Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 46
Healthy volunteers: no

Brief summary:
This is a randomized, cumulative dose, open-label, 2-period crossover, multi-center study to assess the safety, efficacy, PK, and extrapulmonary PD of cumulative doses of AS MDI compared to cumulative doses of Proventil as an active control in subjects with mild to moderate asthma

Detailed description:
This is a randomized, cumulative dose, open-label, 2-period crossover, multi-center study to assess the safety, efficacy, PK, and extrapulmonary pharmacodynamics (PD) of cumulative doses of Albuterol Sulfate Pressurized Inhalation Suspension (hereafter referred to as AS MDI) compared to cumulative doses of Proventil® hydrofluoroalkane (HFA; hereafter referred to as Proventil) as an active control in subjects with mild to moderate asthma.

Arms:
arm 1: AS MDI 1+1+2+4+8 inhalations of 90 μg per inhalation arm 2: Proventil 1+1+2+4+8 inhalations of 90 μg per inhalation

Interventions: intervention 1: AS MDI intervention 2: Proventil
Intervention descriptions: intervention 1: AS MDI 1+1+2+4+8 inhalations of 90 μg per inhalation intervention 2: Proventil 1+1+2+4+8 inhalations of 90 μg per inhalation

Protocol document:
Prot_000.pdf: 


5HYLVHG&OLQLFDO6WXG\3URWRFRO
6WXG\&RGH
'&37
1&7
1&7
'DWH
0$5&+
9HUVLRQ











$OEXWHURO6XOIDWH3UHVVXUL]HG,QKDODWLRQ6XVSHQVLRQ37&XPXODWLYH
'RVH6WXG\LQ6XEMHFWV:LWK0LOGWR0RGHUDWH$VWKPD


7KLVVXEPLVVLRQGRFXPHQWFRQWDLQVWUDGHVHFUHWVDQGFRQILGHQWLDOFRPPHUFLDOLQIRUPDWLRQGLVFORVXUHRIZKLFK
LVSURKLELWHGZLWKRXWSURYLGLQJDGYDQFHQRWLFHWR$VWUD=HQHFDDQGRSSRUWXQLW\WRREMHFW
7KHIROORZLQJ$PHQGPHQWVDUHLQFOXGHGLQWKLVUHYLVHGSURWRFRO

$PHQGPHQW1R
'DWH RI $PHQGPHQW
9HUVLRQ
2&7
9HUVLRQ$PHQGPHQW
129
9HUVLRQ$PHQGPHQW
-$1
9HUVLRQ$PHQGPHQW
0$5







&OLQLFDO6WXG\3URWRFRO&63$1*(/
9HUVLRQ
7HPSODWH)RUP'RF,'/'06BB
3DUHQW'RF,'623$='RF






Revised Clinical Study Protocol

'UXJ6XEVWDQFH
37

6WXG\&RGH
'&37

9HUVLRQ


'DWH
0DUFK


Albuterol Sulfate Pressurized Inhalation Suspension (PT007) Cumulative 
Dose Study in Subjects With Mild to Moderate Asthma
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

VERSION HISTORY
Version 4.0, 15 March 2018
7KH3HU3URWRFRODQDO\VLVVHWLVGHILQHGDQGZLOOVHUYHDVWKHSULPDU\DQDO\VLVVHWIRUWKH
H[WUDSXOPRQDU\SKDUPDFRG\QDPLFSDUDPHWHUV7KHRULJLQDOO\SODQQHG6DIHW\DQDO\VLVVHWLV
DQWLFRQVHUYDWLYHLQDQRQLQIHULRULW\HTXLYDOHQFHWHVWLQJSDUDGLJP6HFWLRQDQGWKH
SURWRFROKDYHEHHQXSGDWHGDFFRUGLQJO\
7KHVSHFLILFDWLRQRIPD[LPXPFKDQJHIURPEDVHOLQHDQGWLPHZHLJKWHGDYHUDJHFKDQJH
IURPEDVHOLQHERWKDIWHUWKHODVWFXPXODWLYHGRVHZHUHDGGHGWRWKHDQDO\VHVRI
H[WUDSXOPRQDU\3'SDUDPHWHUVLQ6HFWLRQ
5HIHUHQFHVWRSODVPDFRQFHQWUDWLRQVRIDOEXWHUROZHUHLQDGYHUWHQWO\FKDQJHGWRVHUXP
FRQFHQWUDWLRQVWKURXJKRXW9HUVLRQRIWKHSURWRFRO6XFKUHIHUHQFHVKDYHEHHQUHYHUWHG
EDFNWRSODVPDFRQFHQWUDWLRQV
Version 3.0, 12 January 2018
3RVWGRVHVSLURPHWU\ZLOOEHFROOHFWHGDWDQGPLQXWHVLQDGGLWLRQWRWKHWLPHSRLQWV
FXUUHQWO\RXWOLQHGLQWKHSURWRFRO7KHDQGPLQXWHWLPHSRLQWVZHUHLQDGYHUWHQWO\
QRWLQFOXGHG7DEOHDQGWKHSURWRFROKDYHEHHQXSGDWHGDFFRUGLQJO\
)LJXUHZDVFRUUHFWHGWRVWDWHWKHIROORZXSSKRQHFDOOSHULRGLV±GD\VYV±GD\V
DVZULWWHQLQ9HUVLRQVDQG
7DEOHZDVXSGDWHGWRDGGWKHVXSHUVFULSW³G´WRVSLURPHWU\7KLVIRRWQRWHDSSOLHVWR
VSLURPHWU\DVZHOODVUHYHUVLELOLW\WHVWLQJ
6HFWLRQDQG9LVLWDFWLYLWLHVFODULILHVWKDWVSLURPHWU\DVVHVVPHQWVVKRXOGEH
SHUIRUPHGRQO\LIVXEMHFWVKHOGWKHLUPRUQLQJGRVHVRIDVWKPDPHGLFDWLRQVDQG6$%$IRU
KRXUVSHU7DEOHDQGLQFOXVLRQFULWHULD7KHSUHYLRXVWH[WZDVFRQIXVLQJWRVLWHV
6HFWLRQPRYHG³FRQGXFWLQJSUHGRVHVSLURPHWU\´IURPDQDIWHUUDQGRPL]DWLRQ
DFWLYLW\WRDEHIRUHUDQGRPL]DWLRQDFWLYLW\$SUHEURQFKRGLODWRU)(9SHUFHQW
SUHGLFWHGQRUPDOYDOXHLVDUDQGRPL]DWLRQFULWHULRQ
Version 2.0, 10 November 2017
*OXFRVHDQGSRWDVVLXPZLOOEHPHDVXUHGLQVHUXPLQVWHDGRISODVPD7KLVLVDJOREDO
FKDQJHWKURXJKRXWWKHSURWRFRO0HDVXULQJJOXFRVHDQGSRWDVVLXPLQVHUXPYVSODVPDLVD
PRUHUHDVRQDEOHDQGSUDFWLFDODSSURDFK




&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Version 1.0, 30 October 2017
,QLWLDOFUHDWLRQ




&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

7KLVFOLQLFDOVWXG\SURWRFROKDVEHHQVXEMHFWWRDSHHUUHYLHZDFFRUGLQJWRWKH6SRQVRU¶V
6WDQGDUGSURFHGXUHV7KHFOLQLFDOVWXG\SURWRFROLVSXEOLFO\UHJLVWHUHGDQGWKHUHVXOWVDUH
GLVFORVHGDQGRUSXEOLVKHGDFFRUGLQJWRWKH6SRQVRU¶V*OREDO3ROLF\RQ%LRHWKLFVDQGLQ
FRPSOLDQFHZLWKSUHYDLOLQJODZVDQGUHJXODWLRQV




CLINICAL STUDY PROTOCOL SYNOPSIS

Albuterol Sulfate Pressurized Inhalation Suspension (PT007) Cumulative 
Dose Study in Subjects With Mild to Moderate Asthma




Study sites and number of subjects planned
7KHVWXG\ZLOOEHFRQGXFWHGDWDSSUR[LPDWHO\VLWHVLQWKH8QLWHG6WDWHV$FURVVWKHVHVLWHVLW
LVSODQQHGWKDWDSSUR[LPDWHO\VXEMHFWVZLOOEHUDQGRPL]HG$SSUR[LPDWHO\RIWKHVH
VXEMHFWVZLOODOVRSDUWLFLSDWHLQWKHSKDUPDFRNLQHWLF3.VXEVWXG\
3KDVHRIGHYHORSPHQW
,,
Study design
7KLVLVDUDQGRPL]HGFXPXODWLYHGRVHRSHQODEHOSHULRGFURVVRYHUPXOWLFHQWHUVWXG\WR
DVVHVVWKHVDIHW\HIILFDF\3.DQGH[WUDSXOPRQDU\SKDUPDFRG\QDPLFV3'RIFXPXODWLYH
GRVHVRI$OEXWHURO6XOIDWH3UHVVXUL]HG,QKDODWLRQ6XVSHQVLRQKHUHDIWHUUHIHUUHGWRDV
$60',FRPSDUHGWRFXPXODWLYHGRVHVRI3URYHQWLOK\GURIOXRURDONDQH+)$KHUHDIWHU
UHIHUUHGWRDV3URYHQWLODVDQDFWLYHFRQWUROLQVXEMHFWVZLWKPLOGWRPRGHUDWHDVWKPD
Objectives
Primary Objective
Outcome Measures
7RDVVHVVWKHHIILFDF\RI$60',FRPSDUHGWR
3URYHQWLORQOXQJIXQFWLRQDIWHUFXPXODWLYH
GRVHVRIXSWRJ
3ULPDU\
%DVHOLQHDGMXVWHGIRUFHGH[SLUDWRU\YROXPHLQ
VHFRQG)(9PLQXWHVDIWHUHDFKFXPXODWLYHGRVH
6HFRQGDU\
%DVHOLQHDGMXVWHG)(9DUHDXQGHUWKHFXUYHIURP
WRKRXUV$8&DIWHUWKHODVWFXPXODWLYHGRVH



&OLQLFDO6WXG\3URWRFRO6\QRSVLV
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Secondary Objective
Outcome Measures
7RDVVHVVWKHH[WUDSXOPRQDU\3'HIIHFWVRI$6
0',DQG3URYHQWLODIWHUHDFKFXPXODWLYHGRVH
XSWRDFXPXODWLYHGRVHRIJ
7KHIROORZLQJYDULDEOHVZLOOEHFROOHFWHGDW
PLQXWHVDIWHUHDFKFXPXODWLYHGRVHDQG
DQGPLQXWHVDIWHUWKHODVW
FXPXODWLYHGRVH
x
)ULGHULFLDFRUUHFWHG47LQWHUYDO47F)DQG
KHDUWUDWH+5
x
6HUXPJOXFRVHDQGSRWDVVLXP
x
'LDVWROLFEORRGSUHVVXUH'%3DQGV\VWROLF
EORRGSUHVVXUH6%3

Safety Objective
Outcome Measure 
7RDVVHVVWKHVDIHW\RIFXPXODWLYHGRVHVRI$6
0',UHODWLYHWR3URYHQWLO
$GYHUVHHYHQWV$(VVHULRXVDGYHUVHHYHQWV6$(V

PK substudy
Outcome Measures
7RFRPSDUHWKHUHODWLYHV\VWHPLF
ELRDYDLODELOLW\RIDOEXWHUROGHOLYHUHGIURP$6
0',DQG3URYHQWLODIWHUFXPXODWLYHGRVHVXS
WRJ
3ODVPDFRQFHQWUDWLRQREVHUYHGDWPLQXWHVSRVW
HDFKFXPXODWLYHGRVH&PLQ
$8&IURPWLPHWRWKHWLPHRIWKHODVWPHDVXUDEOH
SODVPDFRQFHQWUDWLRQ$8&WSRVWWKHILQDO
FXPXODWLYHGRVH
0D[LPXPREVHUYHGSODVPDFRQFHQWUDWLRQ&PD[DQG
WLPHWRUHDFK&PD[7PD[DIWHUWKHODVWGRVH

Target subject population
$GXOWVXEMHFWV\HDUVROGZLWKVWDEOHPLOGWRPRGHUDWHDVWKPDSUHEURQFKRGLODWRU
)(9RIWRSUHGLFWHGQRUPDOYDOXHZLWKGHPRQVWUDWHG)(9UHYHUVLELOLW\WR
9HQWROLQ+)$KHUHDIWHUUHIHUUHGWRDV9HQWROLQ
6XEMHFWVPXVWEHRQHLWKHUDVKRUWDFWLQJȕDJRQLVW6$%$DVQHHGHGDVWKHLURQO\DVWKPD
WKHUDS\RUDORZWRPHGLXPLQKDOHGFRUWLFRVWHURLG,&6GRVHHLWKHUDORQHRULQFRPELQDWLRQ
ZLWKDORQJDFWLQJȕDJRQLVW>/$%$@IRUDWOHDVWGD\VDVDFRQVLVWHQWUHJLPHQEHIRUH
VFUHHQLQJ
Duration of treatment
7KLVLVDSHULRGFURVVRYHUVWXG\(DFK7UHDWPHQW3HULRGZLOOEHGD\ZLWKD:DVKRXW
3HULRGRIWRGD\VEHWZHHQ7UHDWPHQW3HULRGV


&OLQLFDO6WXG\3URWRFRO6\QRSVLV
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

$OOVXEMHFWVLQWKLVVWXG\ZLOOGLVFRQWLQXHWKHLUFXUUHQWDVWKPDPHGLFDWLRQVDW9LVLW
6FUHHQLQJDQGLQLWLDWH6SRQVRUSURYLGHGDVWKPDPHGLFDWLRQWREHXVHGGXULQJWKH6FUHHQLQJ
3HULRGDQGWKURXJKRXWWKHGXUDWLRQRIWKHVWXG\DVIROORZV
x
6XEMHFWVZKRZHUHXVLQJRQO\6$%$DVQHHGHGEHIRUH9LVLWZLOO
GLVFRQWLQXHWKHLU6$%$DQGLQLWLDWH6SRQVRUSURYLGHG9HQWROLQWREH
XVHGDVQHHGHGXQWLOKRXUVEHIRUH9LVLW7KH\ZLOOWKHQGLVFRQWLQXH
6SRQVRUSURYLGHG9HQWROLQDQGLQLWLDWH6SRQVRUSURYLGHG$WURYHQWIRU
WKHGXUDWLRQRIWKHVWXG\WREHXVHGDVQHHGHGXSXQWLOKRXUVEHIRUH
HDFKVWXG\YLVLW
x
6XEMHFWVZKRZHUHUHFHLYLQJUHJXODUO\VFKHGXOHG,&6RU,&6/$%$
EHIRUH9LVLWZLOOGLVFRQWLQXHWKHLU,&6RU,&6/$%$DQGLQLWLDWH
3XOPLFRUW)OH[KDOHUȝJRUȝJWZLFHDGD\LQDGGLWLRQWRWKH
6SRQVRUSURYLGHG9HQWROLQDQG$WURYHQWWREHXVHGDVGHVFULEHGDERYH
(DFKVXEMHFWZLOOSDUWLFLSDWHIRUDPLQLPXPRIGD\VDQGXSWRDPD[LPXPRIGD\V
LQFOXGLQJDWRGD\6FUHHQLQJ3HULRGDQGDWHOHSKRQHFDOOWRGD\VDIWHUWKHILQDOGRVH
RIVWXG\GUXJ7KH6FUHHQLQJ3HULRGLQFOXGHVDPLQLPXPGD\5XQLQ3HULRGIRUVXEMHFWV
ZKRZHUHUHFHLYLQJUHJXODUO\VFKHGXOHG,&6RU,&6/$%$EHIRUHVWXG\HQWU\DQGZKRZLOOEH
VZLWFKHGWR3XOPLFRUW)OH[KDOHUȝJRUȝJWZLFHDGD\
6XEMHFWVHQUROOHGLQWKH3.VXEVWXG\ZLOOKDYHEORRGGUDZQDWHDFK7UHDWPHQW9LVLWIRU
DOEXWHUROFRQFHQWUDWLRQV
Investigational product, dosage, and mode of administration
7HVWSURGXFW$60',JDOEXWHUROEDVHZKLFKHTXDOVJDOEXWHUROVXOIDWHSHU
DFWXDWLRQ
&RPSDUDWRU3URYHQWLOJDOEXWHUROEDVHZKLFKHTXDOVJDOEXWHUROVXOIDWHSHU
DFWXDWLRQ
(DFKSURGXFWLVWDNHQDVDFWXDWLRQVDQGȝJUHVSHFWLYHO\
IRUDFXPXODWLYHGRVHRIJGXULQJRI7UHDWPHQW9LVLWV
Statistical methods
$OOHIILFDF\DVVHVVPHQWVZLOOEHFRPSDUHGZLWK3URYHQWLO7KH0RGLILHG,QWHQWWR7UHDW
DQDO\VLVVHWGHILQHGDVVXEMHFWVZKRUHFHLYHGWUHDWPHQWDQGKDYHSRVWWUHDWPHQWHIILFDF\GDWD
IURPERWK7UHDWPHQW3HULRGVZLOOEHXVHGIRUDOOHIILFDF\DVVHVVPHQWV7KHSULPDU\HQGSRLQW
ZLOODOVREHHYDOXDWHGXVLQJWKH,QWHQWWR7UHDWDQDO\VLVVHWGHILQHGDVVXEMHFWVZKRDUH
UDQGRPL]HGWRWUHDWPHQWDQGUHFHLYHDWOHDVWGRVHRIWKHVWXG\WUHDWPHQW
7KHSULPDU\HQGSRLQWFKDQJHIURPEDVHOLQHLQ)(9PLQXWHVSRVWHDFKRIWKHFXPXODWLYH
GRVHVZLOOEHDQDO\]HGXVLQJDOLQHDUPL[HGHIIHFWPRGHOZLWKDUDQGRPVXEMHFWHIIHFWIRUWKH
FRUUHODWLRQDFURVVSHULRGVDQGDQXQVWUXFWXUHGFRYDULDQFHPDWUL[IRUWKHUHSHDWHGPHDVXUHV


&OLQLFDO6WXG\3URWRFRO6\QRSVLV
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

ZLWKLQVXEMHFWSHULRGV,QWKHHYHQWWKDWWKHXQVWUXFWXUHGPDWUL[IDLOVWRFRQYHUJHWKH
KHWHURJHQHRXV7RHSOLW]VWUXFWXUHZLOOEHILW7KHIL[HGHIIHFWVZLOOLQFOXGHWUHDWPHQWEDVHOLQH
)(9DQGSHULRG1LQHW\SHUFHQWFRQILGHQFHLQWHUYDOV&,VZLOOEHFDOFXODWHGIRUWKH
EHWZHHQWUHDWPHQWGLIIHUHQFHVDIWHUHDFKFXPXODWLYHGRVHDQGZLOOEHHYDOXDWHGIRU
FRQWDLQPHQWZLWKLQWKHHTXLYDOHQFHERXQGVRIP/
7KHVHFRQGDU\HIILFDF\HQGSRLQWFKDQJHIURPEDVHOLQHLQ)(9$8&ZLOOEHDQDO\]HG
XVLQJDOLQHDUPL[HGPRGHOZLWKDUDQGRPVXEMHFWHIIHFW7KHIL[HGHIIHFWVLQWKHPRGHOZLOO
LQFOXGHWUHDWPHQWEDVHOLQH)(9DQGSHULRG$&,IRUWKHEHWZHHQWUHDWPHQWGLIIHUHQFH
ZLOOEHFDOFXODWHGDQGDVVHVVHGIRUFRQWDLQPHQWZLWKWKHHTXLYDOHQFHERXQGVRIP/
%DVHOLQH)(9ZLOOEHGHILQHGDVWKHPHDQRIDYDLODEOHSUHGRVHYDOXHVRQWKHILUVWGD\RI
HDFK7UHDWPHQW3HULRGLHWKHPHDQRISUHGRVHYDOXHVDW9LVLWVDQGZKHUHWKHPHDQRI
WKHDQGPLQXWHYDOXHVIRUHDFKYLVLWGD\LVREWDLQHGDQGWKHQWKHDYHUDJHRIWKHYLVLW
PHDQVLVREWDLQHG
([WUDSXOPRQDU\3'SDUDPHWHUVRI47F)+5VHUXPJOXFRVHVHUXPSRWDVVLXP6%3DQG
'%3ZLOOHDFKEHDQDO\]HGXVLQJDVLPLODUPRGHODVGHVFULEHGDERYHIRU)(9SDUDPHWHUV
SRVWHDFKFXPXODWLYHGRVH%HWZHHQWUHDWPHQWGLIIHUHQFHVDQGFRUUHVSRQGLQJ&,VZLOOEH
SURYLGHG7KHSULPDU\DQDO\VHVRIH[WUDSXOPRQDU\3'SDUDPHWHUVZLOOEHEDVHGRQWKH3HU
3URWRFRODQDO\VLVVHW6XSSRUWLYHDQDO\VHVRIWKHH[WUDSXOPRQDU\3'SDUDPHWHUVZLOOEHEDVHG
RQWKH6DIHW\DQDO\VLVVHW
7KH&PLQYDOXHVIRUDOEXWHURODIWHUHDFKFXPXODWLYHGRVHZLOOEHDQDO\]HGZLWKDSRZHUODZ
PRGHO
$GYHUVHHYHQWVZLOOEHWDEXODWHGE\WUHDWPHQW1RK\SRWKHVLVWHVWVZLOOEHSHUIRUPHG
3.VXEVWXG\1DWXUDOORJWUDQVIRUPHG$8&WDQG&PD[YDOXHVIRUDOEXWHUROSRVWWKHILQDO
FXPXODWLYHGRVHZLOOHDFKEHDQDO\]HGZLWKDOLQHDUPL[HGHIIHFWVPRGHOFRQWDLQLQJIL[HG
HIIHFWVIRUWUHDWPHQWDQGSHULRG6XEMHFWZLOOEHLQFOXGHGDVDUDQGRPHIIHFW(VWLPDWHG
JHRPHWULFPHDQUDWLRVZLWK&,VZLOOEHSURYLGHG
Sample size
5DQGRPL]DWLRQRIVXEMHFWVWRDFKLHYHVXEMHFWVFRPSOHWLQJWKHVWXG\ZLOOSURYLGH
SUREDELOLW\WRGHPRQVWUDWHHTXLYDOHQFHZLWKLQP/DIWHUDOOFXPXODWLYHGRVHV
LQWHUVHFWLRQXQLRQWHVW7KLVFDOFXODWLRQDVVXPHVDWUXHWUHDWPHQWGLIIHUHQFH$60',±
3URYHQWLORIP/LQWUDVXEMHFWVWDQGDUGGHYLDWLRQRIP/DQGWZRRQHVLGHGOHYHO
WHVWV7267
(QUROOPHQWRIVXEMHFWVWRREWDLQVXEMHFWVFRPSOHWLQJWKH3.VXEVWXG\ZLOOSURYLGH
SUREDELOLW\WRREVHUYHDRQHVLGHGXSSHUFRQILGHQFHERXQGIRUWKH&PD[UDWLR
$60',3URYHQWLOWKDWLVOHVVWKDQHYHQLIWKHWUXHUDWLRLVDVKLJKDV7KLV
FDOFXODWLRQDVVXPHVDQLQWUDVXEMHFWFRHIILFLHQWRIYDULDWLRQRIIRU3URYHQWLODQGD
RQHVLGHGWHVW


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

TABLE OF CONTENTS
PAGE
7,7/(3$*( 
9(56,21+,6725< 
&/,1,&$/678'<35272&2/6<1236,6 
7$%/(2)&217(176 
 
,1752'8&7,21 
 
%DFNJURXQGDQGUDWLRQDOHIRUFRQGXFWLQJWKLVVWXG\ 
 
5DWLRQDOHIRUVWXG\GHVLJQGRVHVDQGFRQWUROJURXSV 
 
%HQHILWULVNDQGHWKLFDODVVHVVPHQW 
 
6WXG\GHVLJQ 
 
6WXG\JRYHUQDQFHDQGRYHUVLJKW 
 
678'<2%-(&7,9(6 
 
3ULPDU\REMHFWLYH 
 
6HFRQGDU\REMHFWLYHV 
 
6DIHW\REMHFWLYHV 
 
3.VXEVWXG\ 
 
([SORUDWRU\REMHFWLYHV±QRWDSSOLFDEOH 
 
68%-(&76(/(&7,21(152//0(175$1'20,=$7,21
5(675,&7,216',6&217,18$7,21$1':,7+'5$:$/ 
 
,QFOXVLRQFULWHULD 
 
([FOXVLRQFULWHULD 
 
6XEMHFWHQUROOPHQWDQGUDQGRPL]DWLRQ 
 
5DQGRPL]DWLRQFULWHULD 
 
6XEMHFWLGHQWLILFDWLRQ 
 
6FUHHQIDLOXUHV 
 
3URFHGXUHVIRUKDQGOLQJLQFRUUHFWO\HQUROOHGRUUDQGRPL]HGVXEMHFWV 
 
0HWKRGVIRUDVVLJQLQJWUHDWPHQWJURXSV 
 
0HWKRGVIRUHQVXULQJEOLQGLQJ±QRWDSSOLFDEOH 
 
0HWKRGVIRUXQEOLQGLQJ±QRWDSSOLFDEOH 
 
5HVWULFWLRQV 
 
,OOLFLWGUXJV 
 
'LHWDU\UHVWULFWLRQV 


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

 
'LVFRQWLQXDWLRQRIVWXG\GUXJ 
 
'LVFRQWLQXDWLRQRIWKHVWXG\ 
 
678'<3/$1$1'7,0,1*2)352&('85(6 
 
6FUHHQLQJ3HULRG9LVLWVDQG9LVLWVDELIDSSOLFDEOH 
 
9LVLW 
 
9LVLWD 
 
9LVLWE 
 
7UHDWPHQWSHULRGV 
 
*HQHUDOJXLGDQFHIRU9LVLWVDQG 
 
9LVLW5DQGRPL]DWLRQ9LVLW7UHDWPHQW3HULRG 
 
9LVLW7UHDWPHQW3HULRG 
 
3UHPDWXUH6WXG\:LWKGUDZDO9LVLW 
 
)ROORZXSSHULRG 
 
)ROORZXSWHOHSKRQHFDOO 
 
3UHPDWXUHZLWKGUDZDOIURPWKHVWXG\ 
 
678'<$66(660(176 
 
(IILFDF\DVVHVVPHQWV 
 
6WDQGDUGL]DWLRQRIVSLURPHWU\ 
 
$VVHVVPHQWRI)(9 
 
&KDUDFWHUL]DWLRQRIUHYHUVLELOLW\ 
 
)(9EDVHOLQHVWDELOLW\FULWHULD 
 
6DIHW\DVVHVVPHQWV 
 
0HGLFDOVXUJLFDOKLVWRU\DQGSK\VLFDOH[DPLQDWLRQ 
 
6%3DQG'%3 
 
&OLQLFDOODERUDWRU\WHVWLQJ 
 
(&* 
 
2WKHUDVVHVVPHQWV±QRWDSSOLFDEOH 
 
3.VXEVWXG\ 
 
&ROOHFWLRQRIVDPSOHV 
 
'HWHUPLQDWLRQRIGUXJFRQFHQWUDWLRQ 
 
6WRUDJHDQGGHVWUXFWLRQRI3.VDPSOHV 
 
3KDUPDFRG\QDPLFV 
 
*HQHWLFV±QRWDSSOLFDEOH 
 
%LRPDUNHUDQDO\VLV±QRWDSSOLFDEOH 
 
6$)(7<5(3257,1*$1'0(',&$/0$1$*(0(17 
 
'HILQLWLRQRI$(V 
 
'HILQLWLRQVRI6$( 
 
5HFRUGLQJRI$(V 


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

 
3HUIRUPLQJ$(DVVHVVPHQWV 
 
3UHUDQGRPL]DWLRQ$(V 
 
$(VEDVHGRQVLJQVDQGV\PSWRPV 
 
$(VEDVHGRQH[DPLQDWLRQVDQGWHVWV 
 
'LVHDVHXQGHUVWXG\ 
 
6HYHULW\ 
 
5HODWLRQVKLSWRVWXG\GUXJ 
 
5HSRUWLQJRI6$(V 
 
6XSSOHPHQWDOLQYHVWLJDWLRQVRI6$(V 
 
3RVWVWXG\IROORZXSRI$(V 
 
1RWLILFDWLRQRISRVWWUHDWPHQW6$(V 
 
,5%QRWLILFDWLRQRI6$(V 
 
+HDOWK$XWKRULW\6DIHW\5HSRUWV 
 
2YHUGRVH 
 
3UHJQDQF\ 
 
0DWHUQDOH[SRVXUH 
 
3DWHUQDOH[SRVXUH 
 
0HGLFDWLRQHUURU 
 
0DQDJHPHQWRIVWXG\GUXJUHODWHGWR[LFLWLHV±QRWDSSOLFDEOH 
 
,19(67,*$7,21$/352'8&7$1'27+(575($70(176 
 
,GHQWLW\RILQYHVWLJDWLRQDOSURGXFWV 
 
'RVHDQGWUHDWPHQWUHJLPHQV 
 
,QVWUXFWLRQVIRUSUHSDUDWLRQRIWUHDWPHQWVIRUDGPLQLVWUDWLRQDQGGLVSHQVLQJ 
 
5DQGRPL]HGVWXG\GUXJ 
 
6SRQVRUSURYLGHGEDFNJURXQGDVWKPDWKHUDSLHV 
 
/DEHOLQJ 
 
3ULPDU\SDFNDJLQJDQGODEHOLQJ 
 
6HFRQGDU\SDFNDJLQJDQGODEHOLQJLQIRUPDWLRQER[ 
 
6WRUDJH 
 
&RPSOLDQFH 
 
$FFRXQWDELOLW\ 
 
&RQFRPLWDQWDQGRWKHUWUHDWPHQWV 
 
3ULRUPHGLFDWLRQV 
 
&RQFRPLWDQWPHGLFDWLRQV 
 
5HTXLUHGFRQFRPLWDQWPHGLFDWLRQV 
 
$OORZHGDOOHUJ\PHGLFDWLRQV 
 
3URKLELWHGPHGLFDWLRQV 
 
3URKLELWHGDVWKPDDQGDOOHUJ\PHGLFDWLRQVDQGZDVKRXWSHULRGV 
 
3URKLELWHGQRQDVWKPDDQGQRQUHVSLUDWRU\PHGLFDWLRQV 
 
2WKHUFRQFRPLWDQWWUHDWPHQW 


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

 
67$7,67,&$/$1$/<6(6 
 
6WDWLVWLFDOFRQVLGHUDWLRQV 
 
6DPSOHVL]HHVWLPDWH 
 
'HILQLWLRQVRIDQDO\VLVVHWV 
 
2XWFRPHPHDVXUHVIRUDQDO\VHV 
 
0HWKRGVIRUVWDWLVWLFDODQDO\VHV 
 
3ULPDU\HIILFDF\DQDO\VLV 
 
6HFRQGDU\HIILFDF\DQDO\VLV 
 
'DWDYDOLGDWLRQDQGWUDQVIRUPDWLRQ 
 
([WUDSXOPRQDU\3'DQDO\VLV 
 
3.VXEVWXG\3.DQDO\VLV 
 
3.SDUDPHWHUV 
 
+DQGOLQJRIYDOXHVEHORZWKHOLPLWRITXDQWLILFDWLRQ 
 
6WDWLVWLFDODQDO\VLVRI3.GDWD 
 
6DIHW\DQDO\VHV 
 
+DQGOLQJRIPLVVLQJGDWD 
 
6WDWLVWLFDOVRIWZDUH 
 
678'<$1''$7$0$1$*(0(17%<7+(6321625 
 
7UDLQLQJRIVWXG\VLWHVWDII 
 
0RQLWRULQJRIWKHVWXG\ 
 
6WXG\DJUHHPHQWV 
 
$UFKLYLQJRIVWXG\GRFXPHQWV 
 
6WXG\WLPHWDEOHDQGHQGRIVWXG\ 
 
'DWDPDQDJHPHQW 
 
(7+,&$/$1'5(*8/$725<5(48,5(0(176 
 
(WKLFDOFRQGXFWRIWKHVWXG\ 
 
6XEMHFWGDWDSURWHFWLRQ 
 
(WKLFVDQGUHJXODWRU\UHYLHZ 
 
,QIRUPHGFRQVHQW 
 
&KDQJHVWRWKHFOLQLFDOVWXG\SURWRFRODQG,&) 
 
$XGLWVDQGLQVSHFWLRQV 
 
/,672)5()(5(1&(6 

LIST OF TABLES
7DEOH
6FKHGXOHRI(YHQWV 


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

7DEOH
7LPHG$VVHVVPHQWVDW(DFK7UHDWPHQW9LVLW9LVLWDQG9LVLW 
7DEOH
/LVWRI/DERUDWRU\7HVWVWREH3HUIRUPHGDW6FUHHQLQJ 
7DEOH
5DQGRPL]HG6WXG\'UXJV 
7DEOH
2WKHU6SRQVRUSURYLGHG6WXG\0HGLFDWLRQV 
7DEOH
'RVHRI6SRQVRUSURYLGHG3XOPLFRUW)OH[KDOHUWREH$VVLJQHG
%DVHGRQ3UHVWXG\,&6RU,&6/$%$'RVH 
7DEOH
$OORZHG$OOHUJ\0HGLFDWLRQV 
7DEOH
3URKLELWHG$VWKPDDQG$OOHUJ\0HGLFDWLRQV7KDW0XVWEH
'LVFRQWLQXHGDW9LVLWDQG5HTXLUHG:DVKRXW3HULRG3ULRUWRWKH
1H[W9LVLW 
7DEOH
3URKLELWHG1RQ$VWKPDDQG1RQ5HVSLUDWRU\0HGLFDWLRQV 
7DEOH$
5HFRPPHQGHG0LQLPDO6FDOH)DFWRUVIRU7LPH9ROXPHDQG)ORZ
RQ*UDSKLFDO2XWSXW 
7DEOH$
6XPPDU\RI(TXLSPHQW4XDOLW\&RQWURO 
7DEOH$
5DQJHDQG$FFXUDF\5HFRPPHQGDWLRQV6SHFLILHGIRU)RUFHG
([SLUDWRU\0DQHXYHUV 

LIST OF FIGURES
)LJXUH
6WXG\'HVLJQ)ORZ&KDUW 

LIST OF APPENDICES
$SSHQGL[$
6SLURPHWU\$VVHVVPHQW&ULWHULD 
$SSHQGL[%
6SLURPHWU\3HUIRUPDQFH5HFRPPHQGDWLRQV 
$SSHQGL[&
$GGLWLRQDO6DIHW\,QIRUPDWLRQ 
$SSHQGL['
,QVWUXFWLRQVIRU8VHRI,QKDOHG0HGLFDWLRQV 
$SSHQGL[(
6SRQVRU6LJQDWRU\ 
$SSHQGL[)
,QYHVWLJDWRU¶V$JUHHPHQWDQG6LJQDWXUH3DJH 


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
7KHIROORZLQJDEEUHYLDWLRQVDQGVSHFLDOWHUPVDUHXVHGLQWKLVVWXG\FOLQLFDOVWXG\SURWRFRO
Abbreviation
or special term
Explanation
$(
$GYHUVHHYHQW
$60',
$OEXWHURO6XOIDWH3UHVVXUL]HG,QKDODWLRQ6XVSHQVLRQ
$76
$PHULFDQ7KRUDFLF6RFLHW\
$8&
$UHDXQGHUWKHFXUYH
$8&
$UHDXQGHUWKHFXUYHIURPWRKRXUV
$8&W
$UHDXQGHUWKHFXUYHIURPWRWKHWLPHRIWKHODVWPHDVXUDEOHSODVPD
FRQFHQWUDWLRQ
ȕK&*
ȕKXPDQFKRULRQLFJRQDGRWURSLQ
%,'
7ZLFHDGD\
&PLQ
3ODVPDFRQFHQWUDWLRQREVHUYHGDWPLQXWHVSRVWHDFKFXPXODWLYHGRVH
&)5
&RGHRI)HGHUDO5HJXODWLRQV
&,
&RQILGHQFHLQWHUYDO
&PD[
0D[LPXPREVHUYHGSODVPDFRQFHQWUDWLRQ
&65
&OLQLFDOVWXG\UHSRUW
'%3
'LDVWROLFEORRGSUHVVXUH
(&*
(OHFWURFDUGLRJUDP
H&5)
&DVH5HSRUW)RUPHOHFWURQLFSDSHU
(56
(XURSHDQ5HVSLUDWRU\6RFLHW\
)(9
)RUFHGH[SLUDWRU\YROXPHLQVHFRQG
*&3
*RRG&OLQLFDO3UDFWLFH
+)$
+\GURIOXRURDONDQH
+5
+HDUWUDWH
,&)
,QIRUPHGFRQVHQWIRUP
,&+
,QWHUQDWLRQDO&RQIHUHQFHIRU+DUPRQLVDWLRQ
,&6
,QKDOHGFRUWLFRVWHURLG
,'
,GHQWLILFDWLRQ
,5%
,QVWLWXWLRQDO5HYLHZ%RDUG
,77
,QWHQWWRWUHDW


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Abbreviation
or special term
Explanation
,:56
,QWHUDFWLYH:HE5HVSRQVH6\VWHP
/$%$
/RQJDFWLQJȕDJRQLVW
//4
/RZHUOLPLWRITXDQWLWDWLRQ
0',
0HWHUHGGRVHLQKDOHU
0HG'5$
0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
P,77
0RGLILHG,77
1&$
1RQFRPSDUWPHQWDODQDO\VLV
3'
3KDUPDFRG\QDPLF
3,1
3HUVRQDO,'QXPEHU
3.
3KDUPDFRNLQHWLF
3)7
3XOPRQDU\IXQFWLRQWHVWLQJ
47F
&RUUHFWHG47LQWHUYDO
47F)
)ULGHULFLDFRUUHFWHG47LQWHUYDO
6$%$
6KRUWDFWLQJȕDJRQLVW
6$(
6HULRXVDGYHUVHHYHQW
6$3
6WDWLVWLFDO$QDO\VLV3ODQ
6%3
6\VWROLFEORRGSUHVVXUH
7267
7ZRRQHVLGHGWHVWV
7PD[
7LPHWRUHDFK&PD[



&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

1.
INTRODUCTION
1.1
Background and rationale for conducting this study
$VWKPDLVDKHWHURJHQHRXVGLVHDVHWKDWLVFKDUDFWHUL]HGE\FKURQLFDLUZD\LQIODPPDWLRQDQG
EURQFKLDOK\SHUUHDFWLYLW\,WLVGHILQHGE\DKLVWRU\RIUHVSLUDWRU\V\PSWRPVVXFKDVZKHH]H
VKRUWQHVVRIEUHDWKFKHVWWLJKWQHVVDQGFRXJKWKDWYDU\RYHUWLPHDQGLQLQWHQVLW\WRJHWKHU
ZLWKYDULDEOHH[SLUDWRU\DLUIORZREVWUXFWLRQ:RUVHQLQJDVWKPDV\PSWRPVDLUZD\REVWUXFWLRQ
FDQEHPLOGWRVHYHUH*OREDO,QLWLDWLYHIRU$VWKPD$OEXWHUROVXOIDWHLVDVKRUWDFWLQJ
ȕDJRQLVW6$%$WKDWKDVEHHQXVHGZRUOGZLGHLQWKHPDQDJHPHQWRIDVWKPDV\PSWRPV
DFURVVDOOVHYHULWLHVRIDVWKPDIRURYHU\HDUV*OREDO,QLWLDWLYHIRU$VWKPD
7KHWHVWIRUPXODWLRQWREHHYDOXDWHGLQWKLVVWXG\LVDPHWHUHGGRVHLQKDOHU0',FRQWDLQLQJ
DOEXWHUROVXOIDWH$OEXWHURO6XOIDWH3UHVVXUL]HG,QKDODWLRQ6XVSHQVLRQKHUHDIWHUUHIHUUHGWRDV
$60',7KLVLVDFXPXODWLYHGRVHVWXG\GHVLJQHGWRDVVHVVWKHHIILFDF\RI$60',
FRPSDUHGWR3URYHQWLOK\GURIOXRURDONDQH+)$KHUHDIWHUUHIHUUHGWRDV3URYHQWLORQOXQJ
IXQFWLRQDIWHUFXPXODWLYHGRVHVRIXSWRJ7KHSKDUPDFRNLQHWLFV3.DQGUHODWLYH
V\VWHPLFELRDYDLODELOLW\RI$60',ZLOOEHFRPSDUHGZLWK3URYHQWLO7KHVWXG\ZLOODOVR
DVVHVVH[WUDSXOPRQDU\SKDUPDFRG\QDPLFV3'DVZHOODVWKHVDIHW\DQGWROHUDELOLW\RI
$60',IROORZLQJFXPXODWLYHGRVHVLQDGXOWVXEMHFWVZLWKPLOGWRPRGHUDWHDVWKPD
7KHGUXJSURGXFWLQFOLQLFDOGHYHORSPHQWLVDQ0',IRUPXODWHGDVDVXVSHQVLRQZLWKD
PLFURQL]HGDFWLYHSKDUPDFHXWLFDOLQJUHGLHQWDQG&R6XVSHQVLRQ'HOLYHU\7HFKQRORJ\
ZKLFKFRQVLVWVRIVSUD\GULHGSRURXVSDUWLFOHVFRPSULVHGRIWKHSKRVSKROLSLGGLVWHDUR\O
VQJO\FHURSKRVSKRFKROLQHDQGFDOFLXPFKORULGHVXVSHQGHGLQD+)$SURSHOODQW:KHQ
XVHGLQ0',SURGXFWVWKHVHSDUWLFOHVIRUPVWURQJQRQVSHFLILFDVVRFLDWLRQVZLWKWKHDFWLYH
SKDUPDFHXWLFDOLQJUHGLHQWSURYLGLQJUHSURGXFLEOHGUXJGHOLYHU\DQGORQJWHUPVWDELOLW\
$OOUHIHUHQFHVWRGRVHVRI$60',DQG3URYHQWLOUHIHUWRWKHDOEXWHUROEDVHLHJ
DOEXWHUROEDVHZKLFKHTXDOVJDOEXWHUROVXOIDWH
1.2
Rationale for study design, doses and control groups
7KHSULPDU\JRDORIWKLVVWXG\LVWRDVVHVVWKHVDIHW\DQGHIILFDF\RIFXPXODWLYHGRVHVRI
$60',FRPSDUHGWRFXPXODWLYHGRVHVRI3URYHQWLOLQVXEMHFWVZLWKPLOGWRPRGHUDWHDVWKPD
7KHVWXG\LVEDVHGRQDSHULRGFURVVRYHUGHVLJQWRDOORZWKHFRPSDULVRQRI$60',DJDLQVW
WKHDFWLYHFRPSDUDWRU3URYHQWLO7KHFURVVRYHUGHVLJQZDVVHOHFWHGWRHQVXUHDFFHSWDEOH
SRZHUZLWKOLPLWHGVXEMHFWH[SRVXUHWKURXJKZLWKLQVXEMHFWWUHDWPHQWFRPSDULVRQVWKLV
GHVLJQKDVEHHQXVHGLQRWKHUVWXGLHVFRPSDULQJLQKDOHGDOEXWHUROWUHDWPHQWV.HUZLQHWDO
7ULSSHWDO
7KHGRVHOHYHOVRI$60',DQG3URYHQWLOWREHWHVWHGFXPXODWLYHGRVHVDGPLQLVWHUHG
PLQXWHVDSDUWDVLQKDODWLRQVRIJDOEXWHUROIRUDWRWDODOEXWHUROGRVHRI
JZLOODOORZHYDOXDWLRQRIWKHEURQFKRGLODWLRQHIIHFWRI$60',UHODWLYHWRWKH
UHIHUHQFHSURGXFWDQGZLOODOVRDOORZIRUDFRPSDULVRQRIWKHH[WUDSXOPRQDU\3'RIWKH
SURGXFWV7KHHIILFDF\VDIHW\DQGH[WUDSXOPRQDU\3'HIIHFWVRILQKDOHGDOEXWHUROIROORZLQJ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

WKLVGRVLQJUHJLPHQKDYHEHHQZHOOGRFXPHQWHGLQSUHYLRXVDOEXWHUROFXPXODWLYHGRVHVWXGLHV
.HUZLQHWDO7ULSSHWDO
7KLVLVDQRSHQODEHOVWXG\DQGVWXG\VXEMHFWVDUHQRWEOLQGHG+RZHYHUWRUHGXFHELDV
GRVLQJZLOOEHSHUIRUPHGXQGHUWKHVXSHUYLVLRQRIVWXG\VWDIIDQGVSLURPHWU\DVVHVVPHQWVZLOO
EHSHUIRUPHGE\GLIIHUHQWVWXG\SHUVRQQHOZKRZLOORQO\HQWHUWKHURRPDIWHUGRVLQJLV
FRPSOHWHGWKXVWKHVWXG\SHUVRQQHOFRQGXFWLQJWKHVSLURPHWU\DVVHVVPHQWVZLOOEHEOLQGHGWR
WKHLGHQWLW\RIWKHVWXG\GUXJ
6XEMHFWVHQUROOHGLQWKLVVWXG\DUHVHOHFWHGWRUHSUHVHQWWKHLQWHQGHGSDWLHQWSRSXODWLRQIRUDQ
DOEXWHUROSURGXFWWREHXVHGDVQHHGHGIRUV\PSWRPVLHDGXOWVZLWKPLOGWRPRGHUDWHDVWKPD
FXUUHQWO\WUHDWHGDQGZHOOFRQWUROOHGZLWKDSSURSULDWHEDFNJURXQGVWDQGDUGRIFDUHIRUWKHLU
DVWKPDVHYHULW\
6XEMHFWVZKRZHUHSUHYLRXVO\RQDORZWRPHGLXPGRVHRIDQLQKDOHGFRUWLFRVWHURLG,&6
ZLWKRUZLWKRXWDORQJDFWLQJȕDJRQLVW/$%$EHIRUHVWXG\HQWU\ZLOOEHUHTXLUHGWR
GLVFRQWLQXHWKHLUSUHYLRXVWKHUDS\DQGLQLWLDWH6SRQVRUVXSSOLHG3XOPLFRUW)OH[KDOHUIRUDW
OHDVWGD\VWRVWDQGDUGL]HWKHUDS\DQGWRFRQILUPDVWKPDLVDGHTXDWHO\WUHDWHGSULRUWR
UDQGRPL]DWLRQ
$OOVXEMHFWVZLOOXVHRQO\6SRQVRUSURYLGHGPHGLFDWLRQIRUUHFXHDVQHHGHGGXULQJWKHVWXG\
$W9LVLW6FUHHQLQJVXEMHFWVZLOOGLVFRQWLQXHWKHLU6$%$DQGLQLWLDWH6SRQVRUSURYLGHG
9HQWROLQWREHXVHGDVQHHGHGXQWLOKRXUVEHIRUH9LVLW7KH\ZLOOWKHQGLVFRQWLQXH
6SRQVRUSURYLGHG9HQWROLQDQGLQLWLDWH6SRQVRUSURYLGHG$WURYHQW+)$KHUHDIWHUUHIHUUHG
WRDV$WURYHQWIRUWKHGXUDWLRQRIWKHVWXG\WREHXVHGDVQHHGHGXSXQWLOKRXUVEHIRUHHDFK
VWXG\YLVLW
$60',ZLOOEHFRPSDUHGZLWK3URYHQWLORQWKHSULPDU\HIILFDF\HQGSRLQWEDVHOLQHDGMXVWHG
IRUFHGH[SLUDWRU\YROXPHLQVHFRQG)(9PLQXWHVDIWHUHDFKFXPXODWLYHGRVH$VD
VHFRQGDU\HIILFDF\HQGSRLQWEDVHOLQHDGMXVWHG)(9DUHDXQGHUWKHFXUYH$8&IURPWR
KRXUV$8&DFRPPRQO\DFFHSWHGHQGSRLQWIRUWKHDVVHVVPHQWRIEURQFKRGLODWLRQZLOOEH
GHWHUPLQHGDIWHUWKHODVWFXPXODWLYHGRVH
7RFKDUDFWHUL]HWKH3.RIDOEXWHURODSSUR[LPDWHO\VXEMHFWVZLOOEHHQUROOHGLQD3.
VXEVWXG\3KDUPDFRNLQHWLFSDUDPHWHUVZLOOEHDVVHVVHGIRU$60',UHODWLYHWR3URYHQWLO
PLQXWHVDIWHUHDFKFXPXODWLYHGRVHDQGWKURXJKKRXUVDIWHUWKHODVWFXPXODWLYHGRVH
7KHOHQJWKRIWKH:DVKRXW3HULRGWRGD\VKDVEHHQVHWWRPDNHVXUHWKDWFDUU\RYHU
HIIHFWVDUHQHJOLJLEOHZLWKUHJDUGWR3.DQG3'RQWKHVXEVHTXHQW7UHDWPHQW3HULRG7KH
DSSDUHQWWHUPLQDOSODVPDKDOIOLIHRIDOEXWHUROLVDSSUR[LPDWHO\KRXUV$KUHQV
,WLVZHOONQRZQWKDWȕDGUHQHUJLFDJRQLVWVFDQSURGXFHFDUGLRYDVFXODUHIIHFWVK\SRNDOHPLD
DQGK\SHUJO\FHPLDGXHWRWKHLUSKDUPDFRORJLFDOHIIHFWV3529(17,/+)$SDFNDJHLQVHUW
3KLOLSVRQ7KHUHIRUHWKLVVWXG\ZLOOHYDOXDWHWKHVKRUWWHUPH[SRVXUHUHVSRQVH
UHODWLRQVKLSVRIH[WUDSXOPRQDU\3'HQGSRLQWV7KHH[WUDSXOPRQDU\3'RI$60',DQG
3URYHQWLOZLOOEHDVVHVVHGWKURXJKRXWWKHGRVLQJSHULRGWKURXJKKRXUVDIWHUWKHODVWGRVHE\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

DQDO\VLVRIFKDQJHVIURPEDVHOLQHSUHGRVHLQVHUXPSRWDVVLXPDQGJOXFRVHEORRGSUHVVXUH
DQGHOHFWURFDUGLRJUDPV(&*V
1.3
Benefit/risk and ethical assessment
7KLVVWXG\KDVEHHQGHVLJQHGWRVXSSRUWWKHGRVHVHOHFWLRQIRUDQHZIRUPXODWLRQRIDOEXWHURO
LQVXEMHFWVZLWKPLOGWRPRGHUDWHDVWKPD7KHSURGXFWEHLQJWHVWHGLQWKLVVWXG\$60',LV
EHLQJFRPSDUHGZLWKDQDSSURYHGLQKDOHGDOEXWHUROSURGXFWWRFRQILUPDSKDUPDFRORJLFDOO\
DSSURSULDWHGRVH7KHVXEMHFWVLQWKLVVWXG\ZLOOQRWJDLQDQ\WKHUDSHXWLFEHQHILWIURPWKH
VWXG\DVLWLVFRPSULVHGRIRQO\VLQJOHWUHDWPHQWGD\VZLWKKLJKGRVHVRIDOEXWHURO
$OOVXEMHFWVLQWKLVVWXG\ZLOOEHVZLWFKHGDW9LVLWIURPWKHLUFXUUHQWDVWKPDPHGLFDWLRQWR
6SRQVRUSURYLGHGDVWKPDPHGLFDWLRQWREHXVHGGXULQJWKH6FUHHQLQJ3HULRGDQGWKURXJKRXW
WKHGXUDWLRQRIWKHVWXG\DVGHVFULEHGLQ6HFWLRQ6XEMHFWVUHTXLULQJPHGLFDWLRQVRWKHU
WKDQWKRVHVSHFLILHGLQ6HFWLRQWRFRQWURORUWUHDWWKHLUDVWKPDV\PSWRPVEHIRUHWKHILUVW
6FUHHQLQJ9LVLWZLOOEHH[FOXGHGIURPSDUWLFLSDWLRQLQWKLVVWXG\,QDGGLWLRQWREHHOLJLEOHIRU
UDQGRPL]DWLRQVXEMHFWVPXVWQRWKDYHXVHGPRUHWKDQDFWXDWLRQVSHUGD\LHGRVHVRI
DFWXDWLRQVSHUGD\RI6SRQVRUSURYLGHGUHVFXHPHGLFDWLRQRQPRUHWKDQDQ\GD\VGXULQJ
WKHSUHYLRXVGD\VEHIRUHUDQGRPL]DWLRQ
7KHGRVHVRIDOEXWHURODGPLQLVWHUHGDV$60',DQG3URYHQWLOWREHWHVWHGLQWKLVVWXG\
FXPXODWLYHGRVHVDGPLQLVWHUHGPLQXWHVDSDUWDVLQKDODWLRQVRIJDOEXWHURO
IRUDWRWDODOEXWHUROGRVHRIJKDYHEHHQXVHGLQSUHYLRXVVWXGLHVRILQKDOHGDOEXWHURO
.HUZLQHWDO7ULSSHWDO$OWKRXJKDKLJKHULQFLGHQFHRIDGYHUVHHYHQWV$(V
ZDVUHSRUWHGDWVXSUDWKHUDSHXWLFGRVHVLQWKHVHVWXGLHVWKHRYHUDOOLQFLGHQFHRI$(VZDVORZ
7KHPRVWIUHTXHQWO\UHSRUWHGWUHDWPHQWHPHUJHQW$(VIROORZLQJFXPXODWLYHGRVHVRILQKDOHG
DOEXWHUROZHUHWUHPRUKHDGDFKHDQGSDOSLWDWLRQVZLWKWKHPDMRULW\RI
HYHQWVUHSRUWHGDWWKHFXPXODWLYHGRVHVRIDQGJ.HUZLQHWDO
/DERUDWRU\SDUDPHWHUVVHUXPJOXFRVHDQGSRWDVVLXPDQGFDUGLRYDVFXODUSDUDPHWHUV
)ULGHULFLDFRUUHFWHG47LQWHUYDO>47F)@DQGKHDUWUDWH>+5@ZLOOEHPRQLWRUHGWRDVVHVVWKH
H[SHFWHG3'HIIHFWVFRQVLVWHQWZLWKWKHPHFKDQLVPRIDFWLRQRILQKDOHGDOEXWHURODWWKH
VXSUDSKDUPDFRORJLFGRVHVXVHGLQWKLVVWXG\7KHH[SHFWHGFKDQJHVLQWKHVHSDUDPHWHUVZHUH
GHPRQVWUDWHGDWFXPXODWLYHGRVHVRIDOEXWHUROXSWRJEXWPHDQFKDQJHVLQVHUXP
JOXFRVHOHYHOVHUXPSRWDVVLXPOHYHOFRUUHFWHG47LQWHUYDO47FEORRGSUHVVXUHDQG+5
ZHUHFRQVLGHUHGQRWFOLQLFDOO\VLJQLILFDQW.HUZLQHWDO,QYHVWLJDWRUVZLOOHQVXUH
DGHTXDWHPHGLFDOFDUHRIWKHVWXG\SDUWLFLSDQWVDWDOOWLPHVWKURXJKRXWWKHFRXUVHRIWKHVWXG\
LQFOXGLQJXSWRWKHIROORZXSWHOHSKRQHFDOOWRGD\VDIWHUWKHODVWGRVHRIVWXG\GUXJ
1.4
Study design
7KLVLVDUDQGRPL]HGFXPXODWLYHGRVHRSHQODEHOSHULRGFURVVRYHUPXOWLFHQWHUVWXG\WR
DVVHVVWKHVDIHW\HIILFDF\3.DQGH[WUDSXOPRQDU\3'RIFXPXODWLYHGRVHVRI$60',
FRPSDUHGWRFXPXODWLYHGRVHVRI3URYHQWLODVDQDFWLYHFRQWUROLQVXEMHFWVZLWKPLOGWR
PRGHUDWHDVWKPD)LJXUH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

7KLVVWXG\ZLOOEHFRQGXFWHGDWDSSUR[LPDWHO\VLWHVLQWKH86FRQWULEXWLQJDSSUR[LPDWHO\
VXEMHFWVSHUVLWH$FURVVWKHVHVLWHVLWLVSODQQHGWKDWDSSUR[LPDWHO\VXEMHFWVZLWKPLOGWR
PRGHUDWHDVWKPDZLOOEHUDQGRPL]HGWRSURYLGHDSSUR[LPDWHO\VXEMHFWVWRFRPSOHWHWKH
VWXG\(DFKVXEMHFWZLOOSDUWLFLSDWHIRUDPLQLPXPRIGD\VDQGXSWRDPD[LPXPRI
GD\VLQFOXGLQJDWRGD\6FUHHQLQJ3HULRGDQGDWHOHSKRQHFDOOWRGD\VDIWHUWKH
ILQDOGRVHRIVWXG\GUXJ7KHVWXG\LVDQWLFLSDWHGWRUXQIRUDSSUR[LPDWHO\PRQWKVLQFOXGLQJ
WKHUHFUXLWPHQWSHULRG
7KLVVWXG\FRQVLVWVRID6FUHHQLQJ3HULRGZKLFKLQFOXGHVD5XQLQ3HULRGIRUWKRVHVXEMHFWV
ZKRZLOOEHVZLWFKHGIURP,&6WR6SRQVRUSURYLGHG3XOPLFRUW)OH[KDOHUD7UHDWPHQW3KDVH
ZKLFKLQFOXGHVUDQGRPL]HG7UHDWPHQW3HULRGVDQGDIROORZXSWHOHSKRQHFDOO(DFK
7UHDWPHQW3HULRGZLOOEHGD\ZLWKD:DVKRXW3HULRGRIWRGD\VEHWZHHQ7UHDWPHQW
3HULRGV
7KH6FUHHQLQJ3HULRGEHJLQVDW9LVLW$W9LVLWVXEMHFWVZLOOVLJQDQLQIRUPHGFRQVHQW
IRUP,&)DQGLQFOXVLRQH[FOXVLRQFULWHULDZLOOEHDVVHVVHG7REHHOLJLEOHVXEMHFWVPXVWEH
RQHLWKHUD6$%$DVQHHGHGDVWKHLURQO\DVWKPDWKHUDS\RUDORZWRPHGLXP,&6GRVHHLWKHU
DORQHRULQFRPELQDWLRQZLWKD/$%$IRUDWOHDVWGD\VDVDFRQVLVWHQWUHJLPHQEHIRUH
VFUHHQLQJ6XEMHFWVPXVWKDYHDSUHEURQFKRGLODWRU)(9EHWZHHQDQGSUHGLFWHG
QRUPDOYDOXH
$OOVXEMHFWVPXVWGHPRQVWUDWH)(9UHYHUVLELOLW\WR9HQWROLQGHILQHGDVLPSURYHPHQWLQ
)(9RISRVW9HQWROLQGRVLQJGXULQJWKH6FUHHQLQJ3HULRGKLVWRULFDOUHYHUVLELOLW\LV
QRWDFFHSWDEOH)RUVXEMHFWVZKRGLGQRWDGPLQLVWHUWKHLUPRUQLQJDVWKPDPDLQWHQDQFH
PHGLFDWLRQVDQGRU6$%$UHYHUVLELOLW\ZLOOEHPHDVXUHGDW9LVLW)RUVXEMHFWVZKRUHFHLYHG
WKHLUPRUQLQJDVWKPDPDLQWHQDQFHPHGLFDWLRQVDQGRU6$%$UHYHUVLELOLW\ZLOOEHPHDVXUHG
DW9LVLWDZKLFKZLOORFFXUZLWKLQGD\VRI9LVLWDQGDIWHUWKHVHPHGLFDWLRQVKDYHEHHQ
KHOGIRUWKHDSSURSULDWHWLPHSHULRG7DEOH6XEMHFWVZKRGRQRWPHHWUHYHUVLELOLW\FULWHULD
DW9LVLWRU9LVLWDPD\EHUHWHVWHGDWDVXEVHTXHQW6FUHHQLQJ9LVLWDRUE2QO\
UHYHUVLELOLW\WHVWLQJDWWHPSWVDUHDOORZHG6XEMHFWVQRWPHHWLQJUHYHUVLELOLW\FULWHULDDIWHU
DWWHPSWVPXVWEHVFUHHQIDLOHG
6XEMHFWVPHHWLQJHOLJLELOLW\FULWHULDDW9LVLWZLOOHQWHUD6FUHHQLQJ3HULRG$OOVXEMHFWVLQWKLV
VWXG\ZLOOGLVFRQWLQXHWKHLUFXUUHQWDVWKPDPHGLFDWLRQVDW9LVLWDQGLQLWLDWH6SRQVRU
SURYLGHGDVWKPDPHGLFDWLRQWREHXVHGGXULQJWKH6FUHHQLQJ3HULRGDQGWKURXJKRXWWKH
GXUDWLRQRIWKHVWXG\DVIROORZV
x
6XEMHFWVZKRZHUHXVLQJRQO\6$%$DVQHHGHGEHIRUH9LVLWZLOO
GLVFRQWLQXHWKHLU6$%$DQGLQLWLDWH6SRQVRUSURYLGHG9HQWROLQWREH
XVHGDVQHHGHGXQWLOKRXUVEHIRUH9LVLW7KH\ZLOOWKHQGLVFRQWLQXH
6SRQVRUSURYLGHG9HQWROLQDQGLQLWLDWH6SRQVRUSURYLGHG$WURYHQWIRU
WKHGXUDWLRQRIWKHVWXG\WREHXVHGDVQHHGHGXSXQWLOKRXUVEHIRUH
HDFKVWXG\YLVLW
x
6XEMHFWVZKRZHUHUHFHLYLQJUHJXODUO\VFKHGXOHG,&6RU,&6/$%$
EHIRUH9LVLWZLOOGLVFRQWLQXHWKHLU,&6RU,&6/$%$DQGLQLWLDWH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

3XOPLFRUW)OH[KDOHUȝJRUȝJWZLFHDGD\%,'VHH7DEOHLQ
DGGLWLRQWRWKH6SRQVRUSURYLGHG9HQWROLQDQG$WURYHQWWREHXVHGDV
GHVFULEHGDERYH
)RUVXEMHFWVZKRZHUHXVLQJRQO\6$%$DVQHHGHGIRUUHVFXHEHIRUHVWXG\HQWU\WKH
PLQLPXP6FUHHQLQJ3HULRGZLOOEHGD\V)RUVXEMHFWVZKRZHUHUHFHLYLQJUHJXODUO\
VFKHGXOHG,&6RU,&6/$%$EHIRUHVWXG\HQWU\DQGZKRVZLWFKWR3XOPLFRUW)OH[KDOHUWKH
PLQLPXP5XQLQ3HULRGZLOOEHGD\V)RUDOOVXEMHFWVWKHPD[LPXP6FUHHQLQJ5XQLQ
3HULRGZLOOEHGD\V6XEMHFWVZLOOXVHRQO\WKHVH6SRQVRUSURYLGHGDVWKPDPHGLFDWLRQV
WKURXJKRXWWKH6FUHHQLQJ5XQLQ3HULRGDQGIRUWKHUHPDLQGHURIWKHVWXG\GXULQJERWKWKH
7UHDWPHQW3HULRGVDQG:DVKRXW3HULRG
5DQGRPL]DWLRQZLOOWDNHSODFHDW9LVLW$W9LVLWEHIRUHUDQGRPL]DWLRQVXEMHFWVPXVW
GHPRQVWUDWHDSUHEURQFKRGLODWRU)(9SUHGLFWHGQRUPDOYDOXHDYHUDJHRISUH
EURQFKRGLODWRUDVVHVVPHQWV6XEMHFWVZKRGRQRWPHHWWKLVUDQGRPL]DWLRQFULWHULRQZLOOEH
VFUHHQIDLOHG5DQGRPL]DWLRQZLOOEHFHQWUDOL]HGWKURXJKWKHXVHRIDQ,QWHUDFWLYH:HE
5HVSRQVH6\VWHP,:566XEMHFWVZLOOEHUDQGRPL]HGWRRIWUHDWPHQWVHTXHQFHV$%RU
%$ZKHUH
x
$ $60',LQKDODWLRQVRIȝJSHULQKDODWLRQ
x
% 3URYHQWLOLQKDODWLRQVRIȝJSHULQKDODWLRQ
$WHDFK7UHDWPHQW9LVLW9LVLWVDQGVXEMHFWVZLOOUHFHLYHGRVHVRIRSHQODEHOVWXG\
GUXJ$60',RU3URYHQWLOPLQXWHVDSDUW$WRGD\:DVKRXW3HULRGZLOORFFXU
EHWZHHQ7UHDWPHQW9LVLWV$WHDFK7UHDWPHQW9LVLWEURQFKRGLODWLRQDFWLYLW\RIWKHVWXG\GUXJ
ZLOOEHDVVHVVHGWKURXJKSXOPRQDU\IXQFWLRQWHVWLQJ3)7DQGH[WUDSXOPRQDU\3'YDULDEOHV
ZLOOEHDVVHVVHGVHUXPSRWDVVLXPDQGJOXFRVHGLDVWROLFEORRGSUHVVXUH>'%3@V\VWROLFEORRG
SUHVVXUH>6%3@47F)DQG+5
6XEMHFWVZLOOEHUHTXLUHGWRUHPDLQDWWKHFOLQLFXQWLOFRPSOHWLRQRIDOOSURWRFROGHILQHG
DVVHVVPHQWV7DEOH6DIHW\ZLOODOVREHDVVHVVHGE\HYDOXDWLRQRI$(V
6XEMHFWVZKRSUHPDWXUHO\GLVFRQWLQXHVWXG\GUXJIRUDQ\UHDVRQEHIRUHFRPSOHWLQJDOOVWXG\
YLVLWVZLOOXQGHUJRD3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW$IWHUWKHVHFRQG7UHDWPHQW9LVLWRU
IROORZLQJWKH3UHPDWXUH'LVFRQWLQXDWLRQ9LVLWVXEMHFWVZLOOEHVFKHGXOHGIRUDIROORZXS
WHOHSKRQHFDOOWRGD\VIURPWKHGDWHRIWKHODVWVWXG\GUXJGRVH
7KHHQGRIVWXG\LVGHILQHGDVWKHODVWVXEMHFW¶VIROORZXSWHOHSKRQHFDOO
PK substudy
$SSUR[LPDWHO\VXEMHFWVZLOODOVRSDUWLFLSDWHLQD3.VXEVWXG\3KDUPDFRNLQHWLFVDPSOHV
ZLOOEHFROOHFWHGPLQXWHVDIWHUHDFKFXPXODWLYHGRVHDQGWKURXJKKRXUVDIWHUWKHODVW
GRVHRIVWXG\GUXJVHH7DEOH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Figure 1
Study Design Flow Chart

6XEMHFWVRQ,&6RU,&6/$%$SULRUWR9LVLWZLOOEHUXQLQRQ3XOPLFRUW)OH[KDOHURUJ%,'IRUDPLQLPXPRI
GD\V
$EEUHYLDWLRQV9 YLVLW5 UDQGRPL]DWLRQ



&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

1.5
Study governance and oversight
1RVWXG\JRYHUQDQFHRURYHUVLJKWFRPPLWWHHVZLOOEHXVHGLQWKLVVWXG\
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective
Outcome Measure
7RDVVHVVWKHHIILFDF\RI$60',FRPSDUHGWR
3URYHQWLORQOXQJIXQFWLRQDIWHUFXPXODWLYH
GRVHVRIXSWRJ
3ULPDU\
%DVHOLQHDGMXVWHG)(9PLQXWHVDIWHUHDFK
FXPXODWLYHGRVH
6HFRQGDU\
%DVHOLQHDGMXVWHG)(9$8&DIWHUWKHODVW
FXPXODWLYHGRVH
2.2
Secondary objectives
Secondary Objectives
Outcome Measure 
7RDVVHVVWKHH[WUDSXOPRQDU\3'HIIHFWVRI$6
0',DQG3URYHQWLODIWHUHDFKFXPXODWLYHGRVH
XSWRDFXPXODWLYHGRVHRIJ
7KHIROORZLQJYDULDEOHVZLOOEHFROOHFWHGDW
PLQXWHVDIWHUHDFKFXPXODWLYHGRVHDQG
DQGPLQXWHVDIWHUWKHODVW
FXPXODWLYHGRVH
x
47F)DQG+5
x
6HUXPJOXFRVHDQGSRWDVVLXP
x
'%3DQG6%3
2.3
Safety objectives
Safety Objective
Outcome Measure 
7RDVVHVVWKHVDIHW\RIFXPXODWLYHGRVHVRI$6
0',UHODWLYHWR3URYHQWLO
$(VVHULRXVDGYHUVHHYHQWV6$(V



&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

2.4
PK substudy
PK Objective
Outcome Measure
7RFRPSDUHWKHUHODWLYHV\VWHPLF
ELRDYDLODELOLW\RI$60',DQG3URYHQWLODIWHU
FXPXODWLYHGRVHVXSWRJ
3ODVPDFRQFHQWUDWLRQREVHUYHGDWPLQXWHVSRVW
HDFKFXPXODWLYHGRVH&PLQ
$8&IURPWLPHWRWKHWLPHRIWKHODVWPHDVXUDEOH
SODVPDFRQFHQWUDWLRQ$8&WSRVWWKHILQDO
FXPXODWLYHGRVH
0D[LPXPREVHUYHGSODVPDFRQFHQWUDWLRQ&PD[DQG
WLPHWRUHDFK&PD[7PD[DIWHUWKHODVWGRVH

2.5
Exploratory objectives – not applicable
3.
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL
(DFKVXEMHFWPXVWPHHWDOORIWKHLQFOXVLRQFULWHULDDQGQRQHRIWKHH[FOXVLRQFULWHULDIRUWKLV
VWXG\8QGHUQRFLUFXPVWDQFHVZLOOWKHUHEHH[FHSWLRQVWRWKLVUXOH
3.1
Inclusion criteria
(DFKVXEMHFWPXVWPHHWWKHIROORZLQJFULWHULDLQUHODWLRQVKLSWR9LVLWXQOHVVRWKHUZLVH
QRWHGWREHHQUROOHGLQWKLVVWXG\

*LYHWKHLUVLJQHGZULWWHQLQIRUPHGFRQVHQWWRSDUWLFLSDWH

$UHDWOHDVW\HDUVRIDJHDQGQRROGHUWKDQ\HDUV

+DYHVWDEOHIRUPRQWKVSK\VLFLDQGLDJQRVHGDVWKPDZLWKKLVWRULFDO
GRFXPHQWDWLRQRIWKHGLDJQRVLV

0XVWEHUHFHLYLQJRIWKHIROORZLQJUHTXLUHGLQKDOHGDVWKPDWKHUDSLHVOLVWHGEHORZ
IRUDWOHDVWWKHODVWGD\V
x
2QO\6$%$ZKLFKLVXVHGDVQHHGHGIRUUHVFXH
x
/RZWRPHGLXPGRVHVRI,&6DORQHRULQFRPELQDWLRQZLWK/$%$XVHG
UHJXODUO\DVPDLQWHQDQFHDVWKPDWKHUDS\ZLWKWKH,&6GRVHVDOORZHGLQ
7DEOHZLWKDVWDEOHUHJLPHQ

3UHEURQFKRGLODWRU)(9RIWRSUHGLFWHGQRUPDOYDOXHDIWHUZLWKKROGLQJ
6$%$KRXUVDQGRUDW9LVLWDDQGRUELIDSSOLFDEOH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK


&RQILUPHG)(9UHYHUVLELOLW\WR9HQWROLQGHILQHGDVDSRVW9HQWROLQLQFUHDVHLQ
)(9RIDWHLWKHU9LVLW9LVLWDRU9LVLWERQO\UHYHUVLELOLW\WHVWLQJ
DWWHPSWVDUHDOORZHG

'HPRQVWUDWHDFFHSWDEOHVSLURPHWU\SHUIRUPDQFHLHPHHW$PHULFDQ7KRUDFLF
6RFLHW\>$76@(XURSHDQ5HVSLUDWRU\6RFLHW\>(56@DFFHSWDELOLW\UHSHDWDELOLW\
FULWHULD$SSHQGL[$

:LOOLQJDQGLQWKHRSLQLRQRIWKH,QYHVWLJDWRUDEOHWRDGMXVWFXUUHQWDVWKPD
WKHUDS\DVUHTXLUHGE\WKHSURWRFRO

'HPRQVWUDWHDFFHSWDEOH0',DGPLQLVWUDWLRQWHFKQLTXH
Note8VHRIDVSDFHUGHYLFHGXULQJWKH6FUHHQLQJDQGUDQGRPL]HG7UHDWPHQW
3HULRGVLVQRWSHUPLWWHG

%RG\PDVVLQGH[NJP

,IDIHPDOHRIFKLOGEHDULQJSRWHQWLDOKDYHDQHJDWLYHVHUXPSUHJQDQF\WHVW

:RPHQRIFKLOGEHDULQJSRWHQWLDOPXVWDJUHHWRRIWKHIROORZLQJWRSUHYHQW
SUHJQDQF\
(Note::RPHQDUHFRQVLGHUHGWREHRIQRQFKLOGEHDULQJSRWHQWLDOLIWKH\DUH
SK\VLRORJLFDOO\LQFDSDEOHRIEHFRPLQJSUHJQDQWLQFOXGLQJDQ\IHPDOHZKRLV
\HDUVSRVWPHQRSDXVDORUVXUJLFDOO\VWHULOHGHILQHGDVKDYLQJDELODWHUDO
RRSKRUHFWRP\K\VWHUHFWRP\RUWXEDOOLJDWLRQ)RUSXUSRVHVRIWKLVSURWRFRO
PHQRSDXVDOZRPHQDUHGHILQHGDVZRPHQ\HDUVROGZKRDUHDPHQRUUKHLFIRU
FRQVHFXWLYHPRQWKVRUPRUHIROORZLQJFHVVDWLRQRIDOOH[RJHQRXVKRUPRQDO
WUHDWPHQW
x
3UDFWLFHDEVWLQHQFH
x
,IDIHPDOHRIFKLOGEHDULQJSRWHQWLDODQGVH[XDOO\DFWLYHDJUHHVWRSUHYHQW
SUHJQDQF\E\XVLQJRIWKHIROORZLQJPHWKRGVRIELUWKFRQWUROIURPWKH
GDWHWKH,&)LVVLJQHGXQWLOZHHNVDIWHUWKHILQDOGRVHRIVWXG\GUXJLV
WDNHQ
o
+RUPRQDOFRQWUDFHSWLRQHJRUDOFRQWUDFHSWLYHFRQWUDFHSWLYH
LPSODQWRULQMHFWDEOHKRUPRQDOFRQWUDFHSWLYH
o
'RXEOHEDUULHUELUWKFRQWUROHJFRQGRPSOXVLQWUDXWHULQHGHYLFH
GLDSKUDJPSOXVVSHUPLFLGHRUFRQGRPSOXVVSHUPLFLGH
o
0DLQWHQDQFHRIDPRQRJDPRXVVH[XDOUHODWLRQVKLSZLWKDPDOH
SDUWQHUZKRKDVEHHQVXUJLFDOO\VWHULOL]HGE\YDVHFWRP\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK


0DOHVXEMHFWVZKRDUHVH[XDOO\DFWLYHPXVWEHVXUJLFDOO\VWHULOHRUDJUHHWRXVHD
GRXEOHEDUULHUPHWKRGRIFRQWUDFHSWLRQFRQGRPZLWKVSHUPLFLGHIURPWKHILUVW
GRVHRIUDQGRPL]HGVWXG\GUXJXQWLOZHHNVDIWHUWKHLUODVWGRVHDQGPXVWQRW
GRQDWHVSHUPGXULQJWKHLUVWXG\SDUWLFLSDWLRQSHULRG

&RPSOLDQFHPXVWEHZLOOLQJWRUHPDLQDWWKHVWXG\FHQWHUDVUHTXLUHGSHUSURWRFRO
WRFRPSOHWHDOOYLVLWDVVHVVPHQWV
3.2
Exclusion criteria
6XEMHFWVZKRPHHWDQ\RIWKHIROORZLQJFULWHULDLQUHODWLRQVKLSWR9LVLWXQOHVVRWKHUZLVH
VWDWHGZLOOEHH[FOXGHGIURPWKHVWXG\

&KURQLFREVWUXFWLYHSXOPRQDU\GLVHDVHRURWKHUVLJQLILFDQWOXQJGLVHDVHHJFKURQLF
EURQFKLWLVHPSK\VHPDEURQFKLHFWDVLVZLWKWKHQHHGRIWUHDWPHQWF\VWLFILEURVLVRU
EURQFKRSXOPRQDU\G\VSODVLD

2UDOFRUWLFRVWHURLGXVHDQ\GRVHZLWKLQZHHNV

5HFHLYHGDQ\PDUNHWHGHJRPDOL]XPDEPHSROL]XPDEUHVOL]XPDERU
LQYHVWLJDWLRQDOELRORJLFZLWKLQPRQWKVRUKDOIOLYHVZKLFKHYHULVORQJHURUDQ\
RWKHUPHGLFDWLRQVSHFLILFDOO\SURKLELWHGE\WKHSURWRFROZLWKLQWKHLQGLFDWHG
H[FOXVLRQDU\WLPHSHULRGV7DEOHDQG7DEOH

5HFHLYHGWLRWURSLXPZLWKLQZHHNV

&XUUHQWVPRNHUVIRUPHUVPRNHUVZLWK!SDFN\HDUVKLVWRU\RUIRUPHUVPRNHUV
ZKRVWRSSHGVPRNLQJPRQWKVLQFOXGLQJDOOIRUPVRIWREDFFRHFLJDUHWWHV
>YDSLQJ@DQGPDULMXDQD

/LIHWKUHDWHQLQJDVWKPDDVGHILQHGDVDQ\KLVWRU\RIVLJQLILFDQWDVWKPDHSLVRGHV
UHTXLULQJLQWXEDWLRQDVVRFLDWHGZLWKK\SHUFDSQLDUHVSLUDWRU\DUUHVWK\SR[LF
VHL]XUHVRUDVWKPDUHODWHGV\QFRSDOHSLVRGHV

&RPSOHWHGWUHDWPHQWIRUORZHUUHVSLUDWRU\LQIHFWLRQRUDVWKPDH[DFHUEDWLRQZLWKLQ
ZHHNV

8SSHUUHVSLUDWRU\LQIHFWLRQQRWUHVROYHGZLWKLQGD\V

+RVSLWDOL]DWLRQVIRUDVWKPDZLWKLQPRQWKV

&OLQLFDOO\VLJQLILFDQWODERUDWRU\DEQRUPDOLWLHVRU(&*DEQRUPDOLWLHVLQWKHRSLQLRQ
RIWKH,QYHVWLJDWRU
Note:LIODERUDWRU\WHVWVKDYHWREHUHSHDWHGWKHUHVXOWVVKRXOGEHDYDLODEOHIRU
UHYLHZEHIRUH9LVLW5DQGRPL]DWLRQ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK


+LVWRULFDORUFXUUHQWHYLGHQFHRIDFOLQLFDOO\VLJQLILFDQWGLVHDVHLQFOXGLQJEXWQRW
OLPLWHGWRFDUGLRYDVFXODUHJFRQJHVWLYHKHDUWIDLOXUHNQRZQDRUWLFDQHXU\VP
FOLQLFDOO\VLJQLILFDQWFDUGLDFDUUK\WKPLDFRURQDU\KHDUWGLVHDVHKHSDWLFUHQDO
KHPDWRORJLFDOQHXURSV\FKRORJLFDOHQGRFULQHHJXQFRQWUROOHGGLDEHWHVPHOOLWXV
XQFRQWUROOHGWK\URLGGLVRUGHU$GGLVRQ¶VGLVHDVH&XVKLQJ¶VV\QGURPHRU
JDVWURLQWHVWLQDOHJSRRUO\FRQWUROOHGSHSWLFXOFHUJDVWURHVRSKDJHDOUHIOX[GLVHDVH
6LJQLILFDQWLVGHILQHGDVDQ\GLVHDVHWKDWLQWKHRSLQLRQRIWKH,QYHVWLJDWRUZRXOG
SXWWKHVDIHW\RIWKHVXEMHFWDWULVNWKURXJKVWXG\SDUWLFLSDWLRQRUWKDWFRXOGDIIHFW
WKHHIILFDF\RUVDIHW\DQDO\VLVLIWKHGLVHDVHFRQGLWLRQH[DFHUEDWHGGXULQJWKHVWXG\

&DQFHUQRWLQFRPSOHWHUHPLVVLRQIRUDWOHDVW\HDUV
Note:6XEMHFWVZLWKVTXDPRXVFHOOFDUFLQRPDRIWKHVNLQEDVDOFHOOFDUFLQRPDRI
WKHVNLQLQVLWXFDUFLQRPDRIWKHFHUYL[RUORFDOL]HGSURVWDWHFDQFHUDUHHOLJLEOHLI
LQWKHRSLQLRQRIWKH,QYHVWLJDWRUWKHFRQGLWLRQKDVEHHQDGHTXDWHO\ZRUNHGXSDQG
FOLQLFDOO\FRQWUROOHGDQGWKHVXEMHFW¶VSDUWLFLSDWLRQLQWKHVWXG\ZRXOGQRWUHSUHVHQW
DVDIHW\FRQFHUQ

+RVSLWDOL]HGIRUSV\FKLDWULFGLVRUGHURUDWWHPSWHGVXLFLGHZLWKLQ\HDU

+LVWRU\RISV\FKLDWULFGLVHDVHLQWHOOHFWXDOGHILFLHQF\SRRUPRWLYDWLRQRURWKHU
FRQGLWLRQVOLPLWLQJLQIRUPHGFRQVHQWYDOLGLW\

6LJQLILFDQWLQWKHRSLQLRQRIWKH,QYHVWLJDWRUDEXVHRIDOFRKRORUGUXJV

+\SHUVHQVLWLYLW\WRȕDJRQLVWVRUDQ\FRPSRQHQWRIWKHLQYHVWLJDWLRQDO0',RUDQ\
FRPSRQHQWRI3URYHQWLO9HQWROLQRU$WURYHQWRU3XOPLFRUW)OH[KDOHULI
DSSOLFDEOH

8QDEOHWRDEVWDLQIURPSURWRFROGHILQHGSURKLELWHGPHGLFDWLRQVGXULQJWKHVWXG\

8VLQJDQ\KHUEDOSURGXFWVE\LQKDODWLRQRUQHEXOL]HUZLWKLQZHHNVDQGGRHVQRW
DJUHHWRVWRSGXULQJWKHVWXG\GXUDWLRQ

5HFHLYHGDOLYHDWWHQXDWHGYDFFLQDWLRQZLWKLQGD\V

&XUUHQWO\SUHJQDQWRUQXUVLQJ

6WXG\LQYHVWLJDWRUVVXELQYHVWLJDWRUVFRRUGLQDWRUVDQGWKHLUHPSOR\HHVRU
LPPHGLDWHIDPLO\PHPEHUVRUHPSOR\HHVRIWKH6SRQVRU

7UHDWPHQWZLWKLQYHVWLJDWLRQDOVWXG\GUXJRUGHYLFHLQDQRWKHUFOLQLFDOVWXG\
ZLWKLQWKHODVWGD\VRUKDOIOLYHVZKLFKHYHULVORQJHU

5DQGRPL]HGLQDQ\37VWXG\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

3.3
Subject enrollment and randomization
3.3.1
Randomization criteria
(DFKVXEMHFWPXVWPHHWWKHIROORZLQJFULWHULDRQWKHPRUQLQJRI9LVLWWREHUDQGRPL]HG

6XEMHFWVRIFKLOGEHDULQJSRWHQWLDOPXVWKDYHDQHJDWLYHXULQHSUHJQDQF\WHVW

5HFHLYHGQRDVWKPDPHGLFDWLRQRWKHUWKDQ6SRQVRUSURYLGHG3XOPLFRUW)OH[KDOHU
JRUJ%,'DVDVVLJQHGDQGRU6SRQVRUSURYLGHG9HQWROLQDQG$WURYHQW
IURP9LVLWWR9LVLWH[FHSWIRUDOORZDEOHDOOHUJ\PHGLFDWLRQVGHILQHGLQ7DEOH

7KHODVWGRVHRI3XOPLFRUW)OH[KDOHULIDSSOLFDEOHZDVWKHSUHYLRXVQLJKWLH
PRUQLQJGRVHRI3XOPLFRUW)OH[KDOHUZDVQRWDGPLQLVWHUHGWKHODVWGRVHRI
6SRQVRUSURYLGHG9HQWROLQZDVQRODWHUWKDQKRXUVEHIRUHWKHVWXG\YLVLWDQGWKH
ODVWGRVHRI$WURYHQWZDVQRODWHUWKDQKRXUVEHIRUHWKHVWXG\YLVLWLI6$%$LV
QHHGHGLQWKHPRUQLQJWKHYLVLWPXVWEHUHVFKHGXOHG

3UHEURQFKRGLODWRU)(9SHUFHQWSUHGLFWHGQRUPDOYDOXH

+DVQRWXVHG!DFWXDWLRQVSHUGD\LHGRVHVRIDFWXDWLRQVSHUGD\RI6SRQVRU
SURYLGHGUHVFXHPHGLFDWLRQ9HQWROLQDQG$WURYHQWIRUUHVFXHRQPRUHWKDQDQ\
GD\VGXULQJWKHSUHYLRXVGD\V

1RXSSHUUHVSLUDWRU\LQIHFWLRQORZHUUHVSLUDWRU\LQIHFWLRQRUDVWKPDH[DFHUEDWLRQ
GXULQJWKH6FUHHQLQJ3HULRG

'HPRQVWUDWHDFFHSWDEOH0',DGPLQLVWUDWLRQWHFKQLTXH

$EOHWRFRPSO\ZLWKVWXG\SURFHGXUHV
)RUSURFHGXUHVIRUZLWKGUDZDORILQFRUUHFWO\UDQGRPL]HGVXEMHFWVVHH6HFWLRQ
3.3.2
Subject identification
$OOVXEMHFWVZKRXQGHUJRVFUHHQLQJZLOOEHDVVLJQHGDXQLTXHVFUHHQLQJLGHQWLILFDWLRQQXPEHU
,'DW9LVLW2QO\VXEMHFWVFRQWLQXLQJWRPHHWDOOWKHLQFOXVLRQFULWHULDDQGQRQHRIWKH
H[FOXVLRQFULWHULDDW9LVLWDQGZKRPHHWUDQGRPL]DWLRQFULWHULDDW9LVLWZLOOEHDVVLJQHGD
XQLTXHVXEMHFWUDQGRPL]DWLRQQXPEHU
3.3.3
Screen failures
6FUHHQLQJIDLOXUHVDUHVXEMHFWVZKRGRQRWIXOILOWKHHOLJLELOLW\FULWHULDIRUWKHVWXG\DQG
WKHUHIRUHPXVWQRWEHUDQGRPL]HG


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

3.4
Procedures for handling incorrectly enrolled or randomized 
subjects
6XEMHFWVZKRIDLOWRPHHWWKHHOLJLELOLW\FULWHULDVKRXOGQRWXQGHUDQ\FLUFXPVWDQFHVEH
HQUROOHGLQWRWKH6FUHHQLQJ3HULRGRUUHFHLYHVWXG\GUXJ7KHUHFDQEHQRH[FHSWLRQVWRWKLV
UXOH6XEMHFWVZKRDUHHQUROOHGLQWRWKH6FUHHQLQJ3HULRGEXWVXEVHTXHQWO\IRXQGQRWWRPHHW
DOOWKHHOLJLELOLW\FULWHULDPXVWQRWEHUDQGRPL]HGRULQLWLDWHGRQVWXG\GUXJ
,IDVXEMHFWGRHVQRWPHHWDOOWKHHOLJLELOLW\FULWHULDDQGLVUDQGRPL]HGLQHUURURULVLQFRUUHFWO\
VWDUWHGRQVWXG\GUXJWKH,QYHVWLJDWRUVKRXOGLQIRUPWKH6SRQVRULPPHGLDWHO\DQGWKH
6SRQVRUDQGWKH,QYHVWLJDWRUVKRXOGGLVFXVVZKHWKHUWRFRQWLQXHRUGLVFRQWLQXHWKHVXEMHFW
IURPVWXG\GUXJDQGZLWKGUDZWKHVXEMHFWIURPWKHVWXG\7KH6SRQVRUPXVWHQVXUHDOO
GHFLVLRQVDUHDSSURSULDWHO\GRFXPHQWHG
3.5
Methods for assigning treatment groups
7KHUDQGRPL]DWLRQVFKHPHZLOOEHJHQHUDWHGE\WKH6SRQVRURUGHVLJQHHXVLQJFRPSXWHU
VRIWZDUHLQFRUSRUDWLQJDUDQGRPQXPEHUJHQHUDWRU6XEMHFWVZLOOEHUDQGRPO\DVVLJQHGWR
RIWUHDWPHQWVHTXHQFHV$%RU%$XVLQJDQ,:56(DFKVHTXHQFHZLOOFRPSULVHWKH
IROORZLQJFXPXODWLYHGRVHWUHDWPHQWDUPV
x
$ $60',LQKDODWLRQVRIȝJSHULQKDODWLRQ
x
% 3URYHQWLOLQKDODWLRQVRIȝJSHULQKDODWLRQ
5DQGRPL]DWLRQZLOOEHFHQWUDOL]HG
3.6
Methods for ensuring blinding – not applicable
3.7
Methods for unblinding – not applicable
3.8
Restrictions
3URKLELWHGFRQFRPLWDQWPHGLFDWLRQVDUHGHVFULEHGLQ6HFWLRQ
3.8.1
Illicit drugs
,OOLFLWGUXJVRUGUXJVRIDEXVHZLOOQRWEHDOORZHGIURP9LVLWWRWKHHQGRIWKHIROORZXS
WHOHSKRQHFDOORUWRZKHQHYHUWKHVXEMHFWGLVFRQWLQXHVIURPWKHVWXG\GUXJDQGZLWKGUDZV
IURP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IURP
VWXG\GUXJDQGZLWKGUDZQIURPWKHVWXG\DWWKHGLVFUHWLRQRIWKH,QYHVWLJDWRU0HGLFDO
PDULMXDQDHGLEOHVDQGWLQFWXUHVRQO\LQKDOHGPDULMXDQDLVH[FOXGHGLVQRWDQH[FOXVLRQDU\
GUXJLIXVHGIRUPHGLFDOSXUSRVHVDQGWKHGRVHRUIUHTXHQF\RIFRQVXPSWLRQGRHVQRWFKDQJH
GXULQJWKH6FUHHQLQJ3HULRGRUWKURXJKRXWWKHVWXG\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

3.8.2
Dietary restrictions
6XEMHFWVPXVWQRWLQJHVW[DQWKLQHDQGRU[DQWKLQHDQDORJXHFDIIHLQHFRQWDLQLQJIRRGVRU
EHYHUDJHVRUFDIIHLQHFRQWDLQLQJPHGLFDWLRQVIRUDWOHDVWKRXUVEHIRUHHDFKVWXG\YLVLWDQG
WKURXJKRXWWKHGXUDWLRQRIHDFKVWXG\YLVLW([DPSOHVRIVXFKSURGXFWVLQFOXGHFRIIHHWHD
FKRFRODWHDQGFROD'HFDIIHLQDWHGEHYHUDJHVDUHDFFHSWDEOH
3.9
Discontinuation of study drug
$OOVXEMHFWVZKRGLVFRQWLQXHVWXG\GUXJZLOOEHZLWKGUDZQIURPWKHVWXG\
6XEMHFWVPD\EHZLWKGUDZQIURPWKHVWXG\DWWKHLURZQUHTXHVWDWDQ\WLPHIRUDQ\UHDVRQ
6XEMHFWVH[SHULHQFLQJDQ\RIWKHFKDQJHVRIFRQFHUQOLVWHGEHORZVKRXOGEHGLVFRQWLQXHGIURP
UDQGRPL]HGVWXG\GUXJDQGZLWKGUDZQIURPWKHVWXG\
x
$VWKPDZRUVHQLQJUHTXLULQJFKDQJHLQDVWKPDWUHDWPHQWRWKHUWKDQ
3XOPLFRUW)OH[KDOHULIDVVLJQHGDQGDVQHHGHG6SRQVRUSURYLGHG9HQWROLQ
DQG$WURYHQW
Note:6XEMHFWVH[SHULHQFLQJDQDVWKPDH[DFHUEDWLRQGXULQJWKHVWXG\ZLOO
EHHYDOXDWHGE\WKH,QYHVWLJDWRUDQGWUHDWHGZLWKPHGLFDWLRQVIRUDVWKPD
GHHPHGPHGLFDOO\QHFHVVDU\DQGZLOOEHGLVFRQWLQXHGIURPVWXG\GUXJDQG
ZLWKGUDZQIURPWKHVWXG\
x


x
5HTXLUHPHQWIRUDQ\RIWKHSURKLELWHGPHGLFDWLRQVOLVWHGLQ6HFWLRQ
x
$Q\VDIHW\UHDVRQDVMXGJHGE\WKH,QYHVWLJDWRUDQGRU6SRQVRU
x
3UHJQDQF\
x
7KHVXEMHFW¶VWUHDWPHQWFRGHLVSUHPDWXUHO\EURNHQE\WKH,QYHVWLJDWRU
6XEMHFWVZKRGLVFRQWLQXHVWXG\GUXJDQGZLWKGUDZIURPWKHVWXG\VKRXOGEHHQFRXUDJHGWR
FRPSOHWHWKH3UHPDWXUH'LVFRQWLQXDWLRQ9LVLWVHH6HFWLRQ
Withdrawal of the informed consent
6XEMHFWVDUHIUHHWRZLWKGUDZIURPWKHVWXG\DWDQ\WLPHZLWKRXWSUHMXGLFHWRIXUWKHU
WUHDWPHQW
$VXEMHFWZKRZLWKGUDZVFRQVHQWZLOODOZD\VEHDVNHGDERXWWKHUHDVRQVDQGWKHSUHVHQFHRI
DQ\$(7KH,QYHVWLJDWRUZLOOIROORZXS$(VRXWVLGHRIWKHFOLQLFDOVWXG\
,IDVXEMHFWZLWKGUDZVIURPSDUWLFLSDWLRQLQWKHVWXG\WKHQKLVKHUHQUROOPHQWDQGRU
UDQGRPL]DWLRQFRGHVFDQQRWEHUHXVHG:LWKGUDZQVXEMHFWVZLOOQRWEHUHSODFHG


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

3.10
Discontinuation of the study
7KHVWXG\PD\EHVWRSSHGLILQWKHMXGJPHQWRIWKH6SRQVRUVWXG\VXEMHFWVDUHSODFHGDW
XQGXHULVNEHFDXVHRIFOLQLFDOO\VLJQLILFDQWILQGLQJVWKDW
x
PHHWLQGLYLGXDOVWRSSLQJFULWHULDRUDUHRWKHUZLVHFRQVLGHUHGVLJQLILFDQW
x
DUHDVVHVVHGDVFDXVDOO\UHODWHGWRVWXG\GUXJ
x
DUHQRWFRQVLGHUHGWREHFRQVLVWHQWZLWKFRQWLQXDWLRQRIWKHVWXG\
7KH6SRQVRUUHVHUYHVWKHULJKWWRWHUPLQDWH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\
WKH6SRQVRULQDWLPHIUDPHWKDWLVFRPSDWLEOHZLWKWKHVXEMHFWV¶ZHOOEHLQJ
5HJDUGOHVVRIWKHUHDVRQIRUWHUPLQDWLRQDOOGDWDDYDLODEOHIRUWKHVXEMHFWDWWKHWLPHRI
GLVFRQWLQXDWLRQRIIROORZXSPXVWEHUHFRUGHGLQWKHHOHFWURQLFFDVHUHSRUWIRUPH&5)$OO
UHDVRQVIRUGLVFRQWLQXDWLRQRIVWXG\GUXJPXVWEHGRFXPHQWHG
,QWHUPLQDWLQJWKHVWXG\WKH6SRQVRUZLOOHQVXUHWKDWDGHTXDWHFRQVLGHUDWLRQLVJLYHQWRWKH
SURWHFWLRQRIWKHVXEMHFWV¶LQWHUHVWV
4.
STUDY PLAN AND TIMING OF PROCEDURES 
Note:%HIRUHFRQGXFWLQJDQ\VWXG\UHODWHGSURFHGXUHVVXEMHFWVDUHUHTXLUHGWRSURYLGHWKHLU
ZULWWHQLQIRUPHGFRQVHQWXVLQJWKH,QVWLWXWLRQDO5HYLHZ%RDUG,5%DSSURYHG,&)7KH,&)
VKRXOGEHVLJQHGE\WKHVXEMHFWGXULQJ9LVLW
$OOVWXG\YLVLWVZLOOWDNHSODFHDWDSSUR[LPDWHO\WKHVDPHWLPHRIGD\$WLPHDQGHYHQWV
VFKHGXOHLVSURYLGHGLQ7DEOH$GHWDLOHGVFKHGXOHRIWLPHGDVVHVVPHQWVLVSURYLGHGLQ
7DEOH
:KHQSRVWGRVHGDWDFROOHFWLRQWLPHSRLQWVDUHFRQFXUUHQWYDULDEOHVZLOOEHFROOHFWHGLQWKH
IROORZLQJRUGHUEORRGSUHVVXUH(&*FOLQLFDOODERUDWRU\DVVHVVPHQWV3.EORRGVDPSOHVLI
DSSOLFDEOHDQGVSLURPHWU\



&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table 1
Schedule of Events
Procedures
Screeninga
Treatment Phase
Follow-up
For details see 
Section
Visit 1
Visit 
1a/1b
Visit 2
Randomization 
(TP 1)
Day 1
Visit 3b
(TP 2)
PDV (if 
applicable)c
TC
3-7 days 
after final 
dose
Day -28 to Day -1
,QIRUPHGFRQVHQW
;





6HFWLRQ
(OLJLELOLW\FULWHULD
;





6HFWLRQ
9HULI\UDQGRPL]DWLRQFULWHULD


;



6HFWLRQ
9HULI\FRQWLQXHGHOLJLELOLW\

;

;


6HFWLRQ
0',GHPRQVWUDWLRQWUDLQLQJ
;

;
;


6HFWLRQ
9HQWROLQUHYHUVLELOLW\WHVWG
;
;




6HFWLRQ
0HGLFDOVXUJLFDOKLVWRU\
;





6HFWLRQ
'HPRJUDSKLFV
;





6HFWLRQ
&RQFRPLWDQWPHGLFDWLRQVH
;
;
;
;
;

6HFWLRQ
6SLURPHWU\G
;
;
;
;


6HFWLRQ




;


6HFWLRQ
3K\VLFDOH[DPLQDWLRQI
;


;
;

6HFWLRQ
6%3'%3
;

;
;
;

6HFWLRQ
OHDG(&*
;

;
;
;

6HFWLRQ
3UHJQDQF\WHVWJ
;

;



6HFWLRQ
&OLQLFDOODERUDWRU\WHVWLQJ
;





6HFWLRQ
3'VDPSOHFROOHFWLRQ


;
;
;

6HFWLRQ
$GMXVWDVWKPDPHGLFDWLRQVSHUSURWRFROK
;


;
;

6HFWLRQ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table 1
Schedule of Events
Procedures
Screeninga
Treatment Phase
Follow-up
For details see 
Section
Visit 1
Visit 
1a/1b
Visit 2
Randomization 
(TP 1)
Day 1
Visit 3b
(TP 2)
PDV (if 
applicable)c
TC
3-7 days 
after final 
dose
Day -28 to Day -1
5DQGRPL]DWLRQ


;



6HFWLRQ
5DQGRPL]HGVWXG\GUXJDGPLQLVWHUHG


;
;


6HFWLRQ
3.VDPSOHFROOHFWLRQL


;
;


6HFWLRQ
$(V
;
;
;
;
;
;
6HFWLRQ
7HOHSKRQHFRQWDFW





;
6HFWLRQ
$EEUHYLDWLRQV$( DGYHUVHHYHQW'%3 GLDVWROLFEORRGSUHVVXUH(&* HOHFWURFDUGLRJUDP)(9 IRUFHGH[SLUDWRU\YROXPHLQVHFRQG0', PHWHUHGGRVH
LQKDOHU3'9 3UHPDWXUH'LVFRQWLQXDWLRQ9LVLW3. SKDUPDFRNLQHWLF6$%$ VKRUWDFWLQJȕDJRQLVW6%3 V\VWROLFEORRGSUHVVXUH7& WHOHSKRQHFDOO
73 7UHDWPHQW3HULRG
Note::KHQSRVWGRVHGDWDFROOHFWLRQWLPHSRLQWVDUHFRQFXUUHQWYDULDEOHVZLOOEHFROOHFWHGLQWKHIROORZLQJRUGHUEORRGSUHVVXUH(&*FOLQLFDOODERUDWRU\
DVVHVVPHQWV3.EORRGVDPSOHVLIDSSOLFDEOHDQGVSLURPHWU\
D
6FUHHQLQJ3HULRGZLOOEHWRGD\VIRUVXEMHFWVRQ6$%$RQO\EHIRUHVWXG\HQWU\DQGWRGD\VIRUVXEMHFWVRQ,&6RU,&6/$%$EHIRUHVWXG\
HQWU\
E
6XEMHFWVWRUHWXUQWRFOLQLFZLWKLQWRGD\VIROORZLQJ7UHDWPHQW9LVLW
F
6XEMHFWVZKRSUHPDWXUHO\ZLWKGUDZIURPWKHVWXG\ZLOOXQGHUJRD3UHPDWXUH'LVFRQWLQXDWLRQ9LVLWVHH6HFWLRQ
G
)RUVXEMHFWVZKRUHFHLYHGWKHLUUHJXODUO\LQKDOHGDVWKPDPHGLFDWLRQVDQGRU6$%$RQWKHPRUQLQJRIWKHYLVLWVSLURPHWU\DQGUHYHUVLELOLW\ZLOOEH
PHDVXUHGDW9LVLWDZKLFKZLOORFFXUZLWKLQGD\VRI9LVLW)RUVXEMHFWVZKRGRQRWPHHWUHYHUVLELOLW\FULWHULDDW9LVLWD9LVLWEZLOOEH
VFKHGXOHGIRUDVHFRQGUHYHUVLELOLW\WHVWWRRFFXUZLWKLQGD\V6XEMHFWVZKRGRQRWPHHWUHYHUVLELOLW\FULWHULDDIWHUWKHVHFRQGDWWHPSWZLOOEHVFUHHQ
IDLOHG
H
$WDOOYLVLWVEH\RQG9LVLWQRWHWKHWLPHRIWKHODVWGRVHRIDVWKPDPHGLFDWLRQV7KHYLVLWPXVWEHUHVFKHGXOHGLIWKHODVWGRVHRI9HQWROLQZDV
KRXUVEHIRUH9LVLWRULIWKHODVWGRVHRI$WURYHQWZDVKRXUVEHIRUH9LVLWRU9LVLW
I
,QFOXGHVHYDOXDWLRQRIKHLJKWDQGZHLJKWDW9LVLW
J
$VHUXPSUHJQDQF\WHVWȕKXPDQFKRULRQLFJRQDGRWURSLQ>ȕK&*@ZLOOEHSHUIRUPHGDW9LVLWXULQHȕK&*WHVWZLOOEHSHUIRUPHGEHIRUH
UDQGRPL]DWLRQDW9LVLWIRUZRPHQRIFKLOGEHDULQJSRWHQWLDORQO\
K
$W9LVLWSURKLELWHGDVWKPDPHGLFDWLRQVDUHWREHVWRSSHGDQGDVWKPDPHGLFDWLRQVFKDQJHGDVVSHFLILHGLQ6HFWLRQ$WWKHHQGRI9LVLWRUXSRQ
SUHPDWXUHGLVFRQWLQXDWLRQLIDSSOLFDEOHVXEMHFWVZLOOUHWXUQWRSUHVWXG\RURWKHUDSSURSULDWHLQKDOHGPDLQWHQDQFHDVWKPDPHGLFDWLRQV
L
)RUVXEMHFWVLQWKH3.VXEVWXG\RQO\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table 2
Timed Assessments at Each Treatment Visit (Visit 2 and Visit 3)

Pre-Dose
(minutes) 
Doses 1 through 4
(minutes)
Dose 5
(minutes)
-60
-30
0
15
30
0
15
30
60
120
180
240
300
360
480
600
720
6%3'%3
;D


;


;
;
;
;
;
;
;
;



OHDG(&*E
;D


;


;
;
;
;
;
;
;
;



6DPSOHFROOHFWLRQIRU
JOXFRVHDQGSRWDVVLXP
;D


;


;
;
;
;
;
;
;
;



3.VDPSOHFROOHFWLRQF

;

;


;
;
;
;
;
;
;
;
;
;
;
6SLURPHWU\
;
;


;G

;
;
;
;
;
;
;
;



6WXG\GUXJ
DGPLQLVWUDWLRQ


;


;











$EEUHYLDWLRQV'%3 GLDVWROLFEORRGSUHVVXUH(&* HOHFWURFDUGLRJUDP3. SKDUPDFRNLQHWLF6%3 V\VWROLFEORRGSUHVVXUH
Note::KHQSRVWGRVHGDWDFROOHFWLRQWLPHSRLQWVDUHFRQFXUUHQWYDULDEOHVZLOOEHFROOHFWHGLQWKHIROORZLQJRUGHUEORRGSUHVVXUH(&*VDPSOHVIRUVHUXP
JOXFRVHDQGSRWDVVLXP3.EORRGVDPSOHVLIDSSOLFDEOHDQGVSLURPHWU\
D
3UHGRVHDVVHVVPHQWWREHSHUIRUPHGZLWKLQPLQXWHVEHIRUHWKHILUVWGRVH
E
(&*DVVHVVPHQWRI47FLQWHUYDODQGKHDUWUDWH
F
)RUVXEMHFWVLQWKH3.VXEVWXG\RQO\
G
7KHPLQXWHVSLURPHWU\DVVHVVPHQWVKRXOGEHVWDUWHGDWDSSUR[LPDWHO\PLQXWHVSRVWGRVHWRDOORZIRUFRPSOHWLRQRIWKHWHVWEHIRUHWKHQH[WGRVH
VRDVQRWWRGHOD\GRVLQJ



&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

4.1
Screening Period (Visits 1, and Visits 1a/1b if applicable)
)RUVXEMHFWVZKRZHUHUHFHLYLQJRQO\6$%$DVQHHGHGEHIRUHVWXG\HQWU\WKHPLQLPXPDQG
PD[LPXP6FUHHQLQJ3HULRGZLOOEHDQGGD\VUHVSHFWLYHO\)RUVXEMHFWVZKRZHUH
UHFHLYLQJUHJXODUO\VFKHGXOHG,&6RU,&6/$%$EHIRUHVWXG\HQWU\WKHPLQLPXPDQG
PD[LPXP5XQLQ3HULRGZLOOEHDQGGD\VUHVSHFWLYHO\7KH6FUHHQLQJ3HULRGVKRXOGEH
DVVKRUWDVSRVVLEOHKRZHYHUWKHGXUDWLRQZLOOEHGHWHUPLQHGE\WKH,QYHVWLJDWRU
4.1.1
Visit 1
7KHIROORZLQJDFWLYLWLHVZLOOEHSHUIRUPHGDW9LVLW
x
2EWDLQLQIRUPHGFRQVHQW
x
5HJLVWHUVXEMHFWLQ,:56WRREWDLQVXEMHFWVFUHHQLQJQXPEHU
x
2EWDLQGHPRJUDSKLFGDWDLQFOXGLQJDJHUDFHVPRNLQJKLVWRU\
PHGLFDOVXUJLFDOKLVWRU\DQGDJHRIRQVHWRIDVWKPD
x
2EWDLQPHGLFDWLRQKLVWRU\LQFOXGLQJSULRUDQGFRQFRPLWDQWPHGLFDWLRQVVHH
6HFWLRQ
x
2EWDLQ6%3DQG'%3VHH6HFWLRQ
x
&RQGXFWDFRPSOHWHSK\VLFDOH[DPLQDWLRQVHH6HFWLRQ
x
&RQILUPDFFHSWDEOH0',GHYLFHWHFKQLTXHDQGSURYLGHWUDLQLQJDVQHFHVVDU\
x
&RQILUPWKHVXEMHFWVDWLVILHVLQFOXVLRQH[FOXVLRQFULWHULDVHH6HFWLRQ
DQG6HFWLRQ
x
2EWDLQDOHDG(&*VHH6HFWLRQ
x
2EWDLQFOLQLFDOODERUDWRU\EORRGVDPSOHVLQFOXGLQJEORRGVDPSOHIRUVHUXP
ȕKXPDQFKRULRQLFJRQDGRWURSLQȕK&*IRUDOOZRPHQRIFKLOGEHDULQJ
SRWHQWLDOVHH6HFWLRQ
x
'LVFRQWLQXHWKHVXEMHFW¶VEDVHOLQHDVWKPDPHGLFDWLRQVDQGFKDQJHWR
SURWRFROVSHFLILHGDVWKPDPHGLFDWLRQVDVIROORZVIRUERWKWKH6FUHHQLQJDQG
UDQGRPL]HG7UHDWPHQW3HULRGVVHH6HFWLRQ
x
)RUVXEMHFWVUHFHLYLQJRQO\6$%$DVQHHGHGVZLWFKWR6SRQVRU
SURYLGHG9HQWROLQDQG$WURYHQWDVQHHGHGIRUV\PSWRPVDV
GHVFULEHGLQ6HFWLRQ
x
)RUVXEMHFWVUHFHLYLQJUHJXODUO\VFKHGXOHG,&6RU,&6/$%$VZLWFK
WR6SRQVRUSURYLGHG3XOPLFRUW)OH[KDOHUHLWKHUȝJRUȝJ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

%,'EDVHGRQWKHVXEMHFW¶VSUHYLRXVWKHUDS\VHH7DEOH7KHVH
VXEMHFWVZLOODOVRUHFHLYH6SRQVRUSURYLGHG9HQWROLQDQG$WURYHQWDV
QHHGHGIRUV\PSWRPV
x
5HFRUG$(VLIDQ\
Note:$(VPXVWEHUHFRUGHGGXULQJWKH6FUHHQLQJ3HULRGWKDWLVIURPWKH
WLPHRIVLJQLQJWKH,&)WRWKHVWDUWRIUDQGRPL]HGVWXG\GUXJ$GYHUVH
HYHQWVWKDWRFFXUGXULQJWKH6FUHHQLQJ3HULRGZLOOEHUHFRUGHGDVPHGLFDO
KLVWRU\DQGQRWDVVWXG\$(VXQOHVVWKH\PHHWWKHGHILQLWLRQRIDQ6$(VHH
GHILQLWLRQLQ6HFWLRQ
)RUVXEMHFWVZKRhave not takenWKHLUUHJXODUPRUQLQJGRVHVRILQKDOHGDVWKPDPDLQWHQDQFH
PHGLFDWLRQVDQGRU6$%$ZLWKLQWKHSUHYLRXVKRXUVWKHIROORZLQJDFWLYLW\ZLOODOVREH
SHUIRUPHGDW9LVLW
x
&RQGXFWVSLURPHWU\DVVHVVPHQWV)(9VHH6HFWLRQ
x
3HUIRUP9HQWROLQUHYHUVLELOLW\WHVWGHVFULEHGLQ6HFWLRQ
Note:)RUVXEMHFWVZKRFRPSOHWHWKLVUHYHUVLELOLW\WHVWDW9LVLWDQGGRQRWPHHW9HQWROLQ
UHYHUVLELOLW\FULWHULD9LVLWDZLOOEHVFKHGXOHGIRUDVHFRQGUHYHUVLELOLW\WHVW
)RUVXEMHFWVZKRhave takenWKHLUUHJXODUPRUQLQJGRVHVRILQKDOHGDVWKPDPDLQWHQDQFH
PHGLFDWLRQVDQGRU6$%$ZLWKLQWKHSUHYLRXVKRXUVEHIRUH9LVLWRUDQ\RIWKHPHGLFDWLRQV
OLVWHGLQ7DEOHZLWKLQWKHZDVKRXWSHULRGVOLVWHGLQ7DEOH9LVLWDZLOOEHVFKHGXOHGWR
DOORZIRUZDVKRXWRIDVWKPDPHGLFDWLRQVEHIRUHVSLURPHWU\DQGUHYHUVLELOLW\WHVWLQJ
4.1.2
Visit 1a
7KHIROORZLQJDFWLYLWLHVZLOOEHSHUIRUPHGDW9LVLWDIRUVXEMHFWVZKRGLGQRWFRPSOHWH
VSLURPHWU\DW9LVLWRUZKRGRQRWKDYHDUHYHUVLELOLW\WHVWDW9LVLWRUZKRIDLOWRPHHW
UHYHUVLELOLW\FULWHULDDW9LVLW9LVLWDZLOOEHVFKHGXOHGWRRFFXUZLWKLQGD\VRI9LVLW
x
5HYLHZFOLQLFDOODERUDWRU\UHVXOWVIURP9LVLW
x
5HYLHZFRQFRPLWDQWPHGLFDWLRQVVHH6HFWLRQ
x
&RQILUPWKHVXEMHFWVDWLVILHVLQFOXVLRQH[FOXVLRQFULWHULDVHH6HFWLRQ
DQG6HFWLRQ
x
3HUIRUP9HQWROLQUHYHUVLELOLW\WHVWGHVFULEHGLQ6HFWLRQ
x
5HFRUG$(VLIDQ\
4.1.3
Visit 1b
9LVLWEPD\RQO\EHVFKHGXOHGIRUVXEMHFWVZKRGLGQRWSHUIRUP9HQWROLQUHYHUVLELOLW\WHVWLQJ
DW9LVLWDQGZKRGLGQRWPHHW9HQWROLQUHYHUVLELOLW\FULWHULDDW9LVLWD


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

)RUVXEMHFWVZKRGRQRWPHHWUHYHUVLELOLW\FULWHULDDW9LVLWD9LVLWEZLOOEHVFKHGXOHGWR
RFFXUZLWKLQGD\VRI9LVLWDIRUDVHFRQGUHYHUVLELOLW\WHVW2QO\UHYHUVLELOLW\DWWHPSWV
ZLOOEHDOORZHG6XEMHFWVZKRGRQRWPHHWUHYHUVLELOLW\FULWHULDDIWHUWKHVHFRQGDWWHPSWZLOO
EHVFUHHQIDLOHG
7KHIROORZLQJDFWLYLWLHVZLOOEHSHUIRUPHGDW9LVLWEIRUVXEMHFWVZKRGRQRWPHHW
UHYHUVLELOLW\FULWHULDDW9LVLWD
x
5HYLHZFRQFRPLWDQWPHGLFDWLRQVVHH6HFWLRQ
x
&RQILUPWKHVXEMHFWVDWLVILHVLQFOXVLRQH[FOXVLRQFULWHULDVHH6HFWLRQ
DQG6HFWLRQ
x
3HUIRUP9HQWROLQUHYHUVLELOLW\WHVWGHVFULEHGLQ6HFWLRQ
x
5HFRUG$(VLIDQ\
4.2
Treatment periods
4.2.1
General guidance for Visits 2 and 3
x
$WWKHVWDUWRIHDFK7UHDWPHQW9LVLWSULRUWRDQ\VWXG\SURFHGXUHVEHLQJ
SHUIRUPHGVLWHSHUVRQQHOPXVWFRQILUPWKHVXEMHFWKDVZLWKKHOGDOODVWKPD
PHGLFDWLRQV7KHODVW3XOPLFRUW)OH[KDOHUGRVHVKRXOGEHWKHSUHYLRXVQLJKW
LHWKHPRUQLQJGRVHVKRXOGEHKHOG7KHODVWGRVHRI9HQWROLQVKRXOGEH
QRODWHUWKDQKRXUVEHIRUH9LVLW7KHODVWGRVHRI$WURYHQWVKRXOGEHQR
ODWHUWKDQKRXUVEHIRUH9LVLWDQG9LVLW&RQILUPWKHODVWWLPHRIGRVLQJ
Note:6XEMHFWVZKRKDYHQRWZLWKKHOGWKHLU9HQWROLQDQG$WURYHQWDV
GHVFULEHGDERYHEHIRUHWKHVWXG\YLVLWPXVWKDYHWKHLUYLVLWUHVFKHGXOHGDV
VRRQDVLVSUDFWLFDOEXWZLWKLQWKHVSHFLILHGYLVLWZLQGRZGD\V



x
$W9LVLWWKHILUVWGRVHRIVWXG\GUXJZLOOEHDGPLQLVWHUHGEHIRUHDP$W
9LVLWWKHILUVWGRVHRIVWXG\GUXJZLOOEHDGPLQLVWHUHGEHIRUHDPDQG
ZLWKLQKRXURIWKHWLPHDGPLQLVWHUHGDW9LVLW$WHDFKYLVLWVXEVHTXHQW
GRVHVZLOOEHDGPLQLVWHUHGDWPLQXWHLQWHUYDOV
x
%HIRUH9LVLWVDQGVLWHVVKRXOGFDOOWKHVXEMHFWWRUHPLQGWKHVXEMHFWRI
WKHIROORZLQJ
x
GD\VEHIRUHWKHYLVLW

9HQWROLQVKRXOGEHKHOGIRUWKHWLPHSHULRGGHVFULEHGDERYH
x
7KHGD\EHIRUHWKHYLVLW


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK


$WURYHQWDQG3XOPLFRUW)OH[KDOHUVKRXOGEHKHOGIRUWKHWLPH
SHULRGVGHVFULEHGDERYH

%ULQJWKHLU6SRQVRUSURYLGHG9HQWROLQ9LVLWRQO\
$WURYHQWDQG3XOPLFRUW)OH[KDOHULIDVVLJQHGZLWKWKHPWR
WKHFOLQLF

5HIUDLQIURPLQJHVWLQJ[DQWKLQHFRQWDLQLQJIRRGVDQG
EHYHUDJHVDQGFDIIHLQHFRQWDLQLQJPHGLFDWLRQVIRUDWOHDVW
KRXUVEHIRUHHDFKVWXG\YLVLWDQGIRUWKHGXUDWLRQRIHDFK
VWXG\YLVLWVHH6HFWLRQ
x
6WXG\GUXJVKRXOGEHGLVSHQVHGDVIROORZV
x
$WWRPLQXWHVEHIRUHGRVLQJWKHVHDODURXQGWKHVWXG\GD\
WUHDWPHQWER[VKRXOGEHRSHQHGDQGWKHLQVWUXFWLRQVIRUDGPLQLVWUDWLRQ
RIVWXG\GUXJRQWKHLQQHUIODSRIWKHVWXG\GD\WUHDWPHQWER[VKRXOGEH
IROORZHG
x
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
x
6XEMHFWZLOODGPLQLVWHUWKHGRVHRIDVVLJQHGVWXG\GUXJDWWKHFOLQLF
x
7KHLQFOLQLFGRVLQJWLPHZLOOEHUHFRUGHGDVWKHWLPHRIDGPLQLVWUDWLRQRI
WKHODVWDFWXDWLRQRIVWXG\GUXJIRUHDFKGRVH
x
6LWHSHUVRQQHOZLOOLQVWUXFWVXEMHFWVQRWWRWDNHDQ\QRQVWXG\DVWKPD
PHGLFDWLRQVZLWKRXWVLWHSHUVRQQHOSHUPLVVLRQGXULQJDYLVLWXQWLODOOVWXG\
SURFHGXUHVKDYHEHHQFRPSOHWHGDQGWKHVXEMHFWLVGLVFKDUJHG6LWH
SHUVRQQHOVKRXOGWDNHHYHU\SUHFDXWLRQWRSUHYHQWXVHRIQRQVWXG\DVWKPD
PHGLFDWLRQVGXULQJWKHWHVWGD\6LWHSHUVRQQHOPD\UHTXHVWWKHVXEMHFWWR
VXUUHQGHUDOOQRQVWXG\DVWKPDPHGLFDWLRQVDWWKHVWDUWRIWKHYLVLWEHIRUH
SHUIRUPLQJDQ\VWXG\SURFHGXUHVDQGUHWXUQWKHPWRWKHVXEMHFWDWWKHHQGRI
WKHYLVLWZKHQDOOVWXG\SURFHGXUHVDUHFRPSOHWHG
x
,IDVXEMHFWLVH[SHULHQFLQJVHYHUHV\PSWRPVDQGUHTXLUHV9HQWROLQRU
$WURYHQWIRUUHOLHIRIDVWKPDV\PSWRPVDWDQ\WLPHGXULQJDVWXG\YLVLWVLWH
SHUVRQQHOPXVWQRWHWKHWLPHDQGMXVWLILFDWLRQIRUXVHLQWKHVXEMHFW¶VFKDUW
DQGDOOVSLURPHWU\DVVHVVPHQWVDQGIXUWKHUGRVLQJVKRXOGEHVWRSSHGGXULQJ
WKHFXUUHQW7UHDWPHQW9LVLW6DIHW\DVVHVVPHQWVVKRXOGEHFRQWLQXHGDWWKH
GLVFUHWLRQRIWKH,QYHVWLJDWRU
4.2.2
Visit 2 (Randomization Visit, Treatment Period 1)
7KHIROORZLQJVKRXOGEHSHUIRUPHGEHIRUHUDQGRPL]DWLRQDW9LVLW


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
&ROOHFW9HQWROLQVXEMHFWVZLOOFRQWLQXHWRXVH$WURYHQWIRUUHVFXHQRW
9HQWROLQWKURXJKRXWWKHUDQGRPL]HG7UHDWPHQW3HULRG
x
3HUIRUPDXULQHSUHJQDQF\WHVW
x
&RQILUPUDQGRPL]DWLRQFULWHULD6HFWLRQLQFOXGLQJSUHGRVH
VSLURPHWU\DVVHVVPHQWVVHH6HFWLRQ
x
5HYLHZFRQFRPLWDQWPHGLFDWLRQV
x
5HYLHZFOLQLFDOODERUDWRU\UHVXOWVIURP9LVLW
x
5HFRUG$(VLIDQ\
Note:3UHUDQGRPL]DWLRQ$(VDUHWREHUHFRUGHGDVSDUWRIWKHPHGLFDO
KLVWRU\XQOHVVWKHHYHQWPHHWVWKHGHILQLWLRQRIDQ6$(VHHGHILQLWLRQLQ
6HFWLRQ
x
&RQILUPDFFHSWDEOH0',GHYLFHWHFKQLTXH
x
5HJLVWHUVXEMHFWLQ,:56WRREWDLQVXEMHFWUDQGRPL]DWLRQQXPEHU7KH
VXEMHFWLVWREHFRQVLGHUHGUDQGRPL]HGDIWHUUHFHLYLQJDUDQGRPL]DWLRQ
QXPEHUIURPWKH,:56
7KHIROORZLQJDFWLYLWLHVDUHWREHSHUIRUPHGDIWHUUDQGRPL]DWLRQ
x
3HUIRUPSUHGRVH6%3DQG'%3DVVHVVPHQWVVHH6HFWLRQ
x
3HUIRUPSUHGRVH(&*DVVHVVPHQWVHH6HFWLRQ
x
&ROOHFWSUHGRVHEORRGVDPSOHVIRUVHUXPJOXFRVHDQGSRWDVVLXPVHH
6HFWLRQ
x
)RUVXEMHFWVLQWKH3.VXEVWXG\RQO\FROOHFWSUHGRVH3.VDPSOHVHH
6HFWLRQ
x
'LVSHQVHVWXG\GUXJVHH6HFWLRQEDVHGRQVXEMHFWWUHDWPHQWDVVLJQPHQW
LQIRUPDWLRQIURP,:56DWWKHWLPHSRLQWVVSHFLILHGLQ7DEOH
x
3HUIRUPSRVWGRVH6%3DQG'%3DVVHVVPHQWVDIWHUHDFKVWXG\GUXJGRVHDW
WKHWLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ
x
3HUIRUPSRVWGRVH(&*DVVHVVPHQWDIWHUHDFKVWXG\GUXJGRVHDWWKH
WLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ
x
&ROOHFWSRVWGRVHEORRGVDPSOHVIRUVHUXPJOXFRVHDQGSRWDVVLXPDIWHUHDFK
VWXG\GUXJGRVHDWWKHWLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
)RUVXEMHFWVLQWKH3.VXEVWXG\RQO\FROOHFWSRVWGRVH3.VDPSOHDIWHUHDFK
VWXG\GUXJGRVHDWWKHWLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ
x
3HUIRUPSRVWGRVHVSLURPHWU\DVVHVVPHQWVDWWKHWLPHSRLQWVVSHFLILHGLQ
7DEOHVHH6HFWLRQ
x
5HFRUG$(VLIDQ\
x
6FKHGXOH9LVLWDOORZLQJIRUD:DVKRXW3HULRGRIWRGD\V
x
$VVXUHWKDWWKHVXEMHFWKDVHQRXJK6SRQVRUSURYLGHGDVWKPDPHGLFDWLRQWR
ODVWXQWLOWKHQH[W7UHDWPHQW9LVLW$WURYHQWDQG3XOPLFRUW)OH[KDOHU
JRUJIRUWKRVHVXEMHFWVZKRZHUHRQ,&6RU,&6/$%$EHIRUH
VWXG\HQWU\
4.2.3
Visit 3 (Treatment Period 2)
7KHIROORZLQJVKRXOGEHSHUIRUPHGEHIRUHDQ\RWKHUDFWLYLWLHV
x
&RQILUPHOLJLELOLW\FULWHULDVHH6HFWLRQDQG6HFWLRQ
x
5HYLHZFRQFRPLWDQWPHGLFDWLRQV
x
&RQILUPDFFHSWDEOH0',GHYLFHWHFKQLTXH
7KHQWKHIROORZLQJDFWLYLWLHVDUHWREHSHUIRUPHG
x
3HUIRUPSUHGRVH6%3DQG'%3DVVHVVPHQWVVHH6HFWLRQ
x
3HUIRUPSUHGRVH(&*DVVHVVPHQWVHH6HFWLRQ
x
&ROOHFWSUHGRVHEORRGVDPSOHVIRUVHUXPJOXFRVHDQGSRWDVVLXPVHH
6HFWLRQ
x
3HUIRUPSUHGRVHVSLURPHWU\DVVHVVPHQWVVHH6HFWLRQDQGFRQILUP
WKDWWKHVXEMHFWPHHWV)(9EDVHOLQHVWDELOLW\FULWHULDVHH6HFWLRQ
x
)RUVXEMHFWVLQWKH3.VXEVWXG\RQO\FROOHFWSUHGRVH3.VDPSOHVHH
6HFWLRQ
x
'LVSHQVHVWXG\GUXJVHH6HFWLRQEDVHGRQVXEMHFWWUHDWPHQWDVVLJQPHQW
LQIRUPDWLRQIURP,:56DWWKHWLPHSRLQWVVSHFLILHGLQ7DEOH
x
3HUIRUPSRVWGRVH6%3DQG'%3DVVHVVPHQWVDIWHUHDFKVWXG\GUXJGRVHDW
WKHWLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
3HUIRUPSRVWGRVH(&*DVVHVVPHQWDIWHUHDFKVWXG\GUXJGRVHDWWKH
WLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ
x
&ROOHFWSRVWGRVHEORRGVDPSOHVIRUVHUXPJOXFRVHDQGSRWDVVLXPDIWHUHDFK
VWXG\GUXJGRVHDWWKHWLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ
x
)RUVXEMHFWVLQWKH3.VXEVWXG\RQO\FROOHFWSRVWGRVH3.VDPSOHDIWHUHDFK
VWXG\GUXJGRVHDWWKHWLPHSRLQWVVSHFLILHGLQ7DEOHVHH6HFWLRQ
x
3HUIRUPSRVWGRVHVSLURPHWU\DVVHVVPHQWVDWWKHWLPHSRLQWVVSHFLILHGLQ
7DEOHVHH6HFWLRQ
x
&RQGXFWDFRPSOHWHSK\VLFDOH[DPLQDWLRQVHH6HFWLRQ
x
5HFRUG$(VLIDQ\
x
&ROOHFWDOOXQXVHG6SRQVRUSURYLGHGDVWKPDPHGLFDWLRQ6SRQVRUSURYLGHG
$WURYHQWDQG3XOPLFRUW)OH[KDOHULIDSSOLFDEOH
x
6FKHGXOHWKHIROORZXSWHOHSKRQHFDOOVHH6HFWLRQ
x
5HWXUQVXEMHFWVWRWKHLUSUHVWXG\DVWKPDPDLQWHQDQFHPHGLFDWLRQUHJLPHQ
RURWKHUDSSURSULDWHDVWKPDPHGLFDWLRQV
4.2.4
Premature Study Withdrawal Visit
6HH6HFWLRQ7KHIROORZLQJDFWLYLWLHVVKRXOGRFFXUDWWKH3UHPDWXUH:LWKGUDZDOIURP
9LVLW
x
5HYLHZFRQFRPLWDQWPHGLFDWLRQV
x
3HUIRUP6%3DQG'%3DVVHVVPHQWVVHH6HFWLRQ
x
&RQGXFWDFRPSOHWHSK\VLFDOH[DPLQDWLRQVHH6HFWLRQ
x
2EWDLQDOHDG(&*VHH6HFWLRQ
x
2EWDLQFOLQLFDOODERUDWRU\EORRGVDPSOHVIRUVHUXPJOXFRVHDQGSRWDVVLXP
VHH6HFWLRQ
x
5HFRUG$(VLIDQ\
x
&ROOHFWDOOXQXVHG6SRQVRUSURYLGHGDVWKPDPHGLFDWLRQ6SRQVRUSURYLGHG
9HQWROLQ$WURYHQWDQG3XOPLFRUW)OH[KDOHULIDSSOLFDEOH
x
5HWXUQVXEMHFWVWRWKHLUXVXDOSUHVWXG\DVWKPDPDLQWHQDQFHPHGLFDWLRQ
UHJLPHQ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
6FKHGXOHWKHIROORZXSWHOHSKRQHFDOOVHH6HFWLRQ
4.3
Follow-up period
4.3.1
Follow-up telephone call
6XEMHFWVZLOOEHFRQWDFWHGE\VWXG\SHUVRQQHOWKURXJKDWHOHSKRQHFDOOWRGD\VDIWHUWKH
ODVWGRVHRIVWXG\GUXJWRDVVHVV$(VDQG6$(VLIDQ\
4.3.2
Premature withdrawal from the study
&RPSOHWHWKHVWXG\FRPSOHWLRQSDJHRIWKHH&5)DQGUHFRUGWKHUHDVRQIRUSUHPDWXUHVWXG\
ZLWKGUDZDO7KHIROORZLQJFDWHJRULHVVKRXOGEHXVHGWRGHVFULEHWKHVHHYHQWVLQWKHH&5)
x
6XEMHFWGLVFUHWLRQGRFXPHQWUHDVRQ
x
,QYHVWLJDWRUFRQVLGHUVLWWREHLQWKHEHVWLQWHUHVWRIWKHVXEMHFW
x
$(V
x
$GPLQLVWUDWLYHUHDVRQVHJHDUO\WHUPLQDWLRQRIWKHVWXG\
x
6XEMHFWORVWWRIROORZXS
x
0DMRUSURWRFROGHYLDWLRQ
x
'HDWK
x
3URWRFROVSHFLILHGFULWHULDVXFKDVXVHRISURKLELWHGPHGLFDWLRQVUHIHUWR
6HFWLRQ
5.
STUDY ASSESSMENTS
7KHL'DWDID[V\VWHPZLOOEHXVHGIRUGDWDFROOHFWLRQDQGTXHU\KDQGOLQJ7KH,QYHVWLJDWRUZLOO
HQVXUHWKDWGDWDDUHUHFRUGHGRQWKHH&5)VDVVSHFLILHGLQWKHFOLQLFDOVWXG\SURWRFRODQGLQ
DFFRUGDQFHZLWKWKHLQVWUXFWLRQVSURYLGHG
7KH,QYHVWLJDWRUHQVXUHVWKHDFFXUDF\FRPSOHWHQHVVDQGWLPHOLQHVVRIWKHGDWDUHFRUGHGDQG
RIWKHSURYLVLRQRIDQVZHUVWRGDWDTXHULHVDFFRUGLQJWRWKHFOLQLFDOVWXG\DJUHHPHQW7KH
,QYHVWLJDWRUZLOOVLJQWKHFRPSOHWHGH&5)V$FRS\RIWKHFRPSOHWHGH&5)VZLOOEHDUFKLYHG
DWWKHVWXG\VLWH
5.1
Efficacy assessments
(IILFDF\ZLOOEHDVVHVVHGE\3)7V)RUFHGH[SLUDWRU\VSLURPHWU\IRUGHULYDWLRQRI)(9DV
GHILQHGLQ$76(56JXLGHOLQHVZLOOEHSHUIRUPHGLQDFFRUGDQFHZLWK$76FULWHULD


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

$SSHQGL[$XVLQJDVSLURPHWHUWKDWPHHWVRUH[FHHGVPLQLPXPSHUIRUPDQFH
UHFRPPHQGDWLRQVRIWKH$76VHH$SSHQGL[%
5.1.1
Standardization of spirometry
7RVWDQGDUGL]HVSLURPHWU\DOOVLWHVZLOOEHSURYLGHGZLWKLGHQWLFDOVSLURPHWU\V\VWHPV

ZLWKFXVWRPL]HGVWXG\VSHFLILFVRIWZDUH(YHU\
HIIRUWZLOOEHPDGHWRSURYLGHDOOVLWHVZLWKVWDQGDUGL]HGVSLURPHWU\HTXLSPHQW7KHYROXPH
DFFXUDF\RIWKHVSLURPHWHULVWREHFKHFNHGGDLO\ZLWKDSSURSULDWHGRFXPHQWDWLRQLQD
FDOLEUDWLRQORJSULRUWRWKHFRQGXFWRI3)7VRQHDFKWHVWGD\
7KHYROXPHDFFXUDF\RIWKHVSLURPHWHULVFKHFNHG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QRWEHXVHGEH\RQGWKHH[SLU\GDWH
5HTXLUHGDFFXUDF\LVLH/WR/$76(567KHUHVXOWVZLOOEHSULQWHGDQG
PDLQWDLQHGLQDFDOLEUDWLRQORJZKLFKZLOOEHPRQLWRUHGIRUFRPSOLDQFHGXULQJWKHPRQLWRULQJ
YLVLWV$SSHQGL[%
$OOVWXG\VWDIIUHVSRQVLEOHIRUSHUIRUPLQJ3)7VZLOOUHFHLYHVWDQGDUGL]HGWUDLQLQJDWDQ
,QYHVWLJDWRUPHHWLQJ$OOWHFKQLFLDQVDUHUHTXLUHGWRGHPRQVWUDWHSURILFLHQF\LQWKHXVHRIWKH
HTXLSPHQWDQGWKHDELOLW\WRSHUIRUPWHFKQLFDOO\DFFHSWDEOH3)7V$76FULWHULDSULRUWR
SHUIRUPLQJ3)7VRQVWXG\VXEMHFWV0LOOHUHWDO$IWHUHDFKWHVWLVSHUIRUPHGWKH
VSLURPHWU\VRIWZDUHZLOOSURYLGHLPPHGLDWHIHHGEDFNWRWKHWHFKQLFLDQLQGLFDWLQJZKHWKHUWKH
HIIRUWPHHWV$76DFFHSWDELOLW\DQGUHSHDWDELOLW\VWDQGDUGV$SSHQGL[%$OO3)7WHVWLQJZLOO
EHVWRUHGHOHFWURQLFDOO\$IWHUFRPSOHWLRQRIWHVWLQJWKHVWXG\VWDIIZLOOHOHFWURQLFDOO\WUDQVPLW
WKHVSLURPHWULFPHDVXUHPHQWVIRUFHQWUDOL]HGTXDOLW\DVVXUDQFHUHYLHZ

)HHGEDFNRQWKHTXDOLW\RIWKHPHDVXUHPHQWVZLOOEHSURYLGHGWRWKH
LQYHVWLJDWLRQDOVLWHDQGWRWKH6SRQVRURUGHVLJQHHIRUFHQWUDOGDWDPDQDJHPHQW
5.1.2
Assessment of FEV1
6SLURPHWU\ZLOOEHFRQGXFWHGDWDOOYLVLWVH[FHSWWKH3UHPDWXUH'LVFRQWLQXDWLRQ9LVLWZKHQ
DSSOLFDEOH
6SLURPHWU\DW9LVLWVDDQGRUEDQGZLOOEHXVHGWRVDWLVI\HQUROOPHQWDQG
UDQGRPL]DWLRQFULWHULD0XOWLSOHIRUFHGH[SLUDWRU\HIIRUWVDWOHDVWEXWQRPRUHWKDQZLOO
EHSHUIRUPHGDQGWKHEHVWHIIRUWVWKDWPHHWWKH$76(56DFFHSWDELOLW\DQGUHSURGXFLELOLW\
FULWHULDZLOOEHUHFRUGHG7KHEHVWHIIRUWVZLOOEHEDVHGRQWKHKLJKHVW)(97KHDYHUDJHRI
WKHVHDVVHVVPHQWVZLOOEHXVHGWRFDOFXODWHWKHVFUHHQLQJ)(9

6SLURPHWU\ZLOOEHFRQGXFWHGPLQXWHVDQGPLQXWHVEHIRUHVWXG\GUXJ
DGPLQLVWUDWLRQ7KHDYHUDJHRIWKHVHDVVHVVPHQWVZLOOEHXVHGWRFDOFXODWHPRUQLQJSUHGRVH
)(9
)ROORZLQJVWXG\GUXJDGPLQLVWUDWLRQDW9LVLWVDQGVSLURPHWU\ZLOOEHSHUIRUPHGDW
PLQXWHVDIWHUHDFKRIWKHILUVWFXPXODWLYHGRVHVDQGDW


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

DQGPLQXWHVDIWHUWKHODVWGRVH7KUHHWHVWVZLOOEHSHUIRUPHGDWHDFKWLPHSRLQW7KH
KLJKHVWYDOXHDWHDFKWLPHSRLQWZLOOEHXVHGIRUWKHVHSRVWGRVHDVVHVVPHQWV
5.1.3
Characterization of reversibility
5HYHUVLELOLW\WR9HQWROLQZLOOEHHYDOXDWHGDW9LVLWDDQGRUE6XEMHFWVPXVWGHPRQVWUDWH
UHYHUVLELOLW\WR9HQWROLQWREHUDQGRPL]HGLQWKHVWXG\QRPRUHWKDQUHYHUVLELOLW\WHVW
DWWHPSWVDUHDOORZHG5HYHUVLELOLW\WHVWLQJLVSHUIRUPHGDVIROORZV

'HWHUPLQHLIPRUQLQJGRVHVRIDOOPDLQWHQDQFHDVWKPD,&6/$%$LIDSSOLFDEOH
ZHUHZLWKKHOGDQGWKDWVKRUWDFWLQJEURQFKRGLODWRUVZHUHQRWDGPLQLVWHUHGZLWKLQ
KRXUVRIWHVWLQJ

3HUIRUPSUHEURQFKRGLODWRU3)7VDWPLQXWHVEHIRUHDGPLQLVWUDWLRQRI9HQWROLQ

$GPLQLVWHUDFWXDWLRQVRI9HQWROLQJSHUDFWXDWLRQWRWDOJ)

3HUIRUPSRVWEURQFKRGLODWRU3)7VPLQXWHVDIWHUWKHDGPLQLVWUDWLRQRI9HQWROLQ
5HYHUVLELOLW\ZLOOEHDFRPSDULVRQRIWKHEHVW)(9HIIRUWREWDLQHGDWPLQXWHVSUH
EURQFKRGLODWRUWRWKHEHVW)(9HIIRUWREWDLQHGDWPLQXWHVSRVWEURQFKRGLODWRUIROORZLQJ
DGPLQLVWUDWLRQRI9HQWROLQ$VXEMHFWLVFRQVLGHUHGUHYHUVLEOHWR9HQWROLQLIWKHLPSURYHPHQW
LQ)(9DWPLQXWHVSRVW9HQWROLQLV
5.1.4
FEV1 baseline stability criteria
,WLVLPSRUWDQWWRHQVXUHWKDWOXQJIXQFWLRQDWHDFKVWXG\YLVLWLVVWDEOHDQGUHIOHFWLYHRIDVWKPD
VHYHULW\DWUDQGRPL]DWLRQ$VVXFKWKHDYHUDJHRIWKHPLQXWHDQGPLQXWH)(9YDOXHV
DW9LVLWPXVWEHZLWKLQDEVROXWHYDOXHRIWKHDYHUDJHRIWKHPLQXWH
DQGPLQXWH)(9YDOXHVDW9LVLW$W9LVLWLIWKHSUHGRVH)(9DYHUDJHLVRXWVLGHRI
WKHUDQJHEXWWKHPLQXWHDVVHVVPHQWLVZLWKLQWKHQDQRWKHUDVVHVVPHQWPD\
EHFRQGXFWHGPLQXWHVODWHU,IWKHODVWDVVHVVPHQWVPHHWWKHEDVHOLQHVWDELOLW\
UHTXLUHPHQWVLHZLWKLQWKHLQLWLDOPLQXWHSUHGRVHDVVHVVPHQWZLOOQRWEHXVHG
DQGWKHODVWDVVHVVPHQWVZLOOEHXVHGWRHVWDEOLVKWKHHOLJLELOLW\FULWHULD




5.2
Safety assessments
6RPHVDIHW\DVVHVVPHQWVVHULDO6%3DQG'%347F)LQWHUYDOVDQG+5IURPVHULDO(&*VDQG
VHULDOJOXFRVHDQGSRWDVVLXPFRQFHQWUDWLRQVDUHDOVRFRQVLGHUHG3'HQGSRLQWVLQWKLVVWXG\
6DIHW\ZLOODOVREHDVVHVVHGE\$(VDQG6$(V


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

5.2.1
Medical/surgical history and physical examination
0HGLFDODQGVXUJLFDOKLVWRU\ZLOOEHFROOHFWHGDW9LVLW$FRPSOHWHSK\VLFDOH[DPLQDWLRQZLOO
EHSHUIRUPHGDW9LVLWVDQGRUWKH3UHPDWXUH'LVFRQWLQXDWLRQ9LVLWDVDSSOLFDEOH
$FRPSOHWHSK\VLFDOH[DPLQDWLRQZLOOLQFOXGHWKHIROORZLQJJHQHUDODSSHDUDQFHVNLQKHDG
H\HVHDUVQRVHWKURDWQHFNLQFOXGLQJWK\URLGO\PSKQRGHVFKHVWKHDUWDEGRPHQ
H[WUHPLWLHVDQGQHUYRXVV\VWHP$GGLWLRQDOO\ZHLJKWDVVHVVHGLQRUGLQDU\LQGRRUFORWKLQJ
ZLWKVKRHVRIIDQGKHLJKWZLOOEHUHFRUGHGDW9LVLWRQO\7DEOH
5.2.2
SBP and DBP
%ORRGSUHVVXUH6%3DQG'%3ZLOOEHPHDVXUHGDWWKHWLPHSRLQWVVKRZQLQ7DEOHDQG
7DEOH
$WDOOVWXG\YLVLWV9LVLWVWRDQGWKH3UHPDWXUH'LVFRQWLQXDWLRQ9LVLWLIDSSOLFDEOH6%3
DQG'%3ZLOOEHDVVHVVHGDIWHUWKHVXEMHFWLVVXSLQHRUVHDWHGIRUPLQXWHV,ILQWKHRSLQLRQ
RIWKH,QYHVWLJDWRUDFOLQLFDOO\VLJQLILFDQWFKDQJHRFFXUVWKHQWKHPHDVXUHPHQWVKRXOGEH
UHSHDWHGDWPHGLFDOO\DSSURSULDWHLQWHUYDOVXQWLOWKHYDOXHUHWXUQVWRZLWKLQDQDFFHSWDEOH
UDQJH,IWKHYDOXHGRHVQRWUHWXUQWREDVHOLQHWKH,QYHVWLJDWRUVKRXOGGHWHUPLQHLIWKLVLVDQ
$(VHH6HFWLRQ
5.2.3
Clinical laboratory testing
%ORRGZLOOEHFROOHFWHGIRUFOLQLFDOODERUDWRU\WHVWLQJDWWKHWLPHSRLQWVVKRZQLQ7DEOHDQG
7DEOH$FRPSOHWHFOLQLFDOFKHPLVWU\SDQHOZLOOEHSHUIRUPHGDW9LVLWRQO\7DEOH6LWHV
PXVWHYDOXDWHFOLQLFDOODERUDWRU\GDWDEHIRUHWKHVXEMHFWLVUDQGRPL]HG$WDOORWKHUWLPHSRLQWV
VHH7DEOHVDPSOHVZLOOEHFROOHFWHGIRUWKHPHDVXUHPHQWRIVHUXPJOXFRVHDQGSRWDVVLXP
$GGLWLRQDOEORRGPD\EHGUDZQIRUDVVHVVPHQWRIJOXFRVHSRWDVVLXPRURWKHUODERUDWRU\
SDUDPHWHUVDWDQ\WLPHDWWKHGLVFUHWLRQRIWKH,QYHVWLJDWRU
$W9LVLWVDQGEHIRUH GRVLQJ DQ LQGZHOOLQJ YHQRXV FDQQXOD PD\ EH LQVHUWHG7KH VWXG\
QXUVHZLOOGHFLGHZKHQWRUHPRYHRUUHSODFHWKHYHQRXVFDQQXODEDVHG RQWKHWLPHVLQFH
LQVHUWLRQ RI WKHFDQQXOD RU LI FORWWLQJ RFFXUV,I WKH FDQQXOD LV UHPRYHG WKH VXEVHTXHQW
EORRGVDPSOHVZLOOEHFROOHFWHGE\YHQLSXQFWXUHRUWKHFDQQXODPD\EHUHSODFHG6XEMHFWVZLOO
EHLQDVHDWHGRUVXSLQHSRVLWLRQGXULQJEORRGFROOHFWLRQ
$SSUR[LPDWHO\P/RIEORRGZLOOEHFROOHFWHGSHUVXEMHFWGXULQJWKHVWXG\IRUFOLQLFDO
ODERUDWRU\WHVWV)RUVXEMHFWVSDUWLFLSDWLQJLQWKH3.VXEVWXG\DSSUR[LPDWHO\P/RIEORRG
ZLWKEHFROOHFWHGDW9LVLWVDQGIRU3.DQDO\VLVDWRWDORIP/RIEORRGZLOOEH
FROOHFWHGIRUVXEMHFWVSDUWLFLSDWLQJLQWKH3.VWXG\7KHH[DFWEORRGYROXPHFROOHFWHGPD\
YDU\GHSHQGLQJRQODERUDWRU\SURFHGXUHVRUFKDQJHVLQ3.VDPSOLQJ+RZHYHULWZLOOQRW
H[FHHGP/SHUVXEMHFW
&OLQLFDOODERUDWRU\WHVWVZLOOEHDQDO\]HGE\DFHQWUDOODERUDWRU\DFFRUGLQJWRVWDQGDUGL]HG
YDOLGDWHGDVVD\V7KHODERUDWRU\ZLOOVXSSO\GHWDLOHGSURFHGXUHVIRUWKHSUHSDUDWLRQDQG
FROOHFWLRQRIEORRGVDPSOHVDORQJZLWKDOOFRQWDLQHUVQHHGHGIRUWKHLUFROOHFWLRQ%ORRG
VDPSOHYROXPHVZLOOPHHWWKHODERUDWRU\¶VVSHFLILFDWLRQ



&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table 3.
List of Laboratory Tests to be Performed at Screening
Hematology
+HPRJORELQ
3ODWHOHWFRXQW
+HPDWRFULW
0HDQFRUSXVFXODUKHPRJORELQ
:KLWHEORRGFHOOFRXQWZLWKGLIIHUHQWLDO
0HDQFRUSXVFXODUKHPRJORELQFRQFHQWUDWLRQ
5HGEORRGFHOOFRXQW
0HDQFRUSXVFXODUYROXPH
Clinical chemistry
Liver enzyme and other liver function tests
Other clinical chemistry
$ODQLQHDPLQRWUDQVIHUDVH
$OEXPLQ
$VSDUWDWHDPLQRWUDQVIHUDVH
%ORRGXUHDQLWURJHQ
$ONDOLQHSKRVSKDWDVH
&DOFLXP
%LOLUXELQWRWDO
&KORULGH
*DPPDJOXWDP\OWUDQVIHUDV
&KROHVWHURO

%LFDUERQDWH

&UHDWLQLQH

*OXFRVH

0DJQHVLXP

3RWDVVLXP

3KRVSKDWH

3URWHLQWRWDO

6RGLXP

7ULJO\FHULGHV

8UHD
Other tests:
ȕK&*WHVWIRUSUHJQDQF\D
&UHDWLQLQHFOHDUDQFHZLOOEHHVWLPDWHGE\WKH&.'(3,IRUPXODDW6FUHHQLQJRQO\
$EEUHYLDWLRQV&.'(3, &KURQLF.LGQH\'LVHDVH(SLGHPLRORJ\&ROODERUDWLRQ
D
6HUXPȕK&*WHVWZLOOEHSHUIRUPHGLQDOOZRPHQRIFKLOGEHDULQJSRWHQWLDODW9LVLW8ULQHȕK&*WHVWZLOO
EHSHUIRUPHGDW9LVLWEHIRUHUDQGRPL]DWLRQ

5.2.4
ECG
$VLQJOHOHDG(&*ZLOOEHREWDLQHGDWWKHWLPHSRLQWVVKRZQLQ7DEOHDQG7DEOH7KH
(&*SDUDPHWHUVWREHDVVHVVHGDW9LVLWLQFOXGH+535LQWHUYDO456D[LV456LQWHUYDO
DQG4747F)LQWHUYDO6LWHVPXVWHYDOXDWHDVXEMHFW¶V(&*GDWDEHIRUHWKHVXEMHFWLV
UDQGRPL]HG$WDOORWKHUWLPHSRLQWVRQO\47F)DQG+5ZLOOEHDVVHVVHG


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

7KH47LQWHUYDOVDQGFDOFXODWHG47F)LQWHUYDOVZLOOEHUHYLHZHGDQGFKHFNHGIRUJURVV
LQDFFXUDFLHVE\WKH,QYHVWLJDWRURUGHVLJQDWHG(&*UHYLHZHU
7RVWDQGDUGL]H(&*FROOHFWLRQDOOVLWHVZLOOEHSURYLGHGZLWKLGHQWLFDO(&*HTXLSPHQW

ZLWKFXVWRPL]HGVWXG\VSHFLILFVRIWZDUHRQDODSWRS$OOVWXG\VWDIIUHVSRQVLEOHIRU
SHUIRUPLQJ(&*FROOHFWLRQZLOOUHFHLYHLGHQWLFDOGHWDLOHGWUDLQLQJDWWKH,QYHVWLJDWRUPHHWLQJ
DVZHOODVVLWHSKRQHWUDLQLQJVHVVLRQV(DFKVLWHLVUHTXLUHGWRGHPRQVWUDWHSURILFLHQF\LQWKH
XVHRIWKHHTXLSPHQWDQGWKHDELOLW\WRSHUIRUPWHFKQLFDOO\DFFHSWDEOH(&*VEHIRUH
SHUIRUPLQJWHVWLQJRQVWXG\VXEMHFWV$IWHUHDFKWHVWLVSHUIRUPHGWKHVLWHZLOOHOHFWURQLFDOO\
WUDQVIHUWKH(&*GDWDIRUFHQWUDOL]HGTXDOLW\DVVXUDQFHUHYLHZ

)HHGEDFNRQWKHTXDOLW\RIWKH(&*VZLOOEHSURYLGHGWRWKH
LQYHVWLJDWLRQDOVLWHYLDDVLWHTXDOLILFDWLRQIRUP
5.3
Other assessments – not applicable
5.4
PK substudy
5.4.1
Collection of samples
)RUVXEMHFWVLQWKH3.VXEVWXG\EORRGVDPSOHVIRUWKHGHWHUPLQDWLRQRISODVPDFRQFHQWUDWLRQV
RIDOEXWHUROZLOOEHFROOHFWHGGXULQJWUHDWPHQWSHULRGDWWKHWLPHSRLQWVOLVWHGLQ7DEOH
$W9LVLWVDQGEHIRUH GRVLQJ DQ LQGZHOOLQJ YHQRXV FDQQXOD ZLOO EH LQVHUWHGIRUWKH
FROOHFWLRQRI3.DQGFOLQLFDOODERUDWRU\VDPSOHVVHH6HFWLRQ6DPSOHVZLOOEH
FROOHFWHGKDQGOHGODEHOHGVWRUHGDQGVKLSSHGDVGHWDLOHGLQWKHODERUDWRU\PDQXDO3ODVPD
VDPSOHVZLOOEHDQDO\]HGIRUDOEXWHUROXVLQJDYDOLGDWHGDVVD\
5.4.2
Determination of drug concentration
6DPSOHVIRUGHWHUPLQDWLRQRIDOEXWHUROFRQFHQWUDWLRQVLQSODVPDZLOOEHDQDO\]HGE\

XVLQJYDOLGDWHGDVVD\V$GGLWLRQDODQDO\VHVPD\EHFRQGXFWHGRQWKH
ELRORJLFDOVDPSOHVWRIXUWKHULQYHVWLJDWHWKHSUHVHQFHDQGRULGHQWLW\RIGUXJPHWDEROLWHV$Q\
UHVXOWVIURPVXFKDQDO\VLVZLOOEHUHSRUWHGVHSDUDWHO\IURPWKHFOLQLFDOVWXG\UHSRUW&65
)XOOGHWDLOVRIWKHDQDO\WLFDOPHWKRGDQGDQDO\VHVSHUIRUPHGXVHGZLOOEHGHVFULEHGLQD
VHSDUDWHELRDQDO\WLFDOUHSRUW
5.4.3
Storage and destruction of PK samples
3KDUPDFRNLQHWLFVDPSOHVZLOOEHGLVSRVHGRIDIWHUWKHELRDQDO\WLFDOUHSRUWILQDOL]DWLRQRU
PRQWKVDIWHULVVXDQFHRIWKHGUDIWELRDQDO\WLFDOUHSRUWZKLFKHYHULVHDUOLHUXQOHVV
UHTXHVWHGIRUIXWXUHDQDO\VHV
3KDUPDFRNLQHWLFVDPSOHVPD\EHGLVSRVHGRIRUGHVWUR\HGDQGDQRQ\PL]HGE\SRROLQJ
$GGLWLRQDODQDO\VHVPD\EHFRQGXFWHGRQWKHDQRQ\PL]HGSRROHG3.VDPSOHVWRIXUWKHU
HYDOXDWHDQGYDOLGDWHWKHDQDO\WLFDOPHWKRG$Q\UHVXOWVIURPVXFKDQDO\VHVPD\EHUHSRUWHG
VHSDUDWHO\IURPWKH&65


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

,QFXUUHGVDPSOHUHSURGXFLELOLW\DQDO\VLVLIDQ\ZLOOEHSHUIRUPHGDORQJVLGHWKHELRDQDO\VLV
RIWKHWHVWVDPSOHV7KHUHVXOWVIURPWKHHYDOXDWLRQZLOOQRWEHUHSRUWHGLQWKH&65EXW
VHSDUDWHO\LQDELRDQDO\WLFDOUHSRUW
5.5
Pharmacodynamics
([WUDSXOPRQDU\3'SDUDPHWHUVDUH6%3DQG'%36HFWLRQVHUXPSRWDVVLXPDQG
JOXFRVH6HFWLRQDQG47F)DQG+56HFWLRQ
5.6
Genetics – not applicable
5.7
Biomarker analysis – not applicable
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
7KH3ULQFLSDO,QYHVWLJDWRULVUHVSRQVLEOHIRUHQVXULQJWKDWDOOVWDIILQYROYHGLQWKHVWXG\DUH
IDPLOLDUZLWKWKHFRQWHQWRIWKLVVHFWLRQ
6.1
Definition of AEs
7KHIROORZLQJGHILQLWLRQVRIWHUPVDUHJXLGHGE\WKH,QWHUQDWLRQDO&RQIHUHQFHIRU
+DUPRQLVDWLRQ,&+DQGWKH86&RGHRI)HGHUDO5HJXODWLRQV&)5&)5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
x
DQ\V\PSWRPRUFRQGLWLRQQRWSUHYLRXVO\UHSRUWHGE\WKHVXEMHFWPHGLFDO
KLVWRU\
x
DQH[DFHUEDWLRQRIDSUHH[LVWLQJV\PSWRPRUFRQGLWLRQ
x
DVLJQLILFDQWLQFUHDVHLQIUHTXHQF\RULQWHQVLW\RIDSUHH[LVWLQJHSLVRGLF
HYHQWRUFRQGLWLRQ
x
DGUXJLQWHUDFWLRQ
x
D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QRWLQFOXGH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
PHGLFDORUVXUJLFDOSURFHGXUHVHJVXUJHU\HQGRVFRS\WRRWKH[WUDFWLRQ
EORRGWUDQVIXVLRQWKHFRQGLWLRQWKDWOHGWRWKHSURFHGXUHLVDQ$(HJ
EOHHGLQJHVRSKDJHDOYDULFHVGHQWDOFDULHV
x
RYHUGRVHRIHLWKHUVWXG\GUXJRUFRQFXUUHQWPHGLFDWLRQZLWKRXWDQ\FOLQLFDO
VLJQVRUV\PSWRPV
x
QRQFOLQLFDOO\VLJQLILFDQWDEQRUPDOODERUDWRU\YDOXHVLIDFFRPSDQLHGE\
VLJQVV\PSWRPVWKHVLJQVRUV\PSWRPVDUHFRQVLGHUHGDQ$(
6.2
Definitions of SAE
$Q$(LVFRQVLGHUHG³VHULRXV´LILQWKHYLHZRIWKH,QYHVWLJDWRURU6SRQVRULWUHVXOWVLQDQ\
RIWKHIROORZLQJRXWFRPHV
x
GHDWK
x
DOLIHWKUHDWHQLQJ$(
x
LQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ
x
DSHUVLVWHQWRUVLJQLILFDQWLQFDSDFLW\RUVXEVWDQWLDOGLVUXSWLRQRIWKHDELOLW\WR
FRQGXFWQRUPDOOLIHIXQFWLRQV
x
DFRQJHQLWDODQRPDO\ELUWKGHIHFW
,PSRUWDQWPHGLFDOHYHQWVWKDWPD\QRWUHVXOWLQGHDWKEHOLIHWKUHDWHQLQJRUUHTXLUH
KRVSLWDOL]DWLRQPD\EHFRQVLGHUHGDQ6$(ZKHQEDVHGXSRQDSSURSULDWHPHGLFDOMXGJPHQW
WKH\PD\MHRSDUGL]HWKHVXEMHFWDQGPD\UHTXLUHPHGLFDORUVXUJLFDOLQWHUYHQWLRQWRSUHYHQW
RQHRIWKHRXWFRPHVOLVWHGLQWKLVGHILQLWLRQ([DPSOHVRIVXFKPHGLFDOHYHQWVLQFOXGHDOOHUJLF
EURQFKRVSDVPUHTXLULQJLQWHQVLYHWUHDWPHQWLQDQHPHUJHQF\URRPRUDWKRPHEORRG
G\VFUDVLDVRUFRQYXOVLRQVWKDWGRQRWUHVXOWLQLQSDWLHQWKRVSLWDOL]DWLRQRUWKHGHYHORSPHQWRI
GUXJGHSHQGHQF\RUGUXJDEXVH
+RVSLWDOL]DWLRQIRUDSUHH[LVWLQJFRQGLWLRQLQFOXGLQJDQHOHFWLYHSURFHGXUHZKLFKKDVQRW
ZRUVHQHGGRHVQRWFRQVWLWXWHDQ6$(
$Q$(LVFRQVLGHUHG³OLIHWKUHDWHQLQJ´LILQWKHYLHZRIWKH,QYHVWLJDWRURU6SRQVRULWV
RFFXUUHQFHSODFHVWKHSDWLHQW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
)RUIXUWKHUJXLGDQFHRQWKHGHILQLWLRQRID6$(VHH$SSHQGL[&


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

6.3
Recording of AEs
6.3.1
Performing AE assessments
7KH,QYHVWLJDWRULVUHVSRQVLEOHIRUSURPSWO\GRFXPHQWLQJDQGUHSRUWLQJDOO$(VREVHUYHG
GXULQJWKHVWXG\LQWKHVXEMHFW¶VH&5)DQGRQWKH$(5HSRUWLQJ)RUP,IWKH$(LV
XQH[SHFWHGWKH,QYHVWLJDWRUVKRXOGUHSRUWWKH$(LPPHGLDWHO\WRWKH6SRQVRU,QDGGLWLRQ
FHUWDLQ$(VDVGHVFULEHGLQ6HFWLRQDUHFODVVLILHGDVµVHULRXV¶DQGPXVWEHUHSRUWHGQR
ODWHUWKDQKRXUVDIWHUWKH,QYHVWLJDWRUUHFRJQL]HVFODVVLILHVWKHHYHQWDVDQ6$(WRWKH
6SRQVRURULWVGHVLJQHH
,QWKHFDVHRI6$(VDIWHUGLVFXVVLQJWKHGHWDLOVRIWKHHYHQWWKH,QYHVWLJDWRUDQGWKH0HGLFDO
0RQLWRUPD\GLVFRQWLQXHWKHVXEMHFWIURPUDQGRPL]HGVWXG\GUXJ
6.3.2
Pre-randomization AEs
$GYHUVHHYHQWVRFFXUULQJIURPWKHWLPHWKHVXEMHFWVLJQVLQIRUPHGFRQVHQWXQWLOWKHVXEMHFWLV
UDQGRPL]HGZLOOEHVXPPDUL]HGDVPHGLFDOKLVWRU\DQGQRWDVDQ$(XQOHVVWKHHYHQWPHHWV
WKHGHILQLWLRQRIDQ6$(DVGHILQHGLQ6HFWLRQ
6.3.3
AEs based on signs and symptoms
:KHQFROOHFWLQJ$(VWKHUHFRUGLQJRIGLDJQRVHVLVSUHIHUUHGZKHQSRVVLEOHWRUHFRUGLQJD
OLVWRIVLJQVDQGV\PSWRPV+RZHYHULIDGLDJQRVLVLVNQRZQDQGWKHUHDUHRWKHUVLJQVRU
V\PSWRPVWKDWDUHQRWJHQHUDOO\SDUWRIWKHGLDJQRVLVWKHGLDJQRVLVDQGHDFKVLJQRUV\PSWRP
ZLOOEHUHFRUGHGVHSDUDWHO\
6.3.4
AEs based on examinations and tests
0DQ\ODERUDWRU\DEQRUPDOLWLHVREVHUYHGGXULQJWKHFRXUVHRIDVWXG\ZLOOEHLQFOXGHGXQGHUD
UHSRUWHG$(GHVFULELQJDFOLQLFDOV\QGURPHHJHOHYDWHGEORRGXUHDQLWURJHQDQGFUHDWLQLQHLQ
WKHVHWWLQJRIDQ$(RIUHQDOIDLOXUHRUGHFUHDVHGKHPRJORELQLQDFDVHRIEOHHGLQJHVRSKDJHDO
YDULFHV,VRODWHGODERUDWRU\DEQRUPDOLWLHVVKRXOGEHUHSRUWHGDV$(VLIWKH\DUHFRQVLGHUHGWR
EHFOLQLFDOO\VLJQLILFDQWE\WKH,QYHVWLJDWRU
,IGHWHULRUDWLRQLQDODERUDWRU\YDOXHYLWDOVLJQLVDVVRFLDWHGZLWKFOLQLFDOVLJQVDQGV\PSWRPV
WKHVLJQRUV\PSWRPZLOOEHUHSRUWHGDVDQ$(DQGWKHDVVRFLDWHGODERUDWRU\UHVXOWYLWDOVLJQ
ZLOOEHFRQVLGHUHGDVDGGLWLRQDOLQIRUPDWLRQ:KHUHYHUSRVVLEOHWKHUHSRUWLQJ,QYHVWLJDWRU
XVHVWKHFOLQLFDOUDWKHUWKDQWKHODERUDWRU\WHUPHJDQHPLDYHUVXVORZKHPRJORELQYDOXH,Q
WKHDEVHQFHRIFOLQLFDOVLJQVRUV\PSWRPVFOLQLFDOO\UHOHYDQWGHWHULRUDWLRQVLQQRQPDQGDWHG
SDUDPHWHUVVKRXOGEHUHSRUWHGDV$(V
&ULWHULDIRUD³FOLQLFDOO\VLJQLILFDQW´ODERUDWRU\DEQRUPDOLW\DUH
x
DODERUDWRU\DEQRUPDOLW\WKDWOHDGVWRVWXG\GUXJGRVHVXVSHQVLRQRU
GLVFRQWLQXDWLRQ
x
DODERUDWRU\DEQRUPDOLW\WKDWUHVXOWVLQDQ\WKHUDSHXWLFLQWHUYHQWLRQLH
FRQFRPLWDQWPHGLFDWLRQRUWKHUDS\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
DQ\RWKHU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WKHQRUPDO
UHIHUHQFHUDQJHWKH,QYHVWLJDWRUVKRXOGLQGLFDWHZKHWKHUWKHYDOXHLVFOLQLFDOO\VLJQLILFDQWRU
QRWFOLQLFDOO\VLJQLILFDQWIRUWKHVXEMHFW
$Q\QHZRUDJJUDYDWHGFOLQLFDOO\UHOHYDQWDEQRUPDOPHGLFDOILQGLQJDWDSK\VLFDOH[DPLQDWLRQ
DVFRPSDUHGZLWKWKHEDVHOLQHDVVHVVPHQWZLOOEHUHSRUWHGDVDQ$(
3DUDGR[LFDOEURQFKRVSDVPZLOOEHPRQLWRUHGE\

6.3.5
Disease under study
6\PSWRPVRIWKHGLVHDVHXQGHUVWXG\DUHWKRVHZKLFKPLJKWEHH[SHFWHGWRRFFXUDVDGLUHFW
UHVXOWRIWKHVXEMHFW¶VDVWKPDWLFFRQGLWLRQHJZKHH]HEUHDWKOHVVQHVVFRXJK(YHQWVWKDWDUH
XQHTXLYRFDOO\GXHWRWKHGLVHDVHXQGHUVWXG\VKRXOGQRWEHUHSRUWHGDVDQ$(GXULQJWKHVWXG\
XQOHVVWKH\PHHW6$(FULWHULDRUOHDGWRGLVFRQWLQXDWLRQRIVWXG\GUXJ
6.3.6
Severity
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
6.3.7
Relationship to study drug
7KH,QYHVWLJDWRUZLOODVVHVVFDXVDOUHODWLRQVKLSEHWZHHQWKHVWXG\GUXJDQGHDFK$(DQG
DQVZHUµ\HV¶RUµQR¶WRWKHTXHVWLRQµ'R\RXFRQVLGHUWKDWWKHUHLVDUHDVRQDEOHSRVVLELOLW\WKDW
WKHHYHQWPD\KDYHEHHQFDXVHGE\WKHVWXG\GUXJ"¶
)RU6$(VFDXVDOUHODWLRQVKLSZLOODOVREHDVVHVVHGIRURWKHUPHGLFDWLRQDQGVWXG\SURFHGXUHV
1RWHWKDWIRU6$(VWKDWFRXOGEHDVVRFLDWHGZLWKDQ\VWXG\SURFHGXUHWKHFDXVDOUHODWLRQVKLSLV
LPSOLHGDVµ\HV¶
$JXLGHWRWKHLQWHUSUHWDWLRQRIWKHFDXVDOLW\TXHVWLRQLVIRXQGLQ$SSHQGL[&


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

6.4
Reporting of SAEs
,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WKH6SRQVRURUGHVLJQHH$OO6$(VPXVWEHUHSRUWHGWRWKH6SRQVRURU
GHVLJQHHQRODWHUWKDQKRXUVDIWHUWKH,QYHVWLJDWRUUHFRJQL]HVFODVVLILHVWKHHYHQWDVDQ
6$($OO6$(VVKRXOGEHGRFXPHQWHGDQGUHSRUWHGXVLQJWKHH&5)$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DQ6$(WR
WKH6SRQVRURUGHVLJQHHZLWKLQZRUNLQJGD\VDIWHUUHFHLYLQJWKHLQIRUPDWLRQ)ROORZXS
LQIRUPDWLRQZLOOEHDGHWDLOHGZULWWHQUHSRUWWKDWPD\LQFOXGHFRSLHVRIKRVSLWDOUHFRUGVFDVH
UHSRUWVDXWRSV\UHSRUWVDQGRWKHUSHUWLQHQWGRFXPHQWV
)RUVXEMHFWVGLVFRQWLQXLQJVWXG\GUXJDOO$(V6$(VZLOOEHFROOHFWHGWKURXJKWKHIROORZXS
WHOHSKRQHFDOO
3RVWWUHDWPHQW6$(VIROORZLQJWKHODVWGRVHRIVWXG\GUXJPXVWEHUHSRUWHGWRWKH6SRQVRUDV
GHVFULEHGLQ6HFWLRQ
7KH,QYHVWLJDWRULVUHVSRQVLEOHIRUFRQWLQXLQJWRUHSRUWDQ\QHZRUUHOHYDQWIROORZXS
LQIRUPDWLRQWKDWVKHOHDUQVDERXWWKH6$(
6.4.1
Supplemental investigations of SAEs
7KH,QYHVWLJDWRUDQGVXSSRUWLQJSHUVRQQHOUHVSRQVLEOHIRUVXEMHFWFDUHVKRXOGGLVFXVVZLWKWKH
6SRQVRU0HGLFDO0RQLWRURUGHVLJQHHDQ\QHHGIRUVXSSOHPHQWDOLQYHVWLJDWLRQVRI6$(V,I
DGGLWLRQDODVVHVVPHQWVDUHFRQGXFWHGUHVXOWVPXVWEHUHSRUWHGWRWKH6SRQVRU,IDVXEMHFWGLHV
GXULQJVWXG\SDUWLFLSDWLRQDQGLIDSRVWPRUWHPH[DPLQDWLRQLVSHUIRUPHGDFRS\RIWKH
DXWRSV\UHSRUWVKRXOGEHVXEPLWWHGWRWKH6SRQVRU
6.4.2
Post-study follow-up of AEs
$Q\$(VWKDWDUHXQUHVROYHGDWWKHVXEMHFW¶VODVW$(DVVHVVPHQWLQWKHVWXG\DUHWREH
IROORZHGXSE\WKH,QYHVWLJDWRUIRUDVORQJDVPHGLFDOO\LQGLFDWHGEXWZLWKRXWIXUWKHU
UHFRUGLQJLQWKHH&5)7KH6SRQVRUUHWDLQVWKHULJKWWRUHTXHVWDGGLWLRQDOLQIRUPDWLRQIRUDQ\
VXEMHFWZLWKRQJRLQJ$(V6$(VDWWKHHQGRIWKHVWXG\LIMXGJHGQHFHVVDU\
6.4.3
Notification of post-treatment SAEs
,QYHVWLJDWRUVDUHQRWREOLJDWHGWRDFWLYHO\IROORZVXEMHFWVDIWHUFRPSOHWLRQRIWKHVWXG\
+RZHYHULIWKH,QYHVWLJDWRUEHFRPHVDZDUHRIDSRVWWUHDWPHQW6$(RFFXUULQJZLWKLQWR
GD\VIROORZLQJWKHODVWGRVHRIVWXG\GUXJWKH6$(PXVWEHUHSRUWHGWRWKH6SRQVRU
ZKHWKHURUQRWWKHHYHQWLVDWWULEXWDEOHWRVWXG\GUXJ$OO6$(VPXVWEHUHSRUWHGWRWKH
6SRQVRUQRODWHUWKDQKRXUVDIWHUWKH,QYHVWLJDWRUUHFRJQL]HVFODVVLILHVWKHHYHQWDVDQ6$(


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

6.4.4
IRB notification of SAEs
7KH,QYHVWLJDWRULVUHVSRQVLEOHIRUSURPSWO\QRWLI\LQJKHUKLV,5%RIDOO6$(VLQFOXGLQJDQ\
IROORZXSLQIRUPDWLRQRFFXUULQJDWWKHLUVLWHDQGDQ\6$(UHJXODWRU\UHSRUWLQFOXGLQJDQ\
IROORZXSUHSRUWVUHFHLYHGIURPWKH6SRQVRU'RFXPHQWDWLRQRI,5%VXEPLVVLRQPXVWEH
UHWDLQHGIRUHDFKVDIHW\UHSRUW7KH,QYHVWLJDWRULVDOVRUHVSRQVLEOHIRUQRWLI\LQJWKH6SRQVRULI
WKHLU,5%UHTXLUHVUHYLVLRQVWRWKH,&)RURWKHUPHDVXUHVEDVHGRQLWVUHYLHZRIDQ6$(
5HSRUW
6.4.5
Health Authority Safety Reports
7KH6SRQVRURULWVUHSUHVHQWDWLYHVZLOOVXEPLWDVDIHW\UHSRUWWRWKHDSSURSULDWHUHJXODWRU\
DJHQFLHVIRUDQ\VXVSHFWHGDGYHUVHUHDFWLRQWKDWLVERWKVHULRXVDQGXQH[SHFWHGZLWKLQWKH
WLPHIUDPHVSHFLILHGE\HDFKUHJXODWRU\DJHQF\
7KH6SRQVRURULWVUHSUHVHQWDWLYHVZLOOVHQGFRSLHVRIHDFKVXEPLWWHGVDIHW\UHSRUWWR
,QYHVWLJDWRUVDFWLYHO\SDUWLFLSDWLQJLQWKH6SRQVRU¶VFOLQLFDOVWXGLHV6DIHW\UHSRUWVPXVWDOVR
EHVXEPLWWHGWRWKHDSSURSULDWH,5%VDVVRRQDVSRVVLEOH'RFXPHQWDWLRQRIVXEPLVVLRQWRWKH
,5%PXVWEHUHWDLQHGIRUHDFKVDIHW\UHSRUW
6.5
Overdose
$QRYHUGRVHLVGHILQHGDVDQ\GRVHJUHDWHUWKDQWKHKLJKHVWGRVHLQYHVWLJDWHGLQWKLVVWXG\WKDW
UHVXOWVLQFOLQLFDOVLJQVDQGV\PSWRPV,QWKHHYHQWRIDVWXG\GUXJRYHUGRVHWKH,QYHVWLJDWRU
VKRXOGXVHWKHLUEHVWFOLQLFDOMXGJPHQWLQWUHDWLQJWKHRYHUGRVHDQGWKH6SRQVRU¶V0HGLFDO
0RQLWRUVKRXOGDOVREHFRQWDFWHG,QYHVWLJDWRUVVKRXOGUHIHUWRWKHUHOHYDQWGRFXPHQWVIRU
GHWDLOHGLQIRUPDWLRQUHJDUGLQJZDUQLQJVSUHFDXWLRQVFRQWUDLQGLFDWLRQV$(VDQGRWKHU
VLJQLILFDQWGDWDSHUWDLQLQJWRWKHVWXG\GUXJVEHLQJDGPLQLVWHUHG6XFKGRFXPHQWVPD\
LQFOXGHEXWDUHQRWOLPLWHGWRWKH,QYHVWLJDWRU¶V%URFKXUHIRU$60',DQGDSSURYHGSURGXFW
ODEHOLQJIRURSHQODEHOSURGXFWV
6.6
Pregnancy
$Q\SUHJQDQF\WKDWRFFXUVIURP9LVLWXQWLOVWXG\FRPSOHWLRQPXVWEHUHSRUWHGWRWKH
6SRQVRU7KHSUHJQDQF\PXVWEHIROORZHGXSWRGHWHUPLQHWKHRXWFRPHLQFOXGLQJSUHPDWXUH
WHUPLQDWLRQDQGVWDWXVRIPRWKHUDQGFKLOG
6.6.1
Maternal exposure
,IDVXEMHFWEHFRPHVSUHJQDQWGXULQJWKHFRXUVHRIWKHVWXG\WKHVWXG\GUXJVKRXOGEH
GLVFRQWLQXHGLPPHGLDWHO\
3UHJQDQF\LWVHOILVQRWUHJDUGHGDVDQ$(XQOHVVWKHUHLVDVXVSLFLRQWKDWWKHLQYHVWLJDWLRQDO
SURGXFWXQGHUVWXG\PD\KDYHLQWHUIHUHGZLWKWKHHIIHFWLYHQHVVRIDFRQWUDFHSWLYHPHGLFDWLRQ
&RQJHQLWDODEQRUPDOLWLHVELUWKGHIHFWVDQGVSRQWDQHRXVPLVFDUULDJHVVKRXOGEHUHSRUWHGDQG
KDQGOHGDV6$(V(OHFWLYHDERUWLRQVZLWKRXWFRPSOLFDWLRQVVKRXOGQRWEHKDQGOHGDV$(V7KH
RXWFRPHRIDOOSUHJQDQFLHVVSRQWDQHRXVPLVFDUULDJHHOHFWLYHWHUPLQDWLRQHFWRSLFSUHJQDQF\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

QRUPDOELUWKRUFRQJHQLWDODEQRUPDOLW\VKRXOGEHIROORZHGXSDQGGRFXPHQWHGHYHQLIWKH
VXEMHFWZDVZLWKGUDZQIURPWKHVWXG\
,IDQ\SUHJQDQF\RFFXUVLQWKHFRXUVHRIWKHVWXG\WKHQWKH,QYHVWLJDWRURURWKHUVLWHSHUVRQQHO
VKRXOGLQIRUPWKHDSSURSULDWH6SRQVRUUHSUHVHQWDWLYHVLPPHGLDWHO\EXWno later than 24 
hours RIZKHQKHRUVKHEHFRPHVDZDUHRILW
3UHJQDQF\VKRXOGEHUHFRUGHGRQDSDSHU3UHJQDQF\5HSRUW)RUPDQGUHSRUWHGE\WKH
,QYHVWLJDWRUWRWKH6SRQVRURUGHVLJQHH3UHJQDQF\IROORZXSVKRXOGEHUHFRUGHGRQWKHVDPH
3UHJQDQF\5HSRUW)RUPDQGVKRXOGLQFOXGHSRVVLEOHUHODWLRQVKLSWRWKHVWXG\GUXJLQUHVSRQVH
WRWKHSUHJQDQF\RXWFRPH$Q\6$(H[SHULHQFHGGXULQJSUHJQDQF\PXVWEHUHSRUWHGRQWKH
6$(5HSRUW)RUP
7KHVDPHWLPHOLQHVDSSO\ZKHQRXWFRPHLQIRUPDWLRQLVDYDLODEOH
6.6.2
Paternal exposure 
0DOHVXEMHFWVZKRDUHVH[XDOO\DFWLYHPXVWDJUHHWRXVHDGRXEOHEDUULHUPHWKRGRI
FRQWUDFHSWLRQFRQGRPZLWKVSHUPLFLGHIURPWKHILUVWGRVHRIUDQGRPL]HGWUHDWPHQWXQWLO
ZHHNVDIWHUWKHLUODVWGRVHDQGPXVWQRWGRQDWHVSHUPGXULQJWKHLUVWXG\SDUWLFLSDWLRQ
SHULRG,IDPDOHVXEMHFW
VSDUWQHUEHFRPHVSUHJQDQWGXULQJWKHFRXUVHRIWKHVWXG\LWPXVWEH
UHSRUWHGWRWKH6SRQVRUZLWKLQKRXUVRIWKH,QYHVWLJDWRUOHDUQLQJRILWVRFFXUUHQFH
6.7
Medication error
)RUWKHSXUSRVHVRIWKLVFOLQLFDOVWXG\DPHGLFDWLRQHUURULVDQXQLQWHQGHGIDLOXUHRUPLVWDNHLQ
WKHWUHDWPHQWSURFHVVIRUDVWXG\GUXJWKDWHLWKHUFDXVHVKDUPWRWKHVXEMHFWRUKDVWKH
SRWHQWLDOWRFDXVHKDUPWRWKHVXEMHFW
$PHGLFDWLRQHUURULVQRWODFNRIHIILFDF\RIWKHGUXJEXWUDWKHUDKXPDQRUSURFHVVUHODWHG
IDLOXUHZKLOHWKHGUXJLVLQFRQWURORIWKHVWXG\VLWHVWDIIRUVXEMHFW
0HGLFDWLRQHUURULQFOXGHVVLWXDWLRQVZKHUHDQHUURU
x
RFFXUUHG
x
ZDVLGHQWLILHGDQGLQWHUFHSWHGEHIRUHWKHVXEMHFWUHFHLYHGWKHGUXJ
x
GLGQRWRFFXUEXWFLUFXPVWDQFHVZHUHUHFRJQL]HGWKDWFRXOGKDYHOHGWRDQ
HUURU
([DPSOHVRIHYHQWVWREHUHSRUWHGLQFOLQLFDOVWXGLHVDVPHGLFDWLRQHUURUV
x
GUXJQDPHFRQIXVLRQ
x
GLVSHQVLQJHUURUHJPHGLFDWLRQSUHSDUHGLQFRUUHFWO\HYHQLILWZDVQRW
DFWXDOO\JLYHQWRWKHVXEMHFW


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
GUXJQRWDGPLQLVWHUHGDVLQGLFDWHGIRUH[DPSOHZURQJURXWHRUZURQJVLWH
RIDGPLQLVWUDWLRQ
x
GUXJQRWWDNHQDVLQGLFDWHGHJWDEOHWGLVVROYHGLQZDWHUZKHQLWVKRXOGEH
WDNHQDVDVROLGWDEOHW
x
GUXJQRWVWRUHGDVLQVWUXFWHGHJNHSWLQWKHUHIULJHUDWRUZKHQLWVKRXOGEHDW
URRPWHPSHUDWXUH
x
ZURQJVXEMHFWUHFHLYHGWKHPHGLFDWLRQH[FOXGLQJ,:56HUURUV
x
ZURQJGUXJDGPLQLVWHUHGWRVXEMHFWH[FOXGLQJ,:56HUURUV
([DPSOHVRIHYHQWVWKDWdo notUHTXLUHUHSRUWLQJDVPHGLFDWLRQHUURUVLQFOLQLFDOVWXGLHV
x
HUURUVUHODWHGWRRUUHVXOWLQJIURP,:56LQFOXGLQJWKRVHZKLFKOHDGWRRQH
RIWKHDERYHOLVWHGHYHQWVWKDWZRXOGRWKHUZLVHKDYHEHHQDPHGLFDWLRQHUURU
x
VXEMHFWDFFLGHQWDOO\PLVVHGGUXJGRVHVHJIRUJRWWRWDNHPHGLFDWLRQ
x
DFFLGHQWDORYHUGRVHZLOOEHFDSWXUHGDVDQRYHUGRVH
x
VXEMHFWIDLOHGWRUHWXUQXQXVHGPHGLFDWLRQRUHPSW\SDFNDJLQJ
x
HUURUVUHODWHGWREDFNJURXQGDQGUHVFXHPHGLFDWLRQRUVWDQGDUGRIFDUH
PHGLFDWLRQLQRSHQODEHOVWXGLHV
0HGLFDWLRQHUURUVDUHQRWUHJDUGHGDV$(VEXW$(VPD\RFFXUDVDFRQVHTXHQFHRIWKH
PHGLFDWLRQHUURU
,IDPHGLFDWLRQHUURURFFXUVLQWKHFRXUVHRIWKHVWXG\WKHQWKH,QYHVWLJDWRURURWKHUVLWH
SHUVRQQHOLQIRUPVWKHDSSURSULDWH6SRQVRUUHSUHVHQWDWLYHVLPPHGLDWHO\EXWno later than 
24 hoursRIZKHQKHRUVKHEHFRPHVDZDUHRILW
6.8
Management of study drug-related toxicities – not applicable
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
,QWKLVSURWRFRO³VWXG\GUXJ´UHIHUVWRDQDFWLYHLQJUHGLHQWEHLQJWHVWHGRUXVHGDVDUHIHUHQFH
LQWKLVVWXG\6WXG\GUXJVXVHGLQWKLVVWXG\DUHVXPPDUL]HGLQ7DEOH,QVWUXFWLRQVIRU
SULPLQJDQGXVHDUHSURYLGHGLQ$SSHQGL['


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

$60',LVPDQXIDFWXUHGDQGVXSSOLHGE\WKH6SRQVRU)RURSHQODEHO3URYHQWLODFWLYH
FRQWURO0',VZLOOEHSURYLGHGIURPFRPPHUFLDOVXSSOLHV0DQXIDFWXUHU¶VLQVWUXFWLRQVIRU
VWXG\GUXJDGPLQLVWUDWLRQZLOOEHSURYLGHG
Table 4.
Randomized Study Drugs
Product Name 
and Dose
Product Strength
Manufacturer
Dosage Form/
Fill Count
Administration
$60',J
$60',J
DFWXDWLRQD
3HDUO
0',
DFWXDWLRQV
7DNHQDVRU
LQKDODWLRQV
3URYHQWLOJ
$OEXWHURO
JDFWXDWLRQD
0HUFN6KDUS	
'RKPH&RUS
0',
DFWXDWLRQV
7DNHQDVRU
LQKDODWLRQV
1RWH$OOVWXG\GUXJVZLOOEHDGPLQLVWHUHGE\RUDOLQKDODWLRQ
D
(DFKLQKDODWLRQFRQWDLQVȝJDOEXWHUROVXOIDWHFRUUHVSRQGLQJWRJDOEXWHUROEDVHSHUDFWXDWLRQ

)RUWKH6SRQVRUSURYLGHGEDFNJURXQGDVWKPDPHGLFDWLRQ9HQWROLQ$WURYHQWDQG3XOPLFRUW
)OH[KDOHUDQG9HQWROLQIRUUHYHUVLELOLW\WHVWLQJFRPPHUFLDOGU\SRZGHULQKDOHUV0',VZLWK
GRVHFRXQWHUVDQGPDQXIDFWXUHU¶VLQVWUXFWLRQVIRUXVHZLOOEHSURYLGHG7KHVHPHGLFDWLRQVDUH
OLVWHGLQ7DEOH
Table 5.
Other Sponsor-provided Study Medications
Product Name Product Strength
Manufacturer
Dosage Form/
Fill Count
Administration
$WURYHQW
,SUDWURSLXP
EURPLGH
JDFWXDWLRQ
%RHKULQJHU
,QJHOKHLP
3KDUPDFHXWLFDOV
0',
DFWXDWLRQV
8VHGDVQHHGHGIRU
V\PSWRPVGXULQJWKH
6FUHHQLQJDQG
UDQGRPL]HG7UHDWPHQW
3HULRGV
3XOPLFRUW
)OH[KDOHU
%XGHVRQLGH
J
$VWUD=HQHFD
'3,
DFWXDWLRQV
RULQKDODWLRQV%,'
DVGLUHFWHGDW9LVLW
9HQWROLQ
$OEXWHURO
JDFWXDWLRQD
*OD[R6PLWK.OLQH
0',
DFWXDWLRQV
7DNHQDVGLUHFWHGIRU
UHYHUVLELOLW\WHVWLQJ
9LVLWVDRUEDQG
DVQHHGHGIRUV\PSWRPV
GXULQJ6FUHHQLQJ
$EEUHYLDWLRQV'3, GU\SRZGHULQKDOHU
1RWH$OOVWXG\GUXJVZLOOEHDGPLQLVWHUHGE\RUDOLQKDODWLRQ
D
(DFKLQKDODWLRQFRQWDLQVȝJDOEXWHUROVXOIDWHFRUUHVSRQGLQJWRJDOEXWHUROEDVHSHUDFWXDWLRQ

7.2
Dose and treatment regimens
(DFKRIWKH7UHDWPHQW9LVLWVZLOOLQFOXGHRIWKHIROORZLQJFXPXODWLYHGRVHWUHDWPHQWV
EDVHGRQWKHVXEMHFW¶VUDQGRPL]HGWUHDWPHQWDVVLJQPHQW


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

x
$60',LQFXPXODWLYHGRVHVDFWXDWLRQVDQG
ȝJȝJSHUDFWXDWLRQ
x
3URYHQWLOLQFXPXODWLYHGRVHVDFWXDWLRQVDQG
ȝJȝJSHUDFWXDWLRQ
7.2.1
Instructions for preparation of treatments for administration and dispensing
3ULPLQJVKRXOGEHGRQHE\VWXG\SHUVRQQHOLQDURRPVHSDUDWHIURPWKHGRVLQJDQGVDPSOLQJ
DUHDV%ORRGVDPSOLQJVXSSOLHVPXVWEHNHSWLQDQDUHDVHSDUDWHIURPWKHURRPVZKHUHWKH
SULPLQJDQGDGPLQLVWUDWLRQRI$60',DQG3URYHQWLOWDNHSODFH7KHLQGZHOOLQJFDQQXODIRU
FROOHFWLRQRIEORRGVDPSOHVVKRXOGEHFRYHUHGHJZLWKSODVWLFZUDSGXULQJGRVLQJ
$IWHUWKHDGPLQLVWUDWLRQRI$60',DQG3URYHQWLOWKHVXEMHFWVZLOOFOHDQWKHLUKDQGVDQG
IDFHVZLWKZDWHURUDZHWZLSHWRUHPRYHDQ\UHVLGXDOGUXJDQGDYRLGFURVVFRQWDPLQDWLRQRI
EORRGVDPSOLQJVXSSOLHV6WXG\SHUVRQQHOZLOODOVRFOHDQWKHLUKDQGVDIWHUGRVLQJDQGRU
KDQGOLQJRILQKDOHUV
7.2.2
Randomized study drug
AS MDI
,QGLYLGXDO$60',V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,'QXPEHU&RQILUPWKDWWKHLGHQWLILHUJLYHQE\,:56DQGWKH,'QXPEHUZULWWHQ
RQWKHODEHODUHWKHVDPH7KHWUHDWPHQWER[LVODEHOHGZLWKDSDUWODEHO:ULWHWKHVXEMHFW
QXPEHUDQGWUHDWPHQWYLVLWQXPEHURQHDFKSDUWRIWKHSDUWODEHO7KHWHDURIISDUWRIWKH
ODEHOLVWREHSODFHGRQWRWKH,:56FRQILUPDWLRQUHSRUW
$OO0',VPXVWEHSULPHGE\VWXG\SHUVRQQHOEHIRUHWKHILUVWXVH3ULPLQJLQYROYHVUHOHDVLQJ
VSUD\VLQWRWKHDLUEHIRUHWKHILUVWXVHRIWKHLQKDOHU6KDNLQJDQGSULPLQJWKHLQKDOHUILOOVD
FKDPEHULQVLGHWKHFDQLVWHUZLWKWKHFRUUHFWGRVHDQGPL[RIPHGLFDWLRQVRWKDWLWLVUHDG\WR
XVH
7KH0',PXVWEHSULPHGLQDVHSDUDWHURRPIURPWKHVXEMHFWWUHDWPHQWDUHD6LQFHWKH0',LV
SULPHGLQDVHSDUDWHURRPEHIRUHGRVLQJWKHUHLVDSRVVLELOLW\WKDWWKHUHPD\EHDGHOD\
EHWZHHQSULPLQJDQGGRVLQJDQGWKHUHIRUHWRHQVXUHFRQVLVWHQF\LQWKHDGPLQLVWUDWLRQIRUDOO
VXEMHFWVWKH0',VDUHWREHJHQWO\VKDNHQWRVHFRQGVLPPHGLDWHO\EHIRUHHDFK
DFWXDWLRQLQKDODWLRQ
7RSULPHWKHLQKDOHUJHQWO\VKDNHWKHLQKDOHUIRUWRVHFRQGVDQGWKHQVSUD\RQFHLQWRWKH
DLUDZD\IURP\RXUVHOIDQGRWKHUV:DLWDSSUR[LPDWHO\VHFRQGVDQGUHSHDWWKHSURFHVV
PRUHWLPHV
(DFKGRVHZLOOFRQVLVWRIWRDFWXDWLRQVIURPWKH0',6HH$SSHQGL['IRULQVWUXFWLRQVRQ
WKHDGPLQLVWUDWLRQRI$60',


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Open-label Proventil
,QGLYLGXDO3URYHQWLO0',VZLOOEHFRQWDLQHGLQDQLQGLYLGXDOYLVLWWUHDWPHQWER[7KHYLVLW
WUHDWPHQWER[ZLOOKDYHDSDUWODEHOZLWKDFRPSRQHQW,'QXPEHU&RQILUPWKDWWKH
LGHQWLILHUJLYHQE\,:56DQGWKHFRPSRQHQW,'QXPEHUZULWWHQRQWKHODEHODUHWKHVDPH
:ULWHWKHVXEMHFWQXPEHUDQGWUHDWPHQWYLVLWQXPEHURQHDFKSDUWRIWKHSDUWODEHO7KHWHDU
RIISDUWRIWKHODEHOLVWREHSODFHGRQWRWKH,:56FRQILUPDWLRQUHSRUW
3URYHQWLOVKRXOGEHSULPHGE\VWXG\SHUVRQQHOLQDVHSDUDWHURRPIURPWKHVXEMHFWWUHDWPHQW
DUHDSHUPDQXIDFWXUHU¶VLQVWUXFWLRQVEHIRUHDGPLQLVWHULQJWRVXEMHFW6LQFH3URYHQWLOLV
SULPHGLQDVHSDUDWHURRPEHIRUHGRVLQJWKHUHLVDSRVVLELOLW\WKDWWKHUHPD\EHDGHOD\
EHWZHHQSULPLQJDQGGRVLQJDQGWKHUHIRUHWRHQVXUHFRQVLVWHQF\LQWKHDGPLQLVWUDWLRQIRUDOO
VXEMHFWVWKH0',VDUHWREHJHQWO\VKDNHQWRVHFRQGVLPPHGLDWHO\EHIRUHHDFK
DFWXDWLRQLQKDODWLRQ
(DFKGRVHZLOOFRQVLVWRIWRDFWXDWLRQVIURPWKH0',6HH$SSHQGL['IRUWKH
PDQXIDFWXUHU¶VLQVWUXFWLRQVRQWKHDGPLQLVWUDWLRQRI3URYHQWLO
7.2.3
Sponsor-provided background asthma therapies
Ventolin
2SHQODEHO9HQWROLQZLOOEHSURYLGHGE\WKH6SRQVRU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EHIRUHGLVSHQVLQJWRVXEMHFW6HH
$SSHQGL['IRUWKHPDQXIDFWXUHU¶VLQVWUXFWLRQVRQWKHDGPLQLVWUDWLRQRI9HQWROLQ6WXG\
SHUVRQQHOZLOOUHFRUGWKHQXPEHURQWKHGRVHFRXQWHUDWWKHWLPHRIGLVSHQVLQJIROORZLQJ
SULPLQJDQGXSRQUHWXUQ
Atrovent
2SHQODEHO$WURYHQWZLOOEHSURYLGHGE\WKH6SRQVRUDQGVWRUHGLQDVHFXUHGORFDWLRQZLWKLQ
WKHFOLQLFRUSKDUPDF\IDFLOLWLHV$WURYHQWVKRXOGEHVWRUHGDWURRPWHPSHUDWXUHE\WKH
VXEMHFW$WURYHQWVKRXOGEHSULPHGSHUPDQXIDFWXUHU¶VLQVWUXFWLRQVEHIRUHGLVSHQVLQJWR
VXEMHFW6HH$SSHQGL['IRUWKHPDQXIDFWXUHU¶VLQVWUXFWLRQVRQWKHDGPLQLVWUDWLRQRI
$WURYHQW6WXG\SHUVRQQHOZLOOUHFRUGWKHQXPEHURQWKHGRVHFRXQWHUDWWKHWLPHRI
GLVSHQVLQJIROORZLQJSULPLQJDQGXSRQUHWXUQ
Pulmicort Flexhaler
2SHQODEHO3XOPLFRUW)OH[KDOHUZLOOEHSURYLGHGE\WKH6SRQVRUDQGVWRUHGLQDVHFXUHG
ORFDWLRQZLWKLQWKHFOLQLFRUSKDUPDF\IDFLOLWLHV3XOPLFRUW)OH[KDOHUVKRXOGEHVWRUHGDWURRP
WHPSHUDWXUHE\WKHVXEMHFW3XOPLFRUW)OH[KDOHUVKRXOGEHSULPHGSHUPDQXIDFWXUHU¶V
LQVWUXFWLRQVEHIRUHGLVSHQVLQJWRVXEMHFW6HH$SSHQGL['IRUWKHPDQXIDFWXUHU¶VLQVWUXFWLRQV
RQWKHDGPLQLVWUDWLRQRI3XOPLFRUW)OH[KDOHU6WXG\SHUVRQQHOZLOOUHFRUGWKHQXPEHURQWKH
GRVHFRXQWHUDWWKHWLPHRIGLVSHQVLQJIROORZLQJSULPLQJDQGXSRQUHWXUQ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

7.3
Labeling
$OOVWXG\GUXJVDQGRWKHUPHGLFDWLRQVVXSSOLHGE\WKH6SRQVRUZLOOEHRSHQODEHO$60',
ZLOOEHSDFNDJHGE\WKH6SRQVRU
7.3.1
Primary packaging and labeling
/DEHOVZLOOEHSUHSDUHGLQDFFRUGDQFHZLWK*RRG0DQXIDFWXULQJ3UDFWLFHDQGORFDOUHJXODWRU\
JXLGHOLQHV
Open-label supplies (AS MDI and Proventil)
2SHQODEHO$60',DQG3URYHQWLOZLOOEHSURYLGHGDVLQGLYLGXDOO\ODEHOHG0',V(DFK0',
ZLOOFRQWDLQDVLQJOHODEHO7KHODEHO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LIDSSOLFDEOH
7UDQVODWLRQ.H\LIDSSOLFDEOH

7.3.2
Secondary packaging and labeling information (box)
$60',RSHQODEHO3URYHQWLORSHQODEHO9HQWROLQRSHQODEHO$WURYHQWDQGRSHQODEHO
3XOPLFRUW)OH[KDOHUVXSSOLHVZLOOEHSURYLGHGDV0',SHUER[%R[FRQILJXUDWLRQLVVXEMHFW
WRFKDQJHGXHWRSDFNDJLQJFRQVWUDLQWV


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

(DFKER[ZLOOEHODEHOHGZLWKDSDUWSDQHO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GDWHLIDSSOLFDEOH
'RVLQJ,QVWUXFWLRQVLIDSSOLFDEOH
6WRUDJH&RQGLWLRQV
&RPSRXQG,'3URWRFRO
&RXQWU\UHJXODWRU\UHTXLUHPHQWV
6SRQVRUDGGUHVV,IDSSOLFDEOH
7UDQVODWLRQ.H\,IDSSOLFDEOH

7.4
Storage
$OOVWXG\GUXJVDQG6SRQVRUSURYLGHGPHGLFDWLRQVKRXOGEHNHSWLQDVHFXUHSODFHXQGHU
DSSURSULDWHVWRUDJHFRQGLWLRQV7KHLQYHVWLJDWLRQDOSURGXFWODEHOVSHFLILHVWKHDSSURSULDWH
VWRUDJH&RPPHUFLDOO\VRXUFHGPHGLFDWLRQV3URYHQWLO9HQWROLQ$WURYHQWDQG3XOPLFRUW
)OH[KDOHUVKRXOGEHVWRUHGDVLQGLFDWHGRQWKHUHVSHFWLYHSURGXFWODEHO
Note: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WKH
SURGXFWODEHO'RFXPHQWDWLRQRIWHPSHUDWXUHPRQLWRULQJVKRXOGEHPDLQWDLQHG
7.5
Compliance
7KHWLPHRIDGPLQLVWUDWLRQRIUDQGRPL]HGVWXG\GUXJZLOOEHUHFRUGHGLQWKHDSSURSULDWH
VHFWLRQVRIWKHH&5)
7.6
Accountability
6WXG\SHUVRQQHOZLOOKDYHDFFHVVWRDQ,:56WRDOORFDWHVXEMHFWVWRDVVLJQGUXJWRVXEMHFWV
DQGWRPDQDJHWKHGLVWULEXWLRQRIFOLQLFDOVXSSOLHV&OLQLFDOVXSSOLHVZLOOEHSDFNDJHG
DFFRUGLQJWRDFRPSRQHQWVFKHGXOHJHQHUDWHGE\WKH6SRQVRURUGHVLJQHH(DFKSHUVRQ
DFFHVVLQJWKH,:56PXVWEHDVVLJQHGDQLQGLYLGXDOXQLTXHSHUVRQDO,'QXPEHU3,17KH\
PXVWXVHRQO\WKHLUDVVLJQHG3,1WRDFFHVVWKHV\VWHPDQGWKH\PXVWQRWVKDUHWKHLUDVVLJQHG
3,1ZLWKDQ\RQH
7KHVWXG\GUXJSURYLGHGIRUWKLVVWXG\ZLOOEHXVHGRQO\DVGLUHFWHGLQWKHFOLQLFDOVWXG\
SURWRFRO8QGHUQRFLUFXPVWDQFHVZLOOWKH,QYHVWLJDWRUVDOORZWKHVWXG\GUXJWREHXVHGRWKHU
WKDQDVGLUHFWHGE\WKLVSURWRFRO


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

,QYHVWLJDWLRQDOFOLQLFDOVXSSOLHVPXVWEHUHFHLYHGE\DGHVLJQDWHGSHUVRQDWWKHVWXG\VLWH
KDQGOHGDQGVWRUHGVDIHO\DQGSURSHUO\DQGNHSWLQDVHFXUHG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WKH6SRQVRUWKHDPRXQWGLVSHQVHGWRDQGUHWXUQHGE\WKH
VXEMHFWVDQGWKHDPRXQWUHPDLQLQJDWWKHFRQFOXVLRQRIWKHVWXG\6WXG\GUXJVKRXOGEH
KDQGOHGLQDFFRUGDQFHZLWK*RRG3KDUPDF\3UDFWLFHV7KH&OLQLFDO0RQLWRUVKRXOGEH
FRQWDFWHGZLWKDQ\TXHVWLRQVFRQFHUQLQJLQYHVWLJDWLRQDOSURGXFWVZKHUHVSHFLDORUSURWHFWLYH
KDQGOLQJLVLQGLFDWHG$WWKHHQGRIWKHVWXG\DOOFOLQLFDOVXSSOLHVLQFOXGLQJSDUWLDODQGHPSW\
FRQWDLQHUVPXVWEHUHWXUQHGDVGLUHFWHGE\WKH6SRQVRU
6LWHVVKRXOGFKHFNZLWKWKH6SRQVRUUHSUHVHQWDWLYHIRUDSSURSULDWHGRFXPHQWDWLRQWKDWPXVWEH
FRPSOHWHGIRUGUXJDFFRXQWDELOLW\
7KH,QYHVWLJDWRURUGHVLJQDWHGDVVLVWDQWVKRXOGQRWRSHQLQGLYLGXDOFOLQLFDOVXSSO\FRQWDLQHUV
XQWLODOOSUHGRVHDVVHVVPHQWVKDYHEHHQFRPSOHWHGDQGWKHVXEMHFWLVHOLJLEOHWREH
UDQGRPL]HGFRQWLQXHZLWKWKHVWXG\$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WKH6SRQVRURU
GHVLJQHHNote:8VHGVWXG\GUXJZLOOEHVWRUHGVHSDUDWHO\IURPXQXVHGVWXG\GUXJ
7.7
Concomitant and other treatments 
7.7.1
Prior medications
$OOSUHVFULSWLRQDQGRYHUWKHFRXQWHUPHGLFDWLRQVDVZHOODVDQ\KHUEDORUYLWDPLQ
VXSSOHPHQWVWDNHQE\WKHVXEMHFWZLWKLQGD\VRI9LVLWVKRXOGEHUHFRUGHGRQWKH
3ULRU&RQFRPLWDQW0HGLFDWLRQVH&5)SDJHLQGLFDWLRQWRWDOGDLO\GRVHDQGURXWHDQGGDWHVRI
GUXJDGPLQLVWUDWLRQVKRXOGEHFDSWXUHGWRWKHEHVWRIWKHVXEMHFW¶VDQGVLWH¶VDELOLW\
6RPHVXEMHFWVHOLJLEOHIRUWKLVVWXG\ZLOOEHRQUHJXODULQKDOHGDVWKPDPDLQWHQDQFHWKHUDS\
GHILQHGDVDQ,&6ZLWKRUZLWKRXWD/$%$ZLWKDVWDEOHGRVHIRUDWOHDVWGD\VSULRUWR
9LVLW7KHSHUPLWWHGWRWDOGDLO\,&6GRVDJHWRTXDOLI\,&6XVDJHIRUWKHGD\VSULRUWR
9LVLWDORQJZLWKWKHDVVLJQHGGRVHIRU6SRQVRUSURYLGHG3XOPLFRUW)OH[KDOHULVGHILQHGLQ
7DEOH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table 6
Dose of Sponsor-provided Pulmicort Flexhaler to be Assigned Based 
on Pre-study ICS or ICS/LABA Dose
Pre-study Asthma Inhaled 
Corticosteroid
Total Daily Dose of Pre-
study Inhaled 
Corticosteroid (μg/day)
Dose of Sponsor-provided 
Pulmicort Flexhaler 
(μg/day)
%HFORPHWKDVRQH
WR

%HFORPHWKDVRQH
!WR

%XGHVRQLGH
WR

%XGHVRQLGH
!WR

&LFOHVRQLGH
WR

&LFOHVRQLGH
!WR

)OXWLFDVRQHIXURDWH


)OXWLFDVRQHIXURDWH


)OXWLFDVRQHSURSLRQDWH
WR

)OXWLFDVRQHSURSLRQDWH
!WR

0RPHWDVRQHIXURDWH
WR

0RPHWDVRQHIXURDWH
!WR

7ULDPFLQRORQHDFHWRQLGH
WR

7ULDPFLQRORQHDFHWRQLGH
!WR


7.7.2
Concomitant medications
$Q\FXUUHQWRQJRLQJPHGLFDWLRQVLQFOXGLQJRYHUWKHFRXQWHUPHGLFDWLRQVDQGKHUEDO
VXSSOHPHQWVZLOOEHDOORZHGSURYLGHGWKH\DUHQRWH[SOLFLWO\SURKLELWHGE\WKHSURWRFRO
7DEOHRU7DEOH$OOFRQFRPLWDQWPHGLFDWLRQVWDNHQGXULQJWKHVWXG\ZLOOEHUHFRUGHGRQ
WKH&RQFRPLWDQW0HGLFDWLRQVH&5)SDJHZLWKLQGLFDWLRQWRWDOGDLO\GRVHURXWHRI
DGPLQLVWUDWLRQDQGGDWHVRIGUXJDGPLQLVWUDWLRQ$Q\DGGLWLRQVGHOHWLRQVRUFKDQJHVLQWKH
GRVHRIWKHVHPHGLFDWLRQVZKLOHLQWKHVWXG\VKRXOGEHHQWHUHGLQWKHH&5)6XEMHFWVVKRXOG
DOVREHLQVWUXFWHGWRFRQWDFWWKH,QYHVWLJDWRULIWKH\GHYHORSDQ\LOOQHVVHVHVSHFLDOO\WKRVH
UHTXLULQJPHGLFLQDOLQWHUYHQWLRQ
7.7.2.1
Required concomitant medications
6XEMHFWVZKRZHUHUHFHLYLQJDUHJXODUO\VFKHGXOHG,&6RU,&6/$%$EHIRUHVWXG\HQWU\ZLOO
EHVZLWFKHGWR3XOPLFRUW)OH[KDOHUȝJRUȝJ%,'DQG/$%$LIDSSOLFDEOHZLOOEH
GLVFRQWLQXHG7DEOH7KHVHVXEMHFWVZLOOFRQWLQXHWRXVH6SRQVRUSURYLGHG3XOPLFRUW
)OH[KDOHUJRUJ%,'DVDVVLJQHGDW9LVLWWKURXJKRXWWKH6FUHHQLQJ3HULRGDQG
IRUWKHUHPDLQGHURIWKHVWXG\GXULQJERWKWKHUDQGRPL]HG7UHDWPHQW3HULRGVDQG:DVKRXW
3HULRG


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

1RRWKHUDVWKPDPHGLFDWLRQVDUHDOORZHGIRUWKHUHPDLQGHURIWKHVWXG\H[FHSWIRU6SRQVRU
SURYLGHG9HQWROLQDQG$WURYHQWWREHXVHGDVQHHGHGDVGHVFULEHGLQ6HFWLRQ
7.7.2.2
Allowed allergy medications
7DEOHOLVWVDOOHUJ\PHGLFDWLRQVWKDWDUHDOORZHGDVORQJDVWKHVXEMHFWKDVEHHQRQDVWDEOH
GRVHIRUDWOHDVWGD\VEHIRUH9LVLWDQGUHPDLQVRQDVWDEOHGRVHWKURXJKRXWWKHVWXG\
Table 7
Allowed Allergy Medications
1RQVHGDWLQJORQJDFWLQJDQWLKLVWDPLQHVD
$OOHUJHQLPPXQRWKHUDS\
,QWUDQDVDOFRUWLFRVWHURLGV
,QWUDQDVDODQWLKLVWDPLQHVRUFRPELQDWLRQSURGXFWVRILQWUDQDVDODQWLKLVWDPLQHVFRUWLFRVWHURLGV
D
6KRUWDFWLQJDQWLKLVWDPLQHVHJGLSKHQK\GUDPLQHDUHDOVRSHUPLWWHGIRUXVHDVQHHGHGEXWQRWUHJXODUO\

7.7.3
Prohibited medications
7.7.3.1
Prohibited asthma and allergy medications and washout periods
6SHFLILFSURKLELWHGDVWKPDDQGDOOHUJ\PHGLFDWLRQVDUHOLVWHGLQ7DEOH6XEMHFWVWDNLQJDQ\
RIWKHVHSURKLELWHGPHGLFDWLRQVDUHUHTXLUHGWRVWRSWDNLQJWKHPDW9LVLWDQGDUHUHTXLUHGWR
DWWHQG9LVLWDIRUUHYHUVLELOLW\WHVWLQJ7KHUHTXLUHGZDVKRXWSHULRGIRUHDFKPHGLFDWLRQ
EHIRUH9LVLWDLVVKRZQLQ7DEOH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table 8
Prohibited Asthma and Allergy Medications That Must be 
Discontinued at Visit 1 and Required Washout Period Prior to the 
Next Visit
Medication
Minimum Washout Period Prior to the Next Visit
6KRUWDFWLQJPXVFDULQLFDQWDJRQLVWD
KRXUV
2UDOȕDJRQLVWV
GD\V
7KHRSK\OOLQH
GD\V
&URPRJO\FDWH
GD\V
1HGRFURPLO
GD\V
.HWRWLIHQE
GD\V
=LOHXWRQ
GD\V
/$%$VF

,QGDFDWHURORORGDWHUROYLODQWHURO
GD\V
6DOPHWHUROIRUPRWHURO
KRXUV
/HXNRWULHQHUHFHSWRUDQWDJRQLVWHJ
6LQJXODLU
GD\V
D
$GPLQLVWHUHGDVIL[HGRUORRVHFRPELQDWLRQVNote:$WURYHQWLVDOORZHGIRUXVHGXULQJWKHVWXG\DQGPXVW
EHGLVFRQWLQXHGDWOHDVWKRXUVEHIRUHHDFKVWXG\YLVLW
E
.HWRWLIHQH\HGURSVDUHDOORZHGQRZDVKRXWUHTXLUHG
F
,QFRPELQDWLRQZLWKDQ,&6

7.7.3.2
Prohibited non-asthma and non-respiratory medications
6XEMHFWVUHTXLULQJPHGLFDWLRQVSUHVHQWHGLQ7DEOHDUHSURKLELWHGIURPSDUWLFLSDWLQJLQWKLV
VWXG\6XEMHFWVZKRUHFHQWO\GLVFRQWLQXHGXVHRIWKHVHPHGLFDWLRQVPD\EHFRQVLGHUHGIRU
VWXG\HQUROOPHQWSURYLGHGWKH\KDYHPHWWKHPLQLPXPFHVVDWLRQSHULRGSULRUWR9LVLW7KHVH
PHGLFDWLRQVDUHSURKLELWHGWKURXJKRXWWKHFRXUVHRIWKHVWXG\,IVXEMHFWVUHTXLUHDQ\RIWKH
SURKLELWHGPHGLFDWLRQVOLVWHGLQ7DEOHWKH,QYHVWLJDWRUVKRXOGGLVFXVVZLWKWKHPRQLWRUWKH
VXLWDELOLW\RIWKHVXEMHFWFRQWLQXLQJVWXG\GUXJ
Note:8VHRIV\VWHPLFFRUWLFRVWHURLGVHJRUDOSDUHQWHUDOLQWUDRFXODULQWUDDUWLFXODULV
SURKLELWHGIRUWKHGXUDWLRQRIWKHVWXG\LQFOXGLQJERWKWKH6FUHHQLQJDQGUDQGRPL]HG
7UHDWPHQW3HULRGV,IDVXEMHFWUHTXLUHVDV\VWHPLFFRUWLFRVWHURLGWRWUHDWDQDVWKPDZRUVHQLQJ
RUDVWKPDH[DFHUEDWLRQWKHVXEMHFWZLOOEHGLVFRQWLQXHGIURPVWXG\GUXJDQGZLWKGUDZQIURP
WKHVWXG\


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table 9
Prohibited Non-Asthma and Non-Respiratory Medications
Class of Medication
Minimum Cessation Period Prior to Visit 1 
and Prohibited Throughout the Study
$Q\GUXJZLWKSRWHQWLDOWRVLJQLILFDQWO\SURORQJ
WKH47LQWHUYDODE
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
2WKHULQYHVWLJDWLRQDOGUXJV
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
1RQVHOHFWLYHQRQRFXODUȕEORFNLQJDJHQWV
GD\V
&DUGLDFDQWLDUUK\WKPLFV&ODVV,D,,,
GD\VXQOHVVDPLRGDURQHWKHQPRQWKV
$QWLFRQYXOVDQWVIRUVHL]XUHGLVRUGHUF
$OORZHGLIVWDEOHGRVHIRUPRQWKVDQGIUHHRI
VHL]XUHVIRU\HDU
$QWLSV\FKRWLFGUXJVG
GD\V
7ULF\FOLFDQWLGHSUHVVDQWVG
GD\V
0RQRDPLQHR[LGDVHLQKLELWRUV
GD\V
$QWLWXPRUQHFURVLVIDFWRUĮDQWLERGLHVHJ
LQIOL[LPDEDQGDQ\RWKHUPHPEHUVRIWKLVFODVVRI
GUXJV
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
0RQRFORQDODQWLERGLHVH
GD\VRUKDOIOLYHVZKLFKHYHULVORQJHU
3URWHDVHLQKLELWRUVHJULWRQDYLU
GD\V
Note%HQ]RGLD]HSLQHVDUHQRWH[FOXVLRQDU\6HURWRQLQQRUHSLQHSKULQHUHXSWDNHLQKLELWRUVDQGVHOHFWLYH
VHURWRQLQUHXSWDNHLQKLELWRUVDUHQRWH[FOXGHGDVORQJDVWKHVXEMHFWKDVEHHQRQDVWDEOHGRVHIRUDWOHDVW
GD\VEHIRUH9LVLWDQGWKURXJKRXWWKH6FUHHQLQJDQG7UHDWPHQW3KDVHDQGWKHGRVHGRHVQRWH[FHHGWKH
PD[LPXPUHFRPPHQGHG
D
6XEMHFWVZKRDUHRQPHGLFDWLRQVWKDWKDYHWKHSRWHQWLDOWRSURORQJWKH47FLQWHUYDOPD\EHHQUROOHG
SURYLGHGWKHGRVHKDVUHPDLQHGVWDEOHIRUDWOHDVWPRQWKVEHIRUH9LVLWWKHVXEMHFWPHHWVDOORIWKH(&*
LQFOXVLRQFULWHULDDQGQRQHRIWKH(&*H[FOXVLRQFULWHULDDQGLILQWKHRSLQLRQRIWKH,QYHVWLJDWRUWKHUHDUH
QRVDIHW\FRQFHUQVIRUWKHVXEMHFWWRSDUWLFLSDWHLQWKHVWXG\,QLWLDWLRQRIPHGLFDWLRQVZLWKWKHSRWHQWLDOWR
VLJQLILFDQWO\SURORQJWKH47LQWHUYDOLVSURKLELWHGWKURXJKRXWWKH6FUHHQLQJDQG7UHDWPHQW3HULRGV
E
6KRUWFRXUVHVRIPDFUROLGHDQGTXLQRORQHDQWLELRWLFVWRWUHDWLQIHFWLRQVDUHSHUPLWWHG
F
$QWLFRQYXOVDQWVIRUFRQGLWLRQVRWKHUWKDQVHL]XUHVPD\EHVWDUWHGDQGVWRSSHGDWDQ\WLPHEHIRUHWKHVWXG\
DQGWKURXJKRXWWKH6FUHHQLQJDQG7UHDWPHQW3HULRGV
G
$QWLSV\FKRWLFDJHQWVDQGWULF\FOLFDQWLGHSUHVVDQWVXVHGIRUSUHYLRXVO\GLDJQRVHGXQGHUO\LQJPHGLFDO
FRQGLWLRQVDUHDOORZHGLILQWKHRSLQLRQRIWKH,QYHVWLJDWRUWKHUHDUHQRFRQFHUQVUHJDUGLQJSDWLHQWVDIHW\
DQGLIWKHVXEMHFWKDVEHHQRQDVWDEOHGRVHIRUDWOHDVWZHHNV
H
,QYHVWLJDWRUVVKRXOGFRQWDFWWKH0HGLFDO0RQLWRUWRGHWHUPLQHWKHDSSURSULDWHQHVVDQGVDIHW\RIFRQWLQXLQJ
VWXG\GUXJRQDFDVHE\FDVHEDVLVHJ3UROLD>GHQRVXPDE@IRURVWHRSRURVLVPD\EHDOORZHGDIWHU
FRQVXOWDWLRQ

7.7.4
Other concomitant treatment
0HGLFDWLRQRWKHUWKDQWKDWGHVFULEHGDERYHZKLFKLVFRQVLGHUHGQHFHVVDU\IRUWKHVXEMHFW¶V
VDIHW\DQGZHOOEHLQJPD\EHJLYHQDWWKHGLVFUHWLRQRIWKH,QYHVWLJDWRUDQGUHFRUGHGLQWKH
DSSURSULDWHVHFWLRQVRIWKHH&5)


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

8.
STATISTICAL ANALYSES
8.1
Statistical considerations
$QDO\VHVZLOOEHSHUIRUPHGE\WKH6SRQVRURULWVUHSUHVHQWDWLYHV$OODQDO\VHVZLOOEH
VSHFLILHGLQDGHWDLOHGVWDWLVWLFDODQDO\VLVSODQ6$3WKDWZLOOLQFOXGHWDEOHDQGGDWDOLVWLQJ
VKHOOVZLWKPRFNJUDSKLFDOUHSUHVHQWDWLRQV7KH6$3ZLOOEHVLJQHGEHIRUHGDWDEDVHORFN
7ZRVLGHGFRQILGHQFHLQWHUYDOV&,VZLOOEHSURYLGHGIRUDOOEHWZHHQWUHDWPHQW
FRPSDULVRQV
8.2
Sample size estimate
5DQGRPL]DWLRQRIVXEMHFWVWRDFKLHYHVXEMHFWVFRPSOHWLQJWKHVWXG\ZLOOSURYLGH
SUREDELOLW\WRGHPRQVWUDWHHTXLYDOHQFHZLWKLQP/DIWHUDOOFXPXODWLYHGRVHV
LQWHUVHFWLRQXQLRQWHVW7KLVFDOFXODWLRQDVVXPHVDWUXHWUHDWPHQWGLIIHUHQFH$60',±
3URYHQWLORIP/LQWUDVXEMHFWVWDQGDUGGHYLDWLRQRIP/DQGWZRRQHVLGHGOHYHO
WHVWV7267
(QUROOPHQWRIVXEMHFWVWRREWDLQVXEMHFWVFRPSOHWLQJWKH3.VXEVWXG\ZLOOSURYLGH
SUREDELOLW\WRREVHUYHDRQHVLGHGXSSHUFRQILGHQFHERXQGIRUWKH&PD[UDWLR
$60',3URYHQWLOWKDWLVOHVVWKDQHYHQLIWKHWUXHUDWLRLVDVKLJKDV7KLV
FDOFXODWLRQDVVXPHVDQLQWUDVXEMHFWFRHIILFLHQWRIYDULDWLRQRIIRU3URYHQWLODQGDRQH
VLGHGWHVW
8.3
Definitions of analysis sets
7KHIROORZLQJDQDO\VLVVHWVDUHGHILQHGLQWKLVVWXG\
x
7KHIntent-To-Treat (ITT) analysis setLVGHILQHGDVDOOVXEMHFWVZKRDUH
UDQGRPL]HGWRWUHDWPHQWDQGUHFHLYHDWOHDVWGRVHRIWKHVWXG\WUHDWPHQW
6XEMHFWVZLOOEHDQDO\]HGLQHDFKSHULRGDFFRUGLQJWRWKHWUHDWPHQWWKH\
ZHUHDVVLJQHGWRSHUWKHUDQGRPL]DWLRQVFKHPH1RWHWKDWDVXEMHFWZKR
XVHGDVWXG\WUHDWPHQWEXWWRRNOHVVWKDQIXOOGRVHRIWUHDWPHQWZLOOTXDOLI\
IRUWKLVDQDO\VLVVHW
x
$Modified ITT (mITT) analysis setLVDVXEVHWRIWKH,77DQDO\VLVVHW
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GDWDEDVHORFNDQGH[FOXGHG
SHUWKHVWDWLVWLFDOSURWRFROGHYLDWLRQSODQ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
x
7KHSafety analysis setLVGHILQHGDVDOOVXEMHFWVZKRDUHUDQGRPL]HGWR
WUHDWPHQWDQGUHFHLYHDWOHDVWGRVHRIWKHVWXG\WUHDWPHQW6XEMHFWVZLOOEH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

DQDO\]HGDFFRUGLQJWRWUHDWPHQWUHFHLYHGUDWKHUWKDQSHUWKHUDQGRPL]DWLRQ
VFKHPH
x
7KHPer ProtocolDQDO\VLVVHWLVDVXEVHWRIWKH6DIHW\DQDO\VLVVHWLQFOXGLQJ
VXEMHFWVZKRUHFHLYHGWUHDWPHQWDQGKDYHSRVWWUHDWPHQWH[WUDSXOPRQDU\
SKDUPDFRG\QDPLFGDWD'DWDMXGJHGWREHLPSDFWHGE\PDMRUSURWRFRO
GHYLDWLRQVZLOOEHGHWHUPLQHGSULRUWRGDWDEDVHORFNDQGH[FOXGHGSHUWKH
VWDWLVWLFDOSURWRFROGHYLDWLRQSODQ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
x
7KHPK analysis setLVGHILQHGDVVXEMHFWVLQWKH6DIHW\DQDO\VLVVHWZKR
UHFHLYHGVWXG\GUXJDQGIRUZKRPDWOHDVWSULPDU\3.SDUDPHWHUFDQEH
FDOFXODWHGDQGZLWKQRLPSRUWDQWSURWRFROGHYLDWLRQVWKRXJKWWRLPSDFWWKH
DQDO\VLVRIWKH3.GDWD
x
7KHNot Randomized analysis setLVGHILQHGDVVXEMHFWVZKRGLGQRW
UHFHLYHDUDQGRPL]DWLRQQXPEHUDQGWKHUHIRUHGLGQRWUHFHLYHDGRVHRI
VWXG\WUHDWPHQWHJVXEMHFWVZKRZHUHVFUHHQIDLOXUHVRUVWRSSHG
SDUWLFLSDWLRQEHIRUHEHLQJUDQGRPL]HG
'HPRJUDSKLFVDQGEDVHOLQHFKDUDFWHULVWLFVZLOOEHVXPPDUL]HGIRUWKH,77P,77DQG6DIHW\
DQDO\VLVVHWV([WHQWRIH[SRVXUHZLOOEHVXPPDUL]HGIRUWKH6DIHW\DQDO\VLVVHW7KH6DIHW\
DQDO\VLVVHWZLOOEHXVHGWRVXPPDUL]H$(VDQG6$(V
(IILFDF\DQDO\VHVRI)(9ZLOOEHEDVHGRQWKHP,77DQDO\VLVVHW7KHSULPDU\HQGSRLQWZLOO
DOVREHDQDO\]HGXVLQJWKH,77DQDO\VLVVHW7KHSULPDU\DQDO\VHVRIH[WUDSXOPRQDU\3'
SDUDPHWHUVZLOOEHEDVHGRQWKH3HU3URWRFRODQDO\VLVVHW$VXSSRUWLYHDQDO\VLVRI
H[WUDSXOPRQDU\3'ZLOOEHFRQGXFWHGLQWKH6DIHW\DQDO\VLVVHWDVZHOO3.SDUDPHWHU
DQDO\VHVZLOOEHEDVHGRQWKH3.DQDO\VLVVHW
8.4
Outcome measures for analyses
$OOHIILFDF\DVVHVVPHQWVDUHUHODWLYHWREDVHOLQHDQGZLOOEHFRPSDUHGZLWK3URYHQWLO5HIHUWR
6HFWLRQIRUDFRPSOHWHGHOLQHDWLRQRIHIILFDF\DQGVDIHW\HQGSRLQWV
8.5
Methods for statistical analyses
8.5.1
Primary efficacy analysis
&KDQJHIURPEDVHOLQHLQ)(9PLQXWHVSRVWHDFKRIWKHFXPXODWLYHGRVHVZLOOEHDQDO\]HG
XVLQJDOLQHDUPL[HGHIIHFWPRGHOZLWKDUDQGRPVXEMHFWHIIHFWIRUWKHFRUUHODWLRQDFURVV
SHULRGVDQGDQXQVWUXFWXUHGFRYDULDQFHPDWUL[IRUWKHUHSHDWHGPHDVXUHVZLWKLQVXEMHFW
SHULRGV,QWKHHYHQWWKDWWKHXQVWUXFWXUHGPDWUL[IDLOVWRFRQYHUJHWKHKHWHURJHQHRXV7RHSOLW]
ZLOOEHILW7KHIL[HGHIIHFWVZLOOLQFOXGHWUHDWPHQWEDVHOLQH)(9DQGSHULRG1LQHW\SHUFHQW
&,VZLOOEHFDOFXODWHGIRUWKHEHWZHHQWUHDWPHQWGLIIHUHQFHVDIWHUHDFKFXPXODWLYHGRVHDQG
ZLOOEHHYDOXDWHGIRUFRQWDLQPHQWZLWKLQWKHHTXLYDOHQFHERXQGVRIP/


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

%DVHOLQH)(9ZLOOEHGHILQHGDVWKHPHDQRIDYDLODEOHSUHGRVHYDOXHVRQWKHILUVWGD\RI
HDFK7UHDWPHQW3HULRGLHWKHPHDQRISUHGRVHYDOXHVDW9LVLWVDQGZKHUHWKHPHDQRI
WKHDQGPLQXWHYDOXHVIRUHDFKYLVLWGD\LVREWDLQHGDQGWKHQWKHDYHUDJHRIWKHYLVLW
PHDQVLVREWDLQHG
8.5.2
Secondary efficacy analysis
7KH)(9$8&LVWKHDUHDXQGHUWKHFXUYHIRUFKDQJHIURPEDVHOLQHFDOFXODWHGXVLQJWKH
WUDSH]RLGDOUXOHDQGZLOOEHQRUPDOL]HGE\GLYLGLQJWKH$8&E\WKHOHQJWKRIIROORZXSSRVW
WKHODVWFXPXODWLYHGRVHW\SLFDOO\KRXUV7KH)(9$8&ZLOOEHDQDO\]HGXVLQJDOLQHDU
PL[HGPRGHOZLWKDUDQGRPVXEMHFWHIIHFW7KHIL[HGHIIHFWVLQWKHPRGHOZLOOLQFOXGH
WUHDWPHQWEDVHOLQH)(9DQGSHULRG$&,IRUWKHEHWZHHQWUHDWPHQWGLIIHUHQFHZLOOEH
FDOFXODWHGDQGDVVHVVHGIRUFRQWDLQPHQWZLWKWKHHTXLYDOHQFHERXQGVRIP/
8.5.3
Data validation and transformation
,QJHQHUDOWKHGLVWULEXWLRQRIVSLURPHWU\PHDVXUHVLVZHOODSSUR[LPDWHGE\DQRUPDO
GLVWULEXWLRQ8QGHUVRPHFLUFXPVWDQFHVKRZHYHUHJGXULQJDQH[DFHUEDWLRQXQUHODWHGWR
WUHDWPHQWH[WUHPHDQGDW\SLFDOYDOXHVFDQDULVH6XFKYDOXHVKDYHKLJKLQIOXHQFHRQ
HVWLPDWLRQRIYDULDQFHSDUDPHWHUVDQGRQVWDQGDUGHUURUVRIIL[HGHIIHFWHVWLPDWHV7KH
GLVWULEXWLRQRIVFDOHGPDUJLQDOUHVLGXDOVDQGLQIOXHQFHVWDWLVWLFVZLOOEHH[DPLQHGWRLGHQWLI\
VXFKFDVHV,QWKHHYHQWWKDWDVLQJOHRUVPDOOQXPEHURIVXFKRXWO\LQJYDOXHVDUHIRXQGWR
H[LVWDQGIRXQGWREHKLJKO\LQIOXHQWLDOWKHHIIHFWVPD\EHDPHOLRUDWHGE\HLWKHU
WUDQVIRUPDWLRQRUUHPRYDORIWKHRXWOLHU7UDQVIRUPDWLRQVWREHFRQVLGHUHGPD\LQFOXGHWKH
ORJDULWKPLFWUDQVIRUPDWLRQRUQRUPDOUDQNWUDQVIRUPDWLRQV:KHUHRXWOLHUVDUHUHPRYHG
VHQVLWLYLW\DQDO\VHVLQFOXGLQJWKRVHYDOXHVZLOOEHUHSRUWHG
&KDQJHVLQVSLURPHWU\PHDVXUHVIURPEDVHOLQHDQGIURPWLPHSRLQWWRWLPHSRLQWZLOOEH
H[DPLQHGJUDSKLFDOO\EHIRUHGDWDEDVHORFNDVSDUWRIGDWDTXDOLW\PDQDJHPHQW
8.5.4
Extrapulmonary PD analysis
([WUDSXOPRQDU\3'SDUDPHWHUVRI47F)+5VHUXPJOXFRVHVHUXPSRWDVVLXP6%3DQG
'%3ZLOOHDFKEHDQDO\]HGXVLQJDVLPLODUPRGHODVGHVFULEHGDERYHIRU)(9SDUDPHWHUV
SRVWHDFKFXPXODWLYHGRVH%HWZHHQWUHDWPHQWGLIIHUHQFHVDQGFRUUHVSRQGLQJ&,VZLOOEH
SURYLGHG
'HVFULSWLYHVWDWLVWLFVPHDQPHGLDQVWDQGDUGGHYLDWLRQDQGUDQJHIRUFKDQJHIURPEDVHOLQH
IRUHDFKVFKHGXOHGDVVHVVPHQWWLPHPD[LPXPFKDQJHIURPEDVHOLQHDIWHUWKHODVWFXPXODWLYH
GRVHDQGWLPHZHLJKWHGDYHUDJHFKDQJHIURPEDVHOLQHDIWHUWKHODVWFXPXODWLYHGRVHZLOOEH
WDEXODWHGE\SDUDPHWHUDQGWUHDWPHQW%DVHOLQHZLOOEHGHILQHGDVWKHDYHUDJHRIWKHYDOXHV
SULRUWRGRVLQJRQWKHGD\RIUDQGRPL]DWLRQ,QDGGLWLRQSRWHQWLDOO\FOLQLFDOO\VLJQLILFDQW
YDOXHVZLOOEHLGHQWLILHGDQGVXPPDUL]HG


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

8.5.5
PK substudy: PK analysis
8.5.5.1
PK parameters
3KDUPDFRNLQHWLFSDUDPHWHUVZLOOEHHVWLPDWHGE\QRQFRPSDUWPHQWDODQDO\VLV1&$XVLQJWKH
VRIWZDUH3KRHQL[:LQ1RQOLQ&HUWDUD867KH3.DQDO\VLVVHWZLOOEHXVHGIRUWKH1&$
)URPWKHSODVPDDOEXWHUROFRQFHQWUDWLRQWLPHGDWDWKHIROORZLQJ3.SDUDPHWHUVZLOOEH
HVWLPDWHGIRUHDFKVXEMHFWZKHUHSRVVLEOH
$8&W
7KHDUHDXQGHUWKHSODVPDFRQFHQWUDWLRQWLPHFXUYHIURPWRWKHWLPHRIWKHODVW
PHDVXUDEOHSODVPDFRQFHQWUDWLRQSRVWWKHILQDOFXPXODWLYHGRVH
&PD[
7KHPD[LPXPREVHUYHGSODVPDFRQFHQWUDWLRQH[SUHVVHGLQFRQFHQWUDWLRQXQLWV
SRVWWKHILQDOFXPXODWLYHGRVH
7PD[
7KHWLPHWRUHDFK&PD[H[SUHVVHGLQKRXUVSRVWWKHILQDOFXPXODWLYHGRVH
&PLQ
7KHSODVPDFRQFHQWUDWLRQREVHUYHGDWPLQXWHVSRVWHDFKFXPXODWLYHGRVH

7KH$8&WZLOOEHFDOFXODWHGXVLQJWKHOLQHDUORJWUDSH]RLGDOPHWKRG
7KH3.SDUDPHWHUV&PD[DQG7PD[ZLOOEHREWDLQHGIURPWKHREVHUYHGYDOXHV
8.5.5.2
Handling of values below the limit of quantification
3ODVPDFRQFHQWUDWLRQYDOXHVZKLFKDUHUHSRUWHGDVEHORZWKHORZHUOLPLWRITXDQWLILFDWLRQ
//4ZLOOEHVHWWRPLVVLQJLQWKH1&$$FWXDOVDPSOLQJWLPHSRLQWVUHODWLYHWRGRVLQJZLOO
EHXVHGIRUWKH1&$ZKHUHDYDLODEOH,IWKHDFWXDOVDPSOLQJWLPHLVXQNQRZQWKHVFKHGXOHG
SURWRFROWLPHPD\EHXVHGIRUWKHFDOFXODWLRQRIGHULYHG3.SDUDPHWHUV1RIRUPDO³RXWOLHU´
DQDO\VLVLVSODQQHG
$OOYDOXHVEHORZ//4ZLOOEHDVVLJQHGDYDOXHRIò//4IRUDOOGHVFULSWLYHVWDWLVWLFV
FDWHJRULHVDQGPHDQSODVPDFRQFHQWUDWLRQSURILOHSORWV
8.5.5.3
Statistical analysis of PK data
'HVFULSWLYHVWDWLVWLFVIRUSODVPDFRQFHQWUDWLRQVRIDOEXWHUROE\WUHDWPHQWDQGQRPLQDO
WLPHSRLQWZLOOEHVXPPDUL]HGRQWKHOLQHDUDQGORJOLQHDUVFDOHXVLQJWKH3.DQDO\VLVVHW
,QGLYLGXDOSODVPDFRQFHQWUDWLRQVDWHDFKQRPLQDODQGDFWXDOWLPHSRLQWIRUHDFKWUHDWPHQWZLOO
EHOLVWHGE\VXEMHFWXVLQJWKH6DIHW\DQDO\VLVVHW
1DWXUDOORJWUDQVIRUPHG$8&WDQG&PD[YDOXHVIRUDOEXWHUROSRVWWKHILQDOFXPXODWLYHGRVH
ZLOOHDFKEHDQDO\]HGZLWKDOLQHDUPL[HGHIIHFWVPRGHOFRQWDLQLQJIL[HGHIIHFWVIRUWUHDWPHQW
DQGSHULRG6XEMHFWZLOOEHLQFOXGHGDVDUDQGRPHIIHFW(VWLPDWHGJHRPHWULFPHDQUDWLRVZLWK
&,VZLOOEHSURYLGHG


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

7KH&PLQYDOXHVIRUDOEXWHURODIWHUHDFKFXPXODWLYHGRVHZLOOEHDQDO\]HGZLWKDSRZHUODZ
PRGHO1DWXUDOORJWUDQVIRUPHG&PLQZLOOEHUHJUHVVHGRQWRWKHQDWXUDOORJWUDQVIRUPHG
FXPXODWLYHGRVHOHYHOV7KHPRGHOZLOOLQFOXGHIL[HGHIIHFWVIRUSHULRGDQGWUHDWPHQWD
UDQGRPLQWHUFHSWDQGSRVVLEO\DUDQGRPFRHIILFLHQWIRUORJFXPXODWLYHGRVH
8.5.6
Safety analyses
1RIRUPDOVWDWLVWLFDODQDO\VLVRIVDIHW\GDWDLVSODQQHG6DIHW\GDWDZLOOEHVXPPDUL]HGE\
WUHDWPHQWDQGOLVWHG
Adverse events
$GYHUVHHYHQWVRFFXUULQJGXULQJHDFK7UHDWPHQW3HULRGZLOOEHVXPPDUL]HGE\WKHQXPEHURI
VXEMHFWVH[SHULHQFLQJDQHYHQWDQGWDEXODWHGDWWKHOHYHORIWKH0HGLFDO'LFWLRQDU\IRU
5HJXODWRU\$FWLYLWLHV0HG'5$V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUP7KHYHUVLRQRI
0HG'5$FXUUHQWDWWKHWLPHRIGDWDEDVHORFNZLOOEHXVHGIRUWKHILQDODQDO\VLVRIGDWD
7DEXODWLRQVZLOOEHEURNHQGRZQE\VHYHULW\VHULRXVQHVV$(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
8.5.7
Handling of missing data
3UHGRVHVSLURPHWU\YDOXHVZLOOXVHWKHDYHUDJHRIWKHQRQPLVVLQJPLQXWHDQGPLQXWH
YDOXHV
7KH)(9$8&ZLOOEHFDOFXODWHGLIWKHUHLVDWOHDVWQRQPLVVLQJGDWDSRLQWGXULQJWKH
ILUVWKRXUVSRVWGRVH
8.5.8
Statistical software
'DWDSURFHVVLQJVWDWLVWLFDOVFUHHQLQJGHVFULSWLYHUHSRUWLQJDQGDQDO\VLVRIWKHHIILFDF\DQG
VDIHW\GDWDZLOOEHSHUIRUPHGXVLQJ6$66$6,QVWLWXWH&DU\1&869HUVLRQRU
KLJKHU
9.
STUDY AND DATA MANAGEMENT BY THE SPONSOR
9.1
Training of study site staff
%HIRUHWKHILUVWVXEMHFWLVHQWHUHGLQWRWKHVWXG\D6SRQVRUUHSUHVHQWDWLYHZLOOUHYLHZDQG
GLVFXVVWKHUHTXLUHPHQWVRIWKHFOLQLFDOVWXG\SURWRFRODQGUHODWHGGRFXPHQWVZLWKWKH
LQYHVWLJDWLRQDOVWDIIDQGDOVRWUDLQWKHPLQDQ\VWXG\VSHFLILFSURFHGXUHVDQGVWXG\V\VWHPV
XVHG
7KH3ULQFLSDO,QYHVWLJDWRUZLOOHQVXUHWKDWDSSURSULDWHWUDLQLQJUHOHYDQWWRWKHVWXG\LVJLYHQWR
DOORIWKHVHVWDIIDQGWKDWDQ\QHZLQIRUPDWLRQUHOHYDQWWRWKHSHUIRUPDQFHRIWKLVVWXG\LV
IRUZDUGHGWRWKHVWDIILQYROYHG


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

7KH3ULQFLSDO,QYHVWLJDWRUZLOOPDLQWDLQDUHFRUGRIDOOLQGLYLGXDOVLQYROYHGLQWKHVWXG\
PHGLFDOQXUVLQJDQGRWKHUVWDII
9.2
Monitoring of the study
'XULQJWKHVWXG\D6SRQVRUUHSUHVHQWDWLYHZLOOKDYHUHJXODUFRQWDFWVZLWKWKHVWXG\VLWH
LQFOXGLQJYLVLWVWR
x
SURYLGHLQIRUPDWLRQDQGVXSSRUWWRWKH,QYHVWLJDWRUV
x
FRQILUPWKDWIDFLOLWLHVUHPDLQDFFHSWDEOH
x
FRQILUPWKDWWKHFOLQLFDOVWXG\WHDPLVDGKHULQJWRWKHFOLQLFDOVWXG\
SURWRFROWKDWGDWDDUHEHLQJDFFXUDWHO\DQGWLPHO\UHFRUGHGLQWKHH&5)V
WKDWELRORJLFDOVDPSOHVDUHKDQGOHGLQDFFRUGDQFHZLWKWKH/DERUDWRU\
0DQXDODQGWKDWVWXG\GUXJDFFRXQWDELOLW\FKHFNVDUHEHLQJSHUIRUPHG
x
SHUIRUPVRXUFHGDWDYHULILFDWLRQDFRPSDULVRQRIWKHGDWDLQWKHH&5)V
ZLWKWKHVXEMHFW¶VPHGLFDOUHFRUGVDWWKHKRVSLWDORUSUDFWLFHDQGRWKHU
UHFRUGVUHOHYDQWWRWKHVWXG\LQFOXGLQJYHULILFDWLRQRILQIRUPHGFRQVHQWRI
SDUWLFLSDWLQJVXEMHFWV7KLVZLOOUHTXLUHGLUHFWDFFHVVWRDOORULJLQDOUHFRUGV
IRUHDFKVXEMHFWHJFOLQLFFKDUWV
7KH6SRQVRUUHSUHVHQWDWLYHZLOOEHDYDLODEOHEHWZHHQYLVLWVLIWKH,QYHVWLJDWRUVRURWKHUVWDII
DWWKHVLWHQHHGVLQIRUPDWLRQDQGDGYLFHDERXWWKHVWXG\FRQGXFW
9.2.1
Study agreements
7KH3ULQFLSDO,QYHVWLJDWRUDWHDFKVLWHVKRXOGFRPSO\ZLWKDOOWKHWHUPVFRQGLWLRQVDQG
REOLJDWLRQVRIWKHFOLQLFDOVWXG\DJUHHPHQWRUHTXLYDOHQWIRUWKLVVWXG\,QWKHHYHQWRIDQ\
LQFRQVLVWHQF\EHWZHHQWKLVFOLQLFDOVWXG\SURWRFRODQGWKHFOLQLFDOVWXG\DJUHHPHQWWKHWHUPV
RIFOLQLFDOVWXG\SURWRFROVKDOOSUHYDLOZLWKUHVSHFWWRWKHFRQGXFWRIWKHVWXG\DQGWKH
WUHDWPHQWRIVXEMHFWVDQGLQDOORWKHUUHVSHFWVQRWUHODWLQJWRVWXG\FRQGXFWRUWUHDWPHQWRI
VXEMHFWVWKHWHUPVRIWKHFOLQLFDOVWXG\DJUHHPHQWVKDOOSUHYDLO
$JUHHPHQWVEHWZHHQWKH6SRQVRUDQGWKH3ULQFLSDO,QYHVWLJDWRUVKRXOGEHLQSODFHEHIRUHDQ\
VWXG\UHODWHGSURFHGXUHVFDQWDNHSODFHRUVXEMHFWVDUHHQUROOHG
9.2.2
Archiving of study documents
7KH,QYHVWLJDWRUVKRXOGIROORZWKHSULQFLSOHVRXWOLQHGLQWKH&OLQLFDO6WXG\$JUHHPHQW
9.3
Study timetable and end of study
7KHHQGRIVWXG\LVGHILQHGDVWKHODVWVXEMHFW¶VIROORZXSWHOHSKRQHFDOO
7KHVWXG\PD\EHWHUPLQDWHGDWLQGLYLGXDOVWXG\VLWHVLIWKHVWXG\SURFHGXUHVDUHQRWEHLQJ
SHUIRUPHGDFFRUGLQJWR*RRG&OLQLFDO3UDFWLFH*&3RULIUHFUXLWPHQWLVVORZ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

9.4
Data management 
'DWDPDQDJHPHQWRIWKHVWXG\ZLOOEHSHUIRUPHGE\WKH6SRQVRURUGHVLJQHHDQGVXSHUYLVHG
E\WKH6SRQVRU
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
7KHVWXG\ZLOOEHSHUIRUPHGLQDFFRUGDQFHZLWKHWKLFDOSULQFLSOHVWKDWKDYHWKHLURULJLQLQWKH
'HFODUDWLRQRI+HOVLQNLDQGDUHFRQVLVWHQWZLWK,&+*&3DSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV
DQGWKH$VWUD=HQHFDSROLF\RQ%LRHWKLFVDQG+XPDQ%LRORJLFDO6DPSOHV
10.2
Subject data protection
7KH,&)ZLOOLQFRUSRUDWHRULQVRPHFDVHVEHDFFRPSDQLHGE\DVHSDUDWHGRFXPHQW
LQFRUSRUDWLQJZRUGLQJWKDWFRPSOLHVZLWKUHOHYDQWGDWDSURWHFWLRQDQGSULYDF\OHJLVODWLRQ
10.3
Ethics and regulatory review
$Q,5%VKRXOGDSSURYHWKHILQDOFOLQLFDOVWXG\SURWRFROWKHILQDOYHUVLRQRIWKH,&)DQGDQ\
RWKHUZULWWHQLQIRUPDWLRQDQGRUPDWHULDOVWREHSURYLGHGWRWKHVXEMHFWV7KHRSLQLRQRIWKH
,5%VKRXOGEHJLYHQLQZULWLQJ
7KH,5%VKRXOGDSSURYHDOODGYHUWLVLQJXVHGWRUHFUXLWVXEMHFWVIRUWKHVWXG\
7KH6SRQVRUZLOODSSURYHDQ\PRGLILFDWLRQVWRWKH,&)WKDWDUHQHHGHGWRPHHWORFDO
UHTXLUHPHQWV
,IUHTXLUHGE\ORFDOUHJXODWLRQVWKHFOLQLFDOVWXG\SURWRFROVKRXOGEHUHDSSURYHGE\WKH,5%
DQQXDOO\
%HIRUHHQUROOPHQWRIDQ\VXEMHFWLQWRWKHVWXG\WKHILQDOFOLQLFDOVWXG\SURWRFROLQFOXGLQJWKH
ILQDOYHUVLRQRIWKH,&)LVDSSURYHGE\WKHQDWLRQDOUHJXODWRU\DXWKRULW\RUDQRWLILFDWLRQWR
WKHQDWLRQDOUHJXODWRU\DXWKRULW\LVGRQHDFFRUGLQJWRORFDOUHJXODWLRQV
(DFK3ULQFLSDO,QYHVWLJDWRULVUHVSRQVLEOHIRUSURYLGLQJWKH,5%ZLWKUHSRUWVRIDQ\VHULRXV
DQGXQH[SHFWHGDGYHUVHGUXJUHDFWLRQVIURPDQ\RWKHUVWXG\FRQGXFWHGZLWKWKH
LQYHVWLJDWLRQDOSURGXFW7KH6SRQVRUZLOOSURYLGHWKLVLQIRUPDWLRQWRWKH3ULQFLSDO
,QYHVWLJDWRUVRWKDWKHVKHFDQPHHWWKHVHUHSRUWLQJUHTXLUHPHQWV
7KHKHDGRIWKHVWXG\VLWHVKRXOGVHHNWKHRSLQLRQRIWKH,5%ZLWKUHVSHFWWRWKH
DSSURSULDWHQHVVRIFRQWLQXLQJWKHVWXG\DWWKHVWXG\VLWHDWOHDVWRQFHD\HDUZKHQWKHGXUDWLRQ
RIWKHVWXG\H[FHHGV\HDU7KH3ULQFLSDO,QYHVWLJDWRUVKRXOGVXEPLWSURJUHVVUHSRUWVWRWKH
,5%YLDWKHKHDGRIWKHVWXG\VLWHDWWKHWLPHRIWKHFOLQLFDOVWXG\SURWRFROUHDSSURYDO


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

%HIRUHHQUROOPHQWRIDQ\VXEMHFWLQWRWKHVWXG\WKHILQDOFOLQLFDOVWXG\SURWRFROLQFOXGLQJWKH
ILQDOYHUVLRQRIWKH,&)VKRXOGEHDSSURYHGE\WKHQDWLRQDOUHJXODWRU\DXWKRULW\ZLWK
QRWLILFDWLRQSURYLGHGDFFRUGLQJWRORFDOUHJXODWLRQV7KH6SRQVRUZLOOKDQGOHWKHGLVWULEXWLRQ
RIDQ\RIWKHVHGRFXPHQWVWRWKHQDWLRQDOUHJXODWRU\DXWKRULWLHV
7KH6SRQVRUZLOOSURYLGHUHJXODWRU\DXWKRULWLHV,5%WKHKHDGRIWKHVWXG\VLWHDQGWKH
3ULQFLSDO,QYHVWLJDWRUZLWKVDIHW\XSGDWHVUHSRUWVDFFRUGLQJWRORFDOUHTXLUHPHQWV
10.4
Informed consent
7KH3ULQFLSDO,QYHVWLJDWRUVDWHDFKVWXG\VLWH ZLOO
x
HQVXUHHDFKVXEMHFWLVJLYHQIXOODQGDGHTXDWHRUDODQGZULWWHQLQIRUPDWLRQ
DERXWWKHQDWXUHSXUSRVHSRVVLEOHULVNDQGEHQHILWRIWKHVWXG\
x
HQVXUHHDFKVXEMHFWLVQRWLILHGWKDWWKH\DUHIUHHWRGLVFRQWLQXHIURPWKH
VWXG\DWDQ\WLPH
x
HQVXUHWKDWHDFKVXEMHFWLVJLYHQWKHRSSRUWXQLW\WRDVNTXHVWLRQVDQG
DOORZHGWLPHWRFRQVLGHUWKHLQIRUPDWLRQSURYLGHG
x
HQVXUHHDFKVXEMHFWSURYLGHVVLJQHGDQGGDWHGLQIRUPHGFRQVHQWEHIRUH
FRQGXFWLQJDQ\SURFHGXUHVSHFLILFDOO\IRUWKHVWXG\
x
HQVXUHWKHRULJLQDOVLJQHG,&)VLVDUHVWRUHGLQWKH,QYHVWLJDWRU¶V6WXG\
)LOH
x
HQVXUHDFRS\RIWKHVLJQHG,&)LVJLYHQWRWKHVXEMHFW
x
HQVXUHWKDWDQ\LQFHQWLYHVIRUVXEMHFWVZKRSDUWLFLSDWHLQWKHVWXG\DVZHOODV
DQ\SURYLVLRQVIRUVXEMHFWVKDUPHGDVDFRQVHTXHQFHRIVWXG\SDUWLFLSDWLRQ
DUHGHVFULEHGLQWKH,&)WKDWLVDSSURYHGE\DQ,5%
10.5
Changes to the clinical study protocol and ICF
6WXG\SURFHGXUHVZLOOQRWEHFKDQJHGZLWKRXWWKHPXWXDODJUHHPHQWRIWKH&RRUGLQDWLQJ
,QYHVWLJDWRUDQGWKH6SRQVRU
,IWKHUHDUHDQ\VXEVWDQWLDOFKDQJHVWRWKHFOLQLFDOVWXG\SURWRFROWKHQWKHVHFKDQJHVZLOOEH
GRFXPHQWHGLQDQHZYHUVLRQRIWKHVWXG\SURWRFRO
7KHQHZYHUVLRQRIWKHFOLQLFDOVWXG\SURWRFROLVWREHDSSURYHGE\WKHUHOHYDQW,5%DQGLI
DSSOLFDEOHDOVRWKHQDWLRQDOUHJXODWRU\DXWKRULW\DSSURYDOEHIRUHLPSOHPHQWDWLRQ/RFDO
UHTXLUHPHQWVDUHWREHIROORZHGIRUQHZYHUVLRQVRIFOLQLFDOVWXG\SURWRFROV
7KH6SRQVRUZLOOGLVWULEXWHDQ\QHZYHUVLRQVRIWKHFOLQLFDOVWXG\SURWRFROWRHDFK3ULQFLSDO
,QYHVWLJDWRUV)RUGLVWULEXWLRQWRWKH,5%VVHH6HFWLRQ


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

,IDFKDQJHWRDFOLQLFDOVWXG\SURWRFROUHTXLUHVDFKDQJHWRDVLWH¶V,&)WKH6SRQVRUDQGWKH
VLWH¶V,5%DUHWRDSSURYHWKHUHYLVHG,&)EHIRUHWKHUHYLVHGIRUPLVXVHG
10.6
Audits and inspections
$XWKRUL]HGUHSUHVHQWDWLYHVRIWKH6SRQVRUDUHJXODWRU\DXWKRULW\RUDQ,5%PD\SHUIRUP
DXGLWVRULQVSHFWLRQVDWWKHVWXG\VLWHLQFOXGLQJVRXUFHGDWDYHULILFDWLRQ7KHSXUSRVHRIDQ
DXGLWRULQVSHFWLRQLVWRV\VWHPDWLFDOO\DQGLQGHSHQGHQWO\H[DPLQHDOOVWXG\UHODWHGDFWLYLWLHV
DQGGRFXPHQWVWRGHWHUPLQHZKHWKHUWKHVHDFWLYLWLHVZHUHFRQGXFWHGDQGGDWDZHUHUHFRUGHG
DQDO\]HGDQGDFFXUDWHO\UHSRUWHGDFFRUGLQJWRWKHFOLQLFDOVWXG\SURWRFRO*&3JXLGHOLQHVRI
WKH,&+DQGDQ\DSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV7KH,QYHVWLJDWRUZLOOFRQWDFWWKH
6SRQVRULPPHGLDWHO\LIFRQWDFWHGE\DUHJXODWRU\DJHQF\DERXWDQLQVSHFWLRQDWWKHVLWH


&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

11.
LIST OF REFERENCES
Ahrens 1984
$KUHQV5&6PLWK*'$OEXWHURODQDGUHQHUJLFDJHQWIRUXVHLQWKHWUHDWPHQWRIDVWKPD
SKDUPDFRORJ\SKDUPDFRNLQHWLFVDQGFOLQLFDOXVH3KDUPDFRWKHUDS\
ATS/ERS Task Force 2005
$76(567DVN)RUFH6WDQGDUGL]DWLRQRI/XQJ)XQFWLRQ7HVWLQJ1XPEHULQ6HULHV
(XURSHDQ5HVSLUDWRU\-RXUQDO
EPR-3 2007
([SHUW3DQHO5HSRUW(35*XLGHOLQHVIRUWKH'LDJQRVLVDQG0DQDJHPHQWRI$VWKPD±
6XPPDU\5HSRUW-$OOHUJ\&OLQ,PPXQROVXSSO6
Global Initiative for Asthma 2017
*OREDO,QLWLDWLYHIRU$VWKPD*OREDO6WUDWHJ\IRU$VWKPD0DQDJHPHQWDQG3UHYHQWLRQ
$YDLODEOHIURPZZZJLQDVWKPDRUJ$FFHVVHG$XJXVW



Miller et al 2005
0LOOHU05+DQNLQVRQ-%UXVDVFR9HWDO6WDQGDUGLVDWLRQRIVSLURPHWU\(XU5HVSLU-

Philipson 2002
3KLOLSVRQ/+ȕ$JRQLVWVDQGPHWDEROLVP-$OOHUJ\&OLQ,PPXQROVXSSO6
6
PROVENTIL HFA package insert
3529(17,/+)$DOEXWHUROVXOIDWHLQKDODWLRQDHURVRO>SDFNDJHLQVHUW@:KLWHKRXVH6WDWLRQ1-
0HUFN6KDUS	'RKPH&RUS
Tripp et al 2008
7ULSS.0F9LFDU:.1DLU3HWDO$FXPXODWLYHGRVHVWXG\RIOHYDOEXWHURODQGUDFHPLF
DOEXWHURODGPLQLVWHUHGE\K\GURIOXRURDONDQHDPHWHUHGGRVHLQKDOHULQDVWKPDWLFVXEMHFWV
-$OOHUJ\&OLQ,PPXQRO




&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Appendix A
Spirometry Assessment Criteria
Spirometry Assessment Criteria
Acceptable Versus Usable Tests
Acceptable Tests must meet the following Criteria:
 $FFHSWDEOHVWDUWRIH[KDODWLRQZLWKEULVNXSVWURNHQRKHVLWDWLRQRUIDOVHVWDUWDQG
(9RI)9&RU/ZKLFKHYHULVWKHJUHDWHUVHHH[DPSOHLQ)LJXUH$
 1RFRXJKGXULQJWKHILUVWVHFRQG
 1RYDOVDOYDPDQHXYHU
 1ROHDN
 1RREVWUXFWLRQRIPRXWKSLHFH
 1RH[WUDEUHDWKV
 3ODWHDXDFKLHYHGLHWKHYROXPHWLPHFXUYHVKRZVQRFKDQJHLQYROXPH/
IRUVDQGWKHVXEMHFWKDVWULHGWRH[KDOHIRUDWOHDVWVHFRQGV

$QDFFHSWDEOHWHVWPHHWVDOOVHYHQFULWHULDOLVWHG7KLVLVWREHFRQVLGHUHGWKH³JROGVWDQGDUG´
8VDEOHVSLURPHWU\WUDFLQJVDUHWKRVHWKDWRQO\PHHWFULWHULDDQG:KHQWKLVRFFXUVUHSHDW
WHVWLQJXSWRHLJKWDWWHPSWVIRUSUHGRVHDQGILYHDWWHPSWVIRUSRVWGRVHDVVHVVPHQWVLQDQ
HIIRUWWRREWDLQWKUHHDFFHSWDEOHVSLURJUDPV,IRQO\XVDEOHWHVWVDUHREWDLQHGUHSRUWUHVXOWV
EDVHGRQWKHWKUHHEHVWXVDEOHWULDOVZLWKREVHUYHGOLPLWDWLRQV
Figure A2-1 Example of a Usable Spirogram



&OLQLFDO6WXG\3URWRFRO
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

(9 EDFNH[WUDSRODWLRQYROXPH
7KHH[SDQGHGYHUVLRQRIWKHHDUO\SDUWRIDVXEMHFW¶VYROXPHWLPHVSLURJUDPLOOXVWUDWLQJEDFN
H[WUDSRODWLRQWKURXJKWKHVWHHSHVWSDUWRIWKHFXUYHZKHUHIORZLV3()5WRGHWHUPLQHWKHQHZ
³WLPH]HUR´)RUFHGYLWDOFDSDFLW\/(9±/)9&EDFNH[WUDSRODWLRQ
OLQHWKURXJK3()
Between-Maneuver Reproducibility Criteria
Pre-dose Assessments
$IWHUthreeDFFHSWDEOHVSLURJUDPVKDYHEHHQREWDLQHGDSSO\WKHIROORZLQJWHVWV
7KHWZRODUJHVWYDOXHVRI)9&PXVWEHZLWKLQ/RIHDFKRWKHU
7KHWZRODUJHVWYDOXHVRI)(9PXVWEHZLWKLQ/RIHDFKRWKHU
,IWKHVHFULWHULDDUHPHWWKHVSLURPHWU\WHVWLQJIRUWKDWWLPHSRLQWPD\FRQFOXGH7KHKLJKHVW
)(9DQGWKHKLJKHVW)9&REWDLQHGDWHDFKWHVWLQJWLPHSRLQWHYHQLIIURPGLIIHUHQW
UHSURGXFLEOHWUDFLQJVZLOOEHFROOHFWHG
,IDFFHSWDELOLW\FULWHULDDUHQRWPHWFRQWLQXHWHVWLQJXQWLOWKH\DUHPHWRUWKHVXEMHFWFDQQRW
VKRXOGQRWFRQWLQXHPD[LPXPRIHLJKWDWWHPSWV
Post-dose Assessments
$IWHUtwoDFFHSWDEOHVSLURJUDPVKDYHEHHQREWDLQHGDSSO\WKHIROORZLQJWHVWV
7KHWZRODUJHVWYDOXHVRI)9&DUHZLWKLQ/RIHDFKRWKHUDQGRU
7KHWZRODUJHVWYDOXHVRI)(9DUHZLWKLQ/RIHDFKRWKHU
,IWKHVHFULWHULDDUHPHWWKHVSLURPHWU\WHVWLQJIRUWKDWWLPHSRLQWPD\FRQFOXGH7KHKLJKHVW
)(9DQGWKHKLJKHVW)9&REWDLQHGDWHDFKWHVWLQJWLPHSRLQWHYHQLIIURPGLIIHUHQW
UHSURGXFLEOHWUDFLQJVZLOOEHFROOHFWHG
,IDFFHSWDELOLW\UHSURGXFLELOLW\FULWHULDDUHQRWPHWFRQWLQXHWHVWLQJXQWLOWKH\DUHPHWRUWKH
VXEMHFWFDQQRWVKRXOGQRWFRQWLQXHPD[LPXPRIILYHDWWHPSWV



&OLQLFDO6WXG\3URWRFRO$SSHQGL[$
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Appendix B
Spirometry Performance Recommendations
Spirometry Performance Recommendations
6SLURPHWU\GDWDRIWKHKLJKHVWTXDOLW\PXVWEHREWDLQHGIRUSURSHULQWHUSUHWDWLRQRIWKHUHVXOWV
RIWKLVSURWRFRO7RWKHVHHQGVDVWDQGDUGVSLURPHWHUZLOOEHXVHGSURYLGHGE\3HDUO
7KHUDSHXWLFVFHQWUDOWUDLQLQJSURYLGHGTXDOLILFDWLRQZLOOEHUHTXLUHGDQGVSHFLILFRSHUDWLQJ
LQVWUXFWLRQZLOODOVREHSURYLGHG
6RXUFH$76(567DVN)RUFH
FEV1 MANEUVERS
Equipment Requirements
7KHVSLURPHWHUPXVWEHFDSDEOHRIDFFXPXODWLQJYROXPHIRU!VORQJHUWLPHVDUH
UHFRPPHQGHGDQGPHDVXULQJYROXPHVRI!/ERG\WHPSHUDWXUHLH&DPELHQW
SUHVVXUHVDWXUDWHGZLWKZDWHUYDSRU%736ZLWKDQDFFXUDF\RIDWOHDVWRIUHDGLQJRU
/ZKLFKHYHULVJUHDWHUZLWKIORZVEHWZHHQDQG/V7KHWRWDOUHVLVWDQFHWR
DLUIORZDW/VPXVWEHFP+2/VN3D/V7KHWRWDOUHVLVWDQFHPXVWEH
PHDVXUHGZLWKDQ\WXELQJYDOYHVSUHILOWHUHWFLQFOXGHGWKDWPD\EHLQVHUWHGEHWZHHQWKH
VXEMHFWDQGWKHVSLURPHWHU6RPHGHYLFHVPD\H[KLELWFKDQJHVLQUHVLVWDQFHGXHWRZDWHU
YDSRUFRQGHQVDWLRQDQGDFFXUDF\UHTXLUHPHQWVPXVWEHPHWXQGHU%736FRQGLWLRQVIRUXSWR
VXFFHVVLYH)9&PDQHXYHUVSHUIRUPHGLQDPLQXWHSHULRGZLWKRXWLQVSLUDWLRQIURPWKH
LQVWUXPHQW
Display
)RURSWLPDOTXDOLW\FRQWUROERWKIORZ±YROXPHDQGYROXPH±WLPHGLVSOD\VDUHXVHIXODQGWHVW
RSHUDWRUVVKRXOGYLVXDOO\LQVSHFWWKHSHUIRUPDQFHRIHDFKPDQHXYHUIRUTXDOLW\DVVXUDQFH
EHIRUHSURFHHGLQJZLWKDQRWKHUPDQHXYHU7KLVLQVSHFWLRQUHTXLUHVWUDFLQJVWRPHHWWKH
PLQLPXPVL]HDQGUHVROXWLRQUHTXLUHPHQWVVHWIRUWKLQWKLVVWDQGDUG'LVSOD\VRIIORZYHUVXV
YROXPHSURYLGHPRUHGHWDLOIRUWKHLQLWLDOSRUWLRQILUVWVRIWKH)9&PDQHXYHU6LQFHWKLV
SRUWLRQRIWKHPDQHXYHUSDUWLFXODUO\WKHSHDNH[SLUDWRU\IORZUDWH3()5LVFRUUHODWHGZLWK
WKHSOHXUDOSUHVVXUHGXULQJWKHPDQHXYHUWKHIORZ±YROXPHGLVSOD\LVXVHIXOWRDVVHVVWKH
PDJQLWXGHRIHIIRUWGXULQJWKHLQLWLDOSRUWLRQVRIWKHPDQHXYHU7KHDELOLW\WRRYHUOD\DVHULHV
RIIORZ±YROXPHFXUYHVUHJLVWHUHGDWWKHSRLQWRIPD[LPDOLQKDODWLRQPD\EHKHOSIXOLQ
HYDOXDWLQJUHSHDWDELOLW\DQGGHWHFWLQJVXEPD[LPDOHIIRUWV+RZHYHULIWKHSRLQWRIPD[LPDO
LQKDODWLRQYDULHVEHWZHHQEORZVWKHQWKHLQWHUSUHWDWLRQRIWKHVHUHVXOWVLVGLIILFXOWEHFDXVHWKH
IORZVDWLGHQWLFDOPHDVXUHGYROXPHVDUHEHLQJDFKLHYHGDWGLIIHUHQWDEVROXWHOXQJYROXPHV,Q
FRQWUDVWGLVSOD\RIWKH)9&PDQHXYHUDVDYROXPH±WLPHJUDSKSURYLGHVPRUHGHWDLOIRUWKH
ODWWHUSDUWRIWKHPDQHXYHU$YROXPH±WLPHWUDFLQJRIVXIILFLHQWVL]HDOVRDOORZVLQGHSHQGHQW
PHDVXUHPHQWDQGFDOFXODWLRQRISDUDPHWHUVIURPWKH)9&PDQHXYHUV,QDGLVSOD\RIPXOWLSOH
WULDOVWKHVHTXHQFLQJRIWKHEORZVVKRXOGEHDSSDUHQWWRWKHXVHU)RUWKHVWDUWRIWHVWGLVSOD\
WKHYROXPH±WLPHGLVSOD\VKRXOGLQFOXGH!VDQGSUHIHUDEO\VEHIRUHH[KDODWLRQVWDUWV
]HURYROXPH7KLVWLPHSHULRGEHIRUHWKHUHLVDQ\FKDQJHLQYROXPHLVQHHGHGWRFDOFXODWH
WKHEDFNH[WUDSRODWHGYROXPH(9DQGWRHYDOXDWHHIIRUWGXULQJWKHLQLWLDOSRUWLRQRIWKH


&OLQLFDO6WXG\3URWRFRO$SSHQGL[$
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

PDQHXYHU7LPH]HURDVGHILQHGE\(9PXVWEHSUHVHQWHGDVWKH]HURSRLQWRQWKHJUDSKLFDO
RXWSXW7KHODVWVRIWKHPDQHXYHUVKRXOGEHGLVSOD\HGWRLQGLFDWHDVDWLVIDFWRU\HQGRIWHVW
:KHQDYROXPH±WLPHFXUYHLVSORWWHGDVKDUGFRS\WKHYROXPHVFDOHPXVWEH!PP/
%736)RUDVFUHHQGLVSOD\PP/LVVDWLVIDFWRU\7DEOH$
Table A1-1.
Recommended Minimal Scale Factors for Time, Volume and Flow 
on Graphical Output
Parameter
Instrument Display
Hardcopy Graphical 
Output

Resolution Required
Scale Factor
Resolution Required
9ROXPH
/
PP/
/
)ORZ
/V
PP/V
/V
7LPH
V
PPV
V
7KHFRUUHFWDVSHFWUDWLRIRUIORZYHUVXVYROXPHGLVSOD\LVXQLWVRIIORZSHUXQLWRIYROXPH
7KHWLPHVFDOHVKRXOGEH!PPVDQGODUJHUWLPHVFDOHVDUHSUHIHUUHG!PPVZKHQ
PDQXDOPHDVXUHPHQWVDUHPDGH:KHQWKHYROXPH±WLPHSORWLVXVHGLQFRQMXQFWLRQZLWKD
IORZ±YROXPHFXUYHLHERWKGLVSOD\PHWKRGVDUHSURYLGHGIRULQWHUSUHWDWLRQVDQGQRKDQG
PHDVXUHPHQWVDUHSHUIRUPHGWKHWLPHVFDOHUHTXLUHPHQWLVUHGXFHGWRPPVIURPWKH
XVXDOO\UHTXLUHGPLQLPXPRIPPV7DEOH$7KHUDWLRQDOHIRUWKLVH[FHSWLRQLVWKDW
WKHIORZ±YROXPHFXUYHFDQSURYLGHWKHPHDQVIRUTXDOLW\DVVHVVPHQWGXULQJWKHLQLWLDOSRUWLRQ
RIWKH)9&PDQHXYHU7KHYROXPH±WLPHFXUYHFDQEHXVHGWRHYDOXDWHWKHODWWHUSDUWRIWKH
)9&PDQHXYHUPDNLQJWKHWLPHVFDOHOHVVFULWLFDO
Validation
,WLVVWURQJO\UHFRPPHQGHGWKDWVSLURPHWU\V\VWHPVVKRXOGEHHYDOXDWHGXVLQJDFRPSXWHU
GULYHQPHFKDQLFDOV\ULQJHRULWVHTXLYDOHQWLQRUGHUWRWHVWWKHUDQJHRIH[KDODWLRQVWKDWDUH
OLNHO\WREHHQFRXQWHUHGLQWKHWHVWSRSXODWLRQ7HVWLQJWKHSHUIRUPDQFHRIHTXLSPHQWLVQRW
SDUWRIWKHXVXDOODERUDWRU\SURFHGXUHV
Quality Control
$WWHQWLRQWRHTXLSPHQWTXDOLW\FRQWURODQGFDOLEUDWLRQLVDQLPSRUWDQWSDUWRIJRRGODERUDWRU\
SUDFWLFH$WDPLQLPXPWKHUHTXLUHPHQWVDUHDVIROORZVDORJRIFDOLEUDWLRQUHVXOWVLV
PDLQWDLQHGWKHGRFXPHQWDWLRQRIUHSDLUVRURWKHUDOWHUDWLRQVZKLFKUHWXUQWKHHTXLSPHQWWR
DFFHSWDEOHRSHUDWLRQWKHGDWHVRIFRPSXWHUVRIWZDUHDQGKDUGZDUHXSGDWHVRUFKDQJHVDQG
LIHTXLSPHQWLVFKDQJHGRUUHORFDWHGHJLQGXVWULDOVXUYH\VFDOLEUDWLRQFKHFNVDQGTXDOLW\
FRQWUROSURFHGXUHVPXVWEHUHSHDWHGEHIRUHIXUWKHUWHVWLQJEHJLQV


&OLQLFDO6WXG\3URWRFRO$SSHQGL[$
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

.H\DVSHFWVRIHTXLSPHQWTXDOLW\FRQWURODUHVXPPDUL]HGLQ7DEOH$
Table A1-2.
Summary of Equipment Quality Control
Test
Minimal 
Interval
Action
9ROXPH
'DLO\
&DOLEUDWLRQFKHFNZLWKD/V\ULQJH
/HDN
'DLO\
FP+2N3DFRQVWDQWSUHVVXUHIRUPLQXWH
9ROXPH
/LQHDULW\
4XDUWHUO\
/LQFUHPHQWVZLWKDFDOLEUDWLQJV\ULQJHPHDVXUHGRYHUWKH
HQWLUHYROXPHUDQJH
)ORZ
/LQHDULW\
:HHNO\
7HVWDWOHDVWGLIIHUHQWIORZUDQJHV
7LPH
4XDUWHUO\
0HFKDQLFDOUHFRUGHUFKHFNZLWKVWRSZDWFK
6RIWZDUH
1HZYHUVLRQV
/RJLQVWDOODWLRQGDWHDQGSHUIRUPWHVWXVLQJ³NQRZQ´VXEMHFW
&DOLEUDWLRQLVWKHSURFHGXUHIRUHVWDEOLVKLQJWKHUHODWLRQVKLSEHWZHHQVHQVRUGHWHUPLQHG
YDOXHVRIIORZRUYROXPHDQGWKHDFWXDOIORZRUYROXPH$FDOLEUDWLRQFKHFNLVGLIIHUHQWIURP
FDOLEUDWLRQDQGLVWKHSURFHGXUHXVHGWRYDOLGDWHWKDWWKHGHYLFHLVZLWKLQFDOLEUDWLRQOLPLWVHJ
RIWUXH,IDGHYLFHIDLOVLWVFDOLEUDWLRQFKHFNWKHQQHZFDOLEUDWLRQSURFHGXUHRU
HTXLSPHQWPDLQWHQDQFHLVUHTXLUHG&DOLEUDWLRQFKHFNVPXVWEHXQGHUWDNHQGDLO\RUPRUH
IUHTXHQWO\LIVSHFLILHGE\WKHPDQXIDFWXUHU7KHV\ULQJHXVHGWRFKHFNWKHYROXPHFDOLEUDWLRQ
RIVSLURPHWHUVPXVWKDYHDQDFFXUDF\RIP/RURIWKHIXOOVFDOHP/IRUD/
V\ULQJHDQGWKHPDQXIDFWXUHUPXVWSURYLGHUHFRPPHQGDWLRQVFRQFHUQLQJDSSURSULDWH
LQWHUYDOVEHWZHHQV\ULQJHFDOLEUDWLRQFKHFNV8VHUVVKRXOGEHDZDUHWKDWDV\ULQJHZLWKDQ
DGMXVWDEOHRUYDULDEOHVWRSPD\EHRXWRIFDOLEUDWLRQLIWKHVWRSLVUHVHWRUDFFLGHQWDOO\PRYHG
&DOLEUDWLRQV\ULQJHVVKRXOGEHSHULRGLFDOO\HJPRQWKO\OHDNWHVWHGDWPRUHWKDQYROXPHXS
WRWKHLUPD[LPXPWKLVFDQEHGRQHE\DWWHPSWLQJWRHPSW\WKHPZLWKWKHRXWOHWFRUNHG$
GURSSHGRUGDPDJHGV\ULQJHVKRXOGEHFRQVLGHUHGRXWRIFDOLEUDWLRQXQWLOLWLVFKHFNHG
:LWKUHJDUGWRWLPHDVVHVVLQJPHFKDQLFDOUHFRUGHUWLPHVFDOHDFFXUDF\ZLWKDVWRSZDWFKPXVW
EHSHUIRUPHGDWOHDVWTXDUWHUO\$QDFFXUDF\RIZLWKLQPXVWEHDFKLHYHG
Quality Control for Volume-Measuring Devices
7KHYROXPHDFFXUDF\RIWKHVSLURPHWHUPXVWEHFKHFNHGDWOHDVWGDLO\ZLWKDVLQJOHGLVFKDUJH
RID/FDOLEUDWHGV\ULQJH'DLO\FDOLEUDWLRQFKHFNLQJLVKLJKO\UHFRPPHQGHGVRWKDWWKH
RQVHWRIDSUREOHPFDQEHGHWHUPLQHGZLWKLQGD\DQGDOVRWRKHOSGHILQHGD\WRGD\
ODERUDWRU\YDULDELOLW\0RUHIUHTXHQWFKHFNVPD\EHUHTXLUHGLQVSHFLDOFLUFXPVWDQFHVVXFK
DVGXULQJLQGXVWULDOVXUYH\VRURWKHUVWXGLHVLQZKLFKDODUJHQXPEHURIVXEMHFWPDQHXYHUV
DUHFDUULHGRXWWKHHTXLSPHQW¶VFDOLEUDWLRQVKRXOGEHFKHFNHGPRUHIUHTXHQWO\WKDQGDLO\DQG


&OLQLFDO6WXG\3URWRFRO$SSHQGL[$
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

ZKHQWKHDPELHQWWHPSHUDWXUHLVFKDQJLQJHJILHOGVWXGLHVYROXPHDFFXUDF\PXVWEH
FKHFNHGPRUHIUHTXHQWO\WKDQGDLO\DQGWKH%736FRUUHFWLRQIDFWRUDSSURSULDWHO\XSGDWHG
7KHDFFXUDF\RIWKHV\ULQJHYROXPHPXVWEHFRQVLGHUHGLQGHWHUPLQLQJZKHWKHUWKHPHDVXUHG
YROXPHLVZLWKLQDFFHSWDEOHOLPLWV)RUH[DPSOHLIWKHV\ULQJHKDVDQDFFXUDF\RID
UHDGLQJRILVDSSURSULDWH
7KHFDOLEUDWLRQV\ULQJHVKRXOGEHVWRUHGDQGXVHGLQVXFKDZD\DVWRPDLQWDLQWKHVDPH
WHPSHUDWXUHDQGKXPLGLW\RIWKHWHVWLQJVLWH7KLVLVEHVWDFFRPSOLVKHGE\NHHSLQJWKHV\ULQJH
LQFORVHSUR[LPLW\WRWKHVSLURPHWHUEXWRXWRIGLUHFWVXQOLJKWDQGDZD\IURPKHDWVRXUFHV
9ROXPHW\SHVSLURPHWHUV\VWHPVPXVWEHHYDOXDWHGIRUOHDNVHYHU\GD\7KHLPSRUWDQFHRI
XQGHUWDNLQJWKLVGDLO\WHVWFDQQRWEHRYHUVWUHVVHG/HDNVFDQEHGHWHFWHGE\DSSO\LQJD
FRQVWDQWSRVLWLYHSUHVVXUHRI!FP+2N3DZLWKWKHVSLURPHWHURXWOHWRFFOXGHG
SUHIHUDEO\DWRULQFOXGLQJWKHPRXWKSLHFH$Q\REVHUYHGYROXPHORVVRIP/DIWHU
PLQXWHLQGLFDWHVDOHDNDQGQHHGVWREHFRUUHFWHG
$WOHDVWTXDUWHUO\YROXPHVSLURPHWHUVPXVWKDYHWKHLUFDOLEUDWLRQFKHFNHGRYHUWKHLUHQWLUH
YROXPHUDQJHXVLQJDFDOLEUDWHGV\ULQJHRUDQHTXLYDOHQWYROXPHVWDQGDUG7KHPHDVXUHG
YROXPHVKRXOGEHZLWKLQRIWKHUHDGLQJRUP/ZKLFKHYHULVJUHDWHU7KLVOLPLW
LQFOXGHVWKHDFFXUDF\OLPLWIRUD/V\ULQJH7KHOLQHDULW\FKHFNSURFHGXUHSURYLGHGE\
WKHPDQXIDFWXUHUFDQEHXVHGLILWLVHTXLYDOHQWWRRIWKHIROORZLQJSURFHGXUHV
FRQVHFXWLYHLQMHFWLRQVRI/YROXPHLQFUHPHQWVZKLOHFRPSDULQJREVHUYHGYROXPHZLWKWKH
FRUUHVSRQGLQJFXPXODWLYHPHDVXUHGYROXPHHJ±±±«±DQG±/IRUDQ/
VSLURPHWHUDQGLQMHFWLRQRID/YROXPHVWDUWLQJDWDPLQLPDOVSLURPHWHUYROXPHWKHQ
UHSHDWLQJWKLVZLWKD/LQFUHPHQWLQWKHVWDUWSRVLWLRQHJ±±±±±DQG±
/IRUDQ/VSLURPHWHU7KHOLQHDULW\FKHFNLVFRQVLGHUHGDFFHSWDEOHLIWKHVSLURPHWHUPHHWV
WKHYROXPHDFFXUDF\UHTXLUHPHQWVIRUDOOYROXPHVWHVWHG
Quality Control for Flow-Measuring Devices
:LWKUHJDUGVWRYROXPHDFFXUDF\FDOLEUDWLRQFKHFNVPXVWEHXQGHUWDNHQDWOHDVWGDLO\XVLQJD
/V\ULQJHGLVFKDUJHGDWOHDVWWLPHVWRJLYHDUDQJHRIIORZVYDU\LQJEHWZHHQDQG/
VZLWK/LQMHFWLRQWLPHVRIVDQGV7KHYROXPHDWHDFKIORZVKRXOGPHHWWKH
DFFXUDF\UHTXLUHPHQWRI)RUGHYLFHVXVLQJGLVSRVDEOHIORZVHQVRUVDQHZVHQVRUIURP
WKHVXSSO\XVHGIRUSDWLHQWWHVWVVKRXOGEHWHVWHGHDFKGD\
)RUOLQHDULW\DYROXPHFDOLEUDWLRQFKHFNVKRXOGEHSHUIRUPHGZHHNO\ZLWKD/V\ULQJHWR
GHOLYHUUHODWLYHO\FRQVWDQWIORZVDWDORZIORZWKHQDWDPLGUDQJHIORZDQGILQDOO\DWD
KLJKIORZ7KHYROXPHVDFKLHYHGDWHDFKRIWKHVHIORZVVKRXOGHDFKPHHWWKHDFFXUDF\
UHTXLUHPHQWRI
Equipment
)RUPHDVXUHPHQWVRI9&DQG,&WKHVSLURPHWHURUIORZPHWHUPXVWFRPSO\ZLWKWKH
UHTXLUHPHQWVIRU)9&DVGHVFULEHGSUHYLRXVO\DQGEHFDSDEOHRIDFFXPXODWLQJYROXPHIRU


&OLQLFDO6WXG\3URWRFRO$SSHQGL[$
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

!V([SLUDWRU\PDQHXYHUVRULGHDOO\ERWKLQVSLUDWRU\DQGH[SLUDWRU\PDQHXYHUVVKRXOGEH
LQFOXGHGLQWKHGLVSOD\RI9&PDQHXYHU5HJDUGOHVVRIZKHWKHUWKHLQVSLUDWRU\RUH[SLUDWRU\
PDQHXYHULVXVHGIRUGHULYLQJPHDVXUHPHQWVDGLVSOD\RIWKHHQWLUHUHFRUGHG9&PDQHXYHU
PXVWEHSURYLGHG7KHPD[LPDOH[SLUDWRU\YROXPHPXVWEHDVVHVVHGWRGHWHUPLQHZKHWKHUWKH
VXEMHFWKDVREWDLQHGDSODWHDXLQWKHH[SLUDWRU\HIIRUW)RUGLVSOD\RIWKHVORZ9&WKHWLPH
VFDOHPD\EHUHGXFHGWRPPV
Technical Considerations
Minimal recommendations for spirometry systems
$FFXUDWHUHVXOWVUHTXLUHDFFXUDWHHTXLSPHQW6SLURPHWHUHTXLSPHQWUHFRPPHQGDWLRQVDSSO\WR
DOOVSLURPHWHUVDQGDUHPLQLPDOUHTXLUHPHQWV,QVRPHFLUFXPVWDQFHVLWPD\EHDSSURSULDWHWR
H[FHHGWKHVHUHTXLUHPHQWVLHLQVRPHUHVHDUFKVXUYHLOODQFHDSSOLFDWLRQV,QVWUXPHQWDWLRQ
UHFRPPHQGDWLRQVVKRXOGEHIROORZHGWRSURYLGHDFFXUDWHVSLURPHWULFGDWDDQGLQIRUPDWLRQ
WKDWLVFRPSDUDEOHIURPODERUDWRU\WRODERUDWRU\DQGIURPWLPHSHULRGWRDQRWKHU7KH
DFFXUDF\RIDVSLURPHWU\V\VWHPGHSHQGVRQFKDUDFWHULVWLFVRIWKHHQWLUHV\VWHPIURPWKH
YROXPHRUIORZWUDQVGXFHUDQGWKHXVHRIDQLQOLQHILOWHUWRWKHUHFRUGHUGLVSOD\RUSURFHVVRU
&KDQJHVLQDQ\DVSHFWRIWKHHTXLSPHQWRUHUURUVDWDQ\VWHSLQWKHSURFHVVFDQDIIHFWWKH
DFFXUDF\RIWKHUHVXOWV)RUH[DPSOHLIWKH%736FRUUHFWLRQIDFWRULVZURQJDQDFFXUDWHO\
PHDVXUHG)9&ZLOOEHLQFRUUHFWO\UHSRUWHG6SLURPHWHUVDUHQRWUHTXLUHGWRPHDVXUHDOORIWKH
LQGLFHVLQ7DEOH$EXWPXVWPHHWWKHUHFRPPHQGDWLRQVIRUWKRVHWKDWDUHPHDVXUHG
$FFXUDF\DQGUHSHDWDELOLW\UHFRPPHQGDWLRQVDSSO\RYHUWKHHQWLUHYROXPHUDQJHRIWKH
LQVWUXPHQW
Table A1-3.
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers
Test
Range/Accuracy (BTPS)
Flow 
Range
(L-s-1)
Time (s)
Resistance and 
Back Pressure
Test Signal
9&
±/RIUHDGLQJ
RU/ZKLFKHYHULV
JUHDWHU



/&DOLEUDWLRQ
V\ULQJH
)9&
±/RIUHDGLQJ
RU/ZKLFKHYHULV
JUHDWHU


FP+2/V
N3D/V
$76
ZDYHIRUPV
/&DO6\ULQJH
)(9 ±/RIUHDGLQJ
RU/ZKLFKHYHULV
JUHDWHU


FP+2/V
N3D/V
$76
ZDYHIRUPV
7LPH
7KHWLPHSRLQWIURPZKLFK


%DFNH[WUDSRODWLRQ



&OLQLFDO6WXG\3URWRFRO$SSHQGL[$
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Table A1-3.
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers
Test
Range/Accuracy (BTPS)
Flow 
Range
(L-s-1)
Time (s)
Resistance and 
Back Pressure
Test Signal
=HUR
DOO)(9WPHDVXUHPHQWV
DUHWDNHQ
)(9WIRUFHGH[SLUDWRU\YROXPHLQWVHFRQGV

Body temperature, ambient pressure, saturated with water vapor correction
$OOVSLURPHWU\YDOXHVVKRXOGEHUHSRUWHGDW%736E\DQ\PHWKRGPHDVXULQJWHPSHUDWXUHDQG
EDURPHWULFSUHVVXUHSURYHQHIIHFWLYHE\WKHPDQXIDFWXUHU)RUYROXPHW\SHVSLURPHWHUVWKH
WHPSHUDWXUHLQVLGHWKHVSLURPHWHUVKRXOGEHPHDVXUHGIRUHDFKEUHDWKLQJPDQHXYHU
5HJDUGOHVVRIWKH%736FRUUHFWLRQWHFKQLTXHXVHGWKHDPELHQWWHPSHUDWXUHPXVWDOZD\VEH
UHFRUGHGZLWKDQDFFXUDF\RI&,QVLWXDWLRQVZKHUHWKHDPELHQWDLUWHPSHUDWXUHLV
FKDQJLQJUDSLGO\!&LQPLQFRQWLQXRXVWHPSHUDWXUHFRUUHFWLRQVPD\EHQHFHVVDU\
6SLURPHWHUXVHUVVKRXOGEHDZDUHRISRWHQWLDOSUREOHPVZLWKWHVWLQJSHUIRUPHGDWORZHU
DPELHQWWHPSHUDWXUHV&LVWKHORZHUOLPLWIRUDPELHQWWHPSHUDWXUHXQOHVVDPDQXIDFWXUHU
VWDWHVWKDWWKHLUVSLURPHWHUZLOORSHUDWHDFFXUDWHO\DWORZHUDPELHQWWHPSHUDWXUHV,I
EDURPHWULFSUHVVXUHLVQRWXVHGLQFDOFXODWLQJWKH%736FRUUHFWLRQIDFWRUWKHUDQJHRI
EDURPHWULFSUHVVXUHVRYHUZKLFKWKH%736FRUUHFWLRQIDFWRULVYDOLGPXVWEHSXEOLVKHG


&OLQLFDO6WXG\3URWRFRO$SSHQGL[&
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Appendix C
Additional Safety Information
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
µ/LIHWKUHDWHQLQJ¶PHDQVWKDWWKHVXEMHFWZDVDWLPPHGLDWHULVNRIGHDWKIURPWKH$(DVLW
RFFXUUHGRULWLVVXVSHFWHGWKDWXVHRUFRQWLQXHGXVHRIWKHSURGXFWZRXOGUHVXOWLQWKH
VXEMHFW¶VGHDWKµ/LIHWKUHDWHQLQJ¶GRHVQRWPHDQWKDWKDGDQ$(RFFXUUHGLQDPRUHVHYHUH
IRUPLWPLJKWKDYHFDXVHGGHDWKHJKHSDWLWLVWKDWUHVROYHGZLWKRXWKHSDWLFIDLOXUH
Hospitalization
2XWVXEMHFWWUHDWPHQWLQDQHPHUJHQF\URRPLVQRWLQLWVHOIDVHULRXV$(DOWKRXJKWKHUHDVRQV
IRULWPD\EHHJEURQFKRVSDVPODU\QJHDOHGHPD+RVSLWDODGPLVVLRQVDQGRUVXUJLFDO
RSHUDWLRQVSODQQHGEHIRUHRUGXULQJDVWXG\DUHQRWFRQVLGHUHG$(VLIWKHLOOQHVVRUGLVHDVH
H[LVWHGEHIRUHWKHVXEMHFWZDVHQUROOHGLQWKHVWXG\SURYLGHGWKDWLWGLGQRWGHWHULRUDWHLQDQ
XQH[SHFWHGZD\GXULQJWKHVWXG\
Important medical event or medical intervention
0HGLFDODQGVFLHQWLILFMXGJHPHQWVKRXOGEHH[HUFLVHGLQGHFLGLQJZKHWKHUDFDVHLVVHULRXVLQ
VLWXDWLRQVZKHUHLPSRUWDQWPHGLFDOHYHQWVPD\QRWEHLPPHGLDWHO\OLIHWKUHDWHQLQJRUUHVXOWLQ
GHDWKKRVSLWDOL]DWLRQGLVDELOLW\RULQFDSDFLW\EXWPD\MHRSDUGL]HWKHVXEMHFWRUPD\UHTXLUH
PHGLFDOLQWHUYHQWLRQWRSUHYHQWRQHRUPRUHRXWFRPHVOLVWHGLQWKHGHILQLWLRQRIVHULRXV7KHVH
VKRXOGXVXDOO\EHFRQVLGHUHGDVVHULRXV
6LPSO\VWRSSLQJWKHVXVSHFWGUXJGRHVQRWPHDQWKDWLWLVDQLPSRUWDQWPHGLFDOHYHQWPHGLFDO
MXGJHPHQWPXVWEHXVHG
x
$QJLRHGHPDQRWVHYHUHHQRXJKWRUHTXLUHLQWXEDWLRQEXWUHTXLULQJLYK\GURFRUWLVRQH
WUHDWPHQW
x
+HSDWRWR[LFLW\FDXVHGE\SDUDFHWDPRODFHWDPLQRSKHQRYHUGRVHUHTXLULQJWUHDWPHQW
ZLWK1DFHW\OF\VWHLQH
x
,QWHQVLYHWUHDWPHQWLQDQHPHUJHQF\URRPRUDWKRPHIRUDOOHUJLFEURQFKRVSDVP
x
%ORRGG\VFUDVLDVHJQHXWURSHQLDRUDQHPLDUHTXLULQJEORRGWUDQVIXVLRQHWFRU
FRQYXOVLRQVWKDWGRQRWUHVXOWLQKRVSLWDOL]DWLRQ
'HYHORSPHQWRIGUXJGHSHQGHQF\RUGUXJDEXVH
A Guide to Interpreting the Causality Question


&OLQLFDO6WXG\3URWRFRO$SSHQGL[&
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

:KHQPDNLQJDQDVVHVVPHQWRIFDXVDOLW\FRQVLGHUWKHIROORZLQJIDFWRUVZKHQGHFLGLQJLIWKHUH
LVDµUHDVRQDEOHSRVVLELOLW\¶WKDWDQ$(PD\KDYHEHHQFDXVHGE\WKHGUXJ
x
7LPH&RXUVH([SRVXUHWRVXVSHFWGUXJ+DVWKHVXEMHFWDFWXDOO\UHFHLYHGWKHVXVSHFW
GUXJ"'LGWKH$(RFFXULQDUHDVRQDEOHWHPSRUDOUHODWLRQVKLSWRWKHDGPLQLVWUDWLRQRI
WKHVXVSHFWGUXJ"
x
&RQVLVWHQF\ZLWKNQRZQGUXJSURILOH:DVWKH$(FRQVLVWHQWZLWKWKHSUHYLRXV
NQRZOHGJHRIWKHVXVSHFWGUXJSKDUPDFRORJ\DQGWR[LFRORJ\RUGUXJVRIWKHVDPH
SKDUPDFRORJLFDOFODVV"2UFRXOGWKH$(EHDQWLFLSDWHGIURPLWVSKDUPDFRORJLFDO
SURSHUWLHV"
x
'HFKDOOHQJHH[SHULHQFH'LGWKH$(UHVROYHRULPSURYHRQVWRSSLQJRUUHGXFLQJWKH
GRVHRIWKHVXVSHFWGUXJ"
x
1RDOWHUQDWLYHFDXVH7KH$(FDQQRWEHUHDVRQDEO\H[SODLQHGE\DQRWKHUHWLRORJ\VXFK
DVWKHXQGHUO\LQJGLVHDVHRWKHUGUXJVRWKHUKRVWRUHQYLURQPHQWDOIDFWRUV
x
5HFKDOOHQJHH[SHULHQFH'LGWKH$(UHRFFXULIWKHVXVSHFWHGGUXJZDVUHLQWURGXFHG
DIWHUKDYLQJEHHQVWRSSHG"$VWUD=HQHFDZRXOGQRWQRUPDOO\UHFRPPHQGRUVXSSRUWD
UHFKDOOHQJH
x
/DERUDWRU\WHVWV$VSHFLILFODERUDWRU\LQYHVWLJDWLRQLISHUIRUPHGKDVFRQILUPHGWKH
UHODWLRQVKLS
,QGLIILFXOWFDVHVRWKHUIDFWRUVFRXOGEHFRQVLGHUHGVXFKDV
x
,VWKLVDUHFRJQL]HGIHDWXUHRIRYHUGRVHRIWKHGUXJ"
x
,VWKHUHDNQRZQPHFKDQLVP"
&DXVDOLW\RIµUHODWHG¶LVPDGHLIIROORZLQJDUHYLHZRIWKHUHOHYDQWGDWDWKHUHLVHYLGHQFHIRUD
µUHDVRQDEOHSRVVLELOLW\¶RIDFDXVDOUHODWLRQVKLSIRUWKHLQGLYLGXDOFDVH7KHH[SUHVVLRQ
µUHDVRQDEOHSRVVLELOLW\¶RIDFDXVDOUHODWLRQVKLSLVPHDQWWRFRQYH\LQJHQHUDOWKDWWKHUHDUH
IDFWVHYLGHQFHRUDUJXPHQWVWRVXJJHVWDFDXVDOUHODWLRQVKLS
7KHFDXVDOLW\DVVHVVPHQWLVSHUIRUPHGEDVHGRQWKHDYDLODEOHGDWDLQFOXGLQJHQRXJK
LQIRUPDWLRQWRPDNHDQLQIRUPHGMXGJPHQW:LWKOLPLWHGRULQVXIILFLHQWLQIRUPDWLRQLQWKH
FDVHLWLVOLNHO\WKDWWKHHYHQWVZLOOEHDVVHVVHGDVµQRWUHODWHG¶
&DXVDOUHODWLRQVKLSLQFDVHVZKHUHWKHGLVHDVHXQGHUVWXG\KDVGHWHULRUDWHGGXHWRODFNRI
HIIHFWVKRXOGEHFODVVLILHGDVQRUHDVRQDEOHSRVVLELOLW\


&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Appendix D
Instructions for Use of Inhaled Medications
Instructions for Use of Inhaled Medications
Instructions for Use of the AS MDI and Placebo for AS MDI
1.
How do I store the inhaler?
x
7KHLQKDOHUVKRXOGEHVWRUHGEHWZHHQ&&)DVGLUHFWHG
E\WKHODEHO
2.
Preparation of the Inhaler
x
7DNHWKHLQKDOHURXWRIWKHSRXFK6DIHO\WKURZDZD\WKHSRXFKDQGWKH
GHVLFFDQWSDFNHWWKDWFRPHVLQVLGHWKHSRXFK
x
7DNHWKHFDSRIIWKHLQKDOHUE\JHQWO\VTXHH]LQJWKHVLGHVRIWKHGXVWFDS
DQGSXOOLQJRII
x
,QVSHFW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
x
7KHLQKDOHUPXVWEHSULPHGEHIRUHILUVWXVH3ULPLQJLQYROYHVUHOHDVLQJD
FHUWDLQQXPEHURIVSUD\VLQWRWKHDLUEHIRUH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
x
7RSULPHWKHLQKDOHUJHQWO\VKDNHWKHLQKDOHUIRUVHFRQGVDQGWKHQ
VSUD\RQFHLQWRWKHDLUDZD\IURP\RXUVHOIDQGRWKHUV
127(DQDXGLEOH³FOLFN´PD\EHKHDUGZKLFKLVDGYDQFHPHQWRIWKH
GRVHFRXQWHUDQGFRQVLGHUHGQRUPDO
x
:DLWDSSUR[LPDWHO\VHFRQGVDQGWKHQUHSHDWVWHSWKUHHPRUH
WLPHV
3.
Using the inhaler
x
7KHLQKDOHUVKRXOGEHKHOGXSULJKWZLWKWKHPRXWKSLHFHDWWKHERWWRPDQG
WKHFDQLVWHUDWWKHWRSDVSLFWXUHGLQ)LJXUH
x
6KDNHWKHLQKDOHUIRUWRVHFRQGV
x
%UHDWKHRXWIXOO\WKURXJK\RXUPRXWKH[SHOOLQJDVPXFKDLUIURP\RXU
OXQJVDVSRVVLEOH7LOW\RXUKHDGEDFNVOLJKWO\SODFHWKHPRXWKSLHFHLQWR
\RXUPRXWKKROGLQJWKHLQKDOHUZLWKWKHPRXWKSLHFHGRZQDQGFORVLQJ


&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

\RXUOLSVDURXQGLW7RDOORZWKHPHGLFDWLRQWRHQWHU\RXUOXQJVNHHS
\RXUWRQJXHIODWRQWKHERWWRPRI\RXUPRXWK
x
:KLOHEUHDWKLQJLQGHHSO\DQGVORZO\WKURXJK\RXUPRXWKIXOO\GHSUHVV
WKHWRSRIWKHGRVHFRXQWHUZLWK\RXULQGH[ILQJHU,PPHGLDWHO\DIWHUWKH
VSUD\LVGHOLYHUHGUHOHDVH\RXUILQJHUIURPWKHFDQLVWHU:KHQ\RXKDYH
EUHDWKHGLQIXOO\UHPRYHWKHLQKDOHUIURP\RXUPRXWKDQGFORVH\RXU
PRXWK
x
+ROG\RXUEUHDWKDVORQJDVSRVVLEOHXSWRVHFRQGVDQGWKHQEUHDWKH
QRUPDOO\
x
,IPRUHWKDQRQHVSUD\LVQHFHVVDU\UHSHDWVWHSVWRWKH
QHFHVVDU\QXPEHURIWLPHV
x
,IWKHGHYLFHZLOOEHXVHGDJDLQSODFHWKHGXVWFDSEDFNRQWRWKHGHYLFH

Figure 1.
Metered Dose Inhaler Diagram


$FWXDWRU
'RVH&RXQWHU
'XVW
&


&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Instructions for Use of the PROVENTIL HFA
Attention Health Care Professional: 
Detach Patient's Instructions for Use from package insert and dispense with the product
PROVENTIL® HFA
(albuterol sulfate)
Inhalation Aerosol
FOR ORAL INHALATION ONLY
Patient's Instructions for Use

Figure 1

Figure 2
%HIRUHXVLQJ\RXU3529(17,/+)$DOEXWHUROVXOIDWH,QKDODWLRQ$HURVROUHDGFRPSOHWH
LQVWUXFWLRQVFDUHIXOO\&KLOGUHQVKRXOGXVH3529(17,/+)$,QKDODWLRQ$HURVROXQGHUDGXOW
VXSHUYLVLRQDVLQVWUXFWHGE\WKHSDWLHQW
VGRFWRU
3OHDVHQRWHWKDWLQGLFDWHVWKDWWKLVLQKDODWLRQDHURVROGRHVQRWFRQWDLQFKORURIOXRURFDUERQV&)&V
DVWKHSURSHOODQW
6+$.(7+(,1+$/(5:(//LPPHGLDWHO\EHIRUHHDFKXVHThen remove the cap from the 
mouthpiece VHH)LJXUHCheck mouthpiece for foreign objects prior to use. 0DNHVXUHWKH
FDQLVWHULVIXOO\LQVHUWHGLQWRWKHDFWXDWRU



&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK


$VZLWKDOODHURVROPHGLFDWLRQVLWLVUHFRPPHQGHGWRSULPHWKHLQKDOHUEHIRUHXVLQJIRUWKH
ILUVWWLPHDQGLQFDVHVZKHUHWKHLQKDOHUKDVQRWEHHQXVHGIRUPRUHWKDQZHHNV3ULPHE\
UHOHDVLQJIRXU³WHVWVSUD\V´LQWRWKHDLUDZD\IURP\RXUIDFH
%5($7+(287)8//<7+528*+7+(0287+H[SHOOLQJDVPXFKDLUIURP\RXUOXQJVDV
SRVVLEOH3ODFHWKHPRXWKSLHFHIXOO\LQWRWKHPRXWKKROGLQJWKHLQKDOHULQLWVXSULJKWSRVLWLRQVHH
)LJXUHDQGFORVLQJWKHOLSVDURXQGLW
:+,/(%5($7+,1*,1'((3/<$1'6/2:/<7+528*+7+(0287+)8//<
'(35(667+(7232)7+(0(7$/&$1,67(5ZLWK\RXULQGH[ILQJHUVHH)LJXUH
+2/'<285%5($7+$6/21*$63266,%/(XSWRVHFRQGV%HIRUHEUHDWKLQJRXW
UHPRYHWKHLQKDOHUIURP\RXUPRXWKDQGUHOHDVH\RXUILQJHUIURPWKHFDQLVWHU
,I\RXUSK\VLFLDQKDVSUHVFULEHGDGGLWLRQDOSXIIVZDLWPLQXWHVKDNHWKHLQKDOHUDJDLQDQG
UHSHDWVWHSVWKURXJK5HSODFHWKHFDSDIWHUXVH
.((3,1*7+(3/$67,&0287+3,(&(&/($1,6(;75(0(/<,03257$1772
35(9(170(',&$7,21%8,/'83$1'%/2&.$*(7+(0287+3,(&(6+28/'%(
:$6+('6+$.(1725(029((;&(66:$7(5$1'$,5'5,('7+2528*+/<$7
/($6721&($:((.,1+$/(50$<6723635$<,1*,)1273523(5/<
&/($1('Routine cleaning instructions: 6WHS7RFOHDQUHPRYHWKHFDQLVWHUDQG
PRXWKSLHFHFDS:DVKWKHPRXWKSLHFHWKURXJKWKHWRSDQGERWWRPZLWKZDUPUXQQLQJZDWHUIRU
VHFRQGVDWOHDVWRQFHDZHHNVHH)LJXUH$Never immerse the metal canister in water. 

Figure A
:DVKPRXWKSLHFHXQGHUZDUPUXQQLQJZDWHU


&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Figure B 
$OORZPRXWKSLHFHWRDLUGU\VXFKDVRYHUQLJKW
Figure C
:KHQEORFNHGOLWWOHRUQRPHGLFLQHFRPHVRXW6WHS7RGU\VKDNHRIIH[FHVVZDWHUDQGOHWWKH
PRXWKSLHFHDLUGU\WKRURXJKO\VXFKDVRYHUQLJKWVHH)LJXUH%:KHQWKHPRXWKSLHFHLVGU\
UHSODFHWKHFDQLVWHUDQGWKHPRXWKSLHFHFDS%ORFNDJHIURPPHGLFDWLRQEXLOGXSLVPRUHOLNHO\WR
RFFXULIWKHPRXWKSLHFHLVQRWDOORZHGWRDLUGU\WKRURXJKO\IF YOUR INHALER HAS 
BECOME BLOCKED OLWWOHRUQRPHGLFDWLRQFRPLQJRXWRIWKHPRXWKSLHFHVHH)LJXUH&
ZDVKWKHPRXWKSLHFHDVGHVFULEHGLQ6WHSDQGDLUGU\WKRURXJKO\DVGHVFULEHGLQ6WHSIF 
YOU NEED TO USE YOUR INHALER BEFORE IT IS COMPLETELY DRY, SHAKE 
OFF EXCESS WATER, UHSODFHWKHFDQLVWHUDQGWHVWVSUD\WZLFHLQWRWKHDLUDZD\IURP\RXU
IDFHWRUHPRYHPRVWRIWKHZDWHUUHPDLQLQJLQWKHPRXWKSLHFH7KHQWDNH\RXUGRVHDVSUHVFULEHG
After such use, rewash and air dry thoroughly as described in Steps 1 and 2. 
7KHFRUUHFWDPRXQWRIPHGLFDWLRQLQHDFKLQKDODWLRQFDQQRWEHDVVXUHGDIWHUDFWXDWLRQV
HYHQWKRXJKWKHFDQLVWHULVQRWFRPSOHWHO\HPSW\7KHFDQLVWHUVKRXOGEH



&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK


GLVFDUGHGZKHQWKHODEHOHGQXPEHURIDFWXDWLRQVKDYHEHHQXVHG%HIRUH\RXUHDFKWKHVSHFLILF
QXPEHURIDFWXDWLRQV\RXVKRXOGFRQVXOW\RXUSK\VLFLDQWRGHWHUPLQHZKHWKHUDUHILOOLVQHHGHG
-XVWDV\RXVKRXOGQRWWDNHH[WUDGRVHVZLWKRXWFRQVXOWLQJ\RXUSK\VLFLDQ\RXDOVRVKRXOGQRW
VWRSXVLQJ3529(17,/+)$,QKDODWLRQ$HURVROZLWKRXWFRQVXOWLQJ\RXUSK\VLFLDQ

<RXPD\QRWLFHDVOLJKWO\GLIIHUHQWWDVWHRUVSUD\IRUFHWKDQ\RXDUHXVHGWRZLWK3529(17,/
+)$,QKDODWLRQ$HURVROFRPSDUHGWRRWKHUDOEXWHUROLQKDODWLRQDHURVROSURGXFWV
DOSAGE: 
8VHRQO\DVGLUHFWHGE\\RXUSK\VLFLDQ
WARNINGS: 
7KHDFWLRQRI3529(17,/+)$,QKDODWLRQ$HURVROVKRXOGODVWXSWRWRKRXUV3529(17,/
+)$,QKDODWLRQ$HURVROVKRXOGQRWEHXVHGPRUHIUHTXHQWO\WKDQUHFRPPHQGHG'RQRWLQFUHDVH
WKHQXPEHURISXIIVRUIUHTXHQF\RIGRVHVRI3529(17,/+)$,QKDODWLRQ$HURVROZLWKRXW
FRQVXOWLQJ\RXUSK\VLFLDQ,I\RXILQGWKDWWUHDWPHQWZLWK3529(17,/+)$,QKDODWLRQ$HURVRO
EHFRPHVOHVVHIIHFWLYHIRUV\PSWRPDWLFUHOLHI\RXUV\PSWRPVEHFRPHZRUVHDQGRU\RXQHHGWR
XVHWKHSURGXFWPRUHIUHTXHQWO\WKDQXVXDOPHGLFDODWWHQWLRQVKRXOGEHVRXJKWLPPHGLDWHO\
:KLOH\RXDUHWDNLQJ3529(17,/+)$,QKDODWLRQ$HURVRORWKHULQKDOHGGUXJVVKRXOGEHWDNHQ
RQO\DVGLUHFWHGE\\RXUSK\VLFLDQ,I\RXDUHSUHJQDQWRUQXUVLQJFRQWDFW\RXUSK\VLFLDQDERXW
WKHXVHRI3529(17,/+)$,QKDODWLRQ$HURVRO
&RPPRQDGYHUVHHIIHFWVRIWUHDWPHQWZLWK3529(17,/+)$,QKDODWLRQ$HURVROLQFOXGH
SDOSLWDWLRQVFKHVWSDLQUDSLGKHDUWUDWHWUHPRURUQHUYRXVQHVV(IIHFWLYHDQGVDIHXVHRI
3529(17,/+)$,QKDODWLRQ$HURVROLQFOXGHVDQXQGHUVWDQGLQJRIWKHZD\WKDWLWVKRXOGEH
DGPLQLVWHUHG8VH3529(17,/+)$,QKDODWLRQ$HURVRORQO\ZLWKWKH\HOORZDFWXDWRUVXSSOLHG
ZLWKWKHSURGXFW7KH3529(17,/+)$,QKDODWLRQ$HURVRODFWXDWRUVKRXOGQRWEHXVHGZLWK
RWKHUDHURVROPHGLFDWLRQV
)RUEHVWUHVXOWVXVHDWURRPWHPSHUDWXUH$YRLGH[SRVLQJSURGXFWWRH[WUHPHKHDWDQGFROG
Shake well before use. 
Contents Under Pressure. 
'RQRWSXQFWXUH'RQRWVWRUHQHDUKHDWRURSHQIODPH([SRVXUHWRWHPSHUDWXUHVDERYH)
PD\FDXVHEXUVWLQJ1HYHUWKURZFRQWDLQHULQWRILUHRULQFLQHUDWRU6WRUHEHWZHHQ&
)Store the inhaler with the mouthpiece down. $YRLGVSUD\LQJLQH\HV.HHSRXWRIUHDFK
RIFKLOGUHQ
)XUWKHU,QIRUPDWLRQ<RXU3529(17,/+)$DOEXWHUROVXOIDWH,QKDODWLRQ$HURVROGRHVQRW
FRQWDLQFKORURIOXRURFDUERQV&)&VDVWKHSURSHOODQW,QVWHDGWKHLQKDOHUFRQWDLQVD
K\GURIOXRURDONDQH+)$DDVWKHSURSHOODQW
'HYHORSHGDQG0DQXIDFWXUHGE\0+HDOWK&DUH/LPLWHG
/RXJKERURXJK8.RU0'UXJ'HOLYHU\
6\VWHPV1RUWKULGJH&$86$5HY
&RS\ULJKW0HUFN
6KDUS	'RKPH&RUSDVXEVLGLDU\RI
Merck & Co., Inc. 
$OOULJKWVUHVHUYHG
653300 





&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Instructions for Use of the VENTOLIN HFA



&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK




&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK




&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK




&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Instructions for Use of the ATROVENT HFA



&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK





&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Instructions for Use of PULMICORT FLEXHALER



&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK







&OLQLFDO6WXG\3URWRFRO$SSHQGL['
'UXJ6XEVWDQFH37
6WXG\&RGH'&37
9HUVLRQ
'DWH0DUFK

Appendix F
Investigator’s Agreement and Signature Page
Investigator’s Agreement and Signature Page
Study Title:
$OEXWHURO6XOIDWH3UHVVXUL]HG,QKDODWLRQ6XVSHQVLRQ37
&XPXODWLYH'RVH6WXG\LQ6XEMHFWV:LWK0LOGWR0RGHUDWH
$VWKPD
Study Number:
'&37
Final Date:
0DUFK
,DJUHH
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KHUHDIWHUUHIHUUHGWRDV3HDUO
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IXOO\FRPSO\ZLWK*&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%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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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
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H&5)V7KHH&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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












6LWH1DPH












SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Study Code 
D6930C00002(PT007002) 
NCT #  
NCT03371459 
Date 
30 MARCH 2018 
 
 
 
 
 
 
 
 
 
 
 
Albuterol Sulfate Pressurized Inhalation Suspension(PT007) Cumulative 
Dose Study in Subjects With Mild to Moderate Asthma 
 
 
 
 
 
 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 1 of 46)
Confidential and Proprietary
STATISTICAL ANALYSIS PLAN
Trial Sponsor: 
AstraZeneca AB
Study Number:
D6930C00002 (PT007002)
Study Phase:
II
Product Name:
Albuterol Sulfate Pressurized Inhalation Suspension (AS MDI); 
PT007
PIND Number:
136213
Indication:
Asthma 
Dosage 
Form/Strength/Dose
x
AS MDI 90 μg dosing sequence as
o
1 actuation (90 μg)
o
1 actuation (90 μg)
o
2 actuations (180 μg)
o
4 actuations (360 μg)
o
8 actuations (720 μg)
for a cumulative dose of 1440 μg
Protocol Title: Albuterol Sulfate Pressurized Inhalation Suspension (PT007) Cumulative 
Dose Study in Subjects With Mild to Moderate Asthma
Date of Issue:
30 Mar 2018
Version
1.0




Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 3 of 46)
Confidential and Proprietary
Change Log
Version No.
Effective Date
Reason for the Change/Revision
Supersedes


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 4 of 46)
Confidential and Proprietary
TABLE OF CONTENTS
LIST OF TABLES................................................................................................................................................6
LIST OF FIGURES..............................................................................................................................................6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................................................7
1. 
INTRODUCTION .......................................................................................................................................9
2. 
STUDY OBJECTIVES ...............................................................................................................................9
2.1 
PRIMARY OBJECTIVE ...........................................................................................................................9
2.2 
SECONDARY OBJECTIVE.......................................................................................................................9
2.3 
SAFETY OBJECTIVE..............................................................................................................................9
2.4 
PK OBJECTIVE .....................................................................................................................................9
3. 
STUDY ENDPOINTS .................................................................................................................................9
3.1 
EFFICACY ASSESSMENTS .....................................................................................................................9
3.2 
PRIMARY EFFICACY ENDPOINT..........................................................................................................10
3.3 
SECONDARY EFFICACY ENDPOINT.....................................................................................................10
3.4 
EXTRAPULMONARY PD ENDPOINTS...................................................................................................10
3.5 
SAFETY ENDPOINTS ...........................................................................................................................10
3.6 
ALBUTEROL PK ENDPOINTS ..............................................................................................................10
4. 
STUDY DESIGN .......................................................................................................................................10
4.1 
STUDY DESIGN AND PLAN .................................................................................................................10
4.2 
RANDOMIZATION ...............................................................................................................................16
4.3 
HYPOTHESIS TESTING ........................................................................................................................16
4.4 
INTERIM ANALYSIS ............................................................................................................................16
4.5 
SAMPLE SIZE......................................................................................................................................17
5. 
DATA AND ANALYTICAL QUALITY ASSURANCE........................................................................17
6. 
ANALYSIS SETS ......................................................................................................................................17
6.1 
INTENT-TO-TREAT (ITT) ANALYSIS SET............................................................................................17
6.2 
MODIFIED ITT (MITT) ANALYSIS SET...............................................................................................18
6.3 
SAFETY ANALYSIS SET ......................................................................................................................18
6.4 
PER PROTOCOL ANALYSIS SET ..........................................................................................................18
6.5 
PK ANALYSIS SET..............................................................................................................................18
6.6 
NON-RANDOMIZED ANALYSIS SET.....................................................................................................18
6.7 
ANALYSIS SETS FOR ANALYSES.........................................................................................................18
7. 
STATISTICAL ANALYSIS .....................................................................................................................19
7.1.1 
General Data Handling Rules and Definitions ...................................................................19
7.1.2 
Data Exclusion and Missing Data Imputation ....................................................................19
7.2 
SUBJECT DISPOSITION........................................................................................................................19
7.3 
DEMOGRAPHY....................................................................................................................................20
7.3.1 
Asthma History, Screening Spirometry, and Reversibility.................................................21
7.3.2 
Medical and Surgical History at Screening and Pregnancy Testing...................................21
7.3.3 
Prior, Concomitant, and Post-Treatment Medications/Treatments.....................................21
7.3.4 
Extent of Exposure to Study Medication............................................................................22
7.4 
EFFICACY ANALYSES.........................................................................................................................22
7.4.1 
Primary Efficacy.................................................................................................................22


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 5 of 46)
Confidential and Proprietary
7.4.2 
Study Day...........................................................................................................................22
7.4.3 
Time Points and Time Intervals for Efficacy Endpoints ....................................................22
7.4.4 
Primary Efficacy Analysis..................................................................................................24
7.4.5 
Secondary Efficacy.............................................................................................................24
7.4.1 
PK Substudy.......................................................................................................................28
7.4.2 
Data Validation and Transformation ..................................................................................30
7.5 
SAFETY ANALYSES ............................................................................................................................30
7.5.1 
Adverse Events...................................................................................................................31
7.5.2 
Clinical Laboratory Data ....................................................................................................33
7.5.3 
Vital Signs ..........................................................................................................................33
7.5.4 
Electrocardiogram (ECG)...................................................................................................34
7.5.5 
Physical Examination .........................................................................................................34
8. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ....................................................34
9. 
STATISTICAL SOFTWARE ..................................................................................................................35
10. REFERENCES ..........................................................................................................................................35
APPENDIX 1 DATA HANDLING RULES.....................................................................................................36
APPENDIX 2 ANALYSIS DATASET SPECIFICATIONS...........................................................................43
APPENDIX 3 SAS CODE FOR STATISTICAL ANALYSES ......................................................................44
APPENDIX 4 MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS)....................................................46


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 6 of 46)
Confidential and Proprietary
List of Tables
Table 1 Schedule of Events ................................................................................................................ 13 
Table 2 Timed Assessments at Each Treatment Visit (Visit 2 and Visit 3)........................................ 15 
Table 3 Analysis Study Time Windows for Spirometry Assessments ............................................... 23 
Table 4 Potentially Clinically Significant (PCS) Criteria for ECG Values, QTcF and Heart Rate.... 26 
Table 5 Potentially Clinically Significant (PCS) Laboratory Parameter Criteria............................... 27 
Table 6 Potentially Clinically Significant Criteria for Systolic and Diastolic Blood Pressure 
Parameters.............................................................................................................................. 28 
List of Figures
Figure 1 Study Flow Diagram:............................................................................................................. 12 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 7 of 46)
Confidential and Proprietary
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse event
AS
Albuterol Sulfate
AS MDI
Albuterol Sulfate Pressurized Inhalation Suspension
ATC
Anatomical Therapeutic Chemical
ATS
American Thoracic Society
AUC
Area under the curve
AUC0-6
Area under the curve from time 0 to 6
AUC0-t
Area under the curve from time 0 to the time of the last measurable plasma 
concentration
ȕ-hCG
ȕ-human chorionic gonadotropin
BMI
Body mass index
BPM
Beats per minute
C15min
Plasma concentration observed at 15 minutes post each cumulative dose
CI
Confidence interval
Cmax
Maximum observed plasma concentration
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMP
Data Management Plan
ECG
Electrocardiogram
eCRF
Electronic case report form
ERS
European Respiratory Society
FEF25-75
Forced expiratory flow from 25% to 75% of FVC
FEV1
Forced expiratory volume in 1 second 
FVC
Forced vital capacity
H0
Null hypothesis
H1
Alternative hypothesis
HFA
Hydrofluoroalkane
ICS
Inhaled Corticosteroid
ITT
Intention-to-treat
IUT
Intersection-union test
IWRS
Interactive web response system
LABA
Long-DFWLQJȕ-agonist
LLOQ
Lower limit of quantification
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intent-to-treat
ms
Milliseconds


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 8 of 46)
Confidential and Proprietary
OTC
Over-the-counter
PCS
Potentially clinically significant
PD 
Pharmacodynamic
PFT
Pulmonary function test
QA
Quality assurance
QC
Quality control
QT
Time from electrocardiogram Q wave to the end of the T wave 
corresponding to electrical systole
QTcF
QT corrected using Fridericia’s formula [QT/(RR1/3)]
RR
Time from electrocardiogram R wave to the next R wave corresponding to 
electrical systole
SAE
Serious adverse event
SABA
Short-DFWLQJȕ-agonist
SAP
Statistical analysis plan
SD
Standard deviation
SI
International System of Units (Système International d’Unités)
SOC
System organ class
sPDP
Statistical protocol deviation plan
Tmax
Time to reach Cmax after the last dose
TOST
Two one-sided test


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 9 of 46)
Confidential and Proprietary
1.
INTRODUCTION
The Sponsor is developing a broad range of metered dose inhaler (MDI)-based inhalation 
aerosols using its porous particle technology platform, including Albuterol Sulfate 
Pressurized Inhalation Suspension (AS) MDI.
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, 
summary, and analysis of data collected within the scope of Clinical Trial Protocol 
D6930C00002 (PT007002), Version 4.0 (Amendment 3), dated March 15, 2018.
The SAP should be read in conjunction with the study protocol and the electronic Case 
Report Forms (eCRFs). This version of the SAP has been developed using the final version 
of the protocol mentioned above and the final version of the Case Report Forms (CRFs; 
Revision 02) dated January 30, 2018.
All references to doses of AS MDI and Proventil refer to the albuterol base (i.e.ȝJ
DOEXWHUROEDVHZKLFKHTXDOVȝJDOEXWHUROVXOIDWH
2.
STUDY OBJECTIVES
2.1
Primary Objective
x
To assess the efficacy of AS MDI compared to Proventil on lung function after 
FXPXODWLYHGRVHVRIXSWRȝJ
2.2
Secondary Objective
x
To assess the extrapulmonary pharmacodynamic (PD) effects of AS MDI and Proventil 
DIWHUHDFKFXPXODWLYHGRVHXSWRDFXPXODWLYHGRVHRIȝJ
2.3
Safety Objective
x
To assess the safety of cumulative doses of AS MDI relative to Proventil
2.4
PK Objective
x
To compare the relative systemic bioavailability of AS MDI and Proventil after 
FXPXODWLYHGRVHVXSWRȝJ
3.
STUDY ENDPOINTS
3.1
Efficacy Assessments
This is a 2-period, crossover study. Each Treatment Period will be 1 day, with a Washout 
Period of 3 to 7 days between Treatment Periods. The day of study drug in each Treatment 
Period is Day 1. Baseline forced expiratory volume in 1 second (FEV1) will be calculated 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 10 of 46)
Confidential and Proprietary
using the mean of available pre-dose values on the first day of each Treatment Period (as 
defined in Section 7.4.3.1).
3.2
Primary Efficacy Endpoint
x
Baseline-adjusted change from baseline in FEV1 30 minutes after each cumulative dose
3.3
Secondary Efficacy Endpoint
x
Baseline-adjusted FEV1 area under the curve from time 0 to 6 (AUC0-6) after the last 
cumulative dose
3.4
Extrapulmonary PD Endpoints
x
Extrapulmonary PD will be evaluated at 15 minutes after each cumulative dose and 30, 
60, 120, 180, 240, 300, and 360 minutes after the last cumulative dose. The change from 
baseline at each time point, the maximum change from baseline after the last cumulative 
dose, and the time-weighted average change after the last cumulative dose will be 
calculated for the following:
o
QT corrected using Fridericia’s formula (QTcF) and heart rate (HR)
o
Serum glucose and potassium
o
Diastolic blood pressure (DBP) and systolic blood pressure (SBP)
3.5
Safety Endpoints
The safety endpoints include:
x
Adverse Events (AEs)/serious adverse events (SAEs)
3.6
Albuterol PK Endpoints
x
Plasma concentration observed at 15 minutes post each cumulative dose (C15min)
x
AUC from time 0 to the time of the last measurable plasma concentration (AUC0-t) post 
the final cumulative dose
x
Maximum observed plasma concentration (Cmax) and time to reach Cmax (Tmax) after the 
last dose
4.
STUDY DESIGN
4.1
Study Design and Plan
This is a randomized, cumulative dose, open-label, 2-period crossover, multi-center study to 
assess the safety, efficacy, PK, and extrapulmonary PD of cumulative doses of AS MDI 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 11 of 46)
Confidential and Proprietary
compared to cumulative doses of Proventil as an active control in subjects with mild to 
moderate asthma.  
This study will be conducted at 5 sites in the US, contributing approximately 8 subjects per 
site. Across these sites, it is planned that approximately 38 subjects with mild to moderate 
asthma will be randomized to provide approximately 30 subjects to complete the study. 
Approximately 20 subjects will also participate in a PK substudy. Pharmacokinetic samples 
will be collected 15 minutes after each cumulative dose and through 12 hours after the last 
dose of study drug.  
A Study Flow Diagram is displayed in Figure 1. 
For more details on the study plan please refer to Protocol Section 4.1. 
Inclusion criteria for the study are listed in Section 3.1 of Protocol D6930C00002.  Subjects 
eligible for enrollment in the study must meet all of the inclusion criteria.
Exclusion criteria for the study are listed in Section 3.2 of Protocol D6930C00002. Subjects 
meeting any of the exclusion criteria are to be excluded from the study.
Randomization criteria for the study are listed in Section 3.3.1 of Protocol D6930C00002. 
The sequence of visits is displayed in the Study Flow Diagram (Figure 1).
Detailed schedules for pre- and post-dose procedures to be performed on each study visit are 
provided in Section 4 of the protocol.  A time-and-events schedule is provided below in 
Table 1. 
Visit procedures at each treatment visit (Visit 2 and Visit 3) are provided in Table 2. 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 12 of 46)
Confidential and Proprietary
Figure 1
Study Flow Diagram: 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 13 of 46)
Confidential and Proprietary
Table 1 
Schedule of Events 
Treatment Daya
Screeninga
Treatment Phase
Follow-up
Visit 1
Visit 1a/1b
Visit 2
Randomization
(TP 1)
Visit 3b
(TP 2)
PDV (if 
applicable)c
TC 3-7 days
after final dose
Day -28 to Day -1
Day 1
Procedures
Informed consent
X
Eligibility criteria
X
Verify randomization criteria
X
Verify continued eligibility
X
X
MDI demonstration/training
X
X
X
Ventolin reversibility testd
X
X
Medical/surgical history
X
Demographics
X
Concomitant medicationse
X
X
X
X
X
Spirometryd
X
X
X
X
X
Physical examinationf
X
X
X
SBP/DBP
X
X
X
X
12-lead ECG
X
X
X
X
Pregnancy testg
X
X
Clinical laboratory testing
X
PD sample collection
X
X
X
Adjust asthma medications per protocolh
X
X
X
Randomization
X
Randomized study drug administered
X
X
PK sample collectioni
X
X
AEs
X
X
X
X
X
X


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 14 of 46)
Confidential and Proprietary
Table 1
Schedule of Events (continued)
Treatment Daya
Screeninga
Treatment Phase
Follow-up
Visit 1
Visit 1a/1b
Visit 2
Randomization
(TP 1)
Visit 3b
(TP 2)
PDV (if
applicable)c
TC 3-7 days
after final dose
Day -28 to Day -1
Day 1
Procedures
Telephone contact
X
Abbreviations: AE=adverse event; DBP=diastolic blood pressure; ECG=electrocardiogram; FEV1=forced expiratory volume in 1 second; MDI=metered dose inhaler; 
PDV=Premature Discontinuation Visit; PK=pharmacokinetic; SABA= short-DFWLQJȕ-agonist; SBP=systolic blood pressure; TC=telephone call; TP=Treatment Period.
Note: When post-dose data collection timepoints are concurrent, variables will be collected in the following order: blood pressure, ECG, clinical laboratory assessments, PK blood 
samples (if applicable), and spirometry.
a
Screening Period will be 3 to 28 days for subjects on SABA only before study entry, and 14 to 28 days for subjects on inhaled corticosteroid (ICS) or ICS/long-DFWLQJȕ-
agonist (LABA) before study entry.
b
Subjects to return to clinic within 3 to 7 days following Treatment Visit 2.
c
Subjects who prematurely withdraw from the study will undergo a Premature Discontinuation Visit (see Protocol Section 4.2.4).
d
For subjects who received their regularly inhaled asthma medications and/or SABA on the morning of the visit, reversibility will be measured at Visit 1a, which will occur 
within 10 days of Visit 1. For subjects who do not meet reversibility criteria at Visit 1a, Visit 1b will be scheduled for a second reversibility test, to occur within 7 days. 
Subjects who do not meet reversibility criteria after the second attempt will be screen failed.
e
At all visits beyond Visit 1, note the time of the last dose of asthma medications. The visit must be rescheduled if the last dose of Ventolin was <48 hours before Visit 2, or 
if the last dose of Atrovent was <8 hours before Visit 2 or Visit 3.
f
Includes evaluation of height and weight at Visit 1.
g
$VHUXPSUHJQDQF\WHVWȕ-human chorionic goQDGRWURSLQ>ȕ-K&*@ZLOOEHSHUIRUPHGDW9LVLWXULQHȕ-hCG test will be performed before randomization at Visit 2 (for 
women of child-bearing potential only).
h
At Visit 1, prohibited asthma medications are to be stopped and asthma medications changed as specified in Protocol Section 7.7.2. At the end of Visit 3 (or upon 
premature discontinuation, if applicable), subjects will return to pre-study or other appropriate inhaled maintenance asthma medications.
i
For subjects in the PK substudy only.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 15 of 46)
Confidential and Proprietary
Table 2
Timed Assessments at Each Treatment Visit (Visit 2 and Visit 3)
Pre-Dose 
(minutes)
Doses 1 through 
4 (minutes)
Dose 5 (minutes)
-60
-30
0
15
30
0
15
30
60
120
180
240
300
360
480
600
720
SBP/DBP
Xa
X
X
X
X
X
X
X
X
X
12-lead ECGb
Xa
X
X
X
X
X
X
X
X
X
Sample collection for
glucose and potassium
Xa
X
X
X
X
X
X
X
X
X
PK sample collectionc
X
X
X
X
X
X
X
X
X
X
X
X
X
Spirometry
X
X
Xd
X
X
X
X
X
X
X
X
Study drug
administration
X
X
Abbreviations: DBP=diastolic blood pressure; ECG=electrocardiogram; PK=pharmacokinetic; SBP=systolic blood pressure.
Note: When post-dose data collection timepoints are concurrent, variables will be collected in the following order: blood pressure, ECG, samples for serum glucose and 
potassium, PK blood samples (if applicable), and spirometry.
a.
Pre-dose assessment to be performed within 60 minutes before the first dose.
b.
ECG assessment of QTc interval and heart rate.
c.
For subjects in the PK substudy only.
d.
The 30-minute spirometry assessment should be started at approximately 25 minutes post-dose to allow for completion of the test before the next dose, so as not to delay 
dosing.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 16 of 46)
Confidential and Proprietary
4.2
Randomization
Subjects will be randomly assigned to 1 of 2 treatment sequences, A/B or B/A, using an interactive 
web response system (IWRS). Each sequence will comprise the following cumulative dose 
treatment arms:
$ $60',LQKDODWLRQVRIȝJSHULQKDODWLRQ
% 3URYHQWLOLQKDODWLRQVRIȝJSHULQKDODWLRQ
Randomization will be centralized.
4.3
Hypothesis Testing
Hypothesis testing for safety will not be performed.
Hypothesis testing for efficacy will be performed within the context of a linear mixed model 
analysis, including both treatments.  For the primary efficacy comparisons for change from 
baseline in FEV1 30 minutes post each of the cumulative doses, the primary endpoint, the null 
hypothesis at each individual time point is that the mean test treatment effect is not equal to that of 
Proventil; the alternative hypothesis is that the test treatment effect and that of Proventil are equal.  
Thus, testing will be for equivalence, using a margin of 200 mL and the two, one-sided test 
(TOST) procedure with alpha = 0.05. In practice, TOST can be implemented by comparing the 
90% confidence intervals (CIs) of the between-treatment comparisons for containment within ±
200 mL.
The primary null (H0) and alternative (H1) hypotheses with μ representing the mean will be 
assessed using an intersection-union test (IUT) as follows:
x
H0: ڂ
|Ɋ୅ୗ୑ୈ୍ െ Ɋ ୔୰୭୴ୣ୬୲୧୪ |
ହ
௝ୀଵ
> 200 mL 
that is, following at least 1 of the 5 cumulative doses the difference in treatment means for the 
change from baseline in FEV1 30 minutes post doses is not within the limits ± 200 mL
x
H1: ځ
|Ɋ୅ୗ ୑ୈ୍ െ Ɋ ୔୰୭୴ୣ୬୲୧୪|
ହ
௝ୀଵ
P/
that is, the difference in treatment means for the change from baseline in FEV1 30 minutes post 
all 5 of the cumulative doses are within the limits ± 200 mL
The Type I error rate for the IUT is at most 5% (Berger and Hsu, 1996). Other than the 
specification of secondary endpoints, no adjustments for Type I error will be made.
4.4
Interim Analysis
No interim analyses are planned for this trial.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 17 of 46)
Confidential and Proprietary
4.5
Sample Size
Randomization of 38 subjects to achieve 30 subjects completing the study will provide 95% 
probability to demonstrate equivalence within ±200 mL after all 5 cumulative doses (IUT). This 
calculation assumes a true treatment difference (AS MDI–Proventil) of 35 mL, intra-subject 
standard deviation of 174 mL, and TOST at the 5% level. 
Enrollment of 20 subjects to obtain 14 subjects completing the PK substudy will provide 95% 
probability to observe a one-sided upper 95% confidence bound for the Cmax ratio (AS 
MDI/Proventil) that is less than 1.50 even if the true ratio is as high as 1.15. This calculation 
assumes an intra-subject coefficient of variation of 22% for Proventil and a one-sided 5% test. 
5.
DATA AND ANALYTICAL QUALITY ASSURANCE
The overall quality assurance (QA) procedures for the study data, statistical programming, and 
analyses are described in Standard Operating Procedures (SOPs)
. Detailed data management procedures are documented in the 
study Data Management Plan (DMP), Data Validation Check Specifications, and Integrated Safety 
Data Review Plan. Detailed statistical and programming quality control (QC) and QA procedures 
are documented in the Statistical Analysis and Programming QC/QA Plan.
Transfer of pulmonary function test (PFT) data from the central PFT laboratory 
 
 
 will be defined in the 
DMP, and data 
handling rules related to this data are included in Appendix 1 of this SAP. The quality of all PFTs 
obtained at each timepoint will be graded independently
 by qualified 
personnel. Quality grading assessments will be based on American Thoracic Society 
(ATS)/European Respiratory Society (ERS) criteria and will be included in data transfers. 
6.
ANALYSIS SETS
Any evaluability criteria with a potential impact on efficacy, extrapulmonary PD, and PK results 
will be defined in a statistical protocol deviation plan (sPDP). The evaluability criteria will be 
programmatically identified in a blinded fashion aided by a review of blinded data listings prior to 
database lock. Major protocol deviations (protocol violations), therefore, can result in exclusion of 
all data from a particular subject from the analysis set or require exclusion of data from a specific 
timepoint or treatment period and/or subsequent timepoints or a subsequent treatment period for an 
endpoint(s). Protocol deviations for exclusion of data from the analysis sets will be agreed by the 
clinical study team and documented in the blinded data review meeting minutes prior to database 
lock.  
The following analysis sets are defined in this study. 
6.1
Intent-to-Treat (ITT) Analysis Set
The Intent-To-Treat (ITT) Analysis Set is defined as all subjects who are randomized to study drug 
and receive at least 1 dose of the study drug. Subjects will be analyzed in each period according to 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 18 of 46)
Confidential and Proprietary
the study drug they were assigned to per the randomization scheme (Note that a subject who used a 
study drug but took less than 1 full dose of study drug will qualify for this analysis set).
6.2
Modified ITT (mITT) Analysis Set
The Modified ITT (mITT) Analysis Set is a subset of ITT Analysis Set including subjects who 
received study drug and have post-study drug efficacy data from both Treatment Periods. Data 
judged to be impacted by major protocol deviations will be determined prior to database lock in a 
blinded fashion and excluded per the sPDP. Statistical tabulations and analyses will be by 
randomized study drug, but data obtained after subjects receive an incorrect study drug will be 
excluded from the affected periods.
6.3
Safety Analysis Set
The Safety Analysis Set is defined as all subjects who are randomized to study drug and receive at 
least 1 dose of the study drug. Subjects will be analyzed according to study drug received rather 
than per the randomization scheme.
6.4
Per Protocol Analysis Set
The Per Protocol (PP) Analysis Set is a subset of the Safety Analysis Set including subjects who 
received study drug and have post-study drug extrapulmonary pharmacodynamic data. Data judged 
to be impacted by major protocol deviations will be determined in a blinded fashion prior to 
database lock and excluded per the sPDP. Statistical tabulations and analyses will be by 
randomized study drug, but data obtained after subjects receive an incorrect study drug will be 
excluded from the affected period(s).
6.5
PK Analysis Set
The PK Analysis Set is defined as subjects in the Safety Analysis Set who received study drug and 
for whom at least 1 primary PK parameter can be calculated and with no important protocol 
deviations thought to impact the analysis of the PK data.
6.6
Non-randomized Analysis Set
The Not Randomized Analysis Set is defined as subjects who did not receive a randomization 
number and therefore did not receive a dose of study drug (e.g., subjects who were screen failures 
or stopped participation before being randomized).
6.7
Analysis Sets for Analyses
Analyses will be performed as follows:
Demographics and baseline characteristics will be summarized for the ITT, mITT and Safety 
Analysis Sets. Extent of exposure will be summarized for the mITT and Safety Analysis Sets. The 
Safety Analysis Set will be used to summarize AEs and SAEs.
The primary estimand of interest is the De Jure Estimand, defined as the effect of the randomized 
treatments in all subjects assuming treatments were taken as specified in the protocol. Analysis of 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 19 of 46)
Confidential and Proprietary
the De Jure Estimand will be conducted as follows: for efficacy (FEV1-related) endpoints using the 
mITT Analysis Set; for extrapulmonary PD using the Per Protocol Analysis Set; and for 
pharmacokinetics using the PK Analysis Set.
The primary endpoint will also be analyzed using the ITT Analysis Set as supportive. Supportive 
analyses of the extrapulmonary PD parameters will be based on the Safety Analysis Set. 
7.
STATISTICAL ANALYSIS
7.1.1
General Data Handling Rules and Definitions
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes.  If any randomized 
subject is found to not have valid documented informed consent, that subject’s data will be 
excluded from the report, except as necessary to document the error.
Except where specified all continuous variables will be summarized with descriptive statistics (the 
number of non-missing values, mean, standard deviation, median, minimum, and maximum) and 
all categorical variables will be summarized with frequency counts and percentages, by study drug.
Missing data will be maintained as missing in the analysis datasets, unless specified otherwise.  
For variables where missing data are imputed, another analysis dataset will contain a variable with 
the imputed value.  Thus, the original variable value will be maintained as missing in 1 of the 
analysis datasets.
All efficacy, safety, extrapulmonary PD, and PK parameters will be summarized by study drug 
(unless specified otherwise).
7.1.2
Data Exclusion and Missing Data Imputation
Pre-dose spirometry values will use the average of the non-missing -60 min and -30 min values.  
Unless otherwise specified, all lung function assessments analyzed that have at least 1 effort that 
meets ATS/ERS criteria for acceptability will be considered acceptable and contribute to the post-
dose assessments.  If the PFT assessments at a specific timepoint were deemed to be of 
unacceptable quality, i.e., none of the efforts met ATS/ERS criteria for acceptability, the PFT 
assessments obtained at the timepoint will not be included in any efficacy analysis and will be 
considered missing (Miller et al. 2005).  Thus, all observed data will be included in the ITT 
Analysis Set analysis, with the exception of data at a timepoint which had unacceptable quality 
based on ATS/ERS criteria.
7.2
Subject Disposition
A disposition table for all screened subjects will be provided (Table 1.1.1 and Listing 1.2). This 
tabulation will include the number of subjects who received study drug (by randomized study drug
and for all subjects), who were withdrawn prematurely, and who completed each study drug.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 20 of 46)
Confidential and Proprietary
Length of participation (0 periods, 1 period only, or two periods) will also be tabulated. The 
number of subjects who completed the study will also be provided. The number and percentage of 
screened subjects who were included in the ITT, mITT, Safety and Not Randomized Analysis Sets 
will also be tabulated (Table 1.1.1). 
A summary and a listing of reasons subjects were not randomized will be provided for all subjects 
not randomized (Table 1.1.2 and Listing 1.4). Reasons for Premature discontinuation will be 
summarized for the ITT Analysis set by randomized study drug (Table 1.2.1). The number and 
percentage of subjects in the Safety Analysis set withdrawn for each reason will be tabulated by 
study drug actually received (Table 1.2.2).  
The number and percentage of randomized subjects who were included in the ITT, mITT, Safety, 
PP, and PK Analysis Sets will also be tabulated (Table 1.1.1). The number and percentage of 
randomized subjects who were in each of the analysis sets will be tabulated for each study drug 
(i.e., for the set of subjects who were randomized to receive the study drug [Table 1.3]). 
The reason for exclusion from the mITT Analysis set will be tabulated by study drug for all ITT 
subjects (Table 1.4.1). The reason for exclusion from the PP Analysis Set will be tabulated by 
study drug for the Safety set (Table 1.4.2). The reason for exclusion from the mITT and PP 
Analysis Sets of a subject or of partial data for a subject will be listed for all randomized subjects, 
in addition to listing reasons for any subjects to have been excluded from the ITT, Safety, PP, and 
PK Analysis sets (Table 1.1.3). A listing of subjects who did not comply with use of rescue 
medication and use of xanthine-containing products (protocol deviations requiring removal of data 
from the mITT and PP Analysis Set analyses) just prior to spirometry will be provided in 
Listing 6.1. Use of asthma medications at pre-dose or during the post-dose assessments on each 
specific test day (yes/no), will be provided in Listing 6.4. In addition, the eligibility information 
(inclusion/exclusion criteria with any waivers granted), of all subjects who are randomized will be 
listed (Listing 2). 
  
If there are any subjects who took study drug other than what was randomized during the study, 
both the study drug assigned at randomization and actual study drug(s) received during the 
Treatment Period will be listed (Listing 1.3). All data listings will show the study drug actually 
received.
7.3
Demography 
The demographic variables are age, gender, race, ethnicity, and prior asthma treatment regimen 
(SABA prn use only, ICS, ICS/LABA). The physical characteristics variables are weight, height, 
and BMI (body mass index).  The data handling rules for age, BMI, and number of pack years 
smoked are described in Appendix 1. 
Subject demographics will be summarized for the mITT, ITT, Safety, and PP Analysis Sets and for 
Non-Randomized subjects (Tables 1.5.1 through 1.5.5, respectively, and Listing 1.2). 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 21 of 46)
Confidential and Proprietary
7.3.1
Asthma History, Screening Spirometry, and Reversibility
The number of months since the date of the diagnosis of asthma as shown on the Screening Visit 1 
eCRF, and determined relative to the first dose of study medication in the study (Appendix 1) will 
be summarized for the mITT, ITT, Safety, and PP Analysis Sets (Tables 1.6.1 through 1.6.4, 
respectively, and Listing 4.1). The screening spirometry variables FEV1, Forced expiratory flow 
from 25% to 75% of FVC (FEF25-75), and Forced Vital Capacity (FVC) will be summarized for 
Visit 1 (Tables 1.7.1 and 1.7.2, respectively, for the mITT and ITT Analysis Sets, and Listing 6.4).
For this purpose, Visit 1 data will be derived from Visit 1, 1a, or 1b.  
Per Protocol Section 4.1, reversibility to Ventolin HFA (a short-DFWLQJȕ-agonist [SABA]) will be 
evaluated at Visits 1, 1a (as needed), or 1b (as needed). 
Reversibility (i.e. screening reversibility) to Ventolin HFA is defined as having the following 
condition met at Visit 1, 1a, or Visit 1b: 
x
Reversibility will be a comparison of the best FEV1 effort obtained at 30 minutes pre-
bronchodilator to the best FEV1 effort obtained at 30 minutes post-bronchodilator following 
administration of Ventolin. A subject is considered reversible to Ventolin if the improvement 
in FEV1 at 30 minutes post-9HQWROLQLV
See Appendix 1 for data handling rules and the formula for determination of reversibility variables. 
Bronchodilator reversibility to Ventolin HFA at Screening will be summarized for the mITT and 
ITT Analysis Sets and listed (Tables 1.8.1 and 1.8.2, respectively, and Listing 3).  Also included 
will be a summary of the change in FEV1 from pre-bronchodilator to post-bronchodilator.  
7.3.2
Medical and Surgical History at Screening and Pregnancy Testing
Medical history at Screening will be coded using the current version of the Medical Dictionary for 
Regulatory Activities at the time of data base lock.
Medical and Surgical History at Screening will be summarized for the Safety Analysis Set and 
listed for all randomized subjects (Table 1.9 and Listing 4.2).   
Pregnancy Testing Results will be listed (Listing 4.3). 
7.3.3
Prior, Concomitant, and Post-Treatment Medications/Treatments
All prescription and over-the-counter (OTC) medications, as well as any herbal or vitamin 
supplements, taken by the subject within 30 days of Visit 1 will be recorded on the Prior and 
Concomitant Medications electronic case report form (eCRF) page.  All concomitant medications 
taken during the study will be recorded on the Prior and Concomitant Medications eCRF page.
Coding: Verbatim medication/treatment terms coded
 
will be assigned a preferred term 
and an ATC (anatomic therapeutic chemical class) term using the latest version of the World 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 22 of 46)
Confidential and Proprietary
Health Organization Drug Dictionary Enhanced and World Health Organization Herbal Dictionary 
(WHO DDE and WHO HD) available (Version: Q1; March 2018).
Multiple ATC Assignments: If there are multiple ATC codes assigned to the same concomitant 
medication, the “primary” one based on the Sponsor medical evaluation will be used. 
Additional details for the definition of Prior medication/treatment, Concomitant 
medication/treatment, and Post-Treatment medication/treatment are described in Appendix 1.
Prior Asthma and Non-Asthma Related medications/treatments will be summarized by preferred 
term and actual study drug received for the Safety Analysis Set separately during the Treatment 
Periods (Tables 1.10.1 and 1.10.2, respectively).
Concomitant Asthma and Non-Asthma Related medications/treatments will be summarized by 
preferred term and actual study drug received for the Safety Analysis Set separately during the 
Treatment Periods and the Washout Period between Treatments 1 and 2 (Tables 1.11.1a, 1.11.1b, 
1.11.2a, and 1.11.2b). Prior, concomitant, and post-treatment medications will be displayed in 
separate listings for Asthma and Non-Asthma medications (Listings 4.4 and 4.5, respectively).
Pulmicort Flexhaler and Atrovent dispensing at Visit 2 will be listed (Listing 5.1.2). 
7.3.4
Extent of Exposure to Study Medication
A listing of study drug dosing information will be provided in Listing 5.1.1. Any comments related 
to study drug or any other study comments will be listed (Listing 9.3). 
7.4
Efficacy Analyses
Reasons for missed visits (asthma-related or not) for each subject will be listed (Listing 6.3).
Spirometry measurements will be listed (Listing 6.4).
7.4.1
Primary Efficacy
7.4.2
Study Day
Study day is defined relative to the date of the first study drug administration. Additional 
definitions are provided in Appendix 1. Handling of unscheduled visits for efficacy endpoints is 
discussed in Section 7.4.3.3.
7.4.3
Time Points and Time Intervals for Efficacy Endpoints
The definitions of several terms related to time points and time intervals for efficacy endpoints are 
given in this section.
7.4.3.1
Baselines for Analysis
Pre-dose PFT values are known to be variable, and an isolated timepoint may not accurately reflect 
the true baseline.  For this reason, the average of the Visit 2 and Visit 3 pre-dose values will be 
used as the baseline for analysis.  The analysis baseline for the site-collected PFT (pulmonary 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 23 of 46)
Confidential and Proprietary
function test) parameter FEV1 will be computed as follows: The mean of the -60 and -30 minute 
values for each visit day is calculated.  Then, the means of the pre-dose values at Visits 2 and 3 are 
averaged.  
7.4.3.2
Change from Baseline
Change from baseline denotes the value at a timepoint minus the value at baseline, where baseline 
was defined above in Section 7.4.3.1.
7.4.3.3
Handling of Unscheduled Visits:
Data from unscheduled visits will not be used for efficacy analyses, but will be listed (Listing 6.4).
7.4.3.4
Time Windows for Spirometry Assessments
All available data with the actual timepoints (versus nominal timepoints) will be used for AUC 
calculations, unless an actual time is not available; when an actual time is not available, nominal 
windows will apply to the change from baseline in FEV1 30 minutes post each of the cumulative 
doses analyses. Assessments will be allocated to derived nominal collection time windows using 
the time intervals specified for each below.
Table 3
Analysis Study Time Windows for Spirometry Assessments
Calculated
Study Time Window
Time Interval for the Study Time Window
Pre-dose 60 min
PLQSULRUWRGRVH
Pre-dose 30 min
WRPLQprior to dose
Post-dose 15 min
>0  to 22 min Post-dose
Post-dose 30 min
23 to 44 min Post-dose
Post-dose 1 hr
45 to 89 min Post-dose
Post-dose 2 hrs
90 to 149 min Post-dose
Post-dose 3 hrs
150 to 209 min Post-dose
Post-dose 4 hrs
210 to 269 min Post-dose
Post-dose 5 hrs
270 to 329 min Post-dose
Post-dose 6 hrs
330 to 389 min Post-dose
Note: The time of the study drug dose will be available to the minute. The time of the spirometry 
assessment will be available to the second, and will be truncated downward to whole minutes prior 
to calculation of the study time window. Any assessments for which the time interval is 0 due to 
truncation but are marked as post-dose nominally, will be assigned to the 5 min post dose time 
window. 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 24 of 46)
Confidential and Proprietary
For the change from baseline in FEV1 by timepoint analysis, if there are multiple spirometry 
values for the same parameter within the same post-dose study time window on the same day, the 
last value will be chosen for analysis with one exception: if multiples with the exact same time (in 
minutes and seconds) occur within a window, then the last value based on the nominal time 
window will be chosen for analysis.  Queries to the site (prior to database lock and unblinding) 
will be used to ascertain which assessment actually occurred first. 
7.4.4
Primary Efficacy Analysis
The primary objective of this study is to assess the efficacy of AS MDI compared to Proventil on 
OXQJIXQFWLRQDIWHUFXPXODWLYHGRVHVRIXSWRȝJ
Change from baseline in FEV1 30 minutes post each of the cumulative doses will be analyzed 
using a linear mixed effect model with a random subject effect for the correlation across periods 
and an unstructured covariance matrix for the repeated measures within subject periods. In the 
event that the unstructured matrix fails to converge, the heterogeneous Toeplitz will be fit. The 
fixed effects will include study drug (AS MDI vs Proventil), cumulative dose level, study drug-by-
cumulative dose interaction, and period as categorical covariates, and baseline FEV1 as a 
continuous covariate. The least squares (LS) mean and the standard error of this mean with the 
corresponding two-sided 95% confidence interval will be provided for each study drug.  Ninety-
percent (90%) CIs will be calculated for the between-study drug differences after each cumulative 
dose and will be evaluated for containment within the equivalence bounds of ±200 mL.
The primary analysis will be conducted using the mITT Analysis Set.  Supportive analyses will be 
performed using the ITT Analysis Set.  Assumptions underlying the primary analysis will be 
evaluated and additional analyses may be performed (see Section 7.4.2). 
Summary statistics and the results of statistical testing for this analysis will be provided in Table 
2.1.1 with the LS mean change from baseline plotted, in Figure 2.1.1.1, for the mITT Analysis.  
Note that the LS mean values plotted will be obtained from a model using all timepoints assessed 
during the 8 hours of spirometry testing (the assessments 30 minutes after the first 4 cumulative 
doses and the assessments through 6 hours after the last cumulative dose), and will use all terms 
from the primary model.
7.4.5
Secondary Efficacy
7.4.5.1
FEV1 AUC0-6
The FEV1 AUC0-6 is the area under the curve for change from baseline calculated using the 
trapezoidal rule and will be normalized by dividing the AUC by the length of follow up post the 
last cumulative dose (typically 6 hours).  The FEV1 AUC0-6 will be calculated if there is at least 1 
non-missing data point during the first 2 hours post-dose.  For the purpose of AUC calculations, 
the value of the spirometry parameter at time 0 will be the change from baseline in pre-
bronchodilator FEV1 at the visit.  If AUC is based on just one 1 assessment (i.e., a change from 
baseline value), that change from baseline value will be the value of the AUC (the trapezoidal rule 
and normalization will not apply as the area is 0 and the time interval is 0).


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 25 of 46)
Confidential and Proprietary
The FEV1 AUC0-6 will be analyzed using a linear mixed model with a random subject effect.  The 
fixed effects in the model will include study drug, baseline FEV1, and period.  A 90% CI for the 
between-study drug difference will be calculated and assessed for containment with the 
equivalence bounds of ±200 mL.
The secondary efficacy analysis will be conducted using the mITT Analysis Set (FEV1 AUC0-6:
Table 2.2.1).
7.4.5.2
Extrapulmonary PD
Extrapulmonary PD parameters of change from baseline at each assessment time, maximum 
change from baseline post the last cumulative dose, and time-weighted average change from 
baseline post the last cumulative dose in QTcF, HR, serum glucose, serum potassium, SBP, and 
DBP will each be analyzed using a similar model as described above for FEV1 parameters. Period-
specific baseline for the relevant parameter will be included as the baseline covariate in the model.  
Period-specific baseline is defined as the last available pre-dose measurement taken on Day 1 of 
the treatment period prior to the start of dosing.  In addition, a covariate for average baseline 
(within-subject average across periods) will also be included to remove cross-level bias (Kenward 
and Roger, 2010).  Between-treatment differences and corresponding 90% CIs will be provided.  
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for raw values 
and change from baseline values in heart rate and QTcF interval will be calculated.  These 
assessments will be tabulated for each study drug for each scheduled pre-dose and post-dose 
scheduled timepoint of the Treatment Period (change from baseline in QTcF: Table 2.3.1.1 and 
Figure 2.3.1.1 and Table 2.3.2.1 and Figure 2.3.2.1 for the PP and Safety Analysis Sets,
respectively; maximum change from baseline in QTcF: Table 2.3.1.2 and Table  2.3.2.2 for the PP 
and Safety Analysis Sets, respectively; time-weighted average change from baseline in QTcF: 
Table 2.3.1.3 and Table 2.3.2.3 for the PP and Safety Analysis Sets, respectively; change from 
baseline in HR: Table 2.4.1.1 and Figure 2.4.1.1 and Table 2.4.2.1 and Figure 2.4.2.1 for the PP 
and Safety Analysis Sets, respectively; maximum change from baseline in HR: Table 2.4.1.2 and 
Table 2.4.2.2 for the PP and Safety Analysis Sets, respectively; time-weighted average change 
from baseline in HR: Table 2.4.1.3 and Table 2.4.2.3 for the PP and Safety Analysis Sets 
respectively).  Time windows for tabulations will be those used for spirometry (See Table 3 in 
Section 7.4.3.4).
Potentially clinically significant electrocardiogram (ECG) parameter values will be identified 
based on criteria listed in Table 4.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 26 of 46)
Confidential and Proprietary
Table 4
Potentially Clinically Significant (PCS) Criteria for ECG Values, QTcF and 
Heart Rate
Parameter 
Post-Baseline Criteria 
QTcF Prolongation 
x
Post-baseline value is > 450 ms for male subjects or > 470 milliseconds (ms) for 
female subjects
x
Post-baseline value is > 500 ms 
x
Increase from baseline is > 30 ms
x
Increase from baseline is > 60 ms increase
x
Post-baseline value is > 500 ms and increase > 30 ms 
x
Post-baseline value is > 500 ms and increase > 60 ms 
Tachycardia Event
EHDWVSHUPLQXWHESPDQGLQFUHDVHIURPEDVHOLQH
Bradycardia Event
ESPDQGGHFUHDVHIURPEDVHOLQH
Subjects with potentially clinically significant values for QTcF and heart rate ECG values at any 
time post-baseline during a study visit will be listed by study drug based on the criteria in Table 4
(Table 2.5.1 and Table 2.5.2 for the Safety Analysis Set for QTcF and Tachycardia/Bradycardia 
events, respectively). All available data for a subject post-baseline including data from 
unscheduled visits will be presented in the listing.
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for raw values 
and change from baseline values in serum glucose and serum potassium will be calculated.  These 
assessments will be tabulated for each study drug for each scheduled pre-dose and post-dose 
scheduled timepoint of the Treatment Period (change from baseline in serum glucose: 
Table 2.6.1.1 and Figure 2.6.1.1 and Table 2.6.2.1 and Figure 2.6.2.1 for the PP and Safety 
Analysis Sets, respectively; maximum change from baseline in serum glucose: Table 2.6.1.2 and 
Table 2.6.2.2 for the PP and Safety Analysis Sets, respectively; time-weighted average change 
from baseline in serum glucose: Table 2.6.1.3 and Table 2.6.2.3 for the PP and Safety Analysis 
Sets, respectively; change from baseline in serum potassium: Table 2.7.1.1 and Figure 2.7.1.1 and 
Table 2.7.2.1 and Figure 2.7.2.1 for the PP and Safety Analysis Sets, respectively; maximum 
change from baseline in serum potassium: Table 2.7.1.2 and Table 2.7.2.2 for the PP and Safety 
Analysis Sets, respectively; time-weighted average change from baseline in serum potassium: 
Table 2.7.1.3 and Table 2.7.2.3 for the PP and Safety Analysis Sets, respectively).  
Potentially Clinically Significant Laboratory Values Above/Below a Clinically Relevant 
Threshold on-treatment, based on CTCAE (Common Terminology Criteria for Adverse Events) 
4.03 and other criteria, will be identified based on the thresholds presented in Table 5.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 27 of 46)
Confidential and Proprietary
Table 5
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria
Parameter
Post-Baseline Criteria
Chemistry
Blood Glucose
<2.2 mmol/L
>13.9 mmol/L
Serum Potassium
<3.0 mmol/L
>6.0 mmol/L
ULN denotes upper limit of normal. 
*CTCAE 4.03 criteria are based on fasting glucose values.  However, subjects were not required 
to fast prior to obtaining blood glucose values.
Subjects with newly occurring or worsening potentially clinically significant laboratory values of 
glucose and potassium, above or below a clinically relevant threshold value on-study drug, will be 
listed (Tables 2.8 for the Safety Analysis Set). Pre-dose laboratory assessments on Day 1 of a 
Treatment Period (subsequent to a Washout Period and washout treatment) will not be attributed to 
study drug for the purpose of summarizing clinical significance. All available data for a subject 
post-baseline including data from unscheduled visits will be presented in the listing.
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for raw values 
and change from baseline values in systolic and diastolic blood pressure will be calculated.  These
assessments will be tabulated for each study drug for each scheduled pre-dose and post-dose 
scheduled timepoint of the Treatment Period (change from baseline in systolic blood pressure: 
Table 2.9.1.1 and Figure 2.9.1.1 and Table 2.9.2.1 and Figure 2.9.2.1  for the PP and Safety 
Analysis Sets, respectively; maximum change from baseline in systolic blood pressure: Table 
2.9.1.2 and Table 2.9.2.2 for the PP and Safety Analysis Sets, respectively; time-weighted average 
change from baseline in systolic blood pressure: Table 2.9.1.3 and Table 2.9.2.3 for the PP and 
Safety Analysis Sets, respectively; change from baseline in diastolic blood pressure: Table 2.10.1.1 
and Figure 2.10.1.1 and Table 2.10.2.1 and Figure 2.10.2.1 for the PP and Safety Analysis Sets, 
respectively; maximum change from baseline in diastolic blood pressure: Table 2.10.1.2 and Table 
2.10.2.2 for the PP and Safety Analysis Sets, respectively; time-weighted average change from 
baseline in diastolic blood pressure: Table 2.10.1.3 and Table 2.10.2.3 for the PP and Safety 
Analysis Sets, respectively).
Potentially clinically significant changes in systolic and diastolic blood pressure will be 
defined based on the following criteria provided by the Sponsor:


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 28 of 46)
Confidential and Proprietary
Table 6
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters
Parameter (mmHg)
Post-Baseline Criteria
Systolic Blood Pressure, increase
DQGLQFUHDVHIURPEDVHOLQH
Systolic Blood Pressure, decrease
DQGGHFUHDVHIURPEDVHOLQH
Diastolic Blood Pressure, increase
DQGLQFUHDVHIURPEDVHOLQH
Diastolic Blood Pressure, decrease
DQGGHFUHDVHIURPEDVHOLQH
Subjects with potentially clinically significant values of SBP and DBP at any time post-baseline 
during a Study Treatment will be summarized by study drug based on the criteria in Table 6 (Table 
2.11 for the Safety Analysis Set).  All available data post-baseline including data from unscheduled 
visits will be used for the vital sign listing.
7.4.1
PK Substudy
Pharmacokinetic sample collection will occur prior to dosing and 15 minutes post-dose following 
doses 1 through 4. Additional PK samples will be collected following Dose 5 at 15, 30, 60, 120, 
180, 240, 300, 360, 480, 600, and 720 minutes post-dose. 
Actual sampling time points relative to dosing will be used for PK assessments and analysis where 
available. It is expected that the actual sampling time will generally be available. In any (likely 
rare) cases when the actual sampling time was not recorded, the scheduled time may be used. 
The concentration-time data reported by the bioanalytical laboratory will be evaluated for 
inclusion in the PK analysis dataset.
Pharmacokinetic parameters will be estimated for those subjects who are included in the PK 
Analysis Set and will be estimated by noncompartmental analysis (NCA) using the software 
Phoenix® WinNonlin® (Certara, US).  
From the plasma albuterol concentration-time data, the following PK parameters will be estimated 
for each subject where possible:  
AUC0-t
The area under the plasma concentration-time curve from 0 to the time of the last 
measurable plasma concentration post the final cumulative dose
Cmax
The maximum observed plasma concentration, expressed in concentration units
Tmax
The time to reach Cmax, expressed in hours 
C15min
The plasma concentration observed at 15 minutes post each cumulative dose
The AUC0-t will be calculated using the linear up-log down trapezoidal method. 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 29 of 46)
Confidential and Proprietary
The PK parameters C15min, Cmax, and Tmax will be obtained from the observed values.
For the purposes of parameter estimation, plasma concentration values below the lower limit of 
quantification (LLOQ) will be set to missing in the NCA with the exception of those values 
reported at pre-dose. Pre-dose concentrations that are below the limit of quantification (BLOQ) 
will be set to zero for the NCA. 
Missing values (e.g., no blood sample collected, no value obtained at analysis) will be treated as 
PLVVLQJDQGH[FOXGHGIURPWKH1&$,IWKHUHDUHFRQVHFXWLYHPLVVLQJFRQFHQWUDWLRQYDOXHVWKH
estimation of PK parameters will be evaluated on a case-by-case basis. 
For descriptive statistics of concentration-time data and for the concentration figures, all values 
below LLOQ will be assigned a value of ½ LLOQ except for pre-dose which will be assigned a 
value of 0 (no geometric mean will be calculated for pre-dose).
Descriptive statistics for plasma concentrations of albuterol by study drug and nominal timepoint 
will be summarized using the PK Analysis Set (Table 2.12.1). The number of observations, mean 
(CV%), standard deviation (SD), standard error (SE), median, minimum, maximum, geometric 
mean, and geometric coefficient of variation will be provided for the plasma concentration data at 
each respective timepoint with the exception of the pre-dose timepoint for which the geometric 
mean and geometric CV% will not be calculated.
Plasma concentration data falling outside the following time windows, will be excluded from 
summaries of individual timepoints but included in a listing: Pre-dose (within 30 minutes prior), 15 
minutes (+/- 5 minute) post any of the cumulative doses, and 30 minutes (+/- 5 minutes), 60
minutes (+/-5 minutes), 120 minutes (+/- 15 minutes), 180 minutes (+/- 15 minutes), 240 minutes
(+/- 15 minutes), 300 minutes (+/- 15 minutes), 360 minutes (+/- 15 minutes), 480 minutes (+/- 15
minutes), 600 minutes (+/- 15 minutes), and 720 minutes (+/- 15 minutes) post the last cumulative 
dose.  
Individual plasma concentrations by Subject ID, Study drug, and Timepoint will be listed using the 
Safety Analysis Set (Listing 6.5).  Actual sample collection times will be detailed in the listing.
The serum concentration-time profiles for mean and individual plasma concentrations of albuterol
will be presented for each study drug on the linear/linear scale (Figures 2.12.1.1 and 2.12.1.1a)
and on the linear/log-linear scale (Figures 2.12.1.2 and 2.12.1.1b). Nominal sampling timepoints 
relative to administration of the first cumulative dose will be used for all mean plots. Actual 
sampling timepoints will be used for all individual plots. The PK Analysis Set will be utilized for 
the mean concentration-time profiles, while the Safety Analysis Set will be utilized for individual 
concentration-time profiles.
Descriptive statistics for Cmax, AUC0-t, and Tmax of albuterol following the last cumulative dose 
will be summarized by study drug (Table 2.12.2). The number of observations, CV%, SD, median, 
minimum, maximum, geometric mean, and geometric coefficient of variation will be provided. For 
Tmax, only the number of observations, median, minimum, and maximum will be presented.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 30 of 46)
Confidential and Proprietary
The PK parameters for each study drug will be listed by subject ID and Treatment Period using the 
PK Analysis Set (Listing 6.6).
Natural log-transformed AUC0-t and Cmax values for albuterol will each be analyzed with a linear 
mixed effects model containing fixed effects for study drug and period. Subject will be included as 
a random effect. Estimated geometric mean ratios with 90% CIs will be provided (Tables 2.13).
The C15min values for albuterol after each cumulative dose will be analyzed with a power law 
model. Natural log-transformed C15min will be regressed onto the natural log transformed 
cumulative dose levels. The model will include fixed effects for period and study drug (AS MDI 
vs Proventil), and a random intercept. A test for study drug-by-ln-cumulative dose interaction will 
be conducted. If found to be non-significant at the 5% level, the interaction term will be dropped 
from the model, parallel slopes will be assumed, and the relative potency of AS MDI vs Proventil 
will be assessed (Finney, 1978; Table 2.14). If the linear or parallel line assumptions required for 
the Finney method appear to be violated, then an Emax model will be used to estimate relative 
potency.  The bias-corrected and accelerated bootstrap will be used to construct 90% CIs. While 
not a true assessment of dose proportionality, the proportionality of albuterol C15min after 
cumulative dose administration (cumulative doses of 90, 180, 360, 720, and 1440 μg) will be 
assessed using the above power law model with separate slopes.   The estimates of the slopes and 
corresponding 90% confidence intervals will be reported separately for each product (AS MDI vs
Proventil). Plots of the ln (concentration) by ln (cumulative dose) will be prepared for the PK 
parameter for albuterol sulfate (estimates with individual values plotted will be shown for each 
study drug, Figure 2.14; the slope with 90% confidence limits will be identified on the figures for 
each study drug).
7.4.2
Data Validation and Transformation
In general, the distribution of spirometry measures is well approximated by a normal distribution. 
Under some circumstances, however (e.g., during an exacerbation unrelated to study drug), 
extreme and atypical values can arise. Such values have high influence on estimation of variance 
parameters and on standard errors of fixed effect estimates. The distribution of scaled marginal 
residuals, and influence statistics will be examined to identify such cases. In the event that a single 
or small number of such outlying values are found to exist and found to be highly influential, the 
effects may be ameliorated by either transformation or removal of the outlier. Transformations to 
be considered may include the logarithmic transformation or normal rank transformations. Where 
outliers are removed, sensitivity analyses including those values will be reported.
Changes in spirometry measures from baseline and from timepoint to timepoint will be examined 
graphically before database lock, as part of data quality management.
7.5
Safety Analyses
All safety analyses are based on Safety Analysis Set.  Hypothesis testing will not be performed for 
any safety analyses.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 31 of 46)
Confidential and Proprietary
Time windows for lab, vital sign, and ECG listings (and Extrapulmonary PD tabulations described 
in Section 7.4.5.2) will be those used for spirometry (See Table 3 in Section 7.4.3.4).
7.5.1
Adverse Events
Adverse events will be collected and coded using the latest version (20.1 or later) of the Medical 
Dictionary for Regulatory Activities (MedDRA) available.  A glossary of MedDRA preferred 
terms used for AEs reported in the study along with the associated Investigator’s verbatim will be 
provided in Listing 7.2. The version of MedDRA current at the time of database lock, 21.0, will be 
used for the final analysis of data.
Adverse events occurring from the time the subject signs informed consent until the subject is 
randomized will be summarized as medical history and not as an AE unless the event meets the 
definition of an SAE as defined in Protocol Section 6.2.
An adverse event is considered treatment-emergent if the date of onset is on or after the date of 
first dose of study medication in the study.  An AE would be considered attributable to a treatment 
(corresponding to a treatment period or washout or final follow-up period) if the onset of the AE 
was during the treatment period (or washout period or final follow-up period).  Should there not be 
sufficient information to determine during which period that an AE started, the AE will be counted 
as having occurred in all treatment periods (and washout periods or final follow-up period) prior to 
the end date of the AE if this is reported as long as the subject received study drug during those 
treatment periods.  If both start and end date of an AE are unavailable, the AE will be counted in 
all treatment periods prior to the date of last contact on the Study Completion/Premature 
Termination eCRF (including the study drug taken on the day of the last contact) as long as the 
subject received study drug during those treatment periods.  Any AE with onset after the last 
treatment in the study will be attributed to this last treatment.  Adverse events after the Follow-up
Telephone Call scheduled 5-7 days after Visit 3 or a discontinuation visit will not be considered 
treatment-emergent, but will be listed in adverse event data listings.
Adverse Events Counting Rules per Treatment Period or Washout Period:
A subject with more than 1 different AE in a particular system organ class (SOC) will be 
1.
counted only once in the total of subjects experiencing AEs in that particular SOC.
A subject having experienced the same event (AE preferred term) more than once will be 
2.
counted only once in the number of subjects with that event.
Events with Irregular Start Dates: All AEs will be included in the tabulations regardless of the 
completeness of the onset dates. 
Missing/incomplete (partial) AE start and end dates will not be imputed for data listings.
Both the treatment and the washout periods include treatment with Pulmicort Flexhaler or 
Atrovent. AEs reported as starting during a Washout Period or the final follow-up period will be 
excluded from the main analyses of AEs.  As a supportive analysis, AEs will be assigned to the 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 32 of 46)
Confidential and Proprietary
last randomized study drug received including those occurring during the Washout Period or the 
final Follow-up Period (Table 3.2.2 for AEs and Table 3.6.2 for SAEs).  
All adverse events, whether treatment-emergent or not, will be included in the listings.  Reported 
adverse events by system organ class, preferred term, study drug, center, subject and onset day will 
be provided (Listing 7.1).  Reported adverse events by study drug, center, subject, and onset date 
will also be provided (Listing 7.3).  
The listing of adverse events will provide the severity, relationship to study drug, action taken and 
outcome for each adverse event.  Any SAEs reported will be listed (Table 3.7.1). Suspect drug 
assessment data associated with an SAE (collected on the Suspect Drug Assessment CRF) will be 
listed by SAE (Listing 4.6).   Adverse events leading to discontinuation of study medication will be 
listed (Table 3.5).  A listing of any reported deaths during the study will be provided (Table 3.10); 
the study drug taken most recently prior to the death and the number of days since the dose of this 
study drug at the time of the death will be included in the listing.  For the purpose of determining if 
a death occurred during a Treatment Period (for Table 3.1.1), the end of the Treatment Period will 
be defined as the date of the last day of the washout period following the Treatment Period, the 
date of the Discontinuation Visit in the Treatment Period, or if these dates are both missing, the 
date of the last data collection for the Treatment Period (i.e. date of death).
An overview summary table will be prepared.  The table will provide the incidences of subjects, 
for all subjects and for each study drug, with the following: at least 1 treatment-emergent adverse 
event, at least 1 treatment-emergent related adverse event, at least 1 treatment-emergent serious 
adverse event, at least 1 treatment-emergent serious related adverse event, at least 1 treatment-
emergent adverse event leading to Premature withdrawal, and a report of death (Table 3.1.1, 
washout treatment-emergent adverse events excluded).  As a supportive analysis, AEs will be 
assigned to the last randomized study drug received including those occurring during the Washout 
Period or the final follow-up period (Table 3.1.2).
The incidence of an AE for a study drug will be defined as the number and percent of subjects 
experiencing an event attributable to that study drug.  For each group, the following will be 
prepared for each study drug, for each primary system organ class, and for each preferred term 
within a system organ class:
The incidence of all treatment-emergent adverse events (Table 3.2.1)
1.
The incidence of non-serious treatment-HPHUJHQWDGYHUVHHYHQWVRFFXUULQJLQRIVXEMHFWV
2.
in a study drug (Table 3.2.4)
The incidence of all treatment-related treatment-emergent adverse events (Table 3.3)
3.
The incidence of treatment-emergent adverse events leading to study drug discontinuation 
4.
(Table 3.4)
The incidence of treatment-emergent serious adverse events (Table 3.6.1)
5.
The incidence of treatment-emergent serious related adverse events (Table 3.8)
6.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 33 of 46)
Confidential and Proprietary
The incidence of all treatment-emergent adverse events by highest severity (Tables 3.9.1-
7.
3.9.2). There will be a separate table for each study drug.
The incidence of treatment-emergent adverse events occurring in at least 2% of subjects in any
8.
study drug (Table 3.2.3, sorted by descending frequency of events in a preferred term). 
7.5.2
Clinical Laboratory Data 
Clinically Significant Laboratory Abnormalities as identified by the investigator after the start of 
study drug will be recorded as an Adverse Event and tabulated as an AE in the AE analysis.  
Abnormalities occurring prior to the start of study drug will be noted in medical history and 
presented in a data listing.  Per protocol, the criteria for a "clinically significant" laboratory 
abnormality are:
a.
A laboratory abnormality that leads to study drug dose suspension or discontinuation 
b. A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy)
c.
Any other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g.., significant fall in hemoglobin not requiring transfusion) 
For laboratory abnormalities that do not meet the above criteria but are outside of the normal 
reference range, the investigator should indicate whether the value is clinically significant or not 
clinically significant for the subject.
All laboratory data will be stored in the database with the units in which they are originally 
reported. Laboratory data in subject data listings will be presented in the International System of 
Units (SI units; Système International d’Unités) where available. Laboratory data not reported in 
SI units will be converted to SI units before further processing or data analysis. Individual clinical 
laboratory variables for hematology and clinical chemistry, including creatinine clearance (eGFR), 
at Visit 1, and for serum glucose and serum potassium at Visits 2 and 3, will be provided in listings 
(Listing 8.1 for central laboratory hematology, Listing 8.2 for central laboratory blood chemistry 
and kidney function). Comments for central laboratory testing will be listed (Listing 8.3). For 
listings, laboratory values will be flagged as Low or High based on the reference ranges provided 
by the central laboratory, 
. These flags along with the reference ranges will be provided in 
the laboratory data listings. 
7.5.3
Vital Signs
A Clinically Significant Abnormality in vital signs identified by the investigator will be recorded 
as an Adverse Event if it occurs after the start of study drug.  These adverse events will be 
included in the AE summaries; abnormalities prior to the start of study drug will be noted in 
medical history and listed.
Vital signs, height, weight, BMI, SBP, and DBP, will be listed (Listing 9.1). The analyses of the 
SBP and DBP parameters are described in the extrapulmonary PD parameter section.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 34 of 46)
Confidential and Proprietary
7.5.4
Electrocardiogram (ECG)
A Clinically Significant Abnormality for a 12-Lead ECG measurement identified by the 
investigator as a clinically significant abnormality will be recorded as an Adverse Event if it 
occurred after the start of study drug.  These adverse events will be included in the AE summaries.
The ECG parameters that will be assessed at Visit 1 include heart rate, RR interval, PR interval, 
QRS axis, QRS interval, QT interval, and QTcF (Fridericia’s Formula) interval.  The QTcF 
(Fridericia Corrected QT) is defined as [QT/(RR1/3)]. All 12-Lead ECG measurements for the 
Safety Analysis Set will be listed (Listing 9.2). 
At all other timepoints, only QTcF and heart rate will be assessed. The analyses of the QTcF and 
heart rate parameters are described in the extrapulmonary PD parameter section.
7.5.5
Physical Examination 
Any physical examination abnormality reported after the start of study drug for a subject is to be 
reported as an adverse event and included in the AE summaries.
8.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL 
The protocol was amended on 12 January 2018 to include spirometry assessments 180 and 300 
minutes post-dose) that were inadvertently omitted from Versions 1 and 2 of the protocol. Subjects 
randomized after this amendment have spirometry assessments at 180 and 300 minutes in addition 
to the timepoints outlined in Versions 1 and 2 of the protocol, while those subjects randomized 
prior to the amendment will not have the 180 and 300 minutes assessments.
 All subjects will be included in the efficacy 
analyses irrespective of their spirometry sampling scheme.
The protocol was amended again on 15 March 2018.  In this version, Version 4, the Per Protocol 
analysis set is defined and will serve as the primary analysis set for the extrapulmonary 
pharmacodynamic parameters. The originally planned Safety analysis set is anti-conservative in a 
non-inferiority/equivalence testing paradigm.  In addition, the specification of maximum change 
from baseline and time-weighted average change from baseline, both after the last cumulative 
dose, were added to the analyses of extrapulmonary PD parameters. 
Section 8.5.5.3 of the protocol describes analysis of natural log-transformed AUC0-t and Cmax
values for albuterol post the final cumulative dose.  To be consistent with cumulative dose studies 
of other albuterol products, the calculation of AUC0-t will be implemented using all available 
concentration measurements including the C15min values obtained subsequent to each cumulative 
dose. That is, all available concentration values for a given treatment period will be included in the 
NCA rather than only those following the final cumulative dose. 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 35 of 46)
Confidential and Proprietary
9.
STATISTICAL SOFTWARE
Data processing, statistical screening, descriptive reporting, and analysis of the efficacy, 
pharmacokinetic, and safety data will be performed using SAS (Version 9.4 or higher). Version 6.4 
of Phoenix® WinNonlin® (Certara, US) will be used for the pharmacokinetic NCA analysis. 
10.
REFERENCES
Berger, RL, Hsu, JC. (1996) Bioequivalence Trials, Intersection-Union Tests and Equivalence 
Confidence Sets. Statistical Science 1996; Vol. 11, No. 4, 283-319.
Finney, D.J. (1978). Statistical Method in Biological Assay, 3rd Ed. Griffin, London
Kenward, MG, Roger, JH. (2010) The use of baseline covariates in cross-over studies. Biostatistics 
2010; 11: 1–17.
Miller et al 2005.  Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur 
Respir J 2005; 26(2):319-338.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 36 of 46)
Confidential and Proprietary
APPENDIX 1 DATA HANDLING RULES
Programming of the tables, listings and figures will be performed using SAS Version 9.4 or a more 
recent version.  The following table presents algorithms (not stated elsewhere) to be used in SAS 
to calculate the derived variables, including rules for handling missing data or partial dates, or 
irregular/unexpected data issues.
Category
Description
Data Handling Rules
Pulmonary 
Function 
Testing Data  
 data transferred
x
Only data of rank =1 (best effort) will be 
transferred; data transferred will be grade 1 = 
acceptable, grade 2 = borderline, or grade = 3 
(unacceptable).  Only data of grade = 1 or 
grade = 2 will be included in baseline or 
on-treatment spirometry calculations.
x
All data transferred from
 
 (grade = 1, 2, or 3) will be 
listed in data listings with the grade.
Age (years)
Age (years)
Age = integer part of ((Visit 1 date – Birth date + 
1)/365.25) 
Smoking 
History
Number of pack years 
smoked 
Number of pack years smoked = (number of 
cigarettes per day/20) x number of years smoked.  
It is zero if the number of years smoked is zero or 
if the subject is a non-smoker. 
BMI
Body Mass Index
BMI = (weight(kg))/(height(cm)/100)2
Asthma History
Months Since Diagnosis
Months Since Diagnosis = (Date of First Dose of 
Study Drug in the study – Date Asthma First 
Diagnosed)/30.475.  
Missing Date Asthma First 
Diagnosed
Day of Diagnosis will be imputed for all subjects 
as the 1st of the month.   
Missing month of Date 
Asthma First Diagnosed
Missing month of Diagnosis will be imputed as 
June, or the month in which 1st will be the latest 
before informed consent date, whichever is 
earliest.
Medical 
History  
Medical History Begin 
Date of Condition 
Missing month of Condition will be imputed as 
June, or the month in which 1st will be the latest 
before informed consent date, whichever is 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002) 
Last Revision Date: 30 Mar 2018 
(Page 37 of 46)
Confidential and Proprietary
Category
Description
Data Handling Rules
earliest.  Begin date of Condition will be imputed 
for all subjects as the 1st of the month.
Medical History End Date 
of Condition 
Other than for ‘Ongoing’ conditions, missing 
month of End Date of Condition will be imputed 
as June, or the month in which 1st will be the 
latest before informed consent date, whichever is 
earliest.  End date of Condition will be imputed 
for all subjects as the 1st of the month.
Surgical 
History  
Surgical History Date of 
Surgery
Missing month of Surgery will be imputed as 
June, or the month in which 1st will be the latest 
before informed consent date, whichever is 
earliest.  Begin date of Surgery will be imputed 
for all subjects as the 1st of the month.
Screening 
Reversibility
Screening Percent 
Reversibility
The screening percent reversibility to Ventolin is 
100 x [post-Ventolin FEV1 – pre-Ventolin
FEV1)]/ [pre-Ventolin FEV1].   
For this definition, “post-Ventolin FEV1” and 
“pre-Ventolin FEV1” are the best effort values 
obtained after the dose of Ventolin and before the 
dose of Ventolin, respectively.  
First and Last 
Treatment 
Dates
Date/time of first dose of 
the first study drug taken 
in the study and the 
date/time of the last dose 
of the last study drug taken 
in the study. 
The date and time (24 hr. clock) of the dose of 
study drug will be taken from the Study Drug 
Administration eCRF.  The time of the last dose 
of study drug will be the last time of dosing from 
the 
 dataset.
Last Visit Date
Date of Last Visit
Date of last Visit according to the Visit eCRF.
Last Study 
Participation 
Date (STDM 
variable, 
RFPENDTC)
Last Study Participation 
Date (STDM variable, 
RFPENDTC)
Last study participation date is defined as last 
known date of contact which would be the later 
of the following dates: last visit date, date of the 
last dose, date of last contact if lost-to-follow-up, 
date of telephone follow-up, or death date.   
Study Day 
Definitions
Study Day for 
assessment/event which 
occurs on or after the date 
of a study drug
Study Day = Date of assessment/event – date of 
the dose of study drug + 1. 
Within-Period Study Day 
for an on-treatment 
Within-Period Study Day = Date of 
assessment/event – date of dose of study drug 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 38 of 46)
Confidential and Proprietary
Category
Description
Data Handling Rules
assessment/event study 
drug
within the respective Treatment Period + 1.
Study Day for 
assessments/events on 
days prior to the dose of 
the first study drug in the 
study
Study Day = date of assessment/event - dose date 
of study drug in the study.
Study Day Post-
Treatment of Assessment 
or event which occurs after 
a study drug
Study Day = ‘P’ concatenated with the number of 
days post-treatment that the assessment or event 
occurred which is defined as Date of 
assessment/event – date of dose of study drug in 
the last period (i.e. most recent study drug).
Study Day of 
Randomization
Study Day of Randomization = date of 
randomization – date of the first dose of study 
drug in the study if date of randomization is 
before date of first dose of study drug.  Study 
Day is 1 if the day of first study drug in the study 
is on the day of randomization.
First Dose Date
First Dose Date in the study is defined as the 
date of the first dose of study drug in the study.
Last Dose Date
Last Dose Date in the study is defined as the 
date of the last dose of study drug in the study 
(defined as the last date of dosing from the Study 
Drug Administration eCRF).
Last Study Day
For subjects who did not receive study drug in 
the study (e.g., Non-Randomized Subjects),
Last Study Day is defined as (the later of the last 
visit date or the date of last contact for subjects 
lost-to-follow-up from the End of Treatment 
eCRF) – Date of Screening Visit + 1. 
For subjects who received study drug in the 
study, Last Study Day is defined as (the later of 
the last visit date or the date of last contact for 
subjects lost-to-follow-up from the End of 
Treatment eCRF) – first dose date in the study + 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 39 of 46)
Confidential and Proprietary
Category
Description
Data Handling Rules
1.
Days Since Last Dose for 
event (e.g., Death)
Days Since Last Dose is defined as date of event 
– date of last dose of study drug.
Treatment Day
Treatment Day 1 is the study day of the dose of a 
study drug. 
Treatment 
Period
Treatment Period
A treatment period for a study drug is the date of 
the dose of the study drug (Treatment Day 1 of a 
study drug)
Duration of 
Event
The duration of any event 
(not including duration of 
asthma)
The duration of any event is defined as (stop date 
– start date + 1).
Duration of 
Asthma
Duration of asthma 
(months)
The duration of asthma = (first dose date of study 
drug – date asthma first diagnosed)/30.475, 
where the day of asthma diagnosed is assumed to 
be the 1st of the month. 
Multiple 
Assessments for 
the Same Visit
Laboratory, Vital Signs, 
and ECG assessments
x
All data will be listed in data listings.
x
The last non-missing assessment of multiple 
valid assessments within a pre-dose or post-
dose study time window will be used for 
change from baseline summaries; it will not 
apply to maximum change from baseline and 
AUC summaries. All values will be used for 
AUC summaries.
Spirometry 
Assessments
Spirometry assessments
x
For the change from baseline in FEV1 by 
timepoint analysis, if there are multiple 
spirometry values for the same parameter 
within the same post-dose study time window 
on the same day, the last value will be chosen 
for analysis with one exception: if multiples 
with the exact same time (in minutes and 
seconds) occur within a window, then the last 
value based on the nominal time window will 
be chosen for analysis.  Queries to the site 
(prior to database lock and unblinding) will 
be used to ascertain which assessment 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 40 of 46)
Confidential and Proprietary
Category
Description
Data Handling Rules
actually occurred first. 
x
For AUC parameters, all post-baseline 
assessments in the study time window will be 
used for calculation of AUC for summaries.
AUC calculation
for spirometry 
endpoints
AUC0-6 and AUC04
AUC0-6 and AUC0-4 will be calculated using the 
trapezoidal rule and actual time of assessment 
when available and nominal time of assessment 
otherwise.
Special Lab 
Value Handling 
Lab values with a prefix 
such as: ‘>’, ‘<’, ‘+’ and 
‘Less than’ etc.…
x
‘>’: use the available original value +0.001 in 
the analyses.
x
‘<’: use the available original value –0.001 in 
the analyses.
x
‘+’: use the available original value without 
the prefix in the analyses.
x
‘>=’: use the available original value in the 
analyses.
x
‘<=’: use the available original value in the 
analyses.
Prior, 
Concomitant, 
and Post-
treatment 
Medication/
Treatment
Prior, concomitant, and 
post-treatment 
medication/treatment
1. Prior medication/treatment is any 
medication/treatment taken prior to Visit 1, 
even if this medication continued after Visit 
1.  A medication/treatment will be considered 
prior if:
a.
The start and end date of the 
medication/treatment are missing, or
b. The start date is missing and the end date 
is on or after Visit 1, or
c.
Either the medication/treatment start date 
or end date or both are before Visit 1. 
2. Concomitant medication/treatment is any 
medication/treatment taken on or after Visit 
1and on or before the date prior to the last 
dose of study drug for the subject.  A 
medication/treatment will be identified as 
concomitant if:
a.
Medication/treatment start date is after 
Visit 1 to the date prior to the last dose of 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 41 of 46)
Confidential and Proprietary
Category
Description
Data Handling Rules
study drug, or
b. The end date is after Visit 1 to the date 
prior to the last dose of study drug for the 
subject, or
c.
‘Ongoing’ is checked.
3. A medication with an onset date on or after 
the last dose of study drug for the subject will 
not be considered concomitant, but will be 
considered a Post-Treatment 
medication/treatment.
4. Any medication/treatment which cannot be 
identified as Prior, Concomitant, or Post-
Treatment will be considered as being in each 
of the categories that are possible from the 
available information.
Adverse Event
Missing severity
For the AE summary by severity, an AE with 
missing severity will be deemed as Severe.  
Imputed values will not be listed in data listings.
Missing relationship to 
study drug
For AE summary by relationship, an AE with a 
missing relationship to study drug (yes/no) will 
be deemed as Related.  Imputed values will not 
be listed in data listings. 
Treatment-emergent 
adverse event
An adverse event is considered treatment-
emergent if the date of onset is on or after the 
date of first dose of study drug.  The study site 
will enter a new onset date when there is an 
increase in severity or intensity for a pre-existing 
event after the start of a study drug.
If the AE start date is partial/missing, then
x
If AE start date is completely missing, then 
the AE is considered as treatment emergent.
x
If both AE start month and day are missing 
and AE start year is the same or after the first 
dose year, then the AE is considered as 
treatment emergent.
x
If AE start day is missing and AE start year 
and month are the same or after the first dose 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 42 of 46)
Confidential and Proprietary
Category
Description
Data Handling Rules
year and month, then the AE is considered as 
treatment emergent.
Missing/incomplete (partial) AE start and end 
dates will not be imputed for data listings.
Exposure 
(hours)
Exposure (hours) (Study 
drug Duration)
Exposure is defined as [Time (hr:min) of the last 
dose of a study drug – time (hr:min) of first dose 
of a study drug + 1].  
Hard Coding
Hard Coding
Hard Coding is not allowed during data analysis 
unless it is agreed to in writing by the Sponsor.
PK analysis 
Considerations to be made 
in the calculation of AUC 
The following considerations will be made in the 
calculation of AUC:
x
AUC will be calculated by the linear up-log
down trapezoidal method. 
x
All values below LLQ will be ignored (set to 
missing) in the non-compartmental analysis. 
For the purposes of parameter estimation, 
plasma concentration values below the lower 
limit of quantification (LLOQ) will be set to 
missing in the NCA with the exception of 
those values reported at pre-dose. Pre-dose 
concentrations that are below the limit of 
quantification (BLOQ) will be set to zero for 
the NCA. 
x
Missing values (e.g., no blood sample 
collected, no value obtained at analysis) will 
be treated as missing and excluded from the 
1&$,IWKHUHDUHFRQVHFXWLYHPLVVLQJ
concentration values, the estimation of PK 
parameters will be evaluated on a case-by-
case basis. 
x
For descriptive statistics and the figures, all 
values below LLQ will be assigned a value of 
½ LLQ except for pre-dose which will be 
assigned a value of 0 (no geometric mean will 
be calculated for pre-dose).


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 43 of 46)
Confidential and Proprietary
APPENDIX 2 ANALYSIS DATASET SPECIFICATIONS 
Analysis datasets will be built to gain efficiency and ensure consistency in data analyses and 
presentation for this trial.  The specifications for each analysis data set will be prepared separately 
and will not be a part of this SAP.


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 44 of 46)
Confidential and Proprietary
APPENDIX 3 SAS CODE FOR STATISTICAL ANALYSES
Test
Template SAS Code for Modeling (SAS Version 9.4)
Linear Mixed 
Model analysis 
for a continuous 
efficacy 
endpoint 
involving 
multiple 
measures per 
period.  Use this 
code for the 
primary analysis 
involving Doses 
1-5
*RUN THIS MODEL FOR 30 MIN POST-DOSE TIMEPOINT 
DATA for the PRIMARY EFFICACY ANALYSIS; to obtain 
estimates for the plots associated with this analysis, run a second 
model using all timepoints post-dose;
PROC MIXED PLOTS (ALL) METHOD=REML;
CLASS SUBJECT PERIOD TRT DOSE ;
MODEL Y = BASE PERIOD TRT DOSE TRT*DOSE
/ DDFM=KENWARDROGER SOLUTION OUTP=OUT;
RANDOM SUBJECT;
REPEATED DOSE / TYPE=UN 
SUBJECT=SUBJECT*PERIOD;
LSMEANS TRT TRT*DOSE / PDIFF CL ALPHA=0.10 
CORR COV; *to obtain 90% Cis for non-inferiority 
testing;
LSMEANS TRT TRT*DOSE / PDIFF CL ALPHA=0.05 
CORR COV; *to obtain 95% Cis for the ls mean change
from baseline for each treatment;
ODS OUTPUT LSMEANS=MEANS;
ODS OUTPUT DIFFS=DIFF;
RUN;
Where BASE is the baseline value of the endpoint, TRT is the treatment, 
DOSE is the number (1 to 5) of the dose of the repeated measurement 
within the period.
The non-inclusion of SEQUENCE in the model is in accordance with the 
SAP text.
THE PLOTS (ALL) OPTION FOR PROC MIXED WILL BE USED TO 
GET PLOTS TO PERFORM MODEL DIAGNOSTICS. Influence 
statistics will be requested.
Linear Mixed 
Model analysis 
for a continuous 
efficacy 
endpoint, AUC.
PROC MIXED PLOTS (ALL) METHOD=REML;
CLASS SUBJECT PERIOD TRT ;
MODEL Y = BASE PERIOD TRT
/ DDFM=KENWARDROGER SOLUTION UTP=OUT;
RANDOM SUBJECT;
LSMEANS TRT / PDIFF CL ALPHA=0.10 
CORR COV; *to obtain 90% Cis for non-inferiority 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 45 of 46)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
testing;
LSMEANS TRT / PDIFF CL ALPHA=0.05 
CORR COV; *to obtain 95% Cis for the ls mean change
from baseline for each treatment;
ODS OUTPUT LSMEANS=MEANS;
ODS OUTPUT DIFFS=DIFF;
RUN;
Where BASE is the baseline value of the endpoint and TRT is the 
treatment.
The non-inclusion of SEQUENCE in the model is in accordance with the 
SAP text.
THE PLOTS (ALL) OPTION FOR PROC MIXED WILL BE USED TO 
GET PLOTS TO PERFORM MODEL DIAGNOSTICS. Influence 
statistics will be requested.
Linear Mixed 
Model analysis 
for a continuous 
efficacy 
endpoint 
involving 
multiple 
measures per 
period. Use this 
code for the 
secondary 
analyses of the 
Extrapulmonary 
PD parameters at 
15 minutes post 
doses 1 to 4 and 
30, 60, 120, 180, 
240, 300, and 
360 minutes 
after the last 
cumulative dose 
(Dose 5).
PROC MIXED PLOTS (ALL) METHOD=REML;
CLASS SUBJECT PERIOD TRT DOSETIME;
MODEL Y = PERBASE PERIOD TRT AVEBASE DOSETIME 
TRT*DOSETIME
/ DDFM=KENWARDROGER SOLUTION OUTP=OUT;
RANDOM SUBJECT;
REPEATED DOSETIME / TYPE=UN 
SUBJECT=SUBJECT*PERIOD;
LSMEANS TRT TRT*DOSETIME / PDIFF CL ALPHA=0.10 
CORR COV;
ODS OUTPUT LSMEANS=MEANS;
ODS OUTPUT DIFFS=DIFF;
RUN;
Where BASE is the baseline value of the endpoint, TRT is the treatment, 
DOSETIME is the number (1 to 4) of the dose and the multiple times after 
the last cumulative dose (Dose 5) of the repeated measurement within the 
period. 
The non-inclusion of SEQUENCE in the model is in accordance with the 
SAP text.
THE PLOTS (ALL) OPTION FOR PROC MIXED WILL BE USED TO 


Statistical Analysis Plan
Protocol No. D6930C00002 (PT007002)
Last Revision Date: 30 Mar 2018
(Page 46 of 46)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
GET PLOTS TO PERFORM MODEL DIAGNOSTICS. Influence 
statistics will be requested.
Finney method
for relative 
potency
Finney method for relative potency for C15min;
proc mixed data=<analysis dataset>;
class usubjid period treatment;
model laval=period treatment ldose/ddfm=kr solution covb; 
repeated period/type=un subject=usubjid;
estimate 'a1' int 1 treatment 1 0 period 0 0 0 1 ldose 0; *ASI intercept estimate;
estimate 'a2' int 1 treatment 0 1 period 0 0 0 1 ldose 0; *Proventil intercept 
estimate;
estimate 'b' ldose 1; *common slope (a test for parallelism will be performed 
before assuming a common slope;
run;
*where laval is the natural log of response and ldose is the natural log of 
cumulative dose level;
If the assumptions of linearity and parallelism do not hold, an Emax model will be 
used instead of the Finney method, and will use a bias-corrected accelerated 
bootstrap confidence interval.
APPENDIX 4 MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS)
Mockup tables, listings, and graphs are presented in a separate document.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 1 of 100
APPENDIX 4
SPECIFICATION OF END-OF-TEXT STANDARD OUTPUT
TABLES, LISTINGS, AND FIGURES (TLFs)
Protocol Title: Albuterol Sulfate Pressurized Inhalation Suspension (PT007) Cumulative Dose 
Study in Subjects With Mild to Moderate Asthma
D6930C00002 (PT007002)
Trial Sponsor: 
AstraZeneca AB
Study Number:
D6930C00002 (PT007002)
Study Phase:
II
Product Name:
Albuterol Sulfate Pressurized Inhalation Suspension (AS MDI); PT007
PIND Number:
136213
Indication:
Asthma 
Dosage 
Form/Strength/Dose
x
AS MDI 90 μg ex-actuator dosing sequence as
o
1 actuation (90 μg)
o
1 actuation (90 μg)
o
2 actuations (180 μg)
o
4 actuations (360 μg)
o
8 actuations (720 μg)
for a cumulative dose of 1440 μg
Date of Issue:
30 Mar 2018
Version
1.0


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 2 of 100
Change Log
Version No.
Effective Date
Reason for the Change/Revision
Supersedes


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 3 of 100
General Instructions for End-of-Text TFLs
Following are the specifications for end of text standard tables, listings, and figures (TFLs).
Header
The following header should appear at the very top of each page of a table, a listing, or a figure (TLF):
Protocol D6930C00002 (PT007002)
Albuterol Sulfate Pressurized Inhalation Suspension
Footer
The following footer should appear at the bottom of each page of a TLF generated in SAS:
Report generated by program:/sasdir/PGNAME.sas  Version YYYY-mm-dd hh:mm (Page n of N)
where: PGNAME = SAS program name. Version will be replaced by “Draft” or “Final”.  Page number will be right-justified.
Title
At least two (2) lines should be reserved for the whole title. The first line of the title is for the TLF number (i.e., title index #) and 
the actual title (title); a longer title may continue onto subsequent lines. The analysis set descriptor (Analysis Set) will be 
specified on the line following the title line(s). All titles should be centered, as shown in the following example: 
Table 1.5.3
Demographics
Analysis Set: Safety Analysis Set
Footnotes
x
In general, a footnote serves as a brief explanation/clarification/definition/concept of a flag symbol or a character, an 
abbreviation, a terminology, etc., that appears in or related directly to the displayed content of a TLF. Detailed/technical 
elaboration of, for example, a mathematical/statistical formula, a statistical term/test, or an algorithm for deriving a 
parameter value, should be addressed in the text of the statistical analysis plan (SAP).
x
All footnotes should follow immediately after a horizontal solid line. There should be one and only one space between the 
last footnote and the footer. 
x
Each line of a complete footnote should end with a period. When a footnote needs more than 1 line, one (1) period is 
needed.
x
Large data listings will have footnotes on the first page only.
Row Labels/Column Labels: The mockups will reflect the preferred style of capitalization.
Page Layout
x
All output should be in landscape orientation. A margin of 1.5, 1, 1, and 1 inch should be on the top, right, left, and bottom, 
respectively. 
x
All efforts should be made to present all Treatment groups in one page.
x
When 3 or more Treatment groups are designed for a study and if it is not possible to fit all of them in one page, the 4th and 
5th treatment groups should be displayed on the 2nd page, etc. The Study Biostatistician will pre-determine the order for the 
display of the treatment groups. 
Page Format
x
There should be a solid line at the top of the tables and listings just below the title.
x
There should be a solid line just below the column headings that runs completely across the width of the tables and listings.
x
There should be a solid line at the bottom of the tables and listings just above the footnote(s) on every page.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 4 of 100
Font
x
The default font to be used in the actual study tables/listings should be Courier New 8 point which is approximately 
equivalent to the acceptable font size of Times New Roman 9-10 in accordance with the FDA’s guidance on Electronic 
Common Technical Document Specification. 
x
The use of Courier New 7 point is optional for some tables/listings and will be determined at the study level by the Study 
Biostatistician and Study Programmer. However, it is recommended that this option be used primarily for data listings.
Descriptive Statistics
By default, descriptive statistics in this template covers: n, Mean, Median, Standard Deviation (SD), Minimum (Min), and 
Maximum (Max). Unless otherwise specified in the actual table shells, the mean, standard deviation, standard error of the mean, 
and median should be displayed to one more decimal place than the original data. The standard error of the mean will be 
displayed with at least 2 significant digits for efficacy tables.
Rounding for Percentage
Unless specified in the actual table shells for a study, all percentages will be rounded to 1 decimal place in all TLFs.  Percentage 
signs will not be included in the body of the table (i.e., 99.9 will be displayed, not 99.9%), but may be included in row or column 
headings.
Unless specified in the actual table shells for a study, p-values will be presented with 4 decimal places.
Alignment of Decimals
x
It is recommended that all the decimal places be aligned in summary tables, as shown in the following example:
Decimal Align
n
xxx
Mean
xx.xx
SD
xx.xx 
Median
xx.xx
Minimum, Maximum
xx.x, xx.x
x
When numbers with decimal points are included in brackets (e.g., percentages), have the brackets aligned to the right and 
then padded to allow for all possible percentages and then the left brackets will also be aligned. For example:
Brackets Align
(99.9)
(xx.x)
(  9.9)
(  x.x)
x
It is recommended that all column entries in a summary tables and listings are aligned to the center.
x
Columns for text fields are all left justified. Columns with whole numbers are all right justified.
x
For graphs, the lines are distinguishable and that the symbols for each line are appropriate. Legend is consistent across 
output for Treatment names and abbreviations.
Use of N Versus n
x
N = total number of subjects in the defined analysis set.
x
n = total number of subjects in the specific category.
x
If N is specified in the column heading then any reference to the number of subjects in the body should be small n, as 
shown in the following example: 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 5 of 100
Demographic Parameter
Treatment 
Group A
(N=XXX)
Treatment 
Group B
(N=XXX)
Total
(N=XXX)
Age (years)
n
xxx
xxx
xxx
Mean
xx.x
xx.x
xx.x
SD
          x.x
          x.x
          x.x
Median
xx.x
xx.x
xx.x
Minimum, Maximum  
xx, xx
xx, xx
xx, xx
A Note for Subject Data Listings
x
Observed Dates/AE Severity/Relationship to investigational product are used in subject data listings.
x
Observed values or raw assessment scores are used in data listings along with their derived values used in analyses, e.g., raw 
assessment scores and derived total scores.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 6 of 100
Table of Contents
1. 
SUBJECT DISPOSITION, DEMOGRAPHIC, BASELINE, AND OTHER SUMMARY
TABLES........................................................................................................................................... 16 
Table 1.1.1 
Subject Disposition ........................................................................................................16 
Analysis Set: All Screened Subjects 
Table 1.1.2 
Reasons for Subjects Not Randomized ..........................................................................18 
Analysis Set: All Screened Subjects Not Randomized 
Table 1.1.3 
Exclusions From ITT, mITT, Safety, Per Protocol and PK Analysis Sets.....................19 
Analysis Set: All Subjects 
Table 1.2.1 
Reasons for Premature Treatment Discontinuation........................................................20 
Analysis Set: ITT Analysis Set 
Table 1.2.2 
Reason for Premature Treatment Discontinuation .........................................................20 
Analysis Set: Safety Analysis Set 
Table 1.3 
Analysis Sets by Treatment............................................................................................21 
Analysis Set: All Subjects Randomized 
Table 1.4.1 
Reason for Exclusion From the mITT Analysis Set.......................................................22 
Analysis Set: ITT Analysis Set 
Table 1.4.2 
Reason for Exclusion From the Per Protocol Analysis Set ............................................22 
Analysis Set: Safety Analysis Set 
Table 1.5.1 
Demographics and Baseline Characteristics ..................................................................23 
Analysis Set: All Subjects 
Table 1.5.2 
Demographics and Baseline Characteristics ..................................................................24 
Analysis Set: ITT Analysis Set 
Table 1.5.3 
Demographics and Baseline Characteristics ..................................................................24 
Analysis Set: Safety Analysis Set 
Table 1.5.4 
Demographics and Baseline Characteristics ..................................................................25 
Analysis Set: Per Protocol Analysis Set 
Table 1.5.5 
Demographics and Baseline Characteristics ..................................................................25 
Analysis Set: All Subjects Not Randomized 
Table 1.6.1 
Duration of Asthma........................................................................................................26 
Analysis Set: mITT Analysis Set 
Table 1.6.2 
Duration of Asthma........................................................................................................26 
Analysis Set: ITT Analysis Set 
Table 1.6.3 
Duration of Asthma........................................................................................................26 
Analysis Set: Safety Analysis Set 
Table 1.6.4 
Duration of Asthma........................................................................................................26 
Analysis Set: Per Protocol Analysis Set 
Table 1.7.1 
Screening Pre- and Post-Bronchodilator Spirometry Parameters...................................27 
Analysis Set: mITT Analysis Set 
Table 1.7.2 
Screening Pre- and Post-Bronchodilator Spirometry Parameters...................................28 
Analysis Set: ITT Analysis Set 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 7 of 100
Table 1.8.1 
Reversibility to Ventolin HFA at Screening ..................................................................29 
Analysis Set: mITT Analysis Set 
Table 1.8.2 
Reversibility to Ventolin HFA at Screening ..................................................................29 
Analysis Set: ITT Analysis Set 
Table 1.9 
Medical/Surgical History ...............................................................................................30 
Analysis Set: Safety Analysis Set 
Table 1.10.1 
Prior Medications – Asthma-Related .............................................................................31 
Analysis Set: Safety Analysis Set 
Table 1.10.2 
Prior Medications-Non-Asthma-Related........................................................................31 
Analysis Set: Safety Analysis Set 
Table 1.11.1a 
Concomitant Medications During Treatment Period – Asthma-Related........................32 
Analysis Set: Safety Analysis Set 
Table 1.11.1b 
Concomitant Medications During Washout Period – Asthma-Related..........................32 
Analysis Set: Safety Analysis Set 
Table 1.11.2a 
Concomitant Medications During Treatment Period-Non-Asthma-Related ..................32 
Analysis Set: Safety Analysis Set 
Table 1.11.2b 
Concomitant Medications During Washout Period-Non-Asthma-Related ....................32 
Analysis Set: Safety Analysis Set 
2. 
EFFICACY, EXTRAPULMONARY PD, AND PHARMACOKINETICS SUMMARY 
TABLES AND FIGURES................................................................................................................ 33 
PRIMARY EFFICACY ENDPOINT ......................................................................................................... 33 
Table 2.1.1 
Change from Baseline in FEV1 (L) 30 Minutes Post Each of the Cumulative Doses ....34 
Analysis Set: mITT Analysis Set 
Figure 2.1.1.1 
Mean Change From Baseline in FEV1 ± SE (L) 30 Minutes Post Each of the 
Cumulative Doses and Over the 6 Hours Following the Last Cumulative Dose............35 
Analysis Set: mITT Analysis Set 
SECONDARY EFFICACY ENDPOINTS................................................................................................. 36 
Table 2.2.1 
Change from Baseline in FEV1 AUC0-6 (L) After the Last Cumulative Dose................37 
Analysis Set: mITT Analysis Set 
EXTRAPULMONARY PD........................................................................................................................ 38 
Table 2.3.1.1 
Change from Baseline in QTcF (ms) 15 Minutes Post Each of the Cumulative 
Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last Cumulative 
Dose ...............................................................................................................................38 
Analysis Set: PP Analysis Set 
Figure 2.3.1.1 
Adjusted Mean Change From Baseline in QTcF ± SE (ms) 15 Minutes Post Each of 
the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose....................................................................................................38 
Analysis Set: PP Analysis Set 
Table 2.3.1.2 
Maximum Change from Baseline in QTcF (ms) Over the 6 Hours Post the Last 
Cumulative Dose............................................................................................................38 
Analysis Set: PP Analysis Set 
Table 2.3.1.3 
Time-Weighted Average Change from Baseline in QTcF (ms) Over the 6 Hours 
Post the Last Cumulative Dose ......................................................................................38 
Analysis Set: PP Analysis Set 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 8 of 100
Table 2.3.2.1 
Change from Baseline in QTcF (ms) 15 Minutes Post Each of the Cumulative 
Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last Cumulative 
Dose ...............................................................................................................................39 
Analysis Set: Safety Analysis Set 
Figure 2.3.2.1 
Adjusted Mean Change From Baseline in QTcF ± SE (ms) 15 Minutes Post Each of 
the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose....................................................................................................39 
Analysis Set: Safety Analysis Set 
Table 2.3.2.2 
Maximum Change from Baseline in QTcF (ms) Over the 6 Hours Post the Last 
Cumulative Dose............................................................................................................39 
Analysis Set: Safety Analysis Set 
Table 2.3.2.3 
Time-Weighted Average Change from Baseline in QTcF (ms) Over the 6 Hours 
Post the Last Cumulative Dose ......................................................................................39 
Analysis Set: Safety Analysis Set 
Table 2.4.1.1 
Change from Baseline in Heart Rate (ms) 15 Minutes Post Each of the Cumulative 
Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last Cumulative 
Dose ...............................................................................................................................39 
Analysis Set: PP Analysis Set 
Figure 2.4.1.1 
Adjusted Mean Change From Baseline in Heart Rate ± SE (ms) 15 Minutes Post 
Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose.....................................................................................39 
Analysis Set: PP Analysis Set 
Table 2.4.1.2 
Maximum Change from Baseline in Heart Rate (bpm) Over the 6 Hours Post the 
Last Cumulative Dose....................................................................................................41 
Analysis Set: PP Analysis Set 
Table 2.4.1.3 
Time-Weighted Average Change from Baseline in Heart Rate (bpm) Over the 6 
Hours Post the Last Cumulative Dose............................................................................41 
Analysis Set: PP Analysis Set 
Table 2.4.2.1 
Change from Baseline in Heart Rate (ms) 15 Minutes Post Each of the Cumulative 
Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last Cumulative 
Dose ...............................................................................................................................41 
Analysis Set: Safety Analysis Set 
Figure 2.4.2.1 
Adjusted Mean Change From Baseline in Heart Rate ± SE (ms) 15 Minutes Post 
Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose.....................................................................................41 
Analysis Set: Safety Analysis Set 
Table 2.4.2.2 
Maximum Change from Baseline in Heart Rate (bpm) Over the 6 Hours Post the 
Last Cumulative Dose....................................................................................................41 
Analysis Set: Safety Analysis Set 
Table 2.4.2.3 
Time-Weighted Average Change from Baseline in Heart Rate (bpm) Over the 6 
Hours Post the Last Cumulative Dose............................................................................41 
Analysis Set: Safety Analysis Set 
Table 2.5.1 
Listing of ECGs Meeting QTcF Interval Prolongation Criteria.....................................42 
Analysis Set: Safety Analysis Set 
Table 2.5.2 
Listing of Potentially Clinically Significant Tachycardia and Bradycardia Events .......42 
Analysis Set: Safety Analysis Set 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 9 of 100
Table 2.6.1.1 
Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the 
Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last 
Cumulative Dose............................................................................................................42 
Analysis Set: PP Analysis Set 
Figure 2.6.1.1 
Adjusted Mean Change From Baseline in Serum Glucose ± SE (mmol/L) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................42 
Analysis Set: PP Analysis Set 
Table 2.6.1.2 
Maximum Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post 
Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose.....................................................................................42 
Analysis Set: PP Analysis Set 
Table 2.6.1.3 
Time-Weighted Average Change from Baseline in Serum Glucose (mmol/L) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................42 
Analysis Set: PP Analysis Set 
Table 2.6.2.1 
Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the 
Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last 
Cumulative Dose............................................................................................................43 
Analysis Set: Safety Analysis Set 
Figure 2.6.2.1 
Adjusted Mean Change From Baseline in Serum Glucose ± SE (mmol/L) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................43 
Analysis Set: Safety Analysis Set 
Table 2.6.2.2 
Maximum Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post 
Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose.....................................................................................43 
Analysis Set: Safety Analysis Set 
Table 2.6.2.3 
Time-Weighted Average Change from Baseline in Serum Glucose (mmol/L) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................43 
Analysis Set: Safety Analysis Set 
Table 2.7.1.1 
Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the 
Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last 
Cumulative Dose............................................................................................................43 
Analysis Set: PP Analysis Set 
Figure 2.7.1.1 
Adjusted Mean Change From Baseline in Serum Potassium ± SE (mmol/L) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................43 
Analysis Set: PP Analysis Set 
Table 2.7.1.2 
Maximum Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post 
Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose.....................................................................................44 
Analysis Set: PP Analysis Set 
Table 2.7.1.3 
Time-Weighted Average Change from Baseline in Serum Potassium (mmol/L) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................44 
Analysis Set: PP Analysis Set 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 10 of 100
Table 2.7.2.1 
Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the 
Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the Last 
Cumulative Dose............................................................................................................44 
Analysis Set: Safety Analysis Set 
Figure 2.7.2.1 
Adjusted Mean Change From Baseline in Serum Potassium ± SE (mmol/L) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................44 
Analysis Set: Safety Analysis Set 
Table 2.7.2.2 
Maximum Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post 
Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose.....................................................................................44 
Analysis Set: Safety Analysis Set 
Table 2.7.2.3 
Time-Weighted Average Change from Baseline in Serum Potassium (mmol/L) 15
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................44 
Analysis Set: Safety Analysis Set 
Table 2.8 
Listing of All Records for Subjects With Newly Occurring or Worsening 
Potentially Clinically Significant Serum Glucose and Serum Potassium Laboratory 
Values Post-Baseline......................................................................................................45 
Analysis Set: Safety Analysis Set 
Table 2.9.1.1 
Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each 
of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose....................................................................................................45 
Analysis Set: PP Analysis Set 
Figure 2.9.1.1 
Adjusted Mean Change From Baseline in Systolic Blood Pressure ± SE (mmHg) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................45 
Analysis Set: PP Analysis Set 
Table 2.9.1.2 
Maximum Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes 
Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose.......................................................................45 
Analysis Set: PP Analysis Set 
Table 2.9.1.3 
Time-Weighted Average Change from Baseline in Systolic Blood Pressure 
(mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 
300, and 360 Minutes After the Last Cumulative Dose .................................................45 
Analysis Set: PP Analysis Set 
Table 2.9.2.1 
Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each 
of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose....................................................................................................45 
Analysis Set: Safety Analysis Set 
Figure 2.9.2.1 
Adjusted Mean Change From Baseline in Systolic Blood Pressure ± SE (mmHg) 15 
Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................46 
Analysis Set: Safety Analysis Set 
Table 2.9.2.2 
Maximum Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes 
Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose.......................................................................46 
Analysis Set: Safety Analysis Set 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 11 of 100
Table 2.9.2.3 
Time-Weighted Average Change from Baseline in Systolic Blood Pressure 
(mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 
300, and 360 Minutes After the Last Cumulative Dose .................................................46 
Analysis Set: Safety Analysis Set 
Table 2.10.1.1 
Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each 
of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose....................................................................................................46 
Analysis Set: PP Analysis Set 
Figure 2.10.1.1 
Adjusted Mean Change From Baseline in Diastolic Blood Pressure ± SE (mmHg) 
15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................46 
Analysis Set: PP Analysis Set 
Table 2.10.1.2 
Maximum Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes 
Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose.......................................................................46 
Analysis Set: PP Analysis Set 
Table 2.10.1.3 
Time-Weighted Average Change from Baseline in Diastolic Blood Pressure 
(mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 
300, and 360 Minutes After the Last Cumulative Dose .................................................47 
Analysis Set: PP Analysis Set 
Table 2.10.2.1 
Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each 
of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose....................................................................................................47 
Analysis Set: Safety Analysis Set 
Figure 2.10.2.1 
Adjusted Mean Change From Baseline in Diastolic Blood Pressure ± SE (mmHg) 
15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose................................................................47 
Analysis Set: Safety Analysis Set 
Table 2.10.2.2 
Maximum Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes 
Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose.......................................................................47 
Analysis Set: Safety Analysis Set 
Table 2.10.2.3 
Time-Weighted Average Change from Baseline in Diastolic Blood Pressure 
(mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 
300, and 360 Minutes After the Last Cumulative Dose .................................................47 
Analysis Set: Safety Analysis Set 
Table 2.11 
Listing of Potentially Clinically Significant Systolic and Diastolic Blood Pressure 
(mmHg) Increases and Decreases ..................................................................................47 
Analysis Set: Safety Analysis Set 
PHARMACOKINETIC ANALYSES ........................................................................................................ 48 
Table 2.12.1 
Descriptive Statistics for Plasma Concentrations of Albuterol (pg/mL) by 
Treatment and Timepoint...............................................................................................48 
Analysis Set: PK Analysis Set 
Figure 2.12.1.1 
Mean (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear-Linear Scale)....48 
Analysis Set: PK Analysis Set 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 12 of 100
Figure 2.12.1.1<a> Individual (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear-Linear 
Scale)..............................................................................................................................48 
Analysis Set: Safety Analysis Set 
Figure 2.12.1.2<b> Individual (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear/Log-
Linear Scale) ..................................................................................................................49 
Analysis Set: Safety Analysis Set 
Figure 2.12.1.2 
Mean (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear/Log-Linear 
Scale)..............................................................................................................................49 
Analysis Set: PK Analysis Set 
Table 2.12.2 
Descriptive Statistics for Pharmacokinetic Parameters of Albuterol by Treatment .......50 
Analysis Set: PK Analysis Set 
Table 2.13 
Relative Bioavailability of Albuterol After the Last Cumulative Dose..........................51 
Analysis Set: PK Analysis Set 
Table 2.14 
Relative Potency of Albuterol for AS MDI versus Proventil: Finney............................52 
Analysis Set: PK Analysis Set 
Figure 2.14 
C15min Geometric Mean and Individual Values: Cumulative Dose-Concentration 
Profiles for Albuterol .....................................................................................................53 
Analysis Set: PK Analysis Set 
3. 
SAFETY........................................................................................................................................... 54 
Table 3.1.1 
Overall Summary of Treatment-Emergent Adverse Events...........................................54 
Analysis Set: Safety Analysis Set 
Table 3.1.2 
Overall Summary of Treatment-Emergent Adverse Events Including Adverse 
Events During the Washout or Follow-up Periods.........................................................55 
Analysis Set: Safety Analysis Set 
Table 3.2.1 
Treatment-Emergent Adverse Events by MedDRA Primary System Organ Class 
and Preferred Term ........................................................................................................56 
Analysis Set: Safety Analysis Set 
Table 3.2.2 
Treatment-Emergent Adverse Events by MedDRA Primary System Organ Class 
and Preferred Term Including Events Occurring During the Washout or Follow-up 
Periods: Sensitivity Analysis..........................................................................................56 
Analysis Set: Safety Analysis Set 
Table 3.2.3 
Treatment-Emergent Adverse Events Occurring in >=2% of Subjects in a 
Treatment by Descending Frequency.............................................................................56 
Analysis Set: Safety Analysis Set 
Table 3.2.4 
Non-serious Treatment-Emergent Adverse Events Occurring in  >=5% of Subjects 
in a Treatment by MedDRA Primary System Organ Class and Preferred Term............57 
Analysis Set: Safety Analysis Set 
Table 3.3 
Treatment-Related Treatment-Emergent Adverse Events by MedDRA Primary 
System Organ Class and Preferred Term .......................................................................58 
Analysis Set: Safety Analysis Set 
Table 3.4 
Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
MedDRA Primary System Organ Class and Preferred Term.........................................58 
Analysis Set: Safety Analysis Set 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 13 of 100
Table 3.5 
Listing of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment .......................................................................................................................59 
Analysis Set: All Subjects Randomized 
Table 3.6.1 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred 
Term...............................................................................................................................60 
Analysis Set: Safety Analysis Set 
Table 3.6.2 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred 
Term Including Events Occurring During the Washout and Follow-up Period:
Sensitivity Analysis........................................................................................................60 
Analysis Set: Safety Analysis Set 
Table 3.7.1 
Listing of Serious Adverse Events (SAEs) ....................................................................61 
Analysis Set: All Subjects Screened 
Table 3.7.2 
Listing of SAE-Specific Report Information .................................................................62 
Analysis Set: Screened 
Table 3.8 
Treatment Related Serious Adverse Events by MedDRA Primary System Organ 
Class and Preferred Term...............................................................................................63 
Analysis Set: Safety Analysis Set 
Table 3.9.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity –
AS MDI..........................................................................................................................64 
Analysis Set: Safety Analysis Set 
Table 3.9.2 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity –
Proventil.........................................................................................................................64 
Analysis Set: Safety Analysis Set 
Table 3.10 
Listing of Deaths............................................................................................................65 
Analysis Set: All Subjects Screened 
4. 
SUBJECT DATA LISTINGS .......................................................................................................... 66 
Listing 1.1 
Study Centers .................................................................................................................66 
Analysis Set: All Subjects Screened 
Listing 1.2 
Subject Disposition and Demographic Data...................................................................67 
Analysis Set: All Subjects Screened 
Listing 1.3 
Randomized Treatment, Actual Treatment, and Duration of Treatment........................69 
Analysis Set: All Subjects Randomized 
Listing 1.4 
Reasons Subjects Were Not Randomized ......................................................................70 
Analysis Set: All Subjects Not Randomized 
Listing 2 
Violation of Inclusion/Exclusion Criteria .....................................................................71 
Analysis Set: All Subjects Randomized 
Listing 3 
Screening Lung Function and Ventolin HFA Reversibility ..........................................72 
Analysis Set: All Subjects Randomized 
Listing 4.1 
Asthma Diagnosis ..........................................................................................................73 
Analysis Set: All Subjects Randomized 
Listing 4.2 
Medical and Surgical History.........................................................................................74 
Analysis Set: All Subjects Randomized 
Listing 4.3 
Screening Reproductive Status and Pregnancy Test Results..........................................75 
Analysis Set: All Subjects Randomized – WOCBP Only 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 14 of 100
Listing 4.4 
Prior, Concomitant, and Post-Treatment Asthma Medications......................................76 
Analysis Set: All Subjects Randomized 
Listing 4.5 
Prior, Concomitant, and Post-Treatment Non-Asthma-Related Medications ................76 
Analysis Set: All Subjects Randomized 
Listing 4.6 
Suspect Drug Assessment for SAEs...............................................................................77 
Analysis Set: All Subjects Randomized 
Listing 5.1.1 
Study Drug Administration ............................................................................................78 
Analysis Set: All Subjects Randomized 
Listing 5.1.2 
Ventolin HFA, Atrovent, and Pulmicort Flexhaler Dispensing .....................................79 
Analysis Set: All Subjects Randomized 
Listing 5.2 
Exposure to Study Treatment Overall and by Dose .......................................................80 
Analysis Set: All Subjects Randomized 
Listing 6.1 
Subjects Who Failed Restrictions Prior to Spirometry Assessment...............................81 
Analysis Set: All Subjects Randomized 
Listing 6.2 
Failure of Stability Criteria ............................................................................................82 
Analysis Set: All Subjects Randomized 
Listing 6.3 
Reason for Missed Visit.................................................................................................83 
Analysis Set: All Subjects Randomized 
Listing 6.4 
Spirometry Measurements..............................................................................................84 
Analysis Set: All Subjects Randomized 
Listing 6.5 
Plasma Concentrations of Albuterol by Subject ID, Treatment, and Timepoint............85 
Analysis Set: Safety Analysis Set 
Listing 6.6 
Derived Pharmacokinetic Parameters of Albuterol by Subject ID and Treatment 
Period .............................................................................................................................86 
Analysis Set: PK Analysis Set 
Listing 7.1 
Adverse Events by Primary System Organ Class, Preferred Term, Treatment, 
Center, Subject ID, and Onset Day ................................................................................87 
Analysis Set: All Subjects Randomized 
Listing 7.2 
Glossary of Adverse Event Preferred Terms vs. Investigator’s Verbatim .....................89 
Listing 7.3 
Adverse Events by Treatment, Center, Subject ID, and Onset Day...............................90 
Analysis Set: All Subjects Randomized 
Listing 8.1 
Laboratory Test Results (Hematology Panel) ................................................................92 
Analysis Set: All Subjects Randomized 
Listing 8.2 
Laboratory Test Results (Chemistry Panel and Kidney Function).................................93 
Analysis Set: All Subjects Randomized 
Listing 8.3 
Laboratory Test Comments............................................................................................94 
Analysis Set: All Subjects Randomized 
Listing 9.1 
Vital Signs, Weight, and Height.....................................................................................95 
Analysis Set: All Subjects Randomized 
Listing 9.2 
12-Lead Electrocardiogram (ECG) ................................................................................97 
Analysis Set: All Subjects Randomized 
Listing 9.3 
Comments ......................................................................................................................98 
Analysis Set: All Subjects Randomized 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 15 of 100
5. 
CLINICALTRIALS.GOV: DISPOSITION TABLES..................................................................... 99 
Table 1.1 
Subject Disposition ........................................................................................................99 
Analysis Set: All Subjects Randomized 
Table 1.2 
Subject Disposition: Period 1.......................................................................................100 
Analysis Set: All Subjects Randomized 
Table 1.3 
Subject Disposition: Washout Between Period 1 and Period 2....................................100 
Analysis Set: All Subjects Randomized Who Entered the Washout 
Table 1.4 
Subject Disposition: Period 2.......................................................................................100 
Analysis Set: All Subjects Randomized 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 16 of 100
1. Subject Disposition, Demographic, Baseline, and Other Summary Tables
Table 1.1.1
Subject Disposition
Analysis Set: All Screened Subjects
All Subjects
(N=xxx)
n (%)
Randomized [a]
xx (xx.x)
Not Randomized (Non-Randomized Analysis Set) [a] [b]
xx (xx.x)
Not Treated [c]
xx (xx.x)
Treated [c] 
xx (xx.x)
Treated with AS MDI
xx (xx.x)
Treated with Proventil
xx (xx.x)
Length of Subject Participation in the Study [c] 
2 Treatment Periods
xx (xx.x)
1 Treatment Period only
xx (xx.x)
0 Treatment Periods
xx (xx.x)
Completed Day 1 of Treatment Period
2 Treatment Periods
xx (xx.x)
1 Treatment Period only
xx (xx.x)
0 Treatment Periods
xx (xx.x)
Completed Study [c]
xx (xx.x)
Premature Discontinuation [c]
xx (xx.x)
ITT Analysis Set [c] [d]
xx (xx.x)
mITT Analysis Set [c] [e]
xx (xx.x)
Safety Analysis Set [c] [f]
xx (xx.x)
Per Protocol Analysis Set [c][g]
xx (xx.x)
PK Analysis Set [c][h]
xx (xx.x)
[a] % = 100 x n/N, where n=# of subjects in category and N=# of screened subjects.
[b] The Not Randomized analysis set is defined as subjects who did not receive a randomization number and therefore did not 
receive a dose of study drug (eg, subjects who were screen failures or stopped participation before being randomized).
[c] % = 100 x n/N, where n=# of treated subjects in category and N=# of subjects treated.
[d] The Intent-To-Treat (ITT) Analysis Set was defined as all subjects who were randomized to treatment and received at
least 1 dose of the study treatment.  Subjects were analyzed in each period according to the treatment they were
assigned to per the randomization scheme (Note that a subject who used a study treatment but took less than 1 full dose
of treatment qualified for this analysis set).
[e] The mITT Analysis Set was defined as a subset of the ITT Analysis Set including subjects who received treatment and had
post-treatment efficacy data from both Treatment Periods.  Data judged to be impacted by major protocol deviations were


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 17 of 100
determined prior to database lock in a blinded fashion and excluded per the statistical protocol deviation plan. 
Statistical tabulations and analyses were by randomized treatment, but data obtained after subjects received an 
incorrect treatment were excluded from the affected periods.
[f] The Safety Analysis Set was defined as all subjects who were randomized to treatment and received at least 1 dose of 
the study treatment. Subjects were analyzed according to treatment received rather than per the randomization scheme.
[g] The Per Protocol Analysis Set was defined as a subset of the Safety Analysis Set including subjects who received 
Treatment and have post-treatment extrapulmonary pharmacodynamic data.  Data judged to be impacted by major protocol 
deviations were determined prior to database lock in a blinded fashion and excluded per the statistical protocol 
deviation plan. Statistical tabulations and analyses were by randomized treatment, but data obtained after subjects 
receive an incorrect treatment were excluded from the affected periods.
[h] The PK Analysis Set was defined as subjects in the Safety Analysis Set who received study drug and for whom at least 1 
primary PK parameter could be calculated and with no important protocol deviations thought to impact the analysis of 
the PK data.
Report generated by program: PT007002/sasdir/programs/statout/t010101.sas  Version  YYYY-MM-DD xx:xx  (Page n of N)
Notes to Programmer: Completed Day 1 of Treatment Period is defined as attending the visit and having at least one post-dose spirometry assessment at the treatment visit.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 18 of 100
Table 1.1.2
Reasons for Subjects Not Randomized
Analysis Set: All Screened Subjects Not Randomized
Reason Not Randomized
All Subjects Not Randomized
(N=xxx)
n (%)
Any Inclusion/Exclusion Criterion 
xxx (xx.x)
Exclusion Criterion #x: xxxx xxxx xx xxxxx xxxxx xxxx
xxx (xx.x)
Exclusion Criterion #x: xxx xxxxxxxxxxxx xx xxxxx x
xxx (xx.x)
Inclusion Criterion #x: xx x x xxx xxxx xxxx xxxxxxxxxxxx 
xxx (xx.x)
Inclusion Criterion #x: xxxx xxxx xx xxxxx xxxxx xxxx
xxx (xx.x)
Any Failure of Randomization Criteria
Criteria #X; XXXXXXXXXXXXXXXXXXXXXXXX
xxx (xx.x)
xxx (xx.x)
Report generated by program: PT007002/sasdir/programs/statout/t010102.sas Version  YYYY-MM-DD xx:xx              (Page n of N)
Notes to Programmer: Order by frequency within each category. Display all protocol-specified criteria shown on the End of Treatment/ CRF that have counts> 0.
From Section 3.3.1 of the Protocol, the Randomization Criteria are:
1. Subjects of childbearing potential must have a negative urine pregnancy test
2. Received no asthma medication other than Sponsor-SURYLGHG3XOPLFRUW)OH[KDOHUȝJRUȝJ%,'DVDVVLJQHGDQGRU6SRQVRU-provided Ventolin and Atrovent from Visit 
1 to Visit 2, except for allowable allergy medications defined in Table 7 of the protocol.
3. The last dose of Pulmicort Flexhaler (if applicable) was the previous night (ie, morning dose of Pulmicort Flexhaler was not administered), the last dose of Sponsor-provided 
Ventolin was no later than 48 hours before the study visit, and the last dose of Atrovent was no later than 8 hours before the study visit (if SABA is needed in the morning, the visit 
must be rescheduled) 
4. Pre-EURQFKRGLODWRU)(9SHUFHQWSUHGLFWHGQRUPDOYDOXH
5. Has not used >8 actuations per day (ie, 4 doses of 2 actuations per day) of Sponsor-provided rescue medication (Ventolin and Atrovent) for rescue on more than any 3 days 
during the previous 7 days 
6. No upper respiratory infection, lower respiratory infection, or asthma exacerbation during the Screening Period 
7. Demonstrate acceptable MDI administration technique
8. Able to comply with all study procedures


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 19 of 100
Table 1.1.3
Exclusions From ITT, mITT, Safety, Per Protocol and PK Analysis Sets
Analysis Set: All Subjects
Subject
ID
Treatment
Sequence
Analysis
Set
Excluded
Period
Excluded
Timepoints
Excluded
Variable(s)
Excluded
Reason for Exclusion
Study Center # / (Investigator):  ### / (xxxxxxxxxx)
xxxxx
-/-
ITT
All
All
All
Subject was not randomized
mITT
All
All
All
Subject did not have post-treatment efficacy data from 
both Treatment Periods
Safety
All
All
All
Did not receive at least one dose of the study treatment 
in the study
PK
Period 1
300, 360 
Minutes
All
Subject did not have at least 1 primary PK parameter 
that could be calculated
xxxxx
A/B
Safety
All
All
All
Subject did not receive treatment in at least 1 
treatment period.
xxxxx
B/-
ITT
All
All
All
Subject was not randomized
mITT
All
All
All
Subject did not have post-treatment efficacy data from 
both Treatment Periods
Safety
All
All
All
Did not receive at least one dose of the study treatment 
in the study
xxxxx
A/-
mITT
All
All
All
Subject took incorrect study medication
xxxxx
B/A
mITT
Period 2
All
All
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Subjects may be included in an analysis set as a whole, but have treatment period or timepoint data excluded.
Report generated by program: PT007002/sasdir/programs/statout/t010103.sas  Version  YYYY-MM-DD xx:xx           (Page n of N)
Notes to Programmer: 
Sort by Study Center, Investigator, and Subject within Study Center.  
List records per subject, analysis set excluded, period excluded, and timepoint excluded.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 20 of 100
Table 1.2.1
Reasons for Premature Treatment Discontinuation
Analysis Set: ITT Analysis Set
AS MDI
(N=xxx)
Proventil
(N=xxx)
n (%)
n (%)
Premature Treatment Discontinuation
xx (xx.x)
xx (xx.x)
Reason for Premature Treatment Discontinuation
Administrative Reasons
xx (xx.x)
xx (xx.x)
Adverse Event
xx (xx.x)
xx (xx.x)
Lack of Efficacy
xx (xx.x)
xx (xx.x)
Subject Discretion 
Withdrawal of Consent
xx (xx.x)
xx (xx.x)
Asthma
xx (xx.x)
xx (xx.x)
Other
xx (xx.x)
xx (xx.x)
Investigator or Designee Considers it to be in the Best Interest of the 
Subject
xx (xx.x)
xx (xx.x)
Subject Lost-to-Follow-up
xx (xx.x)
xx (xx.x)
Major Protocol Deviation
xx (xx.x)
xx (xx.x)
Protocol-Specified Discontinuation Criteria
xx (xx.x)
xx (xx.x)
FEV1 Stability Criteria Sec 5.1.4
xx (xx.x)
xx (xx.x)
Requirement of any Prohibited Medications Listed in Sec 7.7.3
xx (xx.x)
xx (xx.x)
Positive Pregnancy Test
xx (xx.x)
xx (xx.x)
Asthma Worsening Requiring Change in Asthma Treatment Sec 3.9
xx (xx.x)
xx (xx.x)
Treatment Code Broken by Investigator
xx (xx.x)
xx (xx.x)
Other
xx (xx.x)
xx (xx.x)
Note: Reasons specified for Other are listed by subject in Listing 1.2
Report generated by program: PT007002/sasdir/programs/statout/t010201.sas Version
YYYY-MM-DD xx:xx                 (Page n of N)
Notes to Programmer: Sort by descending frequency of major reason category using AS MDI column. Within a major reason category, sort by descending frequency of 
subcategory using AS MDI column.
Table 1.2.2
Reason for Premature Treatment Discontinuation
Analysis Set: Safety Analysis Set
Footnotes:
Subjects were included in summaries for a treatment if they received at least one dose of the treatment.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 21 of 100
Table 1.3
Analysis Sets by Treatment
Analysis Set: All Subjects Randomized
AS MDI
(N=xxx)
Proventil
(N=xxx)
n (%)
n (%)
Intent-to-treat Analysis Set [a]
xx (xx.x)
xx (xx.x)
mITT Analysis Set [b]
xx (xx.x)
xx (xx.x)
Safety Analysis Set [c]
xx (xx.x)
xx (xx.x)
Per Protocol Analysis Set [d]
xx (xx.x)
xx (xx.x)
PK Analysis Set [e]
xx (xx.x)
xx (xx.x)
n = number of subjects in the category, N=# of subjects who were randomized to the treatment, % = 100 x n/N.
[a] The Intent-To-Treat (ITT) Analysis Set was defined as all subjects who were randomized to treatment and received at least 1 dose 
of the study treatment.  Subjects were analyzed in each period according to the treatment they were assigned to per the 
randomization scheme (Note that a subject who used a study treatment but took less than 1 full dose of treatment qualified for 
this analysis set).
[b] The mITT Analysis Set was defined as a subset of the ITT analysis set including subjects who received treatment and had post-
treatment efficacy data from both Treatment Periods.
Data judged to be impacted by major protocol deviations were determined
prior to database lock in a blinded fashion and excluded per the statistical protocol deviation plan. Statistical tabulations and
analyses were by randomized treatment, but data obtained after subjects received an incorrect treatment were excluded from the 
affected periods.
[c] The Safety Analysis Set was defined as all subjects who were randomized to treatment and received at least 1 dose of the study 
treatment. Subjects were analyzed according to treatment received rather than per the randomization scheme.
[d] The Per Protocol Analysis Set was defined as a subset of the Safety analysis set including subjects who received Treatment and 
have post-treatment extrapulmonary pharmacodynamic data.  Data judged to be impacted by major protocol deviations were determined 
prior to database lock in a blinded fashion and excluded per the statistical protocol deviation plan. Statistical tabulations and 
analyses were by randomized treatment, but data obtained after subjects receive an incorrect treatment were excluded from the 
affected periods.
[e] The PK analysis set was defined as subjects in the Safety analysis set who received study drug and for whom at least 1 primary PK 
parameter could be calculated and with no important protocol deviations thought to impact the analysis of the PK data.
Report generated by program: PT007002/sasdir/programs/statout/t0103.sas  Version  YYYY-MM-DD xx:xx             (Page n of N)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 22 of 100
Table 1.4.1
Reason for Exclusion From the mITT Analysis Set
Analysis Set: ITT Analysis Set
Reason for
AS MDI
(N=xxx)
Proventil
(N=xxx)
n (%) 
n (%)
Exclusion of a Subject from mITT Analysis Set
xx (xx.x)
xx (xx.x)
<Reason 1>
xx (xx.x)
xx (xx.x)
<Reason 2>
xx (xx.x)
xx (xx.x)
…
Exclusion of a Treatment Period from mITT Analysis Set
xx (xx.x)
xx (xx.x)
<Reason 1>
xx (xx.x)
xx (xx.x)
<Reason 2>
xx (xx.x)
xx (xx.x)
…
Subjects may have multiple reasons for exclusion; therefore, counts for individual reasons may not add up to the total number of 
subjects excluded from the analysis set.
Report generated by program: PT007002/sasdir/programs/statout/t0104.sas  Version  YYYY-MM-DD xx:xx               (Page n of N)
Note to the Programmer: Subjects are to be included in summaries and N= in the column header for a treatment if they attended a visit designated for a treatment in their
treatment sequence.
Table 1.4.2
Reason for Exclusion From the Per Protocol Analysis Set
Analysis Set: Safety Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 23 of 100
Table 1.5.1
Demographics and Baseline Characteristics
Analysis Set: All Subjects
Parameter
All Subjects
(N=xxx)
Age (Years)[a]
n
xxx
Mean
xx.x
SD
xx.x
Median
xx.x
Minimum
xx
Maximum
xx
Gender, n (%)
Male
xxx (xx.x)
Female
xxx (xx.x)
Missing
x (xx.x)
Race, n (%)
Black or African 
American
xx (xx.x)
White
xxx (xx.x)
Native Hawaiian or Other Pacific
Islander
xx (xx.x)
American Indian or Alaska Native
xx (xx.x)
Asian
xx (xx.x)
Other
xx (xx.x)
Missing
xx (xx.x)
Ethnicity, n (%)
Hispanic
xxx (xx.x)
Not Hispanic or Latino
xxx (xx.x)
Unknown
xxx (xx.x)
Not Reported
xx (xx.x)
Prior Asthma Medication
SABA prn only, n (%)
xxx (xx.x)
ICS, n (%)
xxx (xx.x)
ICS/LABA, n (%)
xxx (xx.x)
Weight (kg)
n
xxx
Mean
xx.x
SD
xx.x
Median
xx.x


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 24 of 100
Parameter
All Subjects
(N=xxx)
Minimum
Maximum
xx.x
xx.x
Height (cm)
n
xxx
Mean
xxx.x
SD
xxx.x
Median
xxx.x
Minimum
Maximum
xxx.x
xxx.x
BMI (kg/m^2)
n
xxx
Mean
xx.x
SD
xx.x
Median
xx.x
Minimum
Maximum
xx.x
xx.x
[a]  Age is age at Visit 1.  The remaining characteristics were 
based on data from screening visits prior to randomization.
Report generated by program: 
PT007002/sasdir/programs/statout/t010501.sas Version  YYYY-MM-DD
xx:xx                                     (Page n of N)
Notes to Programmer: 
Repeat titles, column headers, and footnotes on each page. Keep the summary for a parameter in the same page when breaking the table into multiple pages. 
Sort race by decreasing frequency. The race/ethnicities of Native Hawaiian or Other Pacific Islander OR American Indian or Alaska Native can be removed from this table if they 
do not exist in the database. 
Calculate BMI using Height at Visit 1. BMI = weight (kg)/height (m)2.
Please delete Missing row when there are no missing values.
Table 1.5.2
Demographics and Baseline Characteristics
Analysis Set: ITT Analysis Set
Table 1.5.3
Demographics and Baseline Characteristics
Analysis Set: Safety Analysis Set
Note to Programmer: Remove Table 1.5.3 and renumber subsequent 1.5.x tables if Safety Analysis Set is the same as the ITT Analysis Set.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 25 of 100
Table 1.5.4
Demographics and Baseline Characteristics
Analysis Set: Per Protocol Analysis Set
Table 1.5.5
Demographics and Baseline Characteristics
Analysis Set: All Subjects Not Randomized


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 26 of 100
Table 1.6.1
Duration of Asthma
Analysis Set: mITT Analysis Set
All Subjects
(N=xxx)
Duration of Asthma (months) [a]
n
Mean
SD
xxx
xx.x
xx.x
25th Percentile
xx.x
Median
xx.x
75th Percentile
xx.x
Minimum
Maximum
xx.x
xx.x
[a]  The duration of asthma is calculated relative to the first dose of 
study medication.
Report generated by program: PT007002/sasdir/programs/statout/t010601.sas 
Version  YYYY-MM-DD xx:xx            (Page n of N) 
Notes to Programmer: Duration of Asthma = (First dose date of study drug – Date asthma first diagnosed)/30.475, where the day of asthma diagnosed is assumed to be the 1st of 
the month.
Table 1.6.2
Duration of Asthma 
Analysis Set: ITT Analysis Set
Table 1.6.3
Duration of Asthma
Analysis Set: Safety Analysis Set
Note to Programmer: Remove Table 1.6.3 and renumber subsequent 1.6.x tables if Safety Analysis Set is the same as the ITT Analysis Set.
Table 1.6.4
Duration of Asthma
Analysis Set: Per Protocol Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 27 of 100
Table 1.7.1
Screening Pre- and Post-Bronchodilator Spirometry Parameters
Analysis Set: mITT Analysis Set
All Subjects
(N=xxx)
FEV1 (% predicted)
Visit 1 [a]
Pre-Ventolin HFA:
n
Mean
SD
xx
xx.xxx
xx.xxx
25th Percentile
xx.xxx
Median
xx.xxx
75th Percentile
xx.xxx
Minimum
Maximum
xx.xxx
xx.xxx
Post-Ventolin HFA:
n
Mean
SD
xx
xx.xxx
xx.xxx
25th Percentile
xx.xxx
Median
xx.xxx
75th Percentile
xx.xxx
Minimum
Maximum
xx.xxx
xx.xxx
Repeat the above for these parameters:
FEV1 (L) 
FVC (% predicted)
FVC (L)
FEF 25-75 (% predicted)
FEF 25-75 (L/sec)
[a] Visit 1 for this purpose was Visit 1, 1a, or 1b, whichever 
visit at which reversibility was determined.
Report generated by program: 
PT007002/sasdir/programs/statout/t010701.sas Version  YYYY-MM-DD
xx:xx            (Page n of N)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 28 of 100
Table 1.7.2
Screening Pre- and Post-Bronchodilator Spirometry Parameters 
Analysis Set: ITT Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 29 of 100
Table 1.8.1
Reversibility to Ventolin HFA at Screening
Analysis Set: mITT Analysis Set
All Subjects
(N=xxx)
Post-Ventolin HFA FEV1 - Pre-Ventolin HFA FEV1 (mL)
n
Mean
SD
Median
Minimum
Maximum
xx
xx.x
xx.x
xx.x
xx.x
xx.x
Reversibility (%) Post-Ventolin HFA for FEV1 [a]
n
Mean
SD
Median
Minimum
Maximum
xx
xx.x
xx.x
xx.x
xx.x
xx.x
Reversible [b], n (%)
xx (xx.x)
If a subject was missing a Post- or Pre-Ventolin HFA FEV1 value at Screening 
Visit 1, these values were replaced by the Pre- and Post-Ventolin HFA
values from Screening Visit 1a.  Similarly, if values were missing at 
Screening Visits 1 and 1a, the values were replaced by those from Screening 
Visit 1b.
[a]  Reversibility (%) is defined as 100 x (the change from pre-Ventolin
HFA to post for FEV1)/pre-Ventolin HFA FEV1.
[b]  Reversible is defined as Improvement in FEV1 post-Ventolin HFA
administration compared to pre- Ventolin HFA of >=15%.
Report generated by program: PT007002/sasdir/programs/statout/t010801.sas
Version  YYYY-MM-DD xx:xx           (Page n of N) 
Table 1.8.2
Reversibility to Ventolin HFA at Screening 
Analysis Set: ITT Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 30 of 100
Table 1.9
Medical/Surgical History
Analysis Set: Safety Analysis Set
All Subjects
(N=xxx)
n  (%)
Subject Had Medical/Surgical History
No
xxx (xx.x)
Yes
xxx (xx.x)
Respiratory
xxx (xx.x)
Asthma
xxx (xx.x)
Cardiovascular
xxx (xx.x)
CNS/Neurological
xxx (xx.x)
Dermatologic
xxx (xx.x)
Drug Allergy
xxx (xx.x)
EENT
xxx (xx.x)
Endocrine/Metabolic
xxx (xx.x)
Diabetes
xxx (xx.x)
Type I
xxx (xx.x)
Type II
xxx (xx.x)
Gastrointestinal
xxx (xx.x)
Genitourinary
xxx (xx.x)
Hepatic
xxx (xx.x)
Hematologic
xxx (xx.x)
Immunological
xxx (xx.x)
Malignancy
xxx (xx.x)
Musculoskeletal
xxx (xx.x)
Psychiatric
xxx (xx.x)
Renal
xxx (xx.x)
Other
xxx (xx.x)
Report generated by program: 
PT007002/sasdir/programs/statout/t0109.sas  Version  YYYY-MM-DD xx:xx
(Page n of N)
Note to Programmer: Please sort by descending frequency of occurrence in All Subjects. Denominator should be N from the column header for a treatment.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 31 of 100
Table 1.10.1
Prior Medications – Asthma-Related
Analysis Set: Safety Analysis Set
Preferred Term
All Subjects
(N=xxx)
n (%)
Any Prior Asthma Medication [a]
xxx (xx.x)
Medication 1
xxx (xx.x)
Medication 2
xxx (xx.x)
Preferred term is according to WHODRUG DDE + HD version 1Q2018 (March 2018).
[a] Prior medications taken within 30 days of screening.
Report generated by program: PT007002/sasdir/programs/statout/t011001.sas  Version
YYYY-MM-DD xx:xx           (Page n of N)
Notes to Programmer: Sort Medications by descending frequency of use in AS MDI.
Table 1.10.2
Prior Medications-Non-Asthma-Related
Analysis Set: Safety Analysis Set
Notes to Programmer: Sort Medications by descending frequency of use across AS MDI.  Add a row for “Any Prior Non-Asthma Medication”.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 32 of 100
Table 1.11.1a
Concomitant Medications During Treatment Period – Asthma-Related
Analysis Set: Safety Analysis Set
Preferred Term
AS MDI
(N=xxx)
Proventil
(N=xxx)
n (%)
n (%)
Any Concomitant Asthma 
Medication
xxx (xx.x)
xxx (xx.x)
Medication 1
xxx (xx.x)
xxx (xx.x)
Medication 2
xxx (xx.x)
xxx (xx.x)
Preferred term is according to WHODRUG DDE + HD version 1Q2018 (March 
2018).
See Listing 6.4 for the use of Atrovent as rescue medication. 
Report generated by program: PT007002/sasdir/programs/statout/t011101.sas 
Version  YYYY-MM-DD xx:xx              (Page n of N) 
Notes to Programmer: Sort Medications by descending frequency of use in AS MDI.
Table 1.11.1b
Concomitant Medications During Washout Period – Asthma-Related
Analysis Set: Safety Analysis Set
Concomitant medications are tabulated by the treatment received during Treatment Period 1.
All subjects were allowed to use only sponsor-provided Atrovent for relief of symptoms during a Treatment Period and Pulmicort 
Flexhaler during the Washout Period.
See Listing 6.4 for the use of Atrovent as rescue medication. 
Report generated by program: PT007002/sasdir/programs/statout/t011101.sas Version  YYYY-MM-DD xx:xx              (Page n of N)
Table 1.11.2a
Concomitant Medications During Treatment Period-Non-Asthma-Related
Analysis Set: Safety Analysis Set
Notes to Programmer: Sort Medications by descending frequency of use in across AS MDI.  Add a row for “Any Concomitant Non-Asthma Medication”.
Table 1.11.2b
Concomitant Medications During Washout Period-Non-Asthma-Related
Analysis Set: Safety Analysis Set
Notes to Programmer: Sort Medications by descending frequency of use in across AS MDI.  Add a row for “Any Concomitant Non-Asthma Medication”.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 33 of 100
2. Efficacy, Extrapulmonary PD, and Pharmacokinetics Summary Tables and Figures
Efficacy Parameters
Primary Efficacy Endpoint


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 34 of 100
Table 2.1.1
Change from Baseline in FEV1 (L) 30 Minutes Post Each of the Cumulative Doses
Analysis Set: mITT Analysis Set
Treatment
Baseline FEV1
Change From Baseline
LS Mean Differences Between Treatments 
Proventil
Dose 1 – ȝJ
AS MDI
N
xx
xx
Mean
x.xxx
x.xxx
SD
x.xxx
x.xxx
Median
x.xxx
x.xxx
Min-Max
x.xxx-x.xxx
x.xxx-x.xxx
LS Mean (SE)
x.xxx (x.xxxx)
x.xxx (x.xxxx)
95% CI
( x.xxx, x.xxx)
90% CI
( x.xxx, x.xxx)
Proventil
N
xx
xx
Mean
x.xxx
x.xxx
SD
x.xxx
x.xxx
Median
x.xxx
x.xxx
Min-Max
x.xxx-x.xxx
x.xxx-x.xxx
LS Mean (SE)
x.xxx (x.xxxx)
Not Applicable
95% CI
( x.xxx, x.xxx)
90% CI
Repeat rows above for:
Cumulative Dose- ȝJ
Cumulative Dose- ȝJ
Cumulative Dose- ȝJ
Cumulative Dose- ȝJ
Baseline is defined as the mean of evaluable 60 and 30 minute pre-dose values across Visits 2 and 3.
LS Mean = least squares mean from a linear mixed effect model with a random subject effect for the correlation across periods and an 
unstructured covariance matrix for the repeated measures within subject periods.  The fixed effects include treatment (AS MDI vs 
Proventil), cumulative dose level, treatment-by-cumulative dose interaction, baseline FEV1, and period.
Report generated by program: PT007002/sasdir/programs/statout/t020101.sas  Version  YYYY-MM-DD hh:mm                 (Page n of N) 
Note to Programmer: The model will not include treatment sequence.  The baseline summary statistics are based on subjects who had at least one 30 min post-
dose data point on a Day 1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 35 of 100
Figure 2.1.1.1
Mean Change From Baseline in FEV1 ± SE (L) 30 Minutes Post Each of the Cumulative Doses and Over the 6 Hours Following the Last 
Cumulative Dose
Analysis Set: mITT Analysis Set
Source: Table 2.1.1
Report generated by program: PT007002/sasdir/programs/statout/f02010101.sas  Version  YYYY-MM-DD xx:xx     (Page n of N)
Notes to Programmer: Replace the treatment labels with ‘AS MDI’ and ‘Proventil’.Use actual Cumulative Doses for tick marks instead and values plotted for the x-axis.  Use 
Doses:  Dose 1, Dose 2, Dose 3, and Dose 4 and add the assessments through 6 hrs following Dose 5.
Delete the entire caption shown above.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 36 of 100
Secondary Efficacy Endpoints


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 37 of 100
Table 2.2.1
Change from Baseline in FEV1 AUC0-6 (L) After the Last Cumulative Dose
Analysis Set: mITT Analysis Set
Treatment
Baseline FEV1
Change From Baseline in FEV1 
AUC0-6
LS Mean Differences from Proventil
AS MDI
N
xx
xx
Mean
x.xxx
x.xxx
SD
x.xxx
x.xxx
Median
x.xxx
x.xxx
Min-Max
x.xxx-x.xxx
x.xxx-x.xxx
LS Mean (SE)
x.xxx (x.xxxx)
x.xxx (x.xxxx)
95% CI
( x.xxx, x.xxx)
90% CI
( x.xxx, x.xxx)
Proventil
N
xx
xx
Mean
x.xxx
x.xxx
SD
x.xxx
x.xxx
Median
x.xxx
x.xxx
Min-Max
x.xxx-x.xxx
x.xxx-x.xxx
LS Mean (SE)
x.xxx (x.xxxx)
Not Applicable
95% CI
( x.xxx, x.xxx)
90% CI
Baseline is defined as the mean of evaluable 60 and 30 minute pre-dose values across Visits 2 and 3.
LS Mean = least squares mean from a linear mixed effect model with a random subject effect for the correlation across periods.  The 
fixed effects include treatment (AS MDI vs Proventil), cumulative dose level, treatment-by-cumulative dose interaction, baseline FEV1,
and period.
Report generated by program: PT007002/sasdir/programs/statout/t020201.sas  Version  YYYY-MM-DD hh:mm                 (Page n of N) 
Note to Programmer: The model will not include treatment sequence.  The baseline summary statistics are based on subjects who had at least one 30min  post-baseline data point 
on a Day 1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 38 of 100
Extrapulmonary PD
General note to programmers: use the footnotes specified below for Table 2.3.1.1 for all Extrapulmonary PD tables.
Table 2.3.1.1
Change from Baseline in QTcF (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1 and use the following footnote for the extrapulmonary PD model:
Average baseline is defined as the mean of evaluable 60 and 30 minute pre-dose values across Visits 2 and 3.
LS Mean = least squares mean from a linear mixed effect model with a random subject effect for the correlation across periods.  The 
fixed effects include treatment (AS MDI vs Proventil), cumulative dose level, treatment-by-cumulative dose interaction, period-
specific baseline FEV1, average baseline FEV1, and period.
Figure 2.3.1.1
Adjusted Mean Change From Baseline in QTcF ± SE (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-'RVHZLWK'RVHDQG7LPH8VH'RVHVDQG7LPHV&XPXODWLYH'RVHȝJ0LQ&XPXODWLYH'RVHȝJ0LQ&XPXODWLYH'RVHȝJ
(15 Min), &XPXODWLYH'RVHȝJ0LQ&XPXODWLYH'RVHȝJ0LQ&XPXODWLYH'RVHȝJ0LQ&XPXODWLYH'RVHȝJ(60 Min), Cumulative Dose 1440 
ȝJ0LQ&XPXODWLYH'RVHȝJ0LQ&XPXODWLYH'RVHȝJ0LQ&XPXODWLYH'RVH ȝJ0LQDQG&XPXODWLYH'RVHȝJ0LQ
Table 2.3.1.2
Maximum Change from Baseline in QTcF (ms) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Table 2.3.1.3
Time-Weighted Average Change from Baseline in QTcF (ms) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 39 of 100
Table 2.3.2.1
Change from Baseline in QTcF (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes After the 
Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.3.2.1
Adjusted Mean Change From Baseline in QTcF ± SE (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.3.2.2
Maximum Change from Baseline in QTcF (ms) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Table 2.3.2.3
Time-Weighted Average Change from Baseline in QTcF (ms) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Table 2.4.1.1
Change from Baseline in Heart Rate (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.4.1.1
Adjusted Mean Change From Baseline in Heart Rate ± SE (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, 
and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 40 of 100
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 41 of 100
Table 2.4.1.2
Maximum Change from Baseline in Heart Rate (bpm) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Table 2.4.1.3
Time-Weighted Average Change from Baseline in Heart Rate (bpm) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Table 2.4.2.1
Change from Baseline in Heart Rate (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 Minutes 
After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.4.2.1
Adjusted Mean Change From Baseline in Heart Rate ± SE (ms) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, 
and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.4.2.2
Maximum Change from Baseline in Heart Rate (bpm) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Table 2.4.2.3
Time-Weighted Average Change from Baseline in Heart Rate (bpm) Over the 6 Hours Post the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 42 of 100
Table 2.5.1
Listing of ECGs Meeting QTcF Interval Prolongation Criteria
Analysis Set: Safety Analysis Set
Notes to Programmer: Please use Listing 9.2 and add a column after Subject ID identifying which QTcF criteria of the first 6 in the table above is being displayed (criteria shown 
in Table 3.18.2 above). Put age, gender, and race underneath Subject ID in the first column. 
Table 2.5.2
Listing of Potentially Clinically Significant Tachycardia and Bradycardia Events
Analysis Set: Safety Analysis Set
Table 2.6.1.1
Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.6.1.1
Adjusted Mean Change From Baseline in Serum Glucose ± SE (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 
240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.6.1.2
Maximum Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, 
and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Table 2.6.1.3
Time-Weighted Average Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 
180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 43 of 100
Table 2.6.2.1
Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.6.2.1
Adjusted Mean Change From Baseline in Serum Glucose ± SE (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 
240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.6.2.2
Maximum Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, 
and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Table 2.6.2.3
Time-Weighted Average Change from Baseline in Serum Glucose (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120,
180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Table 2.7.1.1
Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.7.1.1
Adjusted Mean Change From Baseline in Serum Potassium ± SE (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 
180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 44 of 100
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.7.1.2
Maximum Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 
300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Table 2.7.1.3
Time-Weighted Average Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 
180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Table 2.7.2.1
Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 360 
Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.7.2.1
Adjusted Mean Change From Baseline in Serum Potassium ± SE (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 
180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.7.2.2
Maximum Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 
300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Table 2.7.2.3
Time-Weighted Average Change from Baseline in Serum Potassium (mmol/L) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 
180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 45 of 100
Table 2.8
Listing of All Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant Serum Glucose and Serum 
Potassium Laboratory Values Post-Baseline
Analysis Set: Safety Analysis Set
Notes to Programmer: Please use the format of Listing 8.1 and add a column after Subject ID identifying which criterion in Table 3.16.7 is used for the PCS value. Put age, 
gender, and race underneath Subject ID in the first column. List all records for a subject, not just those meeting the criteria.
Table 2.9.1.1
Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.9.1.1
Adjusted Mean Change From Baseline in Systolic Blood Pressure ± SE (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 
120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.9.1.2
Maximum Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 
240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Table 2.9.1.3
Time-Weighted Average Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 
120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Table 2.9.2.1
Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 46 of 100
Figure 2.9.2.1
Adjusted Mean Change From Baseline in Systolic Blood Pressure ± SE (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 
120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.9.2.2
Maximum Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 
240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Table 2.9.2.3
Time-Weighted Average Change from Baseline in Systolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 
120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Table 2.10.1.1
Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.10.1.1
Adjusted Mean Change From Baseline in Diastolic Blood Pressure ± SE (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 
120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.10.1.2
Maximum Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180,
240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 47 of 100
Table 2.10.1.3
Time-Weighted Average Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 
60, 120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: PP Analysis Set
Table 2.10.2.1
Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 240, 300, and 
360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Table 2.1.1.
Figure 2.10.2.1
Adjusted Mean Change From Baseline in Diastolic Blood Pressure ± SE (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 
120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Notes to Programmer: 
Follow the format of Figure 2.1.1.1.
Replace Number of Weeks Post-Dose with Dose and Time.  Use Doses and Times:  Dose 1 (15 Min), Dose 2 (15 Min), Dose 3 (15 Min), Dose 4 (15 Min), Dose 5 (15 Min), Dose 5 
(30 Min), Dose 5 (60 Min), Dose 5 (120 Min), Dose 5 (180 Min), Dose 5 (240 Min), Dose 5 (300 Min), and Dose 5 (360 Min).
Table 2.10.2.2
Maximum Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30, 60, 120, 180, 
240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Table 2.10.2.3
Time-Weighted Average Change from Baseline in Diastolic Blood Pressure (mmHg) 15 Minutes Post Each of the Cumulative Doses and 30,
60, 120, 180, 240, 300, and 360 Minutes After the Last Cumulative Dose
Analysis Set: Safety Analysis Set
Table 2.11
Listing of Potentially Clinically Significant Systolic and Diastolic Blood Pressure (mmHg) Increases and Decreases
Analysis Set: Safety Analysis Set
Notes to Programmer: Please use the format of Listing 9.1 and add 2 columns after Subject ID identifying which criteria in the table above are being displayed for a subject
(criteria also shown in Table 3.17.2). Put age, gender, and race underneath Subject ID in the first column. In the last column display Visit 1 Height, Weight, and BMI.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 48 of 100
Pharmacokinetic Analyses
Table 2.12.1
Descriptive Statistics for Plasma Concentrations of Albuterol (pg/mL) by Treatment and Timepoint
Analysis Set: PK Analysis Set
Timepoint
Treatment
AS MDI
(N=xxx)
Proventil
(N=xxx)
Pre-dose
N
xx
xx
Mean (CV %)
xx.x (xx.x)
xx.x (xx.x)
SD
xx.xx
xx.xx
SE
xx.xx
xx.xx
Median
xx.x
xx.x
Minimum, Maximum
xx.xx
xx.xx
Geometric Mean (CV %)
xx.x (xx.x)
xx.x (xx.x)
C15min– 90 μg
N
xx
xx
Mean (CV %)
xx.x (xx.x)
xx.x (xx.x)
SD
xx.xx
xx.xx
SE
xx.xx
xx.xx
Median
xx.x
xx.x
Minimum, Maximum
xx.xx
xx.xx
Geometric Mean (CV %)
xx.x (xx.x)
xx.x (xx.x)
CV % = coefficient of variation in percentage.
With the exception of Day 1 pre-dose values, values below Lower Limit of Quantification (LLQ) are set to LLQ/2 for all descriptive 
statistics categories. Below LLQ values from Day 1 pre-dose will be set to zero.
Albuterol LLQ = 50 pg/mL
Report generated by program: PT007002/sasdir/programs/statout/t0212.sas Version  YYYY-MM-DD xx:xx              (Page n of N)
Notes to Programmer:  
C15min- ȝJ, C15min- ȝJ, C15min- ȝJ, C15min- ȝJ, Cumulative Dose- ȝJPLQSRVWGRVH&XPXODWLYH'RVH- ȝJPLQSRVWGRVH
Cumulative Dose- ȝJPLQSRVWGRVH&XPXODWLYH'RVH- ȝJPLQSRVWGRVH&XPXODWLYH'RVH- ȝJPLQSRVWGRVH&XPXODWLYH
Dose- ȝJPLQSRVWGRVH Cumulative Dose- ȝJPLQSRVWGRVH&XPXODWLYH'RVH- ȝJPLQSRVWGRVH&XPXODWLYH'RVH- ȝJ
(600 min post dose), Cumulative Dose- ȝJPLQSRVWGRVH
Figure 2.12.1.1
Mean (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear-Linear Scale)
Analysis Set: PK Analysis Set
Figure 2.12.1.1<a>
Individual (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear-Linear Scale)
Analysis Set: Safety Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 49 of 100
Figure 2.12.1.2<b>
Individual (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear/Log-Linear Scale)
Analysis Set: Safety Analysis Set
Figure 2.12.1.2
Mean (+/- SE) Plasma Albuterol Concentration-Time Profile (Linear/Log-Linear Scale)
Analysis Set: PK Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 50 of 100
Table 2.12.2
Descriptive Statistics for Pharmacokinetic Parameters of Albuterol by Treatment
Analysis Set: PK Analysis Set
Treatment
Pharmacokinetic Parameter
AS MDI
(N=xx)
Proventil
(N=xx)
Cmax (pg/mL)
n
xx
xx
Mean (CV%)
xx.x (xx.x)
xx.x (xx.x)
SD
xx.xx
xx.xx
Median
xx.x
xx.x
Minimum; Maximum
xx;xx
xx;xx
Geometric Mean (CV%)
xx.x (xx.x)
xx.x (xx.x)
AUC0-t (pg*hr/mL)
n
xx
xx
Mean (CV%)
xx.x (xx.x)
xx.x (xx.x)
SD
xx.xx
xx.xx
Median
xx.x
xx.x
Minimum; Maximum
xx;xx
xx;xx
tmax (hr)
n
xx
xx
Median
xx.x
xx.x
Minimum; Maximum
xx;xx
xx;xx
CV % = coefficient of variation in percentage.
With the exception of Day 1 pre-dose values, values below Lower Limit of 
Quantification (LLQ) are set to LLQ/2 for all descriptive statistics 
categories.
Albuterol LLQ = 50 pg/mL
Source: Listing 6.6
Program:/sasdir/t021202.sas  Version yyyy-mm-dd hh:mm
(Page x of y)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 51 of 100
Table 2.13
Relative Bioavailability of Albuterol After the Last Cumulative Dose
Analysis Set: PK Analysis Set
Treatment
Geometric
Ls Mean
Geometric Mean Ratio (%) 
90% Confidence Interval[a]
Intra-Subject
CV%[b]
Cmax (pg/mL)
AS MDI (n=xx)
xxx.xx
xxx.xx (xxx.xx, xxx.xx)
xxx.xx%
Proventil (n=xx)
xxx.xx
AUC0-t (pg*hr/mL)
AS MDI (n=xx)
xxx.xx
xxx.xx (xxx.xx, xxx.xx)
xxx.xx%
Proventil (n=xx)
xxx.xx
[a] Ratio (expressed as a percentage) of exponentiated mean difference of ln-transformed PK parameters. The confidence interval is 
from a linear mixed effect model with a random subject effect and  fixed effects for treatment and period.
[b] 100*sqrt[exp(residual) – 1] where residual = the residual variance component.
Report generated by program: PT007002/sasdir/programs/statout/t0213.sas
Version  YYYY-MM-DD hh:mm                 (Page n of N) 
Note to Programmer: The model will not include treatment sequence.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 52 of 100
Table 2.14
Relative Potency of Albuterol for AS MDI versus Proventil: Finney
Analysis Set: PK Analysis Set
Pharmacokinetic
Parameter
Intercept Estimate
Common
Slope
Estimate
Relative
Potency
[a]
90%
Confidence
Interval [a]
AS MDI (a1)
Proventil MDI (a2)
C15min (pg/mL)
2.308
2.208
0.875
0.892
0.831, 0.976
The model includes fixed effects for period and treatment (AS MDI vs Proventil), and a random 
intercept.
[a] Relative potency is calculated as exp((a2-a1)/b) with bias-corrected accelerated bootstrap 
confidence interval.
Notes to the Programmer: The C15min values for albuterol after each cumulative dose will be 
analyzed with a power law model. Natural log-transformed C15min will be regressed onto the natural 
log transformed cumulative dose levels. The model will include fixed effects for period and 
treatment (AS MDI vs Proventil), and a random intercept. A test for treatment-by-ln-cumulative
dose interaction will be conducted. If found to be non-significant at the 5% level, the 
interaction term will be dropped from the model, parallel slopes will be assumed, and the 
relative potency of AS MDI vs Proventil will be assessed (Finney, 1978; Table 2.18). If the 
linear or parallel line assumptions required for the Finney method appear to be violated, then an 
Emax model will be used to estimate relative potency.  The bias-corrected and accelerated 
bootstrap will be used for either the Finney or Emax method to construct 90% CIs. While not a 
true assessment of dose proportionality, the proportionality of albuterol C15min after cumulative 
dose administration (cumulative doses of 90, 180, 360, 720, and 1440 μg) will be assessed using 
the above power law model with separate slopes.
If an Emax model is needed, please replace the table above, replacing ‘Finney’ in the title with ‘Emax’, replace
‘Intercept Estimate’ in the column header with ‘ED50’, replace ‘(a1)’ and  ‘a2’ with ‘(e1)’ and ‘(e2)’; replace the
model footnote, and use this footnote for footnote [a]: 
[a] Relative potency is calculated as  (e1/e2) with bias-corrected accelerated bootstrap confidence interval.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 53 of 100
Figure 2.14
C15min Geometric Mean and Individual Values: Cumulative Dose-Concentration Profiles for Albuterol
Analysis Set: PK Analysis Set
Source: Table 2.14
Notes to Programmer: 
The plot is for ln (concentration) by ln (cumulative dose), but show the back-transformed value on the x and y axis tick marks of the plot.
There should be two lines; one for AS MDI and one for Proventil that represent the separate slopes from the power law model. Also, in a text box, include the 
slope estimates and the 90% confidence intervals for each of the treatments.
Do not back-transform the slope. Also, plot the individual subject values for each treatment.
Remove the SE bars.  Instead plot the individual values at each dose.
But if an Emax model is used instead of Finney method, please plot using log(response) and dose instead (not log(dose)). Do not show slope estimates and 90% CIs. 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 54 of 100
3. Safety
Adverse Events
Table 3.1.1
Overall Summary of Treatment-Emergent Adverse Events
Analysis Set: Safety Analysis Set
AS MDI
(N=xxx)
Proventil
(N=xxx)
Any Treatment
(N=xxx)
n (%)
[Events]
n (%)
[Events]
n (%)
[Events]
Subjects With at Least One TEAE [a]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
Subjects With Serious TEAEs
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
Subjects With TEAEs Related to Study 
Treatment [b]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
Subjects With Serious TEAEs Related to Study 
Treatment [b]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
Subjects With TEAEs Leading to Early 
Discontinuation
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
Deaths – All Causes
xx (xx.x)
xx (xx.x)
xx (xx.x)
[a] TEAE = Treatment-Emergent Adverse Event
[b] Related = Yes or No.
Report generated by program: PT007002/sasdir/programs/statout/t030101.sas
Version  YYYY-MM-DD  xx:xx
(Page n of N)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 55 of 100
Table 3.1.2
Overall Summary of Treatment-Emergent Adverse Events Including Adverse Events During the Washout or Follow-up Periods
Analysis Set: Safety Analysis Set
AS MDI
(N=xxx)
Proventil
(N=xxx)
Any Treatment
(N=xxx)
n (%)
[Events]
n (%)
[Events]
n (%)
[Events]
Subjects With at Least One TEAE [a]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
Subjects With Serious TEAEs
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
Subjects With TEAEs Related to Study 
Treatment [b]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
xx (xx.x)
[xxx]
Subjects With Serious TEAEs Related to Study 
Treatment [b]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
Subjects With TEAEs Leading to Early 
Discontinuation
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
xx (xx.x)
[xx.x]
Deaths – All Causes
xx (xx.x)
xx (xx.x)
xx (xx.x)
[a] TEAE = Treatment-Emergent Adverse Event
[b] Related = Yes or No.
Report generated by program: PT007002/sasdir/programs/statout/t030102.sas  Version  YYYY-MM-DD  xx:xx               (Page 
n of N)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 56 of 100
Table 3.2.1
Treatment-Emergent Adverse Events by MedDRA Primary System Organ Class and Preferred Term
Analysis Set: Safety Analysis Set
System Organ Class
Preferred Term
AS MDI
(N=xxx)
Proventil
(N=xxx)
Any Treatment
(N=xxx)
n (%)
[Events]
n (%)
[Events]
n (%)
[Events]
At Least One TEAE [a]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
System Organ Class 1
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
Preferred Term 1
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
Preferred Term 2
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
System Organ Class 2
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
Preferred Term 1
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
Preferred Term 2
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
xx ( xx.x)
[xx]
Etc.…
[a]   TEAE = Treatment-Emergent Adverse Event.
Report generated by program: PT007002/sasdir/programs/statout/t030201.sas
Version  YYYY-MM-DD xx:xx                (Page n 
of N)
Table 3.2.2
Treatment-Emergent Adverse Events by MedDRA Primary System Organ Class and Preferred Term Including Events Occurring During the 
Washout or Follow-up Periods: Sensitivity Analysis
Analysis Set: Safety Analysis Set
Notes to Programmer: Same as Table 3.2.1, however, AEs that occur during the Washout Period or Follow-up periods are attributed to the treatment given in the preceding 
Treatment Period. Add the following footnote: “AEs that occur during the Washout or Follow-up periods are attributed to the treatment given in the preceding Treatment Period.”
Table 3.2.3
Treatment-Emergent Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending Frequency
Analysis Set: Safety Analysis Set
Notes to Programmer: Sort preferred terms by descending frequency of number of events across All Subjects. Use the format of Table 3.2.1, but delete the “At Least One” row 
from this table. SOCs will not be used in this table.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 57 of 100
Table 3.2.4
Non-serious Treatment-Emergent Adverse Events Occurring in  >=5% of Subjects in a Treatment by MedDRA Primary System Organ Class 
and Preferred Term
Analysis Set: Safety Analysis Set
Notes to Programmer: use the format of Table 3.2.1.
If there are 0 AE’s in the table, change cutpoint to 4%, 3%, or 2%. (2%, 3%, and 4% will likely yield the same table which would be same as a table requirement 2 or more 
subjects per preferred term).


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 58 of 100
Table 3.3
Treatment-Related Treatment-Emergent Adverse Events by MedDRA Primary System Organ Class and Preferred Term
Analysis Set: Safety Analysis Set
[a]  Related = Yes or No.
Report generated by program: PT007002/sasdir/programs/statout/t0304.sas    Version YYYY-MM-DD xx:xx   (Page n of N)
Notes to Programmer: use the format of Table 3.2.1.
Table 3.4
Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by MedDRA Primary System Organ Class and Preferred Term
Analysis Set: Safety Analysis Set
[a]  A TEAE leading to treatment discontinuation is an AE with ‘Action Taken’ = ‘Drug withdrawn’, or ‘Outcome’ = ‘Fatal’, 
or ‘Death’ as reason for Seriousness on Adverse Event’ CRF.
Report generated by program: PT007002/sasdir/programs/statout/t0305.sas  Version  YYYY-MM-DD xx:xx   (Page n of N)
Notes to Programmer: use the format of Table 3.2.1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 59 of 100
Table 3.5
Listing of Adverse Events Leading to Permanent Discontinuation of Study Treatment
Analysis Set: All Subjects Randomized
Subject
ID
(Age/
Gender/
Race)
Primary System 
Organ Class
AE Verbatim 
(Preferred Term) 
Treat.
Emerg.
Event
Serious
Onset
Date
(Study
Day)
[a]
Duration
of Event Severity
Relation
-ship
Action
AE
Treated
Outcome
(Death)
Study Day 
Resolved/
Death
Treatment: AS MDI or Proventil
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
(54/F/W)
xxx xxx xxxxx
AE 1
(xxxxxxxxxx)
Yes
No
YYYY-MM-
DD
(T1_2)
Moderate
Not
Related
Dose
not
changed
No
Recoverin
g/Resolvi
ng (No)
xxx xxx xxxx
AE 2 
(xxxxxxxxxx)
Yes
Yes
YYYY-MM-
DD
(T2_P1)
xx
Moderate
Related
Drug
Interru
pted
Yes
Resolved
(Yes)
P3
…
…
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period. 
Report generated by program: PT007002/sasdir/programs/statout/t0305.sas  Version  YYYY-MM-DD xx:xx   (Page n of N)
Notes to Programmer: Sort by Actual Treatment, Center, Subject ID, Primary System Organ Class, and Onset Day of AE. Page by Treatment and not by Treatment and Center.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 60 of 100
Table 3.6.1
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred Term
Analysis Set: Safety Analysis Set
Notes to Programmer: Same as Table 3.2.1.
Table 3.6.2
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred Term Including Events Occurring During the Washout and 
Follow-up Period: Sensitivity Analysis
Analysis Set: Safety Analysis Set
Notes to Programmer: Same as Table 3.2.1, however, SAEs that occur during the Washout or Follow-up periods are attributed to the treatment given in the preceding Treatment 
Period. Add the following footnote: “SAEs that occur during the Washout or Follow-up periods are attributed to the treatment given in the preceding Treatment Period.”


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 61 of 100
Table 3.7.1
Listing of Serious Adverse Events (SAEs)
Analysis Set: All Subjects Screened
Subject
ID
Age
(yrs)/
Gender/
Race
Primary
System Organ 
Class
SAE Verbatim
(Preferred Term)
Reason for Being 
Serious (Day) [a]
Treat.
Emerg.
Onset Day 
[b]
(Day of Most 
Recent Dose)
Duration
of Event 
[b]
Severity/
Relation-
ship
Action/
(Outcome)
(AE Treated)
Study
Day
Resolved
[a]
Treatment: AS MDI or Proventil
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
70/F/W
xxxx xxx xx 
xxxx
xxx xxx xxxxx xxxxxxx
(xxxxxxxxxxxxxxxxxxx)
Hospitalization / 
prolongation of 
existing
Hospitalization
(T1_Day 5-Day 8)
Yes
5
(T2_P1)
4
Moderate / 
Not
Related
None
(Recovered/Re
solved)
(Yes)
8
Interrupted,
Date Stopped: 
YYYY-12-07;
AE abated: 
Yes; Date 
restarted:
YYYY_12_08:
AE reoccur? 
Yes
[a] A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date -
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period.
[b] Duration of event = Stop Day - Onset Day + 1.
Report generated by program: PT007002/sasdir/programs/statout/t030701.sas  Version  YYYY-MM-DD xx:xx               (Page n of N) 
Notes to Programmer: 
Sort by Actual Treatment, Center, Subject ID, Primary System Organ Class, Preferred Term, and Onset Day. 
If Reason for Seriousness is Hospitalization or Prolongation of Existing Hospitalization, also present in parentheses the days subject admitted into and discharged from Hospital 
“(Day xx – Day xx)”. 
If the Reason for Seriousness is death, also present the day of death.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 62 of 100
Table 3.7.2
Listing of SAE-Specific Report Information
Analysis Set: Screened
Subject ID
Diagnosis, Details and
Relevant Diagnostic Tests
Last
Treatment and 
Date
(YYYY-MM-DD)
Date of SAE 
Onset
(YYYY-MM-DD)
And Most 
Recent Dose 
of Treatment 
Prior to 
Onset of SAE
Serious Reason 
(YYYY-MM-DD)
Action Taken With 
Study Drug
Severity/
Relationship/
(Outcome)
(YYYY-MM-DD)
SAE
Treated
Treatment: AS MDI or Proventil
Center # / (Investigator):  ### / (xxxxxxxxxx)
xxxx
Diagnosis:
xxxxxxxxxxxxxxxxxxxxxxx
Details: signs, symptoms, 
time course, and relevant 
medical history. 
Relevant Diagnostic Tests:
Confirmatory procedures and 
Results, if any.
C 2015-07-28 2015-07-24
YYYY-MM-DD
Death (YYYY-MM-DD)
Autopsy: yes or no
Life-threatening
Hospitalization or 
prolongation of 
existing
hospitalization
(YYYY-MM-DD-YYYY-
MM-DD)
A persistent or 
significant
disability/incapac
ity
Congenital
anomaly/birth
defect
A significant 
medical event that 
requires medical 
or surgical 
intervention to 
prevent one of the 
serious outcomes 
listed above.
None
Interrupted (Stopped: 
YYYY-MM-DD
SAE Abated: Yes/No 
Treatment Restarted:
YYYY-MM-DD
SAE Reoccur: Yes/no)
Permanently
Discontinued (YYYY-
MM-DD)
Moderate / 
Possibly / 
(Recovered/Re
solved)
(2015-07-27)
Yes/No
Notes to Programmer: Sort by Center, Subject ID, and Onset Day of SAE. Move ‘Center’ row header to the next page whenever there is not enough room on current page 
to fit at least one row of data underneath this header. In order for the SAE-Specific Report Information to be listed, it will need to be included in the SDTM data sets.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 63 of 100
Table 3.8
Treatment Related Serious Adverse Events by MedDRA Primary System Organ Class and Preferred Term
Analysis Set: Safety Analysis Set
[a]  Related = Yes or No.
Notes to Programmer: Same as Table 3.2.1.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 64 of 100
Table 3.9.1
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – AS MDI
Analysis Set: Safety Analysis Set
Primary System Organ Class
Preferred Term
AS MDI (N=xxx)
Mild
n (%)
Moderate
n (%)
Severe
n (%)
Any Severity
n (%)
At Least One TEAE 
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
System Organ Class 1
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
Preferred Term 1
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
Preferred Term 2
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
System Organ Class 2 
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
Preferred Term 1
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
Preferred Term 2
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
xxx (xxx.x)
….
Only the highest severity is counted for multiple occurrences of the same adverse event in one individual.
Report generated by program: PT007002/sasdir/programs/statout/t030901.sas  Version  YYYY-MM-DD xx:xx                 (Page n of N)
Table 3.9.2
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – Proventil 
Analysis Set: Safety Analysis Set


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 65 of 100
Table 3.10
Listing of Deaths
Analysis Set: All Subjects Screened
Subject ID
Treatment
Sequence
Date of Last Treatment Prior 
to Death
Date and Time
(YYYY-MM-DD) (24 h clock) 
of Death
Days Since 
Last Dose
at Time of 
Death [a]
Adverse Event
Study Center # / (Investigator): ### / (xxxxxxxxxx)
xxxxx
x/x
TRT A
YYYY-MM-DD
YYYY-MM-DD
hh:mm
x
Preferred Term (AE verbatim)
xxxxxx
x/x
TRT B
YYYY-MM-DD
YYYY-MM-DD
hh:mm
x
Preferred Term (AE verbatim)
xxxxx
x/x
TRT A
YYYY-MM-DD
YYYY-MM-DD
hh:mm
x
Preferred Term (AE verbatim)
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
TRT = Treatment.
[a]  Days since Last Dose = Date of death – Date of last dose of study treatment + 1.
Report generated by program: PT007002/sasdir/programs/statout/t0310.sas  Version  YYYY-MM-DD xx:xx   (Page n of N)
Notes to Programmer:  For TRT N, N is the treatment period number of the last treatment received by the subject prior to the death. 
Sort by Study Center and Subject within Study Center.  Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one 
row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 66 of 100
4. Subject Data Listings
4.1 Subject Discontinuations/Completions
Listing 1.1
Study Centers
Analysis Set: All Subjects Screened
Center
Investigator
Location
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxx City Country
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxx City Country
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxx City Country
Source: xxxxxxx.sas7bdat
Report generated by program: /sasdir/programs/statout/l0101.sas
Version                YYYY-MM-DD xx:xx   (Page n of N)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 67 of 100
Listing 1.2
Subject Disposition and Demographic Data
Analysis Set: All Subjects Screened
Subject ID 
(Treatment
Sequence)
Age
(yrs)[a]/
Gender
(Race/Eth
nicity)
Height(cm)/
Weight (kg)/
BMI (kg/m2)
Randomized? (Study Day) [b]
Subject Study Status
(Date of Last Dose [Study 
Day)}
(Follow-up Call? Date)
Date of Death
[c]
Center # (Investigator): Center ### (xxxxxxxxxx)
Xxxxxx
(A/B)
Xx/M
(x/xx)
xxx.x/
xx.x/
xx.x
Yes/No
(xx)
Completed Study
(YYYY-MM-DD [xxx])
(Yes YYYY-DD-MM)
NA
Xxxxxx
(A/-)
Xx/M
(x/xx)
xxx.x/
xx.x/
xx.x
Yes/No
(xx)
Discontinued
Investigator’s Decision
(YYYY-MM-DD [xxx])
(No)
Xxxxxx
(B/A)
Xx/M
(x/xx)
xxx.x/
xx.x/
xx.x
Yes/No
(xx)
Discontinued
Subject Lost to Follow up
(YYYY-MM-DD [xxx])
(No)
Xxxxxx
(B/-)
Xx/M
(x/xx)
xxx.x/
xx.x/
xx.x
No
(NA)
Discontinued
Investigator’s Decision
(YYYY-MM-DD [xxx])
(No)
Xxxxxx
(A/B)
Xx/M
(x/xx)
xxx.x/
xx.x/
xx.x
No
(NA)
Discontinued
Adverse Event
(YYYY-MM-DD [xxx])
(No)
Death: YYYY-MM-DD
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Race: A=Asian, AIAN=American Indian or Alaska Native, B=Black or African American, NHPI=Native Hawaiian or Other Pacific Islander,
O=Other W=White. Ethnicity: H=Hispanic, NH=Not Hispanic, UNK=Unknown, NR=Not Reported.
[a]   Age = integer part of ((Visit 1 date – Birth date +1)/365.25)
[b]
Study Day of randomization = date of randomization – date of the first dose of study drug in the study if date of randomization
is before date of first dose of study drug.  Study Day is 1 if the day of first study drug in the study is on the day of 
randomization.
[c]
Study Day is date of date of the last dose of study drug - date of first dose of study drug + 1. 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 68 of 100
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0102.sas  Version YYYY-MM-DD xx:xx                 (Page n of N)
Notes to Programmer: 
Sort by  Center, and Subject ID within Center.  
Last Contact Date on the End of Treatment/Discontinuation/Discontinuation CRF is date of last contact. 
If Race = Other, concatenate the specified race after ‘O’ within parenthesis, e.g., “O (specified)”. 
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 69 of 100
Listing 1.3
Randomized Treatment, Actual Treatment, and Duration of Treatment
Analysis Set: All Subjects Randomized
Subject ID
Randomized Treatment 
Sequence (Actual Treatment
Sequence)
Period 1
Period 2
Treatment
(Time of First Dose – Time of Last 
Cumulative Dose)/
Washout Length (days) [a]
Treatment
(Time of First Dose – Time of Last 
Cumulative Dose)/
Washout Length (days) [a]
Study Center # / (Investigator): ### / (xxxxxxxxxx)
xxxxx
A/B
(A/B)
AS MDI
(hh:mm -
hh:mm)/
(7)
Proventil
(hh:mm -
hh:mm)/
(7)
xxxxx
B/A
(B/A)
Proventil
(hh:mm -
hh:mm)/
(7)
AS MDI
(hh:mm -
hh:mm)/
(7)
xxxxx
A/B
(A/-)
AS MDI
(hh:mm -
hh:mm)/
(7)
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
NA = not applicable
Time is 24 hour clock time.
[a] Washout length (days) for the subject’s last period is the number of days between the follow-up telephone call and the dose date 
in the last period. The duration of a washout (or follow-up) period = (date of subsequent treatment (or follow-up telephone call)
- date of previous study treatment - 1).
Source: xxxxxxx.sas7bdat 
Report generated by program: PT007002/sasdir/programs/statout/l0103.sas  Version
YYYY-MM-DD xx:              (Page n of N)
Notes to Programmer: Sort by Center and Subject within Center.  Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit 
at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 70 of 100
Listing 1.4
Reasons Subjects Were Not Randomized
Analysis Set: All Subjects Not Randomized
Subject ID
Date of Screening
Age
(yrs)
Gender
Race
Reason Not Randomized
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
YYYY-MM-DD
xx
Male
W
xxxxxxxxxxxxxxx (Inclusion Criterion #n)
xxxxxx
YYYY-MM-DD
xx
Female
W
xxxxxxxxxxxxxx (Inclusion Criterion #n)
xxxxxx
YYYY-MM-DD
xx
Male
W
xxxxxxxxxxxxxx (Inclusion Criterion #n)
xxxxxx
YYYY-MM-DD
xx
Male
W
xxxxxxxxxxxxxx (Inclusion Criterion #n)
Xxxxxx
YYYY-MM-DD
Xx
Female
W
<Reason for discontinuation from the Discontinuation/Completion 
CRF>
Race: A=Asian, AIAN=American Indian or Alaska Native, B=Black or African American, NHPI=Native Hawaiian or Other Pacific Islander,
O=Other W=White.
Source: xxxxxxx.sas7bdat 
Report generated by program: PT007002/sasdir/programs/statout/l0104.sas  Version YYYY-MM-DD xx:xx                 (Page n of N)
Notes to Programmer: 
Sort by Center and Subject ID within Center. 
If Race = Other (“O”), concatenate the specified race after ‘O’ within parenthesis, e.g., “e.g., “O: xxxxxx”.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 71 of 100
4.2 Protocol Deviations
Listing 2
Violation of Inclusion/Exclusion Criteria
Analysis Set: All Subjects Randomized
Subject
ID
Treatment
Sequence
Age
(yrs)/
Gender
Race
[a]
Informed
Consent
Signed
Informed
Consent
Study
Day [a]
Eligibility
Visit
Study Day
[a]
Inclusion/
Exclusion
Criteria
Satisfied
Type of 
Failed
Criteria
Failed
Criteria
Number
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
A/B
xx/F/W
Yes
-xx
Visit 1
-xx
No
Inclusion
6
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Race: A=Asian, AIAN=American Indian or Alaska Native, B=Black or African American, NHPI=Native Hawaiian or Other Pacific 
Islander, O=Other W=White.
[a]   A negative number for study day denotes the number of days prior to the start of study treatment.
Source:xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l02.sas Version YYYY-MM-DD xx:xx       (Page n of N)
Notes to Programmer: 
If Race = Other (“O”), concatenate the specified race after ‘O’ within parenthesis, e.g., “O (specified)”. 
Sort by Actual Treatment, Center, and Subject ID within Center.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 72 of 100
4.3 Screening Lung Function and Reversibility
Listing 3
Screening Lung Function and Ventolin HFA Reversibility
Analysis Set: All Subjects Randomized
Subject
ID
Treatment
Sequence
Age (yrs)
/Gender/
Race [a]
Visit
Effort
Date
Time of 
Ventolin
HFA Dose 
(24 h 
clock)
Pre-Dose
Post-Dose
FEV1 (L)
FVC
(L)
FEV1 (L)
FVC
(L)
Reversibility % (Did 
subject withhold 
asthma maintenance 
medications and/or 
SABA within previous 
6 hours?)
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxx
A/B
70/F/W
1
YYYY-MM-DD
xx:xx
x.xxx
x.xxx
x.xxx
x.xxx
1a
YYYY-MM-DD
xx:xx
x.xxx
x.xxx
x.xxx
x.xxx
xx.x (Yes)
1b
YYYY-MM-DD
x.xxx
x.xxx
x.xxx
x.xxx
xx.x (Yes)
xxxxx
B/A
70/F/W
1
YYYY-MM-DD
xx:xx
x.xxx
x.xxx
x.xxx
x.xxx
xx.x (Yes)
xxxxx
A/B
70/F/W
1
YYYY-MM-DD
x.xxx
x.xxx
x.xxx
x.xxx
xx.x (Yes)
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Race: A=Asian, AIAN=American Indian or Alaska Native, B=Black or African American, NHPI=Native Hawaiian or Other Pacific Islander,
O=Other W=White.
NA = not applicable.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l03.sas  Version YYYY-MM-DD xx:xx   (Page n of N)
Notes to Programmer: Sort by Treatment Sequence, Center, and Subject ID within Center.  Move ‘Study Center/Inv’ row header to the next page whenever there is not enough 
room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 73 of 100
4.4 Baseline Characteristics
Listing 4.1
Asthma Diagnosis
Analysis Set: All Subjects Randomized
Subject ID
Treatment Sequence
Age (yrs)/Gender/Race
Asthma First Diagnosed
Date [a]
Months Prior to First Dose 
[b]
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
A/B
xx / Male/ xxxx
xx / Female / xxxx
YYYY-MM
YYYY-06*
x.x
xx.x
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Race: A=Asian, AIAN=American Indian or Alaska Native, B=Black or African American, NHPI=Native Hawaiian or Other Pacific Islander,
O=Other W=White.
[a]   Missing month of Date Asthma First Diagnosed will be imputed as June, or the month in which 1st was the latest before informed 
consent date; '*' indicates the month displayed was imputed.
[b]   Months Prior to First Dose When Asthma was First Diagnosed = (Date of First Dose of Study treatment in the study - Date Asthma 
First Diagnosed)/30.4375. Day of Diagnosis was imputed for all subjects as the 1st of the month.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0401.sas  Version YYYY-MM-DD xx:xx   (Page n of N)
Notes to Programmer: Sort by Treatment Sequence, Center and Subject ID within Center.  Move ‘Study Center/Inv’ row header to the next page whenever there is not enough 
room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 74 of 100
Listing 4.2
Medical and Surgical History
Analysis Set: All Subjects Randomized
Subject
ID
Treatment
Sequence
Age (yrs)/
Gender/
Race
System Organ
Class
Diagnosis or Surgery/
(Preferred Term)
Onset Date
(Year/
Month)
Onset
Day [a]
Still
Present?
End Date 
(Year/
Month)
End
Day [b]
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
A/B
70/F/W
xxxxxxxx
xxxxx/(xxxx)
YYYY-MM
-xxx
No
YYYY-MM
xxx
xxxxxx
xxxxx/(xxxx)
YYYY-MM
-xxx
No
YYYY-MM
xxx
xxxxxx
B/A
70/F/W
xxxxxxxxxxxxxxxx
xxxxx/(xxxx)
YYYY-MM
-xxx
No
YYYY-MM
xxx
xxxxxxxxxx
xxxxx/(xxxx)
YYYY-MM
-xxx
Yes
Ongoing
xxxxxx
A/B
70/F/W
xxxxxxxxxxxx
xxxxx/(xxxx)
YYYY-MM
-xx
No
YYYY-MM
xxx
xxxxxx
B/A
70/F/W
xxxxxxxxxx
xxxxx/(xxxx)
YYYY-MM
-xxx
No
YYYY-MM
xxx
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]   Onset Day=Onset date of condition – date of the first dose of study treatment. Day was imputed as 1st of the month. Missing month 
was imputed as June, or the month in which 1st was the latest before informed consent date; '*' indicates the month displayed was 
imputed.
[b]   End Day=End date of condition – date of the first dose of study treatment. Day was imputed as 1st of the month. Missing month was 
imputed as June, or the month in which 1st was the latest before informed consent date; ‘*' indicates the month displayed was 
imputed.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0402.sas  Version YYYY-MM-DD xx:xx             (Page n of N) 
Notes to Programmer: Sort by Treatment Sequence, Center, Subject ID, and Onset Day.  Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room 
on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 75 of 100
Listing 4.3
Screening Reproductive Status and Pregnancy Test Results
Analysis Set: All Subjects Randomized – WOCBP Only
Subject
ID
Treatment
Sequence
Age (yrs) 
/ Gender/
Race
Screening
Female
Reproductive
Status
If Subject is 
a WOCBP, Was 
Pregnancy
Test
Performed?
Pregnancy Test
Visit
[a]
Visit Date
Type of 
Pregnancy Test
Study Day of 
Test [a]
Result
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
A/B
70/F/W
Woman of Non-
Childbearing
Potential
(Non-WOCBP)
Visit 1
YYYY-MM-DD
Not Done 
NA
NA
xxxxxx
B/A
70/F/W
Woman of 
Childbearing
Potential
(WOCBP)
Yes
Visit 2
YYYY-MM-DD
Serum Pregnancy 
Test
xxx
Positive
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]    Pregnancy testing at Visit 2 was done prior to randomization.
[b]    Study Day is defined as date of test – date of the first dose of study treatment.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0403.sas  Version YYYY-MM-DD xx:xx                  (Page n of N)
Notes to Programmer: 
Sort by Treatment Sequence, Center, Investigator, Subject ID within Center, Visit, and Study Day of Pregnancy Test.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 76 of 100
Listing 4.4
Prior, Concomitant, and Post-Treatment Asthma Medications
Analysis Set: All Subjects Randomized
Subject
ID
(Treatm
ent
Sequenc
e)
Medication
Verbatim
Term
(Preferred
Term)
(ATC Term)
Dose/
Unit/
Route/
Frequency
Reason
for
Use
Begin Date
(YYYY-MM-DD)
Stop Date
(YYYY-MM-DD)
Ongoi
ng
Duration
(Days)
Study Day
Prior/
Concomitant/Post-
Treatment
Begin
Day
[a]
Stop
Day
[a]
Center # (Investigator): Center ### (xxxxxxxxxx)
1001
(A/B)
xxxxxxxxxxxx
(xxxxxx)
(xxxxxx)
90/ MCG/
IH/ PRN
# xxx
2008-XX-XX
Yes
-22
Yes/Yes/No
Other,
<speci
fy>
2008-XX-XX
Yes
-22
Yes/Yes/No
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
All Asthma-related medications taken within 30 days of Screening and while on study are listed. 
Medications were considered to be prior medications if taken prior to the start of study treatment. Medications were considered
concomitant if they were reported as being taken at any point from the start of randomized study treatment to the last date of study 
treatment. Medications with an onset date on or after the last dose of study treatment were considered post-treatment medications.
All subjects were allowed sponsor provided Ventolin HFA, and Pulmicort if previously using regularly scheduled ICS or ICS/LABA, during 
the Screening period, and Atrovent and/or Pulmicort during the treatment period which were reported on the Concomitant Medications
CRF.
XX = Unknown month or day.
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Pxx = Days after last dose.
Sources: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0404.sas    Version               YYYY-MM-DD xx:xx  (Page n of N)
Notes to Programmer: 
Sort by Treatment Sequence, Center, Subject ID, Preferred Term, and Begin Date of Asthma medication.  Show Anatomic and chemical portion of ATC code. Only medications 
with Reason for Use of Asthma on eCRF will be listed here.  Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at 
least one row of data underneath this header.  
Listing 4.5
Prior, Concomitant, and Post-Treatment Non-Asthma-Related Medications
Analysis Set: All Subjects Randomized
Add the following footnote: All non-Asthma-related medications taken within 30 days of Screening and while on study are listed.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 77 of 100
Listing 4.6
Suspect Drug Assessment for SAEs
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment
Sequence)
SAE Verbatim Term/
Preferred Term/
Onset Date
Additional
Non-IP
Medication
at Onset of 
SAE
Dose/
Unit/
Route/
Frequency
Started
Treatment/
Most
Recent
IP/Date of 
Most
Recent
IP/
Treatment
at Onset 
of AE/Non-
IP at 
onset of 
SAE
Begin Date/
Stop Date
(YYYY-MM-DD)
Con-
tin-
uing
Duration
(Days)
Begin Day/
Stop Day
[a]
SAE Causally 
Related to This 
Product/Does
Principal
Investigator
feel that SAE 
may be related 
to other 
factor?
(Specify)
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxx
(A/B)
Xxxxxxxxxxx/
Xxxxxxxxx/
YYYY-MM-DD
Ventolin
HFA
90/μg/
IH/PRN
Yes/B/
YYYY-MM-
DD/
Yes/Yes
2008-XX-XX
Yes
-22
Yes / Yes 
(Pre-existing
/Underlying
disease or 
Prior or 
Concomitant
Medication
xxxx
(B/A)
Xxxxxxxxxxx/
Xxxxxxxxx/
YYYY-MM-DD
Atrovent
HFA
34/μg/
IH/QID
No
2008-XX-XX/
2008-XX-XX
No
5
T1_P1/
T1_P5
No or Other
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
IP = Investigational Product.
XX = Unknown month or day.
[a] A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx_y = Treatment Period and Day within Treatment Pxx = Days after last dose in period.
Sources: xxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0405.sas   Version    YYYY-MM-DD xx:xx              (Page x of y)
Notes to Programmer: for last column, 2nd question, “Does Principal Investigator feel that SAE may be related to other factor? (Specify)”) is only listed on first line for each 
subject. 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 78 of 100
4.5 Dosing and Compliance
Listing 5.1.1
Study Drug Administration
Analysis Set: All Subjects Randomized
Subject ID
Treatment Sequence
Visit
(Study Day [a])
Dose Sequence
Date and Time of 
On-Site Study Dose
(Study Day [a])
Study
Medication
Component ID
Number of Puffs 
Taken
Study Center # / (Investigator):  ### (xxxxxxxxxx)
xxxxxx
A/-
Visit x (Tx_y)
Dose 1
YYYY-MM-DD (hh:mm)
(Tx_y)
Bxxxxx
x
Visit x (Tx_y)
Dose 2
YYYY-MM-DD (hh:mm)
(Tx_y)
Bxxxxx
x
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]   Study Day is Date – Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx=Days after last 
dose in the Period.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l050101.sas  Version  YYYY-MM-DD xx:xx  (Page n of N)
Notes to Programmer: 
Sort by Center, Subject within Center, Date Dispensed, and Component ID. 
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 79 of 100
Listing 5.1.2
Ventolin HFA, Atrovent, and Pulmicort Flexhaler Dispensing
Analysis Set: All Subjects Randomized
Subject ID
Treatment Sequence
Dispensed
Ventolin HFA/ 
Atrovent/
Pulmicort
Flexhaler
Date Dispensed
Study Day [a]
of Dispensing
Study Medication 
Component ID
Study Center # / (Investigator):  ### (xxxxxxxxxx)
xxxxxx
A/-
Yes
Ventolin HFA
YYYY-MM-DD
Tx_y
Bxxxxx
Yes
Pulmicort
Flexhaler
YYYY-MM-DD
Tx_y
Bxxxxx
Yes
Atrovent
YYYY-MM-DD
Tx_y
Bxxxxx
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]   Study Day is Date – Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after 
last dose in Period.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l050102.sas  Version  YYYY-MM-DD xx:xx  (Page n of N)
Notes to Programmer: 
Sort by Center, Subject within Center, Date Dispensed, and Component ID. 
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 80 of 100
Listing 5.2
Exposure to Study Treatment Overall and by Dose
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment Sequence) 
Age (yrs)/
Gender/
Race
Treatment
Period
Dose
Number of Puffs
Taken
Expected
[a]
Dose Level 
% of 
Expected
Exposure
(%) [b]
Taken
Overall
Overall
% of 
Expected
Exposure
(%) [c]
Center # / (Investigator):  ### (xxxxxxxxxx)
1001 (A/B)
70/F/W
1
Dose 1
1
1
100.00
xx
93.75
70/F/W
Dose 2
1
1
xx.xx
70/F/W
Dose 3
x
2
xx.xx
70/F/W
Dose 4
x
4
xx.xx
70/F/W
Dose 5
x
8
xx.xx
70/F/W
70/F/W
2
Dose 1
1
1
100.00
xx
xx.xx
70/F/W
Dose 2
1
1
xx.xx
70/F/W
Dose 3
x
2
xx.xx
70/F/W
Etc...
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]   The total expected number of puffs for a treatment day was 16 puffs.
[b]   Dose Level % of Expected Exposure = Total number of puffs of a treatment taken for a dose level/total expected puffs of a
treatment taken for the dose level, multiplied by 100.
[c]   Overall % of Expected Exposure = Total number of puffs of a treatment taken on a study day/total expected puffs of a treatment
taken on the study day (16 puffs), multiplied by 100.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0502.sas  Version  YYYY-MM-DD xx:xx              (Page n of N)
Notes to Programmer: 
Sort by Center, Subject within Center, Treatment Period, and Treatment Day. 
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  .


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 81 of 100
4.6 Individual Efficacy Data
4.6.1
Efficacy
Listing 6.1
Subjects Who Failed Restrictions Prior to Spirometry Assessment
Analysis Set: All Subjects Randomized
Subject
ID
Treatment
Sequence
Age (yrs)/
Gender/
Race
Treatment/Visit
Effort
Date
-60 Minute 
Pre-Dose
Effort Time
(24 h clock)
Prior to Study Visit, Subject has
Not Had Xanthine 
Containing Products 
for at Least 6 Hours 
Withheld Asthma 
Medications Including
Corticosteroids for 
at Least 8 Hours
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
A/B
70/F/W
A/Visit 2
YYYY-MM-DD
8:14:57
No
No
B/Visit 3
YYYY-MM-DD
8:14:57
No
No
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Note that subjects with missing data for either of the 2 restrictions are also listed.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0601.sas   Version   YYYY-MM-DD xx:xx              (Page n of N
Notes to Programmer: 
Sort by Center, Subject ID, and Effort Date. 
If Race is ‘O’ (other), concatenate it with the specified race.  Only subjects with ‘No’ or missing responses should be listed.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 82 of 100
Listing 6.2
Failure of Stability Criteria
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment Sequence)
Treatment
Visit
(Date of Spirometry Assessment)
Study Center # / (Investigator):  ### (xxxxxxxxxx)
Xxxxxx (A/B)
AS MDI
Visit 2
YYYY-MM-DD
Visit 3
YYYY-MM-DD
Xxxxxx (B/-)
Proventil
Visit 2
YYYY-MM-DD
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Source: xxxxxxx.sas7bdat 
Report generated by program: PT007002/sasdir/programs/statout/l0602.sas  Version  YYYY-MM-DD xx:xx             (Page n of N)
Notes to Programmer: 
Sort by Center, Subject ID within Center, and Visit. 
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 83 of 100
Listing 6.3
Reason for Missed Visit
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment Sequence)
Visit Missed
Treatment
Missed Due to Asthma Related Issues
Study Center # / (Investigator):  ### (xxxxxxxxxx)
Xxxxxx (A/B)
Visit xx
AS MDI
Yes
Xxxxxx (B/-)
Visit xx
Proventil
No
Visit xx
Unknown
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Source: xxxxxxx.sas7bdat 
Report generated by program: PT007002/sasdir/programs/statout/l0603.sas  Version  YYYY-MM-DD xx:xx                (Page n of N)
Notes to Programmer:
Sort by Center, Subject ID within Center, and Visit.
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 84 of 100
Listing 6.4
Spirometry Measurements
Analysis Set: All Subjects Randomized
Subject
ID
(Treatme
nt
Sequence
)
Age
(yrs)/
Gender/
Race/
Height
(cm)
Visit
Treatment/Tre
atment
Date/Time
(24 h clock)
Assessment
Date (Study 
Day) [a]
Rescue
Medication
used?
(Time)
Nominal
Time of 
Assessment
(Actual
Time of 
Assessment
24 h clock)
Spirometry Assessments
Raw Value
[Predicted Value at Screening]
(Percent of Predicted Value)
(grade) [b] 
FEV1 (L)
FVC (L)
FEV1/ FVC(%)
FEF
25-75
(L/sec)
Center # (Investigator): Center ### (xxxxxxxxxx)
Xxxxxx
(A/B)
53/F/W/xx
x
Visit 1
YYYY-MM-DD
(-xx)
Yes
(xx:xx
AM/PM)
-60 Min 
Pre-Dose
(xx:xx)
x.xxx [x.xxx]
(xx.x%)
(x)
x.xxx
[x.xxx]
(xx.x%)
(x)
xx.x
x.xxx
[x.xxx]
(xx.x%)
Repeat for 
Visit 1a 
or 1b, as 
necessary.
YYYY-MM-DD
(xx)
Yes
(xxxxxx)
15 Min Dose 
1 (xx:xx)
x.xxx (xx.x%)
(x)
x.xxx
(xx.x%)
(x)
xx.x
x.xxx
(xx.x%)
Visit 2
A/YYYY-MM-DD
hh:mm
YYYY-MM-DD
(xx)
Yes
(xxxxxx)
15 Min Dose 
1 (xx:xx)
x.xxx (xx.x%)
(x)
x.xxx
(xx.x%)
(x)
xx.x
x.xxx
(xx.x%)
Repeat for 
Visit 3 or 
Unschedule
d, as 
necessary.
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
NA = Not applicable.
[a]  Study Day is Date – Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after 
last dose in Period.
[b]  Grade is coded: 1=Acceptable  2=Borderline Acceptable  3=Unacceptable. 
Source: xxxxxxx.sas7bdat 
Report generated by program: PT007002/sasdir/programs/statout/l0604.sas   Version YYYY-MM-DD xx:xx            (Page n of N) 
Notes to Programmer: 
Sort by Center, Subject ID, Assessment Date, and Nominal Time of Assessment. 
Show Predicted Value only for Screening Visits. 
Nominal time of assessment  is the SAP-specified derived time window.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 85 of 100
4.6.2
Pharmacokinetics
Listing 6.5
Plasma Concentrations of Albuterol by Subject ID, Treatment, and Timepoint
Analysis Set: Safety Analysis Set
Subject ID
(Treatment
Sequence)
Treatment
Treatment
Period
Date of 
Sample/
Dose Number
Time
Pre/Post-
Dose
(minutes)
[a]
Scheduled
Sample Time 
Relative to 
Dose
(24 Hour 
clock)
Actual
Sample Time 
Relative to 
Dose
(24 Hour 
clock)
Time Deviation 
(Hours)
Plasma Concentration
Albuterol (pg/mL)
Study Center # / (Investigator): ### / (xxxxxxxxxx)
xxxxxx
(A/B)
A
1
Yyyymmdd/
Dose 5
-30 Pre
hh:mm
hh:mm
x.xx
xx.x*
+15 Post
+30 Post
+60 Post
+120 Post
+180 Post
+240 Post
+300 Post
+360 Post
+480 Post
+600 Post
+720 Post
Etc….
B
2
Yyyymmdd/
Dose 1
-30 Pre
hh:mm
hh:mm
x.xx
NA
+15 Post
Etc…
Treatment: A = AS MDI, B = Proventil.
Lower limit of quantification is 50 pg/mL.
BLQ = Below the limit of quantification.
NA = not available.
[a] Nominal timepoint.
*Excluded from summary statistics. Actual sampling time differs from scheduled sampling time by greater than the acceptable 
time deviation specified in the database edit check specifications.
Source: xxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0605.sas  Version  YYYY-MM-DD xx:xx               (Page n of N)
Notes to Programmer: If the serum concentration is missing, populate empty columns with ‘NA’. Sort by Center, Subject ID within Center, Treatment, Date, and Nominal
Timepoint.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 86 of 100
Listing 6.6
Derived Pharmacokinetic Parameters of Albuterol by Subject ID and Treatment Period
Analysis Set: PK Analysis Set
Subject ID 
(Treatment
Sequence)
Age
Gender
Race
Treatment Period
Treatment
PK Parameter
Result
Center # / (Investigator): ### / (xxxxxxxxxx)
Xxxxxx
(A/B)
xx
x
xxxx
1
A
AUC0-t (pg/mL)
xx.x
Cmax (pg/mL)
xx.x
C15min (pg/mL)
xx.x
tmax (min)
xx.x
2
B
Etc.
NA
NA
Treatment: A = AS MDI, B = Proventil.
NA = not available.  NE = not estimable.
Source: xxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0606.sas  Version  YYYY-MM-DD xx:xx
(Page n of N)
Notes to Programmer: If the PK parameter result is missing, populate empty columns with ‘NA’.
Sort by Center, Subject ID within Center, Treatment Period, and PK Parameter.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 87 of 100
4.7 Adverse Event Listings
Listing 7.1
Adverse Events by Primary System Organ Class, Preferred Term, Treatment, Center, Subject ID, and Onset Day
Analysis Set: All Subjects Randomized
Primary System Organ Class:  xxxxxxxxxxxxxxxxx
Preferred Term
Treatment
Center # 
(Investigator)
Subject ID
(Treatment
Sequence)
Age
(yrs)
/Gender
/
Race
Treatment
Emergent
/ Serious 
AE? [c]
Onset
Day
[a]
Duration
of
Event
[b]
Severity / 
Relationship
Action (Outcome) 
(AE Treated)
Study Day 
Resolved
/Death[a]
xxxxxxxxxxxxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxx ### 
(xxxxxxxxxx)
Xxxxxx
(A/B)
70/F/W
Yes / No
T1_P1
xx
Moderate / 
Yes
None(Recovered/R
esolved) (Yes)
Tx_P5
70/F/W
Yes / No
T2_P2
xx
Moderate/
Yes
Drug
Interrupted(Reco
vering/Resolving
)g (Yes)
xxxxxxxxxx
xxxxxx
xxxxxxxxx
###
(xxxxxxxxxx)
Xxxxxx
(A/B)
70/F/W
Yes / 
Yes
T1_P1
xx
xxxxxxxx/
xxxxxxxxx
Dose not changed 
(Recovered/Resol
ved with 
sequelae)(No)
T2_P7
xxxxxxxx
###
(xxxxxxxxxx)
Xxxxxx
(A/B)
70/F/W
Yes / No
T2_P2
xx
xxxxxxxx/
xxxxxxxxx
Dose not changed 
(Recovered/Resol
ved with 
sequelae)(No)
…
xxxxxxxxxxxxxxxxxxx
xxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
###
(xxxxxxxxxx)
Xxxxxx
(A/B)
70/F/W
# /No
xx
xxxxxxxx/
xxxxxxxxx
Dose not changed 
(Recovered/Resol
ved with 
sequelae)(Yes)
Xxxxxx
(A/B)
70/F/W
Yes / 
Yes
T2_P2
xx
xxxxxxxx/
xxxxxxxxx
Drug withdrawn 
(Recovering/Reso
lving)
(Yes)
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]
A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period.
On Study Day 1, an @ indicates that event started before study drug administration.
On Study Day 1, @@ indicates that event started after study drug administration.
[b]  Duration of Event = Stop Day - Onset Day + 1. 
[c]  # indicates that it could not be determined whether the AE had onset during study treatment. 
Source: xxxx.sas7bdat


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 88 of 100
Report generated by program: PT007002/sasdir/programs/statout/l0701.sas  Version YYYY-MM-DD xx:xx                 (Page n of N)
Notes to Programmer: 
Sort by Primary System Organ Class, Preferred Term, Actual Treatment, Center, Subject ID within Center, and Onset Day. 
Put a blank line after each Center. Present the preferred term, treatment, center (investigator name), Subject ID (Actual Treatment and Age/gender/Race only if start a new value 
or at the first line of each page.
When a date of onset or date resolved is only partial, put full date in parenthesis under Study Day.
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 89 of 100
Listing 7.2
Glossary of Adverse Event Preferred Terms vs. Investigator’s Verbatim
MedDRA Adverse Event Coding Dictionary
Investigator’s AE Verbatim
Primary System Organ Class
Preferred Term
xxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
MedDRA Version 21.0 was used for coding.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0702.sas  Version YYYY-MM-DD xx:xx                  (Page n of N)
Notes to Programmer: Sort by Primary System Organ Class, Preferred Term, and Verbatim Term. List all unique investigators’ AE verbatim.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 90 of 100
Listing 7.3
Adverse Events by Treatment, Center, Subject ID, and Onset Day
Analysis Set: All Subjects Randomized
Subject ID
(Treatment
Sequence)
Age
(yrs)/
Gender/
Race
Onset
Date/
Onset
Day/
Occurr
ed on 
or
After
Start
of
Treatm
ent on 
Day 1
[a]
Primary System 
Organ Class
AE Verbatim 
(Preferred Term)
Treat.
Emerg.
[b]
Event
Seriou
s
Duration
of Event Severity
Relation
-ship
Action
AE
Treated
?
Outcome
(Death?)
Day
Resolved/
Death [a]
Treatment: AS MDI
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxx (A/B)70/F/W
YYY-
MM-DD/
T1_1/Y
es
xxx xxx xxxxx
AE 1
(xxxxxxxxxxxx)
Yes
No
xx
Moderate
No
Dose not 
changed
No
Recoveri
ng/Resol
ving
YYY-
MM-DD/
T1_P1/
NA
xxx xxx xxxx
AE 2 
(xxxxxxxxxx)
No
No
xx
Moderate
Yes
Drug
Interrup
ted
Yes
Not
Recovere
d/Not
Resolved
(Yes)
T1_P3
…
…
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period.
On Study Day 1, an @ indicates that event started before study drug administration.
On Study Day 1, @@ indicates that event started after study drug administration.
[b]  # indicates that it could not be determined whether the AE had onset during study treatment.
Sources: adae.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0703.sas  Version YYYY-MM-DD xx:xx                 (Page n of N)
Notes to Programmer: 
Sort by Actual Treatment, Center, Subject ID, Primary System Organ Class, Preferred Term, and Onset Day. 


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 91 of 100
Put a blank line after each subject. 
Present the preferred term, latest treatment, center (investigator name), Subject ID, and Age/gender/Race when value changes start a new value or at the first line of each page
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  
If Ongoing is ticked on CRF, show ‘Ongoing’ under Study Day Resolved.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 92 of 100
4.8 Laboratory Values
Listing 8.1
Laboratory Test Results (Hematology Panel)
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment
Sequence)
Age
(yrs)/
Gender/
Race
Visit
(Study Day 
[a])
Collection
Date
(Study Day)
[a]
Nominal
Time of 
Collection
(24 hr clock)
Lab Name
(LAB ID) 
Lab
Parameter
(Unit)
Assay
Value
Reference
Range
Low-High
Flag [b]
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
(A/B)
70/F/W
Screening
Visit 1 
(-xx)
YYYY-MM-DD (-xx)
Pre-dose
(hh:mm)
xxxxxx
xxxxxxxxx
x
xxx
xxx-xxx
L/H
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
NA = Not Applicable.
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. 
[b]  N = Normal; L = Low; H = High; Abn. = Abnormal; I=Indeterminate; 
Source: adlb.sas7bdat 
Report generated by program: PT007002/sasdir/programs/statout/l0801.sas  Version YYYY-MM-DD xx:xx                  (Page n of N) 
Notes to Programmer: 
Sort by Treatment Sequence, Center, Subject ID, Date of Visit, Nominal Time of Collection, and Lab Parameter.  In footnote [b], delete ‘I=Indeterminate’ if this flag does not exist 
in the data. Delete ‘(LAB ID)’ if this does not exist in the data.
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 93 of 100
Listing 8.2
Laboratory Test Results (Chemistry Panel and Kidney Function)
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment
Sequence)
Age
(yrs)/
Gender/
Race
Visit
(Study
Day [a])
Treatment Time (24 
h clock)
Collection
Date
(Study Day)
[a]
Nominal
Time of 
Collection
(24 hr clock)
Lab Name
(LAB ID) 
Lab
Parameter
(Unit)
Assay
Value
Reference
Range
Low-High
Flag
[b]
Change
From
Baseline
[c]
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx)
xxxxxx
(A/B)
70/F/W
Screening
Visit 1a 
(-xx)
10:13
YYYY-MM-DD (1)
Pre-dose
(hh:mm)
xxxxxx
xxxxxxxxxx
xxx
xxx-xxx
L/H
x.xxx
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
NA = Not Applicable.
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. 
[b]  N = Normal; L = Low; H = High; Abn. = Abnormal; I=Indeterminate; Albuterol has known pharmacodynamic effects on glucose and
potassium. As such, the standard reference ranges for glucose and potassium are not applicable post administration of albuterol.
[c]  For change from baseline, baseline is defined as the last available pre-dose measurement taken prior to the start of treatment on 
Day 1 of the treatment period.
Source: adlb.sas7bdat 
Report generated by program: PT007002/sasdir/programs/statout/l0802.sas  Version YYYY-MM-DD xx:xx                  (Page n of N) 
Notes to Programmer: 
Sort by Actual Treatment, Center, Subject ID, Date of Visit, Nominal Time of Collection, and Lab Parameter.  In footnote [b], delete ‘I=Indeterminate’ if this flag does not exist in 
the data. Delete ‘(LAB ID)’ if this does not exist in the data.
For the post-dose glucose and potassium Reference Range, put “N/A”. 
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 94 of 100
Listing 8.3
Laboratory Test Comments
Analysis Set: All Subjects Randomized
Subject ID
(Treatment
Sequence)
Visit
(Study
Day
[a])
Time of 
Treatment
(24 hr 
clock))
Collection
Date
(Study Day 
[a])
Nominal
(Actual)
Time of 
Collection
(24 h 
clock)
Lab
Name
Lab Group
Lab
Parameter
(Unit)
Assay
Value
Reference
Range
Low-High
Flag
[b]
Result
Comments
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxxx
(A/B)
Visit
2
(T1_1)
hh:mm
YYYY-MM-DD
(T1_1)
-60 Min 
Pre-Dose
(hh:mm)
LabCorp
Chemistry
Glucose
(mmol/L)
xx
xx-xx
L
xxxxxx
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
NA = Not Applicable.
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period.
[b]  N = Normal; L = Low; H = High; Abn. = Abnormal; I=Indeterminate; 
Source: adlb.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0803.sas  Version YYYY-MM-DD xx:xx                 (Page n of N)
Notes to Programmer: 
Sort by Treatment Sequence, Center, Subject ID, Date of Visit, Nominal Time of Collection, and Lab Parameter.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 95 of 100
4.9 Other Clinical Observations and Measurements
Listing 9.1
Vital Signs, Weight, and Height
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment
Sequence)
Age (yrs)/
Gender/
Race
Visit
Visit Date
(Study Day) 
[a]
Time of treatment
(24 h clock)
Nominal Time 
(Actual Time) of 
Assessment
(24 h clock)
Systolic BP
(Change from 
baseline)
[b]
(mmHg)
Diastolic BP
(Change from 
baseline)
[b]
(mmHg)
Height
(cm)
Weight
(kg)
BMI
(kg/m^2)
Center # (Investigator): Center ### (xxxxxxxxxx)
Xxxxxx
(A/B)
70/F/W
Screening
Visit 1 
YYYY-MM-DD
(-xx)
NA
NA (NA)
xxx
xxx
xxx
xxx.x
xxx.x
Screening
Visit 1a
YYYY-MM-DD
(-xx)
NA
NA (NA)
xxx
xxx
xxx
xxx.x
xxx.x
Visit 2 
YYYY-MM-DD
(Tx_y)
hh:mm
-60 Min.Pre-
Dose (xx:xx)
xxx
xxx
xxx
xxx.x
xxx.x
+15 Min. Post-
Dose 1 (xx:xx) 
(xx)
xxx
xxx
+15 Min. Post-
Dose 2 (xx:xx) 
(xx)
xxx (xx)
xxx (xx)
Repeat for 
Visit 3 and 
Unscheduled as
necessary.
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
NA = Not Applicable.
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period.
[b]  For change from baseline, baseline is defined as the last available pre-dose measurement taken on Day 1 of the treatment period
prior to the start of dosing of the treatment period.
Source: advs.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0901.sas  Version    YYYY-MM-DD xx:xx              (Page n of N)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 96 of 100
Notes to Programmer: 
Sort by Treatment Sequence, Center, Subject ID, Date of Visit, and Nominal Time of Assessment.  
Nominal time of assessment  is the SAP-specified derived time window.  
Show Nominal Window of ‘Pre-Dose’ from dataset as “Pre-Dose 60 Min.” here in this listing as indicated above.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 97 of 100
Listing 9.2
12-Lead Electrocardiogram (ECG)
Analysis Set: All Subjects Randomized
Subject ID 
(Treatment
Sequence)
Age
(yrs)/
Gender/
Race
Visit
Visit Date
(Study Day) [a]
Treatment Time 
(24 h clock)
Nominal Time (Actual 
Time) of Assessment
(24 h clock)
Heart
Rate
(Change)
(BPM)
Interval Raw Value
(Change From Baseline) [b]
Any
Clinically
Significant
Abnormalities
on a Study 
Day? [c]
RR
(ms)
PR
(ns)
QRS Axis
(degrees)
QRS
(ms)
QT
(ms)
QTcF
(ms)
Center # (Investigator): Center ### (xxxxxxxxxx)
xxxxx (A/B) 70/F/W
Visit 1
YYYY-MM-DD
(-xx)
NA
NA (NA)
xx.x
xxx
xxx
xx
xxx
xxx
xx
No
Visit 1a or 1b, 
as necessary
YYYY-MM-DD
(-xx)
NA
NA (NA)
xx.x
xxx
xxx
xx
xxx
xxx
xx
No
Visit 2
YYYY-MM-DD
(Tx_y)
Hh:mm
60 Min. Pre-Dose
(xx:xx)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
No
15 Min. Post-Dose
(xx:xx)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
xx.x
(xx.x)
Yes
Repeat for 
Visit 3 and 
Unscheduled
NA
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
Abnormalities at Screening Visits and Pre-Dose on Day 1 of Treatment Period 1 were noted on the Medical History CRF; abnormalities 
Post-Dose on Day 1 of Treatment Period 1 or afterward were noted on the Adverse Events CRF.
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period.
[b]  For change from baseline, baseline is defined as the last available pre-dose measurement taken on Day 1 of the treatment period 
prior to the start of dosing.
Source: eg.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0902.sas  Version YYYY-MM-DD xx:xx                 (Page n of N) 
Notes to Programmer: Sort by Treatment Sequence, Center, Subject ID, Date of Visit, and Nominal Time of Assessment.  
Nominal time of assessment  is the SAP-specified derived time window.  
Show Nominal Window of ‘Pre-Dose’ from dataset as “Pre-Dose 60 Min.” here in this listing as indicated above.  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 98 of 100
Listing 9.3
Comments
Analysis Set: All Subjects Randomized
Subject
ID
Treatment
Sequence
Age (yrs)/
Gender/
Race
Visit
Study Day
[a]
Comment Applies 
To:
Comments
Study Center # / (Investigator):  ### (xxxxxxxxxx)
xxxxx
A/B
70/F/W
Screening Visit 1
Screening Visit 1a
Screening Visit 1b
Visit 2 Treatment 1 
Day 1
Visit 3 Treatment 1 
Day 1
…
Premature
Discontinuation
Telephone
Follow-up
Unscheduled
Tx_y
Subject
Eligibility
Study Medication
Adverse Event
Blood Pressure
12-Lead ECG
Laboratory Test
Spirometry
Visit Scheduling
PK Sampling
Other:
xxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxx
Treatment: A = AS MDI, B = Proventil, - = Not Treated.
[a]
A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date –
Date of first dose in the Period + 1. Tx = Period. Tx_y = Period and Day within Period. Pxx = Days after last dose in Period.
Source: xxxxxxx.sas7bdat
Report generated by program: PT007002/sasdir/programs/statout/l0903.sas  Version  YYYY-MM-DD xx:xx       (Page n of N)
Notes to Programmer: 
Sort by Center, Investigator, Subject ID, Visit, Study Day, and category that comment applies to (Subject Eligibility, Study Medication, etc…).  
Move ‘Study Center/Inv’ row header to the next page whenever there is not enough room on current page to fit at least one row of data underneath this header.  
Column and text in YELLOW is optional for studies where one or more ‘Visits’ are not associated with a Study Day.


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 99 of 100
5. CLINICALTRIALS.GOV: DISPOSITION TABLES
Table 1.1
Subject Disposition
Analysis Set: All Subjects Randomized
Treatment Sequence
AS MDI/
Proventil
(N=xxx)
Proventil/
AS MDI
(N=xxx)
n (%)
n (%)
Started (Randomized)
xx (100.0)
XX (100.0)
Not Treated
xx (xx.x)
xx (xx.x)
Treated in at least one period
Treated in 1 Period Only
xx (xx.x)
xx (xx.x)
Treated in 2 Periods
xx (xx.x)
xx (xx.x)
Completed Treatment <Programmer this is from the End of 
Treatment/Discontinuation CRF>
xx (xx.x)
xx (xx.x)
Premature TreatmentDiscontinuation
xx (xx.x)
xx (xx.x)
Reason for Premature Discontinuation
Administrative Reasons
xx (xx.x)
xx (xx.x)
Adverse Event
xx (xx.x)
xx (xx.x)
Lack of Efficacy
xx (xx.x)
xx (xx.x)
Subject Discretion – Withdrawal of Consent
xx (xx.x)
xx (xx.x)
Subject Discretion – Asthma
xx (xx.x)
xx (xx.x)
Subject Discretion – Other
xx (xx.x)
xx (xx.x)
Investigator or Designee Considers it to be in the Best Interest of the 
Subject
xx (xx.x)
xx (xx.x)
Subject Lost-to-Follow-up
xx (xx.x)
xx (xx.x)
Major Protocol Deviation
xx (xx.x)
xx (xx.x)
Protocol-Specified Discontinuation Criteria
xx (xx.x)
xx (xx.x)
FEV1 Stability Criteria Sec 5.1.4
xx (xx.x)
xx (xx.x)
Requirement OF any Prohibited Medications Listed in Sec 7.7.3
xx (xx.x)
xx (xx.x)
Positive Pregnancy Test
xx (xx.x)
xx (xx.x)
Asthma Worsening Requiring Change in Asthma Treatment Sec 3.9
xx (xx.x)
xx (xx.x)
Treatment Code Broken by Investigator
xx (xx.x)
xx (xx.x)
Other
xx (xx.x)
xx (xx.x)
Report generated by program: PT007002/sasdir/programs/statout/clinicaltrials_gov/t0101.sas Version  YYYY-MM-DD xx:xx   (Page n of N)


Albuterol Sulfate Pressurized Inhalation Suspension
Protocol D6930C00002 (PT007002)
Version 1.0
30 Mar 2018
Page 100 of 100
Notes to Programmer: Sort by descending frequency of major reason category using AS MDI column. Within a major reason category, sort by descending frequency of 
subcategory using AS MDI column. Percentages are percentages of all subjects randomized.
Table 1.2
Subject Disposition: Period 1
Analysis Set: All Subjects Randomized
Notes to Programmer: Replace column header of ‘Treatment Sequence” in Table 1.1 with “Treatment” and the 2 Treatment Sequences with the 2 Treatments in Period 1. 
Percentages are percentages of all subjects randomized. 
Table 1.3
Subject Disposition: Washout Between Period 1 and Period 2
Analysis Set: All Subjects Randomized Who Entered the Washout
Notes to Programmer: Replace column header of ‘Treatment Sequence” in Table 1.1 with “Treatment in Period 1” and the 2 Treatment Sequences with the 2 Treatments in Period 
1. Instead of ‘Started (Randomized)’ in Table 1.1 use ‘Started (Randomized, Completed Period 1 Test Day, and Entered the Washout Period)’. Note that subject who entered the 
washout can be determined from the dates of Period 1 treatment date and the Visit 2 and Visit 3 sometimes, and the subject LTF date from the End of Treatment/Discontinuation 
eCRF. If a subject did not go to Period 2, and dropped during the washout, the only subjects we can count are those LTF and have an LTF date on the End of 
Treatment/Discontinuation eCRF.
The site will be asked to identify if a subject entered the Washout Period between Periods 1 and 2 when the subjects dropped prior to Period 2.
Table 1.4
Subject Disposition: Period 2
Analysis Set: All Subjects Randomized
Notes to Programmer: Replace column header of ‘Treatment Sequence” in Table 1.1 with “Treatment in Period 2” and the 2 Treatment Sequences with the 2 Treatments in Period 
2. Instead of ‘Started (Randomized)’ in Table 1.1 use ‘Started (Randomized and Attended the  Period 2 Test Day)’.