A Placebo-controlled, Double-blind, Randomized, Trial of AMZ001 for the Treatment of Knee Osteoarthritis Symptoms
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Sponsor: Amzell

A placebo-controlled, 
double-blind, randomized, trial of 
Diclofenac Gel AMZ001 3.06% 
for the treatment of 
knee osteoarthritis
NTC03691844
Document Date: 22Nov2018

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 







6\QRSVLV

&OLQLFDO7ULDO3URWRFRO1XPEHU
$0=
7LWOH
$SODFHERFRQWUROOHGGRXEOHEOLQGUDQGRPL]HG
WULDORI'LFORIHQDF*HO$0=IRUWKH
WUHDWPHQWRINQHHRVWHRDUWKULWLVV\PSWRPV
7ULDO3KDVH

,1'1XPEHU

)'$FRYHUHGWULDO
<HV
(XGUD&71XPEHU

6SRQVRU
$P]HOO%9
&KLHI6FLHQWLILF2IILFHU
1DPH'DULR&DUUDUD3K'
$GGUHVV6LULXVGUHHI+RRIGGRUS:7
7KH1HWKHUODQGV
6SRQVRU/HJDO5HSUHVHQWDWLYHLQWKH
(XURSHDQ8QLRQ
$P]HOO%9
6LULXVGUHHI41
+RRIGGRUS:7 
7KH1HWKHUODQGV 
7HOHSKRQH1XPEHU
7ULDOFHQWHUVFRXQWULHV
'HQPDUN
&]HFK5HSXEOLF
8QLWHG6WDWHVRI$PHULFD
3ODQQHGWULDOSHULRG
ILUVWVXEMHFWLQODVWVXEMHFWRXW
)LUVWVXEMHFWLQ$XJXVW
/DVWVXEMHFWRXW0DUFK
2EMHFWLYHV
3ULPDU\2EMHFWLYH
x 7RHYDOXDWHFKDQJHVLQSDLQLQWHQVLW\LQWHUPVRIWKH:20$&SDLQVFRUHRIWKHWDUJHW
NQHH
1

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 






6HFRQGDU\2EMHFWLYHV
x 7RHYDOXDWHFKDQJHVLQV\PSWRPVRI2$
x 7RHYDOXDWHWKHFKDQJHVLQSK\VLFDOIXQFWLRQLQJ
x 7RHYDOXDWHDGPLQLVWUDWLRQUHJLPHQVRI$0=
x 7RHYDOXDWHWKHVDIHW\DQGWROHUDELOLW\RI$0=
x 7RHYDOXDWHFKDQJHVLQTXDOLW\RIOLIH
([SORUDWRU\2EMHFWLYHV
x 7RILQDOL]HWKHYDOLGDWLRQRIWKHSDLQGLDU\DQGWKHVDWLVIDFWLRQTXHVWLRQQDLUH
x 7RH[SORUHWKHRQVHWRIDFWLRQRIWRSLFDO$0=
x 7RH[SORUHWKHHIILFDF\RIWZRUHJLPHQVRI$0=DQG9ROWDUHQ*HO
x 7RH[SORUHWKHOHYHORIGLFORIHQDFLQSODVPD

0HWKRGRORJ\
7KLVLVDPXOWLFHQWHUUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGSDUDOOHOJURXSZHHN
WULDORIDQRYHOIRUPXODWLRQRIGLFORIHQDFJHO$0=RQFHRUWZLFHGDLO\YHUVXVSODFHERWZLFH
GDLO\LQFOXGLQJDVLQJOHEOLQGWUHDWPHQWJURXSZLWKFRPPHUFLDOGLFORIHQDF9ROWDUHQ
JHO IRXU WLPHV GDLO\ $SSUR[LPDWHO\  VXEMHFWV ZLOO EH UDQGRPL]HG WR RQH RI WKH IRXU
WUHDWPHQW JURXSV 7KHVXEMHFWV ZLOOEHUDQGRPL]HGZLWK XSWR VXEMHFWV LQ HDFKRIWKH
GRXEOHEOLQGHGWUHDWPHQWJURXSVDQGXSWRVXEMHFWVLQWKHVLQJOHEOLQGHGWUHDWPHQWJURXS
7KHWUHDWPHQWJURXSVDUH

 $0='LFORIHQDF*HOJUDPVDVWZRSXPSDFWXDWLRQVRIJUDPV
RQFHLQWKHPRUQLQJDQGSODFHERRQFHLQWKHHYHQLQJIRUHDFKNQHHDIIHFWHGWRWDO
GDLO\DPRXQWRIGLFORIHQDFVRGLXPSHUNQHHPJ
 $0='LFORIHQDF*HOJUDPVWZLFHGDLO\SHUNQHHDIIHFWHGWRWDOGDLO\
DPRXQWRIGLFORIHQDFVRGLXPSHUNQHHPJ
 3ODFHER*HOJUDPVWZLFHGDLO\SHUNQHHDIIHFWHG
 &RPPHUFLDO9ROWDUHQJHOJUDPVWLPHVGDLO\VLQJOHEOLQGSHUNQHH
DIIHFWHGWRWDOGDLO\DPRXQWRIGLFORIHQDFVRGLXPSHUNQHHPJ
2

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 






$IWHUZULWWHQLQIRUPHGFRQVHQWLVREWDLQHGVXEMHFWVZLOOEHVFUHHQHGIRUHOLJLELOLW\$WWKH
6FUHHQLQJ9LVLWVXEMHFWVZLOOILUVWXQGHUJRDPHGLFDOKLVWRU\LQWHUYLHZWRYHULI\WKDWWKH\PHHW
GHPRJUDSKLFDQGFOLQLFDOFULWHULDIRULQFOXVLRQLQWRWKHVWXG\6XEMHFWVZLOOVHOIHYDOXDWHSDLQ
DIWHU DGHTXDWH ZDVK RXW RI DQ\ SDLQ PHGLFDWLRQ RQ D :HVWHUQ 2QWDULR DQG 0F0DVWHU
8QLYHUVLWLHV2VWHRDUWKULWLV,QGH[:20$&SDLQVXEVFRUHTXHVWLRQVTXHVWLRQQDLUHIRU
ERWKNQHHVDQGKLSV,IERWKNQHHVPHHWUDGLRJUDSKLFDQGSDLQFULWHULDWKHUHSRUWHGSDLQVFRUH
RIWKHWDUJHWNQHHVKRXOGH[FHHGWKDWRIWKHFRQWUDODWHUDONQHH,IKLSSDLQRIHLWKHUKLSH[FHHGV
WKDWRIWKHWDUJHWNQHHWKHVXEMHFWVKRXOGEHGLVFKDUJHGIURPWKHVWXG\
$SK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVPHDVXUHPHQWRIVLWWLQJGLDVWROLFDQGV\VWROLF
EORRGSUHVVXUHKHDUWUDWHDQGPHDVXUHPHQWRIKHLJKWDQGZHLJKWZLOOEHSHUIRUPHG6XEMHFWV
QRWPHHWLQJWKHGHILQHGFULWHULDZLOOEHGLVFKDUJHGIURPWKHVWXG\
;UD\ LPDJHV RI WKH NQHHV ZLOO EH REWDLQHG XVLQJ D )L[HG)OH[LRQ IUDPH 6\QDIOH[RU RU
VLPLODUDQGDFHQWUDOUDGLRORJLVWUHDGHUZLOOJUDGHRVWHRDUWKULWLVRQWKH.HOOJUHQ/DZUHQFH
VFDOH
%ORRGZLOOEHFROOHFWHGIRUKHPDWRORJ\DQGVDIHW\FKHPLVWU\$VFUHHQLQJVHUXPSUHJQDQF\
WHVWZLOOEHSHUIRUPHGIRUVXEMHFWVZKRDUHZRPHQRIFKLOGEHDULQJSRWHQWLDO
8SRQPHHWLQJDOOHOLJLELOLW\FULWHULDDQGFRPSOHWLQJDOOVFUHHQLQJDVVHVVPHQWVDWDUJHWNQHH
ZLOOEHDVVLJQHGDQGVXEMHFWVZLOOEHUDQGRPL]HGLQWRRQHRIIRXUJURXSV3UHVHQFHRIELODWHUDO
2$RIWKHNQHHVLVDOORZHG,IERWKNQHHVIXOILOOWKHGLDJQRVWLFUDGLRJUDSKLFDQGV\PSWRPDWLF
LQFOXVLRQFULWHULDERWKNQHHVVKRXOGEHWUHDWHGZLWK,03WKURXJKRXWWKHWUHDWPHQWSHULRGEXW
WKHPRUHSDLQIXONQHHLVVHOHFWHGDVWKHWDUJHWNQHH,IVLJQLILFDQWSDLQGHILQHGDVPHHWLQJWKH
SDLQLQFOXVLRQFULWHULDDQGRIWKHFRQWUDODWHUDONQHHDULVHVGXULQJWKHFRXUVHRIWKHWULDO
,03WUHDWPHQWVKRXOGEHLQLWLDWHGRQWKHFRQWUDODWHUDONQHHLQDGGLWLRQWRWKHWDUJHWNQHHDQG
FRQWLQXHG RQ ERWK NQHHV WKURXJK WKH UHPDLQGHU RI WKH WULDO ,QLWLDWLRQ RI WUHDWPHQW RI WKH
FRQWUDODWHUDONQHHVKRXOGRQO\EHLQLWLDWHGDWVWXG\YLVLWVDQGQRWEHWZHHQVWXG\YLVLWV
7KHWUHDWPHQWSKDVHFRQVLVWVRIIRXUZHHNVRIWUHDWPHQWZLWKRQHEDVHOLQH'D\YLVLWDQG
ZHHNO\YLVLWVLQDGGLWLRQWRSHUIRUPLQJGDLO\3DLQ'LDULHVDQG:20$&SDLQVXEVFRUH
TXHVWLRQVTXHVWLRQQDLUHVDWKRPHGXULQJWKHILUVWZHHNRIWUHDWPHQWLQWKHHYHQLQJRIHYHU\
GD\2QHILQDOIROORZXSSKRQHYLVLWZLOOEHSHUIRUPHGDSSUR[LPDWHO\GD\VDIWHUWKHODVW
,03DSSOLFDWLRQKDVEHHQSHUIRUPHG
:20$&,QWHUPLWWHQWDQG&RQVWDQW2VWHRDUWKULWLV3DLQ,&2$3DQGRWKHUTXHVWLRQQDLUHVZLOO
EHSHUIRUPHGRQ'D\V%DVHOLQHDQGDQG,QRUGHUWR³ZDVKRXW´WKHHIIHFWRI
UHVFXHPHGLFDWLRQWKHVXEMHFWVVKRXOGUHIUDLQIURPWDNLQJUHVFXHPHGLFDWLRQZLWKLQKRXUV
SULRUWRDQ\VWXG\YLVLW

3

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 






6XEMHFWVZLOODSSO\,03JHORQWKHSDLQIXOWDUJHWNQHHMRLQWLQDFFRUGDQFHZLWKWKHDOORFDWHG
WUHDWPHQWJURXS$WHDFKSODQQHGGLVSHQVDWLRQRIVWXG\GUXJ'D\DQG'D\
x 7KHVXEMHFWVLQWKHGRXEOHEOLQGHGJURXSVWUHDWPHQWVDQGZLOOEHSURYLGHGZLWK
WZRPHWHUHGGRVHGLVSHQVHUVRIJHOHDFKPDUNHGIRUHLWKHUPRUQLQJRUHYHQLQJXVH
x 7KHVXEMHFWVLQWUHDWPHQWZLOOEHSURYLGHGZLWKWXEHVRI9ROWDUHQJHO
7DEOH$SSOLFDWLRQ6FKHGXOH

$0=
'LFORIHQDF*HO
4'
$0=
'LFORIHQDF*HO
%,'

3ODFHER

9ROWDUHQ
JHO
$FWLYH
3ODFHER $FWLYH
3ODFHER $FWLYH 3ODFHER
0RUQLQJ
;

;


;
;
1RRQ
1$
1$
1$
1$
1$
1$
;
(YHQLQJ

;
;


;
;
%HGWLPH
1$
1$
1$
1$
1$
1$
;
7ZR SXPS DFWXDWLRQV RI HDFK  JUDP RI JHO WR EH DSSOLHG SHU WUHDWHG NQHH DW HDFK
DSSOLFDWLRQ
)RXUJUDPVRIJHOWREHDSSOLHGSHUWUHDWHGNQHHDWHDFKDSSOLFDWLRQ
3ODQQHGQXPEHURIVXEMHFWV
8SWRVXEMHFWVZLOOUHFHLYH$0=RQFHGDLO\DQGSODFHERRQFHGDLO\ZLOO
UHFHLYH$0=WZLFHGDLO\DQGZLOOUHFHLYHSODFHERWZLFHGDLO\$VLQJOHEOLQGHGJURXS
RIVXEMHFWVZLOOUHFHLYH9ROWDUHQJHOWLPHVGDLO\

3ULPDU\HQGSRLQWGRXEOHEOLQGWUHDWPHQWJURXSRQO\
7KHSULPDU\HQGSRLQWRIWKLVWULDOLVWKHFKDQJHIURPEDVHOLQHLQ:20$&SDLQVXEVFRUH
TXHVWLRQVWRLQWKHWDUJHWNQHHDVHYDOXDWHGDWZHHN
4

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 







6HFRQGDU\HQGSRLQWVGRXEOHEOLQGWUHDWPHQWJURXSRQO\
x &KDQJHVIURPEDVHOLQHLQ:20$&WRWDOVFRUHDQGWKH:20$&IXQFWLRQDQGVWLIIQHVV
VFRUHVDWZHHN
x &KDQJHVIURPEDVHOLQHLQFRQVWDQWDQGLQWHUPLWWHQW2$SDLQDVVHVVHGE\,&2$3VFRUHV
DWZHHN
x &KDQJHVIURPEDVHOLQHLQ:20$&SDLQZHLJKWEHDULQJVFRUHTXHVWLRQVDQG
DQGQRQZHLJKWEHDULQJVFRUHTXHVWLRQVDQGDWZHHN
x &KDQJHVIURPEDVHOLQHLQSK\VLFDOIXQFWLRQDVVHVVHGE\WKHFKDLUVWDQGWHVWDWZHHN
x 20(5$&72$56,UHVSRQGHUUDWHDWZHHN
x 7RWDOGRVHRIUHVFXHPHGLFDWLRQFDOFXODWHGDVWKHVXPRIWDEOHWVXVHGEDVHGRQSLOO
FRXQWV
x 7LPHEHWZHHQEDVHOLQHDQGILUVWXVHRIUHVFXHPHGLFDWLRQ
x &KDQJHIURPEDVHOLQHLQ:20$&SDLQVXEVFRUHTXHVWLRQVWREHWZHHQJURXSV
UHFHLYLQJ$0=4'DQG%,'LQWKHWDUJHWNQHHDVHYDOXDWHGDWZHHN
x &KDQJHVIURPEDVHOLQHLQFRQVWDQWDQGLQWHUPLWWHQW2$SDLQDVVHVVHGE\,&2$3VFRUHV
EHWZHHQJURXSVUHFHLYLQJ$0=4'DQG%,'DWZHHN
x &KDQJHVIURPEDVHOLQHLQ:20$&SDLQZHLJKWEHDULQJVFRUHTXHVWLRQVDQG
DQGQRQZHLJKWEHDULQJVFRUHTXHVWLRQVDQGEHWZHHQJURXSVUHFHLYLQJ$0=
4'DQG%,'DWZHHN
x &KDQJHVIURPEDVHOLQHLQSK\VLFDOIXQFWLRQDVVHVVHGE\WKHFKDLUVWDQGWHVWEHWZHHQ
$0=4'DQG%,'DWZHHN
x &KDQJHVIURPEDVHOLQHLQ:20$&WRWDOVFRUHDQGWKH:20$&IXQFWLRQDQGVWLIIQHVV
VFRUHVEHWZHHQ$0=4'DQG%,'DWZHHN
x &KDQJHVIURPEDVHOLQHLQWKHLPSDFWRI2$RQGDLO\OLYLQJDVDVVHVVHGE\WKH3DWLHQW
*OREDO$VVHVVPHQW3*$VFRUHDWZHHN
5

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 






x &KDQJHVIURPEDVHOLQHLQZRUNSURGXFWLYLW\DQGDFWLYLW\DVVHVVHGE\WKH:3$,DWZHHN

x &KDQJHVIURPEDVHOLQHLQTXDOLW\RIOLIHDVVHVVHGE\WKH(4'DWZHHN
([SORUDWRU\HQGSRLQWVDQGVDIHW\DQGWROHUDELOLW\HQGSRLQWVDUHGLVFXVVHGLQ6HFWLRQVDQG
RIWKHSURWRFROUHVSHFWLYHO\


6

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 






'LDJQRVLVDQGLQFOXVLRQDQGH[FOXVLRQFULWHULD
,QFOXVLRQ&ULWHULD
 6XEMHFWLVDEOHWRUHDGDQGXQGHUVWDQGWKHODQJXDJHDQGFRQWHQWRIWKHVWXG\PDWHULDO
XQGHUVWDQGWKHUHTXLUHPHQWVIRUVWXG\YLVLWVDQGLVZLOOLQJWRSURYLGHLQIRUPDWLRQDW
WKHVFKHGXOHGHYDOXDWLRQVDQGDSSURSULDWHZULWWHQLQIRUPHGFRQVHQWKDVEHHQ
REWDLQHG
 )HPRURWLELDORVWHRDUWKULWLVRIWKHNQHHDFFRUGLQJWKH$PHULFDQ&ROOHJHRI
5KHXPDWRORJ\$&5FOLQLFDODQGUDGLRJUDSKLFFULWHULD$OWPDQHWDO
$SSHQGL[$
 5DGLRORJLFDO2$JUDGHRURIWKHWDUJHWNQHHXVLQJWKH.HOOJUHQ/DZUHQFH
PHWKRG.(//*5(1	/$:5(1&(DVJUDGHGE\FHQWUDOLQGHSHQGHQW
UHDGLQJRI;UD\REWDLQHGGXULQJVFUHHQLQJRURQDUHFHQWZLWKLQPRQWKV;UD\
LPDJHZKLFKIXOILOOVWKHVSHFLILFDWLRQVIRUFHQWUDOUHDGLQJ
 $JHEHWZHHQ\HDUVDQG\HDUVDWWKHWLPHRIVFUHHQLQJERWKLQFOXGHGRIHLWKHU
VH[
 3DLQVFRUHUDWHGRQDQSRLQWQXPHULFDOUDWLQJVFDOHRIWKHWDUJHWNQHHRIDQG
RXWRILQUHVSRQVHWRWKH:20$&SDLQVXEVFRUHTXHVWLRQVDWWKHWLPHRI
VFUHHQLQJ7KHVXEMHFWVKRXOGKDYHXQGHUJRQHDZDVKRXWSHULRGRIDWOHDVWKDOIOLYHV
RIDQ\DQDOJHVLFPHGLFDWLRQEHIRUHFRPSOHWLQJWKHVFUHHQLQJTXHVWLRQQDLUH
 :RPHQRIFKLOGEHDULQJSRWHQWLDOPXVWXVHDWOHDVWDQDFFHSWDEO\HIIHFWLYHPHWKRGRI
FRQWUDFHSWLRQSURJHVWRJHQRQO\RUDOKRUPRQDOFRQWUDFHSWLRQZKHUHLQKLELWLRQRI
RYXODWLRQLVQRWWKHSULPDU\PRGHRIDFWLRQPDOHRUIHPDOHFRQGRPZLWKRUZLWKRXW
VSHUPLFLGHFDSGLDSKUDJPRUVSRQJHZLWKVSHUPLFLGH3RVWPHQRSDXVDOVWDWXVLV
GHILQHGDVEHLQJDPHQRUUKHLFIRUDWOHDVW\HDUSULRUWRVFUHHQLQJ6H[XDOO\DFWLYH
PHQZLWKDIHPDOHSDUWQHURIFKLOGEHDULQJSRWHQWLDOPXVWDJUHHWRXVHFRQGRPIURP
HQUROPHQWXSWRDWOHDVWPRQWKVDIWHUWKHVWXG\HQG
 .QHHSDLQLQWKHWDUJHWNQHHIRUGD\VRIWKHSUHFHGLQJPRQWKSHULDUWLFXODUNQHH
SDLQGXHWR2$DQGQRWGXHWRQRQ2$FRQGLWLRQVVXFKDVEXUVLWLVWHQGRQLWLVHWF
EDVHGRQVXEMHFWUHSRUW
 2QVWDEOHSDLQWKHUDS\LHDWOHDVWGD\VSHUZHHNIRUWKHSUHYLRXVPRQWKZLWKDQ
RUDO16$,'RUDFHWDPLQRSKHQSDUDFHWDPROSULRUWRWKH6FUHHQLQJ9LVLW
 ([FHSWIRURVWHRDUWKULWLVWKHVXEMHFWLVLQUHDVRQDEO\JRRGKHDOWKDVGHWHUPLQHGE\WKH
,QYHVWLJDWRU
([FOXVLRQFULWHULD
 .QRZQRUVXVSHFWHGK\SHUVHQVLWLYLW\WRRUSUHYLRXVK\SHUVHQVLWLYLW\UHDFWLRQVWR
GLFORIHQDFRWKHUQRQVWHURLGDODQWLLQIODPPDWRU\GUXJVRUUHODWHGVXEVWDQFHV
LQFOXGLQJDVSLULQDQ\RIWKHH[FLSLHQWVLQHLWKHURIWKHLQYHVWLJDWLRQDOSURGXFWVRUDQ\
SK\VLFDOLPSHGLPHQWWRJHODSSOLFDWLRQRQWKHWDUJHWNQHH
 ,QWUDDUWLFXODUGHOLYHU\RIFRUWLFRVWHURLGVRUK\DOXURQLFDFLGLQWKHWDUJHWNQHHZLWKLQ
PRQWKVRIVFUHHQLQJRULQWRDQ\RWKHUMRLQWZLWKLQGD\VRIVFUHHQLQJ
7

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 






 +LJKGRVHHTXLYDOHQWWR!PJRISUHGQLVRQHGD\V\VWHPLFFRUWLFRVWHURLGWUHDWPHQW
RIPRUHWKDQGD\VGXULQJWKHSDVWPRQWKVSULRUWRVFUHHQLQJ
 0DMRUVXUJHU\RUDUWKURVFRS\RIWKHWDUJHWNQHHZLWKLQWKHSUHYLRXV\HDUSULRUWR
VFUHHQLQJ
 3ODQQHGVXUJHU\RIWKHWDUJHWNQHHZLWKLQWKHQH[WPRQWKV
 8VHRIDFXUUHQWO\XQDSSURYHGLQYHVWLJDWLRQDOGUXJGHYLFHRUELRORJLFZLWKLQ
PRQWKVSULRUWRVFUHHQLQJ
 3UHVHQFHRIFRQFRPLWDQWQRQRVWHRDUWKULWLFGLVHDVHDIIHFWLQJHLWKHUNQHHVXFKDV
UKHXPDWRLGDUWKULWLVSVRULDVLVJRXWRUSVHXGRJRXWLIWKHUHLVUHDVRQWREHOLHYHWKDW
WKHGLVHDVHVPD\VLJQLILFDQWO\LQWHUIHUHZLWKWKHLQWHUSUHWDWLRQRIWKHFOLQLFDO
UHVSRQVHWRWKHVWXG\GUXJ
 0HGLFDOKLVWRU\RIFRURQDU\DUWHU\E\SDVVJUDIWVXUJHU\
 &XUUHQWPDOLJQDQF\RUWUHDWPHQWIRUPDOLJQDQF\ZLWKLQWKHSDVWILYH\HDUVZLWKWKH
H[FHSWLRQRIQRQPHODQRPDVNLQFDQFHUXQOHVVDIIHFWLQJWKHWDUJHWNQHHDUHDRU
FDUFLQRPDLQVLWXHYHQWV
$Q\RWKHUDEQRUPDOODERUDWRU\UHVXOWVRUVLJQLILFDQWPHGLFDOFRQGLWLRQVWKDWWKH
,QYHVWLJDWRUEHOLHYHVVKRXOGSUHFOXGHWKHVXEMHFW
VSDUWLFLSDWLRQLQWKHWULDO
6HFRQGDU\RVWHRDUWKULWLVRIWKHWDUJHWNQHHSUHYLRXVSURFHGXUHVRUWUDXPDDIIHFWLQJ
MRLQWKRPHRVWDVLVLQFOXGLQJWRWDOPHQLVFHFWRP\RUVHSWLFDUWKULWLVRUDQ\RWKHUVHULRXV
FRQGLWLRQOHDGLQJWRVHFRQGDU\2$RIWKHWDUJHWNQHH
5HSRUWHGLQFLGHQFHRIDQ\RIWKHIROORZLQJGLVHDVHVNQRZQRVWHRDUWKULWLVRIWKHKLSV
LISDLQLQHLWKHURUERWKKLSVH[FHHGVWKDWRIWKHWDUJHWNQHHXVLQJWKH:20$&+LS
3DLQVXEVFRUHSUHVHQFHRIVLJQLILFDQWUDGLFXODUEDFNSDLQRUDWOHDVWRQHPLJUDLQH
DWWDFNZLWKLQWKHSDVWPRQWKVEHIRUHVFUHHQLQJDVUHSRUWHGE\WKHVXEMHFW
3UHVHQFHRIVHYHUHSDLQLQHLWKHUNQHHGHILQHGDV!RXWRILQUHVSRQVHWRWKH
:20$&SDLQVXEVFRUHTXHVWLRQVDWWKHWLPHRIVFUHHQLQJUHJDUGOHVVRIWKH
HOLJLELOLW\RIWKHFRQWUDODWHUDONQHH
%RG\0DVV,QGH[!NJP
(VWLPDWHGJORPHUXODUILOWUDWLRQUDWHP/PLQXVLQJWKH0RGLILFDWLRQRI'LHWLQ
5HQDO'LVHDVH0'5'PHWKRG
*HQHUDOL]HGVNLQLUULWDWLRQSUHYLRXVVNLQUHDFWLRQVXSRQXVHRIWRSLFDO16$,'V
FXUUHQWVNLQLUULWDWLRQRUUHGQHVVDWWKHSODQQHGVLWHRIJHODSSOLFDWLRQRUVLJQLILFDQW
VNLQGLVHDVHLQFOXGLQJSVRULDVLVDVMXGJHGE\WKHLQYHVWLJDWRU
.QRZQSUHVHQFHRIJDVWURGXRGHQDOXOFHURUDQ\JDVWURLQWHVWLQDOEOHHGLQJH[FHSW
KHPRUUKRLGDOZLWKLQPRQWKVSULRUWRVFUHHQLQJ
8VHRIDQ\WRSLFDOPHGLFDWLRQRQWKHSODQQHGDSSOLFDWLRQVLWHZLWKLQGD\VRIWKH
WLPHRIUDQGRPL]DWLRQ
8VHRIPRGHUDWHRUKLJKHUGRVHVRIRSLRLGPHGLFDWLRQIRUWKHWUHDWPHQWRISDLQZLWKLQ
ZHHNVEHIRUHWKHVFUHHQLQJYLVLW
8VHRIGXOR[HWLQHSUHJDEDOLQRUJDEDSHQWLQZLWKLQZHHNVEHIRUHWKHVFUHHQLQJ
YLVLW
+LVWRU\RIDOFRKRORUGUXJDEXVHZLWKLQWKHSDVW\HDUSULRUWRUDQGRPL]DWLRQ
8

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 







,QYHVWLJDWLRQDO0HGLFLQDO3URGXFWV
'RXEOHEOLQGWKHUDS\
'LFORIHQDF6RGLXP$0=JHORUPDWFKLQJSODFHERJHOLQDQJPHWHUHGGRVH
GLVSHQVHUJUDPVRIJHOWREHDSSOLHGWZLFHGDLO\PRUQLQJDQGHYHQLQJ
6LQJOHEOLQGWKHUDS\
6LQJOHEOLQGFRPSDUDWRU9ROWDUHQGLFORIHQDFVRGLXPJHOLQDJWXEHJUDPVRI
JHOWREHDSSOLHGIRXUWLPHVGDLO\
5HVFXHPHGLFDWLRQ
3DUDFHWDPROWDEOHWVPJ7KHGRVDJHRIDFHWDPLQRSKHQSDUDFHWDPROWKDWWKHVXEMHFWVZLOO
EHDOORZHGWRWDNHSHUGD\ZLOOEHGHILQHGDFFRUGLQJWRWKHVWDQGDUGRIFDUHLQWKHFRXQWULHV
ZKHUHWKHWULDOZLOOEHFDUULHGRXWKRZHYHUWKHPD[LPXPGRVHVKRXOGQRWH[FHHGJUDPSHU
GRVHDQGJUDPVSHUGD\
3ODQQHGWULDODQGWUHDWPHQWGXUDWLRQSHUVXEMHFW
7KHWUHDWPHQWSKDVHFRQVLVWVRIIRXUZHHNVRIWUHDWPHQWZLWKRQHEDVHOLQH'D\YLVLWDQG
ZHHNO\ YLVLWVIROORZHG E\DIROORZXSYLVLW WZRZHHNV DIWHUODVW DSSOLFDWLRQRI ,037KH
VFUHHQLQJSHULRGLVXSWRGD\VIURPWKHWLPHRISURYLGLQJZULWWHQFRQVHQW ,QWRWDOWKH
H[SHFWHGGXUDWLRQRIWKHWULDOSDUWLFLSDWLRQRIDUDQGRPL]HGVXEMHFWZLOOEHXSWRGD\V

6WDWLVWLFDOPHWKRGV
7UHDWPHQWHIIHFWRIWKHSULPDU\HQGSRLQWRIFKDQJHIURPEDVHOLQHLQ:20$&SDLQVXEVFRUH
ZLOO EH EDVHG RQ D UHSHDWHG PHDVXUHV $129$ PRGHO LQFOXGLQJ WKH EDVHOLQH YDOXH WKH
WUHDWPHQWJURXSWKHYLVLWDQGWUHDWPHQWE\YLVLWDVLQWHUDFWLRQ&RPSDULVRQRI$0=JHO
YHUVXVSODFHERZLOOEHSHUIRUPHGZLWKLQWKHFRQWH[WRIWKLVPRGHO7KHGLIIHUHQFHDQGWKH
FRUUHVSRQGLQJFRQILGHQFHLQWHUYDO&,DQGSYDOXHZLOOEHSUHVHQWHG7KHVDPH$129$
PRGHOXVHGIRUWKHSULPDU\HQGSRLQWZLOOEHXVHGWRDVVHVVWKHWUHDWPHQWHIIHFWRIWKHVHFRQGDU\
HQGSRLQWV7KHVLJQLILFDQFHOHYHOZLOOEHVHWDWWZRVLGHGDQGSYDOXHVZLOOQRWEHDGMXVWHG
IRUPXOWLSOHFRPSDULVRQV
7KHSRZHULVGHWHUPLQHGIURPH[SHFWHGFKDQJHVLQWKHSULPDU\HQGSRLQWRIWKHFKDQJHIURP
EDVHOLQHLQSDLQDVHYDOXDWHGE\WKH:20$&SDLQVXEVFRUH7KHSRZHUFDOFXODWLRQLVEDVHG
RQGDWDIURPDZHHNGRXEOHEOLQGGLFORIHQDFVRGLXPWRSLFDOVROXWLRQWUHDWPHQWVWXG\LQ
NQHHRVWHRDUWKULWLVSDWLHQWV:DGVZRUWKHWDO,QWKLVVWXG\XVLQJWKH:20$&/.
VFDOHIRUHDFKTXHVWLRQDGHFUHDVHIURPEDVHOLQHLQ:20$&SDLQVXEVFRUHTXHVWLRQV
9

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 






ZDVUHFRUGHGLQWKHGLFORIHQDFWUHDWPHQWJURXSRI6'DQGLQWKHSODFHERJURXS
6'
7KHHVWLPDWHGFRPPRQ6'RILQWKH/.VFDOHFDQEHFRQYHUWHGWRD6'RI 
LQWKH156VFDOH:LWKWKHDVVXPSWLRQVRIWKH6'RI156VFDOHVXEMHFWVHQUROOHG
LQHDFKRIWKHGRXEOHEOLQGHGWUHDWPHQWDUPVGURSRXWUDWHQRUPDOGLVWULEXWLRQOHYHO
RI VLJQLILFDQFH WZRVLGHG   SRZHU WKH VWXG\ ZLOO EH SRZHUHG WR GHWHFW D WUHDWPHQW
GLIIHUHQFHLQ:20$&SDLQVXEVFRUHEHWZHHQ$0=%,'DQGSODFHERRIRQWKH156
VFDOH

10

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 


&21),'(17,$/
,1)250$7,21







7DEOH6FKHGXOHRI7ULDO3URFHGXUHV
Activity/Assessment
Screening
1a1
Screening
1b1
Baseline
V2
On Treatment Visits
14-Day
Safety
Follow-up2
V7
V3
V4
V5
V6
Study Week
-
-
0
1
2
3
4
6
Study Day
-21 to - 5
-13 to -1
1
8
15
22
29
43
Visit Window (days)
-
-
0
+/- 2
+/- 2
+/- 2
+/- 2
+/- 5
,QIRUPHG&RQVHQW
;







0HGLFDOKLVWRU\
;







,QFOXVLRQH[FOXVLRQ
FULWHULD
;
;
;





'HPRJUDSKLFGDWD
;







3K\VLFDOH[DPLQDWLRQ
;





;

6NLQ7ROHUDELOLW\
$VVHVVPHQW


;
;
;
;
;

.QHH;UD\ERWKNQHHV
;







,QVWUXFWLRQVRQUHSRUWLQJ
SDLQ
;







:20$&4XHVWLRQQDLUH


;
;
;
;
;
;

,&2$34XHVWLRQQDLUH


;
;
;
;
;

3DLQ'LDU\


;
;
;
;
;

3DWLHQW*OREDO
$VVHVVPHQW


;
;
;
;
;

:3$,


;
;
;

;

(4'


;


;
;

6DWLVIDFWLRQ
TXHVWLRQQDLUH




;

;

&KDLUVWDQGWHVW


;

;

;

6HOHFWLRQRIWDUJHWNQHH


;





+HLJKWDQGZHLJKW
;





;

%ORRGSUHVVXUHDQG
KHDUWUDWH
;

;
;
;
;
;

11

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 


&21),'(17,$/
,1)250$7,21





Activity/Assessment
Screening
1a1
Screening
1b1
Baseline
V2
On Treatment Visits
14-Day
Safety
Follow-up2
V7
V3
V4
V5
V6
Study Week
-
-
0
1
2
3
4
6
Study Day
-21 to - 5
-13 to -1
1
8
15
22
29
43
$GYHUVHHYHQWV
;
;
;
;
;
;
;
;
&RQFRPLWDQWPHGLFDWLRQ
;
;
;
;
;
;
;
;
5DQGRPL]DWLRQ


;





6WXG\GUXJGLVSHQVDWLRQ
DQGZHLJKLQJRINLWV


;

;



'LVSHQVDWLRQRI,03
³LQVWUXFWLRQVIRUXVH´
SDPSKOHW


;

;



,QVWUXFWLRQRIVWXG\GUXJ
DSSOLFDWLRQDQG
IUHTXHQF\RIXVH


;





$SSOLFDWLRQRIPRUQLQJ
VWXG\GUXJRQVLWHXQGHU
VWDIIVXSHUYLVLRQ


;
;
;
;
;

:HLJKLQJRINLWVIRU
FRPSOLDQFHDVVHVVPHQW



;
;
;
;

5HVFXHPHGLFDWLRQ
GLVSHQVH


;

;
;


5HVFXHPHGLFDWLRQ
FROOHFWLRQ




;
;
;

OHDG(&*
;





;

5HVFXH$QDOJHVLF
:DVKRXW

;
;
;
;
;
;

+HPDWRORJ\
;


;
;
;
;

6DIHW\FKHPLVWU\DQG
XULQHGLSVWLFN
;


;
;
;
;

3UHJQDQF\WHVW
;

;

;

;

%ORRGVDPSOHIRUSODVPD
OHYHORIGLFORIHQDF




;

;

(4'(XUR4RO'RPDLQ,&2$3,QWHUPLWWHQWDQG&RQVWDQW2VWHRDUWKULWLV3DLQ:20$&7KH:HVWHUQ2QWDULR
DQG0F0DVWHU8QLYHUVLWLHV2VWHRDUWKULWLV,QGH[:3$,:RUN3URGXFWLYLW\$FWLYLW\,QGH[

 ,IVXEMHFWLVZDVKHGRXWRIDQDOJHVLFVDW6FUHHQLQJ9LVLWDWKHH[DPLQDWLRQVVFKHGXOHGIRU
VFUHHQLQJYLVLWVDDQGEFDQEHSHUIRUPHGRQWKHVDPHGD\
12

CONFIDENTIAL 
Clinical Trial Protocol 
Protocol ID 
AMZ001-006 
Version 1.2 
22NOV2018 
&21),'(17,$/
,1)250$7,21

 3KRQHFDOO
 6NLQDVVHVVPHQWWREHSHUIRUPHGSULRUWRDSSOLFDWLRQRIVWXG\GUXJDWEDVHOLQHYLVLW
 6XEMHFWVZLOOEHHGXFDWHGRQDSSURSULDWHH[SHFWDWLRQVDURXQGWKHLUSDUWLFLSDWLRQLQDFOLQLFDO
VWXG\DQGWKHLPSRUWDQFHRIUHOLDEO\FRQVLVWHQWO\DQGDFFXUDWHO\UHSRUWLQJWKHLUSDLQ
WKURXJKRXWWKHVWXG\
 :20$&SDLQVXEVFRUHTXHVWLRQVWREHDVVHVVHGRQDGDLO\EDVLVRQSDSHUDWKRPH
GXULQJILUVWZHHNRIWUHDWPHQWLHWKHSHULRGEHWZHHQ9LVLWDQG9LVLW
 $VVHVVHGZLWKRXWDQDOJHVLFPHGLFDWLRQIRUILYHKDOIOLYHVRIWKHDQDOJHVLF
 :20$&DVVHVVPHQWRIKLSVVKRXOGRQO\EHSHUIRUPHGDWWKHVFUHHQLQJYLVLW
 7REHFRPSOHWHGGDLO\LQWKHHYHQLQJGXULQJWKHILUVWZHHNRIWUHDWPHQWLHEHWZHHQ9LVLW
DQG9LVLW,QWKHSHULRGEHWZHHQRWKHUVXEVHTXHQWYLVLWVWKHTXHVWLRQQDLUHZLOOEH
FRPSOHWHGGXULQJWKHHYHQLQJRIWKHGD\SULRUWRWKHQH[WYLVLW
 2QO\ZHLJKWFROOHFWHG
 &RQGLWLRQVSUHYLRXVO\XQNQRZQWRWKHVXEMHFWDWWKHWLPHRIWKHVFUHHQLQJYLVLWZLOOEH
UHFRUGHGDVPHGLFDOKLVWRU\$OOVXEVHTXHQWHYHQWVZLOOEHUHFRUGHGDVDGYHUVHHYHQWV
 7REHFROOHFWHGGLVSHQVHGLISUHYLRXVO\GLVSHQVHGVXSSO\RIUHVFXHPHGLFDWLRQZDVGHSOHWHG
DQGHPSW\SDFNDJLQJUHWXUQHGWRVLWH
 &ROOHFWLRQRIUHPDLQLQJUHVFXHPHGLFDWLRQDW9LVLW(PSW\SDFNDJLQJRISUHYLRXVO\
GLVSHQVHGNLWVKRXOGEHUHWXUQHGWRWKHVLWHLIQHZUHVFXHPHGLFDWLRQLVUHTXHVWHG
 6HUXPWHVWDWVFUHHQLQJYLVLWXULQHGLSVWLFNDWDOORWKHUYLVLWV
 7REHGRQHDIWHU,03DSSOLFDWLRQDQGTXHVWLRQQDLUHWHVWFRPSOHWLRQDSSUR[LPDWHO\KRXUV
DIWHU,03DSSOLFDWLRQ([DFWWLPHRI,03DSSOLFDWLRQDQGWLPHRIEORRGVDPSOLQJPXVWEH
GRFXPHQWHG
 'LVSHQVDWLRQLVQRWPDQGDWRU\IRUVXEMHFWVDOORFDWHGWR9ROWDUHQJHO
13