSSOLHV VKRXOG EH REVHUYHG PRQLWRUHG DQG GRFXPHQWHG &OLQLFDO VXSSOLHV DUH WR EH
GLVSHQVHGRQO\LQDFFRUGDQFHZLWKWKHSURWRFRO7KH,QYHVWLJDWRULVUHVSRQVLEOHIRUNHHSLQJ
DFFXUDWHUHFRUGVRIWKHFOLQLFDOVXSSOLHVUHFHLYHGIURP3HDUOWKHDPRXQWGLVSHQVHGWRDQG
UHWXUQHG E\ WKH VXEMHFW DQG WKH DPRXQW UHPDLQLQJ DW WKH FRQFOXVLRQ RI WKH VWXG\ 7KH
&OLQLFDO0RQLWRUVKRXOGEHFRQWDFWHGZLWKDQ\TXHVWLRQVFRQFHUQLQJLQYHVWLJDWLRQDOSURGXFWV
ZKHUHVSHFLDORUSURWHFWLYHKDQGOLQJLVLQGLFDWHG$WWKHHQGRIWKHVWXG\DOOFOLQLFDOVXSSOLHV
LQFOXGLQJSDUWLDODQGHPSW\FRQWDLQHUVPXVWEHUHWXUQHGDVGLUHFWHGE\3HDUO
6LWHVVKRXOGFKHFNZLWKWKH3HDUOUHSUHVHQWDWLYHIRUDSSURSULDWHGRFXPHQWDWLRQWKDWQHHGVWR
EHFRPSOHWHGIRUGUXJDFFRXQWDELOLW\
7KH,QYHVWLJDWRURUGHVLJQDWHGDVVLVWDQWVKRXOGQRWRSHQLQGLYLGXDOFOLQLFDOVXSSO\FRQWDLQHUV
XQWLO DOO SUHGRVH DVVHVVPHQWV KDYH EHHQ FRPSOHWHG DQG WKH VXEMHFW LV HOLJLEOH WR EH
UDQGRPL]HGFRQWLQXH ZLWK WKH VWXG\ $Q\ GHYLDWLRQ IURP WKLV PXVW EH GLVFXVVHG ZLWK WKH
&OLQLFDO0RQLWRU
)RUHDFKVXEMHFWDOOXVHGVWXG\GUXJPDWHULDOVZLOOEHFROOHFWHG8VHGVXEMHFWVXSSOLHVZLOO
EH NHSW DW URRP WHPSHUDWXUH LQ D VHFXUH DQG ORFNHG FDELQHW XQWLO UHWXUQHG WR 3HDUO RU
GHVLJQHH
Note:8VHGVWXG\GUXJZLOOEHVWRUHGVHSDUDWHO\IURPXQXVHGVWXG\GUXJ
$OOSURGXFWFRPSODLQWVLQFOXGLQJGHYLFHPDOIXQFWLRQVPXVWEHUHSRUWHGWR3HDUOXVLQJWKH
3URGXFW&RPSODLQWV)RUPSURYLGHGLQHDFKVLWH¶VLQYHVWLJDWRUILOH3HDUOZLOOFRQWDFWWKHVLWH
WRHYDOXDWHWKHQDWXUHRIWKHFRPSODLQWDQGGHWHUPLQHZKDWIXUWKHUDFWLRQLVQHHGHG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


STUDY PROCEDURES
7KH,&)PXVWEHREWDLQHGprior WRSHUIRUPLQJDQ\DQGDOOVWXG\UHODWHGDFWLYLWLHV7KH,&)
PXVWEHDSSURYHGE\WKH,QGHSHQGHQW(WKLFV&RPPLWWHH,(&,QVWLWXWLRQDO5HYLHZ%RDUG
,5% WKDWLVUHYLHZLQJ WKH VWXG\ GRFXPHQWV ,QIRUPHG FRQVHQW ZLOO EH REWDLQHG IRU DOO
VXEMHFWVSDUWLFLSDWLQJLQWKHVWXG\6XEMHFWVPD\ZLWKGUDZFRQVHQWDWDQ\WLPH3DUWLFLSDWLRQ
LQWKHVWXG\PD\EHWHUPLQDWHGDWDQ\WLPHZLWKRXWWKHVXEMHFW¶VFRQVHQWDVGHWHUPLQHGE\
WKH3ULQFLSDO,QYHVWLJDWRU
$ VFKHGXOH RI HYHQWV LV SURYLGHG LQ 7DEOH 'HWDLOHG VFKHGXOHV IRU SUH DQG SRVWGRVH
SURFHGXUHVWREHSHUIRUPHGRQYLVLWGD\VDUHSURYLGHGLQ7DEOHDQG7DEOH
7.1
(IILFDF\$VVHVVPHQWV
7.1.1
+5&7VFDQV
$+5&7VFDQDVEDVHOLQHPHDVXUHPHQWZLOOEHWDNHQRQ'D\RIHDFK739LVLWDQG9LVLW
7KHSUHGRVH&7VFDQRIWKHWKRUD[ZLOOEHWDNHQRQWZREUHDWKLQJOHYHOV7/&DQG)5&
'XULQJ9LVLWDQDGGLWLRQDOVFDQRIWKH8$ZLOOEHWDNHQ7KHSRVWGRVHPHDVXUHPHQWZLOO
RQO\EHSHUIRUPHGRQRQHEUHDWKLQJOHYHO7/&7KH3RVWGRVH7/&VFDQZLOOEHWDNHQDIWHU
DSSUR[LPDWHO\ZHHNVRIWUHDWPHQWZLWKHLWKHU*))0',RU3ODFHERRQ'D\GD\V
9LVLWDQG9LVLW
2Q'D\RIHDFK739LVLWDQG9LVLWWKH&7VFDQVZLOOEHWDNHQDWOHDVWPLQXWHVSULRU
WRGRVLQJ
3RVWGRVH+5&7VFDQRQ'D\GD\VRIHDFK739LVLWDQG9LVLWVKRXOGEHVWDUWHG
PLQPLQXWHVDIWHUGRVLQJDSSUR[LPDWHO\EHWZHHQSPSP6SLURPHWU\IROORZHGE\
ERG\SOHWK\VPRJUDSK\ZLOOEHSHUIRUPHGDIWHUWKH+5&7VFDQVEXWZLWKLQPLQXWHVDIWHU
GRVLQJ
%HWZHHQWKHWZR73VWKHUHZLOOEHDZDVKRXWSHULRGRIDPLQLPXPRIGD\VWRDPD[LPXP
RIGD\V
:KHQHYHUSRVVLEOHWKHVDPHVFDQQHUVKRXOGEHXVHGDWDOOWKHVWXG\YLVLWV
+5&7VFDQLVSHUIRUPHGZLWKDORZUDGLDWLRQSURWRFRO7KHVHLPDJHVDUHPDGHWRSHUIRUP
&RPSXWDWLRQDOIOXLGG\QDPLFV&)'LQRUGHUWRREWDLQPRUHLQIRUPDWLRQRQUHJLRQDOOXQJ
IXQFWLRQFKDUDFWHULVWLFV)RUPRUHGHWDLOVRIWKHSURWRFRORI&7VFDQDQG&)'SOHDVHUHIHUWR
WKHDGGHQGXPLQ$SSHQGL[


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7.1.2
6SLURPHWU\
)RUFHGH[SLUDWRU\VSLURPHWU\PDQHXYHUVIRUGHULYDWLRQRI)(9)9&)())(9)9&
UDWLRDQG,&ZLOOEHDVVHVVHGXVLQJDVSLURPHWHUWKDWPHHWVRUH[FHHGVPLQLPXPSHUIRUPDQFH
UHFRPPHQGDWLRQVRIWKH$76
6SLURPHWU\ ZLOO EH FRQGXFWHG DW DOO YLVLWV $W 9LVLW  6SLURPHWU\ ZLOO EH FRQGXFWHG
DSSUR[LPDWHO\  PLQXWHV DQG  PLQXWHV SULRU WR EURQFKRGLODWRU DGPLQLVWUDWLRQ DQG
DSSUR[LPDWHO\PLQXWHVSRVWEURQFKRGLODWRUUHIHUWR6HFWLRQ
Note: 6SLURPHWU\ PXVW PHHW WKH VHYHULW\ DQG ERWK DFFHSWDELOLW\ DQG UHSHDWDELOLW\ FULWHULD
UHIHUWR6HFWLRQDQG6HFWLRQ
$W9LVLWDQG9LVLWVSLURPHWU\ZLOOEHREWDLQHGDWWKHEHJLQQLQJRIWKHYLVLW$VHFRQG
VSLURPHWU\ZLOOEHREWDLQHGEHIRUHWKHVWXG\GUXJDGPLQLVWUDWLRQDIWHUWKHSUHGRVH&7VFDQV
DUHWDNHQ7KHPLQXWH)(9YDOXHREWDLQHGDW9LVLWSULRUWRVWXG\GUXJDGPLQLVWUDWLRQ
ZLOOEHXVHGWRFKHFNWKHVWDELOLW\FULWHULD$W9LVLWDQG9LVLWVSLURPHWU\ZLOOEHREWDLQHG
EHIRUHWKHVWXG\GUXJ DGPLQLVWUDWLRQDQGSRVWGRVLQJRIVWXG\GUXJ3RVWGRVHVSLURPHWU\
DVVHVVPHQWVZLOOQRWEHFRQGXFWHGEHIRUHWKH&7VFDQLVWDNHQ$W9LVLWVDQGQRQHRIWKH
SRVWGRVHDVVHVVPHQWVZLOOVWDUWEHIRUHKRXUDIWHUWKHDGPLQLVWUDWLRQRIWKHVWXG\GUXJ$OO
DVVHVVPHQWVVKRXOGEHFRPSOHWHGZLWKLQKRXUVDIWHUGRVLQJ
7.1.2.1
&KDUDFWHUL]DWLRQRI5HYHUVLELOLW\
5HYHUVLELOLW\WR9HQWROLQ+)$6$%$ZLOOEHHYDOXDWHGDW9LVLW
7KHSURFHGXUHZLOOEHDVIROORZV
5HYHUVLELOLW\WHVWLQJWR9HQWROLQ+)$
x
3HUIRUPSUHEURQFKRGLODWRU3)7VDSSUR[LPDWHO\PLQXWHVDQGPLQXWHVSULRUWR
DGPLQLVWUDWLRQRI9HQWROLQ+)$DOEXWHURO
x
$GPLQLVWHUSXIIVRI9HQWROLQ+)$DOEXWHURO
x
3HUIRUP SRVWEURQFKRGLODWRU 3)7  PLQXWHV DIWHU WKH DGPLQLVWUDWLRQ RI
9HQWROLQ+)$

5HYHUVLELOLW\ZLOOEHDFRPSDULVRQRIWKHDYHUDJHEHVW)(9HIIRUWREWDLQHGDWDSSUR[LPDWHO\
PLQXWHV DQG PLQXWHV SUHEURQFKRGLODWRU WR WKH EHVW )(9 HIIRUW REWDLQHG DW
DSSUR[LPDWHO\PLQXWHVSRVWEURQFKRGLODWRU$VXEMHFWLVGHWHUPLQHGWREHUHYHUVLEOHWR
9HQWROLQ+)$ LI WKH LPSURYHPHQW LQ )(9 DSSUR[LPDWHO\  PLQXWHV IROORZLQJ
DGPLQLVWUDWLRQ RI SXIIV RI 9HQWROLQ +)$ UHVSHFWLYHO\ LV  DQG PO
5HYHUVLELOLW\WR 9HQWROLQ +)$ REWDLQHG DW 9LVLW  ZLOO EH XVHG WR FKDUDFWHUL]H WKH
SRSXODWLRQ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7.1.2.2
6WDELOLW\&ULWHULD
,WLVLPSRUWDQWWRHQVXUHWKDWWKHEDVHOLQH)(9LVVWDEOHDQGUHIOHFWLYHRIWKHVXEMHFW¶V&23'
VHYHULW\SULRUWRFRQWLQXDWLRQLQWKHVHFRQGWUHDWPHQWSHULRG
$W9LVLWVSLURPHWU\ZLOOEHREWDLQHGDWWKHEHJLQQLQJRIWKHYLVLW$VHFRQGVSLURPHWU\ZLOO
EHREWDLQHGEHIRUHWKHVWXG\GUXJDGPLQLVWUDWLRQDIWHUWKHSUHGRVH&7VFDQVDUHWDNHQ7KH
DYHUDJHRIWKH)(9YDOXHVREWDLQHGSULRUWRVWXG\GUXJDGPLQLVWUDWLRQPLQDQG
PLQDW9LVLWZLOOEHWKHEDVHOLQHYDOXHXVHGWRFRPSDUHZLWKWKHPLQXWH)(9YDOXH
REWDLQHGDW9LVLW
$W9LVLWLIWKHSUHGRVH)(9LVRXWVLGHRIWKHRUP/UDQJHWKHYLVLWPD\EH
UHVFKHGXOHGDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQRUWKHVXEMHFWPD\EHGLVFRQWLQXHG
7.1.2.3
,QVSLUDWRU\&DSDFLW\
Visit 1 to Visit 5:,&DVVHVVPHQWVZLOOEHFRQGXFWHGZLWKHYHU\VSLURPHWU\$OOVXEMHFWVZLOO
EHLQVWUXFWHGRQWKHSHUIRUPDQFHRIWKH,&PDQHXYHU6XEMHFWVPXVWEHWHVWHGLQWKHVHDWHG
SRVLWLRQZHDULQJDQRVHFOLSZLWKQRDLUOHDNVEHWZHHQWKHPRXWKDQGPRXWKSLHFH6XEMHFWV
VKRXOG EHUHOD[HG ZLWK VKRXOGHUV GRZQ DQG DVNHG WR EUHDWKH UHJXODUO\IRUVHYHUDOEUHDWKV
XQWLO WKH HQGH[SLUDWRU\ OXQJ YROXPH LV VWDEOH WKLV XVXDOO\ UHTXLUHV DW OHDVW ILYH WLGDO
PDQHXYHUV7KH\DUHWKHQXUJHGWRWDNHDGHHSEUHDWKWR7/&ZLWKQRKHVLWDWLRQ)URPDW
OHDVW WKUHH DFFHSWDEOH WULDOV WKH WZR ODUJHVW ,& PHDVXUHPHQWV VKRXOG DJUHH ZLWKLQ  RU
POERWKRIWKHVH,&YDOXHVZLOOEHFDSWXUHGDQGDQDO\]HG
7.1.2.4
6WDQGDUGL]DWLRQRI,&DQG6SLURPHWU\&ROOHFWLRQV
$OOSXOPRQDU\IXQFWLRQWHVWVLQFOXGLQJ)(9)9&)())(9)9&UDWLRDVZHOODVDOO
,& DVVHVVPHQWV DV GHILQHG LQ $76(56 JXLGHOLQHV ZLOO EH SHUIRUPHG LQ DFFRUGDQFH ZLWK
$76FULWHULD0LOOHU
7KH YROXPH DFFXUDF\ RI WKH VSLURPHWHULVWREHFKHFNHGGDLO\XVLQJD /V\ULQJH DFURVV
IORZUDQJHVLHORZPHGLXPDQGKLJKIORZVZLWKWHPSHUDWXUHDQGEDURPHWULFSUHVVXUH
FRUUHFWLRQ 7KH FDOLEUDWLRQ V\ULQJH PXVW PHHW $76 VSHFLILFDWLRQV DQG PXVW QRW EH XVHG
EH\RQG WKH H[SLU\ GDWH 5HTXLUHG DFFXUDF\ LV   LH / WR / $76(56
7KHUHVXOWVRIWKHFDOLEUDWLRQIDFWRUZLOOEHPDLQWDLQHGRQVLWHZKLFKZLOOEHDYDLODEOHLIWKH
VSRQVRUZDQWVWRFKHFNIRUFRPSOLDQFHRUDQDXGLW
7.1.3
%RG\SOHWK\VPRJUDSK\
Visit 2 to Visit 5: 59 7/& )5& 5DZ V5DZ V*DZ ZLOO EH PHDVXUHG XVLQJ ERG\
SOHWK\VPRJUDSK\
2Q'D\RIHDFK739LVLWDQG9LVLWWKHERG\SOHWK\VPRJUDSK\PHDVXUHPHQWZLOOEH
SHUIRUPHGDIWHUWKH&7VFDQEHIRUHWKH,3DGPLQLVWUDWLRQ
2Q 'D\    GD\V RI HDFK 73 9LVLW  DQG 9LVLW  WKH ERG\ SOHWK\VPRJUDSK\
PHDVXUHPHQW ZLOO EH SHUIRUPHG DIWHU WKH &7VFDQ DQG DIWHU WKH SRVWGRVH VSLURPHWU\
PHDVXUHPHQW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
3RVWGRVHDFWLYLWLHVRQ'D\GD\VRIHDFK739LVLWDQG9LVLWZLOOEHVWDUWHG
KRXUDIWHUGRVLQJRQDQGZLOOEHFRQFOXGHGZLWKLQKRXUVDIWHUGRVLQJ
7.1.4
'LIIXVLRQFDSDFLW\
7KH VLQJOHEUHDWK GLIIXVLQJ FDSDFLW\ RI WKH OXQJV IRU FDUERQ PRQR[LGH 7&2 DOYHRODU
YROXPH9$DQG7&29$ZLOOEHPHDVXUHGDW9LVLW7&2PHDVXUHPHQWZLOOEHXVHGWR
FKDUDFWHUL]H WKH VXEMHFWV HQUROOHG LQ WKH WULDO DQG ZLOO QRW EH XVHG WR GHWHUPLQH VXEMHFW
HOLJLELOLW\WRSDUWLFLSDWHLQWKHVWXG\
7.1.5
,QKDODWLRQ3URILOHZLWK%RG\3OHWK\VPRJUDSK\
Visit 2 and Visit 4:,QRUGHUWRGUDZDQDLUIORZYHUVXVWLPHFXUYHWKHVXEMHFW¶VLQKDODWLRQ
SURILOHZLOOEHPHDVXUHG7KHVXEMHFWZLOOEHDVNHGWRLQKDOHDQGH[KDOHPD[LPDOO\WKURXJKD
PRXWKSLHFH ZLWKRXW D QRVH FOLS 7KLV PHDVXUHPHQW LV SHUIRUPHG ZLWK D ERG\
SOHWK\VPRJUDSK $W WKH PRPHQW RI WKLV PHDVXUHPHQW WKH VLJQDO IURP WKH UHVSLUDWLRQ EHOW
XVHGIRUWKHPHDVXUHPHQWRIWKHLQKDODWLRQSURILOHGXULQJWKHVWXG\GUXJDGPLQLVWUDWLRQZLOO
DOVREHORJJHG
7.1.6
,QKDODWLRQ3URILOHGXULQJDGPLQLVWUDWLRQ
Visit 2 and Visit 4: 'XULQJ ,3 DGPLQLVWUDWLRQ RQ 'D\  RI ERWK DFWLYH DQG SODFHER WKH
LQKDODWLRQSURILOHZLOOEHUHFRUGHGZKLOHWKHVXEMHFWLQKDOHVWKURXJKWKHGHYLFHWRJHQHUDWHD
VXEMHFW VSHFLILF LQKDODWLRQ SURILOH E\ XVLQJ D UHVSLUDWLRQ EHOW 7KH WKRUD[ DQG DEGRPHQ
H[SDQVLRQZLOOEHPHDVXUHGZLWK WKH
GLDJQRVWLFGHYLFH7KLVLQKDODWLRQSURILOH
ZKLFKUHSUHVHQWVWKHOXQJH[SDQVLRQGXULQJLQKDODWLRQRIWKHPHGLFDWLRQFDQEHFRXSOHGZLWK
WKHYDOXHVRIWKHFRUUHVSRQGLQJOXQJYROXPHH[SDQVLRQ59±7/&PHDVXUHGZLWKWKHERG\
SOHWK\VPRJUDSK\ZHDULQJWKHUHVSLUDWLRQEHOWV
6HQVRUFDEOHVWUDQVPLWWKHDSSURSULDWHVLJQDOVWRWKH
7KHVLJQDOVDUHVWRUHGRQWKH
UHPRYDEOH PHPRU\ FDUG RU LI FRQILJXUHGWRGRVRWKHVLJQDOVFDQEHGLVSOD\HGIURPWKH
RQDFRPSXWHUUXQQLQJWKH
VRIWZDUHDSSOLFDWLRQ
7.1.7
6XEMHFW'LDU\'DWD&ROOHFWLRQ
$W9LVLWVXEMHFWVZLOOEHSURYLGHGZLWKD'LDU\WREHFRPSOHWHGWZLFHGDLO\PRUQLQJDQG
HYHQLQJ6WXG\SHUVRQQHOZLOOWUDLQVXEMHFWVRQ'LDU\FRPSOHWLRQDQGZLOOLQVWUXFWVXEMHFWV
WRUHWXUQ'LDU\UHVSRQVHVWRWKHFOLQLFIRUDOOLQFOLQLFVWXG\YLVLWV

$W9LVLWVXEMHFWVZLOOEHLQVWUXFWHGWRUHFRUGLQWKH'LDU\$WURYHQW+)$IRXUWLPH
GDLO\XVHDQGUHVFXH9HQWROLQ+)$XVHGXULQJWKH5XQLQ3HULRGSULRUWR9LVLW

$W9LVLWVXEMHFWVZLOOEHLQVWUXFWHGWRUHFRUGLQWKH'LDU\VWXG\PHGLFDWLRQ
DGPLQLVWUDWLRQDQGWKHXVHRIUHVFXH9HQWROLQ+)$

$W9LVLWVXEMHFWVZLOOEHLQVWUXFWHGWRUHFRUGLQWKH'LDU\$WURYHQW+)$IRXUWLPH
GDLO\XVHDQGUHVFXH9HQWROLQ+)$XVHGXULQJWKH:DVKRXW3HULRGEHWZHHQ9LVLWDQG
9LVLW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

$W9LVLWVXEMHFWVZLOOEHLQVWUXFWHGWRUHFRUGLQWKH'LDU\VWXG\PHGLFDWLRQ
DGPLQLVWUDWLRQDQGWKHXVHRIUHVFXH9HQWROLQ+)$

'LDU\&RPSOLDQFH5HTXLUHPHQW6XEMHFWSDUWLFLSDWLRQPD\EHWHUPLQDWHGDWDQ\WLPHGXULQJ
WKHVWXG\IRUWKHIROORZLQJUHDVRQ
&KURQLFIDLOXUHLQWKHMXGJPHQWRIWKH,QYHVWLJDWRUWRFRPSO\ZLWKGLDU\FRPSOHWLRQGHVSLWH
GRFXPHQWDWLRQDWWKHVLWHRIUHSHDWHGHIIRUWVWRUHLQIRUFHFRPSOLDQFH$VGHILQHGIRUWKLV
VWXG\FRPSOLDQFHUHTXLUHV!VXEMHFWFRPSOHWLRQRIGLDU\DVVHVVPHQWV7KH6SRQVRU
PD\DOVRLQVWUXFWDVLWHWRGLVFRQWLQXHDVXEMHFWEDVHGRQFRQVLVWHQWQRQFRPSOLDQFH

6XEMHFWVZKRDUHXQDEOHWRPHHWWKHFRPSOLDQFHUHTXLUHPHQW!VXEMHFWFRPSOHWLRQRI
GLDU\DVVHVVPHQWVLQWKHODVWGD\VSUHFHGLQJWKH5DQGRPL]DWLRQ9LVLW9LVLWPXVWEH
UHWUDLQHG:KHQUHWUDLQLQJLVUHTXLUHGGXHWRQRQFRPSOLDQFHWKH5DQGRPL]DWLRQ9LVLW9LVLW
PXVWEHUHVFKHGXOHG

,QFOLQLFGRVLQJWLPHVDQGGRVHLQGLFDWRUUHDGLQJVZLOOEHGRFXPHQWHGLQWKHH&5)E\WKH
VLWHVWDIIDQGZLOOQRWEHHQWHUHGE\WKHVXEMHFWLQWRWKHLU'LDU\
'XULQJ WKH WUHDWPHQW SHULRGV HDFK VXEMHFW ZLOO UHFRUG KLVKHU V\PSWRPV LQ WKH VWXG\
SURYLGHG'LDU\WZLFHGDLO\PRUQLQJDQGHYHQLQJ7KHVXEMHFWZLOOUHFRUGKLVKHUXVHRI
UHVFXH9HQWROLQ+)$WZLFHGDLO\PRUQLQJDQGHYHQLQJ,QDGGLWLRQWKHVXEMHFWZLOOUHFRUG
VWXG\PHGLFDWLRQXVDJH
7.1.8
5HVFXH9HQWROLQ+)$8VH
6XEMHFWV UHTXLULQJ PRUH WKDQ SXIIV SHU GD\ RQ  FRQVHFXWLYH GD\V ZLWK ZRUVHQLQJ
V\PSWRPV VKRXOG FRQWDFW WKH VLWH 7KH QXPEHU RI ³SXIIV´ RI UHVFXH 9HQWROLQ +)$ LV WKH
QXPEHURIDFWXDWLRQVRIWKHFDQLVWHU)RUH[DPSOHZKHQUHVFXH9HQWROLQ+)$LVUHTXLUHG
DQGDFWXDWLRQVDUHLQKDOHGWKLVVKRXOGEHFRXQWHGDV³SXIIV´ ,QWKHHYHQWWKHVXEMHFW
UHTXLUHVDFWXDWLRQVWKLVVKRXOGEHFRXQWHGDV³SXIIV´
$W 9LVLW  WR  WKH VXEMHFW ZLOO EH DVNHG WR EULQJ WKH UHVFXH 9HQWROLQ +)$ DQG WKH VLWH
SHUVRQQHOZLOOUHFRUGWKHQXPEHURIDFWXDWLRQVRIWKHFDQLVWHU
7.1.9
5HFRUGLQJRI'RVH,QGLFDWRU5HDGLQJ
7KH*))0',DQG3ODFHER0',DUHILWWHGZLWKDGRVHLQGLFDWRUWRWUDFNXVHRIWKH0',
6LWH SHUVRQQHO ZLOO EH LQVWUXFWHG WR UHFRUG WKH GRVH LQGLFDWRU UHDGLQJ IURP WKH 0', DIWHU
SULPLQJSULRUWRWKHILUVWGRVLQJ'D\DQGDIWHUWKHILUVWGRVLQJ'D\ RIERWKWKH73V
9LVLW  DQG 9LVLW  $OO 0',V PXVW EH SULPHG EHIRUH WKH ILUVW XVH 3ULPLQJ LQYROYHV
UHOHDVLQJ D FHUWDLQ QXPEHU RI VSUD\V  LQWR WKH DLU EHIRUH WKH ILUVW XVH RI WKH LQKDOHU
6KDNLQJDQGSULPLQJWKHLQKDOHUILOOVDFKDPEHULQVLGHWKHFDQLVWHUZLWKWKHFRUUHFWGRVHDQG
PL[RIPHGLFDWLRQVRWKDWWKHLQKDOHULVUHDG\WRXVH)RUPRUHGHWDLOVUHIHUWR6HFWLRQ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
3ULRUWRGRVLQJDW'D\GD\VRIHDFK739LVLW9LVLWDQG9LVLWRUDWD3UHPDWXUH
'LVFRQWLQXDWLRQ 9LVLW VLWH SHUVRQQHO ZLOO REVHUYH WKH GRVH LQGLFDWRU UHDGLQJ RQ WKH VWXG\
GUXJUHWXUQHGE\WKHVXEMHFWDQGUHFRUGWKHGRVHLQGLFDWRUUHDGLQJLQWKHVRXUFH
Note:7KHGRVHLQGLFDWRUUHDGLQJUHFRUGHGE\WKHVLWHVWDIIRQ'D\GD\VRIHDFK73
9LVLWDQG9LVLWZLOOEHWKHGRVHLQGLFDWRUUHDGLQJREVHUYHGSULRUWRVXEMHFWGRVLQJ
$WHDFKYLVLWWKHVLWHVWDIIZLOOFRPSDUHWKHGRVHLQGLFDWRUUHDGLQJIURPWKHSULRUHQWHUHG
UHDGLQJRI'D\RIWKDW73)RUPDMRUGLVFUHSDQFLHVLH!SXIIGLIIHUHQFHWKHVLWHVWDII
ZLOO UHYLHZ WKH PDMRU GLVFUHSDQF\ ZLWK WKH VXEMHFW DQG GRFXPHQW UHDVRQ IRU WKH PDMRU
GLVFUHSDQF\LQWKHDSSURSULDWHVWXG\VRXUFHDQGH&5),IDSSURSULDWHVLWHVWDIIZLOOUHWUDLQ
WKHVXEMHFWRQWKHSURSHUXVHRIWKH0',
7.1.10
6XEMHFW4XHVWLRQQDLUHV
7KHIROORZLQJVXEMHFWTXHVWLRQQDLUHVZLOOEHFRPSOHWHGE\VXEMHFWVXVLQJWKHVWXG\VXSSOLHG
TXHVWLRQQDLUHDW9LVLW&$7DQG005&
7.1.10.1
&23'$VVHVVPHQW7HVW
7KH&$7LVDVHOIDGPLQLVWHUHGTXHVWLRQQDLUHGHVLJQHGWRDVVHVVWKHFRQGLWLRQRIVXEMHFWV
DQGRYHUDOOLPSDFWRI&23'6LQFHWKH&$7LVGHVLJQHGWRDVVHVVWKHLPSDFWRI&23'RQWKH
VXEMHFWE\PHDVXULQJRYHUDOOLPSDLUPHQWLWKDVPRGHUDWHFRUUHODWLRQVZLWKRWKHULQVWUXPHQWV
VXFKDVWKH005&'\VSQHD6FDOH
6XEMHFWVZLOOFRPSOHWHWKH&$7UHIHUWR$SSHQGL[DW9LVLW
7KH &$7 VFRUH ZLOO GHVFULEH WKH EXUGHQ DQG V\PSWRPDWLF LPSDFW RI &23' LQ VXEMHFWV
HQUROOHGLQWKHWULDODQGZLOOQRWEHXVHGWRGHWHUPLQHVXEMHFWHOLJLELOLW\WRSDUWLFLSDWHLQWKH
VWXG\
7.1.10.2
0RGLILHG0HGLFDO5HVHDUFK&RXQFLO'\VSQHD6FDOH
7KH 005& '\VSQHD 6FDOH XVHV D VLPSOH JUDGLQJ V\VWHP WR DVVHVV D VXEMHFW
V OHYHO RI
G\VSQHDVKRUWQHVVRIEUHDWK7DEOHDQG$SSHQGL[

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Table 7-7:  
MMRC Dyspnea Scale
Grade
Description of Breathlessness

,RQO\JHWEUHDWKOHVVZLWKVWUHQXRXVH[HUFLVH

,JHWVKRUWRIEUHDWKZKHQKXUU\LQJRQOHYHOJURXQGRUZDONLQJXSDVOLJKWKLOO

2Q OHYHO JURXQG , ZDON VORZHU WKDQ SHRSOH RI WKH VDPH DJH EHFDXVH RI
EUHDWKOHVVQHVVRUKDYHWRVWRSIRUEUHDWKZKHQZDONLQJDWP\RZQSDFH

, VWRS IRU EUHDWK DIWHU ZDONLQJ DERXW  PHWHUV RU DIWHU D IHZPLQXWHVRQ OHYHO
JURXQG

,DPWRREUHDWKOHVVWROHDYHWKHKRXVHRU,DPEUHDWKOHVVZKHQGUHVVLQJ

7KH005& VFDOH LV D ILYHSRLQWVFDOHSXEOLVKHGLQWKDWFRQVLGHUVFHUWDLQDFWLYLWLHV
VXFK DV ZDONLQJ RU FOLPELQJ VWDLUV ZKLFK SURYRNH EUHDWKOHVVQHVV )OHWFKHU 
,QRQHPLQXWH WKH VXEMHFW VHOHFWV D JUDGH RQ WKH 005& VFDOH WKDW PRVW FORVHO\ PDWFKHV
KLVKHUVHYHULW\RIG\VSQHD7KH005&VFDOHLVFRQVLGHUHGDGLVFULPLQDWLYHLQVWUXPHQWWKDW
FDQ FDWHJRUL]H VXEMHFWV ZLWK &23' LQ WHUPV RI WKHLU GLVDELOLW\ 7KH 005& VFDOH LV QRW
VDWLVIDFWRU\DVDQHYDOXDWLYHLQVWUXPHQWWRPHDVXUHFKDQJHVLQG\VSQHDDQGLWVEURDGJUDGHV
DUHJHQHUDOO\XQUHVSRQVLYHWRLQWHUYHQWLRQVVXFKDVSKDUPDFRWKHUDS\
6XEMHFWV ZLOO FRPSOHWH WKH 005& VFDOH DW 9LVLW  DV D GHVFULSWLRQ RI WKH V\PSWRPDWLF
EXUGHQLQVWXG\VXEMHFWV7KH005&VFDOHZLOOQRWEHXVHGWRGHWHUPLQHVXEMHFWHOLJLELOLW\WR
SDUWLFLSDWHLQWKHVWXG\
7.1.11
&23'([DFHUEDWLRQV
6LWHSHUVRQQHOZLOOHYDOXDWHZKHWKHUWKHVXEMHFWKDVH[SHULHQFHGDZRUVHQLQJRIWKHLU&23'
WKDWPHHWVWKHGHILQLWLRQRID&23'H[DFHUEDWLRQVLQFHWKHLUODVWYLVLW$QH[DFHUEDWLRQZLOO
EHGHILQHGDVDFKDQJHLQWKHVXEMHFW¶VEDVHOLQHG\VSQHDFRXJKDQGRUVSXWXPLQFUHDVHLQ
YROXPHRUFKDQJHLQFRORUWRZDUGVSXUXOHQFHWKDWODVWVRUPRUHGD\VLVEH\RQGQRUPDO
GD\WRGD\YDULDWLRQVLVDFXWHLQRQVHWDQGPD\ZDUUDQWDFKDQJHLQUHJXODUPHGLFDWLRQ
$OO&23'H[DFHUEDWLRQVZLOOEHUHSRUWHGDV$(VXQOHVVFRQVLGHUHGDVHULRXVDGYHUVHHYHQW
6$(
7KHVHYHULW\RI&23'H[DFHUEDWLRQVZLOOEHFODVVLILHGDVIROORZV

0LOGH[DFHUEDWLRQVWKDWGRQRWUHTXLUHV\VWHPLFVWHURLGVRUDQWLELRWLFVDQGGRQRWUHVXOW
LQKRVSLWDOL]DWLRQRUGHDWK

0RGHUDWHH[DFHUEDWLRQVWKDWUHTXLUHWUHDWPHQWZLWKV\VWHPLFVWHURLGVDQGRUDQWLELRWLFV
DQGGRQRWUHVXOWLQKRVSLWDOL]DWLRQRUGHDWK

6HYHUHH[DFHUEDWLRQVWKDWUHVXOWLQKRVSLWDOL]DWLRQRUGHDWK

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7.2
6DIHW\$VVHVVPHQWV
7KH VDIHW\ DVVHVVPHQWV LQFOXGH SK\VLFDO H[DPLQDWLRQ ILQGLQJV YLWDO VLJQV (&*V FOLQLFDO
ODERUDWRU\WHVWVLQDGGLWLRQWRUHFRUGLQJRI$(VDQG6$(V
7.2.1
0HGLFDO6XUJLFDO+LVWRU\DQG3K\VLFDO([DPLQDWLRQ
0HGLFDOKLVWRU\LQFOXGLQJVPRNLQJKLVWRU\GHWDLOVZLOOEHFROOHFWHGDW9LVLW6FUHHQLQJ
DQGXSGDWHGGXULQJWKHUXQLQSHULRG9LVLWWR9LVLW7KHQXPEHURI&23'H[DFHUEDWLRQV
UHTXLULQJRUDOVWHURLGVDQGRURUDODQWLELRWLFVRUKRVSLWDOL]DWLRQZLWKLQPRQWKVRI9LVLW
6FUHHQLQJZLOOEHFROOHFWHG$FRPSOHWHSK\VLFDOH[DPLQDWLRQZLOOEHSHUIRUPHGDW9LVLW
6FUHHQLQJ DQG DW 9LVLW  $ FRPSOHWH SK\VLFDO H[DPLQDWLRQ ZLOO LQFOXGH HYDOXDWLRQ RI
UHOHYDQWERG\SDUWVJHQHUDODSSHDUDQFHVNLQKHDGH\HVHDUVQRVHWKURDWQHFNLQFOXGLQJ
WK\URLG O\PSK QRGHV FKHVW KHDUW DEGRPHQ H[WUHPLWLHV DQG QHUYRXV V\VWHP :HLJKW
DVVHVVHGLQRUGLQDU\LQGRRUFORWKLQJZLWKVKRHVUHPRYHGDQGKHLJKWZLOOEHUHFRUGHGDW9LVLW
6FUHHQLQJ
$WDOOYLVLWVLQFOXGLQJWKHIROORZXSWHOHSKRQHFDOO>7&@WKHVXEMHFWZLOOEHDVNHGDERXWDQ\
UHFHQWFKDQJHLQWKHLUVPRNLQJVWDWXVLHZKHWKHUDVXEMHFW¶VVWDWXVKDVFKDQJHGIURPVPRNHU
WRQRQVPRNHURUYLFHYHUVD
7.2.2
9LWDO6LJQ0HDVXUHPHQWV
+HDUW UDWH V\VWROLF DQG GLDVWROLF EORRG SUHVVXUH DQG WHPSHUDWXUH µYLWDO VLJQV¶ ZLOO EH
DVVHVVHG DV RXWOLQHG EHORZ DVVHVVPHQWV PD\ EH REWDLQHG LQ HLWKHU WKH VXSLQH RU VHDWHG
SRVLWLRQREWDLQHGDIWHUWKHVXEMHFWKDVEHHQLQWKHVXSLQHSRVLWLRQIRUPLQXWHV
,ILQWKHRSLQLRQRIWKH,QYHVWLJDWRUDFOLQLFDOO\VLJQLILFDQWYLWDOVLJQFKDQJHRFFXUVWKHQWKH
PHDVXUHPHQW ZLOO EH UHSHDWHG DWPHGLFDOO\ DSSURSULDWHLQWHUYDOV XQWLO WKH YDOXH UHWXUQVWR
ZLWKLQDQDFFHSWDEOHUDQJH 7HPSHUDWXUHZLOOEHFROOHFWHGDW6FUHHQLQJ9LVLWDQGDWSUH
GRVHDWDOOYLVLWVDQGZLOOQRWEHUHSHDWHGSRVWGRVH
2EWDLQKHDUWUDWHDQG6%3'LDVWROLFEORRGSUHVVXUH'%3DVGLUHFWHGEHORZ

At Screening (Visit 1): %DVHOLQHPHDVXUHVZLOOEHREWDLQHG

At Day 1 of each TP (Visits 2 and 4): PriorWRVWXG\GUXJDGPLQLVWUDWLRQDQGafterVWXG\
GUXJDGPLQLVWUDWLRQ

At Day 15 (± 5 days) of each TP (Visits 3 and 5): PriorWRVWXG\GUXJDGPLQLVWUDWLRQ
DQGafterVWXG\GUXJDGPLQLVWUDWLRQ
Note:$Q\FOLQLFDOO\UHOHYDQWILQGLQJVIURPYLWDOVLJQPHDVXUHPHQWVZLOOEHUHSRUWHGDV
DGYHUVHHYHQWV



*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7.2.3
/HDG(OHFWURFDUGLRJUDP
7ZHOYHOHDG(&*VZLOOEHSHUIRUPHGDVGHVFULEHGEHORZ
7ZHOYHOHDG(&*VZLOOEHREWDLQHGGXULQJ6FUHHQLQJ9LVLWDW'D\RIHDFK739LVLW
5DQGRPL]DWLRQ DQG 9LVLW  DQG DW'D\ GD\VRI HDFK739LVLWVDQG DV
IROORZV
x
At Visit 1 (Screening)(DFKVXEMHFWZLOOXQGHUJRDOHDG(&*
x
At Visit 2 (Randomization) and Visit 4: (DFK VXEMHFW ZLOO XQGHUJR D OHDG (&*
REWDLQHGDSSUR[LPDWHO\PLQpriorWRVWXG\GUXJDGPLQLVWUDWLRQDQGDSSUR[LPDWHO\
PLQafterVWXG\GUXJDGPLQLVWUDWLRQ
x
At Visits 3 and 5 (Day 15 ± 5 days of each TP): (DFKVXEMHFWZLOOXQGHUJRDOHDG
(&*DSSUR[LPDWHO\PLQpriorWRVWXG\GUXJDGPLQLVWUDWLRQDQGDSSUR[LPDWHO\PLQ
afterVWXG\GUXJDGPLQLVWUDWLRQ

Note:%DVHOLQH(&*YDOXHVDUHGHILQHGDVWKHODVWYDOXHREWDLQHGSULRUWRGRVLQJRQ'D\RI
7UHDWPHQW3HULRG9LVLWDQG7UHDWPHQW3HULRG9LVLW(OHFWURFDUGLRJUDPSDUDPHWHU
DVVHVVPHQWVLQFOXGHKHDUWUDWH35LQWHUYDO456GXUDWLRQ47LQWHUYDODQG47F)
Note: 7KHVWXG\WHDPLVHQFRXUDJHGWRPDLQWDLQVWXG\WLPHSRLQWV
Note:$Q\FOLQLFDOO\UHOHYDQWILQGLQJVIURP(&*VZLOOEHUHSRUWHGDVDGYHUVHHYHQWV
(&*YDOXHVZLOOEHFKHFNHGE\WKHLQYHVWLJDWRURUGHVLJQHH
47 LQWHUYDOV DQG FDOFXODWHG 47F) LQWHUYDOV ZLOO EH UHYLHZHG DQG FKHFNHG IRU JURVV
LQDFFXUDFLHV E\ WKH ,QYHVWLJDWRU RU GHVLJQDWHG (&* UHYLHZHU ,I WKH FDOFXODWHG 47F)
LQWHUYDOVDUH!PVHFDQGKDYHLQFUHDVHGE\PVHFRYHUWKHEDVHOLQHYDOXHREWDLQHGRQ
'D\RI7UHDWPHQW3HULRG9LVLWDQG7UHDWPHQW3HULRG9LVLWWKH,QYHVWLJDWRUZLOO
PDNH D GHWHUPLQDWLRQ RQ WKH VXLWDELOLW\ RI FRQWLQXLQJ WKH VXEMHFW LQ WKH VWXG\ 5HIHU WR
6HFWLRQIRUVSHFLILFFULWHULDIRU47F)WKDWSURPSWVXEMHFWVWREHGLVFRQWLQXHGIURPWKH
VWXG\,I47F)LQWHUYDOSURORQJDWLRQH[FHHGLQJWKHVHOLPLWVLVYHULILHGGXULQJWUHDWPHQWWKH
VXEMHFW¶V PHGLFDO EDFNJURXQG VKRXOG EH H[DPLQHG FORVHO\ IRU ULVN IDFWRUV WKDW PD\ KDYH
FRQWULEXWHG WR WKH HYHQW LQFOXGLQJ JHQRW\SLQJ IRU KHUHGLWDU\ ORQJ 47V\QGURPHV LI
DSSURSULDWH
(YHU\ FOLQLFDO VLJQLILFDQW GHYLDWLRQ DIWHU WKH VXEMHFW LV UDQGRPL]HG LQ WKLV VWXG\ PXVW EH
UHFRUGHGDVDQ$(DQGUHSRUWHGWRWKH6SRQVRU
7KHGHFLVLRQWRFRQWLQXHWKHWUHDWPHQWRIDQ\VXEMHFWZLWKSURORQJHG47RU47F)LQWHUYDO
PXVWEHGLVFXVVHGDQGDJUHHGXSRQE\WKH,QYHVWLJDWRUDQGWKH6SRQVRU$OOVXFKVXEMHFWV
LQFOXGLQJ VXEMHFWV ZLWK FDUGLDF DUUK\WKPLDV VKRXOG EH PRQLWRUHG FORVHO\ ,I DSSURSULDWH
(&* PRQLWRULQJ VKRXOG EH SHUIRUPHG XQWLO WKH 47 DQG 47F) LQWHUYDO DQG ZDYHIRUP
PRUSKRORJ\KDYHUHWXUQHGWRQRUPDO,IWKHSURORQJDWLRQRUDEQRUPDOUK\WKPSHUVLVWVWKH
6SRQVRUPXVWEHFRQWDFWHG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7.2.4
&OLQLFDO/DERUDWRU\7HVWV
&OLQLFDO VDIHW\ ODERUDWRU\ WHVWV ZLOO EH DQDO\]HG E\ ORFDO ODERUDWRU\ DFFRUGLQJ WR
VWDQGDUGL]HG YDOLGDWHG DVVD\V 7KH ODERUDWRU\ ZLOO VXSSO\ GHWDLOHG LQVWUXFWLRQV DQG DOO
FRQWDLQHUV IRU EORRG DQG XULQH LQYHVWLJDWLRQV %ORRG VDPSOH YROXPHV ZLOO PHHW WKH
ODERUDWRU\¶VVSHFLILFDWLRQ$OOFOLQLFDOODERUDWRU\WHVWVZLOOEHREWDLQHGDW9LVLW6FUHHQLQJ
DQGSULRUWRGRVLQJDW9LVLW'D\RI739LVLW'D\GD\VRI739LVLW'D\
RI73DQG9LVLW'D\GD\VRI73RU3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW
7.2.4.1
+HPDWRORJ\
+HPRJORELQ 0HDQ FRUSXVFXODU KHPRJORELQ 0&+ 0HDQ FRUSXVFXODU KHPRJORELQ
FRQFHQWUDWLRQ0&+&0HDQFRUSXVFXODUYROXPH0&9KHPDWRFULWUHGEORRGFHOOFRXQW
ZKLWH EORRG FHOO FRXQW ZLWK GLIIHUHQWLDO DQG SODWHOHW FRXQW ZLOO EH PHDVXUHG DW
9LVLW6FUHHQLQJDQGSULRUWRGRVLQJDW9LVLW'D\RI739LVLW'D\RI73
9LVLW'D\RI73DQG9LVLW'D\RI73RU3UHPDWXUH'LVFRQWLQXDWLRQ
9LVLW
Note:$Q\FOLQLFDOO\UHOHYDQWILQGLQJVIURP+HPDWRORJ\ZLOOEHUHSRUWHGDVDGYHUVHHYHQWV
7.2.4.2
&OLQLFDO&KHPLVWU\
$OEXPLQ DONDOLQH SKRVSKDWDVH WRWDO ELOLUXELQ FDOFLXP WRWDO FKROHVWHURO PDJQHVLXP
SKRVSKDWH VRGLXP SRWDVVLXP FKORULGH FUHDWLQLQH *DPPDJOXW DP\O WUDQVIHUDVH Ȗ*7
ELFDUERQDWHWULJO\FHULGHVEORRGJOXFRVHWRWDOSURWHLQEORRGXUHDQLWURJHQ%81$67DQG
$/7ZLOOEHPHDVXUHGDW9LVLW6FUHHQLQJDQGSULRUWRGRVLQJDW9LVLW'D\RI73
9LVLW'D\RI739LVLW'D\RI73DQG9LVLW'D\RI73RU
3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW
7KH/DERUDWRU\ZLOOVXSSO\PDWHULDOIRUWKHFROOHFWLRQRIWKHVHVDPSOHVUHIHUWR7DEOHIRU
DQRYHUYLHZRIWKHODESDUDPHWHUVIRUWKHEORRGLQYHVWLJDWLRQV
Note:  $Q\ FOLQLFDOO\ UHOHYDQW ILQGLQJV IURP FOLQLFDO FKHPLVWU\ WHVWV ZLOO EH UHSRUWHG DV
DGYHUVHHYHQWV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Table 7-8:  
Lab Parameters
Hematology 
+HPRJORELQ
0&+
+HPDWRFULW
0&+&
:KLWH%ORRG&HOOFRXQWZLWKGLIIHUHQWLDO
0&9
5HG%ORRG&HOOFRXQW

3ODWHOHW&RXQW
Clinical Blood Chemistry
Liver Enzyme and Other Function Tests
Other Clinical Blood Chemistry
$/7
$OEXPLQ
$67
&DOFLXP
$ONDOLQHSKRVSKDWDVH
&KORULGH
%LOLUXELQWRWDO
&KROHVWHURO
Ȗ*7
%LFDUERQDWH

&UHDWLQLQH

*OXFRVH

0DJQHVLXP

3RWDVVLXP

3KRVSKDWH

3URWHLQWRWDO

6RGLXP

7ULJO\FHULGHV

%81
Other Tests:

&UHDWLQLQHFOHDUDQFHZLOOEHHVWLPDWHGE\WKH*)50'5'IRUPXOD

7.2.4.3
8ULQDO\VLV
8ULQHGLSVWLFNUHGEORRGFHOOFRXQWQLWULWHZKLWHEORRGFHOOFRXQWS+ELOLUXELQSURWHLQ
NHWRQHVJOXFRVHGHQVLW\
0LFURVFRSLFDQDO\VLVZLOORQO\EHSHUIRUPHGLIGLSVWLFNLVSRVLWLYH

8ULQDO\VLVZLOOEHPHDVXUHGDW9LVLW6FUHHQLQJDQGSULRUWRGRVLQJDW9LVLW'D\RI73
9LVLW'D\RI739LVLW'D\RI73DQG9LVLW'D\RI73RU
3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7.2.4.4
3UHJQDQF\7HVW
$ XULQH SUHJQDQF\ WHVW ZLOO EH SHUIRUPHG LQ ZRPHQ RI FKLOGEHDULQJ SRWHQWLDO RQO\ DW
9LVLW6FUHHQLQJDQGSULRUWRGRVLQJDW9LVLW'D\RI739LVLW'D\RI73
9LVLW'D\RI73DQG9LVLW'D\RI73RU3UHPDWXUH'LVFRQWLQXDWLRQ
9LVLW
,I DQ\ RI WKHVH WHVWV DUH SRVLWLYH WKH VXEMHFW PXVW EH GLVFRQWLQXHG IURP WKH VWXG\ 7KH
SUHJQDQF\WHVWVKRXOGEHSHUIRUPHGDWWKHEHJLQQLQJRIWKHYLVLW
7.3
$GYHUVH(YHQWV
7.3.1
3HUIRUPLQJ$GYHUVH(YHQWV$VVHVVPHQWV
7KH ,QYHVWLJDWRU LV UHVSRQVLEOH IRU SURPSWO\ GRFXPHQWLQJ DQG UHSRUWLQJDOO$(VREVHUYHG
GXULQJWKHVWXG\LQWKHVXEMHFW¶VFDVHUHSRUWIRUP,IWKH$(LV³DODUPLQJ´WKH,QYHVWLJDWRU
PXVW UHSRUW WKH $( LPPHGLDWHO\ WR 3HDUO ,Q DGGLWLRQ FHUWDLQ $(V DV GHVFULEHG LQ
6HFWLRQDUHFODVVLILHGDVVHULRXVDQGPXVWEHUHSRUWHGQRODWHUWKDQKRXUVDIWHUWKH
,QYHVWLJDWRUUHFRJQL]HVFODVVLILHVWKHHYHQWDVD6$(WR3HDUORULWVGHVLJQHH
,QWKHFDVHRI6$(VDIWHUGLVFXVVLQJWKHGHWDLOVRIWKH$(WKH,QYHVWLJDWRUDQGWKH6SRQVRU
PD\GLVFRQWLQXHWKHVXEMHFWSUHPDWXUHO\
7.3.2
$GYHUVH(YHQW'HILQLWLRQV
7KH IROORZLQJ GHILQLWLRQV RI WHUPV DUH JXLGHG E\ WKH ,QWHUQDWLRQDO &RQIHUHQFH RQ
+DUPRQL]DWLRQ,&+WKH86&RGHRI)HGHUDO5HJXODWLRQV>&RGHRI)HGHUDO5HJXODWLRQV
&)5@DQG(8'LUHFWLYH(&DQGDUHLQFOXGHGKHUHLQ
$Q$(LVDQ\XQWRZDUGPHGLFDORFFXUUHQFHDVVRFLDWHGZLWKWKHXVHRIDGUXJLQKXPDQV
ZKHWKHURUQRWFRQVLGHUHGGUXJUHODWHG$Q$(DOVRUHIHUUHGWRDVDQDGYHUVHH[SHULHQFH
FDQEHDQ\XQIDYRUDEOHDQGXQLQWHQGHGVLJQHJDQDEQRUPDOODERUDWRU\ILQGLQJV\PSWRP
RU GLVHDVH WHPSRUDOO\ DVVRFLDWHG ZLWK WKH XVH RI D GUXJ ZLWKRXW DQ\ MXGJPHQW DERXW
FDXVDOLW\$Q$(FDQDULVHIURPDQ\XVHRIWKHGUXJHJRIIODEHOXVHXVHLQFRPELQDWLRQ
ZLWKDQRWKHUGUXJDQGIURPDQ\URXWHRIDGPLQLVWUDWLRQIRUPXODWLRQRUGRVHLQFOXGLQJDQ
RYHUGRVH
$GYHUVHHYHQWVLQFOXGHEXWDUHQRWOLPLWHGWR

$Q\V\PSWRPRUFRQGLWLRQQRWSUHYLRXVO\UHSRUWHGE\WKHVXEMHFWPHGLFDOKLVWRU\

$QH[DFHUEDWLRQRIDSUHH[LVWLQJV\PSWRPRUFRQGLWLRQ

$ VLJQLILFDQW LQFUHDVH LQ IUHTXHQF\ RU LQWHQVLW\ RI D SUHH[LVWLQJ HSLVRGLF HYHQW RU
FRQGLWLRQ

$GUXJLQWHUDFWLRQ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

$FRQGLWLRQILUVWGHWHFWHGRUGLDJQRVHGDIWHUVWXG\GUXJDGPLQLVWUDWLRQHYHQWKRXJKLW
PD\KDYHEHHQSUHVHQWSULRUWRWKHVWDUWRIWKHVWXG\
$Q$(GRHVnot LQFOXGH

0HGLFDO RU VXUJLFDO SURFHGXUHV HJ VXUJHU\ HQGRVFRS\ WRRWK H[WUDFWLRQ EORRG
WUDQVIXVLRQWKHFRQGLWLRQWKDWUHVXOWVLQWKHSURFHGXUHLVFRQVLGHUHGDQ$(HJEOHHGLQJ
HVRSKDJHDOYDULFHVGHQWDOFDULHV

2YHUGRVH RI HLWKHU VWXG\ GUXJ RU FRQFXUUHQW PHGLFDWLRQ ZLWKRXW DQ\ FOLQLFDO VLJQV RU
V\PSWRPV

1RQFOLQLFDOO\
VLJQLILFDQW
DEQRUPDO
ODERUDWRU\
YDOXHV
,I
DFFRPSDQLHG
E\
VLJQVV\PSWRPVWKHVLJQVRUV\PSWRPVDUHFRQVLGHUHGDQ$(
7.3.3
3UH5DQGRPL]DWLRQ$GYHUVH(YHQWV
$(VWKDWRFFXUEHWZHHQWKHWLPHVXEMHFWVLJQVWKH,&)IRUWKHVWXG\DQGWKHWLPHZKHQWKDW
VXEMHFW LV UDQGRPL]HG ZLOO EH VXPPDUL]HG DV PHGLFDO KLVWRU\ DQG QRW DV D 7UHDWPHQW
(PHUJHQW $( 7($( XQOHVV WKH HYHQW PHHWV WKH GHILQLWLRQ RI D 6$( DV GHILQHG LQ
6HFWLRQ
7.3.4
6HYHULW\
7KH ,QYHVWLJDWRU PXVW FDWHJRUL]H WKH VHYHULW\ RI HDFK $( DFFRUGLQJ WR WKH IROORZLQJ
JXLGHOLQHV
0LOG$VVRFLDWHGZLWKQROLPLWDWLRQRIXVXDODFWLYLWLHVRURQO\VOLJKWGLVFRPIRUWJHQHUDOO\
QRW UHTXLULQJ DOWHUDWLRQ RU FHVVDWLRQ RI VWXG\ GUXJ DGPLQLVWUDWLRQ DQGRU QRW QHHGLQJ
WKHUDSHXWLFLQWHUYHQWLRQ
0RGHUDWH$VVRFLDWHGZLWKOLPLWDWLRQRIXVXDODFWLYLWLHVRUVLJQLILFDQWGLVFRPIRUWJHQHUDOO\
UHTXLULQJ DOWHUDWLRQ RU FHVVDWLRQ RI VWXG\ GUXJ DGPLQLVWUDWLRQDQGRUUHTXLULQJWKHUDSHXWLF
LQWHUYHQWLRQ
6HYHUH $VVRFLDWHG ZLWK LQDELOLW\ RI VXEMHFW WR FDUU\ RXW XVXDO DFWLYLWLHV RU YHU\
PDUNHG GLVFRPIRUW FRQVLGHUHG WR EH OLIHWKUHDWHQLQJ UHVXOWLQJ LQ VLJQLILFDQW GLVDELOLW\ RU
LQFDSDFLW\DQGUHTXLULQJWKHUDSHXWLFLQWHUYHQWLRQ
7.3.5
5HODWLRQVKLS
7KH UHODWLRQVKLS RI HDFK $( WR WKH VWXG\ GUXJ DGPLQLVWUDWLRQ ZLOO EH DVVHVVHG E\ WKH
,QYHVWLJDWRUDIWHUFDUHIXOFRQVLGHUDWLRQDQGDFFRUGLQJWRWKHIROORZLQJJXLGHOLQHV
'HILQLWHO\$UHDFWLRQWKDWIROORZVDUHDVRQDEOHWHPSRUDOVHTXHQFHIURPDGPLQLVWUDWLRQRI
VWXG\GUXJWKDWIROORZVDNQRZQRUH[SHFWHGUHVSRQVHSDWWHUQWRWKHVWXG\GUXJLWGLVDSSHDUV
RUGHFUHDVHV RQ FHVVDWLRQ RU UHGXFWLRQLQVWXG\ GUXJGRVHDQGRULWUHDSSHDUVRUZRUVHQV
ZKHQWKHVWXG\GUXJLVDGPLQLVWHUHG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
3UREDEO\ $ UHDFWLRQ WKDW IROORZV D UHDVRQDEOH WHPSRUDO VHTXHQFH IURP DGPLQLVWUDWLRQ RI
VWXG\GUXJWKDWIROORZVDNQRZQRUH[SHFWHGUHVSRQVHSDWWHUQWRWKHVWXG\GUXJDQGRUWKDW
FRXOGQRWEHUHDVRQDEO\H[SODLQHGE\RWKHUIDFWRUVVXFKDVXQGHUO\LQJGLVHDVHFRPSOLFDWLRQV
FRQFRPLWDQWGUXJVRUFRQFXUUHQWWUHDWPHQWV
3RVVLEO\ $ UHDFWLRQ WKDW IROORZV D UHDVRQDEOH WHPSRUDO VHTXHQFH IURP DGPLQLVWUDWLRQ RI
VWXG\GUXJWKDWIROORZVDNQRZQRUH[SHFWHGUHVSRQVHSDWWHUQWRWKHVWXG\GUXJEXWWKDW
FRXOG UHDVRQDEO\ KDYH EHHQ SURGXFHG E\ D QXPEHU RI RWKHU IDFWRUV LQFOXGLQJ XQGHUO\LQJ
GLVHDVHFRPSOLFDWLRQVFRQFRPLWDQWGUXJVRUFRQFXUUHQWWUHDWPHQWV
1RW 5HODWHG $ UHDFWLRQ IRU ZKLFK VXIILFLHQW GDWD H[LVW WR LQGLFDWH WKDW WKH HWLRORJ\ LV
XQUHODWHGWRWKHVWXG\GUXJ
7.3.6
&OLQLFDO/DERUDWRU\$GYHUVH(YHQWV
0DQ\ODERUDWRU\DEQRUPDOLWLHVREVHUYHGGXULQJWKHFRXUVHRIDVWXG\ZLOOEHLQFOXGHGXQGHU
DUHSRUWHG$(GHVFULELQJDFOLQLFDOV\QGURPHHJHOHYDWHG%81DQGFUHDWLQLQHLQWKHVHWWLQJ
RIDQ$(RIUHQDOIDLOXUHRUGHFUHDVHGKHPRJORELQLQDFDVHRIEOHHGLQJHVRSKDJHDOYDULFHV
,QVXFKFDVHVWKHODERUDWRU\DEQRUPDOLW\LWVHOIHJHOHYDWHGFUHDWLQLQHLQDVHWWLQJRIUHQDO
IDLOXUHGRHVQRWQHHGWREHUHFRUGHGDVDQ$(+RZHYHULVRODWHGODERUDWRU\DEQRUPDOLWLHV
VKRXOG EH UHSRUWHG DV $(V LI WKH\ DUH FRQVLGHUHG WR EH FOLQLFDOO\ VLJQLILFDQW E\ WKH
,QYHVWLJDWRU
&ULWHULDIRUDFOLQLFDOO\VLJQLILFDQWODERUDWRU\DEQRUPDOLW\DUH

$ODERUDWRU\DEQRUPDOLW\WKDWOHDGVWRDGRVHOLPLWLQJWR[LFLW\HJDQDEQRUPDOLW\WKDW
UHVXOWVLQVWXG\GUXJGRVHUHGXFWLRQVXVSHQVLRQRUGLVFRQWLQXDWLRQ

$ ODERUDWRU\ DEQRUPDOLW\ WKDW UHVXOWV LQ DQ\ WKHUDSHXWLF LQWHUYHQWLRQ LH FRQFRPLWDQW
PHGLFDWLRQRUWKHUDS\

2WKHUODERUDWRU\DEQRUPDOLW\MXGJHGE\WKH,QYHVWLJDWRUWREHRIDQ\SDUWLFXODUFOLQLFDO
FRQFHUQHJVLJQLILFDQWIDOOLQKHPRJORELQQRWUHTXLULQJWUDQVIXVLRQ
)RUODERUDWRU\DEQRUPDOLWLHVWKDWGRQRWPHHWWKHDERYHFULWHULDEXWDUHRXWVLGHRIQRUPDO
UDQJHHJRU!QRUPDOUHIHUHQFHUDQJHWKH,QYHVWLJDWRUVKRXOGLQGLFDWHZKHWKHUWKHYDOXH
LVFOLQLFDOO\VLJQLILFDQWRUQRWFOLQLFDOO\VLJQLILFDQWIRUWKHVXEMHFW
7.3.7
6HULRXV$GYHUVH(YHQWV
$Q$(LVFRQVLGHUHG³VHULRXV´LILQWKHYLHZRIWKH,QYHVWLJDWRURU6SRQVRULWUHVXOWVLQDQ\
RIWKHIROORZLQJRXWFRPHV

'HDWK

$OLIHWKUHDWHQLQJ$(

,QVXEMHFWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

$SHUVLVWHQWRUVLJQLILFDQWLQFDSDFLW\RUVXEVWDQWLDOGLVUXSWLRQRIWKHDELOLW\WRFRQGXFW
QRUPDOOLIHIXQFWLRQV

$FRQJHQLWDODQRPDO\ELUWKGHIHFW

,PSRUWDQW PHGLFDO HYHQWV WKDW PD\ QRW UHVXOW LQ GHDWK EH OLIH WKUHDWHQLQJ RU UHTXLUH
KRVSLWDOL]DWLRQPD\EHFRQVLGHUHGVHULRXVZKHQEDVHGXSRQDSSURSULDWHMXGJPHQWWKH\PD\
MHRSDUGL]HWKHVXEMHFWDQGPD\UHTXLUHPHGLFDORUVXUJLFDOLQWHUYHQWLRQWRSUHYHQWRQHRIWKH
RXWFRPHV OLVWHG LQ WKH GHILQLWLRQ ([DPSOHV RI VXFK PHGLFDO HYHQWV LQFOXGH DOOHUJLF
EURQFKRVSDVPUHTXLULQJLQWHQVLYHWUHDWPHQWLQDQHPHUJHQF\URRP(5RUDWKRPHEORRG
G\VFUDVLDVRUFRQYXOVLRQVWKDWGRQRWUHVXOWLQVXEMHFWKRVSLWDOL]DWLRQRUWKHGHYHORSPHQWRI
GUXJGHSHQGHQF\RUGUXJDEXVH
+RVSLWDOL]DWLRQ IRU D SUHH[LVWLQJ FRQGLWLRQ LQFOXGLQJ HOHFWLYH SURFHGXUHV ZKLFK KDV QRW
ZRUVHQHGGRHVQRWFRQVWLWXWHD6$(
$Q $( LV FRQVLGHUHG ³OLIHWKUHDWHQLQJ¶ LI LQ WKH YLHZ RI WKH ,QYHVWLJDWRU RU 6SRQVRU LWV
RFFXUUHQFHSODFHVWKHVXEMHFWRUVXEMHFWDWLPPHGLDWHULVNRIGHDWK,WGRHVQRWLQFOXGHDQ
DGYHUVHUHDFWLRQRUVXVSHFWHGDGYHUVHUHDFWLRQWKDWKDGLWRFFXUUHGLQDPRUHVHYHUHIRUP
PLJKWKDYHFDXVHGGHDWK
$QXQH[SHFWHG$(PHDQVDQ\$(IRUZKLFKWKHVSHFLILFLW\RUVHYHULW\LVQRWFRQVLVWHQWZLWK
WKHFXUUHQW,%
7.3.7.1
5HSRUWLQJ6HULRXV$GYHUVH(YHQWV
,QDJUHHLQJWRWKHSURYLVLRQVRIWKLVSURWRFROWKH,QYHVWLJDWRUDFFHSWVDOOOHJDOUHVSRQVLELOLWLHV
IRU $( LGHQWLILFDWLRQ GRFXPHQWDWLRQ JUDGLQJ DVVLJQPHQW RI FDXVDOLW\ DQG SURPSW
QRWLILFDWLRQRI6$(VWR3HDUO3KDUPDFRYLJLODQFHRUGHVLJQHH$OO6$(VPXVWEHUHSRUWHGWR
3HDUO 3KDUPDFRYLJLODQFH RU GHVLJQHH QR ODWHU WKDQ  KRXUV DIWHU WKH ,QYHVWLJDWRU
UHFRJQL]HVFODVVLILHVWKHHYHQWDVD6$($WDPLQLPXPDGHVFULSWLRQRIWKHHYHQWDQGWKH
,QYHVWLJDWRU¶VMXGJPHQWRIFDXVDOLW\PXVWEHSURYLGHGDWWKHWLPHRIWKHLQLWLDOUHSRUWXVLQJ
WKH DSSURSULDWH IRUP HJ 6$( 5HSRUW )RUP $IWHU WKH LQLWLDO UHSRUW DV QHFHVVDU\ WKH
,QYHVWLJDWRUPXVWSURYLGHDQ\DGGLWLRQDOLQIRUPDWLRQRQD6$(WR3HDUO3KDUPDFRYLJLODQFH
RUGHVLJQHHZLWKLQZRUNLQJGD\VDIWHUKHVKHUHFHLYHVDGGLWLRQDOIROORZXSLQIRUPDWLRQWKLV
IROORZXSLQIRUPDWLRQZLOOEHDGHWDLOHGZULWWHQUHSRUWWKDWPD\LQFOXGHFRSLHVRIKRVSLWDO
UHFRUGVFDVHUHSRUWVDQGDXWRSV\UHSRUWVDQGRWKHUSHUWLQHQWGRFXPHQWV
3RVWVWXG\6$(VIROORZLQJWKHODVWGRVHRIVWXG\GUXJPXVWEHUHSRUWHGWR3HDUODVGHVFULEHG
LQ6HFWLRQ
7KH ,QYHVWLJDWRU LV UHVSRQVLEOH IRU FRQWLQXLQJ WR UHSRUW DQ\ QHZ RU UHOHYDQW IROORZXS
LQIRUPDWLRQWKDWKHVKHOHDUQVDERXWWKH6$(

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7.3.7.2
6XSSOHPHQWDO,QYHVWLJDWLRQVRI6$(V
7KH,QYHVWLJDWRUDQGVXSSRUWLQJSHUVRQQHOUHVSRQVLEOHIRUVXEMHFWFDUHVKRXOGGLVFXVVZLWK
WKH0HGLFDO0RQLWRUDQ\QHHGIRUVXSSOHPHQWDOLQYHVWLJDWLRQVRI6$(V7KHUHVXOWVRIWKHVH
DGGLWLRQDO DVVHVVPHQWV FRQGXFWHG PXVW EH UHSRUWHG WR 3HDUO ,I D VXEMHFW GLHV GXULQJ
SDUWLFLSDWLRQLQWKHVWXG\DQGDSRVWPRUWHPH[DPLQDWLRQLVSHUIRUPHGDFRS\RIWKHDXWRSV\
UHSRUWPXVWEHVXEPLWWHGWR3HDUO3KDUPDFRYLJLODQFH
7.3.7.3
3RVW6WXG\)ROORZ8SRI$GYHUVH(YHQWV
$Q\$(VWKDWDUHXQUHVROYHGDWWKHVXEMHFW¶VODVW$(DVVHVVPHQWLQWKHVWXG\DUHIROORZHGXS
E\WKH,QYHVWLJDWRUIRUDVORQJDVPHGLFDOO\LQGLFDWHGEXWZLWKRXWIXUWKHUUHFRUGLQJLQWKH
H&5)3HDUOUHWDLQVWKHULJKWWRUHTXHVWDGGLWLRQDOLQIRUPDWLRQIRUDQ\VXEMHFWZLWKRQJRLQJ
$(V6$(VDWWKHHQGRIWKHVWXG\LIMXGJHGQHFHVVDU\
7.3.7.4
1RWLILFDWLRQRI3RVW6WXG\6HULRXV$GYHUVH(YHQWV
7KHIROORZXSWHOHSKRQHFDOOZLOOEHSHUIRUPHG±GD\VDIWHU9LVLWVRSRVWVWXG\6$(V
RFFXUULQJ XS WR GD\V IROORZLQJ WKH ODVW GRVH RI VWXG\ GUXJ PXVW EH UHSRUWHG WR 3HDUO
ZKHWKHURUQRWWKHHYHQWLVDWWULEXWDEOHWRVWXG\GUXJ$OO6$(VPXVWEHUHSRUWHGWR3HDUOQR
ODWHUWKDQKRXUVDIWHUWKH,QYHVWLJDWRUUHFRJQL]HVFODVVLILHVWKHHYHQWDVD6$(
7.3.7.5
,5%,(&1RWLILFDWLRQRI6HULRXV$GYHUVH(YHQWV
7KH ,QYHVWLJDWRU LV UHVSRQVLEOH IRU QRWLI\LQJ KHUKLV ,5%,(& RI DOO 6$(V LQFOXGLQJ DQ\
IROORZXSLQIRUPDWLRQRFFXUULQJDWKHUKLVVLWHDQGDQ\6$(UHJXODWRU\UHSRUWLQFOXGLQJDQ\
IROORZXSUHSRUWVWKDWKHVKHUHFHLYHVIURP3HDUO'RFXPHQWDWLRQRIWKHVXEPLVVLRQWRWKH
,5%,(& PXVW EH UHWDLQHG IRU HDFK VDIHW\ UHSRUW 7KH ,QYHVWLJDWRU LV DOVR UHVSRQVLEOH IRU
QRWLI\LQJ 3HDUO LI WKHLU ,5%,(& UHTXLUHV UHYLVLRQV WR WKH LQIRUPHG FRQVHQW IRUP RU RWKHU
PHDVXUHVEDVHGRQLWVUHYLHZRID6$(UHSRUW
7.3.7.6
+HDOWK$XWKRULW\6DIHW\5HSRUWV
3HDUORULWVUHSUHVHQWDWLYHVZLOOVXEPLWDVDIHW\UHSRUWWRWKH)RRGDQG'UXJ$GPLQLVWUDWLRQ
)'$DQGRUDQ\RWKHUDSSURSULDWHUHJXODWRU\DJHQFLHVIRUDQ\VXVSHFWHGDGYHUVHUHDFWLRQ
WKDWLVERWKVHULRXVDQGXQH[SHFWHGZLWKLQWKHDSSURSULDWHWLPHIUDPH
3HDUORULWVUHSUHVHQWDWLYHVZLOOVHQGFRSLHVRIHDFKVDIHW\UHSRUWVXEPLWWHGWRWKH)'$DQGRU
RWKHU UHJXODWRU\ DJHQFLHV WR WKH ,QYHVWLJDWRUV ZKR DUH DFWLYHO\ SDUWLFLSDWLQJ LQ 3HDUO
VSRQVRUHGFOLQLFDOVWXGLHV6DIHW\UHSRUWVPXVWEHVXEPLWWHGWRWKHDSSURSULDWH,5%,(&DV
VRRQDVSRVVLEOHDVGHVFULEHGLQ6HFWLRQ
7.3.8
2YHUGRVH
$QRYHUGRVHLVGHILQHGDVDGRVHJUHDWHUWKDQWKHKLJKGRVHOHYHOHYDOXDWHGLQWKLVVWXG\DV
GHVFULEHGLQ6HFWLRQ3URGXFW'HVFULSWLRQVWKDWUHVXOWVLQFOLQLFDOVLJQVDQGV\PSWRPV
,Q WKH HYHQW RI DQ RYHUGRVH RI VWXG\ PHGLFDWLRQ WKH ,QYHVWLJDWRU VKRXOG XVH FOLQLFDO
MXGJPHQWLQWUHDWLQJWKHRYHUGRVHDQGFRQWDFWWKHVWXG\0HGLFDO0RQLWRU7KH,QYHVWLJDWRU

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
VKRXOG UHIHU WR WKH UHOHYDQW GRFXPHQWV IRU GHWDLOHG LQIRUPDWLRQ UHJDUGLQJ ZDUQLQJV
SUHFDXWLRQVFRQWUDLQGLFDWLRQV$(VDQGRWKHUVLJQLILFDQWGDWDSHUWDLQLQJWRWKHVWXG\GUXJV
EHLQJXVHGLQWKLVVWXG\6XFKGRFXPHQWPD\LQFOXGHEXWQRWEHOLPLWHGWRWKH,%
7.3.9
3UHJQDQF\
7RHQVXUHVXEMHFWVDIHW\HDFKSUHJQDQF\LQDIHPDOHVXEMHFWIURP9LVLW6FUHHQLQJXQWLO
VWXG\FRPSOHWLRQPXVWEHUHSRUWHGWR3HDUOZLWKLQKRXUVRIOHDUQLQJRILWVRFFXUUHQFH
7KH SUHJQDQF\ VKRXOG EH IROORZHG XS WR GHWHUPLQH RXWFRPH LQFOXGLQJ VSRQWDQHRXV RU
YROXQWDU\WHUPLQDWLRQGHWDLOVRIWKHELUWKDQGWKHSUHVHQFHRUDEVHQFHRIDQ\ELUWKGHIHFWV
FRQJHQLWDODEQRUPDOLWLHVRUPDWHUQDO DQGRUQHZERUQFRPSOLFDWLRQV3UHJQDQF\VKRXOGEH
UHFRUGHG RQ D 3DSHU 3UHJQDQF\ 5HSRUW )RUP DQG UHSRUWHG E\ WKH ,QYHVWLJDWRU WR 3HDUO
3KDUPDFRYLJLODQFHRUGHVLJQHH3UHJQDQF\IROORZXSLQFOXGLQJSUHJQDQF\RXWFRPHVKRXOG
EHUHFRUGHGRQWKHVDPHIRUPDQGVKRXOGLQFOXGHDQDVVHVVPHQWRIWKHSRVVLEOHUHODWLRQVKLS
WR WKH 3HDUO 7KHUDSHXWLFV VWXG\ GUXJ $Q\ 6$( H[SHULHQFHG GXULQJ SUHJQDQF\ PXVW EH
UHSRUWHGRQWKH6$(5HSRUW)RUP
7.4
7HUPLQDWLRQRIWKH6WXG\
$Q ,QYHVWLJDWRU PD\ FKRRVH WR GLVFRQWLQXH VWXG\ SDUWLFLSDWLRQ DW DQ\ WLPH ZLWK VXIILFLHQW
QRWLFHE\WKH,QYHVWLJDWRUIRUDQ\UHDVRQDVSHUWKHWHUPVRIWKHFRQWUDFWZLWK3HDUO
3HDUO UHVHUYHV WKH ULJKW WR GLVFRQWLQXH WKH VWXG\ DW DQ\ WLPH IRU FOLQLFDO RU DGPLQLVWUDWLYH
UHDVRQV6XFKDWHUPLQDWLRQPXVWEHLPSOHPHQWHGE\WKH,QYHVWLJDWRULILQVWUXFWHGWRGRVR
E\3HDUOLQDWLPHIUDPHWKDWLVFRPSDWLEOHZLWKWKHVXEMHFWV¶ZHOOEHLQJ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


STUDY ACTIVITIES
$ WLPH DQG HYHQWV VFKHGXOH IRU WKH VWXG\ LV SUHVHQWHG LQ 7DEOH 7DEOH  DQG
7DEOHSUHVHQWGHWDLOVDERXWDFWLYLWLHVFRQGXFWHGSUHDQGSRVWGRVHDW9LVLWVWKURXJK


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7DEOH
6FKHGXOHRI(YHQWV
Clinical Variable
Screening
Treatment Period 1
Treatment Period 2
Follow-up
Visit 1
Visit 2n
Day 1
Visit 3n
Day 15
Visit 4n
Day 1
Visit 5n
Day 15
Telephone
Call
Study Day
-7 up to -21a
Day 1a
Day 15
'D\V
Day 1
Day 15
'D\V
7 to10 days
Informed Consent
;





Review of Inclusion/Exclusion 
Criteria
;
;

;


Diary Training 
;





Review of Diary

;X
;
;
;

Chest X-rayh
;





Reversibility
;





Demographics and 
Medical/Surgical History
;V





COPD Assessment Test (CAT)
;





MMRC
;





Smoking Status
;
;
;
;
;
;
Prior/Concomitant 
Medicationsb
;U
;
;
;
;
;
Diffusion Capacity
;





Spirometryc
;
;
;
;
;

Body Plethysmography

;
;
;
;

Physical Examinationd
;



;

Vital Signse
;
;
;
;
;

12-lead ECGf
;
;
;
;
;

Pregnancy Testp
;
;
;
;
;

Clinical Laboratory Testingg
;
;
;
;
;


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Clinical Variable
Screening
Treatment Period 1
Treatment Period 2
Follow-up
Visit 1
Visit 2n
Day 1
Visit 3n
Day 15
Visit 4n
Day 1
Visit 5n
Day 15
Telephone
Call
Study Day
-7 up to -21a
Day 1a
Day 15
'D\V
Day 1
Day 15
'D\V
7 to10 days
Adjust COPD Medicationsi
;



;

Adverse Eventsq

;
;
;
;
;
Inhalation Device Trainingk
;M





Inhalation Profileo  

;

;


Recording of Inhalation Profile 
with Respiration Belto

;

;


HRCT scant

;
;
;
;

Study Drug 
Dispensing/Collectionl
;
;
;
;
;

Randomization

;




Study Drug Administrationl

;
;
;
;

Review/Record Study Drug 
Dose Indicator Readingm

;
;
;
;

Review/Record Ventolin Dose 
Indicator Readingu
;
;
;
;
;

Telephone contact





;
$EEUHYLDWLRQV&$7 &23'DVVHVVPHQWWHVW005& 0RGLILHG0HGLFDO5HVHDUFK&RXQFLO(&* HOHFWURFDUGLRJUDP
&23' &KURQLFREVWUXFWLYHSXOPRQDU\GLVHDVH+5&7 +LJKUHVROXWLRQFRPSXWHGWRPRJUDSK\,&6 LQKDOHGFRUWLFRVWHURLGV
0', PHWHUHGGRVHLQKDOHU)5& IXQFWLRQDOUHVLGXDOFDSDFLW\7/& WRWDOOXQJFDSDFLW\

D
6FKHGXOLQJYLVLWV7KHPD[LPXPUXQLQSHULRGLVGD\V7KHHDUOLHVWDVXEMHFWFDQEHUDQGRPL]HGIURPWKH9LVLWGDWHLV
GD\VGD\VIRU/$%$ZDVKRXW7KHVLWHVKRXOGPDNHHYHU\HIIRUWWRPDLQWDLQVXEMHFWVZLWKLQWKHVFKHGXOHGYLVLW
ZLQGRZ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
E
$WDOOYLVLWVEH\RQG9LVLW6FUHHQLQJQRWHWKHWLPHRIODVWGRVHRI&23'PHGLFDWLRQVLQFOXGLQJUHVFXHPHGLFDWLRQDQG,&6
LIKRXUVYLVLWVKRXOGEHUHVFKHGXOHGH[FHSWIRUVSRQVRUSURYLGHG$WURYHQW+)$DWH9LVLWDQG9LVLW
F
5HIHUWR6HFWLRQIRUVSLURPHWU\DVVHVVPHQWVDQGVSHFLILFWLPHSRLQWVWREHSHUIRUPHGDWHDFKWUHDWPHQWYLVLW
G
,QFOXGHVHYDOXDWLRQRIKHLJKWDQGZHLJKWDW9LVLW
H
5HIHUWR6HFWLRQIRUYLWDOVLJQDVVHVVPHQWVDQGVSHFLILFWLPHSRLQWVWREHSHUIRUPHGDWHDFKYLVLW
I
5HIHUWR6HFWLRQIRU(&*DVVHVVPHQWVDQGVSHFLILFWLPHSRLQWVWREHSHUIRUPHGDWHDFKYLVLW
J
5HIHUWR6HFWLRQIRUFOLQLFDOODERUDWRU\DVVHVVPHQWVKHPDWRORJ\FKHPLVWU\DQGXULQDO\VLVDQGVSHFLILFWLPHSRLQWVDWHDFK
VWXG\YLVLW
K
2EWDLQDQHZFKHVW[UD\LIWKHFKHVW[UD\RU&7VFDQSHUIRUPHGZLWKLQPRQWKVRI9LVLW6FUHHQLQJLVQRWDYDLODEOH
L
$IWHUREWDLQLQJLQIRUPHGFRQVHQWVXEMHFWVZLOOEHLQVWUXFWHGWRZLWKKROGSURKLELWHG&23'PHGLFDWLRQVKRXUVWRKRXUV
EHIRUH9LVLW6FUHHQLQJ$W9LVLW6FUHHQLQJVXEMHFWVZLOOEHJLYHQ6SRQVRUSURYLGHG$WURYHQW+)$ZLWKRU
ZLWKRXW,&6UHVFXH9HQWROLQ+)$RQO\DIWHUDVXEMHFWLVGHWHUPLQHGWREHHOLJLEOHWRSURFHHGWR9LVLW'D\LH
RQO\LIDVXEMHFWPHHWVWKHGHILQLWLRQRI&23'IROORZLQJVSLURPHWU\DVVHVVPHQWVDW6FUHHQLQJ
M
$W 9LVLW  &23' PHGLFDWLRQV ZLOO EH FKDQJHG DV VSHFLILHG LQ WKH SURWRFRO LH 6SRQVRU SURYLGHG $WURYHQW +)$ ZLWK RU
ZLWKRXW ,&6  $W WKH HQG RI 9LVLW  UHWXUQ VXEMHFW WR SUHVWXG\ RU RWKHU DSSURSULDWH LQKDOHG PDLQWHQDQFH &23'
PHGLFDWLRQV
N
6LWHVKRXOGXVHWKHVSRQVRUSURYLGHGSODFHER0',WRWUDLQVXEMHFWVRQWKHXVHRI0',V
O
,QFOLQLFGRVLQJWLPHLVUHFRUGHGDVWLPHRIWKHVHFRQGSXIILQKDODWLRQ
P
5HIHUWR$SSHQGL[IRUGHWDLOVDQGLQVWUXFWLRQVRQUHFRUGLQJGRVHLQGLFDWRUUHDGLQJV
Q
9LVLWZLQGRZVGXULQJHDFK7UHDWPHQW3HULRGDUHUHODWLYHWR'D\RIWKDW7UHDWPHQW3HULRG:DVKRXWSHULRGEHWZHHQ9LVLW
DQG9LVLWVLVDPLQLPXPRIGD\VWRDPD[LPXPRIGD\V
R
7KHLQKDODWLRQSURILOHZLWKWKHXVHRIWKHUHVSLUDWLRQEHOWZLOOEHPHDVXUHGVLPXOWDQHRXVO\ZLWKWKHGUXJDGPLQLVWUDWLRQ
S
2QO\LQIHPDOHRIFKLOGEHDULQJSRWHQWLDO
T
$(VWKDWRFFXUEHIRUHUDQGRPL]DWLRQZLOOEHVXPPDUL]HGDVPHGLFDOKLVWRU\DQGQRWDVD7($(XQOHVVWKHHYHQWPHHWVWKH
GHILQLWLRQRID6$(5HIHUWR6HFWLRQ
U
$OOSUHVFULSWLRQDQG27&PHGLFDWLRQVWDNHQE\WKHVXEMHFWZLWKLQGD\VEHIRUH9LVLW6FUHHQLQJZLOOEHUHFRUGHG
V
7KHQXPEHURI&23'H[DFHUEDWLRQVUHTXLULQJRUDOVWHURLGVDQGRURUDODQWLELRWLFVRUKRVSLWDOL]DWLRQZLWKLQPRQWKVRI9LVLW
6FUHHQLQJZLOOEHFROOHFWHG
W
$W9LVLWDQGWZREUHDWKLQJOHYHOV7/&DQG)5&'XULQJ9LVLWDQDGGLWLRQDOVFDQRIWKH8$ZLOOEHWDNHQ$W9LVLWDQG
RQHEUHDWKLQJOHYHO7/&
X
6XEMHFWVZKRDUHXQDEOHWRPHHWWKHFRPSOLDQFHUHTXLUHPHQW!VXEMHFWFRPSOHWLRQRIGLDU\DVVHVVPHQWVLQWKHODVWGD\V
SUHFHGLQJWKH5DQGRPL]DWLRQ9LVLW9LVLWPXVWEHUHWUDLQHG:KHQUHWUDLQLQJLVUHTXLUHGGXHWRQRQFRPSOLDQFHWKH
5DQGRPL]DWLRQ9LVLW9LVLWPXVWEHUHVFKHGXOHG


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Note:6LWHVKRXOGSODQWRSHUIRUPWKHVHDFWLYLWLHVVRDVQRWWRLQWHUIHUHZLWKFROOHFWLRQRIWLPHGDVVHVVPHQWVVXFKDVVSLURPHWU\
:KHUHGDWDFROOHFWLRQWLPHSRLQWVDUHFRQFXUUHQWYDULDEOHVPXVWEHFROOHFWHGLQWKHIROORZLQJRUGHU2Q'D\RIHDFK
WUHDWPHQWSHULRGPredose:8ULQHSUHJQDQF\WHVW6SLURPHWU\REWDLQ)(9WRHYDOXDWHVWDELOLW\FULWHULDYLWDOVLJQV
(&*FOLQLFDOODERUDWRU\DVVHVVPHQWV$EQRUPDOH*)5DW9LVLWVFUHHQLQJPXVWEHUHSHDWHGSULRUWR9LVLWDQG
KDYHWKHUHVXOWVDYDLODEOHDW9LVLWWRFRQILUPHOLJLELOLW\3UHGRVH&7VFDQV6SLURPHWU\%RG\3OHWK\VPRJUDSK\
,QKDODWLRQ3URILOHPostdose:YLWDOVLJQV(&*2Q'D\GD\VRIHDFK73Predose:8ULQHSUHJQDQF\WHVWYLWDO
VLJQV (&* FOLQLFDO ODERUDWRU\ DVVHVVPHQWV Postdose: 9LWDO VLJQV (&* SRVWGRVH &7 6FDQ 6SLURPHWU\ %RG\
3OHWK\VPRJUDSK\

7DEOH 7LPHG$VVHVVPHQWVDW9LVLWDQG9LVLW

Visit 2 (Day 1 TP 1)
Visit 4 (Day 1 TP 2)
Clinical Variablea
Pre-dosing
Post-
dosing
Pre-dosing
Post-
dosing
PLQK

PLQK
PLQK

PLQK
PLQK
PLQK
Vital Signsb,c,d
;

;
;

;
ECGb,c  
;

;
;

;
Clinical Laboratory Testingb,c
;


;


Urine pregnancy teste
;


;


Spirometryc  
;L
;I

;L
;I

HRCT Scansc

;


;

Body Plethysmographyc

;I


;I

Inhalation Profilec

;J


;J


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
D
$WWKHVWDUWRIHDFKWUHDWPHQWYLVLWVXEMHFWPXVWZLWKKROGDOOLQKDOHG&23'PHGLFDWLRQVLQFOXGLQJVWXG\
PHGLFDWLRQUHVFXH9HQWROLQ+)$DQG,&6IRUDWOHDVWKRXUVSULRUWRVWDUWRIWHVWGD\SURFHGXUHVH[FHSWIRU
VSRQVRUSURYLGHG$WURYHQW+)$DW9LVLWDQG9LVLW
E
7KLVLVQRWDWLPHGDVVHVVPHQW6LWHVVKRXOGSODQWRSHUIRUPWKHVHDFWLYLWLHVVRDVQRWWRLQWHUIHUHZLWK
FROOHFWLRQRIWLPHGDVVHVVPHQWVVXFKDVVSLURPHWU\
Note:6XEMHFWVZLWKDFDOFXODWHGFUHDWLQLQHFOHDUDQFHPOPLQPA0'5'DW9LVLWPXVWKDYHD
H*)50'5'!POPLQPARQWKHUHSHDWWHVWLQJSULRUWR9LVLWWREHUDQGRPL]HGLQWKLVVWXG\
F
5HIHUWR6HFWLRQIRUVSHFLILFDVVHVVPHQWVDQGVSHFLILFWLPHSRLQWVWREHSHUIRUPHGDWHDFKWUHDWPHQWYLVLW
G
3UHGRVHYLWDOVLJQVLQFOXGHWKHWHPSHUDWXUHPHDVXUHPHQW
H
8ULQHSUHJQDQF\WHVWVKRXOGEHSHUIRUPHGDWWKHEHJLQQLQJRIWKHYLVLW
I
6SLURPHWU\DQGERG\SOHWK\VPRJUDSK\ZLOOEHPHDVXUHGDIWHUWKH+5&7VFDQLVWDNHQ
J
$WWKHPRPHQWRIWKLVPHDVXUHPHQWWKHVLJQDOIURPWKHUHVSLUDWLRQEHOWXVHGIRUWKHPHDVXUHPHQWRIWKH
LQKDODWLRQSURILOHGXULQJWKHVWXG\GUXJDGPLQLVWUDWLRQZLOODOVREHORJJHG
K
7KHWLPHSRLQWVDUHSUHIHUUHGWLPHSRLQWVWKHVLWHVKRXOGPDNHHYHU\HIIRUWWRUHVSHFWWKHWLPHSRLQWVDVJRRGDV
SRVVLEOH
L
:LOOEHSHUIRUPHGDWWKHEHJLQQLQJRIWKHYLVLW$W9LVLWWKHREWDLQHGPLQXWH)(9YDOXHZLOOEHXVHG
WRFKHFNWKHVWDELOLW\FULWHULD
Note:6LWHVKRXOGSODQWRSHUIRUPWKHVHDFWLYLWLHVVRDVQRWWRLQWHUIHUHZLWKFROOHFWLRQRIWLPHGDVVHVVPHQWV
VXFKDVVSLURPHWU\:KHUHGDWDFROOHFWLRQWLPHSRLQWVDUHFRQFXUUHQWYDULDEOHVPXVWEHFROOHFWHGLQWKH
IROORZLQJRUGHUPredose:8ULQHSUHJQDQF\WHVWVSLURPHWU\REWDLQLQJ)(9WRFKHFNVWDELOLW\FULWHULD
YLWDOVLJQV(&*FOLQLFDOODERUDWRU\DVVHVVPHQWVSUHGRVH&7VFDQVVSLURPHWU\ERG\SOHWK\VPRJUDSK\
LQKDODWLRQSURILOHPostdose:9LWDOVLJQV(&*


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
7DEOH 7LPHG$VVHVVPHQWVDW9LVLWDQG9LVLW

Visit 3 (Day 15 TP 1)
Visit 5 (Day 15 TP 2)
Clinical Variablea
Pre-dosing
Post-
dosing
Pre-dosing
Post-
dosing
-60 ming
-30 ming
90
ming
-60
ming
-30
ming
90 ming
9LWDO6LJQVEFG
;

;
;
X 
(&*EF
;
;
;
;
&OLQLFDO/DERUDWRU\7HVWLQJEF
;
8ULQHSUHJQDQF\WHVW
;K
;K
+5&76FDQVF

;H

;H
%RG\3OHWK\VPRJUDSK\F

;I

;I
6SLURPHWU\F
;

;I
;

;I

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
D
$WWKHVWDUWRIHDFKWUHDWPHQWYLVLWVXEMHFWPXVWZLWKKROGDOOLQKDOHG&23'PHGLFDWLRQVLQFOXGLQJVWXG\
PHGLFDWLRQUHVFXH9HQWROLQ+)$DQG,&6IRUDWOHDVWKRXUVSULRUWRVWDUWRIWHVWGD\SURFHGXUHV
E
7KLVLVQRWDWLPHGDVVHVVPHQW6LWHVVKRXOGSODQWRSHUIRUPWKHVHDFWLYLWLHVVRDVQRWWRLQWHUIHUHZLWK
FROOHFWLRQRIWLPHGDVVHVVPHQWVVXFKDVVSLURPHWU\
F
5HIHUWR6HFWLRQIRUVSHFLILFDVVHVVPHQWVDQGVSHFLILFWLPHSRLQWVWREHSHUIRUPHGDWHDFKWUHDWPHQWYLVLW
G
3UHGRVHYLWDOVLJQVLQFOXGHWKHWHPSHUDWXUHPHDVXUHPHQW
H
$WRQHEUHDWKLQJOHYHO7/&:LOOEHSHUIRUPHGEHIRUHWKHSRVWGRVHVSLURPHWU\DQGERG\SOHWK\VPRJUDSK\
I
6SLURPHWU\IROORZHGE\ERG\SOHWK\VPRJUDSK\ZLOOEHSHUIRUPHGDIWHUWKH+5&7VFDQVEXWZLWKLQPLQ
DIWHUGRVLQJ
J
7KHWLPHSRLQWVDUHSUHIHUUHGWLPHSRLQWVWKHVLWHVKRXOGPDNHHYHU\HIIRUWWRUHVSHFWWKHWLPHSRLQWVDVJRRG
DVSRVVLEOH1RQHRIWKHSRVWGRVHDVVHVVPHQWVZLOOVWDUWEHIRUHKRXUDIWHUWKHDGPLQLVWUDWLRQDQGDOO
DVVHVVPHQVWZLOOEHFRQFOXGHGZLWKLQKRXUVDIWHUGRVLQJ
K
8ULQHSUHJQDQF\WHVWVKRXOGEHSHUIRUPHGDWWKHEHJLQQLQJRIWKHYLVLW
Note6LWHVKRXOGSODQWRSHUIRUPWKHVHDFWLYLWLHVVRDVQRWWRLQWHUIHUHZLWKFROOHFWLRQRIWLPHGDVVHVVPHQWV
VXFKDVVSLURPHWU\:KHUHGDWDFROOHFWLRQWLPHSRLQWVDUHFRQFXUUHQWYDULDEOHVPXVWEHFROOHFWHGLQWKH
IROORZLQJRUGHU3UHGRVH8ULQHSUHJQDQF\WHVWVSLURPHWU\YLWDOVLJQV(&*FOLQLFDOODERUDWRU\DVVHVVPHQWV
3RVWGRVH9LWDOVLJQV(&*SRVWGRVH&7VFDQVSLURPHWU\ERG\SOHWK\VPRJUDSK\


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

8.1
9LVLW6FUHHQLQJ

2EWDLQLQIRUPHGFRQVHQWSULRUWRRUDWWKHEHJLQQLQJRI9LVLWSULRUWRFRQGXFWLQJDQ\
VWXG\UHODWHGSURFHGXUHV

'HWHUPLQHWLPHRIODVWGRVHRISURKLELWHG&23'PHGLFDWLRQDVGHILQHGLQWDEOH

6LWHZLOODVVLJQVXEMHFWVFUHHQLQJQXPEHU

5HYLHZLQFOXVLRQH[FOXVLRQFULWHULD

2EWDLQGHPRJUDSKLFGDWDLQFOXGLQJDJHUDFHVPRNLQJKLVWRU\PHGLFDOVXUJLFDOKLVWRU\
DQGDJHRIRQVHWRI&23'

2EWDLQPHGLFDWLRQKLVWRU\LQFOXGLQJ&23'PHGLFDWLRQV

&RQGXFWDXULQHSUHJQDQF\WHVWIRUDOOIHPDOHVXEMHFWVRIFKLOGEHDULQJSRWHQWLDOXQOHVVLW
LV GRFXPHQWHG LQ WKH PHGLFDO KLVWRU\ WKDW WKH VXEMHFW KDV EHHQ LUUHYHUVLEO\ VXUJLFDOO\
VWHULOL]HGK\VWHUHFWRP\RRSKRUHFWRP\RUELODWHUDOWXEDOOLJDWLRQRUWKH\DUHDWOHDVW
\HDUVSRVWPHQRSDXVDO

&RQGXFWDFRPSOHWHSK\VLFDOH[DPLQDWLRQRIUHOHYDQWERG\SDUWV

2EWDLQKHLJKWZHLJKWDQGYLWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRU
VHDWHGIRUPLQXWHVDQGRUDORUW\PSDQLFWHPSHUDWXUH

2EWDLQDOHDG(&*

2EWDLQ&$7DQG005&

&RQGXFWVSLURPHWU\DVVHVVPHQWVLQFOXGLQJ,&DQGGLIIXVLRQFDSDFLW\

3HUIRUPUHYHUVLELOLW\WHVWWR9HQWROLQ+)$UHIHUWR6HFWLRQIRULQVWUXFWLRQV
Note: &RQILUP VXEMHFW FRQWLQXHV WR PHHW HQWU\ FULWHULD EDVHG RQ SUH DQG SRVWGRVH
VSLURPHWU\TXDOLW\UHIHUWR6HFWLRQ

&RQILUPVXEMHFW¶VDELOLW\WRXVH0',FRUUHFWO\SURYLGHFRDFKLQJZLWKVSRQVRUSURYLGHG
SODFHER0',

,IVXEMHFWTXDOLILHVWRFRQWLQXHWR9LVLWSHUIRUPWKHIROORZLQJ

2EWDLQODERUDWRU\VDPSOHVKHPDWRORJ\FKHPLVWU\DQGXULQDO\VLV

,I&KHVW;UD\RU&7ZLWKLQPRQWKVRI9LVLW6FUHHQLQJLVQRWDYDLODEOHREWDLQ
DQHZ&KHVW;UD\

&KDQJH FRQFXUUHQW &23' PHGLFDWLRQV DV VSHFLILHG LQ SURWRFRO UHIHU WR 6HFWLRQ
6SRQVRUZLOOSURYLGH$WURYHQW+)$4,'IRU&23'PDLQWHQDQFHDQG9HQWROLQ
+)$DVQHHGHGIRUV\PSWRPDWLFUHOLHI

6FKHGXOH9LVLW

,QRUGHUWRDOORZIRUDQDGHTXDWHZDVKRXWRISUHYLRXVPDLQWHQDQFHPHGLFDWLRQVVXEMHFWV
ZLOOXQGHUJRDUXQLQSHULRGRIDWOHDVWZHHNEXWQRWJUHDWHUWKDQGD\VZHHNVLI
VXEMHFW LV WDNLQJ 6SLULYD RU RWKHU /RQJDFWLQJ DQWLFKROLQHUJLFV LQ GXUDWLRQ SULRU WR
UHWXUQLQJWRWKHFOLQLFIRU9LVLW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


'LVSHQVHDQGWUDLQVXEMHFWRQ'LDU\XVH

(QVXUH VXEMHFW KDV DGHTXDWH VXSSO\ RI VSRQVRUSURYLGHG $WURYHQW +)$ DQG
VSRQVRUSURYLGHGUHVFXH9HQWROLQ+)$

5HFRUG WKH QXPEHU RI DFWXDWLRQV RI WKH 9HQWROLQ FDQLVWHU DW WKH WLPH RI GLVSHQVLQJ
IROORZLQJSULPLQJDQGFKDUDFWHUL]DWLRQRIUHYHUVLELOLW\

6XEMHFWVZLOOEHLQVWUXFWHGWREULQJWKH'LDU\WKHVSRQVRUSURYLGHG9HQWROLQ+)$DQG
$WURYHQW+)$WRWKHQH[WVFKHGXOHGFOLQLFYLVLW

6XEMHFWVZLOOEHLQVWUXFWHGWRDGPLQLVWHUVSRQVRUSURYLGHG$WURYHQW+)$WKHPRUQLQJ
RI9LVLWKRXUVSULRUWRWKHDQWLFLSDWHGWLPHRIWKHSRVWGRVH&7VFDQ

$(VPXVWEHUHFRUGHGGXULQJWKHUXQLQSHULRGWKDWLVIURPWKHWLPHRIFRQVHQWWRWKH
VWDUWRIVWXG\WUHDWPHQW
Note:$(VWKDWRFFXUEHWZHHQWKHWLPHWKHVXEMHFWVLJQVWKH,&)IRUWKHVWXG\DQGWKH
WLPHZKHQWKDWVXEMHFWLVGRVHGZLWKVWXG\GUXJZLOOEHVXPPDUL]HGDVPHGLFDOKLVWRU\
DQGQRWDVDVWXG\$(XQOHVVWKHHYHQWPHHWVWKHGHILQLWLRQRID6$(
8.2
9LVLW5DQGRPL]DWLRQ'D\RI73

5HYLHZVXEMHFWGLDU\HQWULHVDQGUHWUDLQVXEMHFWLIVXEMHFWKDVQRWPHWGLDU\FRPSOLDQFH
UHTXLUHPHQWRI!VXEMHFWFRPSOHWLRQRIGLDU\DVVHVVPHQWV

&ROOHFWVSRQVRUSURYLGHG$WURYHQW+)$DQGVSRQVRUSURYLGHG9HQWROLQ+)$GLVSHQVHG
GXULQJWKH6FUHHQLQJUXQLQSHULRG

5HFRUGWKHQXPEHURIDFWXDWLRQVRIWKH9HQWROLQ+)$FDQLVWHU

'HWHUPLQH WLPH RI ODVW GRVH RI VKRUWDFWLQJ EURQFKRGLODWRU DQG RWKHU LQKDOHG &23'
PHGLFDWLRQV

5HYLHZDOOSULRUPHGLFDWLRQVDQGHQVXUHDGKHUHQFHWR&23'UHJLPHQ

5HYLHZLQFOXVLRQH[FOXVLRQFULWHULDDQGFRQILUPVXEMHFWHOLJLELOLW\WRFRQWLQXH

,I QRW SUHYLRXVO\ UHYLHZHG UHYLHZ RI FOLQLFDO ODERUDWRU\ UHVXOWV IURP 9LVLW 
3OHDVHQRWHZKHWKHU WKH UHVXOWV DUH FOLQLFDOO\ VLJQLILFDQW DQG LQFOXGH FRPPHQWV ZKHUH
DSSOLFDEOH
Note:6XEMHFWVZLWKDFDOFXODWHGFUHDWLQLQHFOHDUDQFHPOPLQPAHVWLPDWHG
XVLQJWKH0RGLILFDWLRQRI'LHWLQ5HQDO'LVHDVH(TXDWLRQH*)50'5'DW9LVLWDQGRQ
UHSHDWWHVWLQJSULRUWR9LVLWZLOOEHH[FOXGHG

5HFRUG$(VLIDQ\
Note:$(VWKDWRFFXUGXULQJWKHUXQLQSHULRG9LVLWWR9LVLWZLOOEHVXPPDUL]HGDV
PHGLFDOKLVWRU\DQGQRWDVDVWXG\$(XQOHVVWKHHYHQWPHHWVWKHGHILQLWLRQRID6$(
x
8SGDWHPHGLFDOKLVWRU\LIQHHGHG
x
8SGDWHVPRNLQJVWDWXVLIQHHGHG
x
&RQGXFWDXULQHSUHJQDQF\WHVWIRUDOOIHPDOHVXEMHFWVRIFKLOGEHDULQJSRWHQWLDOXQOHVVLW
LV GRFXPHQWHG LQ WKH PHGLFDO KLVWRU\ WKDW WKH VXEMHFW KDV EHHQ LUUHYHUVLEO\ VXUJLFDOO\

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

VWHULOL]HGK\VWHUHFWRP\RRSKRUHFWRP\RUELODWHUDOWXEDOOLJDWLRQRUWKH\DUHDWOHDVW
\HDUVSRVWPHQRSDXVDO
x
3HUIRUPDOOSUHGRVHDVVHVVPHQWVUHIHUWR7DEOH
x
2EWDLQ6SLURPHWU\EDVHOLQH)(9ZLOOEHREWDLQHG
x
2EWDLQ9LWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRUVHDWHGIRU
PLQXWHVDQGRUDORUW\PSDQLFWHPSHUDWXUH
x
2EWDLQOHDG(&*
x
2EWDLQODERUDWRU\VDPSOHVKHPDWRORJ\FKHPLVWU\DQGXULQDO\VLV
x
2EWDLQ+5&7VFDQV7/&)5&8$
Note:5HYLHZLQFOXVLRQH[FOXVLRQFULWHULDUHSHDWWHVWLQJRIWKHFUHDWLQLQHFOHDUDQFHSULRU
WR9LVLWLIQHFHVVDU\&UHDWQLQHFOHDUDQFHHOLJLELOLW\PXVWEHNQRZQEHIRUHWKH+5&7
VFDQFDQEHWDNHQ
x
2EWDLQ6SLURPHWU\LQFOXGLQJ,&
x
2EWDLQERG\SOHWK\VPRJUDSK\
x
2EWDLQ,QKDODWLRQ3URILOHERG\SOHWK\VPRJUDSKZKLOHZHDULQJUHVSLUDWLRQEHOWV
x
2EWDLQVXEMHFWUDQGRPL]DWLRQQXPEHUDQGWUHDWPHQWDVVLJQPHQWLQIRUPDWLRQ7KHVXEMHFW
LVWREHFRQVLGHUHGUDQGRPL]HGDIWHUUHFHLYLQJDUDQGRPL]DWLRQQXPEHU
x
7RDOORZIRUSURSHUSUHSDUDWLRQRIVWXG\GUXJLWLVUHFRPPHQGHGWKDWWKHVHDODURXQGWKH
VWXG\GD\WUHDWPHQWER[LVRSHQHGPLQXWHVSULRUWRGRVLQJDQGWKHLQVWUXFWLRQVIRU
DGPLQLVWUDWLRQRIVWXG\GUXJIROORZHG5HIHUWR6HFWLRQIRUGHWDLOHGLQVWUXFWLRQVIRU
SUHSDUDWLRQRIWUHDWPHQWVIRUDGPLQLVWUDWLRQ7KHVHLQVWUXFWLRQVDUHWREHDGKHUHGWRDQG
DUHUHOHYDQWWRDOOVWXG\WUHDWPHQWYLVLWV

5HFRUGGRFXPHQWWKHGRVHLQGLFDWRUUHDGLQJ7KHGRVHLQGLFDWRUFRXQWUHFRUGHGE\WKH
VLWHVWDIIRQ 'D\RIWKH73ZLOOEH DIWHUSULPLQJWKHPHGLFDWLRQSULRUWRWKH ILUVW
GRVLQJDQGDIWHUWKHILUVWGRVLQJ5HIHUWR6HFWLRQIRUPRUHGHWDLOV

6XEMHFW ZLOO DGPLQLVWHU ILUVW GRVH RI QHZO\ DVVLJQHG VWXG\ GUXJ DW WKH FOLQLF 'XULQJ
GRVLQJWKHLQKDODWLRQSURILOHZLWKWKHUHVSLUDWLRQEHOWVZLOOEHUHFRUGHG

5HFRUGGRFXPHQWWKHGRVHLQGLFDWRUUHDGLQJDIWHUVXEMHFWGRVLQJ

6XEMHFWZLOOEHLQVWUXFWHGWRGRVHZKLOHDWKRPHIURPWKHVLWHSULPHG0',onlyXQOHVV
DOORIWKHIROORZLQJreplacement conditionsDUHPHW

'RVH LQGLFDWRU LV LQ WKH UHG ]RQH UHIHU WR $SSHQGL[  IRU GRVH LQGLFDWRU UHDGLQJ
LQVWUXFWLRQV

7KH GRVH LQGLFDWRU UHJLVWHUV  SXIIV UHPDLQLQJ and WKHLU QH[W VFKHGXOHG VWXG\
FOLQLFYLVLWLVQRWWKHIROORZLQJGD\
,I WKHVH UHSODFHPHQW FRQGLWLRQV DUH PHW VXEMHFWV ZLOO EH LQVWUXFWHG WR RSHQ WKHLU
UHSODFHPHQW NLW SULPH WKH 0', DQG VWDUW XVLQJ IRU DW KRPH GRVLQJ XQWLO WKH QH[W
VFKHGXOHGVWXG\FOLQLFYLVLW

3HUIRUPDOOSRVWGRVLQJDVVHVVPHQWVUHIHUWR7DEOH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


2EWDLQ SRVWGRVH 9LWDO VLJQV KHDUW UDWH DQG EORRG SUHVVXUH DIWHU EHLQJ VXSLQH RU
VHDWHGIRUPLQXWHV

2EWDLQSRVWGRVHOHDG(&*

6FKHGXOH9LVLW
Note:9LVLWVKRXOGEHVFKHGXOHGDWPLQLPXPGD\VDIWHU9LVLWDQGQRODWHUWKDQ
GD\VDIWHU9LVLW

(QVXUH VXEMHFW KDV DGHTXDWH VXSSO\ RI VWXG\ PHGLFDWLRQ LQFOXGLQJ VSRQVRUSURYLGHG
UHVFXH9HQWROLQ+)$

6XEMHFWV ZLOO EH LQVWUXFWHG WR EULQJ DOO VWXG\ PHGLFDWLRQ LQFOXGLQJ XVHG VWXG\ GUXJ
UHSODFHPHQW0',NLWDQGVSRQVRUSURYLGHGUHVFXH9HQWROLQ+)$DQGWKH'LDU\WRWKH
QH[WVFKHGXOHGFOLQLFYLVLW
8.3
9LVLW'D\GD\VRI73

'HWHUPLQH WLPH RI ODVW GRVH RI VKRUWDFWLQJ EURQFKRGLODWRU DQG RWKHU LQKDOHG &23'
PHGLFDWLRQVLIKRXUVWKHYLVLWPXVWEHUHVFKHGXOHG

&RQILUPWKHVXEMHFWWRRNWKHLUODVWGRVHRIUDQGRPL]HGVWXG\PHGLFDWLRQDVVFKHGXOHGWKH
SULRUHYHQLQJ

5HFRUGGRFXPHQWWKHGRVHLQGLFDWRUUHDGLQJRIWKHXVHG0',

5HFRUGWKHQXPEHURIDFWXDWLRQVRIWKH9HQWROLQ+)$FDQLVWHU

5HFRUG&23'H[DFHUEDWLRQVDQG$(VLIDQ\

5HYLHZDOOFRQFRPLWDQWPHGLFDWLRQVDQGHQVXUHDGKHUHQFHWR&23'UHJLPHQ

8SGDWHVPRNLQJVWDWXVLIQHHGHG

5HYLHZVXEMHFWGLDU\HQWULHV

&RQGXFW D XULQH SUHJQDQF\ WHVW IRU DOO IHPDOH VXEMHFWV XQOHVV LW LV GRFXPHQWHG LQ WKH
PHGLFDOKLVWRU\WKDWWKHVXEMHFWKDVEHHQLUUHYHUVLEO\VXUJLFDOO\VWHULOL]HGK\VWHUHFWRP\
RRSKRUHFWRP\RUELODWHUDOWXEDOOLJDWLRQRUWKH\DUHDWOHDVW\HDUVSRVWPHQRSDXVDO

3HUIRUPDOOSUHGRVHDVVHVVPHQWVUHIHUWR7DEOH
x
2EWDLQ9LWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRUVHDWHGIRU
PLQXWHVDQGRUDORUW\PSDQLFWHPSHUDWXUH
x
2EWDLQOHDG(&*
x
2EWDLQODERUDWRU\VDPSOHVKHPDWRORJ\FKHPLVWU\DQGXULQDO\VLV
x
2EWDLQ6SLURPHWU\LQFOXGLQJ,&
x
$GPLQLVWHUODVWLQFOLQLFVWXG\GUXJGRVHRI73
x
3HUIRUP DOO SRVWGRVLQJ DVVHVVPHQWV UHIHU WR 7DEOH  $OO SRVWGRVH DVVHVVPHQWV
PXVWEHSHUIRUPHGEHWZHHQWRKRXUVDIWHUGUXJDGPLQLVWUDWLRQ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

x
2EWDLQ9LWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRUVHDWHGIRU
PLQXWHV
x
2EWDLQOHDG(&*
x
2EWDLQ+5&7VFDQ7/&
x
2EWDLQ6SLURPHWU\LQFOXGLQJ,&
x
2EWDLQERG\SOHWK\VPRJUDSK\

6FKHGXOH9LVLW
Note:9LVLWVKRXOGEHVFKHGXOHGDWPLQLPXPGD\VDIWHU9LVLWDQGQRODWHUWKDQ
GD\VDIWHU9LVLW

(QVXUH VXEMHFW KDV DGHTXDWH VXSSO\ RI VSRQVRUSURYLGHG $WURYHQW +)$ DQG VSRQVRU
SURYLGHGUHVFXH9HQWROLQ+)$

6XEMHFWVZLOOEHLQVWUXFWHGWREULQJWKH'LDU\WKHVSRQVRUSURYLGHG$WURYHQW+)$DQG
9HQWROLQ+)$WRWKHQH[WVFKHGXOHGFOLQLFYLVLW

6XEMHFWVZLOOEHLQVWUXFWHGWRDGPLQLVWHUVSRQVRUSURYLGHG$WURYHQW+)$WKHPRUQLQJ
RI9LVLWKRXUVSULRUWRWKHDQWLFLSDWHGWLPHRIWKHSRVWGRVH&7VFDQ
8.4
9LVLW'D\RI73

&ROOHFWVSRQVRUSURYLGHG$WURYHQW+)$DQGVSRQVRUSURYLGHG9HQWROLQ+)$GLVSHQVHG
GXULQJWKHZDVKRXWSHULRG

5HFRUGWKHQXPEHURIDFWXDWLRQVRIWKH9HQWROLQ+)$FDQLVWHU

'HWHUPLQHWLPHRIODVWGRVHRIVKRUWDFWLQJEURQFKRGLODWRUDQGRWKHU&23'PHGLFDWLRQV

5HYLHZDOOFRQFRPLWDQWPHGLFDWLRQVDQGHQVXUHDGKHUHQFHWR&23'UHJLPHQ

8SGDWHVPRNLQJVWDWXVLIQHHGHG

5HYLHZLQFOXVLRQH[FOXVLRQFULWHULDDQGFRQILUPVXEMHFWHOLJLELOLW\WRFRQWLQXH

5HFRUG&23'H[DFHUEDWLRQVDQG$(VLIDQ\
x
&RQGXFWDXULQHSUHJQDQF\WHVWIRUDOOIHPDOHVXEMHFWVRIFKLOGEHDULQJSRWHQWLDOXQOHVVLW
LV GRFXPHQWHG LQ WKH PHGLFDO KLVWRU\ WKDW WKH VXEMHFW KDV EHHQ LUUHYHUVLEO\ VXUJLFDOO\
VWHULOL]HGK\VWHUHFWRP\RRSKRUHFWRP\RUELODWHUDOWXEDOOLJDWLRQRUWKH\DUHDWOHDVW
\HDUVSRVWPHQRSDXVDO
x
&RPSOHWHDOOSUHGRVHDVVHVVPHQWVUHIHUWR7DEOH
x
2EWDLQ6SLURPHWU\
Note&RQILUPLISDWLHQWPHHWVVWDELOLW\UHTXLUHPHQWVLIQRWWKHYLVLWPD\EHUHVFKHGXOHG
ZLWKLQWKHDOORZHGYLVLWZLQGRZDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQRUWKHVXEMHFWPD\EH
GLVFRQWLQXHG
x
2EWDLQ9LWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRUVHDWHGIRU
PLQXWHVDQGRUDORUW\PSDQLFWHPSHUDWXUH
x
2EWDLQOHDG(&*

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

x
2EWDLQODERUDWRU\VDPSOHVKHPDWRORJ\FKHPLVWU\DQGXULQDO\VLV
x
2EWDLQ+5&7VFDQV7/&)5&
Note:5HYLHZLQFOXVLRQH[FOXVLRQFULWHULDEHIRUHWKH+5&7VFDQFDQEHWDNHQ
x
2EWDLQ6SLURPHWU\LQFOXGLQJ,&
x
2EWDLQERG\SOHWK\VPRJUDSK\
x
2EWDLQLQKDODWLRQSURILOHERG\SOHWK\VPRJUDSKZKLOHZHDULQJUHVSLUDWLRQEHOWV

7RDOORZIRUSURSHUSUHSDUDWLRQRIVWXG\GUXJLWLVUHFRPPHQGHGWKDWWKHVHDODURXQGWKH
VWXG\GD\WUHDWPHQWER[LVRSHQHGPLQXWHVSULRUWRGRVLQJDQGWKHLQVWUXFWLRQVIRU
DGPLQLVWUDWLRQRIVWXG\GUXJIROORZHG5HIHUWR6HFWLRQIRUGHWDLOHGLQVWUXFWLRQVIRU
SUHSDUDWLRQRIWUHDWPHQWVIRUDGPLQLVWUDWLRQ7KHVHLQVWUXFWLRQVDUHWREHDGKHUHGWRDQG
DUHUHOHYDQWWRDOOVWXG\WUHDWPHQWYLVLWV

5HFRUGGRFXPHQWWKHGRVHLQGLFDWRUUHDGLQJ7KHGRVHLQGLFDWRUFRXQWUHFRUGHGE\WKH
VLWHVWDIIZLOOEHGRVHLQGLFDWRUFRXQWREVHUYHGDIWHUSULPLQJWKHPHGLFDWLRQDQGSULRU
VXEMHFWGRVLQJ5HIHUWR6HFWLRQIRUPRUHGHWDLOV

6XEMHFW ZLOO DGPLQLVWHU ILUVW GRVH RI QHZO\ DVVLJQHG VWXG\ GUXJ DW WKH FOLQLF 'XULQJ
GRVLQJWKHLQKDODWLRQSURILOHZLWKWKHUHVSLUDWLRQEHOWVZLOOEHUHFRUGHG

5HFRUGGRFXPHQWWKHGRVHLQGLFDWRUUHDGLQJDIWHUVXEMHFWGRVLQJ

6XEMHFWZLOOEHLQVWUXFWHGWRGRVHZKLOHDWKRPHIURPWKHVLWHSULPHG0',onlyXQOHVV
DOORIWKHIROORZLQJreplacement conditionsDUHPHW

'RVH LQGLFDWRU LV LQ WKH UHG ]RQH UHIHU WR $SSHQGL[  IRU GRVH LQGLFDWRU UHDGLQJ
LQVWUXFWLRQV

7KH GRVH LQGLFDWRU UHJLVWHUV  SXIIV UHPDLQLQJ and WKHLU QH[W VFKHGXOHG VWXG\
FOLQLFYLVLWLVQRWWKHIROORZLQJGD\
,I WKHVH UHSODFHPHQW FRQGLWLRQV DUH PHW VXEMHFWV ZLOO EH LQVWUXFWHG WR RSHQ WKHLU
UHSODFHPHQW NLW SULPH WKH 0', DQG VWDUW XVLQJ IRU DW KRPH GRVLQJ XQWLO WKH QH[W
VFKHGXOHGVWXG\FOLQLFYLVLW

3HUIRUPDOOSRVWGRVLQJDVVHVVPHQWVUHIHUWR7DEOH

2EWDLQ9LWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRUVHDWHGIRU
PLQXWHV

2EWDLQOHDG(&*

6FKHGXOH9LVLW
Note:9LVLWVKRXOGEHVFKHGXOHGDWPLQLPXPGD\VDIWHU9LVLWDQGQRODWHUWKDQ
GD\VDIWHU9LVLW

(QVXUHVXEMHFWKDVDGHTXDWHVXSSO\RIDOOVWXG\PHGLFDWLRQLQFOXGLQJVSRQVRUSURYLGHG
UHVFXH9HQWROLQ+)$

6XEMHFWV ZLOO EH LQVWUXFWHG WR EULQJ DOO VWXG\ PHGLFDWLRQ LQFOXGLQJ XVHG VWXG\ GUXJ
UHSODFHPHQW 0', NLW DQG UHVFXH 9HQWROLQ +)$ DQG WKH 'LDU\ WRWKH QH[W VFKHGXOHG
FOLQLFYLVLW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


8.5
9LVLW'D\GD\VRI73

'HWHUPLQH WLPH RI ODVW GRVH RI VKRUWDFWLQJ EURQFKRGLODWRU DQG RWKHU LQKDOHG &23'
PHGLFDWLRQVLIKRXUVWKHYLVLWPXVWEHUHVFKHGXOHG

&RQILUPWKHVXEMHFWWRRNWKHLUODVWGRVHRIUDQGRPL]HGVWXG\PHGLFDWLRQDVVFKHGXOHGWKH
SULRUHYHQLQJ

5HFRUGGRFXPHQWWKHGRVHLQGLFDWRUUHDGLQJRIWKHXVHG0',

5HFRUGWKHQXPEHURIDFWXDWLRQVRIWKH9HQWROLQ+)$FDQLVWHU

5HFRUG&23'H[DFHUEDWLRQVDQG$(VLIDQ\

5HYLHZDOOFRQFRPLWDQWPHGLFDWLRQVDQGHQVXUHDGKHUHQFHWR&23'UHJLPHQ

8SGDWHVPRNLQJVWDWXVLIQHHGHG

5HYLHZVXEMHFWGLDU\HQWULHV

&RQGXFW D XULQH SUHJQDQF\ WHVW IRU DOO IHPDOH VXEMHFWV XQOHVV LW LV GRFXPHQWHG LQ WKH
PHGLFDOKLVWRU\WKDWWKHVXEMHFWKDVEHHQLUUHYHUVLEO\VXUJLFDOO\VWHULOL]HGK\VWHUHFWRP\
RRSKRUHFWRP\RUELODWHUDOWXEDOOLJDWLRQRUWKH\DUHDWOHDVW\HDUVSRVWPHQRSDXVDO

3HUIRUPDOOSUHGRVHDVVHVVPHQWVUHIHUWR7DEOH
x
2EWDLQ9LWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRUVHDWHGIRU
PLQXWHVDQGRUDORUW\PSDQLFWHPSHUDWXUH
x
2EWDLQOHDG(&*
x
2EWDLQODERUDWRU\VDPSOHVKHPDWRORJ\FKHPLVWU\DQGXULQDO\VLV
x
2EWDLQ6SLURPHWU\LQFOXGLQJ,&
x
$GPLQLVWHULQFOLQLFODVWVWXG\GUXJGRVHRI73
x
3HUIRUP DOO SRVWGRVLQJ DVVHVVPHQWV UHIHU WR 7DEOH  $OO SRVWGRVH DVVHVVPHQWV
PXVWEHSHUIRUPHGEHWZHHQWRKRXUVDIWHUGUXJDGPLQLVWUDWLRQ
x
2EWDLQ9LWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHUEHLQJVXSLQHRUVHDWHGIRU
PLQXWHV
x
2EWDLQOHDG(&*
x
2EWDLQ+5&7VFDQ7/&
x
2EWDLQ6SLURPHWU\LQFOXGLQJ,&
x
2EWDLQERG\SOHWK\VPRJUDSK\
x
&RQGXFWDFRPSOHWHSK\VLFDOH[DPLQDWLRQRIUHOHYDQWERG\SDUWV

6FKHGXOHDIROORZXS7&WRGD\VSRVWODVWVWXG\GUXJGRVLQJ

&ROOHFWDOOVWXG\PHGLFDWLRQLQFOXGLQJVSRQVRUSURYLGHG9HQWROLQ+)$

$W FRPSOHWLRQ RI DOO 9LVLW  DVVHVVPHQWV UHWXUQ VXEMHFW WR SUHVWXG\ RU DSSURSULDWH
PDLQWHQDQFH&23'PHGLFDWLRQV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

8.6
8QVFKHGXOHG9LVLW3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW
5HSHDWDVVHVVPHQWVLIQHHGHGZLOOEHFDSWXUHGLQXQVFKHGXOHGYLVLWV
3UHPDWXUH 'LVFRQWLQXDWLRQV 9LVLWV ZLOO EH FDSWXUHG DV XQVFKHGXOHG YLVLWV 7KH IROORZLQJ
PLQLPXPSURFHGXUHVVKRXOGEHFRPSOHWHGDWWKH3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW

5HFRUG&23'H[DFHUEDWLRQVDQG$(VLIDQ\

5HYLHZFRQFRPLWDQWPHGLFDWLRQV

&RQGXFWDSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVKHDUWUDWHDQGEORRGSUHVVXUHDIWHU
EHLQJVXSLQHRUVHDWHGIRUPLQXWHVDQGRUDORUW\PSDQLFWHPSHUDWXUH

3HUIRUP(&*DQGFROOHFWEORRGVDPSOHVIRUKHPDWRORJ\DQGFKHPLVWU\

&ROOHFWDXULQHVDPSOHIRUXULQDO\VLVIRUODEVDIHW\

&RQGXFWDXULQHSUHJQDQF\WHVWIRUDOOIHPDOHVXEMHFWVRIFKLOGEHDULQJSRWHQWLDO

&ROOHFWDOOVWXG\GUXJV

,QIRUPVXEMHFWDERXWUHSRUWLQJDOO6$(VXSWRGD\VIROORZLQJWKHODVWGRVHRIVWXG\
GUXJ

5HWXUQVXEMHFWWRSUHVWXG\RUDSSURSULDWHPDLQWHQDQFH&23'PHGLFDWLRQV

&DSWXUHWKHVXEMHFWGLVFRQWLQXDWLRQUHDVRQ

6FKHGXOHDIROORZXS7&GD\VSRVWODVWVWXG\GUXJGRVLQJ,IWKHGLVFRQWLQXDWLRQYLVLW
LVSHUIRUPHG!GD\VSRVWODVWVWXG\GUXJGRVLQJDIROORZXS7&ZLOOQRWEHUHTXLUHG
8.7
)ROORZ8S7HOHSKRQH&DOO
6XEMHFWV ZLOO EH IROORZHGXS WKURXJK WHOHSKRQH FRQWDFW  WR  GD\V SRVW ODVW VWXG\ GUXJ
GRVLQJ7KHIROORZLQJLQIRUPDWLRQZLOOEHUHTXHVWHG

5HYLHZSUHYLRXVO\RQJRLQJ6$(VDQGUHFRUGQHZ6$(VLIDQ\

5HYLHZFRQFRPLWDQWPHGLFDWLRQV

5HYLHZVPRNLQJVWDWXV
8.8
&RPSOHWLRQRIWKH6WXG\
7KH ,QYHVWLJDWRU ZLOO GRFXPHQW WKH FRPSOHWLRQ RU WKH UHDVRQ IRU HDUO\ ZLWKGUDZDO E\ D
VXEMHFWLQWKH H&5)7KHIROORZLQJ FDWHJRULHV VKRXOG EH XVHG WRGHVFULEHWKHVHHYHQWVLQ
WKHH&5)

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


6XEMHFWGLVFUHWLRQGRFXPHQWUHDVRQ

,QYHVWLJDWRUFRQVLGHUVLWWREHLQWKHEHVWLQWHUHVWRIWKHVXEMHFW

$(V

$GPLQLVWUDWLYHUHDVRQVHJHDUO\WHUPLQDWLRQRIWKHVWXG\

6XEMHFWORVWWRIROORZXS

/DFNRIHIILFDF\

0DMRUSURWRFROYLRODWLRQ

'HDWK

&RPSOHWLRQRIWKHVWXG\

3URWRFROVSHFLILHGFULWHULDVXFKDVKHDUWUDWHV\VWROLFRUGLDVWROLFEORRGSUHVVXUHRUXVH
RISURKLELWHGPHGLFDWLRQVUHIHUWR6HFWLRQ



















*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI



PLANNED STATISTICAL METHODS 
9.1
,QWURGXFWLRQ
7KLVVWXG\ZLOOEHFRQGXFWHGDVDVLQJOHFHQWHUUDQGRPL]HGGRXEOHEOLQG*))DQG3ODFHER
0',VWZRWUHDWPHQWSHULRGFKURQLFGRVLQJZHHNVWZRWUHDWPHQWDQGFURVVRYHUGHVLJQ
HYDOXDWLQJWKHIROORZLQJWZRWUHDWPHQWVLQDSSUR[LPDWHO\VXEMHFWV

*))0',J%,'

3ODFHER0',%,'

7KH SULPDU\ REMHFWLYH RI WKLV VWXG\ LV WR DVVHVV WKH HIIHFW RI WUHDWPHQW ZLWK *)) 0',
 ȝJ H[ DFWXDWRU %,' UHODWLYH WR 3ODFHER 0', RQ VSHFLILF LPDJH EDVHG DLUZD\
YROXPHVDQGUHVLVWDQFHLQVXEMHFWVZLWKPRGHUDWHWRVHYHUH&23'
9.2
3URWRFRO9DULDEOHV
9.2.1
(IILFDF\(QGSRLQWV
7KHILUVWGD\RIWUHDWPHQWLQHDFK73LV'D\(DFK73LVSODQQHGWRFRQWDLQGD\V
GD\VEHWZHHQWKHILUVWDQGODVWGRVHFRUUHVSRQGLQJWRDVSDQRIFDOHQGDUGD\V7KHUHIRUH
DVVHVVPHQWVFROOHFWHGRQ'D\9LVLWVDQGZLOORFFXUIROORZLQJGD\VRIWUHDWPHQW
$OO)5,VSLURPHWU\DQGERG\SOHWK\VPRJUDSK\HQGSRLQWVZLOOXWLOL]HFKDQJHVIURPEDVHOLQH
9.2.1.1
3ULPDU\(IILFDF\(QGSRLQWVRQ'D\DQG'D\H[FHSWDV
RWKHUZLVHQRWHG
FRI Parameters:

VL9DZ

VL5DZ

9.2.1.2
6HFRQGDU\(IILFDF\(QGSRLQWVPHDVXUHGRQ'D\DQG'D\
H[FHSWDVRWKHUZLVHQRWHG
FRI Parameters:

$LUZD\YROXPHL9DZ

$LUZD\UHVLVWDQFHL5DZ

Spirometry Parameters:

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


)RUFHGH[SLUDWRU\YROXPHLQRQHVHFRQG)(9

Body Plethysmography Parameters: 

)5&

9.2.1.3
2WKHU(IILFDF\(QGSRLQWVPHDVXUHGRQ'D\DQG'D\H[FHSW
DVRWKHUZLVHQRWHG
FRI Parameters:

/REHYROXPHVL9OREHV

$LUWUDSSLQJ

,QWHUQDOOREDUDLUIORZGLVWULEXWLRQ

/RZDWWHQXDWLRQRUHPSK\VHPDVFRUH

%ORRGYHVVHOGHQVLW\RUILEURVLVVFRUH

$LUZD\ZDOOWKLFNQHVV

0DVVRIGHSRVLWHGSDUWLFOHVSHUGHILQHGDLUZD\VHFWLRQ

Spirometry Parameters:

)RUFHGYLWDOFDSDFLW\)9&

7LIIHQHDXLQGH[)(9)9&UDWLR

)RUFHGH[SLUDWRU\IORZ)()

,QVSLUDWRU\FDSDFLW\,&

Body Plethysmography Parameters: 

5HVLGXDOYROXPH59

7/&

$LUZD\UHVLVWDQFH5DZ

6SHFLILFDLUZD\UHVLVWDQFHV5DZ

6SHFLILFDLUZD\FRQGXFWDQFHV*DZ



*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

9.2.1.4
6DIHW\(QGSRLQWV

$(V

9.3
(IILFDF\$QDO\VHV
9.3.1
(IILFDF\$QDO\VLV
)RUWKHHIILFDF\DQDO\VHVWKHQXOOK\SRWKHVLVIRUHDFKSDLUZLVHFRPSDULVRQZLOOEHWKDWWKH
PHDQ*))0',WUHDWPHQWHIIHFWLVHTXDOWRWKDWRI3ODFHER0',WKHDOWHUQDWLYHK\SRWKHVLVLV
WKHQ WKDW WKH *)) 0', WUHDWPHQW HIIHFW DQG WKDW RI 3ODFHER 0', RUDQLQGLYLGXDO
FRPSRQHQWDUHQRWHTXDO3YDOXHVZLOOWKXVEHUHSRUWHGDVWZRVLGHG7KHHIIHFWLVGHILQHG
DVWKHGLIIHUHQFHEHWZHHQWKHYDOXHDW'D\GD\VDQGWKHYDOXHDW'D\(IIHFWLV
WKXV GHILQHG DV WKH FKDQJH IURP EDVHOLQH WR SODFHER IRU D SODFHER WUHDWPHQW DQG DV WKH
FKDQJHIURPEDVHOLQHWR*))0',IRUD*))0',WUHDWPHQW7KHQXOO+DQGDOWHUQDWLYH
+K\SRWKHVHVZLWKUHSUHVHQWLQJWKHPHDQYDOXHRIWKHHIIHFWDUH
+*)) SODFHER
+*))SODFHER
)RUHDFKSDUDPHWHULQHDFKJURXSSULPDU\HIILFDF\HQGSRLQWV)5,VHFRQGDU\HIILFDF\
HQGSRLQWV)5,VSLURPHWU\DQGERG\SOHWK\VPRJUDSK\RWKHUHIILFDF\HQGSRLQWVDOO)5,
SDUDPHWHUVH[FHSWWKHPDVVRIGHSRVLWHGSDUWLFOHVVSLURPHWU\DQGERG\SOHWK\VPRJUDSK\
WKLVQXOOK\SRWKHVLVZLOOEHWHVWHG$OLQHDUPL[HGPRGHODSSURDFKZLOOEHFKRVHQDQG
VSHFLILHGIXOO\LQWKHVWDWLVWLFDODQDO\VLVSODQ

,QRUGHUWRJDLQH[WUDLQVLJKWVLQWKHPRGHRIDFWLRQRIWKHSURGXFWDGGLWLRQDOH[SORUDWRU\
DQDO\VHVFDQEHH[HFXWHGXVLQJUREXVWOLQHDUUHJUHVVLRQRUPL[HGPRGHOV

7KH,QWHQWWR7UHDW,773RSXODWLRQZLOOEHFRQVLGHUHGWKHSULPDU\DQDO\VLVSRSXODWLRQIRU
HIILFDF\6XSSRUWLYHDQDO\VHVZLOOEHFRQGXFWHGZLWKWKH0RGLILHG,QWHQWWR7UHDWP,77
3RSXODWLRQ
9.3.2
&RQWURORI7\SH,HUURU
)RUWKHSULPDU\HIILFDF\HQGSRLQWV+RFKEHUJ
VVWHSXSSURFHGXUHZLOOEHXVHGDVPXOWLSOLFLW\
DGMXVWPHQW 1R FRUUHFWLRQ ZLOO EH SHUIRUPHG IRU WKH VHFRQGDU\ DQG WKH RWKHU HIILFDF\
HQGSRLQWV

9.3.3
6DIHW\$QDO\VLV
9.3.3.1
$GYHUVH(YHQWV
$GYHUVHHYHQWVGXULQJHDFK73ZLOOEHVXPPDUL]HGE\WKHQXPEHURIVXEMHFWVH[SHULHQFLQJ
DQ HYHQW 7DEXODWLRQV ZLOO EH EURNHQ GRZQ E\ VHYHULW\ VHULRXVQHVV $(V OHDGLQJ WR
GLVFRQWLQXDWLRQDQGE\ UHODWLRQVKLSWRVWXG\GUXJ1RK\SRWKHVLVWHVWVZLOOEHSHUIRUPHG
7DEOHVZLOOVKRZWKHRYHUDOOLQFLGHQFHRI$(VDQGWKHLQFLGHQFHIRUHDFKWUHDWPHQW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


Note:$Q\FOLQLFDOO\UHOHYDQWILQGLQJVIURP(&*VFOLQLFDOODERUDWRU\WHVWVHJ+HPDWRORJ\
&OLQLFDO&KHPLVWU\RUYLWDOVLJQPHDVXUHPHQWVZLOOEHUHSRUWHGDVDGYHUVHHYHQWV
9.4
5DQGRPL]DWLRQ
6XEMHFWVZLOOEHUDQGRPO\DVVLJQHGWRRQHRIWZRWUHDWPHQWVHTXHQFHVLQDEORFNVL]HRIIRU
WKHWZRVHTXHQFHV(DFKVHTXHQFHZLOOLQFOXGHH[DFWO\RQHRIWKHWZRWUHDWPHQWJURXSV
LQFOXGHGLQWKLVVWXG\SHU73$OOVXEMHFWVZLOOUHFHLYH*))0',ȝJDQG3ODFHER
0',
7KHWZRWUHDWPHQWVHTXHQFHVDUHVKRZQEHORZ

7DEOH 5DQGRPL]DWLRQ6FKHGXOH


Treatment period 1
Treatment period 2
Treatment sequence 1 
*))0',37
JH[DFWXDWRU
3ODFHER0',
Treatment sequence 2
3ODFHER0',
*))0',37
JH[DFWXDWRU

9.5
([SHULPHQWDOGHVLJQ
7KHH[SHULPHQWDOGHVLJQZDVFKRVHQWREHEDODQFHGZLWKUHVSHFWWRSHULRGDQGILUVWRUGHU
FDUU\RYHUHIIHFWV
9.6
6DPSOH6L]H&RQVLGHUDWLRQ
,QDGRXEOHEOLQGFURVVRYHUVWXG\ZKHUH&23'*OREDO,QLWLDWLYHIRU&KURQLF2EVWUXFWLYH
/XQJ'LVHDVH*2/',,,VXEMHFWVUHFHLYHGDEXGHVRQLGHIRUPRWHUROFRPELQDWLRQ)5,ZDV
DEOHWRTXDQWLI\WKHHIIHFWVRIWKHDFWLYHFRPSRXQGUHODWLYHWRSODFHER$VDPSOHVL]H
FDOFXODWLRQSRZHUJRDODOSKDUHYHDOHGWKDWLQRUGHUWRKDYHDZHOOSRZHUHGVWXG\
ZLWKFKDQJHLQLPDJLQJEDVHGDLUZD\YROXPHDVSULPDU\RXWFRPHSDUDPHWHUDWRWDORI
VXEMHFWVZRXOGEHUHTXLUHG'H%DFNHUZKLOHVXEMHFWVZRXOGQHHGWREHLQFOXGHG
IRUWKHLPDJHEDVHGDLUZD\UHVLVWDQFH'H%DFNHU,IWKHVLJQLILFDQFHOHYHOIRUWKH
YROXPHLVVHWWRE\WKH+RFKEHUJ
VVWHSXSSURFHGXUHVXEMHFWVZRXOGEHUHTXLUHG,W
FDQEHDVVXPHGWKDWDJRRGSRZHUZLOOEHREWDLQHGZKHQLQFOXGLQJVXEMHFWV
9.7
'DWD9DOLGDWLRQDQG7UDQVIRUPDWLRQ
$OO PHDVXUHG YDOXHV ZLOO EH LQFOXGHG LQ WKH DQDO\VHV 'HSHQGLQJ RQ WKH SORWV RI WKH
VWDQGDUGL]HGUHVLGXDOVYHUVXVILWWHGYDOXHVRIWKHPL[HGHIIHFWPRGHOVGDWDWUDQVIRUPDWLRQV
ZLOOEHFRQVLGHUHG

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

9.8
$QDO\VLV3ODQ
$OODQDO\VHVZLOOEHVSHFLILHGLQDGHWDLOHG6WDWLVWLFDO$QDO\VLV3ODQ6$3WKDWZLOOLQFOXGH
WDEOHDQG GDWD OLVWLQJ VKHOOV ZLWK PRFN JUDSKLFDO UHSUHVHQWDWLRQV 7KH 6$3 ZLOO EH VLJQHG
EHIRUHGDWDEDVHORFNDQGXQEOLQGLQJ
9.9
6WXG\3RSXODWLRQV
7KHIROORZLQJDQDO\VLVSRSXODWLRQVDUHGHILQHGLQWKLVVWXG\

7KH ITT Population LV GHILQHG DV DOO VXEMHFWV ZKR DUH UDQGRPL]HG WR WUHDWPHQW
7UHDWPHQWLVDVVLJQHGDVUDQGRPL]HGUHJDUGOHVVRIWKHWUHDWPHQWDFWXDOO\UHFHLYHG

7KHmodified Intent-to-TreatmITT Population)LVDVXEVHWRIWKH,773RSXODWLRQ
LQFOXGLQJVXEMHFWVZKRUHFHLYHGWUHDWPHQWDQGKDYHSRVWWUHDWPHQWHIILFDF\GDWDIURP
ERWK7UHDWPHQW3HULRGV'DWDMXGJHGWREHLPSDFWHGE\PDMRUSURWRFROGHYLDWLRQVZLOO
EHGHWHUPLQHGSULRUWRXQEOLQGLQJDQGH[FOXGHG6WDWLVWLFDOWDEXODWLRQVDQGDQDO\VHV
ZLOOEHE\UDQGRPL]HGWUHDWPHQWEXWGDWDREWDLQHGDIWHUVXEMHFWVUHFHLYHDQLQFRUUHFW
WUHDWPHQWZLOOEHH[FOXGHGIURPWKHDIIHFWHGSHULRGV

7KHSafety Population LVGHILQHGDVDOOVXEMHFWVZKRDUHUDQGRPL]HGWRWUHDWPHQW
DQG UHFHLYH DW OHDVW RQH GRVH RI WKH VWXG\ WUHDWPHQW 6WDWLVWLFDO DQDO\VHV DQG
WDEXODWLRQVZLOOEHE\WKHWUHDWPHQWDFWXDOO\UHFHLYHG

$QDO\VHVZLOOEHSHUIRUPHGDVIROORZV
'HPRJUDSKLFV ZLOO EH VXPPDUL]HG IRU WKH ,77 P,77 DQG 6DIHW\ SRSXODWLRQV ([WHQW RI
H[SRVXUHZLOOEHVXPPDUL]HGIRUWKH6DIHW\3RSXODWLRQ7KH6DIHW\3RSXODWLRQZLOOEHXVHG
WRVXPPDUL]HVDIHW\GDWD
(IILFDF\ DQDO\VHV ZLOO EH SHUIRUPHG IRU WKH ,77 DQG P,77 3RSXODWLRQV ZLWK WKH ,77
3RSXODWLRQEHLQJFRQVLGHUHGWKHSULPDU\SRSXODWLRQIRUWKHVHDQDO\VHV
9.10 +DQGOLQJRI0LVVLQJ'DWD
1RLPSXWDWLRQIRUPLVVLQJYDOXHVLVSODQQHG
9.11 6WDWLVWLFDO6RIWZDUH
$OODQDO\VHVZLOOEHSHUIRUPHGXVLQJWKHRSHQVRXUFHVWDWLVWLFDOHQYLURQPHQW




*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

 ADMINISTRATIVE CONSIDERATIONS
10.1 5HJXODWRU\$XWKRULW\$SSURYDO
3HDUOZLOOREWDLQ DSSURYDOWRFRQGXFWWKHVWXG\ IURPWKH DSSURSULDWHUHJXODWRU\DJHQF\LQ
DFFRUGDQFH ZLWK DQ\ DSSOLFDEOH FRXQWU\VSHFLILF UHJXODWRU\ UHTXLUHPHQWV SULRU WR D VLWH
LQLWLDWLQJWKHVWXG\LQWKDWFRXQWU\
10.2 (WKLFDO&RQGXFWRIWKH6WXG\DQG,QVWLWXWLRQDO5HYLHZ%RDUG,5%
RU,QGHSHQGHQW(WKLFV&RPPLWWHH,(&$SSURYDO
7KH VWXG\ ZLOO EH FRQGXFWHG LQ DFFRUGDQFH ZLWK *RRG &OLQLFDO 3UDFWLFH *&3
7KHVHVWDQGDUGVUHVSHFWWKHIROORZLQJJXLGHOLQHV

*XLGHOLQHIRU*RRG&OLQLFDO3UDFWLFH(5&RQVROLGDWHG*XLGHOLQH,&+RI
7HFKQLFDO5HTXLUHPHQWVIRUWKH5HJLVWUDWLRQRI3KDUPDFHXWLFDOVIRU+XPDQ8VH0D\


86&)5GHDOLQJZLWKFOLQLFDOVWXGLHV&)5SDUWVDQG

'HFODUDWLRQRI+HOVLQNLFRQFHUQLQJPHGLFDOUHVHDUFKLQKXPDQV(WKLFDO3ULQFLSOHVIRU
0HGLFDO5HVHDUFK,QYROYLQJ+XPDQ6XEMHFWV
>KWWSZZZZPDQHWHQKRPHLQGH[KWPO@

$Q\DGGLWLRQDOUHJXODWRU\UHTXLUHPHQWV
7KH,QYHVWLJDWRURU3HDUOZKHUHDSSOLFDEOHLVUHVSRQVLEOHIRUHQVXULQJWKDWWKLVSURWRFRO
WKH VLWH¶V ,&) DQG DQ\ RWKHU LQIRUPDWLRQ WKDW ZLOO EH SUHVHQWHG WR SRWHQWLDO VXEMHFWV HJ
DGYHUWLVHPHQWV RU LQIRUPDWLRQ WKDW VXSSRUWV RU VXSSOHPHQWV WKH ,&) DUH UHYLHZHG DQG
DSSURYHGE\WKHDSSURSULDWH,5%,(&7KH,QYHVWLJDWRUDJUHHVWRDOORZWKH,5%,(&GLUHFW
DFFHVVWRDOOUHOHYDQWGRFXPHQWV7KH,5%,(&PXVWEHFRQVWLWXWHGLQDFFRUGDQFHZLWKDOO
DSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV
3HDUO ZLOO SURYLGH WKH ,QYHVWLJDWRU ZLWK UHOHYDQW GRFXPHQWVGDWD WKDW DUH QHHGHG IRU
,5%,(&UHYLHZDQGDSSURYDORIWKHVWXG\,IWKHSURWRFROWKH,&)RUDQ\RWKHULQIRUPDWLRQ
WKDWWKH,5%,(&KDVDSSURYHGIRUSUHVHQWDWLRQWRSRWHQWLDOVXEMHFWVLVDPHQGHGGXULQJWKH
VWXG\WKH,QYHVWLJDWRULVUHVSRQVLEOHIRUHQVXULQJWKH,5%,(&UHYLHZVDQGDSSURYHVZKHUH
DSSOLFDEOHWKHVHDPHQGHGGRFXPHQWV7KH,QYHVWLJDWRUPXVWIROORZDOODSSOLFDEOHUHJXODWRU\
UHTXLUHPHQWVSHUWDLQLQJWRWKHXVHRIDQDPHQGHG,&)LQFOXGLQJREWDLQLQJ,5%,(&DSSURYDO
RIWKHDPHQGHGIRUPEHIRUHQHZVXEMHFWVFRQVHQWWRWDNHSDUWLQWKHVWXG\XVLQJWKLVYHUVLRQ
RIWKHIRUP7KH,5%,(&DSSURYDORIWKHDPHQGHG,&)RWKHULQIRUPDWLRQDQGWKHDSSURYHG
DPHQGHG,&)RWKHULQIRUPDWLRQPXVWEHIRUZDUGHGWR3HDUOSURPSWO\
10.3 6XEMHFW,QIRUPDWLRQDQG&RQVHQW
7KH VWXG\ ZLOO EH FRQGXFWHG LQ DFFRUGDQFH ZLWK DSSOLFDEOH VXEMHFW SULYDF\ UHTXLUHPHQWV
7KH SURSRVHG ,&) ZKLFK PXVW EH LQ FRPSOLDQFH ZLWK DSSOLFDEOH UHJXODWLRQV PXVW EH
UHYLHZHGDQGDSSURYHGE\WKH,5%,(&DQG3HDUOSULRUWRLQLWLDWLRQRIWKHVWXG\

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

7KH,QYHVWLJDWRUZLOOEHUHVSRQVLEOHIRUREWDLQLQJZULWWHQLQIRUPHGFRQVHQWIURPSRWHQWLDO
VXEMHFWVSULRUWRDQ\VWXG\VSHFLILFVFUHHQLQJDQGHQWU\LQWRWKHVWXG\$FRS\RIWKHVLJQHG
,&)ZLOOEHSURYLGHGWRWKHVXEMHFW7KHRULJLQDOZLOOEHUHWDLQHGE\WKH,QYHVWLJDWRU
10.4 /DERUDWRU\$FFUHGLWDWLRQ
$Q\ ODERUDWRU\ IDFLOLW\ LQWHQGHG WR EH XVHG IRU DQDO\VLV RI FOLQLFDO ODERUDWRU\ VDPSOHV
UHTXLUHG E\ WKLV SURWRFRO PXVW SURYLGH HYLGHQFH RI DGHTXDWH OLFHQVXUH RU DFFUHGLWDWLRQ
DFFRUGLQJWRWKHSUHYDLOLQJUHJXODWLRQVLQWKDWVWDWHDQGRUFRXQWU\5HIHUHQFHYDOXHVDQGRU
QRUPDOUDQJHVIRUWKHWHVWUHVXOWVPXVWEHSURYLGHGWR3HDUO3HDUOPXVWEHQRWLILHGSURPSWO\
LQZULWLQJRIDQ\FKDQJHVRFFXUULQJLQUHIHUHQFHYDOXHVGXULQJWKHFRXUVHRIWKHVWXG\
10.5 &RQILGHQWLDOLW\
10.5.1
&RQILGHQWLDOLW\RI'DWD
%\VLJQLQJWKLVSURWRFROWKH,QYHVWLJDWRUDIILUPVWR3HDUOWKDWLQIRUPDWLRQIXUQLVKHGWRWKH
,QYHVWLJDWRUE\3HDUOZLOOEHPDLQWDLQHGLQFRQILGHQFHDQGVXFKLQIRUPDWLRQZLOOEHGLYXOJHG
WR WKH ,5%,(&RUVLPLODURUH[SHUWFRPPLWWHHDIILOLDWHGLQVWLWXWLRQDQGHPSOR\HHV RQO\
XQGHU DQ DSSURSULDWH XQGHUVWDQGLQJ RI FRQILGHQWLDOLW\ ZLWK VXFK ERDUG RU FRPPLWWHH
DIILOLDWHG LQVWLWXWLRQ DQG HPSOR\HHV 'DWD JHQHUDWHG E\ WKLV VWXG\ ZLOO EH FRQVLGHUHG
FRQILGHQWLDOE\WKH,QYHVWLJDWRUH[FHSWWRWKHH[WHQWWKDWLWLVLQFOXGHGLQDSXEOLFDWLRQ
10.5.2
&RQILGHQWLDOLW\RI6XEMHFW6XEMHFW5HFRUGV
%\VLJQLQJWKLVSURWRFROWKH,QYHVWLJDWRUDJUHHVWKDW3HDUORUUHSUHVHQWDWLYH,5%,(&RU
5HJXODWRU\ $JHQF\ UHSUHVHQWDWLYHV PD\ FRQVXOW DQGRU FRS\ VWXG\ GRFXPHQWV LQ RUGHU WR
YHULI\ ZRUNVKHHWFDVH UHSRUW IRUP GDWD %\ VLJQLQJ WKH FRQVHQW IRUP WKH VXEMHFWVXEMHFW
DJUHHVWRWKLVSURFHVV,IVWXG\GRFXPHQWVZLOOEHSKRWRFRSLHGGXULQJWKHSURFHVVRIYHULI\LQJ
ZRUNVKHHWFDVHUHSRUWIRUPLQIRUPDWLRQWKHVXEMHFWVXEMHFWZLOOEHLGHQWLILHGE\XQLTXHFRGH
RQO\IXOOQDPHVLQLWLDOVDQGIXOOELUWK\HDUZLOOEHPDVNHGSULRUWRWUDQVPLVVLRQWR3HDUO,Q
DGGLWLRQ WKH ,QYHVWLJDWRU DJUHHV WRWUHDW DOOVXEMHFWGDWDXVHGDQGGLVFORVHGLQFRQQHFWLRQ
ZLWKWKLVVWXG\LQDFFRUGDQFHZLWKDOODSSOLFDEOHODZVLH+HDOWK,QVXUDQFH3RUWDELOLW\DQG
$FFRXQWDELOLW\$FWUXOHVDQGUHJXODWLRQV
10.6 4XDOLW\&RQWURODQG$VVXUDQFH
 LV UHVSRQVLEOH IRU LPSOHPHQWLQJ DQG PDLQWDLQLQJ TXDOLW\ FRQWURO DQG TXDOLW\
DVVXUDQFHV\VWHPVZLWKZULWWHQVWDQGDUGRSHUDWLQJSURFHGXUHV623VWRHQVXUHWKDWWULDOVDUH
FRQGXFWHGDQGGDWDDUHJHQHUDWHGGRFXPHQWHGDQGUHSRUWHGLQFRPSOLDQFHZLWKWKHSURWRFRO
DFFHSWHG VWDQGDUGV RI *&3 DQG DOO DSSOLFDEOH IHGHUDO VWDWH DQG ORFDO ODZV UXOHV DQG
UHJXODWLRQVUHODWLQJWRWKHFRQGXFWRIWKHFOLQLFDOVWXG\
10.7 'DWD0DQDJHPHQW
'DWDPDQDJHPHQWSURFHGXUHVDQGLQIRUPDWLRQIRUWKLVSURWRFROZLOOEHSURYLGHGE\3HDUORU
WKHLUGHVLJQHH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

10.8 6WXG\0RQLWRULQJ
,QDFFRUGDQFHZLWKDSSOLFDEOHUHJXODWLRQV*&3DQG3HDUOSURFHGXUHVFOLQLFDOPRQLWRUVZLOO
FRQWDFW WKH VLWH SULRU WR VXEMHFW HQUROOPHQW WR UHYLHZ WKH SURWRFRO DQG GDWD FROOHFWLRQ
SURFHGXUHVZLWKVLWHVWDII,QDGGLWLRQWKHPRQLWRUZLOOSHULRGLFDOO\FRQWDFWWKHVLWHLQFOXGLQJ
FRQGXFWLQJRQVLWHYLVLWV7KHH[WHQWQDWXUHDQGIUHTXHQF\RIRQVLWHYLVLWVZLOOEHEDVHGRQ
VXFKFRQVLGHUDWLRQVDVWKHVWXG\REMHFWLYHDQGRUHQGSRLQWVWKHSXUSRVHRIWKHVWXG\VWXG\
GHVLJQFRPSOH[LW\DQGHQUROOPHQWUDWH
'XULQJWKHVHFRQWDFWVWKHPRQLWRUZLOO

&KHFNWKHSURJUHVVRIWKHVWXG\

5HYLHZVWXG\GDWDFROOHFWHG

&RQGXFWVRXUFHGRFXPHQWYHULILFDWLRQ

,GHQWLI\DQ\LVVXHVDQGDGGUHVVWKHLUUHVROXWLRQ

7KLVZLOOEHGRQHLQRUGHUWRYHULI\WKDWWKH

'DWDDUHDXWKHQWLFDFFXUDWHDQGFRPSOHWH

6DIHW\DQGULJKWVRIVXEMHFWVDUHEHLQJSURWHFWHG

6WXG\ LV FRQGXFWHG LQ DFFRUGDQFH ZLWK WKH FXUUHQWO\ DSSURYHG SURWRFRO DQG DQ\
DPHQGPHQWV*&3DQGDOODSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV

7KH,QYHVWLJDWRUDJUHHVWRDOORZWKHPRQLWRUGLUHFWDFFHVVWRDOOUHOHYDQWGRFXPHQWVDQGWR
DOORFDWHKLVKHUWLPHDQGWKHWLPHRIKLVKHUVWDIIWRWKHPRQLWRUWRGLVFXVVILQGLQJVDQGDQ\
UHOHYDQWLVVXHV
8SRQ FRPSOHWLRQ RI WKH VWXG\ WKH PRQLWRU ZLOO FRQGXFW WKH IROORZLQJ DFWLYLWLHV LQ
FRQMXQFWLRQZLWKWKH,QYHVWLJDWRURUVLWHVWDIIDVDSSURSULDWH

5HWXUQRIDOOVWXG\GDWDWR3HDUO

'DWDTXHULHV

$FFRXQWDELOLW\UHFRQFLOLDWLRQDQGDUUDQJHPHQWVIRUXQXVHGLQYHVWLJDWLRQDOSURGXFWV

5HYLHZRIVLWHVWXG\UHFRUGVIRUFRPSOHWHQHVV

$IWHUWKHILQDOUHYLHZRIWKHVWXG\ILOHVWKHILOHVVKRXOGEHVHFXUHGIRUWKHDSSURSULDWHWLPH
SHULRGDVVSHFLILHGLQ6HFWLRQ7KH,QYHVWLJDWRUZLOODOVRSHUPLWLQVSHFWLRQRIWKHVWXG\
ILOHVE\3HDUO¶4XDOLW\$VVXUDQFHDXGLWRUVDQGDXWKRUL]HGUHSUHVHQWDWLYHVRIWKH)$**RU
RWKHUDSSOLFDEOHUHJXODWRU\DJHQFLHV

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

10.9 5HWHQWLRQRI'DWD
'RFXPHQWVWKDWLQGLYLGXDOO\DQGFROOHFWLYHO\SHUPLWHYDOXDWLRQRIWKHFRQGXFWRIWKHVWXG\
DQG WKH TXDOLW\ RI WKH GDWD SURGXFHG PXVW EH PDLQWDLQHG IRU UHYLHZ E\ 3HDUOV
 TXDOLW\
DVVXUDQFH DXGLWRUV DQG E\ DOO DSSOLFDEOH UHJXODWRU\ DXWKRULWLHV 7KH SHULRG RI WLPH WKHVH
GRFXPHQWVPXVWEHPDLQWDLQHGLVJRYHUQHGE\DSSOLFDEOHUHJXODWLRQV3HDUORULWVGHVLJQHH
ZLOOLQIRUPWKH,QYHVWLJDWRUZKHQWKHVHGRFXPHQWVPD\EHGHVWUR\HG
10.10 )LQDQFLDO'LVFORVXUH
7KHSULQFLSDO,QYHVWLJDWRURUVXE,QYHVWLJDWRUVQDPHGRQWKH)RUP)'$ZLOOQHHGWR
FRPSOHWHDILQDQFLDOGLVFORVXUHIRUPSULRUWRVWXG\LQLWLDWLRQDWDQ\WLPHGXULQJWKHVWXG\
H[HFXWLRQLIQHZLQIRUPDWLRQQHHGVWREHGLVFORVHGDQGIRU\HDUDIWHUVWXG\FRPSOHWLRQ
,QYHVWLJDWRUVVKRXOGPDNHWKH,5%,(&DZDUHRIDQ\ILQDQFLDOLQWHUHVWVWKDWWKH,QYHVWLJDWRU
KDVLQWKHLQYHVWLJDWLRQDOSURGXFW
10.11 ,QYHVWLJDWRU
V)LQDO5HSRUW
6KRUWO\DIWHUFRPSOHWLRQRIWKH,QYHVWLJDWRU
VSDUWLFLSDWLRQLQWKHVWXG\WKH,QYHVWLJDWRUZLOO
VXEPLWDZULWWHQUHSRUWWR3HDUO
10.12 3XEOLFDWLRQ3ROLF\
3HDUOLQWHQGVWRSXEOLVKWKHUHVXOWVRIDOORIWKHFOLQLFDOVWXGLHVWKDWLWVSRQVRUVLQFRPSOLDQFH
ZLWK WKH 'HFODUDWLRQ RI +HOVLQNL KWWSZZZZPDQHWHQKRPHLQGH[KWPO &RQVLVWHQW
ZLWKWKHUHFRPPHQGDWLRQVRIWKHHGLWRUVRIVHYHUDOOHDGLQJPHGLFDOMRXUQDOVWKH,QWHUQDWLRQDO
&RPPLWWHHRI0HGLFDO-RXUQDO(GLWRUV,&0-(DXWKRUVKLSRISXEOLFDWLRQVUHVXOWLQJIURP
3HDUO VSRQVRUHG VWXGLHV VKRXOG IDLUO\ UHFRJQL]H WKH DFWLYLWLHV RI WKRVH WKDW KDYH PDGH D
VLJQLILFDQWFRQWULEXWLRQWRWKHVWXG\7KXVLWLVDQWLFLSDWHGWKDWDXWKRUVKLSZLOOUHIOHFWWKH
FRQWULEXWLRQ PDGH E\ 3HDUO SHUVRQQHO WKH ,QYHVWLJDWRUV DQG RWKHUV LQYROYHG VXFK DV
VWDWLVWLFLDQV
,QUHFHQW\HDUVLVVXHVDERXWFRQIOLFWVRILQWHUHVWDQGDFFXUDF\RIWKHVWXG\GDWDKDYHEHHQ
UDLVHG LQ WKH PHGLFDO SUHVV $FFRUGLQJO\ 3HDUO KDV GHYHORSHG SXEOLFDWLRQ JXLGHOLQHV DV
GHVFULEHGEHORZ
 Responsibility: (DFK SULQFLSDO ,QYHVWLJDWRU LV UHVSRQVLEOH IRU WKH DFFXUDF\ DQG
FRPSOHWHQHVVRIDOOGDWDIURPWKHLUVLWH3HDUORULWVUHSUHVHQWDWLYHVLVUHVSRQVLEOHIRUWKH
DFFXUDF\RIWKHGDWDHQWHUHGLQWRWKHVWXG\GDWDEDVHVDQGIRUWKHDFFXUDF\RIWKHDQDO\VHV
FRQGXFWHG
 Authorship and Publication Committee: 3HDUOLQFROODERUDWLRQZLWKWKH,QYHVWLJDWRUV
ZLOOHVWDEOLVKWKHDSSURSULDWHDXWKRUVKLSDQGUHVSRQVLELOLW\IRUGUDIWLQJVWXG\GRFXPHQWV
LQ DFFRUGDQFH ZLWK WKH SULQFLSOHV RI WKH ,&0-( ,W LV DQWLFLSDWHG WKDW D SXEOLFDWLRQ
FRPPLWWHHZLOOEHIRUPHGWRDVVXPHRYHUVLJKWRIWKHVHDFWLYLWLHV$OOPDQXVFULSWVZLOOEH
UHYLHZHGDQGDJUHHGXSRQEHIRUHVXEPLVVLRQIRUSXEOLFDWLRQE\DOODXWKRUV
 Sponsor Review of External Manuscripts: &RQVLVWHQWZLWKWKHSUHYLRXVEXOOHWSRLQW
GUDIWVRIDQ\DQGDOOSXEOLFDWLRQVRUSUHVHQWDWLRQVWKDWPD\DULVHIURPWKLVVWXG\PXVWEH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

VXEPLWWHGDWOHDVWGD\VSULRUWRVXEPLVVLRQIRUSXEOLFDWLRQRUSUHVHQWDWLRQWR3HDUOIRU
UHYLHZDSSURYDODQGWRHQVXUHFRQVLVWHQF\ZLWKWKHSROLF\LQWKLVSURWRFRO3HDUOZLOO
KDYH WKH ULJKW WR UHTXHVW DSSURSULDWH PRGLILFDWLRQ WR FRUUHFW IDFWV DQG WR UHSUHVHQW LWV
RSLQLRQVRUWKHRSLQLRQVRIWKHSXEOLFDWLRQFRPPLWWHHLIWKHVHGLIIHUZLWKWKHSURSRVHG
SXEOLFDWLRQ
 Confidentiality: ,QYHVWLJDWRUV ZLOO FRQGXFW DOO LQWHUDFWLRQV ZLWK 3HDUO DQG ZLWK WKLUG
SDUWLHV FRQVLVWHQW ZLWK WKH H[HFXWHG FRQILGHQWLDOLW\ DJUHHPHQWV :KLOH SXEOLFDWLRQ E\
LQWHQWLRQSUHVHQWVWKHFULWLFDOVFLHQWLILFGDWDLQDSXEOLFIRUXPVRPHLQIRUPDWLRQVXFKDV
IXWXUHSODQVUHVXOWVRIQRQFOLQLFDOVWXGLHVRUFKHPLFDOIRUPXODHPD\VWLOOQHHGWRUHPDLQ
FRQILGHQWLDO
 Medical Journal Review: &RQVLVWHQWZLWKWKHLQWHQWLRQRI3HDUOWRSXEOLVKWKHVWXG\LQD
IDLUDQGDFFXUDWHPDQQHU3HDUOVXSSRUWVGLOLJHQFHLQWKHSXEOLFDWLRQUHYLHZSURFHVVRI
PHGLFDOMRXUQDOV$FFRUGLQJO\XSRQUHTXHVWDOOSHUWLQHQWVWXG\GDWDDQGLQIRUPDWLRQZLOO
EH PDGH DYDLODEOH DV VXSSOHPHQWDO LQIRUPDWLRQ IRU MRXUQDO HGLWRUV DQG UHYLHZHUV WR
HYDOXDWHDQGDXGLWHJSURWRFRODQGDPHQGPHQWVGDWDWDEXODWLRQVHWF. 7KHMRXUQDODQG
UHYLHZHUV ZLOO QHHG WR PDNH DUUDQJHPHQWV WR PDLQWDLQ WKH FRQILGHQWLDOLW\ RI VXFK
VXSSOHPHQWDOLQIRUPDWLRQZKHUHUHOHYDQWDQG3HDUOZLOOPDNHVXLWDEOHDUUDQJHPHQWVWR
HQVXUH WKDW WKH LGHQWLW\ RI MRXUQDO UHYLHZHUV LV NHSW FRQILGHQWLDO 5HFRUGV ZLOO EH
PDLQWDLQHGRIUHYLHZHUVDQGWKHUHVSHFWLYHGRFXPHQWVDQGGDWDVHWVWKDWZHUHUHYLHZHGE\
HDFKRIWKHP
 Reporting of Clinical Trials Results: 7R SURYLGH WUDQVSDUHQF\ LQ WKH FRQGXFW DQG
UHSRUWLQJ RI UDQGRPL]HG FOLQLFDO WULDOV 3HDUO UHSRUWV FOLQLFDO ILQGLQJV EDVHG RQ WKH
JXLGDQFH RI 7KH &216257 &RQVROLGDWHG 6WDQGDUGV RI 5HSRUWLQJ 7ULDOV 6WDWHPHQW
>&216257@DQGDLWHPFKHFNOLVWZKLFKLVLQWHQGHGWRLPSURYHWKHUHSRUWLQJRI
DUDQGRPL]HGFRQWUROOHGWULDODQGWRIDFLOLWDWHUHDGHUXQGHUVWDQGLQJRIWKHWULDOGHVLJQ
FRQGXFWDQDO\VLVDQGLQWHUSUHWDWLRQDQGWRVXSSRUWWKHLUDELOLW\WRDVVHVVWKHYDOLGLW\RI
LWVUHVXOWV
 Internet Clinical Trial Listing: ,QDGGLWLRQDOVRFRQVLVWHQWZLWKWKHUHFRPPHQGDWLRQVRI
WKH,&0-(3HDUOZLOOPDNHDYDLODEOHDSSURSULDWHLQIRUPDWLRQUHJDUGLQJWKHVWXG\YLDWKH
LQWHUQHW7KLVZLOOLQFOXGHUHJLVWUDWLRQDQGOLVWLQJRIWKHVWXG\RQZZZFOLQLFDOWULDOVJRY
WKH 86 1DWLRQDO ,QVWLWXWHV RI +HDOWK OLVWLQJ RI FOLQLFDO WULDOV DQG RWKHU FOLQLFDO WULDO
OLVWLQJVDVDSSURSULDWH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


 REFERENCE LIST
$WURYHQW3UHVFULELQJ,QIRUPDWLRQ86

&DOYHUOH\3/HH$7RZVH/HWDO(IIHFWRIWLRWURSLXPEURPLGHRQFLUFDGLDQYDULDWLRQLQ
DLUIORZOLPLWDWLRQLQFKURQLFREVWUXFWLYHSXOPRQDU\GLVHDVH%U0HGLFDO-±

&RQVROLGDWHG 6WDQGDUGV RI 5HSRUWLQJ 7ULDOV &216257 6WDWHPHQW   $FFHVVHG RQ
-XO\$YDLODEOHRQOLQHDWKWWSZZZFRQVRUWVWDWHPHQWRUJFRQVRUW
&23'$VVHVVPHQW7HVW&$7KWWSZZZFDWHVWRQOLQHRUJ
&HOOL%0D1HH:$JXVWL$HWDO6WDQGDUGVIRUWKHGLDJQRVLVDQGWUHDWPHQWRIVXEMHFWVZLWK
&23'DVXPPDU\RIWKH$76(56SRVLWLRQSDSHU(XU5HVSLU-
'H%DFNHU/9RV:'H%DFNHU-9DQ+ROVEHNH&9LQFKXUNDU6'H%DFNHU:7KHDFXWH
HIIHFW RI EXGHVRQLGHIRUPRWHURO LQ &23' D PXOWLVOLFH FRPSXWHG WRPRJUDSK\ DQG OXQJ
IXQFWLRQVWXG\(XU5HVSLU-$XJ±
'H%DFNHU/9RV:6DOJDGR5'H%DFNHU-'HYROGHU$9HUKXOVW6HWDO)XQFWLRQDO
LPDJLQJ XVLQJ FRPSXWHU PHWKRGV WR FRPSDUH WKH HIIHFW RI VDOEXWDPRO DQG LSUDWURSLXP
EURPLGH LQ VXEMHFWVSHFLILF DLUZD\ PRGHOV RI &23' ,QW - &KURQ 2EVWUXFW 3XOPRQ 'LV
±
(XURSHDQ0HGLFLQHV$JHQF\(0$&+03&RPPLWWHHIRU0HGLFLQDO3URGXFWV
IRU+XPDQ8VH&+03$VVHVVPHQW5HSRUW6HHEUL%UHH]KDOHU$FFHVVHGRQ-XO\
RQOLQHKWWSZZZHPDHXURSDHXGRFVHQB*%GRFXPHQWBOLEUDU\(3$5B
B3XEOLFBDVVHVVPHQWBUHSRUWKXPDQ:&SGI
)HHQVWUD7/YDQ*HQXJWHQ0/+RRJHQYHHQ57HWDO7KHLPSDFWRIDJLQJDQGVPRNLQJRQ
WKH IXWXUH EXUGHQ RI FKURQLF REVWUXFWLYH SXOPRQDU\ GLVHDVH D PRGHO DQDO\VLV LQ WKH
1HWKHUODQGV$P-5HVSLU&ULW&DUH0HG
)HUUHU $ORQVR -0RUHUD - HW DO &KURQLF REVWUXFWLYH SXOPRQDU\ GLVHDVH 3DUW DQG KHDOWK
UHODWHGTXDOLW\RIOLIH$QQ,QWHUQ0HG
)OHWFKHU&0(OPHV3&)DLUEDLUQ0%HWDO7KHVLJQLILFDQFHRIUHVSLUDWRU\V\PSWRPVDQG
WKHGLDJQRVLVRIFKURQLFEURQFKLWLVLQDZRUNLQJSRSXODWLRQ%U0HG-
*2/' *OREDO ,QLWLDWLYH IRU &KURQLF 2EVWUXFWLYH /XQJ 'LVHDVH *OREDO VWUDWHJ\ IRU WKH
GLDJQRVLVPDQDJHPHQWDQGSUHYHQWLRQRIFKURQLFREVWUXFWLYHSXOPRQDU\GLVHDVH1DWLRQDO
,QVWLWXWHVRI+HDOWKXSGDWHGZZZJROGFRSGFRP
+DOEHUW5-,VRQDND6*HRUJH',TEDO$,QWHUSUHWLQJ&23'SUHYDOHQFHHVWLPDWHVZKDWLV
WKHWUXHEXUGHQRIGLVHDVH"&KHVW

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

+DOEHUW5-1DWROL-/*DQR$HWDO*OREDOEXUGHQRI&23'V\VWHPLFUHYLHZDQGPHWD
DQDO\VLV(XU5HVSLU-
0LOOHU05&UDSR5+DQNLQVRQ-HWDO$76(567DVN)RUFH*HQHUDOFRQVLGHUDWLRQVIRU
OXQJIXQFWLRQWHVWLQJ (XU5HVSLU-(XU5HVSLU-
0XUUD\ &- /RSH] $' $OWHUQDWLYHSURMHFWLRQV RIPRUWDOLW\ DQGGLVDELOLW\E\ FDXVH
*OREDO%XUGHQRI'LVHDVH6WXG\/DQFHW
1DWLRQDO +HDOWK DQG 1XWULWLRQ ([DPLQDWLRQ 6XUYH\ 1+$1(6 ,,,  $FFHVVHG RQ
-XO\$YDLODEOHRQOLQHDWKWWSZZZFGFJRYQLRVKWRSLFVVSLURPHWU\QKDQHVKWPO
1HZ<RUN+HDUW$VVRFLDWLRQ1<+$1<+$&ODVVLILFDWLRQWKH6WDJHVRI+HDUW)DLOXUH
$FFHVVHG RQ  -XO\   $YDLODEOH RQOLQH DW +HDUW )DLOXUH 6RFLHW\ RI $PHULFD
KWWSZZZDERXWKIRUJTXHVWLRQVBVWDJHVKWP
5'HYHORSPHQW&RUH7HDP@5'HYHORSPHQW&RUH7HDP5$ODQJXDJHDQG
HQYLURQPHQW IRU VWDWLVWLFDO FRPSXWLQJ 5 )RXQGDWLRQ IRU 6WDWLVWLFDO &RPSXWLQJ 9LHQQD
$XVWULD
6XOOLYDQ6'5DPVH\6'/HH7$7KHHFRQRPLFEXUGHQRI&23'&KHVW66
YDQ1RRUG -$ &RPSDULVRQ RI WLRWURSLXP RQFH GDLO\ IRUPRWHURO WZLFH GDLO\ DQG ERWK
FRPELQHG RQFH GDLO\ LQ VXEMHFWV ZLWK &23' (XURSHDQ 5HVSLUDWRU\ -RXUQDO 
±
YDQ1RRUG-$$XPDQQ-/-DQVVHQV(9HUKDHUW-6PHHWV--0XHOOHU$&RUQHOLVVHQ3-*
(IIHFWV RI 7LRWURSLXP :LWK DQG :LWKRXW )RUPRWHURO RQ $LUIORZ 2EVWUXFWLRQ DQG 5HVWLQJ
+\SHULQIODWLRQLQ6XEMHFWV:LWK&23'&KHVW
9HQWROLQ DOEXWHURO VXOIDWH LQKDODWLRQDHURVRO+)$+LJKOLJKWVRI3UHVFULELQJ ,QIRUPDWLRQ


9RJHOPHLHU&.DUGRV3+DUDUL6*DQV6-06WHQJOHLQ67KLUOZHOO-)RUPRWHUROPRQR
DQG FRPELQDWLRQ WKHUDS\ ZLWK WLRWURSLXP LQ VXEMHFWV ZLWK &23' $ PRQWK VWXG\
5HVSLUDWRU\0HGLFLQH
9RV:'H%DFNHU-3ROL*'H9ROGHU$*K\V/9DQ+ROVEHNH&HWDO1RYHOIXQFWLRQDO
LPDJLQJ
RI
FKDQJHV
LQ
VPDOO
DLUZD\V
RI
VXEMHFWV
WUHDWHG
ZLWK
H[WUDILQH
EHFORPHWKDVRQHIRUPRWHURO5HVSLUDWLRQ±






*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

 $33(1',&(6
$SSHQGL[
Subject Instructions for Use of GFF and Placebo MDI
Before using GFF MDI and Placebo MDI
 7DNHWKHLQKDOHURXWRIWKHIRLOSRXFK6DIHO\WKURZDZD\WKHSRXFKDQGWKHGU\LQJSDFNHW
WKDWFRPHVLQVLGHWKHSRXFK&KHFNWKHLQGLFDWRUDWWKHWRSRIWKHFDQLVWHUWKHLQGLFDWRU
VKRXOGUHDGDVVKRZQLQ)LJXUH$

Figure A1-1. Indicator at Top of Canister

 7DNHWKHFDSRIIWKHLQKDOHUDQGLQVSHFWWKHIURQWRIWKHLQKDOHUDQGPDNHVXUHWKHUHLV
QRWKLQJLQVLGHWKHPRXWKSLHFHRIWKHLQKDOHU0DNHVXUHWKHFDQLVWHULVIXOO\DQGILUPO\
LQVHUWHGLQWRWKHDFWXDWRU
 7KHLQKDOHUVKRXOGEHVWRUHGDWURRPWHPSHUDWXUH

How to prime GFF MDI and Placebo MDI
 7KH LQKDOHU PXVW EH SULPHG EHIRUH WKH ILUVW XVH 3ULPLQJ LQYROYHV UHOHDVLQJ D FHUWDLQ
QXPEHURIVSUD\VLQWRWKHDLUEHIRUHWKHILUVWXVHRIWKHLQKDOHU6KDNLQJDQGSULPLQJ
WKHLQKDOHUILOOVDFKDPEHULQVLGHWKHFDQLVWHUZLWKWKHFRUUHFWGRVHDQGPL[RIPHGLFDWLRQ
VRWKDWWKHLQKDOHULVUHDG\WRXVH
 7DNHWKHFDSRIIWKHPRXWKSLHFHRIWKHDFWXDWRU
 7RSULPHWKHLQKDOHUJHQWO\VKDNHWKHLQKDOHUIRUVHFRQGVDQGWKHQVSUD\RQFHLQWR
WKHDLUDZD\IURP\RXUVHOIDQGRWKHUV
 :DLWDSSUR[LPDWHO\VHFRQGVDQGUHSHDWWKHSURFHVVWKUHHPRUHWLPHV

How to take a dose from GFF MDI and Placebo MDI 
6WHSVEHORZVKRXOGEHGRQHRQHDIWHUWKHRWKHU
 7DNHWKHFDSRIIWKHPRXWKSLHFHRIWKHDFWXDWRU
 +ROGWKHLQKDOHUZLWKWKHPRXWKSLHFHGRZQ
 6KDNHWKHFDQLVWHUIRUVHFRQGV
 %UHDWKHRXWIXOO\WKURXJKPRXWKH[SHOOLQJDVPXFKDLUIURPWKHOXQJVDVSRVVLEOH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

 7LOWKHDGEDFNVOLJKWO\SODFHWKH PRXWKSLHFH LQWR PRXWK DQGFORVHOLSVDURXQG LW 7R
DOORZ WKH PHGLFDWLRQ WR HQWHU WKH OXQJV NHHS WRQJXH IODW RQ WKH IORRU RI \RXU PRXWK
.HHSWKHPRXWKSLHFHDWWKHERWWRPDQGWKHGRVHLQGLFDWRUDWWKHWRS
 :KLOHEUHDWKLQJLQGHHSO\DQGVORZO\SUHVVGRZQRQWKHFHQWHURIWKHGRVHLQGLFDWRUZLWK
ILQJHU)XOO\GHSUHVVWKHFDQLVWHUXQWLOLWVWRSVPRYLQJLQWKHDFWXDWRUZKLOHGHOLYHULQJWKH
GRVH
Note:,WLVQRUPDOWRKHDUDVRIWFOLFNIURPWKHLQGLFDWRUDVLWFRXQWVGRZQGXULQJXVH
 +ROGEUHDWKDVORQJDVSRVVLEOHXSWRVHFRQGVDQGWKHQEUHDWKHQRUPDOO\
 5HSHDWVWHSVWRZLWKJHQWOHVKDNLQJIRUVHFRQGVEHIRUHWKHVHFRQGVSUD\
 3XWWKHFDSEDFNRQWKHPRXWKSLHFHDIWHUHYHU\WLPHWKHLQKDOHULVXVHGDQGPDNHVXUHLW
LVILUPO\VHDWHGLQSODFH

How to clean GFF MDI and Placebo MDI
,WLVYHU\LPSRUWDQWWRNHHSWKHSODVWLFDFWXDWRUFOHDQVRWKHPHGLFLQHGRHVQRWEXLOGXSDQG
EORFNWKHVSUD\7KHLQKDOHUPD\VWRSVSUD\LQJLILWLVQRWFOHDQHGFRUUHFWO\'RQRWFOHDQWKH
PHWDOFDQLVWHURUOHWLWJHWZHW
:DVKWKHDFWXDWRURQFHDZHHNIRUWKHILUVWWKUHHZHHNVDVGLUHFWHGEHORZ

 7DNHWKHFDQLVWHURXWRIWKHDFWXDWRUDQGWDNHWKHFDSRIIWKHPRXWKSLHFH
 :DVK WKH DFWXDWRU WKURXJK WKH WRS RI WKH DFWXDWRU ZLWK ZDUP UXQQLQJ ZDWHU IRU
VHFRQGVVHH)LJXUH$

Figure A1-2. Wash Actuator through Top of Actuator 


 7KHQZDVKWKHDFWXDWRUDJDLQWKURXJKWKHPRXWKSLHFHVHH)LJXUH$

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

Figure A1-3. Wash Actuator through Mouthpiece


 6KDNHRIIDVPXFKZDWHUIURPWKHDFWXDWRUDV\RXFDQ/RRNLQWRWKHPRXWKSLHFHWRPDNH
VXUH DQ\ PHGLFLQH EXLOGXS KDV EHHQ FRPSOHWHO\ ZDVKHG DZD\ ,I WKHUH LV DQ\ YLVLEOH
EXLOGXSUHSHDWVWHSVDQG
 /HWWKHDFWXDWRUDLUGU\FRPSOHWHO\VXFKDVRYHUQLJKW
 :KHQWKHDFWXDWRULVGU\SXWWKHFDQLVWHULQWKHDFWXDWRUPDNLQJVXUHWKHFDQLVWHULVIXOO\
DQGILUPO\ILWWHGLQWRWKHDFWXDWRU6KDNHWKHLQKDOHUJHQWO\IRUVHFRQGVDQGVSUD\LW
WLPHVLQWRWKHDLUDZD\IURP\RXUIDFHVKDNLQJJHQWO\VHFRQGVEHIRUHHDFKVSUD\
3XWWKHFDSEDFNRQWKHPRXWKSLHFH
If the actuator becomes blocked
%ORFNDJHIURPPHGLFLQHEXLOGXSLVPRUHOLNHO\WRKDSSHQLIWKHDFWXDWRULVQRWURXWLQHO\
FOHDQHGDQGWKHDFWXDWRULVQRWDLUGULHGFRPSOHWHO\,IWKHDFWXDWRUJHWVEORFNHGVRWKDWOLWWOH
RUQRPHGLFLQHFRPHVRXWRIWKHPRXWKSLHFHZDVKWKHDFWXDWRUDVGHVFULEHGLQFOHDQLQJVWHSV

,IWKHLQKDOHULVQHHGHGEHIRUHWKHDFWXDWRULVFRPSOHWHO\GU\VKDNHDVPXFKZDWHURIIWKH
DFWXDWRUDVSRVVLEOH3XWWKHFDQLVWHULQWKHDFWXDWRUDQGPDNHVXUHLWILWVILUPO\6KDNHWKH
LQKDOHUJHQWO\IRUVHFRQGVDQGVSUD\LWWLPHVLQWRWKHDLUDZD\IURP\RXUIDFHVKDNLQJ
JHQWO\VHFRQGVEHIRUHHDFKVSUD\7KHQWDNHWKHGRVHDVSUHVFULEHGDQGGHVFULEHGDERYH
7KHQFOHDQDQGDLUGU\LWFRPSOHWHO\
How to read the inhaler dose indicator
7KHLQKDOHULVILWWHGZLWKDGRVHLQGLFDWRUZKLFKVKRZVKRZPXFKPHGLFLQHLVOHIWGXULQJXVH
7KHGRVHLQGLFDWRUGLVSOD\ZLOOPRYHDIWHUHYHU\WHQWKSXII7KHGRVHLQGLFDWRUSRLQWHUZLOO
VWDUWWRSRLQWWRWKHUHGDUHDZKHQWKHUHDUHSXIIVUHPDLQLQJ7KLVPHDQVWKDWWKHLQKDOHU
QHHGVWREHUHSODFHGVRRQ

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Figure A1-4. Metered Dose Inhaler Parts


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
$SSHQGL[
Instructions for Use of Atrovent HFA Inhalation Aerosol Device 


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
$SSHQGL[
Instructions for Use of Ventolin HFA Inhaler
Instructions for Use
For Oral Inhalation Only 
Your VENTOLIN HFA inhaler


7KHPHWDOFDQLVWHUKROGVWKHPHGLFLQHSee )LJXUH$
Figure A

)LJXUH$
7KHFDQLVWHUKDVDFRXQWHUWRVKRZKRZPDQ\VSUD\VRIPHGLFLQH\RXKDYHOHIW7KH
QXPEHUVKRZVWKURXJKDZLQGRZLQWKHEDFNRIWKHDFWXDWRU6HH)LJXUH%

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Figure B


7KHFRXQWHUVWDUWVDWHLWKHU204 or 064, GHSHQGLQJRQZKLFKVL]HLQKDOHU\RXKDYH7KH
QXPEHUZLOOFRXQWGRZQE\HDFKWLPH\RXVSUD\WKHLQKDOHU7KHFRXQWHUZLOOVWRS
FRXQWLQJDW000

'RQRWWU\WRFKDQJHWKHQXPEHUVRUWDNHWKHFRXQWHURIIWKHPHWDOFDQLVWHU7KHFRXQWHU
FDQQRWEHUHVHWDQGLWLVSHUPDQHQWO\DWWDFKHGWRWKHFDQLVWHU

7KHEOXHSODVWLFDFWXDWRUVSUD\VWKHPHGLFLQHIURPWKHFDQLVWHU7KHDFWXDWRUKDVD
SURWHFWLYHFDSWKDWFRYHUVWKHPRXWKSLHFH6HH)LJXUH$ .HHSWKHSURWHFWLYHFDSRQWKH
PRXWKSLHFHZKHQWKHFDQLVWHULVQRWLQXVH7KHVWUDSNHHSVWKHFDSDWWDFKHGWRWKH
DFWXDWRU

Do not XVHWKHDFWXDWRUZLWKDFDQLVWHURIPHGLFLQHIURPDQ\RWKHULQKDOHU

Do not XVHD9(172/,1+)$FDQLVWHUZLWKDQDFWXDWRUIURPDQ\RWKHULQKDOHU


Before using your VENTOLIN HFA inhaler
Before you use VENTOLIN HFA for the first time, you must prime the inhaler so 
that you will get the right amount of medicine when you use it.
7RSULPHWKHLQKDOHUWDNHWKHFDSRIIWKHPRXWKSLHFHDQGVKDNHWKHLQKDOHUZHOO7KHQ
VSUD\WKHLQKDOHUWLPHLQWRWKHDLUDZD\IURP\RXUIDFHSee )LJXUH&Avoid spraying 
in eyes.

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Figure C




6KDNHDQGVSUD\WKHLQKDOHUOLNHWKLVPRUHWLPHVWRILQLVKSULPLQJLW7KHFRXQWHU
VKRXOGQRZUHDG200 RU060GHSHQGLQJRQZKLFKVL]HLQKDOHU\RXKDYHSee )LJXUH'
Figure D


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
<RXPXVWSULPH\RXULQKDOHUDJDLQLI\RXKDYHQRWXVHGLWLQPRUHWKDQGD\VRULI\RX
GURSLW7DNHWKHFDSRIIWKHPRXWKSLHFHDQGVKDNHDQGVSUD\WKHLQKDOHUWLPHVLQWRWKH
DLUDZD\IURP\RXUIDFH
How to use your VENTOLIN HFA inhaler 
Follow these steps every time you use VENTOLIN HFA.
Step 1. 0DNHVXUHWKHFDQLVWHUILWVILUPO\LQWKHDFWXDWRU7KHFRXQWHUVKRXOGVKRZWKURXJK
WKHZLQGRZLQWKHDFWXDWRU
Shake the inhaler well EHIRUHHDFKVSUD\
7DNHWKHFDSRIIWKHPRXWKSLHFHRIWKHDFWXDWRU/RRNLQVLGHWKHPRXWKSLHFHIRUIRUHLJQ
REMHFWVDQGWDNHRXWDQ\\RXVHH
Step 2. +ROGWKHLQKDOHUZLWKWKHPRXWKSLHFHGRZQSee )LJXUH(
Figure E


Step 3. %UHDWKHRXWWKURXJK\RXUPRXWKDQGSXVKDVPXFKDLUIURP\RXUOXQJVDV\RXFDQ
3XWWKHPRXWKSLHFHLQ\RXUPRXWKDQGFORVH\RXUOLSVDURXQGLWSee )LJXUH)












*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Figure F

Step 4. 3XVKWKHWRSRIWKHFDQLVWHUall the way down ZKLOH\RXEUHDWKHLQGHHSO\DQGVORZO\
WKURXJK\RXUPRXWKSee )LJXUH)
Step 5. $IWHUWKHVSUD\FRPHVRXWWDNH\RXUILQJHURIIWKHFDQLVWHU$IWHU\RXKDYHEUHDWKHG
LQDOOWKHZD\WDNHWKHLQKDOHURXWRI\RXUPRXWKDQGFORVH\RXUPRXWK
Step 6Hold your breath for about 10 seconds, RUIRUDVORQJDVLVFRPIRUWDEOHBreathe 
out slowly as long as you can. 
If your healthcare provider has told you to use more spraysZDLWPLQXWHDQGVKDNHWKH
LQKDOHUDJDLQ5HSHDW6WHSVWKURXJK6WHS
Step 7. 3XWWKHFDSEDFNRQWKHPRXWKSLHFHDIWHUHYHU\WLPH\RXXVHWKHLQKDOHU0DNHVXUHLW
VQDSVILUPO\LQWRSODFH
Cleaning your VENTOLIN HFA inhaler
&OHDQ\RXULQKDOHUDWOHDVWWLPHHDFKZHHN<RXPD\QRWVHHDQ\PHGLFLQHEXLOGXSRQWKH
LQKDOHUEXWLWLVLPSRUWDQWWRNHHSLWFOHDQVRPHGLFLQHEXLOGXSZLOOQRWEORFNWKHVSUD\See 
)LJXUH*

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Figure G


Step 8. 7DNHWKHFDQLVWHURXWRIWKHDFWXDWRUDQGWDNHWKHFDSRIIWKHPRXWKSLHFH7KHVWUDS
RQWKHFDSZLOOVWD\DWWDFKHGWRWKHDFWXDWRU
Step 9. +ROGWKHDFWXDWRUXQGHUWKHIDXFHWDQGUXQZDUPZDWHUWKURXJKLWIRUDERXW
VHFRQGVSee )LJXUH+
Figure H



Step 10. 7XUQWKHDFWXDWRUXSVLGHGRZQDQGUXQZDUPZDWHUWKURXJKWKHPRXWKSLHFHIRU
DERXWVHFRQGVSee )LJXUH,


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
Figure I

Step 11. 6KDNHRIIDVPXFKZDWHUIURPWKHDFWXDWRUDV\RXFDQ/RRNLQWRWKHPRXWKSLHFHWR
PDNHVXUHDQ\PHGLFLQHEXLOGXSKDVEHHQFRPSOHWHO\ZDVKHGDZD\,IWKHUHLVDQ\EXLOGXS
UHSHDW6WHSVDQG
Step 12. /HWWKHDFWXDWRUDLUGU\RYHUQLJKWSee )LJXUH-
Figure J

Step 13. :KHQWKHDFWXDWRULVGU\SXWWKHSURWHFWLYHFDSRQWKHPRXWKSLHFHDQGWKHQSXWWKH
FDQLVWHULQWKHDFWXDWRUDQGPDNHVXUHLWILWVILUPO\6KDNHWKHLQKDOHUZHOOUHPRYHWKHFDS

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

DQGVSUD\WKHLQKDOHURQFHLQWRWKHDLUDZD\IURP\RXUIDFH7KHFRXQWHUZLOOFRXQWGRZQE\
QXPEHU3XWWKHFDSEDFNRQ
WKHPRXWKSLHFH
If you need to use your inhaler before the actuator is completely dry:

6KDNHDVPXFKZDWHURIIWKHDFWXDWRUDV\RXFDQ

3XWWKHFDSRQWKHPRXWKSLHFHDQGWKHQSXWWKHFDQLVWHULQWKHDFWXDWRUDQGPDNHVXUH
LWILWVILUPO\

6KDNHWKHLQKDOHUZHOODQGVSUD\LWWLPHLQWRWKHDLUDZD\IURP\RXUIDFH

7DNH\RXU9(172/,1+)$GRVHDVSUHVFULEHG

)ROORZFOHDQLQJ6WHSVWKURXJKDERYH

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\
&RQILGHQWLDODQG3URSULHWDU\
3DJHRI
$SSHQGL[
COPD Assessment Test
8QGHUQHDWKDQH[DPSOHRIWKH&$7WHVWLVYLVLEOH'XULQJWKHVWXG\&$7WHVWLQWKHORFDO
ODQJXDJHZLOOEHXVHG


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI


$SSHQGL[
Modified Medical Research Council Dyspnea Scale Assessment
8QGHUQHDWKDQH[DPSOHRIWKH005&TXHVWLRQQDLUHLVYLVLEOH'XULQJWKHVWXG\005&LQ
WKHORFDOODQJXDJHZLOOEHXVHG

Grade Description of Breathlessness

,RQO\JHWEUHDWKOHVVZLWKVWUHQXRXVH[HUFLVH

,JHWVKRUWRIEUHDWKZKHQKXUU\LQJRQOHYHOJURXQGRUZDONLQJXSDVOLJKWKLOO

2Q OHYHO JURXQG , ZDON VORZHU WKDQ SHRSOH RI WKH VDPH DJH EHFDXVH RI
EUHDWKOHVVQHVVRUKDYHWRVWRSIRUEUHDWKZKHQZDONLQJDWP\RZQSDFH

, VWRS IRU EUHDWK DIWHU ZDONLQJ DERXW  PHWHUV RU DIWHU D IHZ PLQXWHV RQ OHYHO
JURXQG

,DPWRREUHDWKOHVVWROHDYHWKHKRXVHRU,DPEUHDWKOHVVZKHQGUHVVLQJ




















*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

$SSHQGL[
Dose Indicator Display Reading Instructions 
)RUWKHSXUSRVHVRIWKLVVWXG\ZKHQUHFRUGLQJWKHGRVHLQGLFDWRUGLVSOD\YDOXHUHYLHZWKH
LQGLFDWRUGLVSOD\DWWKHWRSRIWKH0',DQGUHFRUGWKHQXPEHURILQKDODWLRQVUHPDLQLQJWKDW
PDWFKHVWKHFKDUWEHORZ
130 Count (Actuation) Version Shown

,I
\RXU
GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNH WKLV UHFRUG
120+

,I
\RXU
GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNH WKLV UHFRUG
120

,I
\RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNH WKLV UHFRUG
110

,I \RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNH WKLV UHFRUG
100

,I \RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNH WKLV UHFRUG
90

,I
\RXU
GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNHWKLVUHFRUG
80

,I
\RXU
GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNHWKLVUHFRUG
70

,I
\RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNHWKLVUHFRUG
60

,I \RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNH WKLV UHFRUG
50

,I \RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNH WKLV UHFRUG
40

,I
\RXU
GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNHWKLVUHFRUG
30

,I
\RXU
GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNHWKLVUHFRUG
20

,I
\RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNHWKLVUHFRUG
10

,I \RXU GRVH
LQGLFDWRU
GLVSOD\
ORRNV
OLNHWKLVUHFRUG
0 






*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

$SSHQGL[
Protocol of HRCT scan and CFD method 
10.1 
Protocol of CT scan 
)RUVPDOODLUZD\VVFDQQLQJWKRUD[+5&7VFDQVDUHWDNHQDW9LVLW9LVLW9LVLWDQG9LVLW
7KHVFDQVRQ9LVLWDQG9LVLWDUHWDNHQDWWZRGLIIHUHQWOXQJYROXPHVLH7/&DQG
)5&GXULQJEUHDWKKROG7KHVFDQVRQ9LVLWDQG9LVLWDUHRQO\WDNHQDW7/&OHYHO,Q
RUGHUWRFRQWUROWKHOXQJYROXPHWKHVXEMHFWV¶EUHDWKLQJVLJQDOLVPRQLWRUHG'XULQJ9LVLW
DQDGGLWLRQDOVFDQRIWKHXSSHUDLUZD\ZLOOEHWDNHQ7KHVFDQVZLOOEHWDNHQZLWKD

VOLFHVFDQQHURUDVFDQQHU\LHOGLQJHTXLYDOHQWUHVXOWV

Monitoring the breathing signal: 
,Q RUGHU WR PRQLWRU WKH EUHDWKLQJ VLJQDO WKH VXEMHFW EUHDWKV WKURXJK D PRXWKSLHFH 7KLV
PRXWKSLHFH LV FRQQHFWHG ZLWK D ODSWRS YLD D QHWZRUNFDEOH ORQJ HQRXJK WR EULGJH WKH
GLVWDQFH EHWZHHQ VXEMHFW LQ WKH &7 URRP DQG WKH FRQWURO URRP RQ ZKLFK VSHFLDOL]HG
VRIWZDUH LV UXQQLQJ 7KURXJK D SQHXPRWDFK LQ WKH PRXWKSLHFH WKH IORZ SDWWHUQ FDQ EH
IROORZHG)RU7/&ZHDVNWKHVXEMHFWWREUHDWKLQIXOO\DQGWRKROGKLVEUHDWKIRUWKHGXUDWLRQ
RIWKHVFDQ:KHQZHVHHWKHVXEMHFWLVFRUUHFWO\KROGLQJKLVEUHDWKD&7VFDQLVWDNHQ7KH
VDPHSURFHGXUHLVUHSHDWHGDW)5&:HDVNWKHVXEMHFWWREUHDWKLQDELWDQGWRVORZO\EORZ
RXWXQWLO)5&DQGWRKROGKLVEUHDWK$WWKDWPRPHQWWKHVHFRQG&7VFDQLVWDNHQ)RUWKH
XSSHUDLUZD\VFDQZHDVNWKHVXEMHFWWREUHDWKLQVORZO\ZKLOHWKHVFDQLVWDNHQ

Scanning protocols:
)RUWKH7/&6FDQDQG)5&VFDQ
5RWDWLRQWLPHRIV
'HWHFWRUFRYHUDJHRIPP
+HOLFDOWKLFNQHVVRIPP
3LWFKDQGVSHHGRIDQGPPV
7XEHYROWDJHN9
7XEHFXUUHQWYDULDEOHEHWZHHQDQGP$V
1RLVHLQGH[
7KHILHOGRIYLHZLVVHWDVVPDOODVSRVVLEOHEXWWKHOXQJVKRXOGEHVHHQFRPSOHWHO\LQDOO
D[LDOVOLFHV6FDQWLPHOLHVDURXQGVHFRQGV,PDJHVDUHUHFRQVWUXFWHGDWPPLQWHUYDO
XVLQJDOXQJILOWHU7KHUHVXOWLQJGDWDVHWKDVLPDJHVZLWKDSL[HOVL]HRI
PP

8$VFDQ
5RWDWLRQWLPHRIV
'HWHFWRUFRYHUDJHRIPP
+HOLFDOWKLFNQHVVRIPP
3LWFKDQGVSHHGRIDQGPPV
7XEHYROWDJHN9

*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

7XEHFXUUHQWYDULDEOHEHWZHHQDQGP$V
1RLVHLQGH[
7KH ILHOG RI YLHZ LV VHW DV VPDOO DV SRVVLEOH EXW WKH XSSHU DLUZD\ WUDFW VKRXOG EH VHHQ
FRPSOHWHGLQDOOD[LDOVOLFHV6FDQWLPHOLHVDURXQGVHFRQGV,PDJHVDUHUHFRQVWUXFWHGDW
PPLQWHUYDOXVLQJDVWDQGDUGILOWHU7KHUHVXOWLQJGDWDVHWKDVLPDJHVZLWKD
SL[HOVL]HRIPP

7KH VFDQV WDNHQ GXULQJ DOO YLVLWV VKDOO EH REWDLQHG ZLWK WKH VDPH UDGLRORJLF WHFKQLFDO
FRQGLWLRQV ,I WKH VFDQQLQJ HTXLSPHQW FDQ QRW FRPSO\ ZLWK WKH DERYH PHQWLRQHG
UHTXLUHPHQWVVHWWLQJV\LHOGLQJHTXLYDOHQWUHVXOWVFDQEHDSSOLHG

10.2
Detailed description of the FRI method
+5&7 LPDJHV DUH LPSRUWHG LQWR
 D FRPPHUFLDO )'$ DSSURYHG PHGLFDO LPDJH
SURFHVVLQJVRIWZDUHSDFNDJH

7KLVVRIWZDUHSDFNDJHFRQYHUWVWKH+5&7LPDJHVLQWRVXEMHFWVSHFLILF
WKUHHGLPHQVLRQDOFRPSXWHUPRGHOVRIWKHOXQJOREHVWKHDLUZD\OXPHQDQGZDOODQGWKH
YDVFXODU WUHH 7KHVH PRGHOV FDQ EH XVHG IRU UHJLRQDO YROXPH FDOFXODWLRQV DQG IXUWKHU
HYDOXDWLRQVRIUHJLRQDOUHVLVWDQFH7KHDLUZD\DQGYDVFXODUWUHHDUHHYDOXDWHGDW)5&DQG
7/&OHYHODQGFDQEHVHJPHQWHGGRZQWREURQFKLYHVVHOVZLWKDGLDPHWHURIDURXQGPP
%H\RQGWKLVSRLQWWKH+5&7UHVROXWLRQLVLQVXIILFLHQWWRGLVWLQJXLVKDOYHRODUDQGLQWUDOXPLQDO
DLURUEORRGYHVVHOWLVVXHDQGVXUURXQGLQJOXQJWLVVXHV$W\SLFDODLUZD\PRGHOLQFOXGHV
JHQHUDWLRQVGHSHQGLQJPDLQO\RQWKHGLVHDVHVWDWHRIWKHLQGLYLGXDOVXEMHFW$LUZD\OXPHQ
L9DZ DLUZD\ ZDOO L9DZZ DQG EORRG YHVVHO YROXPH 9EY FDQ EH DVVHVVHG DW LQGLYLGXDO
DLUZD\VYHVVHOV RU LQ GLIIHUHQW UHJLRQV %\ HYDOXDWLQJ WKH OREDU YROXPHV DW WZR GLIIHUHQW
OHYHOVOREDUH[SDQVLRQDQGFRQVHTXHQWO\LQWHUQDOPDVVIORZGLVWULEXWLRQFDQEHGHWHUPLQHG
)XUWKHUPRUHWKH)5&DQG7/&VFDQFDQEHXVHGWRTXDQWLI\WKHUHJLRQDOSUHVHQFHRIDLU
WUDSSLQJDQGHPSK\VHPDUHVSHFWLYHO\

$IWHUZDUGV WKH DLUZD\ OXPHQ PRGHOVZLOOEHVPRRWKHG7KHVPRRWKHGDLUZD\PRGHOVDUH
VXEVHTXHQWO\WULPPHGDWWKHWUDFKHDDQGDWWKHWHUPLQDOEURQFKLWRREWDLQDPRGHOWKDWLV
VXLWDEOH IRU IORZ FDOFXODWLRQV 1H[W WKHVH PRGHOV DUH H[SRUWHG WR D PHVKLQJ VRIWZDUH
SDFNDJHZKHUHWKH\DUHGLYLGHGLQWRGLVFUHWHWHWUDKHGUDOHOHPHQWV0HVKVL]HIRUWKLVVWXG\
ZLOO EH GHWHUPLQHG DIWHU SURSHU PHVK FRQYHUJHQFH DQDO\VLV %DVHG RQ WKH UHVXOWLQJ
FRPSXWDWLRQDO PHVK IORZ SURSHUWLHV DUH REWDLQHG WKURXJKRXW WKH HQWLUH IORZ GRPDLQ E\
PHDQVRI5H\QROGVDYHUDJHG1DYLHU6WRNHV5$16&)'$VWHDG\QRUPDOLQVSLUDWRU\IORZ
RI/PLQLVVLPXODWHGIRUDOOVXEMHFWVWRPLPLFWKHIORZSURSHUWLHVDWWLGDOEUHDWKLQJ)RU
HDFKLQGLYLGXDOVXEMHFWWKHRXWIORZWRHDFKOREHLVDGMXVWHGLWHUDWLYHO\WRPDWFKWKHLQWHUQDO
IORZUDWHGLVWULEXWLRQWKDWLVREWDLQHGIURPWKH+5&7VFDQV)URPWKH&)'FDOFXODWLRQVWKH
UHVLVWDQFH L5DZ LQ LQGLYLGXDO DLUZD\V RU GLIIHUHQW UHJLRQV FRUUHVSRQGLQJ WR WKH YROXPH
PHDVXUHPHQWVDUHREWDLQHG5HVLVWDQFHLVGHILQHGDVWKHWRWDOSUHVVXUHGURSRYHUDQDLUZD\
GLYLGHGE\WKHIORZUDWHWKURXJKWKDWDLUZD\


*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH,QKDODWLRQ$HURVRO
3HDUO7KHUDSHXWLFV,QF
&OLQLFDO7ULDO3URWRFRO37)/8,
9HUVLRQ0D\

&RQILGHQWLDODQG3URSULHWDU\
3DJHRI

$SSHQGL[
Investigator’s Agreement and Signature Page 
Study Title:
$ 5DQGRPL]HG 'RXEOH%OLQG 7ZR 7UHDWPHQW 7ZR 3HULRG
&KURQLF 'RVLQJ  :HHNV &URVV2YHU 6LQJOH&HQWHU 6WXG\ WR
(YDOXDWHWKH(IIHFWVRI37DQG3ODFHER0',RQ6SHFLILF,PDJH
%DVHG$LUZD\9ROXPHVDQG5HVLVWDQFHLQ6XEMHFWV:LWK0RGHUDWH
WR6HYHUH&23'
Study Number:
37)/8,
Final Date:
0D\
I agree:

7RDVVXPHUHVSRQVLELOLW\IRUWKHSURSHUFRQGXFWRIWKHVWXG\DWWKLVVLWH

7RFRQGXFWWKHVWXG\LQFRPSOLDQFHZLWKWKHSURWRFRODQGZLWKDQ\RWKHUVWXG\FRQGXFWSURFHGXUHVSURYLGHGE\3HDUO
7KHUDSHXWLFV,QF

1RW WR LPSOHPHQW DQ\ FKDQJHV WR WKH SURWRFRO ZLWKRXW DJUHHPHQW IURP WKH 6SRQVRU DQG SULRU UHYLHZ DQG ZULWWHQ
DSSURYDO IURP WKH ,5%,(& H[FHSW ZKHUH QHFHVVDU\ WR HOLPLQDWH DQ LPPHGLDWH KD]DUG WR WKH VXEMHFWV RU IRU
DGPLQLVWUDWLYHDVSHFWVRIWKHVWXG\ZKHUHSHUPLWWHGE\DOODSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV

7KDW,DPDZDUHRIDQGZLOOFRPSO\ZLWKJRRGFOLQLFDOSUDFWLFHV*&3DQGDOODSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV

7KDW , DP WKRURXJKO\ IDPLOLDU ZLWK WKH DSSURSULDWH XVH RI WKH LQYHVWLJDWLRQDO SURGXFWV DQG RWKHU LQIRUPDWLRQ
SURYLGHG E\ WKH 6SRQVRU LQFOXGLQJ EXW QRW OLPLWHG WR WKH IROORZLQJ WKH SURWRFRO DQG WKH FXUUHQW ,QYHVWLJDWRU¶V
%URFKXUH,%

7RHQVXUH WKDW DOO SHUVRQV DVVLVWLQJ PH ZLWK WKH VWXG\ DUH TXDOLILHG DGHTXDWHO\ LQIRUPHG DERXW WKH LQYHVWLJDWLRQDO
SURGXFWVDQGRIWKHLUVWXG\UHODWHGGXWLHVDQGIXQFWLRQV

7RVXSSO\3HDUO7KHUDSHXWLF,QFZLWKDQ\QHFHVVDU\LQIRUPDWLRQUHJDUGLQJRZQHUVKLSLQWHUHVWDQGILQDQFLDOWLHVWR
SURPSWO\XSGDWHWKLVLQIRUPDWLRQLIDQ\UHOHYDQWFKDQJHVRFFXUGXULQJWKHFRXUVHRIWKHVWXG\DQGIRU\HDUIROORZLQJ
FRPSOHWLRQ RI WKH VWXG\ DQG DJUHH WKDW 3HDUO 7KHUDSHXWLFV ,QF PD\ GLVFORVH DQ\ LQIRUPDWLRQ LW KDV DERXW VXFK
RZQHUVKLSLQWHUHVWVDQGILQDQFLDOWLHVWRUHJXODWRU\DXWKRULWLHV

, DJUHH WR UHSRUW DOO LQIRUPDWLRQ RU GDWD LQ DFFRUGDQFH ZLWK WKH SURWRFRO DQG DQ\ RWKHU VWXG\ FRQGXFW SURFHGXUHV
SURYLGHGE\3HDUO7KHUDSHXWLFV,QF

7KDWVLQFHWKHLQIRUPDWLRQLQWKLVSURWRFRODQG,%LVFRQILGHQWLDO,XQGHUVWDQGWKDWLWVGLVFORVXUHWRDQ\WKLUGSDUWLHV
RWKHUWKDQWKRVHLQYROYHGLQDSSURYDOVXSHUYLVLRQRUFRQGXFWRIWKHVWXG\LVSURKLELWHG

7RDFFXUDWHO\WUDQVIHUDOOUHTXLUHGGDWDIURPHDFKVXEMHFW¶VVRXUFHGRFXPHQWWRWKHFDVHUHSRUWIRUPV&5)V7KH
&5)VZLOOEHSURYLGHGWRWKH6SRQVRULQDWLPHO\PDQQHUDWWKHFRPSOHWLRQRIWKHVWXG\RUDVRWKHUZLVHVSHFLILHGE\
WKH6SRQVRU

7RDOORZDXWKRUL]HGUHSUHVHQWDWLYHVRI3HDUO7KHUDSHXWLFV,QFRUUHJXODWRU\DXWKRULW\UHSUHVHQWDWLYHVWRFRQGXFWRQ
VLWHYLVLWVWRUHYLHZDXGLWDQGFRS\VWXG\GRFXPHQWV,ZLOOSHUVRQDOO\PHHWZLWKWKHVHUHSUHVHQWDWLYHVWRDQVZHUDQ\
VWXG\UHODWHGTXHVWLRQV

6LJQDWXUH

'DWH 

1DPH












$IILOLDWLRQ














