Randomized, Double-Blind, Study to Assess Low-Dose Naltrexone and Acetaminophen Combination in the Prevention of Episodic Migraine in Adults
Phase: PHASE2
Conditions: Migraine With or Without Aura
Sponsor: Allodynic Therapeutics, Inc

CLINICAL STUDY PROTOCOL
A Migraine Prevention Study (ANODYNE-3)  
A Single Center, Phase 2B, Randomized, Double Blind, Study to Assess the Efficacy, Safety, and 
Tolerability of Oral Twice Daily ALLOD-2 vs. Placebo in the Prevention of Episodic Migraine in 
Adults
Brief Title:
Efficacy, Safety, and Tolerability of Twice Daily Oral ALLOD-2 vs. Placebo in Episodic Migraine 
Prevention (ANODYNE-3) 
The Study’s Treatment Groups:
Experimental: Naltrexone 
 mg/acetaminophen 
 mg (ALLOD-2),
Placebo comparator: Placebo.
Study Phase: 2B
Investigational New Drug (IND) number: 
Study and Protocol Name: ANODYNE-3 
Version 1.0, Submitted to DNP on May 5, 2017 
Version 1.1, Approved by IRB on July 28, 2017
ALLOD-2 is being investigated for treatment of chronic low back pain
Sponsor/Investigator: Annette C. Toledano, M.D.
1785 NE 123rd Street, North Miami, FL 33181  
Telephone: Office-305-895-6808, Cellular-
Email Address:
Study Pharmacist: Ayman Mohamed, 
&RQWDFW'U0RKDPHGLQWKHHYHQWRIQHHGWRXQPDVNDVWXG\SDUWLFLSDQW
6WXG\,5%6FKXOPDQ$VVRFLDWHV,5%,QFDPSP0)
7KHVWXG\ZLOOEHFRQGXFWHGLQDFFRUGDQFHZLWKWKH,QWHUQDWLRQDO&RQIHUHQFHRQ+DUPRQL]DWLRQ
JXLGHOLQHVIRU*RRG&OLQLFDO3UDFWLFH,&+(DQGWKH&RGHRI)HGHUDO5HJXODWLRQVRQWKH
3URWHFWLRQRI+XPDQ3DWLHQWV&)53DUW$OOPDWHULDOKHUHLQLVFRQILGHQWLDODQG
SURSULHWDU\LQIRUPDWLRQRI$OORG\QLF7KHUDSHXWLFV//&$OOGLVFORVXUHUHSURGXFWLRQ
GLVVHPLQDWLRQLQFOXGLQJEXWQRWOLPLWHGWRYLHZLQJRIVXFKLQIRUPDWLRQLVVWULFWO\SURKLELWHG
DEVHQWSULRUZULWWHQDXWKRUL]DWLRQE\$OORG\QLF7KHUDSHXWLFV
CONFIDENTIAL AND PROPRIETARY INFORMATION 
ClinicalTrials.gov Identifier: NCT03194555

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\,
Study Protocol Signature Page 
7KH$OORG\QLF7KHUDSHXWLFVUHSUHVHQWDWLYHOLVWHGEHORZKDVDSSURYHGWKLVSURWRFRO
$QQHWWH&7ROHGDQR0'
$OORG\QLF7KHUDSHXWLFV//&
5ROH
3URWRFRO$XWKRU6SRQVRU
6LJQDWXUH
'DWH
Protocol Title: $6LQJOH&HQWHU3KDVH%5DQGRPL]HG'RXEOH%OLQG6WXG\WR$VVHVVWKH
(IILFDF\6DIHW\DQG7ROHUDELOLW\RI2UDO7ZLFH'DLO\$//2'YV3ODFHERLQWKH3UHYHQWLRQ
RI(SLVRGLF0LJUDLQHLQ$GXOWV
,QYHVWLJDWRU$JUHHPHQW
,KDYHUHDGDQGXQGHUVWRRGWKLV$OORG\QLF7KHUDSHXWLFVSURWRFROLQFOXGLQJDOODSSHQGLFHV
DWWDFKPHQWVDQGWKH,QYHVWLJDWRU¶V%URFKXUH
,IXOO\XQGHUVWDQGWKHREMHFWLYHVRIWKLVVWXG\,FOHDUO\DQGXQHTXLYRFDOO\XQGHUVWDQGWKDWDOO
LQIRUPDWLRQFRQWDLQHGLQWKLVSURWRFROLVFRQILGHQWLDODQGVKDOOQRWEHGLVFORVHGZLWKRXWSULRU
ZULWWHQDXWKRUL]DWLRQRIWKHVSRQVRU'LVFORVXUHWRDSDWLHQWRIWKLVVWXG\PD\RQO\EHSHUPLVVLEOH
IRUSXUSRVHVRIREWDLQLQJDSDWLHQW¶VFRQVHQWWRSDUWLFLSDWHLQWKLV6WXG\
,DJUHHWRFRQGXFWDOODVSHFWVRIWKLV6WXG\LQDGKHUHQFHZLWKWKLVSURWRFRODQGWKHLQDFFRUGDQFH
RIWKHWHUPVRXWOLQHGLQWKH&OLQLFDO6WXG\6LWH$JUHHPHQW,DJUHHWRFRQGXFWWKLVVWXG\LQ
DFFRUGDQFHZLWK*RRG&OLQLFDO3UDFWLFHVLQFOXGLQJHWKLFDODQGVDIHW\FRQVLGHUDWLRQV,ZLOO
HQVXUHWKDWDOOLQGLYLGXDOVDVVLVWLQJZLWKWKHVWXG\DUHDGHTXDWHO\WUDLQHG
,DFNQRZOHGJHDJUHHDQGXQGHUVWDQGWKDWSUHPDWXUHWHUPLQDWLRQRUVXVSHQVLRQRIWKLVVWXG\PD\
RFFXUDWDQ\WLPHIRUZKDWHYHUUHDVRQZLWKRUZLWKRXWFDXVHE\WKHVSRQVRU1RWLFHRIVXFK
WHUPLQDWLRQRUVXVSHQVLRQVKDOOEHFRPPXQLFDWHGWRPHLQZULWLQJ+RZHYHULQWKHHYHQWRIP\
ZLWKGUDZDOIURPWKLVVWXG\RUH[HFXWLRQWKHUHRI,VKDOOLPPHGLDWHO\FRPPXQLFDWHP\GHFLVLRQ
RULQWHQWLQZULWLQJWRWKHVSRQVRUZLWKRXWXQGXHGHOD\
,DJUHHWRNHHSUHFRUGVRQDOOSDWLHQWLQIRUPDWLRQFDVHUHSRUWIRUPVVKLSPHQWDQGGUXJUHWXUQ
IRUPVDQGDOORWKHULQIRUPDWLRQFROOHFWHGGXULQJWKHVWXG\LQDFFRUGDQFHZLWKWKHFXUUHQW*&3
DQGORFDOUHJXODWLRQV
6KRXOGDQ\GLVFUHSDQF\DULVHEHWZHHQWKLVVWXG\SURWRFRODQGWKH&OLQLFDO6WXG\6LWH$JUHHPHQW
WKHWHUPVRIVWXG\SURWRFROVKDOOSUHYDLOUHJDUGLQJWKHFRQGXFWRIWKHVWXG\DQGWKHWUHDWPHQWRI
SDWLHQWVDQGLQDOORWKHUUHVSHFWVQRWUHODWLQJWRVWXG\FRQGXFWRUWUHDWPHQWRISDWLHQWVWKHWHUPV
RIWKH&OLQLFDO6WXG\6LWH$JUHHPHQWVKDOOSUHYDLO
$QQHWWH&7ROHGDQR0'
,QYHVWLJDWRU
6LJQDWXUH
'DWH
 

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\ , 
Protocol Synopsis
7KH3URGXFW
7KH,QYHVWLJDWLRQDO3URGXFW FRGHQDPHG$//2'LVDVROLGRUDOIL[HG
GRVHFRPELQDWLRQRIQDOWUH[RQHK\GURFKORULGH
PJZLWK
DFHWDPLQRSKHQ
PJ
6WXG\1DPH
$12'<1(
3URWRFRO1
$12'<1(9HUVLRQ
6WXG\3KDVH
%
%ULHI7LWOH
(IILFDF\6DIHW\DQG7ROHUDELOLW\RI7ZLFH'DLO\2UDO$//2'LQ
(SLVRGLF0LJUDLQH3UHYHQWLRQ$12'<1(
6WXG\7LWOH
$6LQJOH&HQWHU3KDVH%5DQGRPL]HG'RXEOH%OLQG6WXG\WR$VVHVV
WKH(IILFDF\6DIHW\DQG7ROHUDELOLW\RI2UDO7ZLFH'DLO\ $//2'YV
3ODFHERLQWKH3UHYHQWLRQRI(SLVRGLF0LJUDLQH LQ$GXOWV
,QGLFDWLRQ
3UHYHQWLRQ RIHSLVRGLFPLJUDLQHZLWKRUZLWKRXW DXUDLQDGXOWV
%ULHI
'HVFULSWLRQRI
WKH
,QYHVWLJDWLRQDO
3URGXFW
$//2'LVDQLQYHVWLJDWLRQDO FRPELQDWLRQRID7ROO/LNH5HFHSWRU
7/5DQWDJRQLVWQDOWUH[RQHK\GURFKORULGHZLWKDKLJKO\VHOHFWLYH
&\FORR[\JHQDVH&2;LQKLELWRUDFHWDPLQRSKHQLQWHQGHGIRUXVHLQ
WKLVVWXG\IRU SUHYHQWLRQ RIHSLVRGLFPLJUDLQH DVVRFLDWHGZLWKPRGHUDWH
WRVHYHUHQDXVHD
1DOWUH[RQH LVDQRSLRLGDQWDJRQLVWZKLFKKDVEHHQPDUNHWHGLQWKH
8QLWHG6WDWHVIRUWUHDWPHQWRIRSLRLG DQGDOFRKROGHSHQGHQFH VLQFH
+RZHYHUWKHZKROHWLPHLWVDQDOJHVLFSURSHUWLHVKDYHQRWEHHQZLOGO\
DFNQRZOHGJHG5HFHQWEDVLFVFLHQFHUHVHDUFKIRXQGQDOWUH[RQHWRDFWDOVR
DVD7/5DQWDJRQLVWZKLFKLVWKHSXUSRUWHGPHFKDQLVPRIDFWLRQ RILWV
DQDOJHVLFDFWLRQ $FHWDPLQRSKHQZDVILUVWDSSURYHGLQWKH8QLWHG6WDWHV
LQE\DFHWDPLQRSKHQZDVDOUHDG\HVWDEOLVKHGIRU27&XVH
IRUWHPSRUDU\UHOLHIRIPLQRUDFKHVDQGSDLQVDVVRFLDWHGZLWKWKH
FRPPRQFROGKHDGDFKHSDLQWRRWKDFKHPXVFXODUDFKHVDQGEDFNDFKH
1DOWUH[RQHDQG$FHWDPLQRSKHQ LQKLELWWZRGLVWLQFWQHXURLQIODPPDWLRQ
SURGXFLQJWDUJHWVLQWKH7/5VLJQDOLQJFDVFDGHSDWKZD\1DOWUH[RQH
LQKLELWV7/5LQGXFHGUHOHDVHRISURLQIODPPDWRU\F\WRNLQHVDQG
DFHWDPLQRSKHQLQKLELWV7/5LQGXFHG&2;H[SUHVVLRQ%RWK
FRPSRQHQWVDUHSUHVHQWLQWKH,QYHVWLJDWLRQDO3URGXFWLQDQLPPHGLDWH
UHOHDVHIRUPXODWLRQ
0HFKDQLVPRI
$FWLRQ
7/5GHWHFWVDQGUHDFWVWRHQGRJHQRXVOLJDQGVWKDWRFFXUDIWHUWLVVXH
LQMXU\RUFHOOXODUVWUHVVNQRZQDVGDPDJHDVVRFLDWHGPROHFXODUSDWWHUQV
5H9LDQDOWUH[RQHK\GURFKORULGH1'$
 1'$DFHWDPLQRSKHQWDEOHW

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\ , 
'$03V $FWLYDWLRQRIWKH7/5VLJQDOLQJSDWKZD\LQWKHJOLD
LQGXFHVUHOHDVHRISURLQIODPPDWRU\F\WRNLQHV>QLWULFR[LGH12WXPRU
QHFURVLVIDFWRUĮ71)ĮDQGUHDFWLYHR[\JHQVSHFLHV526@ FDXVLQJ
QHXURLQIODPPDWLRQ,QDGGLWLRQDFWLYDWLRQRIWKH7/5VLJQDOLQJ
SDWKZD\LQGXFHVH[SUHVVLRQRI&2;WKH7/5&2;SURVWDJODQGLQ
(D[LVDOVRFDXVLQJQHXURLQIODPPDWLRQ 7/5LQGXFHGQHXUR
LQIODPPDWLRQQHDUE\VSLQDOQHUYHURRWVRUWKHWULJHPLQDOQHUYHV\VWHP
OHDGVLQSUHGLVSRVHGLQGLYLGXDOVWRQHXURSDWKLFSDLQPDQLIHVWHG
FOLQLFDOO\DVUDGLFXODUEDFNSDLQRU PLJUDLQH DQGRWKHUFOLQLFDO
SUHVHQWDWLRQV
7KHUHLVDVWURQJELRORJLFDOUDWLRQDOHIRUWKHXVHRIQDOWUH[RQHDQG
DFHWDPLQRSKHQLQFRPELQDWLRQVLQFHHDFKLQKLELWVDGLVWLQFWWDUJHWLQWKH
VDPHPROHFXODUSDWKZD\ WKH7/5VLJQDOLQJFDVFDGH
7/5DFWLYDWLRQLQUHVSRQVHWRHQGRJHQRXV'$03VLVDQRWKHUH[DPSOH
RIH[XEHUDQWLQQDWHLPPXQLW\UHVSRQVHWKDWLVGHWULPHQWDOWRWKHKRVW
1DOWUH[RQHDQGDFHWDPLQRSKHQFDOPWKH LPPXQHRYHUDFWLYDWLRQDQG
QHXURLQIODPPDWLRQQHDUE\ VSLQDOQHUYHURRWVDQGWKHWULJHPLQDOQHUYH
V\VWHPHOLPLQDWLQJ EDFNSDLQDQGPLJUDLQH,QSDWLHQWVVXIIHULQJIURP
FKURQLFEDFNSDLQDQLQMXU\QHDUE\DVSLQDOQHUYHURRWHJGLVN
KHUQLDWLRQFDQDFWLYDWH7/5DQGFDXVHQHXURSDWKLFSDLQDORQJLWV
DQDWRPLFDOGLVWULEXWLRQ
&OLQLFDOWULDOVJRY
VXPPHU\
,GHQWLILHU
1&7
:KLOHPDQ\LQGLYLGXDOVDUHDEOHWROLPLWWKHUDS\WRWUHDWPHQWRIPLJUDLQH
DWWDFNVRWKHUVQHHGPHGLFDWLRQWRUHGXFHWKHIUHTXHQF\DQGRUVHYHULW\
RIDWWDFNV3DWLHQWVZLWKSURORQJHGRUVHYHUHDWWDFNVOHDGLQJWR
VXEVWDQWLDOGLVDELOLW\RUSDWLHQWVZKRDUHUHIUDFWRU\WRDERUWLYH
WUHDWPHQWVFDQEHQHILWIURPPLJUDLQHSUHYHQWLRQ
7KHLQYHVWLJDWLRQDOSURGXFWLVDFRPELQDWLRQRIWZRUHSXUSRVHG
PDUNHWHGGUXJVXVHGIRUPLJUDLQHSUHYHQWLRQWKURXJKWKHGLVFRYHU\RI
ELRORJLFDOO\DQGFOLQLFDOO\UHOHYDQWDIILQLW\IRUQHZWDUJHWV%RWKGUXJV
DUHEHLQJUHSXUSRVHGDWDVLJQLILFDQWO\ORZHUGRVDJHFRPSDUHGWRWKH
DSSURYHGPDUNHWHGLQGLFDWLRQVGRVDJH
7KHFRPELQDWLRQLVD)LUVWLQ&ODVVGUXJGXHLWVQHZDQGXQLTXH
PHFKDQLVPRIDFWLRQ
7KHLQYHVWLJDWRUVSURSRVHWKDWLQSUHGLVSRVHGLQGLYLGXDOVPLJUDLQH
DWWDFNVRFFXUGXHWRH[XEHUDQWLQQDWHLPPXQHV\VWHPDFWLYDWLRQQHDUE\
 /LX7*DR<--L55(PHUJLQJUROHRI7ROOOLNHUHFHSWRUVLQWKHFRQWURORISDLQDQGLWFK1HXURVFL%XOO

 :DQJ;=KDQJ<3HQJ<HWDO3KDUPDFRORJLFDOFKDUDFWHUL]DWLRQRIWKHRSLRLGLQDFWLYHLVRPHUVQDOWUH[RQH
DQGQDOR[RQHDVDQWDJRQLVWVRIWROOOLNHUHFHSWRU%U-3KDUPDFRO
 +HUQDQGH]<6RWRORQJR-)XNDWD07ROOOLNHUHFHSWRUVLJQDOLQJLQWHJUDWHVLQWHVWLQDOLQIODPPDWLRQZLWK
WXPRULJHQHVLVOHVVRQVIURPWKHPXULQHPRGHORIFROLWLVDVVRFLDWHGFDQFHU&DQFHUV%DVHO
'UDIWJXLGDQFHIRU,QGXVWU\IRU&RGHYHORSPHQWRI7ZRRU0RUH1HZ,QYHVWLJDWLRQDO 'UXJVIRU8VHLQ
&RPELQDWLRQ
KWWSZZZIGDJRYGRZQORDGVGUXJVJXLGDQFHFRPSOLDQFHUHJXODWRU\LQIRUPDWLRQJXLGDQFHVXFPSGI

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\ , 
WKHWULJHPLQDOQHUYHDQGRWKHUFUDQLDOQHUYHV7KHLQQDWHLPPXQLW\
DFWLYDWLRQOHDGVWRUHOHDVHRISURLQIODPPDWRU\F\WRNLQHV>QLWULFR[LGH
12WXPRUQHFURVLVIDFWRUĮ71)ĮDQGUHDFWLYHR[\JHQVSHFLHV
526@DQGWR&2;DFWLYDWLRQZKLFKSURGXFHVQHXURLQIODPPDWLRQ
FDXVLQJSDLQDQGYDULRXVPLJUDLQHDVVRFLDWHGV\PSWRPV
$//2'UHYHUVHVWKHQHXURLQIODPPDWLRQWKURXJKGXDODFWLRQ
LQKLELWLRQRIWKHUHOHDVHRIWKHSURLQIODPPDWRU\F\WRNLQHVDQGLQKLELWLRQ
RIWKH&2;DFWLYDWLRQ(IILFDF\RIWKLVSURGXFWIRUPLJUDLQHKHDGDFKH
SDLQDQGIRUPLJUDLQHDVVRFLDWHGV\PSWRPVHVSHFLDOO\QDXVHDZKLFKLV
UHIUDFWRU\WRRWKHUNQRZQPLJUDLQHWUHDWPHQWVPD\VXJJHVWWKHSURGXFW
DGGUHVVHVWKHURRWFDXVHRIPLJUDLQH
'HILQLWLRQV
0LJUDLQHZLWKRUZLWKRXWDXUDLVGHILQHGDFFRUGLQJWRWKH,QWHUQDWLRQDO
&ODVVLILFDWLRQRI+HDGDFKH'LVRUGHUV,&+'UGHGLWLRQEHWDYHUVLRQ
3UREDEOHPLJUDLQHLVGHILQHGDFFRUGLQJWRWKH,&+'±EHWDYHUVLRQ
FULWHULDDVDWWDFNVIXOILOOLQJDOOEXWRQHRIFULWHULD$'IRUPLJUDLQHZLWK
RUZLWKRXW DXUDZKHUHFULWHULD%LVKHDGDFKHDWWDFNVODVWLQJKRXUV
XQWUHDWHGRUXQVXFFHVVIXOO\WUHDWHG
$PLJUDLQHSUREDEOHPLJUDLQHKHDGDFKHVPXVWEHPRGHUDWHRU VHYHUHDQG
ODVWLQJPLQXWHV:KHQWKHSDWLHQWIDOOVDVOHHSGXULQJPLJUDLQHDQG
ZDNHVXSZLWKRXWLWGXUDWLRQRIWKHDWWDFNLVUHFNRQHGXQWLOWKHWLPHRI
DZDNHQLQJ
6WXG\2EMHFWLYHV
7KHSULPDU\REMHFWLYHLVWRFRPSDUH WKHUHGXFWLRQLQWKHPHDQ
PLJUDLQHSUREDEOHPLJUDLQHKHDGDFKHGD\V IURPEDVHOLQHWRWKHODVW
GD\VRIWKHZHHN7UHDWPHQW3HULRG
$VHFRQGDU\REMHFWLYHLVWRFRPSDUH WKHUHGXFWLRQLQWKHPHDQ KHDGDFKH
GD\VIURPEDVHOLQHWRWKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG
$QRWKHU VHFRQGDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQ
SURSRUWLRQRISDWLHQWVUHVSRQGLQJ WRWUHDWPHQWDVPHDVXUHGE\D RU
PRUHUHGXFWLRQLQGD\ PLJUDLQH IUHTXHQF\ IURPEDVHOLQHWRWKHODVW
GD\VRIWKHZHHN7UHDWPHQW3HULRG
$QRWKHU VHFRQGDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQ
PLJUDLQHKHDGDFKHVHYHULW\KHDGDFKHGXUDWLRQQDXVHD VHYHULW\OLJKW
VHQVLWLYLW\QRLVHVHQVLWLYLW\DQGQXPEHURIGD\VRIUHVFXHPHGLFDWLRQV
LQWDNHIURPEDVHOLQHWRWKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG
$QRWKHU VHFRQGDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQ
PLJUDLQHGLVDELOLW\DVVHVVPHQWVFDOH0,'$6 DQGKHDGDFKHLPSDFWWHVW
+,7IURPEDVHOLQHWR(QGRI7UHDWPHQW9LVLW
$QH[SORUDWRU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQRI PHDQ3LWWVEXUJK
,QVRPQLD5DWLQJ6FDOH3,56IURPEDVHOLQHWR(QGRI7UHDWPHQW
9LVLW

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\ , 
&RQFRPLWDQW
(PRWLRQDO3DLQ
DQGRU &KURQLF
/RZ%DFN3DLQ
&/%3
3LORWVWXG\GDWDGHPRQVWUDWHGHPRWLRQDOSDLQUHOLHIE\ WKHLQYHVWLJDWLRQDO
SURGXFW7KHLQYHVWLJDWRUSRVWXODWHVWKDWWKHLQYHVWLJDWLRQDOSURGXFWUHOLHI
RIHPRWLRQDOSDLQLV JUHDWHUWKDQWKDWRIDFHWDPLQRSKHQDORQH
$GGLWLRQDOO\SLORWVWXG\GDWDGHPRQVWUDWHGHIILFDF\RIWKH
LQYHVWLJDWLRQDOSURGXFWIRU&/%3
3DWLHQWVIRXQGDWWKHVFUHHQLQJYLVLWWRKDYHFRQFRPLWDQWHPRWLRQDOSDLQ
FRH[LVWLQJZLWKHSLVRGLFPLJUDLQH ZRXOG EHDVNHGWRFRPSOHWHDQ
HPRWLRQDOGDLO\GLDU\DVZHOODVWKHPLJUDLQHSUHYHQWLRQGDLO\GLDU\ 7KH
VWUHVVRUVFDXVLQJHPRWLRQDOSDLQDVH[SODLQHGWRSDWLHQWVLQFOXGH
DGMXVWPHQWWRQHZOLIHIRULPPLJUDQWVDGMXVWPHQWWRVHSDUDWLRQIURP
FKLOGUHQZKRUHFHQWO\OHIWKRPHRUDGMXVWPHQWWRORVVRIDSHW7KHVH
FRPSODLQWVDUHFXUUHQWO\WUHDWHGZLWKSV\FKRWKHUDS\7KH,&'&0
GLDJQRVLVFRGHLV)³DGMXVWPHQWGLVRUGHUXQVSHFLILHG´
$GGLWLRQDOO\SDWLHQWVZLWKFRQFRPLWDQWHPRWLRQDOSDLQZLOOFRPSOHWHWKH
%HFN
V'HSUHVVLRQ,QYHQWRU\ LQVWUXPHQWRQHYHU\VLWHYLVLW
,I DSDWLHQWLVIRXQGDWWKHVFUHHQLQJYLVLWWRKDYHFRQFRPLWDQW&/%3 FR
H[LVWLQJZLWKHSLVRGLFPLJUDLQH WKH\ZLOOEHDVNHGWRFRPSOHWH D&/%3
GDLO\GLDU\DVZHOO DVWKHPLJUDLQHSUHYHQWLRQGDLO\GLDU\6HHWKH
DWWDFKHGGDLO\GLDU\IRUPV$GGLWLRQDOO\SDWLHQWZLWKFRQFRPLWDQW
&/%3ZLOOFRPSOHWHWKH2VZHVWU\'LVDELOLW\,QGH[LQVWUXPHQWRQHYHU\
VLWHYLVLW
7KH6WXG\
7UHDWPHQW
*URXSV
3DWLHQWVZLOOEHUDQGRPL]HGWRRQHRIWZR WUHDWPHQWJURXSV
 1DOWUH[RQH
PJDFHWDPLQRSKHQ
PJ$//2'
 3ODFHER
&RPSDULQJWKHQDOWUH[RQHDFHWDPLQRSKHQ JURXS WRWKHSODFHER JURXS
ZLOOSURYLGHGDWDWRVXSSRUWHIILFDF\RIWKHSURGXFW IRUHSLVRGLFPLJUDLQH
SUHYHQWLRQ
7KHVWXG\SODQVWRHQUROOSDWLHQWVUDQGRPL]HGWRRQHRIWZRWUHDWPHQW
JURXSVLQDUDWLRRIIRUSDWLHQWVLQHDFKJURXS,QYHVWLJDWRUVVLWH
SHUVRQQHODQGSDWLHQWVZLOOEHPDVNHGWRWKHWUHDWPHQWDVVLJQPHQW
3UH(QUROOPHQW
0LJUDLQH
$VVHVVPHQW
7KHLQYHVWLJDWRUZLOOREWDLQPHGLFDOUHFRUGVFRQILUPLQJ DGLDJQRVLVRI
PLJUDLQHSK\VLFLDQ¶VQRWHSKDUPDF\UHFRUGVIRUPLJUDLQHVSHFLILF
PHGLFDWLRQVHWF $GGLWLRQDOO\WKHLQYHVWLJDWRUZLOOUHYLHZWKH
FRPSOHWHGPLJUDLQHLQWDNHIRUP7KHLQYHVWLJDWRUZLOOIRUZDUG
DQRQ\PL]HGPHGLFDOUHFRUGVDQGWKHFRPSOHWHGPLJUDLQHLQWDNHIRUPWR
WKHVSRQVRUSULRUWRHQUROOLQJDSDWLHQW
6WXG\3RSXODWLRQ
7KHVWXG\SRSXODWLRQZLOOLQFOXGHQRQSUHJQDQWQRQODFWDWLQJIHPDOHV
DQGPDOHV%RWKPXVWEH\HDUVRIDJH RUROGHU
3DWLHQWVKDYHDQDYHUDJHRIDWOHDVWPRGHUDWHWRVHYHUHPLJUDLQH
HSLVRGHVEXW  RUOHVV KHDGDFKHGD\VSHUPRQWKLQWKHSUHYLRXV
PRQWKV DQGGXULQJWKHEDVHOLQHSHULRG
3DWLHQWVKDYHKLVWRU\RIPLJUDLQHZLWKRUZLWKRXWDXUDDFFRUGLQJWRWKH
,QWHUQDWLRQDO&ODVVLILFDWLRQRI+HDGDFKH'LVRUGHUV,&+'UGHGLWLRQ
EHWDYHUVLRQIRUDWOHDVWRQH\HDUZLWKRQVHWRIPLJUDLQHSULRUWRDJH

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\ , 
\HDUVRIDJH
3DWLHQWVZLWKFRH[LVWLQJW\SHVRIKHDGDFKHSDLQVHJWHQVLRQW\SH
KHDGDFKHFDQEHLQFOXGHGLIWKH\ FDQGLVWLQJXLVKPLJUDLQHKHDGDFKH
IURPWKHRWKHUKHDGDFKHV
3DWLHQWVPXVWKDYHKLJKIUHTXHQF\PRGHUDWHWRVHYHUHPLJUDLQH
DVVRFLDWHGQDXVHDLHDVVRFLDWHGQDXVHDKDOIWKHPLJUDLQHDWWDFNVWR
EHDGPLWWHGLQWRWKHVWXG\3DWLHQWVZKRH[SHULHQFHYRPLWLQJFDQEH
DGPLWWHGKRZHYHUWKH\ZLOOEHDGYLVHG WKDWYRPLWLQJZLWKLQPLQ
DIWHUWDNLQJWKHVWXG\GUXJFDQSXUJHWKHVWXG\GUXJ3DWLHQWVZLOOEH
DVNHG WRWDNHWKHVWXG\GUXJZKHQWKH\FDQDVVXPH WKDWWKH\ZLOOQRW
YRPLWZLWKLQPLQV
3DWLHQWVZKRLQWKHRSLQLRQRIWKHLQYHVWLJDWRU PD\KDYHPHGLFDWLRQ
RYHUXVHKHDGDFKHVDVGHILQHGE\,&+'±EHWDYHUVLRQ FULWHULDIRU
PHGLFDWLRQRYHUXVHKHDGDFKH7KHGHILQLWLRQRIPHGLFDWLRQRYHUXVHIRU
WKLVVWXG\LVXVDJHRIGD\VPRQWK RIDFHWDPLQRSKHQ16$,'VRU
XVDJHRIHUJRWDPLQH DQGWULSWDQV GD\VPRQWK RUXVDJHRIRSLRLGV
DQG EDUELWXUDWHV!GD\VPRQWK GXULQJ WKHPRQWKVSUHFHGLQJVFUHHQLQJ
RUGXULQJWKHEDVHOLQHSHULRG
3DWLHQWVZKRLQWKHRSLQLRQRIWKHLQYHVWLJDWRUKDYHFKURQLFPLJUDLQHDV
GHILQHGE\,&+'±EHWDYHUVLRQFULWHULDIRUFKURQLFPLJUDLQH
KHDGDFKHWHQVLRQW\SHOLNHDQGRUPLJUDLQHOLNHRQGD\VSHU
PRQWKGXULQJWKHPRQWKVSUHFHGLQJVFUHHQLQJRUGXULQJWKHEDVHOLQH
SHULRGZLOOEHH[FOXGHG
,QDGGLWLRQSDWLHQWVXVLQJDQ\GLVDOORZHGFRQFRPLWDQWPHGLFDWLRQVRU
SDWLHQWVZKRXVHGDQLQYHVWLJDWLRQDOPHGLFDWLRQZLWKLQZHHNVEHIRUH
WKH6FUHHQLQJ9LVLW ZLOOQRWTXDOLI\
&DUHVKRXOGEHWDNHQWRH[FOXGHRWKHUSRWHQWLDOO\VHULRXVQHXURORJLF
FRQGLWLRQVEHIRUHHQUROOLQJ SDWLHQWVQRWSUHYLRXVO\GLDJQRVHGZLWK
PLJUDLQHKHDGDFKHRUZKRH[SHULHQFHKHDGDFKHWKDWLVDW\SLFDOIRUWKHP
6WXG\'XUDWLRQ
7KHVWXG\LQFOXGHV VHYHQVLWHYLVLWVDQGILYHWHOHSKRQHFRQWDFWVRFFXUULQJ
RYHUDPRQWKSHULRG
Study visits schedule: 
9LVLW
6FUHHQLQJ
9LVLW
9LVLW
UDQGRPL]DWL
RQ 9LVLW
9LVLW
7UHDWPHQW
3HULRG
9LVLW
9LVLW
7UHDWPHQW
3HULRG
9LVLW
9LVLW
7UHDWPHQW
3HULRG
9LVLW
9LVLW
(QGRI
7UHDWPHQW
3HULRG
9LVLW
9LVLW
3RVW
7UHDWPHQW
3HULRG
9LVLW
6WXG\'D\







$OOYLVLWVPD\KDYHGD\YLVLWZLQGRZH[FHSWYLVLWZKLFKPXVWWDNHSODFHQRVRRQHUWKDQ GD\V IURP
WKHEHJLQQLQJRIWKHGRXEOHEOLQG7UHDWPHQW3HULRG'D\RIWKH7UHDWPHQW3HULRG LVFRQVLGHUHGWKHODVWGD\
RIWUHDWPHQWIRUGDWDDQDO\VLVSXUSRVHV
Telephone contacts Schedule: 
7HOHSKRQH
FRQWDFWV
3KRQH
%DVHOLQH
3HULRG
3KRQH
7UHDWPHQW
3HULRG
3KRQH
7UHDWPHQW
3HULRG
3KRQH
7UHDWPHQW
3HULRG
3KRQH3RVW
7UHDWPHQW
3HULRG
6WXG\'D\





$OO3KRQH9LVLWVPD\KDYHGD\ YLVLWZLQGRZ

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\ , 
6WXG\'HVLJQ
7KLVLVDZHHNVLQJOHFHQWHUGRXEOHEOLQGUDQGRPL]HGSODFHER
FRQWUROOHGSDUDOOHODUPVWXG\IRUSDWLHQWVUHTXLULQJPLJUDLQHSUHYHQWLRQ
3DWLHQWVZLOOEHWUHDWHGIRUZHHNVZLWKRUDO%,'FRPELQDWLRQRI
QDOWUH[RQH
PJ$3$3
PJRU SODFHER7KHVWXG\FRQVLVWVRIWKUHH
VWXG\SHULRGVDGD\ EDVHOLQHSHULRGDZHHNGRXEOHEOLQG
7UHDWPHQW3HULRGDQGGD\ 3RVW7UHDWPHQW )ROORZXS3HULRG
7KHGD\ GXUDWLRQRIWKHEDVHOLQHSHULRGLVGHVLJQHGWRDVVHVVWKH
EDVHOLQHIUHTXHQF\DQGVHYHULW\RIPLJUDLQH7KHZHHNGXUDWLRQRIWKH
7UHDWPHQW3HULRGLVGHVLJQHGWRPHHWWKHUHTXLUHPHQWIRUDPLJUDLQH
SUHYHQWLRQ VWXGLHV$GD\ 3RVW7UHDWPHQW )ROORZXS3HULRG LV
GHVLJQHGWRDVVHVVDQ\ VDIHW\LVVXHVZLWKWKHVWXG\GUXJ$GGLWLRQDOO\LW
ZLOODVVHVVZKHWKHUWKHUHLVDFDUU\RYHUHIIHFWRIWKHVWXG\GUXJRQ
PLJUDLQHSUHYHQWLRQ
*LYHQWKHULVNIRUERWKQDOWUH[RQHDQGDFHWDPLQRSKHQWRFDXVH
KHSDWRWR[LFLW\ ODERUDWRU\DVVHVVPHQWVKHPDWRORJ\KHSDWLFDQGUHQDO
IXQFWLRQZLOOEHREWDLQHGSUHGRVH 9LVLW DQGPRQWKO\WKHUHDIWHULH
9LVLW9LVLWDQG9LVLW
2Q'D\RIWKH7UHDWPHQW3HULRGWKHGD\RI9LVLWSDWLHQWVZLOOWDNH
WKHILUVWGRVHRIWKHVWXG\GUXJDWKRPHDWSP
3DWLHQWVZLOOFRPSOHWHWKH0LJUDLQH'LDU\DVVHVVPHQWVDSSUR[LPDWHO\DW
SPRUDWEHGWLPHHYHU\GD\ZKLFKHYHULVHDUOLHU HYHU\GD\RI
WKHVWXG\
'XULQJHDFKYLVLWRIWKHVWXG\H[FHSW9LVLWSDWLHQWVZLOOFRPSOHWHWKH
+HDGDFKH,PSDFW7HVW+,73DWLHQWV ZLOOFRPSOHWH WKH3LWWVEXUJK
,QVRPQLD5DWLQJ6FDOH3,56 HYHU\VLWHYLVLW3DWLHQWV ZLOO
FRPSOHWHWKH0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6 2Q9LVLW
DQG
3DWLHQWVZLOODQGUHFHLYHVWXG\GUXJRQYLVLWDQG
Study Visit 1 - Screening Visit: GXULQJWKLVYLVLWSDWLHQWVZKRPHW
LQFOXVLRQ H[FOXVLRQFULWHULD ZLOOJLYHDQ LQIRUPHG FRQVHQWDIWHUWKH
QDWXUHRI WKHVWXG\LV H[SODLQHGDQGEHIRUHDQ\VWXG\VSHFLILFSURFHGXUHV
DUH SHUIRUPHG
'XULQJWKHVFUHHQLQJYLVLWWKHLQYHVWLJDWRUZLOOREWDLQPHGLFDOKLVWRU\
PLJUDLQHKHDGDFKHKLVWRU\KLVWRU\RIVXEVWDQFHDEXVHDQGRU
GHSHQGHQF\DQGPHGLFDWLRQKLVWRU\,QDGGLWLRQWKHLQYHVWLJDWRUZLOO
SHUIRUPDFRPSOHWHSK\VLFDOH[DPLQDWLRQYLWDOVLJQVPHDVXUHPHQWVD
OHDG(&*DXULQHGUXJVFUHHQDQGDXULQHSUHJQDQF\WHVWIRU
FKLOGEHDULQJDJHIHPDOHV$GGLWLRQDOO\WKHLQYHVWLJDWRUZLOOGUDZEORRG
VDPSOHIRUODERUDWRU\DVVHVVPHQWVKHPDWRORJ\KHSDWLFDQGUHQDO
IXQFWLRQ
7KHSDQHOXULQHGUXJVFUHHQFRFDLQH PDULMXDQD RSLDWHV
PHWKDPSKHWDPLQHVDQG2[\FRGRQHDQGWKHSUHJQDQF\WHVWPXVWEH
QHJDWLYHWRFRQWLQXHZLWKWKHVFUHHQLQJYLVLWSURFHGXUHV
$WWKHVFUHHQLQJYLVLWWKH0,'$6 VFRUHPXVWEHKLJKHUWKDQ
PRGHUDWHRUVHYHUHGLVDELOLW\DQGWKH+,7VFRUHPXVWEHKLJKHUWKDQ
VXEVWDQWLDORUYHU\VHYHUHLPSDFW

3URWRFRO$12'<1(

3DJHRI
9HUVLRQ
-XO\ , 
'XULQJWKH6FUHHQLQJ9LVLWWKHLQYHVWLJDWRUZLOO JRRYHU WKHIROORZLQJ
LWHPV
x
+RZWRUDWHWKHLQWHQVLW\RIKHDGDFKHSDLQQDXVHDDQG
VDWLVIDFWLRQZLWKPLJUDLQHSUHYHQWLRQRQDSRLQWVFDOH
x
+RZWRUDWHOLJKWVHQVLWLYLW\QRLVHVHQVLWLYLW\QHFNVKRXOGHU SDLQ
DQGYRPLWLQJ DVDEVHQWRUSUHVHQW
x
+RZWRGLVWLQJXLVKPLJUDLQHKHDGDFKHIURPQRQPLJUDLQH
KHDGDFKH
x
+RZWRWDNHUHVFXHPHGLFDWLRQVZDLWòKRXUDIWHUDPLJUDLQH
VWDUWHGEHIRUHWDNLQJ WKHLURZQXVXDOPLJUDLQHPHGLFDWLRQV
x
+RZ DQGZKHQ WRFRPSOHWHWKH0LJUDLQH'LDU\DVVHVVPHQWV
x
+RZWRUHFRUGUHVFXHPHGLFDWLRQV
x
$ERXWWKH ³SODFHERHIIHFW´
7KHLQYHVWLJDWRUZLOOHQUROORQO\SDWLHQWVLQWRWKHEDVHOLQHSHULRGLIWKH\
GHPRQVWUDWHDELOLW\WRFRPSOHWHWKH0LJUDLQH'LDU\
$WWKHFRQFOXVLRQRIWKH6FUHHQLQJ9LVLWSDWLHQWVZLOOUHFHLYHDSDSHU
PLJUDLQHGLDU\WREHFRPSOHWHGGDLO\IRUDGD\ EDVHOLQHSHULRG
3DWLHQWVZLOOKDYHDSKRQH FRQWDFWRQGD\DQGGD\RIWKHEDVHOLQH
SHULRG$IWHUFRPSOHWLRQRIWKHGD\ EDVHOLQHSHULRGSDWLHQWVZLOO
UHWXUQIRUWKH5DQGRPL]DWLRQ9LVLW
Study Visit 2 - Randomization Visit: ,QWKLVYLVLWWKHLQYHVWLJDWRUZLOO
UHYLHZWKHEDVHOLQHSHULRG0LJUDLQH'LDU\3DWLHQWVZKRKDGDWOHDVW
PRGHUDWHWRVHYHUHPLJUDLQHHSLVRGHVEXW RUOHVV KHDGDFKHGD\V
GXULQJWKHGD\ EDVHOLQH SHULRGDQG FRQWLQXHGWRPHHWDOORWKHU
LQFOXVLRQDQGH[FOXVLRQFULWHULDZLOOEH HOLJLEOHIRUUDQGRPL]DWLRQ
3DWLHQWPXVWFRPSOHWHWKHDVVHVVPHQWVIRUDOOWKHGD\VRIWKHEDVHOLQH
SHULRGWRTXDOLI\IRUUDQGRPL]DWLRQ
,QDGGLWLRQDW WKH5DQGRPL]DWLRQ9LVLWWKH0,'$6 VFRUHPXVWEHKLJKHU
WKDQPRGHUDWHRUVHYHUHGLVDELOLW\DQGWKH+,7VFRUHPXVWEH
KLJKHUWKDQVXEVWDQWLDORUYHU\VHYHUHLPSDFW
'XULQJWKH5DQGRPL]DWLRQ9LVLWWKHLQYHVWLJDWRUZLOO JRRYHU WKH
IROORZLQJLWHPV
x
+RZWRWDNHWKHVWXG\GUXJ
x
+RZWRWDNHUHVFXHPHGLFDWLRQVZDLWòKRXUDIWHUDPLJUDLQH
VWDUWHGEHIRUHWDNLQJRZQXVXDOPLJUDLQHPHGLFDWLRQV
x
+RZWRUHFRUGUHVFXHPHGLFDWLRQV
3DWLHQWVZLOOEHUDQGRPL]HG LQ D UDWLRWRQDOWUH[RQH

PJDFHWDPLQRSKHQ
PJ$//2'RU SODFHERDQGHQWHULQWRWKH
ZHHN7UHDWPHQW3HULRG
5DQGRPL]HGSDWLHQWVZLOOUHFHLYHDSDSHU0LJUDLQH'LDU\ IRUPDQGD
EOLQGHGVWXG\GUXJWRXVHLQWKHRXWSDWLHQWVHWWLQJV
Study Visit 3 – 1 week after the Treatment Period started: GXULQJWKLV
YLVLWWKHLQYHVWLJDWRU ZLOOFRQILUPWKHSDWLHQW XQGHUVWDQGV RIKRZWRWDNH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
WKHVWXG\GUXJDQGKRZWRFRPSOHWHWKH0LJUDLQH'LDU\ 'XULQJWKLVYLVLW
DVVHVVPHQWRIDGYHUVHHYHQWVDQGDGMXVWPHQWWRWKHVWXG\GUXJGRVDJH
ZLOOEH PDGH
Study Visits 4 and 5: WKHVHYLVLWV ZLOORFFXURQGD\VDQGGD\
YLVLWZLQGRZ RIWKH7UHDWPHQW3HULRG$GGLWLRQDOO\WKHUHZLOOEH
WHOHSKRQHFRQWDFWVWZRZHHNVDIWHUWKHVH YLVLWVGD\YLVLWZLQGRZ
Study Visit 6 - End-of-Treatment Period Visit: 7KLVYLVLWZLOOWDNH
SODFHQRVRRQHU WKDQGD\GD\VIURPWKHEHJLQQLQJRIWKH
7UHDWPHQW3HULRG'XULQJWKLVYLVLWSDWLHQWVILQDOFRXQWDQG
UHFRQFLOLDWLRQRIWKHVWXG\GUXJ
Study Visit 7 - End-of-Study Visit:7KLVYLVLWZLOOWDNHSODFHRQGD\
GD\YLVLWZLQGRZRIWKH)ROORZXS3HULRG'XULQJWKH)ROORZXS3HULRG
SDWLHQWVZLOOFRQWLQXHWRFRPSOHWHWKHGDLO\GLDU\EXWWKH\ZLOOQRWFRQVXPH
WKHVWXG\GUXJ
7KH0LJUDLQH
'LDU\
DVVHVVPHQWV DQG
RWKHUVWXG\
DVVHVVPHQWV
The Migraine Daily Diary assessments: 
x
6WXG\GUXJPRUQLQJGRVHFRQVXPSWLRQ
x
6WXG\GUXJHYHQLQJGRVHFRQVXPSWLRQ
x
3UHVHQFHRIDKHDGDFKH\HVQR
x
6WDUWWLPHDQGWKHHQGWLPHRIWKH KHDGDFKH
x
,QWDNHRIDGGLWLRQDOPLJUDLQHPHGLFDWLRQV
x
6HYHULW\ RIWKHKHDGDFKHSDLQ QRQH PLOG PRGHUDWH
 VHYHUH
x
6HYHULW\ RIWKHQDXVHDYRPLWLQJ QRQH PLOG PRGHUDWH
 VHYHUH
x
3UHVHQFH2QHVLGHGKHDGDFKH\HVQR
x
3XOVDWLQJ TXDOLW\\HVQR
x
:RUVHQLQJ ZLWKDFWLYLW\\HVQR
x
/LJKWVHQVLWLYLW\\HVQR
x
1RLVHVHQVLWLYLW\\HVQR
x
1HFNSDLQ\HVQR
Other assessments: 
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6PRQWK
DVVHVVPHQW9LVLWVDQG
x
+HDGDFKH,PSDFW7HVW+,7ZHHNDVVHVVPHQWHYHU\YLVLW
H[FHSW9LVLW
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56GD\
DVVHVVPHQWHYHU\YLVLW
x
3DWLHQW*OREDO,PSUHVVLRQRI&KDQJH3*,&
x
3DWLHQWVDWLVIDFWLRQZLWKPLJUDLQHSUHYHQWLRQ9LVLWV9LVLW
 QRWDWDOOVDWLVILHG SDUWO\VDWLVILHG VDWLVILHG YHU\
VDWLVILHG
&RQFRPLWDQW
0HGLFDWLRQV
5HVWULFWLRQV
3DWLHQWVUHFHLYLQJFKURQLFRSLRLGVFDQQRWWDNHWKHVWXG\GUXJVLQFH
QDOWUH[RQHPD\SUHFLSLWDWHRSLRLGZLWKGUDZDOV\PSWRPV3DWLHQWVPXVW
KDYHDQHJDWLYHXULQHGUXJVFUHHQGXULQJWKH6FUHHQLQJ9LVLWDQGGXULQJ
WKH5DQGRPL]DWLRQ9LVLW3DWLHQWVFDQQRWWDNHDQ\RSLRLGPHGLFDWLRQV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
IURPWKHGD\VEHIRUHWKH6FUHHQLQJ9LVLWWRGD\VDIWHUWDNLQJWKHODVW
GRVHRIWKHVWXG\GUXJ
3DWLHQWVZLOOEHHOLJLEOHLIWKH\KDYH EHHQWDNLQJDVWDEOHGRVHRID
PHGLFDWLRQZLWKPLJUDLQHSUHYHQWLRQSRWHQWLDOIRUDWOHDVWPRQWKSULRU
WRWKHVFUHHQLQJYLVLWDQGDJUHHWRQRWVWDUWVWRSRUFKDQJHGRVDJHRIDQ\
PHGLFDWLRQZLWKPLJUDLQHSUHYHQWLRQSRWHQWLDOGXULQJWKHVWXG\SHULRG
(JEHWDEORFNHUVFDOFLXPFKDQQHOEORFNHUVWULF\FOLFDQWLGHSUHVVDQWV
DQWLFRQYXOVDQWVVHOHFWLYHVHURWRQLQUHXSWDNHLQKLELWRUV665,V
VHURWRQLQQRUHSLQHSKULQHUHXSWDNHLQKLELWRUV615,VPDJQHVLXPRU
ULERIODYLQVXSSOHPHQWVDWKLJKGRVHVKHUEDOSUHSDUDWLRQVHJIHYHUIHZ
RU6WMRKQ¶VZRUW%RWXOLQXPWR[LQPXVWEHGLVFRQWLQXHGRQH\HDUSULRU
WR9LVLW
8VHRI5HVFXH
0HGLFDWLRQV
3DWLHQWVFDQXVHWKHLURZQXVXDOPLJUDLQH PHGLFDWLRQGXULQJWKHVWXG\ IRU
XQWUHDWHGRUSDUWLDOO\WUHDWHGPLJUDLQHLQFOXGLQJGXULQJWKH EDVHOLQH
SHULRG DQGWKH3RVW7UHDWPHQW )ROORZXS3HULRG3DWLHQWVZLOOZDLWò
KRXUDIWHUDPLJUDLQHVWDUWHGWRWDNHDUHVFXH PHGLFDWLRQV3DWLHQWV ZLOO
UHFRUGHYHU\ UHVFXHPHGLFDWLRQLQWKHPLJUDLQHGLDU\
3HUPLWWHG UHVFXHPHGLFDWLRQVLQFOXGH DVSLULQDFHWDPLQRSKHQ16$,'V
HUJRWGHULYDWLYHVDQGWULSWDQV
2SLRLGVDUHQRWSHUPLWWHG
7KHDFHWDPLQRSKHQGRVHFRQWDLQHGLQWKHVWXG\GUXJLVPJSHUGD\
7KHPD[LPDOGRVHRIDFHWDPLQRSKHQIURPWKHVWXG\GUXJDQGDQ\RWKHU
DFHWDPLQRSKHQFRQWDLQLQJSURGXFWPXVWQRWH[FHHGPJSHUGD\
,QVWUXFWLRQVIRU
WDNLQJWKH6WXG\
'UXJDQGIRU
FRPSOHWLQJWKH
0LJUDLQH'LDU\
7KHVWXG\GUXJLVSURYLGHGLQWZRYLDOV 'XULQJWKH7UHDWPHQW3HULRG
SDWLHQWVZLOO WDNHone capsule from each vial twice a day
DSSUR[LPDWHO\DPDQGSP3DWLHQWVZLOOWDNHWKHVWXG\
GUXJZLWKVXIILFLHQWDPRXQWRIZDWHU7KH\ PD\WDNHWKHVWXG\GUXJZLWK
IRRGWRGHFUHDVHVWRPDFKXSVHW7KHVWXG\GUXJPD\FDXVHGURZVLQHVV
SDWLHQWVVKRXOGDYRLGGULYLQJXQWLOWKH\ NQRZKRZWKHVWXG\GUXJDIIHFWV
WKHP,IGHHPHGQHFHVVDU\GXHWRLQWROHUDQFHWKHLQYHVWLJDWRUZLOO
GHFUHDVHWKHGRVDJH WRRQHGRVHDGD\WKHSPGRVHIRUWKH
GXUDWLRQRIWKH7UHDWPHQW3HULRG
2Q'D\RIWKH7UHDWPHQW3HULRG
WKHGD\RI9LVLWSDWLHQWVZLOO
WDNHWKHILUVWGRVHRIWKHVWXG\GUXJ
DWKRPHDWSP
3DWLHQWVZLOOFRPSOHWHWKH0LJUDLQH
'LDU\DVVHVVPHQWVDSSUR[LPDWHO\DW
SPRUDWEHGWLPHHYHU\GD\
ZKLFKHYHULVHDUOLHU
,QFOXVLRQ
&ULWHULD
$OOSDWLHQWVPXVWPHHWWKHIROORZLQJLQFOXVLRQFULWHULD
,QFOXVLRQ&ULWHULD

7KHSDWLHQWLVDPDOHRUDIHPDOH\HDUVRIDJHRUROGHU

+LVWRU\RIPLJUDLQHZLWKRUZLWKRXWDXUDDFFRUGLQJWRWKH
Figure 1: Medication vials for the 
Migraine Prevention Study 

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
,QWHUQDWLRQDO&ODVVLILFDWLRQRI+HDGDFKH'LVRUGHUV,&+'UG
HGLWLRQEHWDYHUVLRQIRUDWOHDVWRQH\HDUZLWKRQVHWRIPLJUDLQH
SULRUWR\HDUVRIDJH0LJUDLQHDWWDFNVPHHWWKHIROORZLQJFULWHULD
x
+HDGDFKHDWWDFNVODVWLQJKRXUVXQWUHDWHGRUXQVXFFHVVIXOO\
WUHDWHG
x
0LJUDLQHDWWDFNVDUHVHSDUDWHGE\DWOHDVWKRXUVRIDEVHQFHRI
KHDGDFKHSDLQ
x
+HDGDFKHKDVDWOHDVWWZRRIWKHIROORZLQJWKUHHFKDUDFWHULVWLFV
8QLODWHUDOORFDWLRQ3XOVDWLQJTXDOLW\$JJUDYDWLRQE\RUFDXVLQJ
DYRLGDQFHRIURXWLQHSK\VLFDODFWLYLW\HJZDONLQJRUFOLPELQJ
VWDLUV
x
'XULQJWKHKHDGDFKHERWKRIWKHIROORZLQJQDXVHDDQGRU
YRPLWLQJSKRWRSKRELDRUSKRQRSKRELD

0LJUDLQHDVVRFLDWHGQDXVHDZLWKKDOIRIPLJUDLQHDWWDFNV

PLJUDLQHSUREDEOHPLJUDLQH KHDGDFKHGD\VRQDYHUDJHSHU
PRQWKLQWKHWKUHHPRQWKVSULRUWR9LVLWDQGGXULQJWKH%DVHOLQH
3HULRG

7KHSDWLHQWDJUHHVWRUHIUDLQIURPWDNLQJRSLDWHPHGLFDWLRQVIURP
9LVLWWRGD\VDIWHUWKHODVWGRVHRIWKHVWXG\GUXJ

7KHSDWLHQWLVDEOHWRFRPSOHWHVWXG\TXHVWLRQQDLUHVFRPSO\ZLWK
WKHVWXG\UHTXLUHPHQWVDQGUHVWULFWLRQVDQGZLOOLQJWRSURYLGH
ZULWWHQLQIRUPHGFRQVHQWDQGDXWKRUL]H+,3$$

7KHSDWLHQWKDVEHHQWDNLQJDVWDEOHGRVHRIDPHGLFDWLRQZLWK
PLJUDLQHSUHYHQWLRQSRWHQWLDOIRUDWOHDVWPRQWKSULRUWRWKH
VFUHHQLQJYLVLWDQGDJUHHVWRQRWVWDUWVWRSRUFKDQJHGRVDJHRI
DQ\PHGLFDWLRQ ZLWKPLJUDLQHSUHYHQWLRQSRWHQWLDOGXULQJWKH
VWXG\SHULRG(JEHWDEORFNHUVFDOFLXPFKDQQHOEORFNHUV
WULF\FOLFDQWLGHSUHVVDQWVDQWLFRQYXOVDQWVVHOHFWLYHVHURWRQLQUH
XSWDNHLQKLELWRUV665,VVHURWRQLQQRUHSLQHSKULQHUHXSWDNH
LQKLELWRUV615,VPDJQHVLXPRUULERIODYLQVXSSOHPHQWVDWKLJK
GRVHVKHUEDOSUHSDUDWLRQVHJIHYHUIHZRU6WMRKQ¶VZRUW
%RWXOLQXPWR[LQPXVWEHGLVFRQWLQXHGRQH\HDUSULRUWR9LVLW

7KHSDWLHQWDJUHHVWRIRUJRDQ\HOHFWLYHVXUJHU\IRUWKHGXUDWLRQRI
WKHVWXG\

7KHIHPDOHSDWLHQWZKRLVSUHPHQRSDXVDORUSRVWPHQRSDXVDOOHVV
WKDQ\HDURUKDYHQRWKDGVXUJLFDOVWHULOL]DWLRQLHWXEDO
OLJDWLRQSDUWLDORUFRPSOHWHK\VWHUHFWRP\PXVWKDYHDQHJDWLYH
XULQHSUHJQDQF\WHVWEHQRQODFWDWLQJDQGFRPPLWWRXVLQJ
PHWKRGVRI DGHTXDWHDQGUHOLDEOHFRQWUDFHSWLRQWKURXJKRXWWKH
VWXG\ DQGIRUGD\VDIWHUWDNLQJWKHODVWGRVHRIWKHVWXG\
GUXJ HJEDUULHUZLWKDGGLWLRQDOVSHUPLFLGDOLQWUDXWHULQH
GHYLFHKRUPRQDOFRQWUDFHSWLRQ0DOHSDWLHQWVPXVWEHVXUJLFDOO\
VWHULOHRUFRPPLWWRWKHXVHRIGLIIHUHQWPHWKRGVRIELUWKFRQWURO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
GXULQJWKHVWXG\DQGIRUGD\VDIWHUWKHVWXG\
([FOXVLRQ
&ULWHULD
3DWLHQWV ZLOOEHH[FOXGHGLIWKH\KDYHPHWDQ\RIWKHH[FOXVLRQFULWHULD
([FOXVLRQ&ULWHULD

8VDJHRIDFHWDPLQRSKHQDQGQRQVWHURLGDODQWLLQIODPPDWRU\
GUXJV16$,'VGD\VPRQWKRUHUJRWDPLQHDQGWULSWDQV!
GD\VPRQWKRURSLRLGVDQGEDUELWXUDWHV!GD\VPRQWKLQWKH
PRQWKVSULRUWR9LVLWRUGXULQJWKH%DVHOLQH3HULRG

7HQVLRQW\SHOLNHDQGRUPLJUDLQHOLNHKHDGDFKHRQGD\VSHU
PRQWKLQWKHPRQWKVSULRUWR9LVLWRUGXULQJWKH%DVHOLQH3HULRG
'LDJQRVLVRIFKURQLFPLJUDLQHFOXVWHUKHDGDFKHRUQHXURORJLFDOO\
FRPSOLFDWHGPLJUDLQHKHPLSOHJLFEDVLODUUHWLQDORSKWKDOPRSOHJLF
PLJUDLQH

5HJXODUXVHRIWKHIROORZLQJPHGLFDWLRQVIRUDQ\UHDVRQ
DFHWDPLQRSKHQQRQVWHURLGDODQWLLQIODPPDWRU\GUXJV16$,'V
DQWLSV\FKRWLFGUXJVPRQRDPLQHR[LGDVHLQKLELWRUV
EHQ]RGLD]HSLQHVVOHHSPHGLFDWLRQVPXVFOHUHOD[DQWVDQWLHPHWLF
PHGLFDWLRQVEORRGWKLQQLQJPHGLFDWLRQVHJZDUIDULQRUKHSDULQ
FDQQDELQRLGVRUERWXOLQXPWR[LQWRKHDGDQGQHFNUHJLRQV/RZ
GRVHDVSLULQIRUFDUGLRYDVFXODUGLVHDVHSURSK\OD[LVLVSHUPLWWHG

&RQIRXQGLQJSDLQIXOFRQGLWLRQVHJILEURP\DOJLDFKURQLFORZ
EDFNSDLQFRPSOH[UHJLRQDOSDLQV\QGURPHHWF

'LDJQRVLVRIDQ\FRQFXUUHQWPHGLFDORUSV\FKLDWULFFRQGLWLRQWKLV
LQFOXGHVFKURQLFXQVWDEOHGHELOLWDWLQJGLVHDVHVVXFKDV3DUNLQVRQ¶V
GLVHDVHPXOWLSOHVFOHURVLVFDQFHUVLJQLILFDQWUHQDOLPSDLUPHQW
VLJQLILFDQWKHSDWLFLPSDLUPHQWHWF

7KHSDWLHQWKDVDKLVWRU\RUGLDJQRVLVRIPRGHUDWHWRVHYHUHKHSDWLF
RUUHQDOLPSDLUPHQW!îWKHXSSHUOLPLWRIQRUPDO>8/1@IRU
DODQLQHWUDQVDPLQDVHRUDVSDUWDWHWUDQVDPLQDVHî8/1IRU
DONDOLQH3KRVSKDWDVHELOLUXELQ%81 RUFUHDWLQLQH3DWLHQWVZLWK
HOHYDWHGELOLUXELQOHYHOGXHWR*LOEHUW
VV\QGURPHDUHDOORZHG

7KHSDWLHQWKDVDKLVWRU\ZLWKLQWKHSUHYLRXV\HDUVRIDEXVHRIDQ\
GUXJSUHVFULSWLRQLOOLFLWRUDOFRKRO

7KH)HPDOHSDWLHQWLVSUHJQDQWDFWLYHO\WU\LQJWREHFRPHSUHJQDQW
RUEUHDVWIHHGLQJ7KH0DOHSDWLHQWLVQRWSUDFWLFLQJGLIIHUHQW
PHWKRGVRIELUWKFRQWUROZLWKWKHLUSDUWQHUGXULQJWKHVWXG\DQGIRU
GD\VDIWHUWKHLQYHVWLJDWLRQDOGUXJODVWGRVHRUZLOOQRWUHPDLQ
DEVWLQHQWGXULQJWKHVWXG\DQGIRUGD\VDIWHUWKHODVWGRVH

7KHSDWLHQWKDVNQRZQDOOHUJ\WRDQ\RIWKHFRPSRQHQWVRIWKH
LQYHVWLJDWLRQDOGUXJ

3DUWLFLSDWLRQLQDQRWKHUVWXG\ZLWKDQLQYHVWLJDWLRQDOGUXJZLWKLQ
GD\VEHIRUH9LVLWRUGXULQJWKHVWXG\

8VHRIHPHUJHQF\FDUHWUHDWPHQWPRUHWKDQWLPHVLQWKHSUHYLRXV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
PRQWKV

7KHSDWLHQWLVLQWKHRSLQLRQRIWKHLQYHVWLJDWRULVXQVXLWDEOH WR
SDUWLFLSDWHLQWKLVVWXG\IRUDQ\RWKHUUHDVRQ
6WXG\'UXJ
'LVSHQVDWLRQ
7KHVWXG\GUXJZLOOEHVHTXHQWLDOO\QXPEHUHGDFFRUGLQJWRD
UDQGRPL]DWLRQOLVW7KHVWXG\GUXJ ZLOOEHDGPLQLVWHUHGVHTXHQWLDOO\
5DQGRPL]DWLRQZDVEDODQFHGE\XVLQJEORFN UDQGRPL]DWLRQ3DWLHQWVDQG
LQYHVWLJDWRUVZLOOEHEOLQGHGWRVWXG\GUXJDVVLJQPHQW
6DPSOH6L]H
'HWHUPLQDWLRQ
7KLVVWXG\LVDSURRIRIFRQFHSWVWXG\IRU$//2'IRUPLJUDLQH
SUHYHQWLRQ
7KHLQYHVWLJDWRUK\SRWKHVLVDUHGXFWLRQLQ PLJUDLQHKHDGDFKHGD\VLQWKH
$//2'JURXSYHUVXVWKHSODFHER JURXSIRUZKLFKSDWLHQWVLQHDFK
JURXSFDQSURYLGHVWDWLVWLFDOVLJQLILFDQFH
,QQRYDWLRQ
7KLVSURGXFWLVDILUVWLQFODVV 7/5VLJQDOLQJFDVFDGHLQKLELWRU IRUWKH
WUHDWPHQWRIPLJUDLQH'XHWRSRWHQWLDOVXSHULRULW\RYHUH[LVWLQJ
WKHUDSLHVLWUHSUHVHQWVDVLJQLILFDQWLQQRYDWLRQ7KHKLJKHIILFDF\VKRZQ
LQWKHSLORWVWXG\PD\LQGLFDWHWKDWLWVPHFKDQLVPRIDFWLRQDGGUHVVHV WKH
IXQGDPHQWDOSDWKRJHQHVLVRIPLJUDLQH
6WDWLVWLFV
$OOVWDWLVWLFDODQDO\VLVZLOOVXPPDUL]HWKHQXPEHUDQGSHUFHQWRI
SDWLHQWV'HVFULSWLYHVWDWLVWLFVE\WUHDWPHQWJURXSPHDQVWDQGDUG
GHYLDWLRQPHGLDQPLQLPXPPD[LPXPDQGFRQILGHQFHLQWHUYDOVZLOO
EHSURYLGHG
$KHDGDFKHGD\ LV GHILQHGDV DFDOHQGDUGD\GXULQJZKLFKDSDWLHQWKDGD
PLJUDLQHKHDGDFKHODVWLQJPLQXWHVDPLJUDLQHKHDGDFKHLVGHILQHG
DVPRGHUDWHWRVHYHUHKHDGDFKHZLWKDWOHDVWRQHPLJUDLQHDVVRFLDWHG
V\PSWRPLHOLJKWVHQVLWLYLW\QRLVHVHQVLWLYLW\QDXVHD
6WDWLVWLFDODQDO\VLVZLOOEHSHUIRUPHGRQSDWLHQWUHSRUWHGGDWDIURPWKH
PLJUDLQHGLDU\SDWLHQWUHSRUWHGGDWDIURPVLWHYLVLWVDQGGDWDFROOHFWHG
GXULQJVLWHYLVLWV
$QDO\VLVZLOOEHSHUIRUPHGIRUWKHFRPSDULVRQRI WKHUHGXFWLRQLQWKH
PHDQ PLJUDLQHKHDGDFKHGD\VKHDGDFKHGD\V RUPRUHUHGXFWLRQLQ
PRQWKO\PLJUDLQH IUHTXHQF\VHYHULW\GXUDWLRQQDXVHD VHYHULW\OLJKW
VHQVLWLYLW\ QRLVHVHQVLWLYLW\ DQGGD\VRIUHVFXHPHGLFDWLRQLQWDNH IURP
EDVHOLQHWRWKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG$QDO\VLVZLOO
EHSHUIRUPHGIRUWKHFRPSDULVRQRI WKHUHGXFWLRQLQ0,'$6+,7DQG
3,56IURPEDVHOLQHWR(QGRIWUHDWPHQW9LVLW
6WDWLVWLFDO
$QDO\VHVRIWKH
6WXG\¶V
(QGSRLQWV
3ULPDU\(QGSRLQW

&KDQJHIURPEDVHOLQHLQWKHPHDQ QXPEHURIPLJUDLQHSUREDEOH
PLJUDLQHKHDGDFKHGD\V
'HVFULSWLRQ0LJUDLQHZLWKRUZLWKRXWDXUDLVGHILQHGDFFRUGLQJWR
WKH,QWHUQDWLRQDO&ODVVLILFDWLRQRI+HDGDFKH'LVRUGHUV,&+'
UGHGLWLRQEHWDYHUVLRQ
3UREDEOHPLJUDLQHLVGHILQHGDFFRUGLQJWRWKH,&+'±EHWD
YHUVLRQFULWHULDDVDWWDFNVIXOILOOLQJDOOEXWRQHRIFULWHULD$'

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
IRUPLJUDLQHZLWKRUZLWKRXW DXUDZKHUHFULWHULD%LVKHDGDFKH
DWWDFNVODVWLQJKRXUVXQWUHDWHGRUXQVXFFHVVIXOO\WUHDWHG
0LJUDLQHSUREDEOHPLJUDLQHKHDGDFKHVPXVWEHPRGHUDWHRU
VHYHUHDQGODVWLQJPLQXWHV:KHQWKHSDWLHQWIDOOVDVOHHS
GXULQJPLJUDLQHDQGZDNHVXSZLWKRXWLWGXUDWLRQRIWKHDWWDFNLV
UHFNRQHGXQWLOWKHWLPHRIDZDNHQLQJ
7LPH)UDPH )URPWKHGD\EDVHOLQHSHULRGWRWKHODVWGD\V
RIWKH ZHHN7UHDWPHQW 3HULRG
6HFRQGDU\(QGSRLQWV

&KDQJHIURPEDVHOLQHLQWKHPHDQ QXPEHURIKHDGDFKHGD\V
'HVFULSWLRQ +HDGDFKHGD\VDUHGHILQHGDVQRQHPLJUDLQH
KHDGDFKHGD\VSOXVPLJUDLQHKHDGDFKHGD\V
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\V
RIWKHZHHN7UHDWPHQW3HULRG

3URSRUWLRQRISDWLHQWVZLWKRUPRUHUHGXFWLRQLQ
PLJUDLQHSUREDEOHPLJUDLQHKHDGDFKHGD\V
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\V
RIWKHZHHN7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ PLJUDLQHVHYHULW\
'HVFULSWLRQ0HDVXUHGRQDSRLQWUDWLQJ VFDOH QRQH
 PLOG PRGHUDWH VHYHUH
7LPH)UDPH)URPWKHGD\EDVHOLQHSHULRGWRWKHODVWGD\VRI
WKHZHHN7UHDWPHQW3HULRG

&KDQJH IURPEDVHOLQH LQWKHPHDQ PLJUDLQHGXUDWLRQ
7LPH)UDPH)URPWKHGD\EDVHOLQHSHULRGWRWKHODVWGD\VRI
WKHZHHN7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ QDXVHDVHYHULW\
'HVFULSWLRQ0HDVXUHGRQDSRLQWUDWLQJ VFDOH QRQH
 PLOG PRGHUDWH VHYHUH
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\V
RIWKHZHHN7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ QXPEHURIDFXWHPLJUDLQH
PHGLFDWLRQVLQWDNHGD\V
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\V
RIWKHZHHN7UHDWPHQW3HULRG

3URSRUWLRQRISDWLHQWVVDWLVILHGRUH[WUHPHO\VDWLVILHGZLWK
PLJUDLQHSUHYHQWLRQ
7LPH)UDPH ZHHN

&KDQJHIURPEDVHOLQHLQWKHPHDQPLJUDLQHGLVDELOLW\DVVHVVPHQW
VFDOH0,'$6
7LPH)UDPH )URPEDVHOLQHWRZHHN RIWKH 7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ KHDGDFKHLPSDFWWHVW+,7
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\V
RIWKHZHHN7UHDWPHQW3HULRG
 &KDQJHIURPEDVHOLQHLQWKHPHDQ 3LWWVEXUJK,QVRPQLD5DWLQJ
6FDOH3,56

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7LPH)UDPH )URPEDVHOLQHWRZHHN RIWKH 7UHDWPHQW3HULRG
6DIHW\(QGSRLQWV

&RPSDULVRQRIWKHSURSRUWLRQRISDWLHQWVZKRH[SHULHQFHG
DGYHUVHHYHQWVGHILQHGDVDQ\XQWRZDUGPHGLFDORFFXUUHQFHV
UHJDUGOHVVRIWKHLUVXVSHFWHGFDXVH
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG

&RPSDULVRQRIWKHSURSRUWLRQRISDWLHQWVZKRH[SHULHQFHG
WUHDWPHQWHPHUJHQW DGYHUVHHYHQWV
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG

&RPSDULVRQRIWKHFKDQJHIURPVFUHHQLQJLQWKHPHDQ EORRG
FRXQWVKHSDWLFDQGUHQDOIXQFWLRQ
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG

&RPSDULVRQRIWKHFKDQJHIURPVFUHHQLQJ LQWKHPHDQ V\VWROLF
EORRGSUHVVXUHGLDVWROLFEORRGSUHVVXUHDQGSXOVH
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG

3URWRFRO$12'<1(
3DJH RI
9HUVLRQ
-XO\ , 
Table of Contents
1
BACKGROUND.......................................................................................................... 22
2
STUDY DESIGN OUTLINE........................................................................................... 32
3
STUDY CONDUCT...................................................................................................... 41
WƌŽƚŽĐŽů^ǇŶŽƉƐŝƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯ
dĂďůĞŽĨŽŶƚĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϳ
dĂďůĞŽĨ&ŝŐƵƌĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϭ
ĐƌŽŶǇŵƐĂŶĚďďƌĞǀŝĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϭ
ϭ͘ϭƌŝĞĨĞƐĐƌŝƉƚŝŽŶŽĨƚŚĞ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůWƌŽĚƵĐƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϮϮ
ϭ͘ϮĞƐĐƌŝƉƚŝŽŶŽĨƚŚĞŚĞŵŝĐĂů&ŽƌŵƵůĂĞŽĨEĂůƚƌĞǆŽŶĞĂŶĚĐĞƚĂŵŝŶŽƉŚĞŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϮϮ
ϭ͘ϯďƐŽƌƉƚŝŽŶͬWŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐŽĨEĂůƚƌĞǆŽŶĞĂŶĚĐĞƚĂŵŝŶŽƉŚĞŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϯ
ϭ͘ϭϮϰͲ,ŽƵƌŝƐƚƌŝďƵƚŝŽŶŽĨDŝŐƌĂŝŶĞƚƚĂĐŬƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϯ
ϭ͘ϰZĞůĂƚŝŽŶƚŽ&ĞĚŽŶĚŝƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϰ
ϭ͘ϱdŚĞ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐŽŵƉŽŶĞŶƚƐ͕ŶĂůƚƌĞǆŽŶĞĂŶĚĐĞƚĂŵŝŶŽƉŚĞŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϰ
ϭ͘ϲd>ZϰͲWĂƚƚĞƌŶZĞĐŽŐŶŝƚŝŽŶZĞĐĞƉƚŽƌͲĞƚĞĐƚƐ/ŶĨĞĐƚŝŽŶͬdŝƐƐƵĞ/ŶũƵƌǇĂŶĚWƌŽŵŽƚĞƐ/ŶĨůĂŵŵĂƚŝŽŶ͘͘͘͘͘͘͘Ϯϰ
ϭ͘ϳWƌŽƉŽƐĞĚDĞĐŚĂŶŝƐŵŽĨĐƚŝŽŶŽĨEĂůƚƌĞǆŽŶĞͬĐĞƚĂŵŝŶŽƉŚĞŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϱ
ϭ͘ϴůŝŶŝĐĂůƚƌŝĂůƐ͘ŐŽǀƐƵŵŵĂƌǇ;/ĚĞŶƚŝĨŝĞƌ͗EdϬϯϭϵϰϱϱϱͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϲ
ϭ͘ϵŽƐĞ^ĞůĞĐƚŝŽŶZĂƚŝŽŶĂůĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϲ
ϭ͘ϭϬDŝŐƌĂŝŶĞͲĂƐƐŽĐŝĂƚĞĚŶĂƵƐĞĂŝƐĂŶ/ŵƉŽƌƚĂŶƚdĂƌŐĞƚĨŽƌdƌĞĂƚŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϳ
ϭ͘ϭϭEĂƵƐĞĂƐƐŽĐŝĂƚĞĚǁŝƚŚĐƵƚĞDŝŐƌĂŝŶĞZĞƉƌĞƐĞŶƚƐĂ^ŝŐŶŝĨŝĐĂŶƚhŶŵĞƚdƌĞĂƚŵĞŶƚEĞĞĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϳ
ϭ͘ϭϮůĂŝŵĞĚ/ŶŶŽǀĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϴ
ϭ͘ϭϯƉƉƌŽǀĞĚDŝŐƌĂŝŶĞWƌĞǀĞŶƚŝŽŶKƌĂůdƌĞĂƚŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϴ
ϭ͘ϭϰDŝŐƌĂŝŶĞWĂƚŚŽŐĞŶĞƐŝƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϵ
ϭ͘ϭϱdŚĞWƌĞǀĂůĞŶĐĞ͕/ŵƉĂĐƚ͕ĂŶĚĐŽŶŽŵŝĐƵƌĚĞŶƐŽĨDŝŐƌĂŝŶĞŝŶƚŚĞhŶŝƚĞĚ^ƚĂƚĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϵ
ϭ͘ϭϲhŶŵĞƚdƌĞĂƚŵĞŶƚEĞĞĚƐĨŽƌDŝŐƌĂŝŶĞĂŶĚ>ŝŵŝƚĂƚŝŽŶƐŽĨǆŝƐƚŝŶŐdƌĞĂƚŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϬ
ϭ͘ϭϳŵŽƚŝŽŶĂůWĂŝŶZĞůŝĞĨWƌŽƉĞƌƚŝĞƐŽĨĐĞƚĂŵŝŶŽƉŚĞŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϬ
ϭ͘ϭϴŽŶĐŽŵŝƚĂŶƚŵŽƚŝŽŶĂůWĂŝŶĂŶĚͬŽƌŚƌŽŶŝĐ>ŽǁĂĐŬWĂŝŶ;>WͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϭ
ϭ͘ϭϵWŽƚĞŶƚŝĂůĚǀĂŶƚĂŐĞƐŽĨĂ>ŽǁͲŽƐĞEĂůƚƌĞǆŽŶĞͬĐĞƚĂŵŝŶŽƉŚĞŶWƌŽĚƵĐƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϭ
Ϯ͘ϭ^ƚƵĚǇKďũĞĐƚŝǀĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϮ
Ϯ͘Ϯ/ŶĐůƵƐŝŽŶƌŝƚĞƌŝĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϮ
Ϯ͘ϯǆĐůƵƐŝŽŶƌŝƚĞƌŝĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϯ
Ϯ͘ϰ^ƚƵĚǇĞƐŝŐŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϰ
Ϯ͘ϱDŝŐƌĂŝŶĞŝĂƌǇĂŶĚKƚŚĞƌ^ƚƵĚǇƐƐĞƐƐŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ
Ϯ͘ϲWĂƚŝĞŶƚƐĂƚŝƐĨĂĐƚŝŽŶǁŝƚŚŵŝŐƌĂŝŶĞƉƌĞǀĞŶƚŝŽŶ͕sŝƐŝƚƐϯͲsŝƐŝƚϳ͕;ϬсŶŽƚĂƚĂůůƐĂƚŝƐĨŝĞĚ͕ϭсƉĂƌƚůǇƐĂƚŝƐĨŝĞĚ͕
ϮсƐĂƚŝƐĨŝĞĚ͕ϯсǀĞƌǇƐĂƚŝƐĨŝĞĚͿ͘^ƚƵĚǇƵƌĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ
Ϯ͘ϳ^ƚƵĚǇWŽƉƵůĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ
Ϯ͘ϴǆĐůƵƐŝŽŶƐƵĞƚŽŽĞǆŝƐƚŝŶŐŽŶĚŝƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϴ
Ϯ͘ϵ^ƵďƐƚĂŶĐĞďƵƐĞĂŶĚůĐŽŚŽůhƐĞZĞƐƚƌŝĐƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϵ
Ϯ͘ϭϬŽŶĐŽŵŝƚĂŶƚDĞĚŝĐĂƚŝŽŶƐZĞƐƚƌŝĐƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϵ
Ϯ͘ϭϭZĞƐĐƵĞDĞĚŝĐĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϬ
Ϯ͘ϭϮ/ŶƐƚƌƵĐƚŝŽŶƐĨŽƌdĂŬŝŶŐƚŚĞ^ƚƵĚǇƌƵŐĂŶĚĨŽƌĐŽŵƉůĞƚŝŶŐƚŚĞDŝŐƌĂŝŶĞŝĂƌǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϬ
Ϯ͘ϭϯZĂŶĚŽŵŝǌĂƚŝŽŶ^ĐŚĞŵĞĂŶĚdƌĞĂƚŵĞŶƚ'ƌŽƵƉƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϬ
ϯ͘ϭ/ĚĞŶƚŝĨŝĐĂƚŝŽŶĂŶĚZĞĐƌƵŝƚŵĞŶƚŽĨ^ƚƵĚǇWĂƚŝĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ
ϯ͘Ϯ^ĐƌĞĞŶĞĚWĂƚŝĞŶƚƐΖ>ŽŐZĞĐŽƌĚ<ĞĞƉŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ
ϯ͘ϯ,/WŽŵƉůŝĂŶĐĞǁŝƚŚƌĞŐĂƌĚƐƚŽƉƌĞǀŝŽƵƐŵĞĚŝĐĂůƌĞĐŽƌĚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ
ϯ͘ϰWƌŽƚŽĐŽůĞǀŝĂƚŝŽŶͬsŝŽůĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϮ
ϯ͘ϱWƌŽƚŽĐŽůĚŚĞƌĞŶĐĞĂŶĚŽŵƉůŝĂŶĐĞǁŝƚŚWƌŽƚŽĐŽůZĞǀŝƐŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϯ
ϯ͘ϲ/ŶĨŽƌŵĞĚŽŶƐĞŶƚWƌŽĐĞĚƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϯ
ϯ͘ϳZĞŐƵůĂƚŽƌǇŽŵƉůŝĂŶĐĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϰ
ϯ͘ϴŽŶĐŽŵŝƚĂŶƚŝĂŐŶŽƐŝƐĂŶĚDĞĚŝĐĂƚŝŽŶZĞĐŽƌĚŝŶŐZĞƋƵŝƌĞŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϰ
ϯ͘ϵĞŵŽŐƌĂƉŚŝĐƐ͕ĂƐĞůŝŶĞDĞĂƐƵƌĞƐ͕ĂŶĚĂƌĚŝŽǀĂƐĐƵůĂƌZŝƐŬƐƐĞƐƐŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϰ

3URWRFRO$12'<1(
3DJH RI
9HUVLRQ
-XO\ , 
4
STUDY TREATMENT SCHEDULE ................................................................................. 45
5
DEFINITION OF EVALUATIONS AND SPECIAL INSTRUCTIONS ..................................... 50
6
DRUG INTERACTIONS WITH THE IP AND POSSIBLE ADVERSE REACTIONS................... 53
7
MANAGEMENT OF THE INVESTIGATIONAL DRUG...................................................... 57
8
SAFETY AND ADVERSE EVENTS MANAGEMENT......................................................... 60
ϯ͘ϭϬdƌĞĂƚŵĞŶƚ'ƌŽƵƉƐƐŝŐŶŵĞŶƚWƌŽĐĞĚƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϰ
ϯ͘ϭϭĂƌůǇtŝƚŚĚƌĂǁĂůĂŶĚĂƌůǇǁŝƚŚĚƌĂǁĂůWƌŽĐĞĚƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϱ
ϯ͘ϭϮWĂƚŝĞŶƚƐ>ŽƐƚƚŽ&ŽůůŽǁͲƵƉWƌŝŽƌƚŽƚŚĞŶĚŽĨƚŚĞdƌŝĂů͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϱ
ϰ͘ϭWƌĞͲĞŶƌŽůůŵĞŶƚZĞǀŝĞǁ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϱ
ϰ͘ϮZƵůĞƐĨŽƌZĞƐĐƌĞĞŶŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϱ
ϰ͘ϯ^ƚƵĚǇsŝƐŝƚϭͲƚŚĞ^ĐƌĞĞŶŝŶŐsŝƐŝƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϱ
ϰ͘ϰ^ƚƵĚǇsŝƐŝƚϮͲƚŚĞZĂŶĚŽŵŝǌĂƚŝŽŶsŝƐŝƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϳ
ϰ͘ϱϭϮͲtĞĞŬKƵƚƉĂƚŝĞŶƚdƌĞĂƚŵĞŶƚWĞƌŝŽĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ
ϰ͘ϲ^ƚƵĚǇsŝƐŝƚϯͲϭǁĞĞŬĂĨƚĞƌƚŚĞdƌĞĂƚŵĞŶƚWĞƌŝŽĚƐƚĂƌƚĞĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ
ϰ͘ϳ^ƚƵĚǇsŝƐŝƚϯĂŶĚ^ƚƵĚǇsŝƐŝƚϰ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϴ
ϰ͘ϴ^ƚƵĚǇsŝƐŝƚϱͲŶĚͲŽĨͲdƌĞĂƚŵĞŶƚsŝƐŝƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϵ
ϰ͘ϵ^ƚƵĚǇsŝƐŝƚϲ͕ŶĚͲŽĨͲ^ƚƵĚǇsŝƐŝƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϬ
ϱ͘ϭ/ŶĨŽƌŵĞĚŽŶƐĞŶƚWƌŽĐĞĚƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϭ
ϱ͘Ϯ/ŶĐůƵƐŝŽŶͬǆĐůƵƐŝŽŶƌŝƚĞƌŝĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϭ
ϱ͘ϯWĂƚŝĞŶƚĚƵĐĂƚŝŽŶĂŶĚƚŚĞ&ŽƵƌͲWŽŝŶƚ>ŝŬĞƌƚ^ĐĂůĞ/ŶƐƚƌƵŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϭ
ϱ͘ϰdŚĞDŝŐƌĂŝŶĞŝĂƌǇ/ŶƐƚƌƵŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϭ
ϱ͘ϱDĞĚŝĐĂů,ŝƐƚŽƌǇ͕WŚǇƐŝĐĂůǆĂŵŝŶĂƚŝŽŶĂŶĚsŝƚĂů^ŝŐŶƐƐƐĞƐƐŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϭ
ϱ͘ϲ ůĞĐƚƌŽĐĂƌĚŝŽŐƌĂŵ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϮ
ϱ͘ϳ͕,ĞƉĂƚŝĐĂŶĚZĞŶĂů&ƵŶĐƚŝŽŶƐƐĞƐƐŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϮ
ϱ͘ϴ&ŝǀĞWĂŶĞůhƌŝŶĞƌƵŐdĞƐƚĂŶĚƵƌŝŶĞWƌĞŐŶĂŶĐǇdĞƐƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϮ
ϱ͘ϵ ŽŶĐŽŵŝƚĂŶƚŝĂŐŶŽƐŝƐĂŶĚdƌĞĂƚŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϮ
ϱ͘ϭϬŽŶĐŽŵŝƚĂŶƚDĞĚŝĐĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϮ
ϱ͘ϭϭĚǀĞƌƐĞǀĞŶƚƐƐƐĞƐƐŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϮ
ϱ͘ϭϮWĂƚŝĞŶƚΖƐŽŶƚĂĐƚ/ŶĨŽƌŵĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ
ϱ͘ϭϯĂƌĚŝŽǀĂƐĐƵůĂƌZŝƐŬ&ĂĐƚŽƌƐƐĞƐƐŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ
ϲ͘ϭĨĨĞĐƚƐŽĨĐĞƚĂŵŝŶŽƉŚĞŶĂŶĚƚŚĂŶŽůŽŶ>ŝǀĞƌ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ
ϲ͘ϮĨĨĞĐƚƐŽĨŶƚŝĐŽĂŐƵůĂŶƚƐŽŶĐĞƚĂŵŝŶŽƉŚĞŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ
ϲ͘ϯEĂůƚƌĞǆŽŶĞ,ĞƉĂƚŽƚŽǆŝĐŝƚǇtĂƌŶŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ
ϲ͘ϰsƵůŶĞƌĂďŝůŝƚǇƚŽKƉŝŽŝĚKǀĞƌĚŽƐĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϰ
ϲ͘ϱWƌĞĐŝƉŝƚĂƚĞĚKƉŝŽŝĚtŝƚŚĚƌĂǁĂů͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϰ
ϲ͘ϲĞƉƌĞƐƐŝŽŶĂŶĚ^ƵŝĐŝĚĂůŝƚǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϰ
ϲ͘ϳWŽƚĞŶƚŝĂů,ĞƉĂƚŽƚŽǆŝĐŝƚǇZŝƐŬƐŽĨƚŚĞ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϱ
ϲ͘ϴ,ĞƉĂƚŽƚŽǆŝĐŝƚǇ^ƚŽƉƉŝŶŐZƵůĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϱ
ϲ͘ϵDĂŶĂŐĞŵĞŶƚŽĨ>ŝǀĞƌdƌĂŶƐĂŵŝŶĂƐĞůĞǀĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϲ
ϳ͘ϭ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐůůŽĐĂƚŝŽŶ͕ŝƐƉĞŶƐĂƚŝŽŶ͕>ĂďĞůŝŶŐĂŶĚWĂĐŬĂŐŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϳ
ϳ͘ϮZĞĐĞŝƉƚŽĨ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐ^ƵƉƉůŝĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϳ
ϳ͘ϯ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůĚƌƵŐŝƐƉĞŶƐĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϴ
ϳ͘ϰŽƵďůĞͲŚĞĐŬŝŶŐWƌŽĐĞĚƵƌĞĚƵƌŝŶŐŝƐƉĞŶƐĂƚŝŽŶŽĨƚŚĞ^ƚƵĚǇƌƵŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϴ
ϳ͘ϱŶƐƵƌŝŶŐŽŵƉůŝĂŶĐĞǁŝƚŚƚŚĞ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐĂŶĚZĞĐŽŶĐŝůŝĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϴ
ϳ͘ϲƌƵŐĐĐŽƵŶƚĂďŝůŝƚǇDŽŶŝƚŽƌŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϵ
ϳ͘ϳ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐ^ƚŽƌĂŐĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϵ
ϳ͘ϴŵĞƌŐĞŶĐǇWƌĞƉĂƌĞĚŶĞƐƐDĞĂƐƵƌĞƐĨŽƌ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůĚƌƵŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϵ
ϳ͘ϵůŝŶĚŝŶŐĂŶĚŵĞƌŐĞŶĐǇhŶͲůŝŶĚŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϵ
ϳ͘ϭϬƌƵŐWƌŽĚƵĐƚYƵĂůŝƚǇŽŵƉůĂŝŶƚƐ;WYͿZĞƉŽƌƚŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϬ
ϳ͘ϭϭ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐZĞƚƵƌŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϬ
ϴ͘ϭĚǀĞƌƐĞǀĞŶƚĞĨŝŶŝƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϬ

3URWRFRO$12'<1(
3DJH RI
9HUVLRQ
-XO\ , 
9
DATA HANDLING AND RECORD KEEPING .................................................................. 67
10
STATISTICAL METHODS............................................................................................. 68
11
STUDY ADMINISTRATION ......................................................................................... 72
12
DUTIES OF THE SPONSOR AND THE INVESTIGATORS................................................. 78
ϴ͘ϮĚǀĞƌƐĞǀĞŶƚWƌŽŵƉƚŝŶŐWƌŽĐĞĚƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϭ
ϴ͘ϯZĞĐŽƌĚŝŶŐŽĨĚǀĞƌƐĞǀĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϭ
ϴ͘ϰĚǀĞƌƐĞǀĞŶƚZĞƉŽƌƚŝŶŐWĞƌŝŽĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϮ
ϴ͘ϱWƌĞĞǆŝƐƚŝŶŐŽŶĚŝƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϮ
ϴ͘ϲWŽƐƚͲƐƚƵĚǇĚǀĞƌƐĞǀĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϮ
ϴ͘ϳĞƚĞƌŵŝŶĂƚŝŽŶŽĨďŶŽƌŵĂů>ĂďŽƌĂƚŽƌǇsĂůƵĞƐĂƐĚǀĞƌƐĞǀĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϮ
ϴ͘ϴ,ŽƐƉŝƚĂůŝǌĂƚŝŽŶ͕WƌŽůŽŶŐĞĚ,ŽƐƉŝƚĂůŝǌĂƚŝŽŶŽƌ^ƵƌŐĞƌǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϯ
ϴ͘ϵZĞƉŽƌƚŝŶŐŽĨ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐĂŶĚhŶĂŶƚŝĐŝƉĂƚĞĚWƌŽďůĞŵƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϯ
ϴ͘ϭϬůŝŶŝĐĂů/ŶǀĞƐƚŝŐĂƚŽƌƌĞƉŽƌƚŝŶŐĂŶĚŶŽƚŝĨǇŝŶŐƚŚĞƐƚƵĚǇƐƉŽŶƐŽƌ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϯ
ϴ͘ϭϭĂƚĞŐŽƌŝǌŝŶŐZĞůĂƚŝŽŶƐŚŝƉŽĨΖƐƚŽ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůĚƌƵŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϰ
ϴ͘ϭϮEŽŶͲ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϰ
ϴ͘ϭϯKƚŚĞƌZĞƉŽƌƚĂďůĞǀĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϰ
ϴ͘ϭϰ^ƉŽŶƐŽƌZĞƉŽƌƚŝŶŐĂŶĚEŽƚŝĨǇŝŶŐƚŚĞ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϱ
ϴ͘ϭϱ&ZĞƉŽƌƚŝŶŐWƌŽĐĞƐƐĂŶĚ^ƉŽŶƐŽƌEŽƚŝĨǇŝŶŐWĂƌƚŝĐŝƉĂƚŝŶŐ/ŶǀĞƐƚŝŐĂƚŽƌƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϲ
ϴ͘ϭϲWƌĞŐŶĂŶĐǇWƌĞǀĞŶƚŝŽŶĂŶĚŽƵŶƐĞůŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϲ
ϴ͘ϭϳďƵƐĞ͕DŝƐƵƐĞ͕KǀĞƌĚŽƐĞĂŶĚDĞĚŝĐĂƚŝŽŶƌƌŽƌŽĨ/ŶǀĞƐƚŝŐĂƚŝŽŶĂůƌƵŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϳ
ϵ͘ϭĂƚĂDĂŶĂŐĞŵĞŶƚZĞƐƉŽŶƐŝďŝůŝƚŝĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϳ
ϵ͘Ϯ^ŽƵƌĐĞŽĐƵŵĞŶƚĂƚŝŽŶZĞƋƵŝƌĞŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϳ
ϵ͘ϯĂƚĂĐŽůůĞĐƚŝŽŶŝŶƚŽĂƐĞZĞƉŽƌƚ&ŽƌŵƐ;Z&Ϳ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϴ
ϵ͘ϰĂƚĂŶƚƌǇƌƌŽƌƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϴ
ϭϭ͘ϭ^ƚƵĚǇKǀĞƌƐŝŐŚƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϮ
ϭϭ͘ϮZĞƐƉŽŶƐŝďŝůŝƚŝĞƐŽĨƚŚĞ^ƚƵĚǇ^ŝƚĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϮ
ϭϭ͘ϯ/ŶǀĞƐƚŝŐĂƚŽƌZĞƐƉŽŶƐŝďŝůŝƚŝĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϮ
ϭϭ͘ϰZĞƐƉŽŶƐŝďŝůŝƚŝĞƐŽĨƚŚĞůŝŶŝĐĂůZĞƐĞĂƌĐŚŽŽƌĚŝŶĂƚŽƌ;ZͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϯ
ϭϭ͘ϱZĞŐƵůĂƚŽƌǇZĞƋƵŝƌĞŵĞŶƚƐ͕ƐƐĞŶƚŝĂůŽĐƵŵĞŶƚĂŶĚƌĐŚŝǀŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϯ
ϭϭ͘ϲŵĞƌŐĞŶĐǇWƌĞƉĂƌĞĚŶĞƐƐDĞĂƐƵƌĞƐĨŽƌ^ƚƵĚǇZĞĐŽƌĚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϰ
ϭϭ͘ϳ/ŶƐƚŝƚƵƚŝŽŶĂůZĞǀŝĞǁŽĂƌĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϰ
ϭϭ͘ϴƐƐĞŶƚŝĂůŽĐƵŵĞŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϰ
ϭϭ͘ϵ/ŶǀĞƐƚŝŐĂƚŽƌDĞĞƚŝŶŐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϱ
ϭϭ͘ϭϬdƌĂŝŶŝŶŐŽĨ^ƚƵĚǇ^ŝƚĞ^ƚĂĨĨĂŶĚZŽƵƚŝŶĞŽŶƚĂĐƚǁŝƚŚƚŚĞ^ƉŽŶƐŽƌΖƐ^ƚƵĚǇdĞĂŵ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϱ
ϭϭ͘ϭϭdƌŝĂůDŽŶŝƚŽƌŝŶŐWůĂŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϱ
ϭϭ͘ϭϮƵĚŝƚŝŶŐĂŶĚ/ŶƐƉĞĐƚŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϲ
ϭϭ͘ϭϯůŝŶŝĐĂůdƌŝĂůŐƌĞĞŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϳ
ϭϭ͘ϭϰŽŶĨŝĚĞŶƚŝĂůŝƚǇŽĨƚŚĞWƌŽƚŽĐŽů͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϳ
ϭϭ͘ϭϱ,/W͕ŝƐĐůŽƐƵƌĞĂŶĚŽŶĨŝĚĞŶƚŝĂůŝƚǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϳ
ϭϭ͘ϭϲ/ŶƐƉĞĐƚŝŽŶWƌŽĐĞĚƵƌĞƐ͕^ƚƵĚǇdŝŵĞƚĂďůĞĂŶĚŶĚŽĨ^ƚƵĚǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϴ
ϭϬ͘ϭDĂŶĂŐĞŵĞŶƚŽĨƚŚĞ^ƚĂƚŝƐƚŝĐĂůŶĂůǇƐŝƐWůĂŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϴ
ϭϬ͘Ϯ^ĂŵƉůĞ^ŝǌĞĞƚĞƌŵŝŶĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϴ
ϭϬ͘ϯŶĂůǇƐŝƐWŽƉƵůĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϵ
ϭϬ͘ϰ^ƚĂƚŝƐƚŝĐĂůŶĂůǇƐĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ
ϭϬ͘ϱDŝƐƐŝŶŐĂƚĂ/ŵƉƵƚĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ
ϭϬ͘ϲŶĂůǇƐŝƐŽĨWĂƚŝĞŶƚƐĂĐŬŐƌŽƵŶĚĂƚĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ
ϭϬ͘ϳ^ƚĂƚŝƐƚŝĐĂůŶĂůǇƐŝƐŽĨƚŚĞ^ƚƵĚǇŶĚƉŽŝŶƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ
ϭϬ͘ϴ^ĂĨĞƚǇŶĂůǇƐŝƐŽŶƐŝĚĞƌĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϭ
ϭϬ͘ϵĚǀĞƌƐĞǀĞŶƚůĂƐƐŝĨŝĐĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϮ
ϭϬ͘ϭϬ/ŶƚĞƌŝŵŶĂůǇƐŝƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϮ
ϭϮ͘ϭZĞĐƌƵŝƚŵĞŶƚͬZĞƚĞŶƚŝŽŶĂŶĚ'WŽŵƉůŝĂŶĐĞďǇƚŚĞ/ŶǀĞƐƚŝŐĂƚŽƌ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϴ

3URWRFRO$12'<1(
3DJH RI
9HUVLRQ
-XO\ , 
13
ETHICS/PROTECTION OF HUMAN PATIENTS.............................................................. 80
14
APPENDICES............................................................................................................. 81
15
ATTACHMENTS: STUDY FORMS ................................................................................ 88
17
INSTRUMENTS.........................................................................................................105
18
ATTACHMENTS: REGULATORY BINDER DOCUMENTS ...............................................113
ϭϮ͘Ϯ^ƚƵĚǇ^ƚĂĨĨdƌĂŝŶŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϴ
ϭϮ͘ϯWƌŽƚŽĐŽůĚŚĞƌĞŶĐĞĂŶĚ/ŶǀĞƐƚŝŐĂƚŽƌŐƌĞĞŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϵ
ϭϮ͘ϰZĞŝŵďƵƌƐĞŵĞŶƚĂŶĚ/ŶƐƵƌĂŶĐĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϵ
ϭϮ͘ϱ^ƚƵĚǇDŽĚŝĨŝĐĂƚŝŽŶͬŝƐĐŽŶƚŝŶƵĂƚŝŽŶŽƌ^ƵƐƉĞŶƐŝŽŶͬdĞƌŵŝŶĂƚŝŽŶďǇƚŚĞƐƉŽŶƐŽƌ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϵ
ϭϮ͘ϲWƵďůŝĐWŽƐƚŝŶŐŽĨ^ƚƵĚǇ/ŶĨŽƌŵĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϵ
ϭϮ͘ϳWƵďůŝĐĂƚŝŽŶWŽůŝĐǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϵ
ϭϯ͘ϭƚŚŝĐĂů^ƚĂŶĚĂƌĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϬ
ϭϯ͘Ϯ/ŶƐƚŝƚƵƚŝŽŶĂůZĞǀŝĞǁŽĂƌĚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϬ
ϭϯ͘ϯ/ŶĨŽƌŵĞĚŽŶƐĞŶƚWƌŽĐĞƐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϬ
ϭϯ͘ϰWĂƌƚŝĐŝƉĂŶƚŽŶĨŝĚĞŶƚŝĂůŝƚǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϭ
ϭϰ͘ϭƉƉĞŶĚŝǆϭ͗dŚĞ/ŶƚĞƌŶĂƚŝŽŶĂůůĂƐƐŝĨŝĐĂƚŝŽŶKĨ,ĞĂĚĂĐŚĞŝƐŽƌĚĞƌƐͲϯ;ĞƚĂǀĞƌƐŝŽŶͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϭ
ϭϰ͘ϮƉƉĞŶĚŝǆϮ͗&ŽƵƌͲWŽŝŶƚ>ŝŬĞƌƚ^ĐĂůĞĨŽƌƐƐĞƐƐŝŶŐ,ĞĂĚĂĐŚĞWĂŝŶĂŶĚEĂƵƐĞĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϯ
ϭϰ͘ϯWĂƚŝĞŶƚ'ůŽďĂů/ŵƉƌĞƐƐŝŽŶŽĨŚĂŶŐĞ;W'/Ϳ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϯ
ϭϰ͘ϰƉƉĞŶĚŝǆϯ͗ƌŝƚĞƌŝĂĨŽƌ/ĚĞŶƚŝĨǇŝŶŐ>ĂďŽƌĂƚŽƌǇsĂůƵĞƐŽĨWŽƚĞŶƚŝĂůůŝŶŝĐĂůZĞůĞǀĂŶĐĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϰ
ϭϰ͘ϱƉƉĞŶĚŝǆϰ͗>ŝŵŝƚƐĨŽƌďĂƐĞůŝŶĞǀŝƚĂůƐŝŐŶƐǀĂůƵĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϰ
ϭϰ͘ϲƉƉĞŶĚŝǆϱ͗>ŝƐƚŽĨEĂƌĐŽƚŝĐWĂŝŶDĞĚŝĐĂƚŝŽŶƐ;WĂŝŶŬŝůůĞƌƐͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϰ
ϭϰ͘ϳƉƉĞŶĚŝǆϲ͗>ŝƐƚKƉŝĂƚĞŶƚĂŐŽŶŝƐƚƐDĞĚŝĐĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϱ
ϭϰ͘ϴƉƉĞŶĚŝǆϳ͗>ŝƐƚEŽŶͲ^ƚĞƌŽŝĚĂůŶƚŝͲ/ŶĨůĂŵŵĂƚŽƌǇƌƵŐƐ;E^/ƐͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϲ
ϭϰ͘ϵƉƉĞŶĚŝǆϴ͗>ŝƐƚŽĨƚŚĞ^ƚƵĚǇΖƐůŝŶŝĐĂů>ĂďŽƌĂƚŽƌǇǀĂůƵĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϲ
ϭϰ͘ϭϬƉƉĞŶĚŝǆϵ͗ůŽŽĚŽůůĞĐƚŝŽŶWƌŽĐĞĚƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϳ
ϭϰ͘ϭϭƉƉĞŶĚŝǆϭϬ͗ůŽŽĚƉƌĞƐƐƵƌĞƉƌŽĐĞĚƵƌĞŝŶƐƚƌƵĐƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϳ
ϭϰ͘ϭϮƉƉĞŶĚŝǆϭϭ͗WƵůƐĞDĞĂƐƵƌĞŵĞŶƚWƌŽĐĞĚƵƌĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϴ
ϭϱ͘ϭWĂƚŝĞŶƚ/ŶƚĂŬĞ&Žƌŵ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϵ
ϭϱ͘ϮWĂƚŝĞŶƚ,ĂŶĚŽƵƚĨŽƌDŝŐƌĂŝŶĞWƌĞǀĞŶƚŝŽŶ^ƚƵĚǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϭ
ϭϱ͘ϯWĂƚŝĞŶƚĚƵĐĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϯ
ϭϱ͘ϰ/ŶĐůƵƐŝŽŶͬǆĐůƵƐŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϰ
ϭϱ͘ϱĂŝůǇŝĂƌǇĨŽƌƚŚĞDŝŐƌĂŝŶĞWƌĞǀĞŶƚŝŽŶƐƚƵĚǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϱ
ϭϱ͘ϲĂŝůǇŝĂƌǇĨŽƌƚŚĞDŝŐƌĂŝŶĞWƌĞǀĞŶƚŝŽŶƐƚƵĚǇ;ƉĂŐĞϮͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϲ
ϭϱ͘ϳĂŝůǇŝĂƌǇĨŽƌŵŽƚŝŽŶĂůWĂŝŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϳ
ϭϱ͘ϴĂŝůǇŝĂƌǇĨŽƌŵŽƚŝŽĂŶƉĂŝŶ;ƉĂŐĞϮͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϴ
ϭϱ͘ϵ^ĐŚĞĚƵůĞŽĨǀĂůƵĂƚŝŽŶƐŚĞĐŬůŝƐƚĨŽƌƚŚĞDŝŐƌĂŝŶĞWƌĞǀĞŶƚŝŽŶ^ƚƵĚǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϵ
ϭϱ͘ϭϬĞŵŽŐƌĂƉŚŝĐƐ͕ŽŶDĞĚƐ͕ŽŶǆ͕hƌŝŶĞdĞƐƚƐ͕sŝƚĂů^ŝŐŶƐ͕Θ>ĂďDŝŐƌĂŝŶĞͲWƌĞǀĞŶƚŝŽŶ^ƚƵĚǇ;Z&Ϳ͘͘͘͘͘ϭϬϬ
ϭϱ͘ϭϭDĞĚŝĐĂů,ŝƐƚŽƌǇ͕WŚǇƐŝĐĂůǆĂŵ;ƐŽƵƌĐĞͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϭ
ϭϱ͘ϭϮĚǀĞƌƐĞǀĞŶƚƐZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϮ
ϭϱ͘ϭϯ^ƚƵĚǇƌƵŐZĞĐŽŶĐŝůŝĂƚŝŽŶtŽƌŬƐŚĞĞƚĨŽƌDŝŐƌĂŝŶĞͲWƌĞǀĞŶƚŝŽŶ^ƚƵĚǇ;Z&Ϳ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϯ
ϭϱ͘ϭϰW'/ĂŶĚWĂƚŝĞŶƚ^ĂƚŝƐĨĂĐƚŝŽŶǁŝƚŚDŝŐƌĂŝŶĞWƌĞǀĞŶƚŝŽŶ;Z&Ϳ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϰ
ϭϳ͘ϭD/^;DŝŐƌĂŝŶĞŝƐĂďŝůŝƚǇƐƐĞƐƐŵĞŶƚdĞƐƚͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϲ
ϭϳ͘Ϯ,/dͲϲ;,ĞĂĚĂĐŚĞ/ŵƉĂĐƚdĞƐƚͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϳ
ϭϳ͘ϯKƐǁĞƐƚƌǇŝƐĂďŝůŝƚǇ/ŶĚĞǆͲ>ŽǁĂĐŬ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϵ
ϭϳ͘ϰĞĐŬΖƐĞƉƌĞƐƐŝŽŶ/ŶǀĞŶƚŽƌǇ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϬ
ϭϴ͘ϭ^ƚƵĚǇĚƌƵŐ^ŚŝƉŵĞŶƚDĂŶŝĨĞƐƚZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϯ
ϭϴ͘Ϯ^ŝƚĞWĞƌƐŽŶŶĞůĞůĞŐĂƚŝŽŶŽĨƵƚŚŽƌŝƚǇZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϰ
ϭϴ͘ϯ^ƚƵĚǇĚƌƵŐ>ŽŐZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϱ
ϭϴ͘ϰ^ĐƌĞĞŶĞĚWĂƚŝĞŶƚƐ>ŽŐ;^ŽƵƌĐĞͿ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϲ
ϭϴ͘ϱ^ĐƌĞĞŶĞĚWĂƚŝĞŶƚƐůŽŐZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϳ
ϭϴ͘ϲWĂƚŝĞŶƚŽŶƚĂĐƚ/ŶĨŽƌŵĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϴ

3URWRFRO$12'<1(
3DJH RI
9HUVLRQ
-XO\ , 
Table of Figures
Figure 1: Medication vials for the Migraine Prevention Study....................................................................................11
Figure 2: 24-hour distribution of migraine attacks......................................................................................................23
Figure 3: Working hypothesis for activated glia induced pain generation as it relates to migraine ...........................25
Figure 4: Nausea frequency in an acute migraine study .............................................................................................28
Figure 5: Study Design Illustration...............................................................................................................................36
Figure 6: Concomitant Medications Restrictions.........................................................................................................39
Acronyms and Abbreviations
$&521<06$1'$%%5(9,$7,216
$(
$GYHUVHHYHQW
$/3
$ONDOLQHSKRVSKDWDVHVHUXP
$/7
$ODQLQHDPLQRWUDQVIHUDVH
$3$3
$FHWDPLQRSKHQ
$67
$VSDUWDWHDPLQRWUDQVIHUDVH
$//2'
,QYHVWLJDWLRQDOGUXJFRQWDLQLQJQDOWUH[RQHDFHWDPLQRSKHQ
$71&
1DOWUH[RQHFORQLGLQHFRPELQDWLRQLQYHVWLJDWHGLQWKHSKDVH,1'WULDO
$8&
$UHDXQGHUWKHFXUYH
ESP
%HDWVSHUPLQ
&PD[
0D[LPXPRUSHDNVHUXPFRQFHQWUDWLRQ
&)5
&RGHRIIHGHUDOUHJXODWLRQV
&5)
&DVHUHSRUWIRUP
&/%3
&KURQLFORZEDFNSDLQ
&2;
&\FORR[\JHQDVHW\SH
'$03
'DPDJHDVVRFLDWHGPROHFXODUSDWWHUQV
'&)
'DWDFRUUHFWLRQIRUP
',/,
'UXJLQGXFHGOLYHULQMXU\
(&*
(OHFWURFDUGLRJUDP
)'$
)RRGDQGGUXJDGPLQLVWUDWLRQ
*&3
*RRGFOLQLFDOSUDFWLFH
+,3$$
+HDOWKLQVXUDQFHSRUWDELOLW\DQGDFFRXQWDELOLW\DFW
,&
,QIRUPHGFRQVHQW
,&+
,QWHUQDWLRQDOFRQIHUHQFHRQKDUPRQL]DWLRQ
,1'
,QYHVWLJDWLRQDOQHZGUXJ
,5%
,QVWLWXWLRQDOUHYLHZERDUG
,77
,QWHQWWRWUHDW
0$&(
0DMRUDGYHUVHFDUGLRYDVFXODUHYHQWV
0HG'5$
0HGLFDOGLFWLRQDU\IRUUHJXODWRU\DFWLYLWLHV
156
1XPHULFUDWLQJVFDOH
16$,'
1RQVWHURLGDODQWLLQIODPPDWRU\GUXJV
3$03
3DWKRJHQDVVRFLDWHGPROHFXODUSDWWHUQV
6$(
6HYHUHDGYHUVHHYHQWV
615,
6HURWRQLQQRUHSLQHSKULQHUHXSWDNHLQKLELWRU
665,
6HOHFWLYHVHURWRQLQUHXSWDNHLQKLELWRU
7%/
7RWDOELOLUXELQVHUXP
ϭϴ͘ϳEŽƚŝĐĞŽĨWƌŝǀĂĐǇWƌĂĐƚŝĐĞƐĂŶĚWĞƌŵŝƐƐŝŽŶƚŽŝƐĐůŽƐĞW,ů͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϵ
ϭϴ͘ϴDĂũŽƌWƌŽƚŽĐŽůĞǀŝĂƚŝŽŶƐZĞƉŽƌƚZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϮϬ
ϭϴ͘ϵWƌŽƚŽĐŽůĞǀŝĂƚŝŽŶƐ>ŽŐZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϮϭ
ϭϴ͘ϭϬ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚ;^ͿZĞƉŽƌƚŝŶŐZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϮϮ
ϭϴ͘ϭϭĂƚĂŽƌƌĞĐƚŝŽŶ&ŽƌŵZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϮϯ
ϭϴ͘ϭϮDĞĚŝĐĂƚŝŽŶ^ƚŽƌĂŐĞZŽŽŵŵďŝĞŶƚdĞŵƉĞƌĂƚƵƌĞͬ,ƵŵŝĚŝƚǇ>ŽŐZ&͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϮϰ

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7/5
7ROOOLNHUHFHSWRUV
8/1
8SSHUOLPLWRIQRUPDO
1
BACKGROUND
1.1
Brief Description of the Investigational Product
$//2'LVDQLQYHVWLJDWLRQDOFRPELQDWLRQRID7ROO/LNH5HFHSWRU7/5DQWDJRQLVW
QDOWUH[RQHK\GURFKORULGHZLWKDKLJKO\VHOHFWLYH&\FORR[\JHQDVH&2;LQKLELWRU
DFHWDPLQRSKHQLQWHQGHGIRUXVHLQWKLVVWXG\IRUWKHDFXWHWUHDWPHQWRIPRGHUDWHWRVHYHUH
PLJUDLQHDVVRFLDWHGZLWKQDXVHD
1DOWUH[RQHLVDQRSLRLGDQWDJRQLVWZKLFKKDVEHHQPDUNHWHGLQWKH8QLWHG6WDWHVIRU
WUHDWPHQWRIRSLRLGDQGDOFRKROGHSHQGHQFHVLQFH+RZHYHUWKHZKROHWLPHLWV
DQDOJHVLFSURSHUWLHVKDYHQRWEHHQZLOGO\DFNQRZOHGJHG5HFHQWEDVLFVFLHQFHUHVHDUFK
IRXQGQDOWUH[RQHWRDFWDOVRDVD7/5DQWDJRQLVWZKLFKLVWKHSXUSRUWHGPHFKDQLVPRI
DFWLRQRILWVDQDOJHVLFDFWLRQ$FHWDPLQRSKHQZDVILUVWDSSURYHGLQWKH8QLWHG6WDWHVLQ
E\DFHWDPLQRSKHQZDVDOUHDG\HVWDEOLVKHGIRU27&XVHIRUWHPSRUDU\UHOLHIRI
PLQRUDFKHVDQGSDLQVDVVRFLDWHGZLWKWKHFRPPRQFROGKHDGDFKHSDLQWRRWKDFKH
PXVFXODUDFKHVDQGEDFNDFKH
1DOWUH[RQHDQG$FHWDPLQRSKHQLQKLELWWZRGLVWLQFWQHXURLQIODPPDWLRQSURGXFLQJWDUJHWVLQWKH
7/5VLJQDOLQJFDVFDGHSDWKZD\1DOWUH[RQHLQKLELWV7/5LQGXFHGUHOHDVHRISUR
LQIODPPDWRU\F\WRNLQHVDQGDFHWDPLQRSKHQLQKLELWV7/5LQGXFHG&2;H[SUHVVLRQ7KH
FRPELQDWLRQLVH[SHFWHGWRVKRZWKHPRVWV\QHUJLVWLFHIIHFWVKRUWO\DIWHUWUHDWPHQWLQWKHILUVW
WZRKRXUVVLQFHFRQWLQXHV7/5EORFNDGHZRXOGSUHYHQWHYHQWXDOGRZQVWUHDPDFWLYDWLRQRI
&2;
%RWKFRPSRQHQWVDUHSUHVHQWLQWKH,QYHVWLJDWLRQDO3URGXFWLQDQLPPHGLDWHUHOHDVHIRUPXODWLRQ
1.2
Description of the Chemical Formulae of Naltrexone and Acetaminophen 
1DOWUH[RQHK\GURFKORULGHLVFKHPLFDOO\GHVLJQDWHGDVĮF\FORSURS\OPHWK\O
GLK\GUR[\HSR[\PRUSKLQDQRQHK\GURFKORULGHDQGKDVWKHIROORZLQJVWUXFWXUH
,WVFKHPLFDOIRUPXODLV&+&O12UHSUHVHQWLQJDPROHFXODUZHLJKWRI'D,W LVD
ZKLWHWRRIIZKLWHSRZGHUZLWKDELWWHUWDVWHUHDGLO\VROXEOHLQZDWHUDQGVDOLQH
 5(9,$QDOWUH[RQHK\GURFKORULGHWDEOHWV863PJ2SLRLG$QWDJRQLVWSDFNDJLQJLQVHUW$YDLODEOHDW
KWWSZZZDFFHVVGDWDIGDJRYGUXJVDWIGDBGRFVODEHOVOEO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
$FHWDPLQRSKHQLVDPHGLFDWLRQXVHGWRWUHDWSDLQDQGIHYHU,WVFKHPLFDOQDPHLV1DFHW\OS
DPLQRSKHQRODQGLWVFKHPLFDOIRUPXODLV&+12$FHWDPLQRSKHQ¶VPROHFXODUZHLJKWLV
'D,WLVDZKLWHFU\VWDOOLQHSRZGHUZLWKELWWHUWDVWH$FHWDPLQRSKHQKDVWKHIROORZLQJ
VWUXFWXUH 
1.3
Absorption/Pharmacokinetics of Naltrexone and Acetaminophen
1DOWUH[RQH³)ROORZLQJRUDODGPLQLVWUDWLRQQDOWUH[RQHXQGHUJRHVUDSLGDQGQHDUO\FRPSOHWH
DEVRUSWLRQZLWKDSSUR[LPDWHO\RIWKHGRVHDEVRUEHGIURPWKHJDVWURLQWHVWLQDOWUDFW´³3HDN
SODVPDOHYHOVRIERWKQDOWUH[RQHDQGQDOWUH[RODPDMRUDFWLYHPHWDEROLWHRIQDOWUH[RQH
RFFXUZLWKLQRQHKRXURIGRVLQJ7KHPHDQHOLPLQDWLRQKDOIOLIH7YDOXHVIRUQDOWUH[RQH
DQGQDOWUH[RODUHKRXUVDQGKRXUVUHVSHFWLYHO\´
$FHWDPLQRSKHQ³,QIDVWLQJKHDOWK\SDWLHQWVDEVRUSWLRQRISDUDFHWDPROLQVROXWLRQLVYHU\UDSLG
ZLWKSHDNSODVPDFRQFHQWUDWLRQVRIWHQRFFXUULQJZLWKLQPLQRILQJHVWLRQ$EVRUSWLRQIURP
WDEOHWVLVXVXDOO\VORZHU$EVRUSWLRQLVVORZHGLIJDVWULFHPSW\LQJLVGHOD\HGE\IRRGSRVWXUH
GLVHDVHRUGUXJVVXFKDVSURSDQWKHOLQHDQGQDUFRWLFDQDOJHVLFVEXWWKHWRWDODPRXQWDEVRUEHGLV
QRWGHFUHDVHG³ 3DUDFHWDPROLVH[WHQVLYHO\PHWDEROL]HGDQGWKHSODVPDKDOIOLIHLV
KRXUV´
1.1
24-Hour Distribution of Migraine Attacks
0LJUDLQHDWWDFNVWHQGWRUHFXULQDKDUPRQLFKRXUF\FOLFPDQQHUZLWKDSHDNDURXQGWKH
PLGGOHRIWKHGD\DQGWKDWWKHUHLVQRGLIIHUHQFHEHWZHHQPLJUDLQHZLWKDXUDDQGPLJUDLQH
ZLWKRXWDXUDUHJDUGLQJWKLV 
Figure 2: 24-hour distribution of migraine attacks
 KWWSVXSORDGZLNLPHGLDRUJZLNLSHGLDFRPPRQVWKXPEDD1$FHW\OSDPLQRSKHQROVYJS[1$FHW\OS
DPLQRSKHQROVYJSQJ
 3UHVFRWW/).LQHWLFVDQGPHWDEROLVPRISDUDFHWDPRODQGSKHQDFHWLQ%U-&OLQ3KDUPDFRO6XSSO6
6
 $OVWDGKDXJHWDOKRXUGLVWULEXWLRQRIPLJUDLQHDWWDFNV+HDGDFKH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
1.4
Relation to Fed Conditions
³0LJUDLQHXUVPD\KDYHGHOD\HGJDVWULFHPSW\LQJHYHQZKHQQRWH[SHULHQFLQJPLJUDLQHDQG
JDVWULFVWDVLVRFFXUVGXULQJPLJUDLQHDWWDFNV7KXVHYHQIRUPLJUDLQHZLWKQRFWXUQDORQVHW
IDVWLQJFRQGLWLRQVPLJKWQRWEHPHW5HFHQWHYLGHQFHVXJJHVWVWKDWSHDNLQFLGHQFHRIPLJUDLQH
PLJKWDFWXDOO\RFFXULQWKHPLGGOHRIWKHGD\SRWHQWLDOO\ZLWKLQDIHZKRXUVRIHDWLQJ,QWKH
86SKDVHVWXG\DERXWUGRISDWLHQWVUHSRUWHGHDWLQJZLWKLQKRXUEHIRUHWDNLQJVWXG\
PHGLFDWLRQDQGDODUJHPDMRULW\RIPLJUDLQHVKDGRQVHWGXULQJWKHGD\SRWHQWLDOO\ZLWKLQDIHZ
KRXUVRIHDWLQJ)LJXUH,WVHHPVUHDVRQDEOHWRFRQFOXGHWKDW3.SDUDPHWHUVLQFOLQLFDOXVH
ZRXOGRIWHQIDOOEHWZHHQIHGDQGIDVWHGVWDWH´
1.5
The Investigational Drug Components, naltrexone and Acetaminophen 
1DOWUH[RQHLVDFRPPRQO\XVHGRSLRLGDQWDJRQLVWZKLFKLVDFRPSHWLWLYHDQWDJRQLVWWKDWELQGVWR
WKHRSLRLGUHFHSWRUVZLWKKLJKHUDIILQLW\WKDQWKHDJRQLVWVELQGEXWGRHVQRWDFWLYDWHWKHUHFHSWRU
1DOWUH[RQHZDVPDUNHWHGDV5H9LD IRUWUHDWPHQWRIRSLRLGGHSHQGHQFHLQDQGIRU
WUHDWPHQWRIDOFRKROGHSHQGHQFHLQ,W LVQRZDYDLODEOHLQVHYHUDOJHQHULFIRUPXODWLRQV
$FHWDPLQRSKHQLVRQHRIWKHPRVWFRPPRQO\XVHGPHGLFDWLRQVLQWKH8QLWHG6WDWHV LWZDVILUVW
DSSURYHGLQWKH8QLWHG6WDWHVLQ%\DFHWDPLQRSKHQZDVDOUHDG\HVWDEOLVKHGIRU27&
XVHIRUWHPSRUDU\UHOLHIRIPLQRUDFKHVDQGSDLQVDVVRFLDWHGZLWKWKHFRPPRQFROGKHDGDFKH
SDLQWRRWKDFKHPXVFXODUDFKHVDQGEDFNDFKH$FHWDPLQRSKHQKDVEHHQPDUNHWHGLQWKH8QLWHG
6WDWHVXQGHUWKHWUDGHQDPH7\OHQRO$FHWDPLQRSKHQLVXVHGE\RIDGXOWVLQWKH8QLWHG
6WDWHVLQDQ\JLYHQZHHN3UHVFULELQJLQIRUPDWLRQIRUDFHWDPLQRSKHQLVDYDLODEOHIRU
2),50(9LQWUDYHQRXVDFHWDPLQRSKHQ
1.6
TLR4 - A Pattern Recognition Receptor - Detects Infection/Tissue Injury and Promotes 
Inflammation
³7ROOOLNHUHFHSWRUV7/5VDUHJHUPOLQHHQFRGHGSDWWHUQUHFRJQLWLRQUHFHSWRUVWKDWLQLWLDWH
 $XURUD6HWDO*DVWULFVWDVLVRFFXUVLQVSRQWDQHRXVYLVXDOO\LQGXFHGDQGLQWHULFWDOPLJUDLQH+HDGDFKH

 5RQDOG)DUNDV0'3K'&OLQLFDO5HYLHZ IRU&DPELD
KWWSZZZDFFHVVGDWDIGDJRYGUXJVDWIGDBGRFVQGDV0HG5SGI
 .DXIPDQ':.HOO\-35RVHQEHUJ/HWDO5HFHQWSDWWHUQVRIPHGLFDWLRQXVHLQWKHDPEXODWRU\DGXOWSRSXODWLRQ
RIWKH8QLWHG6WDWHV7KH6ORQHVXUYH\-$0$
 )XOOSUHVFULELQJLQIRUPDWLRQIRU2),50(9$YDLODEOHDW
KWWSZZZDFFHVVGDWDIGDJRYGUXJVDWIGDBGRFVODEHOOEO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
LQQDWHLPPXQHUHVSRQVHVE\UHFRJQL]LQJPROHFXODUVWUXFWXUHVVKDUHGE\DZLGHUDQJHRI
SDWKRJHQVNQRZQDVSDWKRJHQDVVRFLDWHGPROHFXODUSDWWHUQV3$03V$IWHUWLVVXHLQMXU\RU
FHOOXODUVWUHVV7/5VDOVRGHWHFWHQGRJHQRXVOLJDQGVNQRZQDVGDPDJHDVVRFLDWHGPROHFXODU
SDWWHUQV'$03V7/5VDUHH[SUHVVHGLQERWKQRQQHXURQDODQGQHXURQDOFHOOW\SHVLQWKH
FHQWUDOQHUYRXVV\VWHP&16DQGFRQWULEXWHWRERWKLQIHFWLRXVDQGQRQLQIHFWLRXVGLVRUGHUVLQ
WKH&16)ROORZLQJWLVVXHLQVXOWDQGQHUYHLQMXU\7/5VVXFKDV7/57/5DQG7/5
LQGXFHWKHDFWLYDWLRQRIPLFURJOLDDQGDVWURF\WHVDQGWKHSURGXFWLRQRIWKHSURLQIODPPDWRU\
F\WRNLQHVLQWKHVSLQDOFRUGOHDGLQJWRWKHGHYHORSPHQWDQGPDLQWHQDQFHRILQIODPPDWRU\SDLQ
DQGQHXURSDWKLFSDLQ´³$FWLYDWLRQRI7/5VLVNQRZQWRSURGXFHYDULRXVLQIODPPDWRU\
PHGLDWRUVLQFOXGLQJF\WRNLQHVHJ71)ĮFKHPRNLQHVHJ0&3DQGHQ]\PHVHJ&2;
DQG003DVZHOODVRWKHULQIODPPDWRU\PHGLDWRUVHJSURVWDJODQGLQV´
1.7
Proposed Mechanism of Action of Naltrexone/Acetaminophen
7/5GHWHFWVDQGUHDFWVWRHQGRJHQRXVOLJDQGVWKDWRFFXUDIWHUWLVVXHLQMXU\RUFHOOXODU
VWUHVVNQRZQDVGDPDJHDVVRFLDWHGPROHFXODUSDWWHUQV'$03V$FWLYDWLRQRIWKH7/5
VLJQDOLQJSDWKZD\LQWKHJOLDLQGXFHVUHOHDVHRISURLQIODPPDWRU\F\WRNLQHV>QLWULFR[LGH
12WXPRUQHFURVLVIDFWRUĮ71)ĮDQG UHDFWLYHR[\JHQVSHFLHV526@ FDXVLQJQHXUR
LQIODPPDWLRQ,QDGGLWLRQDFWLYDWLRQRIWKH7/5VLJQDOLQJSDWKZD\LQGXFHVH[SUHVVLRQRI
&2;WKH7/5&2;SURVWDJODQGLQ(D[LVDOVRFDXVLQJQHXURLQIODPPDWLRQ7/5
LQGXFHGQHXURLQIODPPDWLRQQHDUE\VSLQDOQHUYHURRWVRUWKHWULJHPLQDOQHUYHV\VWHPOHDGV
LQSUHGLVSRVHGLQGLYLGXDOVWRQHXURSDWKLFSDLQPDQLIHVWHGFOLQLFDOO\DVUDGLFXODUEDFNSDLQ
RUPLJUDLQHDQGRWKHUFOLQLFDOSUHVHQWDWLRQV
7KHUHLVDVWURQJELRORJLFDOUDWLRQDOHIRUWKHXVHRIQDOWUH[RQHDQGDFHWDPLQRSKHQLQ
FRPELQDWLRQVLQFHHDFKLQKLELWVDGLVWLQFWWDUJHWLQWKHVDPHPROHFXODUSDWKZD\WKH7/5
VLJQDOLQJFDVFDGH
7/5DFWLYDWLRQLQUHVSRQVHWRHQGRJHQRXV'$03VLVDQRWKHUH[DPSOHRIH[XEHUDQWLQQDWH
LPPXQLW\UHVSRQVHWKDWLVGHWULPHQWDOWRWKHKRVW1DOWUH[RQH DQGDFHWDPLQRSKHQFDOPWKH
LPPXQHRYHUDFWLYDWLRQDQGQHXURLQIODPPDWLRQQHDUE\VSLQDOQHUYHURRWVDQGWKH
WULJHPLQDOQHUYHV\VWHPHOLPLQDWLQJEDFNSDLQDQGPLJUDLQH,QSDWLHQWVVXIIHULQJIURP
FKURQLFEDFNSDLQDQLQMXU\QHDUE\DVSLQDOQHUYHURRWHJGLVNKHUQLDWLRQFDQDFWLYDWH
7/5DQGFDXVHQHXURSDWKLFSDLQDORQJLWVDQDWRPLFDOGLVWULEXWLRQ
Figure 3: Working hypothesis for activated glia induced pain generation as it relates to migraine
 /LX7*DR<--L55(PHUJLQJUROHRI7ROOOLNHUHFHSWRUVLQWKHFRQWURORISDLQDQGLWFK1HXURVFL%XOO


3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
1.8
Clinicaltrials.gov summery (Identifier: NCT03194555)
:KLOHPDQ\LQGLYLGXDOVDUHDEOHWROLPLWWKHUDS\WRWUHDWPHQWRIPLJUDLQHDWWDFNVRWKHUV
QHHGPHGLFDWLRQWRUHGXFHWKHIUHTXHQF\DQGRUVHYHULW\RIDWWDFNV3DWLHQWVZLWKSURORQJHG
RUVHYHUHDWWDFNVOHDGLQJWRVXEVWDQWLDOGLVDELOLW\RUSDWLHQWVZKRDUHUHIUDFWRU\WRDERUWLYH
WUHDWPHQWVFDQEHQHILWIURPPLJUDLQHSUHYHQWLRQ
7KHLQYHVWLJDWLRQDOSURGXFWLVDFRPELQDWLRQRIWZRUHSXUSRVHGPDUNHWHGGUXJVXVHGIRU
PLJUDLQHSUHYHQWLRQWKURXJKWKHGLVFRYHU\RIELRORJLFDOO\DQGFOLQLFDOO\UHOHYDQWDIILQLW\IRU
QHZWDUJHWV%RWKGUXJVDUHEHLQJUHSXUSRVHGDWDVLJQLILFDQWO\ORZHUGRVDJHFRPSDUHGWR
WKHDSSURYHGPDUNHWHGLQGLFDWLRQVGRVDJH
7KHFRPELQDWLRQLVD)LUVWLQ&ODVVGUXJGXHLWVQHZDQGXQLTXHPHFKDQLVPRIDFWLRQ
7KHLQYHVWLJDWRUVSURSRVHWKDWLQSUHGLVSRVHGLQGLYLGXDOVPLJUDLQHDWWDFNVRFFXUGXHWR
H[XEHUDQWLQQDWHLPPXQHV\VWHPDFWLYDWLRQQHDUE\WKHWULJHPLQDOQHUYHDQGRWKHUFUDQLDO
QHUYHV7KHLQQDWHLPPXQLW\DFWLYDWLRQOHDGVWRUHOHDVHRISURLQIODPPDWRU\F\WRNLQHV
>QLWULFR[LGH12WXPRUQHFURVLVIDFWRUĮ71)ĮDQGUHDFWLYHR[\JHQVSHFLHV526@
DQGWR&2;DFWLYDWLRQZKLFKSURGXFHVQHXURLQIODPPDWLRQFDXVLQJSDLQDQGYDULRXV
PLJUDLQHDVVRFLDWHGV\PSWRPV
$//2'UHYHUVHVWKHQHXURLQIODPPDWLRQWKURXJKGXDODFWLRQLQKLELWLRQRIWKHUHOHDVHRIWKH
SURLQIODPPDWRU\F\WRNLQHVDQGLQKLELWLRQRIWKH&2;DFWLYDWLRQ(IILFDF\RIWKLVSURGXFWIRU
PLJUDLQHKHDGDFKHSDLQDQGIRUPLJUDLQHDVVRFLDWHGV\PSWRPVHVSHFLDOO\QDXVHDZKLFKLV
UHIUDFWRU\WRRWKHUNQRZQPLJUDLQHWUHDWPHQWVPD\VXJJHVWWKHSURGXFWDGGUHVVHVWKHURRWFDXVH
RIPLJUDLQH
1.9
Dose Selection Rationale
0DUNHWHGQDOWUH[RQHPJWDEOHWHJ5HYLDDQG7\OHQRO
PJDUHWKHUHIHUHQFHOLVWHG
SURGXFWVIRU$OORG\QLF¶VSODQQHGEVXEPLVVLRQ
7KHGRVHRIDFHWDPLQRSKHQ
PJLVWKHKLJKHVWDOORZHGLQSUHVFULSWLRQFRPELQDWLRQGUXJ

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
SURGXFWVFRQWDLQLQJDFHWDPLQRSKHQVLQFH-DQXDU\
1DOWUH[RQHLVPDUNHWHGDVDPJWDEOHWWREHWDNHQRQFHDGD\1DOWUH[RQH
PJDGD\LQ
PJ%,'WRUHGXFHOLNHOLKRRGRIVLGHHIIHFWVIURPWKHHQWLUHGRVHWDNHQDWRQFHZDVXVHGLQ
$OORG\QLF¶V,1'SKDVHFOLQLFDOWULDORQSDWLHQWVZLWKFKURQLFEDFNSDLQ7KH
PJGRVHZDV
EDVHGRQ'RFWRU%LKDUL¶VVWXGLHVZLWKORZGRVHQDOWUH[RQH
PJGD\IRUWKHWUHDWPHQWRI
DXWRLPPXQHGLVRUGHUV DQGRQVWXGLHVIRUWUHDWPHQWRIILEURP\DOJLDWKDWXVHGPJRI
QDOWUH[RQHE\<RXQJHUHWDO
1.10
Migraine-associated nausea is an Important Target for Treatment
7KHSXEOLFDWLRQ³)UHTXHQF\DQG%XUGHQRI+HDGDFKH5HODWHG1DXVHD5HVXOWVIURPWKH
$PHULFDQ0LJUDLQH3UHYDOHQFHDQG3UHYHQWLRQ$0336WXG\´ VWDWHV
³$PRQJWKHUHVSRQGHQWVZLWKHSLVRGLFPLJUDLQHDSSUR[LPDWHO\KDOIUHSRUWHG
KLJKIUHTXHQF\QDXVHDLHKDOIWKHWLPHZLWKKHDGDFKH+LJKIUHTXHQF\QDXVHDZDVPRUH
FRPPRQLQIHPDOHV3HUVRQVZLWKKLJKIUHTXHQF\QDXVHDFRPSDUHGZLWKWKHQRUDUHRUOHVVWKDQ
KDOIWKHWLPHQDXVHDJURXSVUHSRUWHGVLJQLILFDQWO\PRUHKHDGDFKHV\PSWRPVDQGPRUH
KHDGDFKHUHODWHGLPSDFW
+LJKIUHTXHQF\PLJUDLQHDVVRFLDWHGQDXVHDLVFRPPRQDQGLVDPDUNHUIRUVHYHUHGHELOLWDWLQJ
PLJUDLQH1DXVHDPDNHVDQLQGHSHQGHQWFRQWULEXWLRQWRPLJUDLQHDVVRFLDWHGGLVDELOLW\DQG
LPSDFW0DQDJHPHQWVWUDWHJLHVWKDWWDNHQDXVHDLQWRDFFRXQWFRXOGUHGXFHWKHEXUGHQRI
PLJUDLQH1DXVHDLVDQLPSRUWDQWWDUJHWIRUPRQLWRULQJDQGWUHDWPHQW´
1.11
Nausea Associated with Acute Migraine Represents a Significant Unmet Treatment 
Need
)'$*XLGDQFHIRU,QGXVWU\0LJUDLQH'HYHORSLQJ'UXJVIRU$FXWH7UHDWPHQWVWDWHV³%HFDXVH
PLJUDLQHLVDFRPSOH[GLVRUGHUFKDUDFWHUL]HGE\LQDGGLWLRQWRKHDGDFKHVHYHUDODVVRFLDWHG
V\PSWRPVLHQDXVHDSKRWRSKRELDDQGSKRQRSKRELDDGUXJHIIHFWRQKHDGDFKHSDLQDORQHLV
QRWFRQVLGHUHGVXIILFLHQWWRJUDQWDFODLPIRUWKHDFXWHWUHDWPHQWRIPLJUDLQH,QWKHSDVW
GHFDGHVDSSURYDORIGUXJVIRUWKHDFXWHWUHDWPHQWRIPLJUDLQHLQYROYHGWKHGHPRQVWUDWLRQRIDQ
HIIHFWRQFRSULPDU\HQGSRLQWVSDLQQDXVHDSKRWRSKRELDDQGSKRQRSKRELD0RUHUHFHQWO\
DSSURYDOEDVHGRQDQHIIHFWRQKHDGDFKHSDLQDQGQDXVHDDVFRSULPDU\HQGSRLQWVKDVEHHQ
FRQVLGHUHG´
7KHJRDORIWKLVVWXG\LVWRHVWDEOLVKWKHLQYHVWLJDWLRQDOSURGXFWDGGUHVVHVQRWRQO\KHDGDFKHSDLQ
EXWDOVRRWKHUPLJUDLQHDVVRFLDWHGV\PSWRPVVSHFLILFDOO\QDXVHD0LJUDLQHDVVRFLDWHGQDXVHD
)'$UHFRPPHQGVKHDOWKFDUHSURIHVVLRQDOVGLVFRQWLQXHSUHVFULELQJDQGGLVSHQVLQJSUHVFULSWLRQFRPELQDWLRQ
GUXJSURGXFWVZLWKPRUHWKDQ
PJRIDFHWDPLQRSKHQWRSURWHFWFRQVXPHUV-DQXDU\
KWWSZZZIGDJRY'UXJV'UXJ6DIHW\XFP
 %LKDUL%%HUQDUG%LKDUL0'ORZGRVHQDOWUH[RQHIRUQRUPDOL]LQJLPPXQHV\VWHPIXQFWLRQ$OWHUQ7KHU+HDOWK
0HG±>3XE0HG@
 /LSWRQ5% %XVH'&6DLHUV-)DQQLQJ.06HUUDQR'5HHG0/)UHTXHQF\DQGEXUGHQRIKHDGDFKHUHODWHG
QDXVHDUHVXOWVIURPWKH$PHULFDQ0LJUDLQH3UHYDOHQFHDQG3UHYHQWLRQ$033VWXG\+HDGDFKH


3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
SXUSRUWHGO\UHSUHVHQWVDVLJQLILFDQWXQPHWWUHDWPHQWQHHG(IILFDF\IRUPLJUDLQHDVVRFLDWHG
V\PSWRPVHVSHFLDOO\QDXVHDLWZLOOLQGLFDWHWKHSURGXFW¶VPHFKDQLVPRIDFWLRQDGGUHVVHVWKH
IXQGDPHQWDOSDWKRJHQHVLVRIPLJUDLQH
&OLQLFDOWULDOVZLWKPHGLFDWLRQVWKDWUHSUHVHQWWKHFXUUHQWVWDQGDUGRIFDUHIRUPLJUDLQH
VXPDWULSWDQ16$,'6DQGDFRPELQDWLRQRIWKHWZRVXPDWULSWDQQDSUR[HQVKRZHGQR
GLIIHUHQFHIURPSODFHERIRUDEVHQFHRIQDXVHDDWKRXUVDIWHUGRVLQJ7KLVVXSSRUWVWKH
DUJXPHQWWKDWQDXVHDLQHSLVRGLFPLJUDLQHUHSUHVHQWVDKLJKGHJUHHRIXQPHWWUHDWPHQWQHHG$
VXPPDU\RIILQGLQJVRIWKHVWXG\³6XPDWULSWDQ1DSUR[HQIRU$FXWH7UHDWPHQWRI0LJUDLQH
&OLQLFDO7ULDO´LVSUHVHQWHGLQWKHWDEOHEHORZ
Figure 4: Nausea frequency in an acute migraine study
$EVHQFHRIQDXVHDDWKRXUV
6XPDWULSWDQ
1DSUR[HQ
6RGLXP
1R
6XPDWULSWDQ
1R
1DSUR[HQ
6RGLXP
1R
3ODFHER
1R
P 9DOXH
6XPDWULSWDQ
1DSUR[HQ
6RGLXPYV
3ODFHER
P 9DOXH
6XPDWULSWDQ
1DSUR[HQ
6RGLXPYV
6XPDWULSWDQ
6WXG\






%UDQGHV-/.XGURZ'6WDUN65HWDO6XPDWULSWDQQDSUR[HQIRUDFXWHWUHDWPHQWRIPLJUDLQHDUDQGRPL]HGWULDO
1.12
Claimed Innovation
7KLVSURGXFWLVDILUVWLQFODVV7/5VLJQDOLQJFDVFDGHLQKLELWRUWREHXVHGIRUWUHDWPHQWRI
PLJUDLQH'XHWRSRWHQWLDOVXSHULRULW\RYHUH[LVWLQJWKHUDSLHVLWUHSUHVHQWVDVLJQLILFDQW
LQQRYDWLRQ7KHKLJKHIILFDF\VKRZQLQWKHSLORWVWXG\PD\LQGLFDWHWKDWLWVPHFKDQLVPRIDFWLRQ
DGGUHVVHVWKHIXQGDPHQWDOSDWKRJHQHVLVRIPLJUDLQH
1.13
Approved Migraine Prevention Oral Treatments
:KLOHPDQ\LQGLYLGXDOVDUHDEOHWROLPLWWKHUDS\WRDFXWHWUHDWPHQWRIPLJUDLQHDWWDFNV
RWKHUVQHHGPHGLFDWLRQWRUHGXFHWKHIUHTXHQF\DQGRUVHYHULW\RIDWWDFNV3DWLHQWVZLWK
SURORQJHGRUVHYHUHDWWDFNVOHDGLQJWRVXEVWDQWLDOGLVDELOLW\RUSDWLHQWVZKR DUHUHIUDFWRU\
WRDERUWLYHWUHDWPHQWVFDQEHQHILWIURPPLJUDLQHSURSK\OD[LV
7KHIROORZLQJWUHDWPHQWVKDYHEHHQDSSURYHGLQWKH86IRUHSLVRGLFPLJUDLQHSUHYHQWLRQ
x
7RSLUDPDWH
x
6RGLXPYDOSURDWHDQG([WHQGHGUHOHDVHGLYDOSURH[VRGLXP
x
3URSUDQRORO
 %UDQGHV-/.XGURZ'6WDUN65HWDO6XPDWULSWDQQDSUR[HQIRUDFXWHWUHDWPHQWRIPLJUDLQHDUDQGRPL]HGWULDO
-$0$
 %UDQGHV-/6DSHU-5'LDPRQG0HWDO7RSLUDPDWHIRUPLJUDLQHSUHYHQWLRQDUDQGRPL]HGFRQWUROOHGWULDO
-$0$
 )UHLWDJ)*&ROOLQV6'&DUOVRQ+$HWDO$UDQGRPL]HGWULDORIGLYDOSURH[VRGLXPH[WHQGHGUHOHDVHWDEOHWVLQ
PLJUDLQHSURSK\OD[LV1HXURORJ\
 'LHQHU+&7IHOWKDQVHQ3'DKO|I&HWDO7RSLUDPDWHLQPLJUDLQHSURSK\OD[LVUHVXOWVIURPDSODFHER
FRQWUROOHGWULDOZLWKSURSUDQRORODVDQDFWLYHFRQWURO-1HXURO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
x
7LPROROEUDQG%ORFDGUHQ
x
RQDERWXOLQXP7R[LQ7\SH$EUDQG%RWR[DSSURYHGIRUFKURQLF0LJUDLQHRQO\
0LJUDLQHRFFXUULQJRUPRUHGD\VDPRQWK
$UHGXFWLRQLQWKHIUHTXHQF\RIPLJUDLQHVLVJHQHUDOO\GHHPHGVXFFHVVIXO&RPSOLDQFHLVD
PDMRULVVXHEHFDXVHSDWLHQWVH[SHULHQFHPHGLFDWLRQVLGHHIIHFWVEHIRUHDQ\EHQHILWIURP
SURSK\ODFWLFGUXJV
$QDJHQWWKDWKDVWKHSRWHQWLDOIRUWKHKLJKEHQHILWDQGORZULVNWRWKHSDWLHQWLVQHHGHG
1.14
Migraine Pathogenesis
³0LJUDLQHUHSUHVHQWVDFHQWUDOQHXUDOK\SHUVHQVLWLYLW\'XULQJDQDWWDFNPLJUDLQHVXIIHUHUVFDQ
EHK\SHUVHQVLWLYHWRQRUPDOOHYHOVRIVRXQGOLJKWVPHOODQGPRYHPHQW,IWKHFHQWUDOQHXURQDO
K\SHUVHQVLWLYLW\DVVRFLDWHGZLWKPLJUDLQHUHSUHVHQWVJOLDOFHOODFWLYDWLRQGUXJVWKDWEORFNJOLDO
FHOODFWLYDWLRQDQGWKHVXEVHTXHQWUHOHDVHRIQHXURH[FLWDWRU\VXEVWDQFHVFRXOGKDYHWKHUDSHXWLF
SRWHQWLDOLQERWKDFXWHPLJUDLQHWUHDWPHQWDQGPLJUDLQHSURSK\OD[LV´ 
7KHJOLDZKHQDFWLYDWHGSURGXFHVDQGUHOHDVHVDYDULHW\RIQHXURH[FLWDWRU\VXEVWDQFHV
LQFOXGLQJUHDFWLYHR[\JHQVSHFLHVQLWULFR[LGHDQGLQIODPPDWRU\F\WRNLQHV*OLDODFWLYDWLRQDQG
WKHVXEVHTXHQWUHOHDVHRISURLQIODPPDWRU\PHGLDWRUVKDVEHHQLPSOLFDWHGLQWKHLQLWLDWLRQDQG
PDLQWHQDQFHRIDQXPEHURISDLQVWDWHV
(QGRJHQRXV7/5DJRQLVWVOLJDQGVPD\LQFOXGHFRPSRQHQWVRIGDPDJHGWLVVXHWHUPHG
'DPDJH$VVRFLDWHG0ROHFXODU3DWWHUQV'$03V'$03VPD\FRQVLVWRIH[WUDFHOOXODUPDWUL[
GHJUDGDWLRQSURGXFWVRUGHDGFHOOFRPSRQHQWVVXFKDV'1$51$RUSODVPDSURWHLQV
1.15
The Prevalence, Impact, and Economic Burdens of Migraine in the United States
3RSXODWLRQZLGHVWXGLHVKDYHIRXQGWKDWDSSUR[LPDWHO\RIWKH86SRSXODWLRQ±
DSSUR[LPDWHO\PLOOLRQ$PHULFDQVKDYHPLJUDLQHKHDGDFKH 2YHUDOOPLJUDLQHDIIHFWV
RIZRPHQDQGRIPHQDJHG\HDUVDQGROGHU
³7KHEXUGHQRIKHDGDFKHSDLQZDVKLJKHVWLQIHPDOHVZKHUHWKHPRQWKSUHYDOHQFHRI
PLJUDLQHRUVHYHUHKHDGDFKHSDLQZDVDQGKHDGSDLQZDVWKHWKLUGOHDGLQJFDXVHRI('
YLVLWV7ULSWDQVDFFRXQWHGIRUDOPRVWRIDQWLPLJUDLQHDQDOJHVLFVSUHVFULEHGDWRIILFHYLVLWVLQ
QHDUO\KDOIRIZKLFKZHUHIRU6XPDWULSWDQ0LJUDLQHLVDVVRFLDWHGZLWKLQFUHDVHGULVNIRU
 %ORFDGUHQSDFNDJHLQVHUWKWWSVZZZGUXJVFRPSUREORFDGUHQKWPO
 $XURUD6.:LQQHU3)UHHPDQ0&HWDO2QDERWXOLQXPWR[LQ$IRUWUHDWPHQWRIFKURQLFPLJUDLQHSRROHG
DQDO\VHVRIWKHZHHN35((037FOLQLFDOSURJUDP+HDGDFKH
 %DUWOH\- &RXOGJOLDODFWLYDWLRQEHDIDFWRULQPLJUDLQH"0HG+\SRWKHVHV0DUGRL
MPHK\(SXE1RY
 .DWR-6YHQVVRQ&,5ROHRI([WUDFHOOXODU'DPDJH$VVRFLDWHG0ROHFXODU3DWWHUQ0ROHFXOHV'$03VDV
0HGLDWRUVRI3HUVLVWHQW3DLQ3URJ0RO%LRO7UDQVO6FLGRLEVSPEWV(SXE
-DQ
,PSDFWRIPLJUDLQHKHDGDFKHLQWKHXQLWHGVWDWHV±-HQQLIHU+/RIODQG$GY6WXG3KDUP
$YDLODEOHDWKWWSXWDVLSFRPILOHVDUWLFOHILOHVSGI$6,3BBSB

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
RWKHUSK\VLFDODQGSV\FKLDWULFFRPRUELGLWLHVDQGWKLVULVNLQFUHDVHVZLWKKHDGDFKHSDLQ
IUHTXHQF\´
$FFRUGLQJWRWKH:RUOG+HDOWK2UJDQL]DWLRQ¶VUHFHQW*OREDO%XUGHQRI'LVHDVHUHSRUWZKLFK
LQFOXGHGGLVHDVHVPLJUDLQHZDVJOREDOO\WKHVHYHQWKPRVWGLVDEOLQJ
7HQVLRQW\SHKHDGDFKHSDLQ 77+HVWLPDWHGJOREDOSUHYDOHQFHDQGPLJUDLQH
UDQNHGUHVSHFWLYHO\DVVHFRQGDQGWKLUGPRVWFRPPRQGLVHDVHVLQWKHZRUOGEHKLQGGHQWDO
FDULHVLQERWKPDOHVDQGIHPDOHV)RUPLJUDLQHWKHHVWLPDWHGSURSRUWLRQRIWLPHVSHQWLQWKH
LFWDOVWDWHGXULQJDWWDFNVZDVDQGWKHGLVDELOLW\DVVLJQHGWRPLJUDLQHDWWDFNVZDV
GLVDELOLW\0LJUDLQHZDVE\DZLGHPDUJLQWKHOHDGLQJFDXVHRIGLVDELOLW\DPRQJQHXURORJLFDO
GLVRUGHUV
+HDGDFKHSDLQGLVRUGHUVLPSRVHDUHFRJQL]DEOHEXUGHQRQVXIIHUHUVLQFOXGLQJVRPHWLPHV
VXEVWDQWLDOSHUVRQDOVXIIHULQJLPSDLUHGTXDOLW\RIOLIHDQGILQDQFLDOFRVW5HSHDWHGKHDGDFKHSDLQ
DWWDFNVDQGRIWHQWKHFRQVWDQWIHDURIWKHQH[WRQHGDPDJHIDPLO\OLIHVRFLDOOLIHDQG
HPSOR\PHQW7KHORQJWHUPHIIRUWRIFRSLQJZLWKDFKURQLFKHDGDFKHSDLQGLVRUGHUPD\DOVR
SUHGLVSRVHWKHLQGLYLGXDOWRRWKHULOOQHVVHV)RUH[DPSOHDQ[LHW\DQGGHSUHVVLRQDUHVLJQLILFDQWO\
PRUHFRPPRQLQSHRSOHZLWKPLJUDLQHWKDQLQKHDOWK\LQGLYLGXDOV
1.16
Unmet Treatment Needs for Migraine and Limitations of Existing Treatments  
16$,'VDQGWULSWDQVDUHWKHPDLQVWD\VRIDFXWHPLJUDLQHWKHUDS\DQGDQWLHPHWLFGUXJVFDQEH
DGGHGDVQHFHVVDU\2SLRLGVDQGFRPELQDWLRQDQDOJHVLFVFRQWDLQLQJRSLRLGVVKRXOGQRWEHXVHG
URXWLQHO\ Most current treatments are not viewed as being completely effective.
$VHDFKRIWKHPRVWSUHVFULEHGSURGXFWVIRUDFXWHWUHDWPHQWRIPLJUDLQH16$,'67ULSWDQVDQG
RSLRLGFDUU\VLJQLILFDQWULVNVWKHUHLVDUHDOXQPHWQHHGIRUDVDIHQRQQDUFRWLFDOWHUQDWLYH
PHGLFDWLRQIRUWKLVFRQGLWLRQ,QDVLJQLILFDQWQXPEHURISDWLHQWVWULSWDQV FDUU\DFDUGLRYDVFXODU
ULVN16$,'DQGRSLDWHVDUHLQHIIHFWLYHIRUWKHVHSDWLHQWVQDOWUH[RQH$3$3FDQRIIHUDQ
HIIHFWLYH DQGVDIHDOWHUQDWLYH
1.17
Emotional Pain Relief Properties of Acetaminophen
'H:DOOHWDOIRXQGWKDWDFHWDPLQRSKHQPJGD\UHGXFHVVHOIUHSRUWHGIHHOLQJVRI
KXUWUHSRUWHGLQDGLDU\VWXG\S,QDVHFRQGVWXG\DIWHUWDNLQJWKHVWXG\GUXJ ZLWK
 6PLWKHUPDQ7$%XUFK56KHLNK+/RGHU(7KHSUHYDOHQFHLPSDFWDQGWUHDWPHQWRIPLJUDLQHDQGVHYHUH
KHDGDFKHVLQWKH8QLWHG6WDWHVDUHYLHZRIVWDWLVWLFVIURPQDWLRQDOVXUYHLOODQFHVWXGLHV+HDGDFKH
0DU
 6WHLQHU7-6WRYQHU/-%LUEHFN*/0LJUDLQHWKHVHYHQWKGLVDEOHU-+HDGDFKH3DLQ
 0XUUD\&-$WNLQVRQ&%KDOOD.HWDO7KHVWDWHRI86KHDOWKEXUGHQRIGLVHDVHVLQMXULHVDQGULVN
IDFWRUV-$0$
 %HFNHU:-$FXWH0LJUDLQH7UHDWPHQW&RQWLQXXP0LQQHDS0LQQ$XJ+HDGDFKH
KWWSVZZZQFELQOPQLKJRYSXEPHG
 'H:DOO&1HW DO$FHWDPLQRSKHQUHGXFHVVRFLDOSDLQ%HKDYLRUDODQGQHXUDOHYLGHQFH3V\FKRORJLFDO6FLHQFH


3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
DFHWDPLQRSKHQPJGD\IRUZHHNVI05,IXQFWLRQDO05,  QHXUDODFWLYLW\LQWKHG$&&
'RUVDODQWHULRUFLQJXODWHFRUWH[DQGDP\JGDODZDVJUHDWHUIRUSDUWLFLSDQWVZKRWRRNSODFHER
WKDQIRUWKRVHZKRWRRNDFHWDPLQRSKHQ7KHG$&&DQGDP\JGDODDUHEUDLQUHJLRQVWKDWKDYH
EHHQOLQNHGWRDJJUHVVLRQ+HSRVWXODWHV³3K\VLFDOSDLQDQGVRFLDOSDLQPD\UHO\RQVRPHRIWKH
VDPHEHKDYLRUDODQGQHXUDOPHFKDQLVPVWKDWUHJLVWHUSDLQUHODWHGDIIHFW´+HH[SODLQV
³2YHUODSSLQJVRFLDODQGSK\VLFDOSDLQV\VWHPVSUREDEO\FRQIHUUHGDQDGYDQWDJHDPRQJRXU
HYROXWLRQDU\DQFHVWRUV´DQG³7KHVRFLDODWWDFKPHQWV\VWHPLQKXPDQVPD\KDYHHYROYHGE\
SLJJ\EDFNLQJGLUHFWO\RQWRWKHSK\VLFDOSDLQV\VWHPWRSURPRWHVXUYLYDO´+LVZRUN
GHPRQVWUDWHGVXEVWDQWLDORYHUODSEHWZHHQVRFLDODQGSK\VLFDOSDLQ%DOGZLQ0:D\LVFXUUHQWO\
LQYHVWLJDWLQJ$FHWDPLQRSKHQDQG6RFLDO3URFHVVHVLQERUGHUOLQHSHUVRQDOLW\GLVRUGHU%3' 
1.18
Concomitant Emotional Pain and/or Chronic Low Back Pain (CLBP)
3LORWVWXG\GDWDGHPRQVWUDWHGHPRWLRQDOSDLQUHOLHIE\WKHLQYHVWLJDWLRQDOSURGXFW7KH
LQYHVWLJDWRUSRVWXODWHVWKDWWKHLQYHVWLJDWLRQDOSURGXFWUHOLHIRIHPRWLRQDOSDLQLVJUHDWHUWKDQWKDW
RIDFHWDPLQRSKHQDORQH
$GGLWLRQDOO\SLORWVWXG\GDWDGHPRQVWUDWHGHIILFDF\RIWKHLQYHVWLJDWLRQDOSURGXFWIRU&/%3
3DWLHQWVIRXQGDWWKHVFUHHQLQJYLVLWWRKDYHFRQFRPLWDQWHPRWLRQDOSDLQFRH[LVWLQJZLWK
HSLVRGLFPLJUDLQHWKH\ZLOOEHDVNHGWRFRPSOHWHDQHPRWLRQDOGDLO\GLDU\DVZHOODVWKHPLJUDLQH
SUHYHQWLRQGDLO\GLDU\7KHVWUHVVRUVFDXVLQJHPRWLRQDOSDLQDVH[SODLQHGWRSDWLHQWVLQFOXGH
DGMXVWPHQWWRQHZOLIHIRULPPLJUDQWVDGMXVWPHQWWRVHSDUDWLRQIURPFKLOGUHQZKRUHFHQWO\OHIW
KRPHRUDGMXVWPHQWWRORVVRIDSHW7KHVHFRPSODLQWVDUHFXUUHQWO\WUHDWHGZLWKSV\FKRWKHUDS\
7KH,&'&0GLDJQRVLVFRGHLV)³DGMXVWPHQWGLVRUGHUXQVSHFLILHG´$GGLWLRQDOO\
SDWLHQWVZLWKFRQFRPLWDQWHPRWLRQDOSDLQZLOOFRPSOHWHWKH%HFN
V'HSUHVVLRQ,QYHQWRU\
LQVWUXPHQWRQHYHU\VLWHYLVLW
,IDSDWLHQWLVIRXQGDWWKHVFUHHQLQJYLVLWWRKDYHFRQFRPLWDQW&/%3FRH[LVWLQJZLWKHSLVRGLF
PLJUDLQHWKH\ZLOOEHDVNHGWRFRPSOHWHD&/%3GDLO\GLDU\DVZHOODVWKHPLJUDLQHSUHYHQWLRQ
GDLO\GLDU\6HHWKHDWWDFKHGGDLO\GLDU\IRUPV$GGLWLRQDOO\SDWLHQWZLWKFRQFRPLWDQW&/%3
ZLOOFRPSOHWHWKH2VZHVWU\'LVDELOLW\,QGH[LQVWUXPHQWRQHYHU\VLWHYLVLW
1.19
Potential Advantages of a Low-Dose Naltrexone/Acetaminophen Product
3HRSOHZKRDUHQRUPDOO\UHVLVWDQWWRFRQVXPLQJSUHVFULSWLRQPHGLFDWLRQVRUSHRSOHZKRKDYH
H[SHULHQFHGQHJDWLYHVLGHHIIHFWVIURPPHGLFDWLRQVPD\DFFHSWORZGRVHQDOWUH[RQH
DFHWDPLQRSKHQEHFDXVHRIWKH³ORZGRVH´RIWKHWZRPHGLFDWLRQVDQGWKHZLGHDFFHSWDQFHRI
DFHWDPLQRSKHQ
)XQFWLRQDO05,I05,LVDIXQFWLRQDOQHXURLPDJLQJSURFHGXUHXVLQJ05,WHFKQRORJ\WKDWPHDVXUHVEUDLQ
DFWLYLW\E\GHWHFWLQJFKDQJHVDVVRFLDWHGZLWKEORRGIORZ
 $FHWDPLQRSKHQDQG6RFLDO3URFHVVHVKWWSVFOLQLFDOWULDOVJRYFWVKRZ1&7

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
2
STUDY DESIGN OUTLINE
2.1
Study Objectives 
7KHSULPDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQPLJUDLQHSUREDEOHPLJUDLQH
KHDGDFKHGD\VIURPEDVHOLQHWRWKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG
$VHFRQGDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQKHDGDFKHGD\VIURPEDVHOLQHWR
WKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG
$QRWKHUVHFRQGDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQSURSRUWLRQRISDWLHQWV
UHVSRQGLQJWRWUHDWPHQWDVPHDVXUHGE\DRUPRUHUHGXFWLRQLQGD\PLJUDLQHIUHTXHQF\
IURPEDVHOLQHWRWKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG
$QRWKHUVHFRQGDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQPLJUDLQHKHDGDFKHVHYHULW\
KHDGDFKHGXUDWLRQQDXVHDVHYHULW\OLJKWVHQVLWLYLW\QRLVHVHQVLWLYLW\DQGQXPEHURIGD\VRI
UHVFXHPHGLFDWLRQVLQWDNHIURPEDVHOLQHWRWKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG
$QRWKHUVHFRQGDU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQLQWKHPHDQPLJUDLQHGLVDELOLW\
DVVHVVPHQWVFDOH0,'$6DQGKHDGDFKHLPSDFWWHVW+,7IURPEDVHOLQHWR(QGRI7UHDWPHQW
9LVLW
$QH[SORUDWRU\REMHFWLYHLVWRFRPSDUHWKHUHGXFWLRQRIPHDQ3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH
3,56IURPEDVHOLQHWR(QGRI7UHDWPHQW9LVLW
2.2
Inclusion Criteria
$OOSDWLHQWV PXVWPHHWWKHIROORZLQJLQFOXVLRQFULWHULD
Inclusion Criteria (Mark each met criteria)

7KHSDWLHQWLVDPDOHRUDIHPDOH\HDUVRIDJHRUROGHU

+LVWRU\RIPLJUDLQHZLWKRUZLWKRXWDXUDDFFRUGLQJWRWKH,QWHUQDWLRQDO&ODVVLILFDWLRQRI
+HDGDFKH'LVRUGHUV,&+'UGHGLWLRQEHWDYHUVLRQIRUDWOHDVWRQH\HDUZLWKILUVW
PLJUDLQHSULRUWRDJH0LJUDLQHDWWDFNVPHHWWKHIROORZLQJFULWHULD
x
+HDGDFKHDWWDFNVODVWLQJKRXUVXQWUHDWHGRUXQVXFFHVVIXOO\WUHDWHG
x
0LJUDLQHDWWDFNVDUHVHSDUDWHGE\DWOHDVWKRXUVRIDEVHQFHRIKHDGDFKHSDLQ
x
+HDGDFKHKDVDWOHDVWWZRRIWKHIROORZLQJWKUHHFKDUDFWHULVWLFV8QLODWHUDOORFDWLRQ
3XOVDWLQJTXDOLW\$JJUDYDWLRQE\RUFDXVLQJDYRLGDQFHRIURXWLQHSK\VLFDO
DFWLYLW\HJZDONLQJRUFOLPELQJVWDLUV
x
'XULQJWKHKHDGDFKHERWKRIWKHIROORZLQJQDXVHDDQGRUYRPLWLQJSKRWRSKRELDRU
SKRQRSKRELD

0LJUDLQHDVVRFLDWHGQDXVHDZLWKKDOIRIPLJUDLQHDWWDFNV

PLJUDLQHKHDGDFKHGD\VRQDYHUDJHSHUPRQWKLQWKHWKUHHPRQWKVSULRUWR9LVLW
DQGGXULQJWKH%DVHOLQH3HULRG

7KHSDWLHQWDJUHHVWRUHIUDLQIURPWDNLQJRSLDWHPHGLFDWLRQVIURP9LVLWWRGD\V
DIWHUWKHODVWGRVHRIWKHVWXG\GUXJ

7KHSDWLHQWLVDEOHWRFRPSOHWHVWXG\TXHVWLRQQDLUHVFRPSO\ZLWKWKHVWXG\
UHTXLUHPHQWVDQGUHVWULFWLRQVDQGZLOOLQJWRSURYLGHZULWWHQLQIRUPHGFRQVHQWDQG
DXWKRUL]H+,3$$

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 

7KHSDWLHQWVLVHOLJLEOHLIKHVKHKDVEHHQWDNLQJDVWDEOHGRVHRIDPHGLFDWLRQZLWK
PLJUDLQHSUHYHQWLRQSRWHQWLDOIRUDWOHDVWPRQWKSULRUWRWKHVFUHHQLQJYLVLWDQGDJUHHV
WRQRWVWDUWVWRSRUFKDQJHGRVDJHRIDQ\PHGLFDWLRQZLWKPLJUDLQHSUHYHQWLRQSRWHQWLDO
GXULQJWKHVWXG\SHULRG(JEHWDEORFNHUVFDOFLXPFKDQQHOEORFNHUVWULF\FOLF
DQWLGHSUHVVDQWVDQWLFRQYXOVDQWVVHOHFWLYHVHURWRQLQUHXSWDNHLQKLELWRUV665,V
VHURWRQLQQRUHSLQHSKULQHUHXSWDNHLQKLELWRUV615,VPDJQHVLXPRUULERIODYLQ
VXSSOHPHQWVDWKLJKGRVHVKHUEDOSUHSDUDWLRQVHJIHYHUIHZRU6WMRKQ¶VZRUW
%RWXOLQXPWR[LQPXVWEHGLVFRQWLQXHGRQH\HDUSULRUWR9LVLW

7KHSDWLHQWDJUHHVWRIRUJRDQ\HOHFWLYHVXUJHU\IRUWKHGXUDWLRQRIWKHVWXG\

7KHIHPDOHSDWLHQWZKRLVSUHPHQRSDXVDORUSRVWPHQRSDXVDOOHVVWKDQ\HDURU
KDYHQRWKDGVXUJLFDOVWHULOL]DWLRQLHWXEDOOLJDWLRQSDUWLDORUFRPSOHWH
K\VWHUHFWRP\PXVWKDYHDQHJDWLYHXULQHSUHJQDQF\WHVWEHQRQODFWDWLQJDQG
FRPPLWWRXVLQJ PHWKRGVRI DGHTXDWHDQGUHOLDEOHFRQWUDFHSWLRQWKURXJKRXWWKH
VWXG\ DQGIRUGD\VDIWHUWDNLQJWKHODVWGRVHRIWKHVWXG\GUXJ HJEDUULHUZLWK
DGGLWLRQDOVSHUPLFLGDOLQWUDXWHULQHGHYLFHKRUPRQDOFRQWUDFHSWLRQ0DOHSDWLHQWV
PXVWEHVXUJLFDOO\VWHULOHRUFRPPLWWRWKHXVHRIGLIIHUHQWPHWKRGVRIELUWKFRQWURO
GXULQJWKHVWXG\DQGIRUGD\VDIWHUWKHVWXG\
2.3
Exclusion Criteria
3DWLHQWV ZLOOEHH[FOXGHGIURPWKHVWXG\LIWKH\KDYHPHWDQ\RIWKHH[FOXVLRQFULWHULD
([FOXVLRQ&ULWHULD

8VDJHRIDFHWDPLQRSKHQDQG16$,'VGD\VPRQWKHUJRWDPLQHDQGWULSWDQV!
GD\VPRQWKRSLRLGVDQGEDUELWXUDWHV!GD\VPRQWKLQWKHPRQWKVSULRUWR9LVLW
RUGXULQJWKH%DVHOLQH3HULRG

7HQVLRQW\SHOLNHDQGRUPLJUDLQHOLNHKHDGDFKHRQGD\VSHUPRQWKLQWKHPRQWKV
SULRUWR9LVLWRUGXULQJWKH%DVHOLQH3HULRG'LDJQRVLVRIFKURQLFPLJUDLQHFOXVWHU
KHDGDFKHRUQHXURORJLFDOO\FRPSOLFDWHGPLJUDLQHKHPLSOHJLFEDVLODUUHWLQDO
RSKWKDOPRSOHJLFPLJUDLQH

5HJXODUXVHWKHIROORZLQJPHGLFDWLRQVIRUDQ\UHDVRQDFHWDPLQRSKHQQRQVWHURLGDO
DQWLLQIODPPDWRU\GUXJV16$,'VDQWLSV\FKRWLFGUXJVPRQRDPLQHR[LGDVHLQKLELWRUV
EHQ]RGLD]HSLQHVVOHHSPHGLFDWLRQVPXVFOHUHOD[DQWVDQWLHPHWLFPHGLFDWLRQVEORRG
WKLQQLQJPHGLFDWLRQVHJZDUIDULQRUKHSDULQFDQQDELQRLGVRUERWXOLQXPWR[LQWR
KHDGDQGQHFNUHJLRQV/RZGRVHDVSLULQIRUFDUGLRYDVFXODUGLVHDVHSURSK\OD[LVLV
SHUPLWWHG

&RQIRXQGLQJSDLQIXOFRQGLWLRQVHJILEURP\DOJLDFKURQLFORZEDFNSDLQFRPSOH[
UHJLRQDOSDLQV\QGURPHHWF

'LDJQRVLVRIDQ\FRQFXUUHQWPHGLFDORUSV\FKLDWULFFRQGLWLRQWKLVLQFOXGHVFKURQLF
XQVWDEOHGHELOLWDWLQJGLVHDVHVVXFKDV3DUNLQVRQ¶VGLVHDVHPXOWLSOHVFOHURVLVFDQFHU
VLJQLILFDQWUHQDOLPSDLUPHQWVLJQLILFDQWKHSDWLFLPSDLUPHQWHWF

7KHSDWLHQWKDVDKLVWRU\RUGLDJQRVLVRIPRGHUDWHWRVHYHUHKHSDWLFRUUHQDOLPSDLUPHQW
!îWKHXSSHUOLPLWRIQRUPDO>8/1@IRUDODQLQHWUDQVDPLQDVHRUDVSDUWDWH
WUDQVDPLQDVHî8/1IRUDONDOLQH3KRVSKDWDVHELOLUXELQ%81 RUFUHDWLQLQH
3DWLHQWVZLWKHOHYDWHGELOLUXELQOHYHOGXHWR*LOEHUW
VV\QGURPHDUHDOORZHG

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 

7KHSDWLHQWKDVDKLVWRU\ZLWKLQWKHSUHYLRXV\HDUVRIDEXVHRIDQ\GUXJSUHVFULSWLRQ
LOOLFLWRUDOFRKRO

7KH)HPDOHSDWLHQWLVSUHJQDQWRUEUHDVWIHHGLQJ7KH0DOHSDWLHQWLVQRWSUDFWLFLQJ
GLIIHUHQWPHWKRGVRIELUWKFRQWUROZLWKWKHLUSDUWQHUGXULQJWKHVWXG\DQGIRUGD\V
DIWHUWKHLQYHVWLJDWLRQDOGUXJODVWGRVHRUZLOOQRWUHPDLQDEVWLQHQWGXULQJWKHVWXG\DQG
IRUGD\VDIWHUWKHODVWGRVH

7KHSDWLHQWKDVNQRZQDOOHUJ\WRDQ\RIWKHFRPSRQHQWVRIWKHLQYHVWLJDWLRQDOGUXJ

3DUWLFLSDWLRQLQDQRWKHUVWXG\ZLWKDQLQYHVWLJDWLRQDOGUXJZLWKLQGD\VEHIRUH9LVLW
RUGXULQJWKHVWXG\

8VHRIHPHUJHQF\FDUHWUHDWPHQWPRUHWKDQWLPHVLQWKHSUHYLRXVPRQWKV

7KHSDWLHQWLVLQWKHRSLQLRQRIWKHLQYHVWLJDWRUXQVXLWDEOHWRSDUWLFLSDWHLQWKLVVWXG\IRU
DQ\RWKHUUHDVRQ
2.4
Study Design 
7KLVLVDZHHNVLQJOHFHQWHUGRXEOHEOLQGUDQGRPL]HGSODFHERFRQWUROOHGSDUDOOHODUP
VWXG\IRUSDWLHQWVUHTXLULQJPLJUDLQHSUHYHQWLRQ3DWLHQWVZLOOEHWUHDWHGIRUZHHNVZLWKRUDO
%,'FRPELQDWLRQRIQDOWUH[RQH
PJ$3$3
PJRUSODFHER7KHVWXG\FRQVLVWVRIWKUHH
VWXG\SHULRGVDGD\EDVHOLQHSHULRGDZHHNGRXEOHEOLQG7UHDWPHQW3HULRGDQGGD\
3RVW7UHDWPHQW)ROORZXS3HULRG
7KHGD\GXUDWLRQRIWKHEDVHOLQHSHULRGLVGHVLJQHGWRDVVHVVWKHEDVHOLQHIUHTXHQF\DQG
VHYHULW\RIPLJUDLQH7KHZHHNGXUDWLRQRIWKH7UHDWPHQW3HULRGLVGHVLJQHGWRPHHWWKH
UHTXLUHPHQWIRUDPLJUDLQHSUHYHQWLRQVWXGLHV$GD\3RVW7UHDWPHQW)ROORZXS3HULRGLV
GHVLJQHGWRDVVHVVDQ\VDIHW\LVVXHVZLWKWKHVWXG\GUXJ$GGLWLRQDOO\LWZLOODVVHVVZKHWKHU
WKHUHLVDFDUU\RYHUHIIHFWRIWKHVWXG\GUXJRQPLJUDLQHSUHYHQWLRQ
*LYHQWKHULVNIRUERWKQDOWUH[RQHDQGDFHWDPLQRSKHQWRFDXVHKHSDWRWR[LFLW\ODERUDWRU\
DVVHVVPHQWVKHPDWRORJ\KHSDWLFDQGUHQDOIXQFWLRQZLOOEHREWDLQHGSUHGRVH9LVLWDQG
PRQWKO\WKHUHDIWHULH9LVLW9LVLWDQG9LVLW
2Q'D\RIWKH7UHDWPHQW3HULRGWKHGD\RI9LVLWSDWLHQWVZLOOWDNHWKHILUVWGRVHRIWKH
VWXG\GUXJDWKRPHDWSP
3DWLHQWVZLOOFRPSOHWHWKH0LJUDLQH'LDU\DVVHVVPHQWVDSSUR[LPDWHO\DWSPRUDWEHGWLPH
HYHU\GD\ZKLFKHYHULVHDUOLHUHYHU\GD\RIWKHVWXG\
'XULQJHDFKYLVLWRIWKHVWXG\H[FHSW9LVLWSDWLHQWVZLOOFRPSOHWHWKH+HDGDFKH,PSDFW7HVW
+,73DWLHQWV ZLOOFRPSOHWH WKH3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56HYHU\VLWH
YLVLW3DWLHQWVZLOOFRPSOHWHWKH0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$62Q9LVLW
DQG
3DWLHQWVZLOODQGUHFHLYHVWXG\GUXJRQYLVLWDQG
Study Visit 1 - Screening Visit;GXULQJWKLVYLVLWSDWLHQWVZKRPHWLQFOXVLRQH[FOXVLRQFULWHULD
ZLOOJLYHDQ LQIRUPHG FRQVHQWDIWHUWKHQDWXUHRIWKHVWXG\LV H[SODLQHGDQGEHIRUHDQ\VWXG\
VSHFLILFSURFHGXUHVDUH SHUIRUPHG
'XULQJWKHVFUHHQLQJYLVLWWKHLQYHVWLJDWRUZLOOREWDLQPHGLFDOKLVWRU\PLJUDLQHKHDGDFKH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
KLVWRU\KLVWRU\RIVXEVWDQFHDEXVHDQGRUGHSHQGHQF\DQGPHGLFDWLRQKLVWRU\,QDGGLWLRQWKH
LQYHVWLJDWRUZLOOSHUIRUPDFRPSOHWHSK\VLFDOH[DPLQDWLRQYLWDOVLJQVPHDVXUHPHQWVDOHDG
(&*DXULQHGUXJVFUHHQDQGDXULQHSUHJQDQF\WHVWIRUFKLOGEHDULQJDJHIHPDOHV
$GGLWLRQDOO\WKHLQYHVWLJDWRUZLOOGUDZEORRGVDPSOHIRUODERUDWRU\DVVHVVPHQWVKHPDWRORJ\
KHSDWLFDQGUHQDOIXQFWLRQ
7KHSDQHOXULQHGUXJVFUHHQFRFDLQH PDULMXDQDRSLDWHVPHWKDPSKHWDPLQHVDQG2[\FRGRQH
DQGWKHSUHJQDQF\WHVWPXVWEHQHJDWLYHWRFRQWLQXHZLWKWKHVFUHHQLQJYLVLWSURFHGXUHV
$WWKHVFUHHQLQJYLVLWWKH0,'$6VFRUHPXVWEHKLJKHUWKDQPRGHUDWHRUVHYHUHGLVDELOLW\
DQGWKH+,7VFRUHPXVWEHKLJKHUWKDQVXEVWDQWLDORUYHU\VHYHUHLPSDFW
'XULQJWKH6FUHHQLQJ9LVLWWKHLQYHVWLJDWRUZLOOJRRYHUWKHIROORZLQJLWHPV
x
+RZWRUDWHWKHLQWHQVLW\RIKHDGDFKHSDLQQDXVHDDQGVDWLVIDFWLRQZLWKPLJUDLQH
SUHYHQWLRQRQDSRLQWVFDOH
x
+RZWRUDWHOLJKWVHQVLWLYLW\QRLVHVHQVLWLYLW\QHFNVKRXOGHUSDLQDQGYRPLWLQJDV
DEVHQWRUSUHVHQW
x
+RZWRGLVWLQJXLVKPLJUDLQHKHDGDFKHIURPQRQPLJUDLQH KHDGDFKH
x
+RZWRWDNHUHVFXHPHGLFDWLRQVZDLWòKRXUDIWHUDPLJUDLQHVWDUWHGEHIRUH WDNLQJ
WKHLURZQXVXDOPLJUDLQHPHGLFDWLRQV
x
+RZDQGZKHQWRFRPSOHWHWKH0LJUDLQH'LDU\DVVHVVPHQWV
x
+RZWRUHFRUGUHVFXHPHGLFDWLRQV
x
$ERXWWKH ³SODFHERHIIHFW´
7KHLQYHVWLJDWRUZLOOHQUROORQO\SDWLHQWVLQWRWKHEDVHOLQHSHULRGLIWKH\GHPRQVWUDWHDELOLW\WR
FRPSOHWHWKH0LJUDLQH'LDU\
$WWKHFRQFOXVLRQRIWKH6FUHHQLQJ9LVLWSDWLHQWVZLOOUHFHLYHDSDSHUPLJUDLQHGLDU\WREH
FRPSOHWHGGDLO\IRUDGD\EDVHOLQHSHULRG
3DWLHQWVZLOOKDYHDSKRQHFRQWDFWRQGD\DQGGD\RIWKHEDVHOLQHSHULRG$IWHUFRPSOHWLRQ
RIWKHGD\EDVHOLQHSHULRGSDWLHQWVZLOOUHWXUQIRUWKH5DQGRPL]DWLRQ9LVLW
Study Visit 2 - Randomization Visit: ,QWKLVYLVLWWKHLQYHVWLJDWRUZLOOUHYLHZWKHEDVHOLQH
SHULRG0LJUDLQH'LDU\3DWLHQWVZKRKDGDWOHDVWPRGHUDWHWRVHYHUHPLJUDLQHHSLVRGHVEXW
RUOHVV KHDGDFKHGD\VGXULQJWKHGD\ EDVHOLQHSHULRGDQGFRQWLQXHGWRPHHWDOORWKHULQFOXVLRQ
DQGH[FOXVLRQFULWHULDZLOOEH HOLJLEOHIRUUDQGRPL]DWLRQ3DWLHQWPXVWFRPSOHWHWKHDVVHVVPHQWV
IRUDOOWKHGD\VRIWKHEDVHOLQHSHULRGWRTXDOLI\IRUUDQGRPL]DWLRQ
,QDGGLWLRQDWWKH5DQGRPL]DWLRQ9LVLWWKH0,'$6VFRUHPXVWEHKLJKHUWKDQPRGHUDWHRU
VHYHUHGLVDELOLW\DQGWKH+,7VFRUHPXVWEHKLJKHUWKDQVXEVWDQWLDORUYHU\VHYHUH
LPSDFW
'XULQJWKH5DQGRPL]DWLRQ9LVLWWKHLQYHVWLJDWRUZLOOJRRYHUWKHIROORZLQJLWHPV
+RZWRWDNHWKHVWXG\GUXJ
+RZWRWDNHUHVFXHPHGLFDWLRQVZDLWòKRXUDIWHUDPLJUDLQHVWDUWHGEHIRUHWDNLQJRZQXVXDO
PLJUDLQHPHGLFDWLRQV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
+RZWRUHFRUGUHVFXHPHGLFDWLRQV
3DWLHQWVZLOOEHUDQGRPL]HG LQ DUDWLRWRQDOWUH[RQH
PJDFHWDPLQRSKHQ
PJ
$//2'RUSODFHERDQGHQWHULQWRWKHZHHN7UHDWPHQW3HULRG
5DQGRPL]HGSDWLHQWVZLOOUHFHLYHDSDSHU0LJUDLQH'LDU\ IRUPDQGDEOLQGHGVWXG\GUXJWRXVHLQ
WKHRXWSDWLHQWVHWWLQJV
Study Visit 3 – 1 week after the Treatment Period started: GXULQJWKLVYLVLWWKHLQYHVWLJDWRU
ZLOOFRQILUPWKHSDWLHQWXQGHUVWDQGLQJRIKRZWRWDNHWKHVWXG\GUXJDQGKRZWRFRPSOHWHWKH
GDLO\0LJUDLQHGLDU\'XULQJWKLVYLVLWDVVHVVPHQWRIDGYHUVHHYHQWVDQGDGMXVWPHQWWRWKHVWXG\
GUXJGRVHFDQEHPDGH
Study Visits 4 and 5: WKHVHYLVLWV ZLOORFFXURQGD\VDQGGD\YLVLWZLQGRZRIWKH
7UHDWPHQW3HULRG$GGLWLRQDOO\WKHUHZLOOEHWHOHSKRQHFRQWDFWVWZRZHHNVDIWHUWKHVHYLVLWV
GD\YLVLWZLQGRZ
Study Visit 6 - End-of-Treatment Period Visit: 7KLVYLVLWZLOOWDNHSODFHQRVRRQHUWKDQGD\
GD\VIURPWKHEHJLQQLQJRIWKH7UHDWPHQW3HULRG'XULQJWKLVYLVLWSDWLHQWVILQDOFRXQWDQG
UHFRQFLOLDWLRQRIWKHVWXG\GUXJ
Study Visit 7 - End-of-Study Visit:7KLVYLVLWZLOOWDNHSODFHRQGD\GD\YLVLWZLQGRZ
RIWKH)ROORZXS3HULRG'XULQJWKH)ROORZXS3HULRGSDWLHQWVZLOOFRQWLQXHWRFRPSOHWHWKH
GDLO\GLDU\EXWWKH\ZLOOQRWFRQVXPHWKHVWXG\GUXJ
Figure 5: Study Design Illustration

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
2.5
Migraine Diary and  Other Study Assessments
x
6WXG\GUXJPRUQLQJGRVHFRQVXPSWLRQ
x
6WXG\GUXJHYHQLQJGRVHFRQVXPSWLRQ
x
3UHVHQFHRIDKHDGDFKH\HVQR
x
6WDUWWLPHDQGWKHHQGWLPHRIWKHKHDGDFKH
x
,QWDNHRIDGGLWLRQDOPLJUDLQHPHGLFDWLRQV
x
6HYHULW\ RIWKHKHDGDFKHSDLQ QRQH PLOG PRGHUDWH VHYHUH
x
6HYHULW\ RIWKHQDXVHDYRPLWLQJ QRQH PLOG PRGHUDWH VHYHUH
x
3UHVHQFH2QHVLGHGKHDGDFKH\HVQR
x
3XOVDWLQJ TXDOLW\\HVQR
x
:RUVHQLQJ ZLWKDFWLYLW\\HVQR
x
/LJKWVHQVLWLYLW\\HVQR
x
1RLVHVHQVLWLYLW\\HVQR
x
1HFNSDLQ\HVQR
Other assessments: 
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH 0,'$6PRQWKDVVHVVPHQW9LVLWV
DQG
x
+HDGDFKH,PSDFW7HVW+,7ZHHNDVVHVVPHQWHYHU\YLVLWH[FHSW9LVLW
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56GD\DVVHVVPHQWHYHU\YLVLW
x
3DWLHQW*OREDO,PSUHVVLRQRI&KDQJH3*,&
2.6
Patient satisfaction with migraine prevention, Visits 3 - Visit 7, (0=not at all satisfied, 
1=partly satisfied, 2=satisfied, 3=very satisfied).Study Duration
7KHVWXG\FRQVLVWVRIVHYHQYLVLWVDQGILYHWHOHSKRQHFRQWDFWVRFFXUULQJRYHUDPRQWKSHULRG
Study visits schedule: 
9LVLW
6FUHHQLQJ
9LVLW
9LVLW
UDQGRPL]DWLRQ
9LVLW
9LVLW
7UHDWPHQW
3HULRG 9LVLW
9LVLW
7UHDWPHQW
3HULRG 9LVLW
9LVLW
7UHDWPHQW
3HULRG 9LVLW
9LVLW(QG
RI
7UHDWPHQW
3HULRG 9LVLW
9LVLW3RVW
7UHDWPHQW3HULRG
9LVLW
6WXG\'D\







$OOYLVLWVPD\KDYHGD\YLVLWZLQGRZH[FHSWYLVLWZKLFKPXVWWDNHSODFHQRVRRQHUWKDQ GD\V IURPWKHEHJLQQLQJRIWKHGRXEOH
EOLQG7UHDWPHQW3HULRG'D\RIWKH7UHDWPHQW3HULRG LVFRQVLGHUHGWKHODVWGD\RIWUHDWPHQWIRUGDWDDQDO\VLVSXUSRVHV
Phone contacts Schedule: 
3KRQHFRQWDFW
3KRQH%DVHOLQH
3HULRG
3KRQH
7UHDWPHQW3HULRG
3KRQH
7UHDWPHQW3HULRG
3KRQH
7UHDWPHQW3HULRG
3KRQH3RVW
7UHDWPHQW3HULRG
6WXG\'D\





$OO3KRQH9LVLWVPD\KDYHGD\ YLVLWZLQGRZ
2.7
Study Population
7KHVWXG\SRSXODWLRQZLOOLQFOXGHQRQSUHJQDQWQRQODFWDWLQJIHPDOHVDQGPDOHV%RWKPXVWEH
\HDUVRIDJHRUROGHU
3DWLHQWVKDYHDQDYHUDJHRIDWOHDVWPRGHUDWHWRVHYHUHPLJUDLQHHSLVRGHVEXWRUOHVV
KHDGDFKHGD\VSHUPRQWKLQWKHSUHYLRXVPRQWKVDQGGXULQJWKHEDVHOLQHSHULRG
3DWLHQWVKDYHKLVWRU\RIPLJUDLQHZLWKRUZLWKRXWDXUDDFFRUGLQJWRWKH,QWHUQDWLRQDO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
&ODVVLILFDWLRQRI+HDGDFKH'LVRUGHUV,&+'UGHGLWLRQEHWDYHUVLRQIRUDWOHDVWRQH\HDUZLWK
RQVHWRIPLJUDLQHSULRUWRDJH\HDUVRIDJH
3DWLHQWVZLWKFRH[LVWLQJW\SHVRIKHDGDFKHSDLQVHJWHQVLRQW\SHKHDGDFKHFDQEHLQFOXGHGLI
WKH\FDQGLVWLQJXLVKPLJUDLQHKHDGDFKHIURPWKHRWKHUKHDGDFKHV
3DWLHQWVPXVWKDYHKLJKIUHTXHQF\PRGHUDWHWRVHYHUHPLJUDLQHDVVRFLDWHGQDXVHDLH
DVVRFLDWHGQDXVHDKDOIWKHPLJUDLQHDWWDFNVWREHDGPLWWHGLQWRWKHVWXG\3DWLHQWVZKR
H[SHULHQFHYRPLWLQJFDQEHDGPLWWHGKRZHYHUWKH\ZLOOEHDGYLVHGWKDWYRPLWLQJZLWKLQPLQ
DIWHUWDNLQJWKHVWXG\GUXJFDQSXUJHWKHVWXG\GUXJ3DWLHQWVZLOOEHDVNHGWRWDNHWKHVWXG\GUXJ
ZKHQWKH\FDQDVVXPHWKDWWKH\ZLOOQRWYRPLWZLWKLQPLQV
3DWLHQWVZKRLQWKHRSLQLRQRIWKHLQYHVWLJDWRUPD\KDYHPHGLFDWLRQRYHUXVHKHDGDFKHVDV
GHILQHGE\,&+'±EHWDYHUVLRQFULWHULDIRUPHGLFDWLRQRYHUXVHKHDGDFKH7KHGHILQLWLRQRI
PHGLFDWLRQRYHUXVHIRUWKLVVWXG\LVXVDJHRIGD\VPRQWKRIDFHWDPLQRSKHQ16$,'VRU
XVDJHRIHUJRWDPLQHDQGWULSWDQVGD\VPRQWKRUXVDJHRIRSLRLGVDQG EDUELWXUDWHV!
GD\VPRQWKGXULQJWKHPRQWKVSUHFHGLQJVFUHHQLQJRUGXULQJWKHEDVHOLQHSHULRG
3DWLHQWVZKRLQWKHRSLQLRQRIWKHLQYHVWLJDWRUKDYHFKURQLFPLJUDLQHDVGHILQHGE\,&+'±
EHWDYHUVLRQFULWHULDIRUFKURQLFPLJUDLQHKHDGDFKHWHQVLRQW\SHOLNHDQGRUPLJUDLQHOLNHRQ
GD\VSHUPRQWKGXULQJWKHPRQWKVSUHFHGLQJVFUHHQLQJRUGXULQJWKHEDVHOLQHSHULRGZLOO
EHH[FOXGHG
,QDGGLWLRQSDWLHQWVXVLQJDQ\GLVDOORZHGFRQFRPLWDQWPHGLFDWLRQVRUSDWLHQWVZKRXVHGDQ
LQYHVWLJDWLRQDOPHGLFDWLRQZLWKLQZHHNVEHIRUHWKH6FUHHQLQJ9LVLW ZLOOQRWTXDOLI\
&DUHVKRXOGEHWDNHQWRH[FOXGHRWKHUSRWHQWLDOO\VHULRXVQHXURORJLFFRQGLWLRQVEHIRUHHQUROOLQJ
SDWLHQWVQRWSUHYLRXVO\GLDJQRVHGZLWKPLJUDLQHKHDGDFKHRUZKRH[SHULHQFHKHDGDFKHWKDWLV
DW\SLFDOIRUWKHP
2.8
Exclusions Due to Coexisting Conditions 
3DWLHQWVZKRWHVWHGSRVLWLYHIRUDFRFDLQHPDULMXDQDRSLDWHVPHWKDPSKHWDPLQHVRUR[\FRGRQH
LQWKHILYHSDQHOXULQHGUXJWHVWDW6FUHHQLQJ9LVLW ZLOOQRWTXDOLI\GXHWRSRVVLEOHSUHFLSLWDWLRQ
RIGUXJZLWKGUDZDOV\PSWRPVZKHQFRPELQHGZLWKQDOWUH[RQH
3DWLHQWWDNLQJZDUIDULQZLOOQRWTXDOLI\$QLQWHUDFWLRQEHWZHHQZDUIDULQDQGDFHWDPLQRSKHQ
PD\UHVXOWLQVLJQLILFDQWHOHYDWLRQVRILQWHUQDWLRQDOQRUPDOL]HGUDWLR,15SXWWLQJSDWLHQWVDW
LQFUHDVHGULVNIRUKHPRUUKDJLFFRPSOLFDWLRQV
3DWLHQWVGLDJQRVHGZLWK3DUNLQVRQ¶VGLVHDVHRUGHPHQWLDIRUZKLFKWUHDWPHQWZLWKVSHFLILF
PHGLFDWLRQVLVUHTXLUHGZLOOEHH[FOXGHGIURPWKHVWXG\
3DWLHQWVZKRKDYHDQ\FOLQLFDOO\VLJQLILFDQWDEQRUPDOLW\LQWKHOHDG(&*KDYHXQFRQWUROOHG
KHDUWIDLOXUHP\RFDUGLDOLQIUDFWLRQRUDVWURNHZLWKLQWKHODVWPRQWKVRUV\PSWRPDWLFZLWK
DQJLQDSDOSLWDWLRQVG\VSQHDDUUK\WKPLDZLOOEHH[FOXGHGGXHWRULVNWRWKHLUKHDOWK3DWLHQWV
 *UHJRU\-+XJKHVHWDO(IIHFWRI$FHWDPLQRSKHQRQ,QWHUQDWLRQDO1RUPDOL]HG5DWLRLQ3DWLHQWV5HFHLYLQJ
:DUIDULQ7KHUDS\3KDUPDFRORJ\DQG'UXJ 7KHUDS\ 9ROXPH,VVXHSDJHV±-XQH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
ZKRKDYHVLJQLILFDQWXQFRQWUROOHGQHXURORJLFDOSV\FKLDWULFKHSDWLFUHQDOHQGRFULQHFDUGLR
YDVFXODUJDVWURLQWHVWLQDOSXOPRQDU\KHPDWRORJLFRUPHWDEROLFGLVHDVHDUHQRWFDQGLGDWHVIRU
H[SHULPHQWDOFOLQLFDOVWXGLHVGXHWRWKHULVNWRWKHLUKHDOWK
3DWLHQWVZKRKDYHEHHQGLDJQRVHGZLWKVHYHUHSV\FKRWLFRUELSRODUGLVRUGHUVZLOOQRWTXDOLI\GXH
WRLQDELOLW\WRSHUVRQDOO\SURYLGHDQ,QIRUPHG&RQVHQWDQGWKHOLNHO\KLQGUDQFHWRWKHSDWLHQW¶V
DELOLW\WR DGKHUHWRWKHVWXG\SURWRFRO
2.9
Substance Abuse and Alcohol Use Restrictions
'XHWRWKHQDOWUH[RQHFRPSRQHQWRIWKHLQYHVWLJDWLRQDOGUXJDQRSLRLGDQWDJRQLVWSDWLHQWVZLWK
VXEVWDQFHDEXVHPD\EHYXOQHUDEOHWRRSLRLGRYHUGRVHDQGRUDQDOWUH[RQHSUHFLSLWDWHGRSLRLG
ZLWKGUDZDO 3DWLHQWVZLWKDSDVWRUSUHVHQWKLVWRU\RIVXEVWDQFHDEXVHDQGRUDKLVWRU\RI
DGPLVVLRQWRDGUXJUHKDELOLWDWLRQIDFLOLW\ZLOOEHH[FOXGHGIURPWKHVWXG\
3DWLHQWV PXVWDJUHHWR UHIUDLQIURPH[FHVVLYHDOFRKROFRQVXPSWLRQGXULQJWKHVWXG\7KH
DOORZDEOHOLPLWLVIRXUGULQNVSHUZHHN3DWLHQWVZLWKDKLVWRU\RIVLJQLILFDQWDOFRKRO
FRQVXPSWLRQUHTXLUHVL[PRQWKVRIVREULHW\DQGDGKHUHQFHWROHVVWKDQIRXUGULQNVSHUZHHN$
VWDQGDUGGULQNLVHTXDOWRJUDPVRXQFHVRISXUHDOFRKRO*HQHUDOO\WKLVDPRXQWRI
SXUHDOFRKROLVIRXQGLQRXQFHVRIEHHUDOFRKROFRQWHQWRXQFHVRIPDOWOLTXRU
DOFRKROFRQWHQWRXQFHVRIZLQHDOFRKROFRQWHQWDQGRXQFHVRUD³VKRW´RISURRI
DOFRKROFRQWHQWGLVWLOOHGVSLULWVRUOLTXRUHJJLQUXPYRGNDZKLVNH\
2.10
Concomitant Medications Restrictions
3DWLHQWVUHFHLYLQJFKURQLFRSLRLGVFDQQRWWDNHWKHVWXG\GUXJVLQFHQDOWUH[RQHPD\SUHFLSLWDWH
RSLRLGZLWKGUDZDOV\PSWRPV3DWLHQWVPXVWKDYHDQHJDWLYHXULQHGUXJVFUHHQGXULQJWKH
6FUHHQLQJ9LVLWDQGGXULQJWKH5DQGRPL]DWLRQ9LVLW3DWLHQWVFDQQRWWDNHDQ\RSLRLG
PHGLFDWLRQVIURPWKHGD\VEHIRUHWKH6FUHHQLQJ9LVLWWRGD\VDIWHUWDNLQJWKHODVWGRVHRIWKH
VWXG\GUXJ
3DWLHQWVZLOOEHHOLJLEOHLIWKH\KDYHEHHQWDNLQJDVWDEOHGRVHRIDPHGLFDWLRQZLWKPLJUDLQH
SUHYHQWLRQSRWHQWLDOIRUDWOHDVWPRQWKSULRUWRWKHVFUHHQLQJYLVLWDQGDJUHHWRQRWVWDUWVWRSRU
FKDQJHGRVDJHRIDQ\PHGLFDWLRQZLWKPLJUDLQHSUHYHQWLRQSRWHQWLDOGXULQJWKHVWXG\SHULRG
(JEHWDEORFNHUVFDOFLXPFKDQQHOEORFNHUVWULF\FOLFDQWLGHSUHVVDQWVDQWLFRQYXOVDQWV
VHOHFWLYHVHURWRQLQUHXSWDNHLQKLELWRUV665,VVHURWRQLQQRUHSLQHSKULQHUHXSWDNHLQKLELWRUV
615,VPDJQHVLXPRUULERIODYLQVXSSOHPHQWVDWKLJKGRVHVKHUEDOSUHSDUDWLRQVHJIHYHUIHZ
RU6WMRKQ¶VZRUW%RWXOLQXPWR[LQPXVWEHGLVFRQWLQXHGRQH\HDUSULRUWR9LVLW
Figure 6: Concomitant Medications Restrictions
0HGLFDWLRQFODVV0RVW&RPPRQO\8VHG([DPSOHV
5HVWULFWLRQ
2SLDWHVLQFOXGLQJWUDPDGRO
1RWSHUPLWWHGIURPGD\VEHIRUHVFUHHQLQJYLVLW WR
GD\VDIWHUWDNLQJWKHVWXG\GUXJ
2SLDWH$QWDJRQLVW
1RWSHUPLWWHG
$FHWDPLQRSKHQ
7KHDFHWDPLQRSKHQGRVHFRQWDLQHGLQWKHVWXG\GUXJ
LVPJSHUGD\7KHPD[LPDOGRVHRI
DFHWDPLQRSKHQIURPWKHVWXG\GUXJDQGDQ\RWKHU
DFHWDPLQRSKHQFRQWDLQLQJSURGXFWPXVWQRWH[FHHG
PJSHUGD\

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7ULSWDQVHUJRWDPLQHSUHSDUDWLRQV
/HVVWKDQGD\VPRQWK
1RQVWHURLGDODQWLLQIODPPDWRU\GUXJV16$,'
F\FORR[\JHQDVHW\SH&2;,QKLELWRUV
(TXDORUOHVVWKDQ GD\VPRQWK
%DUELWXUDWHSUHSDUDWLRQV RSLDWHV
/HVVWKDQ GD\VPRQWK
$QJLRWHQVLQLQKLELWRUV
3HUPLWWHG
$QWLFRQYXOVDQWV WULF\FOLFDQWLGHSUHVVDQWVFDOFLXP
FKDQQHOEORFNHUV%HWDEORFNHUV6HOHFWLYHVHURWRQLQUH
XSWDNHLQKLELWRUV665,VVHOHFWLYHVHURWRQLQ
QRUHSLQHSKULQHUHXSWDNHLQKLELWRUV615,V
'RVHPXVWEHVWDEOHIRUPRQWKV SULRUWR 9LVLW DQG
UHPDLQWKHVDPHGXULQJWKHVWXG\
$VSLULQPJGD\
3HUPLWWHGIRU&9'SURSK\OD[LV
%HQ]RGLD]HSLQHVPXVFOHUHOD[DQWVVOHHSLQJSLOOVDQWL
HPHWLFV
1RWSHUPLWWHG
$QWLSV\FKRWLFVPRRGVWDELOL]HUV0$2%LQKLELWRUV
1RWSHUPLWWHG
&DQQDELQRLGV
1RWSHUPLWWHG
'RSDPLQHDJRQLVWV
1RWSHUPLWWHG
EORRGWKLQQLQJPHGLFDWLRQHJZDUIDULQRUKHSDULQ
1RWSHUPLWWHG
%RWR[2QDERWXOLQXPWR[LQ$,QMHFWLRQ
1RQHLQ\HDU SULRUWRVFUHHQLQJ
2.11
Rescue Medications 
3DWLHQWVFDQXVHWKHLURZQXVXDOPLJUDLQHPHGLFDWLRQGXULQJWKHVWXG\IRUXQWUHDWHGRUSDUWLDOO\
WUHDWHGPLJUDLQHLQFOXGLQJGXULQJWKHEDVHOLQHSHULRGDQGWKH3RVW7UHDWPHQW)ROORZXS3HULRG
3DWLHQWVZLOOZDLWòKRXUDIWHUDPLJUDLQHVWDUWHGWRWDNHDUHVFXHPHGLFDWLRQV3DWLHQWVZLOO
UHFRUGHYHU\UHVFXHPHGLFDWLRQLQWKHPLJUDLQHGLDU\
3HUPLWWHGUHVFXHPHGLFDWLRQVLQFOXGHDVSLULQDFHWDPLQRSKHQ16$,'VHUJRWGHULYDWLYHVDQG
WULSWDQV
2SLRLGVDUHQRWSHUPLWWHG7KHDFHWDPLQRSKHQGRVHFRQWDLQHGLQWKHVWXG\GUXJLVPJSHU
GD\7KHPD[LPDOGRVHRIDFHWDPLQRSKHQIURPWKHVWXG\GUXJDQGDQ\RWKHUDFHWDPLQRSKHQ
FRQWDLQLQJSURGXFWPXVWQRWH[FHHGPJSHUGD\
2.12
Instructions for Taking the Study Drug and for completing the Migraine Diary
7KHVWXG\GUXJLVSURYLGHGLQWZRYLDOV'XULQJWKH7UHDWPHQW3HULRGSDWLHQWVZLOOWDNHone 
capsule from each vial twice a dayDSSUR[LPDWHO\DPDQGSP3DWLHQWVZLOOWDNH
WKHVWXG\GUXJZLWKVXIILFLHQWDPRXQWRIZDWHU7KH\PD\WDNHWKHVWXG\GUXJZLWKIRRGWR
GHFUHDVHVWRPDFKXSVHW7KHVWXG\GUXJPD\FDXVHGURZVLQHVVSDWLHQWVVKRXOGDYRLGGULYLQJ
XQWLOWKH\NQRZKRZWKHVWXG\GUXJDIIHFWVWKHP,IGHHPHGQHFHVVDU\GXHWRLQWROHUDQFHWKH
LQYHVWLJDWRUZLOOGHFUHDVHWKHGRVDJHWRRQHGRVHDGD\WKHSPGRVHIRUWKHGXUDWLRQRI
WKH7UHDWPHQW3HULRG
2Q'D\RIWKH7UHDWPHQW3HULRGWKHGD\RI9LVLW SDWLHQWVZLOOWDNHWKHILUVWGRVHRIWKH
VWXG\GUXJDWKRPHDWSP
3DWLHQWVZLOOFRPSOHWHWKH0LJUDLQH'LDU\DVVHVVPHQWVDSSUR[LPDWHO\DWSPRUDWEHGWLPH
HYHU\GD\ZKLFKHYHULVHDUOLHU
2.13
Randomization Scheme and Treatment Groups 
3DWLHQWV ZLOOEHUDQGRPL]HGWRRQHRIWZR WUHDWPHQW JURXSV
 1DOWUH[RQH
PJDFHWDPLQRSKHQ
PJ$//2'

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
 3ODFHER
7KHSODFHERJURXSZLOOSURYLGHGDWDWRVXSSRUWHIILFDF\RIWKHSURGXFW
7KHVWXG\SODQVWRHQUROOSDWLHQWVUDQGRPL]HGLQWRWZR WUHDWPHQWJURXSVLQDUDWLRRIZLWK
SDWLHQWVLQHDFKJURXS,QYHVWLJDWRUVVLWHSHUVRQQHODQGSDWLHQWVZLOOEHPDVNHGWRWKH
WUHDWPHQWDVVLJQPHQW
3
STUDY CONDUCT  
3.1
Identification and Recruitment of Study Patients
7KH&OLQLFDO,QYHVWLJDWRU ZLOOGHVLJQDUHFUXLWPHQWSURFHVVWKDWLV OLNHO\WROHDGWRLGHQWLILFDWLRQ
RISRWHQWLDOVWXG\FDQGLGDWHVWKDWPHHWWKHSURWRFROFULWHULD +HVKH ZLOOHQVXUHWKDWWKH
UHFUXLWPHQWSURFHVVLQFOXGHVVDIHJXDUGVIRUWKHSURWHFWLRQRIYXOQHUDEOHSRSXODWLRQV
7KHVFUHHQLQJ RILQWHUHVWHGYROXQWHHUVFDQEHFRQGXFWHGYLDSKRQHDQGHPDLODQGLQFOXGH
DVVHVVPHQWRIPLJUDLQHKLVWRU\JHQHUDOSK\VLFDODQGPHQWDOKHDOWKGUXJDQGPHGLFDWLRQXVH
$IWHU LQLWLDOVFUHHQLQJSDWLHQWVZLOOEHLQYLWHGWRSDUWLFLSDWHLQWKHSURFHGXUHVXQGHUOLQHGLQWKH
VWXG\SURWRFRO
3.2
Screened Patients’ Log Record Keeping
7KHVLWHZLOOPDLQWDLQDORJRIDOOWKHVFUHHQHGSDWLHQWV6FUHHQHGSDWLHQWV DUHSDWLHQWVZKR
VLJQHGWKH,QIRUPHG&RQVHQWLQFRPSOLDQFHZLWK,&+*&3DOOVFUHHQHGSDWLHQWVPXVWEH
GRFXPHQWHG7KHVFUHHQHGSDWLHQWV ORJZLOOLQFOXGHWKHSDWLHQWVIXOOQDPHVH[GDWHRIELUWK
JHQGHUZKHWKHULQFOXVLRQH[FOXVLRQFULWHULDZHUHPHWDQGLIQRWDOLVWRIHDFKIDLOHG
,QFOXVLRQ([FOXVLRQFULWHULRQDQGGDWHRI,QIRUPHG&RQVHQW7KHVFUHHQHGSDWLHQW OLVWZLOOEH
XSGDWHGWRLQFOXGHWKHLGHQWLILFDWLRQ,' IRUSDWLHQWVZKRZHUHUDQGRPL]HG
(YHU\SURVSHFWLYHSDWLHQW ZLOOFRPSOHWHDFRQWDFWLQIRUPDWLRQIRUPZKLFKZLOOLQFOXGHFRQWDFW
LQIRUPDWLRQDQGKRZSDWLHQWVOHDUQHGDERXWWKHVWXG\7KHFRQWDFWLQIRUPDWLRQZLOOEH
DXWKHQWLFDWHGZLWKDSKRWR,'$FRS\RIGULYHU¶VOLFHQVHRURWKHUYDOLGIRUPRISKRWR,' ZLOO
EHREWDLQHGIRUHDFKSDWLHQW VFUHHQHGSDWLHQWV
6FUHHQIDLOXUH LVGHILQHGDVDSDWLHQW ZKR KDVJLYHQ,QIRUPHG&RQVHQWDQGIDLOHGWRPHHWDWOHDVW
RQHRIWKHH[FOXVLRQFULWHULDDQGRUKDVQRWEHHQUDQGRPL]HGRUDGPLQLVWHUHGWKHLQYHVWLJDWLRQDO
GUXJDVGHILQHGE\WKHSURWRFRO
3.3
HIPAA Compliance with regards to previous medical records
7KH&OLQLFDO,QYHVWLJDWRU ZLOOREWDLQ WKHSDWLHQW¶VPLJUDLQHTXDOLI\LQJGRFXPHQWDWLRQUHTXLUHGE\
WKHVWXG\SURWRFRODIWHUHQVXULQJDOODXWKRUL]DWLRQVIRUUHOHDVHRIPHGLFDOUHFRUGVZHUHREWDLQHG
7KH &OLQLFDO,QYHVWLJDWRU ZLOODQRQ\PL]HWKHPHGLFDO UHFRUGVLQDFFRUGDQFHZLWK+,3$$
UHJXODWLRQV&)53DUWVDQGSULRUWRVXEPLVVLRQWRWKHVSRQVRU7KHIROORZLQJ
SHUVRQDOLGHQWLILDEOHLQIRUPDWLRQPXVWEHUHGDFWHGSULRUWRVXEPLVVLRQWRWKHVSRQVRUIXOOQDPH
LQFOXGLQJQDPHGHULYHG LQLWLDOVKRPHDGGUHVVELUWKGDWH H[FHSWELUWK\HDUHPDLODGGUHVV
VRFLDOVHFXULW\QXPEHUPHGLFDOUHFRUGVQXPEHUVKHDOWKSODQEHQHILFLDU\QXPEHUVDFFRXQW
QXPEHUVYHKLFXODU OLFHQVHQXPEHUFUHGLWFDUGQXPEHUVWHOHSKRQHQXPEHUDQGDQ\RWKHUXQLTXH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
LGHQWLI\LQJQXPEHUFKDUDFWHULVWLF RUFRGH7KHUHFRUGVDUHSHUPLWWHGWRLQFOXGHRQO\WKH
SURVSHFWLYHSDWLHQW¶V ,'\HDU RIELUWK DQGJHQGHU
3.4
Protocol Deviation/Violations 
$SURWRFROGHYLDWLRQYLRODWLRQLVJHQHUDOO\DQXQSODQQHGH[FXUVLRQIURPWKHSURWRFROWKDWLVQRW
LPSOHPHQWHGRULQWHQGHGDVDV\VWHPDWLFFKDQJH
$SURWRFROPLQRUGHYLDWLRQYLRODWLRQRFFXUVZKHQZLWKRXWVLJQLILFDQWFRQVHTXHQFHVWKH
DFWLYLWLHVRQDVWXG\GLYHUJHIURPWKH,QVWLWXWLRQDO5HYLHZ%RDUGDSSURYHGSURWRFRO
([DPSOHVRISURWRFROYLRODWLRQVLQFOXGHEXWDUHQRWOLPLWHGWRWKHIROORZLQJ
x
3DUWLFLSDQWGRHVQRWVKRZXSIRUVFKHGXOHGUHVHDUFKYLVLW
x
)DLOXUHRISDUWLFLSDQWWRUHWXUQLQYHVWLJDWLRQDOGUXJV
x
0LVVLQJRULJLQDOVLJQHGDQGGDWHGFRQVHQWIRUPRQO\DSKRWRFRS\LVDYDLODEOH
x
$IDLOXUHWRIROORZWKHDSSURYHGVWXG\SURFHGXUHWKDWLQWKHRSLQLRQRIWKH3,GRHV
QRWDIIHFWSDWLHQW VDIHW\RUGDWDLQWHJULW\
$SURWRFROPDMRUGHYLDWLRQYLRODWLRQ LVGHILQHGDVDGHYLDWLRQIURPWKH,5%DSSURYHGSURWRFRO
WKDWPD\DIIHFWWKHSDWLHQW¶V ULJKWVVDIHW\ RUZHOOEHLQJDQGRUWKHFRPSOHWHQHVVDFFXUDF\DQG
UHOLDELOLW\RIWKHVWXG\GDWD([DPSOHVRISURWRFROYLRODWLRQVLQFOXGHEXWDUHQRWOLPLWHGWRWKH
IROORZLQJ
x
$UHVHDUFKSDWLHQW UHFHLYHGWKHZURQJWUHDWPHQWRULQFRUUHFWGRVH
x
3HUIRUPDQFHRIDVWXG\SURFHGXUHQRWDSSURYHGE\WKH,5%
x
$UHVHDUFKSDWLHQW PHWZLWKGUDZDOFULWHULDGXULQJWKHVWXG\EXWZDVQRWZLWKGUDZQ
x
$UHVHDUFKSDWLHQW UHFHLYHGDQH[FOXGHGFRQFRPLWDQWPHGLFDWLRQ
x
%UHDFKHVRIFRQILGHQWLDOLW\
x
$UHVHDUFKSDWLHQWZDVHQUROOHGEXWGRHVQRWPHHWWKHSURWRFRO¶VHOLJLELOLW\
LQFOXVLRQH[FOXVLRQFULWHULD
x
)DLOXUHWRWUHDWUHVHDUFKSDWLHQWV SHUSURWRFROSURFHGXUHVWKDWVSHFLILFDOO\UHODWHWR
SULPDU\HIILFDF\RXWFRPHV
x
,QDGYHUWHQWORVVRIGDWD
x
)DLOXUHWRREWDLQ,QIRUPHG&RQVHQWSULRUWRLQLWLDWLRQRIVWXG\UHODWHGSURFHGXUHV
x
)DLOXUHWRUHSRUWVHULRXVDGYHUVHHYHQWVZLWKLQUHTXLUHGWLPHIUDPHWRWKH,5%DQGRU
VSRQVRUDQG)'$
x
)DOVLI\LQJUHVHDUFKRUPHGLFDOUHFRUGV
x
3HUIRUPLQJWHVWVRUSURFHGXUHVEH\RQGWKHLQGLYLGXDO¶VSURIHVVLRQDOVFRSHRU
SULYLOHJHVWDWXVFUHGHQWLDOLQJ
,QWKHHYHQWRIDVLJQLILFDQWGHYLDWLRQIURPWKHSURWRFROWKH&OLQLFDO,QYHVWLJDWRU ZLOOFRQWDFWWKH
VSRQVRUDWWKHHDUOLHVWSRVVLEOHWLPHE\WHOHSKRQH7KH&OLQLFDO,QYHVWLJDWRUDQGWKHVSRQVRU¶V

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
VWXG\WHDPZLOOFRPHWRDMRLQWGHFLVLRQUHJDUGLQJWKHSDWLHQW¶VFRQWLQXDWLRQLQWKHVWXG\7KH
GHFLVLRQZLOOEHGRFXPHQWHGE\WKH&OLQLFDO,QYHVWLJDWRU DQGWKHVSRQVRU
$Q\YLRODWLRQIURPVWXG\SURFHGXUHVVKRXOGEHQRWHGLQWKHVRXUFHGRFXPHQWVDQGDGGHGWRWKH
SURWRFROGHYLDWLRQVORJ 0DMRUSURWRFROGHYLDWLRQVVKRXOGEHUHSRUWHGWRWKHVSRQVRU
LPPHGLDWHO\3URWRFROYLRODWLRQVDUHGLYLGHGLQWRWKHIROORZLQJFDWHJRULHV
3URWRFRO9LRODWLRQ &DWHJRULHV
Ƒ&RQVHQW3URFHGXUH
Ƒ6WXG\3URFHGXUHV
Ƒ5DQGRPL]DWLRQ3URFHGXUHV
Ƒ,QFOXVLRQ([FOXVLRQ&ULWHULD
Ƒ,QYHVWLJDWLRQDOGUXJ 'RVLQJ
Ƒ9LVLW6FKHGXOH,QWHUYDO
Ƒ&RQFRPLWDQW0HGLFDWLRQ7KHUDS\
Ƒ6$(5HSRUWLQJ
Ƒ2WKHU
Ƒ/DERUDWRU\$VVHVVPHQWV
3.5
Protocol Adherence and Compliance with Protocol Revisions
3ULRUWREHJLQQLQJWKHVWXG\WKH&OLQLFDO,QYHVWLJDWRU PXVWVLJQWKH&OLQLFDO6WXG\$JUHHPHQW
DQGWKH&OLQLFDO,QYHVWLJDWRU
VVLJQDWXUHSDJHGRFXPHQWLQJKLVKHUDJUHHPHQWWRFRQGXFWWKH
VWXG\LQDFFRUGDQFHZLWKWKHSURWRFRO7KH&OLQLFDO,QYHVWLJDWRU PXVWQRWGHYLDWHIURPWKLV
SURWRFROH[FHSWWRSURWHFWWKHOLIHDQGSK\VLFDOZHOOEHLQJRIDSDWLHQWLQDQHPHUJHQF\
7KH3HU3URWRFRO336DPSOHZLOOFRQVLVWRIDOOSDWLHQWV ZKRGLGQRWSUHVHQWZLWKDQ\PDMRU
SURWRFROYLRODWLRQVLQDFFRUGDQFHZLWKWKHVWXG\VSHFLILFLQFOXVLRQH[FOXVLRQFULWHULD
7KHVWXG\PXVWEHFRQGXFWHGDVGHVFULEHGLQWKLVDSSURYHGSURWRFRO7KHVSRQVRULVUHVSRQVLEOH
IRUSUHSDUDWLRQRIDOOUHYLVLRQVWRWKHSURWRFRO7KH&OLQLFDO,QYHVWLJDWRUVKRXOGQRWLPSOHPHQW
DQ\YLRODWLRQRUFKDQJHWRWKHSURWRFROZLWKRXWSULRUUHYLHZDQGGRFXPHQWHGDSSURYDOIURPWKH
,5%RIDQDPHQGPHQWH[FHSWZKHUHQHFHVVDU\WRHOLPLQDWHDQLPPHGLDWHKD]DUGVWRVWXG\
SDWLHQWV
3.6
Informed Consent Procedure
7KH&OLQLFDO,QYHVWLJDWRU ZLOO REWDLQZULWWHQ,QIRUPHG&RQVHQWIURPDOOVWXG\SDWLHQWVSULRUWR
SHUIRUPLQJ DQ\VWXG\UHODWHGSURFHGXUHV7KH,QIRUPHG&RQVHQWGRFXPHQWZLOOEHDSSURYHGE\
WKH,5% 7KH&OLQLFDO,QYHVWLJDWRU DQG WKHVWXG\VLWHVWDIIZLOOEHWUDLQHGLQ WKHDGPLQLVWUDWLRQRI
WKH,QIRUPHG&RQVHQWSURFHGXUH
3ULRU WRLQLWLDWLQJWKH,QIRUPHG&RQVHQWGRFXPHQWDWLRQSURFHVVWKH&OLQLFDO,QYHVWLJDWRU ZLOO
GHWHUPLQHZKHWKHUWKHSURVSHFWLYHSDWLHQW LVOHJDOO\FDSDEOH WRSDUWLFLSDWHLQWKH,QIRUPHG
&RQVHQWSURFHVV7KH&OLQLFDO,QYHVWLJDWRU ZLOO H[FOXGHOHJDOO\LQFDSDFLWDWHGSHUVRQVOHJDO
JXDUGLDQVPD\QRWFRQVHQWRQEHKDOIRILQFDSDFLWDWHGSHUVRQVIRUWKLVWULDO7KH&OLQLFDO
,QYHVWLJDWRUZLOOFRPPXQLFDWHLQIRUPDWLRQUHJDUGLQJWKHQDWXUHRIWKHVWXG\SRWHQWLDOULVNVDQG
SRWHQWLDOEHQHILWVWRWKHSDWLHQW)XOODQGDGHTXDWHRUDODQGZULWWHQLQIRUPDWLRQPXVWEHSURYLGHG
WRHDFKSURVSHFWLYHWULDO SDWLHQW7KH LQIRUPDWLRQ ZLOOEH FRPPXQLFDWHGLQDPDQQHUWKDWHQVXUHV
WULDO SDWLHQWVKDYHDPHDQLQJIXOXQGHUVWDQGLQJRIWKHLQIRUPDWLRQ7KH&OLQLFDO,QYHVWLJDWRU ZLOO
JLYHWKHSDWLHQWV DQRSSRUWXQLW\WRDVNTXHVWLRQVSURYLGHLQIRUPDWLRQUHJDUGLQJZKRPWRFRQWDFW
LI SDWLHQWVKDYHDQ\PRUHTXHVWLRQVDQGHQVXUHWKDWWKHSDWLHQW KDVWKHULJKWWRGLVFRQWLQXH
SDUWLFLSDWLRQLQWKHWULDO DWDQ\WLPH7KH&OLQLFDO,QYHVWLJDWRU ZLOO H[SODLQDQ\SD\PHQWVWRWULDO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
SDWLHQWVDQGWKHUHTXLUHPHQWVWKHSDWLHQWV PXVWIXOILOOWRUHFHLYHWKHSD\PHQWV ,WLVWKH&OLQLFDO
,QYHVWLJDWRU¶VGXW\WRERWKDVVHVVWKHSDWLHQWV¶FDSDFLW\WRFRQVHQWDQGWRDQVZHUSDWLHQWV¶
TXHVWLRQVWKURXJKRXWWKHWULDO7KHSDWLHQWV ZLOO UHFHLYHDFRPSOHWHFRS\RIWKHIXOO\H[HFXWHG
,QIRUPHG&RQVHQWGRFXPHQWDWLRQ
7KH&OLQLFDO,QYHVWLJDWRU ZLOO H[SODLQWRDOOSDWLHQWVWKDWFRQVXPSWLRQRIRSLDWHPHGLFDWLRQV
GXULQJWKHWULDO PD\SUHFLSLWDWHRSLDWHZLWKGUDZDOV\QGURPHGXHWRWKHQDOWUH[RQHFRPSRQHQWRI
WKHLQYHVWLJDWLRQDOGUXJZKLFKLVDQRSLRLGUHFHSWRUDQWDJRQLVW
3ULRUWRWKHLQLWLDWLRQRIDQ\VWXG\VSHFLILFSURFHGXUHVWKH&OLQLFDO,QYHVWLJDWRU ZLOO YHULI\WKDW
DOO,QIRUPHG&RQVHQWGRFXPHQWDWLRQDUHSURSHUO\VLJQHG DQGGDWHGE\WKHSDWLHQW$FRPSOHWH
FRS\RIDOO,QIRUPHG&RQVHQWGRFXPHQWDWLRQLQFOXGHVERWKDFRPSOHWHVHWRIDOOZULWWHQ
LQIRUPDWLRQSURYLGHGWRWKHSDWLHQWDQGWKHIXOO\H[HFXWHG,QIRUPHG&RQVHQWGRFXPHQWDWLRQ7KH
RULJLQDOFRS\ ZLOOEH UHWDLQHGLQWKHSDWLHQW¶VVWXG\ILOH
3.7
Regulatory Compliance
%HIRUHWKHVWXG\FDQVWDUW WKH,5%ZLOOUHYLHZDQGDSSURYDODOOWKHVWXG\GRFXPHQWVIRUHWKLFDO
FRQVLGHUDWLRQVDFFRUGLQJWRORFDOUHJXODWLRQV7KH,5%ZLOOLGHQWLI\DOOGRFXPHQWV UHYLHZHGE\
QDPHDQGYHUVLRQ7KHVSRQVRUVKRXOGVXEPLWIRU,5%DSSURYDOSDWLHQW LQIRUPDWLRQ,QIRUPHG
&RQVHQWIRUPWKHLQYHVWLJDWRUEURFKXUHDQ\ZULWWHQLQVWUXFWLRQVWREHJLYHQWRDSDWLHQWSDWLHQW
UHFUXLWPHQWSURFHGXUHVHJDGYHUWLVHPHQWVLQIRUPDWLRQDERXWSD\PHQWVDQGFRPSHQVDWLRQWR
WKHSDWLHQWVDQGGRFXPHQWDWLRQUHJDUGLQJ WKHLQYHVWLJDWRUUHTXLUHGTXDOLILFDWLRQV3URWRFRO
DPHQGPHQWZLOOEHLVVXHGIRUFKDQJHVLQWKHFRQGXFWRIWKHVWXG\
7KHLQYHVWLJDWRUPXVWREWDLQDSSURYDOIURPWKH,5%7KHLQYHVWLJDWRUZLOOQRWLI\WKH,5%RI
GHYLDWLRQVIURPWKHSURWRFRORUVHULRXVDGYHUVHHYHQWV6$(VRFFXUULQJDWWKHFOLQLF
3.8
Concomitant Diagnosis and Medication Recording Requirements 
6LJQLILFDQWPHGLFDOKLVWRU\LQFOXGLQJHYHQWVXSWR WKH6FUHHQLQJ9LVLW ZLOO EHUHFRUGHG
)ROORZLQJFRQVHQWDOOHYHQWVWKDWRFFXUZLOOEHUHFRUGHGLQWKHDGYHUVHHYHQWORJ
'XULQJWKH6FUHHQLQJ9LVLWWKH&OLQLFDO,QYHVWLJDWRU ZLOOUHFRUGDOORYHUWKHFRXQWHUDQG
SUHVFULSWLRQ PHGLFDWLRQVWKHUDSLHVDQGSURFHGXUHVZLWKLQGD\VSULRUWR WKHEHJLQQLQJRIWKH
VWXG\&RQFRPLWDQWPHGLFDWLRQVFRQVXPHGDQGWKHUDSLHVXQGHUJRQHE\ DSDWLHQWGXULQJWKH
FRXUVHRIWKHVWXG\LQFOXGLQJWKRVHXVHGLQUHVSRQVHWRDQ$(6$(DVZHOO DV QHZFRQFRPLWDQW
GLDJQRVHV ZLOOEHUHFRUGHG 7KHSDWLHQW ZLOOUHFRUGFRQFRPLWDQWUHVFXHDQDOJHVLFVLQWKH0LJUDLQH
'LDU\
3.9
Demographics, Baseline Measures, and Cardiovascular Risk Assessment
%DVHOLQHDQGGHPRJUDSKLFPHDVXUHVZLOOEHFROOHFWHGIURPHDFKSDWLHQWLQFOXGLQJ\HDURIELUWK
DJHJHQGHUHWKQLFLW\UDFHPLJUDLQHGXUDWLRQPLJUDLQHVHYHULW\ PLJUDLQHDVVRFLDWHGV\PSWRPV
FRQFRPLWDQWPHGLFDWLRQVDQGWUHDWPHQWVE\FODVV DQGVHOIUHSRUWHGFDUGLRYDVFXODUULVNIDFWRUV
3.10
Treatment Group Assignment Procedure
7KH&OLQLFDO,QYHVWLJDWRULVWKHRQO\DXWKRUL]HGLQGLYLGXDODOORZHGWRUDQGRPL]HSDWLHQWV$IWHU
FRQILUPLQJWKDWWKHSDWLHQWKDVPHWDOOHOLJLELOLW\FULWHULDWKH&OLQLFDO,QYHVWLJDWRU FDQSURFHHGWR

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
WKHUDQGRPL]DWLRQSURFHGXUH7KHLQYHVWLJDWRUZLOOFRQILUP WKDWWKHSDWLHQWLQWHQWVWRFRQVXPH
WKHLQYHVWLJDWLRQDOGUXJDQGGLVSHQVHWKHPHGLFDWLRQYLDOXVLQJGRXEOHFKHFNLQJPHGLFDWLRQ
GLVSHQVDWLRQSURFHGXUH
3.11
Early Withdrawal  and Early withdrawal Procedure
6LQFHWKLVVWXG\LVDVLQJOHGRVHVWXG\HDUO\ZLWKGUDZDOUHIHUVWRZLWKGUDZDODIWHUWKHSDWLHQWZDV
UDQGRPL]HGDQGEHIRUHWKHSDWLHQWWUHDWHGDPLJUDLQHDWWDFN3DWLHQWVLQYHVWLJDWRUVRUWKH
VSRQVRUPD\LQLWLDWHHDUO\ZLWKGUDZDO3DWLHQWV DUHHQFRXUDJHGWRFRPPXQLFDWHHDUO\ZLWKGUDZDO
GHFLVLRQVDVVRRQDVSRVVLEOH7KH&OLQLFDO,QYHVWLJDWRU RUVSRQVRUPD\WHUPLQDWHSDWLHQW
SDUWLFLSDWLRQLQWKHWULDO DWDQ\WLPHRXWRIVDIHW\FRQFHUQV7KH&OLQLFDO,QYHVWLJDWRUVKRXOG
GLVFXVVHDUO\ZLWKGUDZDORIDSDWLHQW ZLWKWKHVSRQVRUEHIRUHFDUU\LQJLWRXW
3.12
Patients Lost to Follow-up Prior to the End of the Trial  
)RUSDWLHQWVZKRFRQVXPHGWKHVWXG\GUXJEXWGLGQRWDWWHQGWKHHQGRIWUHDWPHQWYLVLWDWWHPSWV
ZLOOEHPDGHWRFROOHFWHIILFDF\DQGVDIHW\GDWDE\WHOHSKRQH7KH&OLQLFDO,QYHVWLJDWRU ZLOOPDNH
DWOHDVW WKUHH GRFXPHQWHGDWWHPSWVWRFRQWDFWWKHSDWLHQW E\WHOHSKRQH,IDOOWHOHSKRQHDWWHPSWV
IDLOWKH&OLQLFDO,QYHVWLJDWRU ZLOODWWHPSWFRQWDFWE\PDLOLQJDOHWWHUWRWKHSDWLHQW¶VODVWNQRZQ
DGGUHVVE\FHUWLILHGPDLODQGLQFOXGLQJDUHTXHVWIRUUHWXUQUHFHLSW7KLVFRQWDFWZLOODVNWKH
SDWLHQWWRUHWXUQWRWKHVLWH IRUWKHILQDOVDIHW\HYDOXDWLRQ 3DWLHQWVZKRGLGQRWFRQVXPHWKH
VWXG\GUXJZLWKLQWZRPRQWKVIURPUDQGRPL]DWLRQZLOOEHDVNHGWRUHWXUQWKHVWXG\GUXJDQGWKH
VWXG\IRUPV
4
STUDY TREATMENT SCHEDULE
4.1
Pre-enrollment Review 
7KHLQYHVWLJDWRUZLOOREWDLQPHGLFDOUHFRUGVFRQILUPLQJDGLDJQRVLVRIPLJUDLQHSK\VLFLDQ¶V
QRWHSKDUPDF\UHFRUGVIRUPLJUDLQHVSHFLILFPHGLFDWLRQVHWF$GGLWLRQDOO\WKHLQYHVWLJDWRU
ZLOOUHYLHZWKHFRPSOHWHGPLJUDLQHLQWDNHIRUP7KHLQYHVWLJDWRUZLOOIRUZDUGDQRQ\PL]HG
PHGLFDOUHFRUGVDQGWKHFRPSOHWHGPLJUDLQHLQWDNHIRUPWRWKHVSRQVRUSULRUWRHQUROOLQJD
SDWLHQW
4.2
Rules for Rescreening
5HVFUHHQZLOOQRWEHSHUPLWWHG
4.3
Study Visit 1 - the Screening Visit  
7KHILUVWREMHFWLYHRIWKLVYLVLWLVWRFRQILUPWKDWWKHSURVSHFWLYHSDWLHQW PHHWVDOOWKHLQFOXVLRQ
DQGH[FOXVLRQFULWHULD
3URVSHFWLYHSDWLHQWVLGHQWLILHGE\WKHLQYHVWLJDWRUZLOOFRPSOHWHWKH³3DWLHQW,QWDNH)RUPIRUWKH
0LJUDLQH3UHYHQWLRQ6WXG\´VHFWLRQ7KHVSRQVRUPXVWUHYLHZWKHPHGLFDOUHFRUGVWKH
(&*WKHFRPSOHWHG3DWLHQW,QWDNH)RUPDQGDSSURYHWKHSDWLHQW¶VSDUWLFLSDWLRQEHIRUH
SURFHHGLQJ
$OOSURVSHFWLYHVWXG\SDUWLFLSDQWV ZLOOFRPSOHWHD FRQWDFWLQIRUPDWLRQIRUPDQGSURYLGHDSKRWR
,'DFRS\RIWKHSKRWR,'ZLOOEHREWDLQHG6LWHSHUVRQQHOZLOOYHULI\FRQWDFWLQIRUPDWLRQ

3URWRFRO$12'<1(
3DJH RI
9HUVLRQ
-XO\ , 
PDWFKHVWKHLQIRUPDWLRQRQWKHSKRWR,'
7KHLQYHVWLJDWRUZLOOUHYLHZZLWKWKHSDWLHQWWKH³3DWLHQW+DQGRXWIRUWKH0LJUDLQH3UHYHQWLRQ
6WXG\´VHFWLRQ
7KHLQYHVWLJDWRUZLOOJRRYHUZLWKSDWLHQWVWKHIROORZLQJDVSHFWV
x
7KHSRLQWUDWLQJVFDOH
x
6HOIDVVHVVPHQWRISDLQLQWHQVLW\
x
6HOIDVVHVVPHQWRIQDXVHD
x
6HOIDVVHVVPHQWRIVDWLVIDFWLRQZLWKPLJUDLQHSUHYHQWLRQ
x
&RPSOHWLRQRIWKH0LJUDLQH'LDU\
x
7KH3ODFHER(IIHFW DQG
x
3URKLELWHGPHGLFDWLRQV
7KHLQYHVWLJDWRUZLOORQO\HQUROOSDWLHQWVZKRGHPRQVWUDWHGDELOLW\WRSHUIRUPWKHVWXG\WDVNDV
RXWOLQHGLQWKHSDWLHQWKDQGRXW
3ULRUWRFRQGXFWLQJDQ\VWXG\VSHFLILFSURFHGXUHVSDWLHQWVPXVWVLJQWKH,QIRUPHG&RQVHQW7KH
LQIRUPHGFRQVHQWSURFHGXUHPXVWEHH[HFXWHGDVRXWOLQHGLQ6HFWLRQ7KHLQYHVWLJDWRU PXVW
EHDYDLODEOHWRDQVZHUDQ\TXHVWLRQVSDWLHQWVPD\KDYH7KHLQYHVWLJDWRUZLOOSURYLGHSDWLHQWV
ZLWKDFRS\RIWKHVLJQHG,QIRUPHG&RQVHQWGRFXPHQWIRUWKHLUUHFRUGV
)LUVWDOOSDWLHQWVZLOOKDYHDQRQVLWHXULQHGUXJVFUHHQ SDQHOXULQHGUXJVFUHHQWRWHVWIRU
FRFDLQH PDULMXDQDRSLDWHVPHWKDPSKHWDPLQHVDQGR[\FRGRQHDQGSUHPHQRSDXVDOZRPHQ
RUZLWKLQRQH\HDURIPHQRSDXVHZLOOKDYHDXULQHSUHJQDQF\WHVW6FUHHQLQJXULQHWHVWVPXVW
EHQHJDWLYHWRSURFHHG
7KHLQYHVWLJDWRUZLOOUHYLHZWKHSDWLHQWV¶PHGLFDOKLVWRU\VHFWLRQPLJUDLQHWUHDWPHQW
KLVWRU\DQGKLVWRU\RIVXEVWDQFHDEXVH+HVKHZLOOSHUIRUPDSK\VLFDOH[DPLQDWLRQ7KHSDWLHQW
ZLOOKDYHDQ HOHFWURFDUGLRJUDP (&*SHUIRUPHGGXULQJWKHVFUHHQLQJYLVLWVHFWLRQ
7KHKHLJKW ZLOOEHPHDVXUHGLQLQFKHVZLWKRXWVKRHV7KHZHLJKWZLOOEHPHDVXUHGLQSRXQGV
ZLWKSDWLHQWVGUHVVHGLQLQGRRUFORWKLQJVKRHVUHPRYHG'XULQJPHDVXUHPHQWRIEORRGSUHVVXUH
DQGSXOVHSDWLHQWVDUHUHTXLUHGWRVLWLQFKDLUVZLWKOHJVXQFURVVHGIRUILYHPLQXWHV EHIRUH
PHDVXUHPHQWVDUHFROOHFWHG6HFWLRQDQG
3URFHGXUHVRIWKH6FUHHQLQJ9LVLW
x
+HLJKWZHLJKW
x
%ORRGSUHVVXUHSXOVHYDOXHVPXVWEHLQWKHUDQJHRXWOLQHGLQDSSHQGL[
x
(OHFWURFDUGLRJUDP
x
'UDZEORRGVDPSOHVIRUODERUDWRU\DVVHVVPHQWEORRGFRXQWKHSDWLFDQG UHQDOIXQFWLRQ
,ILWLVGHWHUPLQHGGXULQJWKH6FUHHQLQJ9LVLW WKDWDSDWLHQW FDQQRWSDUWLFLSDWHLQWKHWULDOIRUDQ\
UHDVRQ RULIWKHVFUHHQLQJYLVLWODERUDWRU\DVVHVVPHQWVDUHRXWVLGHWKHDFFHSWDEOHUDQJHWKH
SDWLHQWZLOOEHFRQVLGHUHGDVVFUHHQLQJIDLOXUH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
'XULQJWKH6FUHHQLQJ9LVLWWKHLQYHVWLJDWRUZLOOFRPSOHWHWKHIROORZLQJGRFXPHQWV
x
6FUHHQLQJ9LVLWSURJUHVVQRWH
x
,QFOXVLRQ([FOXVLRQ&ULWHULD
x
'HPRJUDSKLFV%DVHOLQH,QIRUPDWLRQ0HGLFDWLRQV'LDJQRVHV6WXG\'UXJ1XPEHU
$VVLJQPHQW&5)DQG
x
0HGLFDO+LVWRU\3K\VLFDO([DP
7KHLQYHVWLJDWRUZLOOFRPSOHWHWKH&5)IRUPLQWZRSDUWFDUERQOHVVSDSHUIRUPVSURYLGHGE\
WKHVSRQVRUFRSLHVRIWKHIRUPDUHDYDLODEOHLQWKHSURWRFRODWWDFKPHQWVVHFWLRQ
'XULQJWKHVFUHHQLQJYLVLWSDWLHQWVZLOOEHDVNHGWRUDWHWKHLUVDWLVIDFWLRQZLWKPLJUDLQH
SUHYHQWLRQ 1RWDWDOOVDWLVILHG 3DUWO\VDWLVILHG 6DWLVILHG YHU\VDWLVILHGDQGWR
FRPSOHWHWKHIROORZLQJLQVWUXPHQWV
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6
x
+HDGDFKH,PSDFW7HVW+,7DQG
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56
3DWLHQWVZLWKFRQFRPLWDQWHPRWLRQDOSDLQFRH[LVWLQJZLWKHSLVRGLFPLJUDLQHZRXOGEHDVNHGWR
FRPSOHWHWKHHPRWLRQDOGDLO\GLDU\DVZHOODVWKHPLJUDLQHSUHYHQWLRQGDLO\GLDU\$GGLWLRQDOO\
WKH\ZLOOFRPSOHWHWKH%HFN¶VGHSUHVVLRQLQYHQWRU\HYHU\YLVLW
3DWLHQWZLWKFRQFRPLWDQW&/%3ZRXOGEHDVNHGWRFRPSOHWHD&/%3GDLO\GLDU\DVZHOODVWKH
PLJUDLQHSUHYHQWLRQGDLO\GLDU\$GGLWLRQDOO\WKH\ZLOOFRPSOHWHWKH2VZHVWU\'LVDELOLW\,QGH[
LQVWUXPHQWRQHYHU\VLWHYLVLW
7KHVLWHZLOOFRQWDFWWKHSDWLHQWE\SKRQHRQGD\DQGGD\GD\VRIWKHEDVHOLQHSHULRG
4.4
Study Visit 2 - the Randomization Visit  
$IWHUFRPSOHWLQJDGD\EDVHOLQHSHULRGSDWLHQWVZLOOUHWXUQIRUWKH5DQGRPL]DWLRQ9LVLW
3DWLHQWVZKRPWKHEDVHOLQHSHULRG0LJUDLQH'LDU\VKRZHGDWOHDVW PRGHUDWHWRVHYHUH
PLJUDLQHKHDGDFKHGD\VEXWRUOHVV KHDGDFKHGD\V6FUHHQLQJ9LVLWEORRGZRUNLVLQWKH
DFFHSWDEOHUDQJHDQGFRQWLQXHGWRPHHWDOORWKHULQFOXVLRQH[FOXVLRQFULWHULDZLOOEH HOLJLEOHWR
FRQWLQXH
3DWLHQWPXVWKDYHLQ9LVLW DQHJDWLYH XULQHGUXJVFUHHQDQGXULQHSUHJQDQF\WHVWIRU
FKLOGEHDULQJDJHZRPHQ7KHEORRGSUHVVXUHDQGSXOVHPXVWEHLQWKHDFFHSWDEOHUDQJH
3DWLHQWVZLOOEHUDQGRPL]HGLQ DUDWLRWRQDOWUH[RQH
PJDFHWDPLQRSKHQ
PJ
$//2'RUSODFHERDQGHQWHULQWRWKHZHHN7UHDWPHQW3HULRG
7KHLQYHVWLJDWRUPXVWEHWKHSHUVRQSHUIRUPLQJWKHUDQGRPL]DWLRQSURFHGXUH7KHLQYHVWLJDWRU
ZLOOODEHOHDFKRIWKHIRXUYLDOVLQWKHDVVLJQHGVWXG\GUXJ EDJZLWKWKHELUWK\HDU'RXEOH
FKHFNLQJSURFHGXUHLVUHTXLUHGGXULQJWKHGLVSHQVLQJRIWKHVWXG\GUXJ
5DQGRPL]HGSDWLHQWVZLOOUHFHLYHDSDSHU0LJUDLQH'LDU\ IRUPDQGVWXG\GUXJRQHYLDO
FRQWDLQLQJODUJHFDSVXOHVDQGRQHYLDOFRQWDLQLQJVPDOOFDSVXOHVWRXVHLQWKHRXWSDWLHQW

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
VHWWLQJV
'XULQJWKH5DQGRPL]DWLRQ9LVLW SDWLHQWVZLOOFRPSOHWHWKHIROORZLQJLQVWUXPHQWV
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6
x
+HDGDFKH,PSDFW7HVW+,7DQG
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56
7KHLQYHVWLJDWRUZLOOLQVWUXFWWKHSDWLHQWRQKRZWRXVHWKHVWXG\GUXJZKDWWRGRLQWKHHYHQWRI
DGYHUVHHIIHFWVDQGWRUHWXUQWKHPHGLFDWLRQYLDOVLQWKHQH[WVLWH YLVLW 7KHLQYHVWLJDWRUZLOOVHW
XSDOOWKHXSFRPLQJIROORZXSVLWHYLVLWDSSRLQWPHQWVDQGSKRQHFRQWDFWV
4.5
12-Week Outpatient Treatment Period
2Q'D\WKHGD\RI9LVLWRIWKH7UHDWPHQW3HULRG SDWLHQWVZLOOWDNHWKHILUVWGRVHRIWKHVWXG\
GUXJDWSPDQGFRQWLQXHWRWDNHRQHFDSVXOHIURPHDFKRIWKHWZRYLDOVWZLFHDGD\
DSSUR[LPDWHO\DPDQGSPGXULQJHDFKGD\WKHZHHN7UHDWPHQW3HULRG,I
GHHPHGQHFHVVDU\GXHWRLQWROHUDQFHWKHLQYHVWLJDWRUZLOOGHFUHDVHWKHSDWLHQW¶VGRVHWRRQHGRVH
DGD\WKHSPGRVHIRUWKHGXUDWLRQRIWKH7UHDWPHQW3HULRG
3DWLHQWVZLOOFRPSOHWHWKH0LJUDLQH'LDU\DWSPHYHU\GD\ RUDWEHGWLPHZKLFKHYHULV
HDUOLHU
4.6
Study Visit 3 – 1 week after the Treatment Period started 
'XULQJWKLVYLVLWWKHLQYHVWLJDWRUZLOOFRQILUPWKHSDWLHQWXQGHUVWDQGLQJRIKRZWRWDNHWKH
VWXG\GUXJDQGKRZWRFRPSOHWHWKHGDLO\0LJUDLQHGLDU\'XULQJWKLVYLVLWDVVHVVPHQWRI
DGYHUVHHYHQWVDQGDGMXVWPHQWWRWKHVWXG\GUXJGRVHFDQEHPDGH7KHSDWLHQWZLOO
FRPSOHWHWKH3,56DQGUHFHLYHVWXG\GUXJ
4.7
Study Visit 3 and Study Visit 4 
7KH7UHDWPHQW3HULRGIROORZXSYLVLWVWDNHSODFHDWWKHHQGRI:HHNDQGZHHNRIWKH
7UHDWPHQW3HULRG
7KHLQYHVWLJDWRUZLOOHQVXUHWKDWWKHVXEMHFWKDVQRWZLWKGUDZQWKHLQIRUPHGFRQVHQWDQG
FRQWLQXHVWRPHHWVLQFOXVLRQH[FOXVLRQFULWHULD7KHLQYHVWLJDWRUZLOOUHYLHZWKHFRPSOHWHG
0LJUDLQH'LDU\ IRUPUHFRQFLOHWKHVWXG\GUXJDQGLQWHUYLHZVXEMHFWVUHJDUGLQJDGYHUVHHYHQWV
E\GLUHFWO\DVNLQJ ³+DYH\RXKDGDQ\KHDOWKFRQFHUQVVLQFHWKHODVWWLPH\RXZHUHVHHQ"´7KH
VXEMHFWVKRXOGEHTXHVWLRQHGUHJDUGLQJ$(VLQDJHQHUDOZD\ZLWKRXWDVNLQJDERXWH[LVWHQFHRI
VSHFLILFV\PSWRPV7KHLQYHVWLJDWRUZLOOTXHVWLRQXVHRIFRQFRPLWDQWPHGLFDWLRQVRUDQ\
SURKLELWHGPHGLFDWLRQVVLQFHWKHODVWYLVLW
:HLJKWEORRGSUHVVXUHDQGSXOVHZLOOEHPHDVXUHG
,Q9LVLWSDWLHQWVZLOOUHFHLYHWKHVHFRQGYLDOFRQWDLQLQJODUJHFDSVXOHVDQGWKHVHFRQGYLDO
FRQWDLQLQJVPDOOFDSVXOHV,Q9LVLWSDWLHQWV¶VWXG\GUXJYLDOVZLOOEHFRXQWHGUHFRQFLOHGDQG
UHWXUQHGWRWKHSDWLHQWV
9LVLWDQG 9LVLWSURFHGXUHV
 5HYLHZWKH0LJUDLQH'LDU\IRUPIRUFRPSOHWHQHVV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
 5HYLHZXVHRIDGGLWLRQDOSDLQPHGLFDWLRQV
 ,QWHUYLHZSDWLHQWVUHJDUGLQJDGYHUVHHIIHFW
 9LWDOVLJQV%3SXOVHZHLJKW
 8ULQHSUHJQDQF\IRUZRPHQRIFKLOGEHDULQJDJH
 5HFRQFLOHVWXG\GUXJ
 'UDZEORRGVDPSOHVIRUODERUDWRU\DVVHVVPHQWV
7KHLQYHVWLJDWRUZLOOFRPSOHWHWKHIROORZLQJIRUPV
 8SGDWHWKHSDWLHQWFRQWDFWLQIRUPDWLRQLI QHFHVVDU\
 8SGDWHWKHFRQFRPLWDQWPHGLFDWLRQVFRQFRPLWDQWGLDJQRVHV&5)
 &RPSOHWHSURJUHVVQRWH
6RXUFH&5)IRUPVDUHDYDLODEOHLQWKHSURWRFRODWWDFKPHQWVVHFWLRQ
'XULQJWKH9LVLWDQG9LVLWSDWLHQWVZLOOEHDVNHGWRUDWHWKHLUVDWLVIDFWLRQZLWKPLJUDLQH
SUHYHQWLRQ 1RWDWDOOVDWLVILHG 3DUWO\VDWLVILHG 6DWLVILHG YHU\VDWLVILHGDQGWR
FRPSOHWHWKHIROORZLQJLQVWUXPHQWV
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6
x
+HDGDFKH,PSDFW 7HVW+,7DQG
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56
7KHLQYHVWLJDWRUZLOOFRPSOHWHWKHIROORZLQJIRUPVIRUWKHHQGRIVWXG\YLVLW
 8SGDWHWKHSDWLHQWFRQWDFWLQIRUPDWLRQLIQHFHVVDU\
 8SGDWHWKHFRQFRPLWDQWPHGLFDWLRQVFRQFRPLWDQWGLDJQRVHV&5)
&RPSOHWHSURJUHVVQRWH
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6
x
+HDGDFKH,PSDFW7HVW+,7DQG
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56
4.8
Study Visit 5 - End-of-Treatment Visit
7KH(QGRI7UHDWPHQW YLVLW ZLOOWDNHSODFHRQGD\GD\V
'XULQJWKHHQGRIWUHDWPHQW YLVLWSDWLHQWV ZLOOUHWXUQWKHFRPSOHWHG0LJUDLQH'LDU\ IRUP
DQGWKHVWXG\GUXJYLDOV
7KHHQGRIVWXG\YLVLWSURFHGXUHV
 5HYLHZWKH0LJUDLQH'LDU\ IRUP IRUFRPSOHWHQHVV
 5HYLHZXVHRIDGGLWLRQDOSDLQPHGLFDWLRQV
 ,QWHUYLHZSDWLHQWVUHJDUGLQJDGYHUVHHIIHFW
 %ULHISK\VLFDOH[DPLQDWLRQ
 9LWDOVLJQV%3SXOVHZHLJKW

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
 'UDZEORRGVDPSOHVFRPSOHWHEORRGFRXQWKHSDWLFIXQFWLRQDQGUHQDOIXQFWLRQ
 8ULQHSUHJQDQF\IRUZRPHQ RIFKLOGEHDULQJDJH
 5HFRQFLOHVWXG\GUXJ
'XULQJ9LVLWSDWLHQWVZLOOEHDVNHGWRUDWHWKHLUVDWLVIDFWLRQZLWKPLJUDLQHSUHYHQWLRQ 1RW
DWDOOVDWLVILHG 3DUWO\VDWLVILHG 6DWLVILHG YHU\VDWLVILHGDQGWRFRPSOHWHWKHIROORZLQJ
LQVWUXPHQWV
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6
x
+HDGDFKH,PSDFW7HVW+,7DQG
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56
7KHLQYHVWLJDWRUZLOOFRPSOHWHWKHIROORZLQJIRUPVIRUWKHHQGRIVWXG\YLVLW
 8SGDWHWKHSDWLHQWFRQWDFWLQIRUPDWLRQLIQHFHVVDU\
 8SGDWHWKHFRQFRPLWDQWPHGLFDWLRQVFRQFRPLWDQWGLDJQRVHV&5)
 &RPSOHWHSURJUHVVQRWH
6RXUFH&5)IRUPVDUHDYDLODEOHLQWKHSURWRFRODWWDFKPHQWVVHFWLRQ
,IDSDWLHQWGLVFRQWLQXHVSDUWLFLSDWLRQLQWKHVWXG\DIWHUWDNLQJ WKHVWXG\GUXJHYHU\DWWHPSW
VKRXOGEHPDGHWRFROOHFWHIILFDF\DQG VDIHW\GDWD6HFWLRQ
4.9
Study Visit 6, End-of-Study Visit 
7KLVYLVLWZLOOWDNHSODFHRQGD\GD\YLVLWZLQGRZRIWKH)ROORZXS3HULRG'XULQJWKH
)ROORZXS3HULRGSDWLHQWVZLOOFRQWLQXHWRFRPSOHWHWKHGDLO\GLDU\EXWWKH\ZLOOQRWFRQVXPH
WKHVWXG\GUXJ3DWLHQWVPD\UHVXPHRSLRLGPHGLFDWLRQVGD\VDIWHUWDNLQJWKHODVWGRVH RIWKH
VWXG\GUXJ
'XULQJ9LVLWSDWLHQWVZLOOEHDVNHGWRUDWHWKHLUVDWLVIDFWLRQZLWKPLJUDLQHSUHYHQWLRQ 1RW
DWDOOVDWLVILHG 3DUWO\VDWLVILHG 6DWLVILHG YHU\VDWLVILHGDQGWRFRPSOHWHWKHIROORZLQJ
LQVWUXPHQWV
x
0LJUDLQH'LVDELOLW\$VVHVVPHQW6FDOH0,'$6
x
+HDGDFKH,PSDFW7HVW+,7DQG
x
3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56
7KHLQYHVWLJDWRUZLOOFRPSOHWHWKHIROORZLQJIRUPVIRUWKHHQGRIVWXG\YLVLW
 8SGDWHWKHSDWLHQWFRQWDFWLQIRUPDWLRQLIQHFHVVDU\
 8SGDWHWKHFRQFRPLWDQWPHGLFDWLRQVFRQFRPLWDQWGLDJQRVHV&5)
 &RPSOHWHSURJUHVVQRWH
5
DEFINITION OF EVALUATIONS AND SPECIAL INSTRUCTIONS  
7KLVVHFWLRQH[SODLQVWKHSURFHGXUHVIRXQGLQ9LVLW(QFRXQWHUIRUWKH0LJUDLQH3UHYHQWLRQ6WXG\
6HFWLRQ

3URWRFRO$12'<1(
3DJH RI
9HUVLRQ
-XO\ , 
5.1
Informed Consent Procedure
7KH,QIRUPHG&RQVHQWSURFHVVZLOORFFXUGXULQJWKH6FUHHQLQJYLVLW7KH&OLQLFDO,QYHVWLJDWRU
ZLOOGLVFXVVWKHWULDOSURWRFROZLWKWKHSDWLHQWZKDWLVH[SHFWHGRIWKHSDWLHQWDQGWKHIDFWWKDW
WKHSDWLHQW LVIUHHWRZLWKGUDZIURPWKHWULDO DWDQ\WLPHIRUDQ\UHDVRQ7KHLQYHVWLJDWRUPXVWEH
SUHVHQWWRDQVZHUTXHVWLRQVREWDLQZULWWHQFRQVHQWDQGWRVLJQWKH,QIRUPHG&RQVHQW,&
5.2
Inclusion/Exclusion Criteria
7KH&OLQLFDO,QYHVWLJDWRU ZLOOVLJQRIIRQWKHLQFOXVLRQH[FOXVLRQFULWHULD
5.3
Patient Education and the Four-Point Likert Scale Instrument 
7KHLQYHVWLJDWRUZLOOHGXFDWHSDWLHQWVDVGHVFULEHGLQ6HFWLRQ$IRXUSRLQWXQLSRODU/LNHUW
VFDOHLV XVHGIRUKHDGDFKHSDLQ DQG$(DVVHVVPHQWVLH QRQH PLOG PRGHUDWH
 VHYHUH7$%/(ZKLOHDELQDU\VFDOHSUHVHQWRUDEVHQWLVXVHG IRUPLJUDLQHDVVRFLDWHG
V\PSWRPV
5.4
The Migraine Diary Instrument
7KH0LJUDLQH'LDU\LVDFDUERQOHVVSDSHUGXSOLFDWHIRUP7KH0LJUDLQH'LDU\ LVDSDWLHQW
UHSRUWHGGDLO\DVVHVVPHQWVRIKHDGDFKHV,WLQFOXGHV DVVHVVPHQWRIWKHVHYHULW\DQGGXUDWLRQRI
KHDGDFKHVDVVRFLDWHGPLJUDLQHV\PSWRPVDQGVDWLVIDFWLRQZLWKPLJUDLQHSUHYHQWLRQ,WLQFOXGHV
XVDJHRIUHVFXHPHGLFDWLRQ
(DFK GDLO\ DVVHVVPHQWLQFOXGHV
x
8VHRIWKHVWXG\GUXJ
x
8VHRI$GG3DLQ0HGV
x
+HDGDFKH3DLQ 1RQH 0LOG 0RG 6HYHUH
x
/LJKW6HQVLWLYLW\1RLVH6HQVLWLYLW\1HFN6KRXOGHU3DLQ$EVHQW 3UHVHQW 
x
1DXVHD 1RQH 0LOG 0RGHUDWH 6HYHUH
5.5
Medical History, Physical Examination and Vital Signs Assessment
$ 3K\VLFDO ([DPLQDWLRQ ZLOOEHFRQGXFWHGEHIRUHSDWLHQWV DUHUDQGRPL]HGDQGDV QHHGHG GXULQJ
RWKHUVLWH YLVLWVWKHVWXG\SK\VLFLDQRUDQXUVHSUDFWLWLRQHU FDQ FRQGXFW WKH SK\VLFDO H[DPLQDWLRQ
7KHSK\VLFDOH[DPLQDWLRQVKRXOGLQFOXGHHYDOXDWLRQRIWKHJHQHUDO DSSHDUDQFH KHDGH\HVHDUV
QRVHWKURDWQHFNWK\URLGFKHVWOXQJVFDUGLRYDVFXODU DEGRPHQPXVFXORVNHOHWDOO\PSK QRGHV
H[WUHPLWLHVVNLQ DQG QHXURORJLFDO H[DPLQDWLRQ
7KHSDWLHQW ZLOOKDYH WKHLU YLWDOVLJQV WDNHQ 7KHKHLJKW ZLOOEHPHDVXUHGZLWKRXWVKRHVLQ
LQFKHVGXULQJWKH6FUHHQLQJ9LVLW7KHZHLJKWZLOO EHPHDVXUHGLQSRXQGVDQGURXQGHGWRWKH
QHDUHVWKDOISRXQG:LWK WKHSDWLHQWGUHVVHGLQLQGRRUFORWKLQJVKRHVUHPRYHG3DWLHQWV VKRXOG
EHZHLJKHGRQWKHVDPHVFDOH HYHU\ YLVLW )RUEORRGSUHVVXUHDQGSXOVHPHDVXUHPHQWVSDWLHQWV
DUHUHTXLUHGWRVLWLQFKDLUVZLWKOHJVXQFURVVHGIRUILYHPLQ EHIRUHPHDVXUHPHQWV DUHFROOHFWHG
UHIHUWR DSSHQGLFHV DQGIRU PRUH GHWDLOV RQEORRGDQGSXOVHPHDVXUHPHQWV
)RUEORRGSUHVVXUHDQG SXOVHPHDVXUHPHQWV SDWLHQWVKRXOGUHPRYH DOOFORWKLQJ WKDWFRYHUV WKH
ORFDWLRQRIFXIISODFHPHQW7KH3DWLHQWVKRXOGUHIUDLQIURPWDONLQJGXULQJWKHSURFHGXUH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
:HLJKWSXOVHDQGEORRGSUHVVXUHZLOOEHPHDVXUHGGXULQJHYHU\VLWHYLVLW
5.6
Electrocardiogram
7KH&OLQLFDO,QYHVWLJDWRU ZLOOUHYLHZWKHVWDQGDUGOHDG(&*EHIRUHUDQGRPL]DWLRQ
5.7
CBC, Hepatic and Renal Function Assessments 
3DWLHQWV ZLOOKDYHQRQIDVWLQJEORRGVDPSOHVGUDZQDW9LVLWDQG$QDO\VLVRIWKHEORRG
ZLOOLQFOXGH&%&KHSDWLFIXQFWLRQ6*27$676*37$/77RWDO%LOLUXELQ$ONDOLQH
3KRVSKDWDVHDQGUHQDOIXQFWLRQ%81DQG&UHDWLQLQH7KHSXUSRVHRIHYDOXDWLRQLVWRVFUHHQ
RXWSDWLHQWV ZLWKKHSDWLFRUUHQDOGLVHDVHDQGWRIROORZXSSRWHQWLDOHIIHFWRIWKHLQYHVWLJDWLRQDO
GUXJRQWKHKHSDWLFDQGWKHUHQDOIXQFWLRQ
3DWLHQWVZKRDUHNQRZQWRKDYHDEQRUPDOUHQDODQGRUKHSDWLFIXQFWLRQZLOOEHH[FOXGHGIURP
SDUWLFLSDWLRQLQWKHWULDO LIWKHLUYDOXHVDUH
x
$EQRUPDOOLYHUIXQFWLRQWHVWVZLWKYDOXHVWLPHVWKHXSSHUOLPLWWKHQRUPDOUDQJH
8/1IRUDVSDUWDWHWUDQVDPLQDVH$676*27DODQLQHWUDQVDPLQDVH$/76*37RU
DONDOLQH3KRVSKDWDVHRUWRWDOELOLUXELQOHYHO!WLPHVWKH8/13DWLHQWV ZLWKDWRWDO
ELOLUXELQOHYHO!WLPHVWKH8/1GXHWR*LOEHUW
VV\QGURPHZLOOEHDOORZHGLQWKH
WULDO
x
,PSDLUHGNLGQH\IXQFWLRQZLWK%81RUVHUXPFUHDWLQLQH!WLPHVWKH8/1
7KHVLWHSKOHERWRPLVWZLOOFROOHFWWKHEORRGVDPSOHVLQWRRQHWLJHUWRSWXEHDQGRQHODYHQGHUWRS
WXEHV/DERUDWRU\&RUSRUDWLRQRI$PHULFD7DPSD)/ ZLOODQDO\]HWKHEORRGVDPSOH
5.8
Five Panel Urine Drug Test and urine Pregnancy Test
$WWKH6FUHHQLQJ9LVLWSDWLHQWV ZLOOEH WHVWHGZLWKDILYHSDQHOXULQHGUXJWHVWIRUWKHSUHVHQFH
RIFRFDLQH PDULMXDQDRSLDWHVPHWKDPSKHWDPLQHVDQG2[\FRGRQH
)HPDOHSDWLHQWV RIFKLOGEHDULQJDJHZLOOKDYHD XULQHSUHJQDQF\WHVW
5.9
Concomitant Diagnosis and Treatments
0HGLFDOKLVWRU\GHPRJUDSKLFVLQIRUPDWLRQDQGSULRUFRQFRPLWDQWPHGLFDWLRQLQIRUPDWLRQZLOO
EHFROOHFWHG6LJQLILFDQWPHGLFDOKLVWRU\LQFOXGLQJHYHQWVXSWRWKH6FUHHQLQJ9LVLWGLDJQRVHV
DQGSURFHGXUHVDSSUR[LPDWHVWDUWGDWHVWRSGDWHGLVSRVLWLRQDQG WUHDWPHQWVZLOOEHUHFRUGHG
5.10
Concomitant Medications 
7KH&OLQLFDO,QYHVWLJDWRU ZLOOUHYLHZFRQFRPLWDQWPHGLFDWLRQVDQGWUHDWPHQWV$Q\SUHVFULSWLRQ
RURYHUWKHFRXQWHUPHGLFDWLRQVSDWLHQWV DUHWDNLQJUHJXODUO\ZLOOEHUHFRUGHG7KHIROORZLQJ
LQIRUPDWLRQZLOOEHREWDLQHGJHQHULFQDPHGRVHXQLWURXWHRIDGPLQLVWUDWLRQIUHTXHQF\RI
DGPLQLVWUDWLRQSHUGD\DSSUR[LPDWHVWDUWGDWHVWRSGDWHDQGGLVSRVLWLRQRQJRLQJRU
GLVFRQWLQXHG
5.11
Adverse Events Assessment
3DWLHQWV ZLOOEHLQWHUYLHZHGGXULQJWKH(QG2I6WXG\9LVLWDERXWDQ\DGYHUVHHYHQWVWKH\PD\
KDYHH[SHULHQFHGDIWHU WDNLQJWKHVWXG\GUXJ

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
5.12
Patient’s Contact Information
7KHSDWLHQW¶VFRQWDFWLQIRUPDWLRQIRUPZLOO EHFRPSOHWHGEHIRUHRUGXULQJWKH6FUHHQLQJ9LVLW
7KHSHUVRQDOFRQWDFWLQIRUPDWLRQLQFOXGHVQDPHDGGUHVVSKRQHQXPEHUHPDLODGGUHVVZRUN
FRQWDFWLQIRUPDWLRQWKHQDPHDQGFRQWDFWLQIRUPDWLRQRIWKHWUHDWLQJSK\VLFLDQHPHUJHQF\
FRQWDFWKRZGLGWKHSDWLHQWOHDUQDERXWWKHVWXG\DQGZKRUHIHUUHGWKHPWRWKHVWXG\
7KHLQIRUPDWLRQVKRXOGEHUHYLHZHGZLWKWKHSDWLHQWDQGXSGDWHGWKURXJKWKHWULDOWKHFRQWDFW
LQIRUPDWLRQIRUPZLOOEH SODFHGLQSDWLHQW¶V ILOH DVZHOODVDFRS\RIWKHSDWLHQW¶VYDOLGIRUPRI
SKRWR,'
5.13
Cardiovascular Risk Factor Assessment
3DWLHQWV¶FDUGLRYDVFXODUULVNDVVHVVPHQWZLOOEHFRQGXFWHGGXULQJWKH6FUHHQLQJ9LVLW7KH
IROORZLQJSDUDPHWHUV ZLOOEH DVVHVVHG+\SHUWHQVLRQKLVWRU\RIRURQWUHDWPHQWIRULW
'LDEHWHVKLVWRU\)%*PJRURQWUHDWPHQWIRULW2EHVLW\%0,!+LVWRU\RI
FKROHVWHURO+LVWRU\RIVPRNLQJSDFN\HDUV3DUHQWKDGDVWURNH3DUHQWZLWK'LDEHWHV
$OWHUQDWLYHO\QRWRDOO
6
DRUG INTERACTIONS WITH THE IP AND POSSIBLE ADVERSE REACTIONS 
6.1
Effects of Acetaminophen and Ethanol on Liver
6XEVWDQFHVWKDWLQGXFHRUUHJXODWHKHSDWLFF\WRFKURPHHQ]\PH&<3(PD\DOWHUWKH
PHWDEROLVP RIDFHWDPLQRSKHQDQGLQFUHDVHLWVKHSDWRWR[LFSRWHQWLDO7KHFOLQLFDOFRQVHTXHQFHV
RIWKHVHHIIHFWVKDYHQRWEHHQHVWDEOLVKHG(IIHFWVRIHWKDQRODUHFRPSOH[VLQFH H[FHVVLYH
DOFRKROXVDJHFDQLQGXFHKHSDWLFF\WRFKURPHVEXWHWKDQRODOVRDFWVDVDFRPSHWLWLYHLQKLELWRURI
WKHPHWDEROLVPRIDFHWDPLQRSKHQ
$GPLQLVWUDWLRQRIDFHWDPLQRSKHQJGD\XSWRPRQWKVZDVZHOOWROHUDWHGLQWKHWUHDWPHQWRI
RVWHRDUWKULWLVRIWKHKLSRUNQHH
6.2
Effects of Anticoagulants on Acetaminophen 
&KURQLFRUDODFHWDPLQRSKHQXVHDWDGRVHRIPJGD\KDVEHHQVKRZQWRFDXVHDQLQFUHDVH
LQLQWHUQDWLRQDOQRUPDOL]HGUDWLR,15LQVRPHSDWLHQWVZKRKDYHEHHQVWDELOL]HGRQVRGLXP
ZDUIDULQDVDQDQWLFRDJXODQW 
6.3
Naltrexone Hepatotoxicity Warning
1DOWUH[RQHSDFNDJLQJLQVHUWFDUULHVDZDUQLQJIRUKHSDWRWR[LFLW\³&DVHVRIKHSDWLWLVDQG
FOLQLFDOO\VLJQLILFDQWOLYHUG\VIXQFWLRQZHUHREVHUYHGLQDVVRFLDWLRQZLWKQDOWUH[RQH
 )'$$FHWDPLQRSKHQ2YHUGRVHDQG/LYHU,QMXU\²%DFNJURXQGDQG2SWLRQVIRU5HGXFLQJ,QMXU\0D\
KWWSZZZIGDJRYGRZQORDGV$GYLVRU\&RPPLWWHHV&RPPLWWHHV0HHWLQJ0DWHULDOV'UXJV'UXJ6DIHW\DQG5LVN0DQD
JHPHQW$GYLVRU\&RPPLWWHH8&0
 $QWKRQ\57HPSOHHWDO0XOWLFHQWHUUDQGRPL]HGGRXEOHEOLQGDFWLYHFRQWUROOHGSDUDOOHOJURXSWULDORIWKH
ORQJWHUP±PRQWKVVDIHW\RIDFHWDPLQRSKHQLQDGXOWSDWLHQWVZLWKRVWHRDUWKULWLV&OLQLFDOWKHUDSHXWLFV
)HEUXDU\9ROXPH,VVXH3DJHV±
 *UHJRU\-+XJKHVHWDO(IIHFWRI$FHWDPLQRSKHQRQ,QWHUQDWLRQDO1RUPDOL]HG5DWLRLQ3DWLHQWV5HFHLYLQJ
:DUIDULQ7KHUDS\3KDUPDFRORJ\DQG'UXJ7KHUDS\ 9ROXPH,VVXHSDJHV±

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
K\GURFKORULGHH[SRVXUHGXULQJWKHFOLQLFDOGHYHORSPHQWSURJUDPDQGLQWKHSRVWPDUNHWLQJ
SHULRG7UDQVLHQWDV\PSWRPDWLFKHSDWLFWUDQVDPLQDVHHOHYDWLRQVZHUHDOVRREVHUYHGLQWKH
FOLQLFDOWULDOVDQGSRVWPDUNHWLQJSHULRG:KHQSDWLHQWVSUHVHQWHGZLWKHOHYDWHGWUDQVDPLQDVHV
WKHUHZHUHRIWHQRWKHUSRWHQWLDOFDXVDWLYHRUFRQWULEXWRU\HWLRORJLHVLGHQWLILHGLQFOXGLQJSUH
H[LVWLQJDOFRKROLFOLYHUGLVHDVHKHSDWLWLV%DQGRU&LQIHFWLRQDQGFRQFRPLWDQWXVDJHRIRWKHU
SRWHQWLDOO\KHSDWRWR[LFGUXJV´ 3ODFHERFRQWUROOHGVWXGLHVHPSOR\LQJXSWRILYHIROGKLJKHUGRVHV
RI5(9,$XSWRPJSHUGD\WKDQWKDWUHFRPPHQGHGIRUXVHLQRSLDWHUHFHSWRUEORFNDGH
KDYHVKRZQWKDW5(9,$FDXVHVKHSDWRFHOOXODULQMXU\LQDVXEVWDQWLDOSURSRUWLRQRISDWLHQWV
H[SRVHGDWKLJKHUGRVHV´
³$QLQFUHDVHLQQDOWUH[RQH$8&RIDSSUR[LPDWHO\DQGIROGLQSDWLHQWVZLWKFRPSHQVDWHG
DQGGHFRPSHQVDWHGOLYHUcirrhosisUHVSHFWLYHO\FRPSDUHGZLWKVXEMHFWVZLWKQRUPDOOLYHU
IXQFWLRQKDVEHHQUHSRUWHG7KHVHGDWDDOVRVXJJHVWWKDWDOWHUDWLRQVLQQDOWUH[RQHELRDYDLODELOLW\
DUHUHODWHGWR liver disease VHYHULW\´39  
6.4
Vulnerability to Opioid Overdose
7KHQDOWUH[RQHSDFNDJLQJLQVHUWFDUULHVDZDUQLQJIRUYXOQHUDELOLW\WRRSLRLGRYHUGRVH³$IWHU
RSLRLGGHWR[LILFDWLRQSDWLHQWVDUHOLNHO\WRKDYHUHGXFHGWROHUDQFHWRRSLRLGV$VWKHEORFNDGHRI
H[RJHQRXVRSLRLGVSURYLGHGE\QDOWUH[RQHK\GURFKORULGHZDQHVDQGHYHQWXDOO\GLVVLSDWHV
FRPSOHWHO\SDWLHQWVZKRKDYHEHHQWUHDWHGZLWKQDOWUH[RQHK\GURFKORULGHPD\UHVSRQGWRORZHU
GRVHVRIRSLRLGVWKDQSUHYLRXVO\XVHGMXVWDVWKH\ZRXOGVKRUWO\DIWHUFRPSOHWLQJ
GHWR[LILFDWLRQ´
6.5
Precipitated Opioid Withdrawal
³7KHV\PSWRPVRIVSRQWDQHRXVRSLRLGZLWKGUDZDOZKLFKDUHDVVRFLDWHGZLWKWKHGLVFRQWLQXDWLRQ
RIRSLRLGLQDGHSHQGHQWLQGLYLGXDODUHXQFRPIRUWDEOHEXWWKH\DUHQRWJHQHUDOO\EHOLHYHGWREH
VHYHUHRUQHFHVVLWDWHKRVSLWDOL]DWLRQ+RZHYHUZKHQZLWKGUDZDOLVSUHFLSLWDWHGDEUXSWO\E\WKH
DGPLQLVWUDWLRQRIDQRSLRLGDQWDJRQLVWWRDQRSLRLGGHSHQGHQWSDWLHQWWKHUHVXOWLQJZLWKGUDZDO
V\QGURPHFDQEHVHYHUHHQRXJKWRUHTXLUHKRVSLWDOL]DWLRQ6\PSWRPVRIZLWKGUDZDOKDYHXVXDOO\
DSSHDUHGZLWKLQILYHPLQRILQJHVWLRQRI5(9,$DQGKDYHODVWHGIRUXSWRKRXUV0HQWDO
VWDWXVFKDQJHVLQFOXGLQJFRQIXVLRQVRPQROHQFHDQGYLVXDOKDOOXFLQDWLRQVKDYHRFFXUUHG
6LJQLILFDQWIOXLGORVVHVIURPYRPLWLQJDQGGLDUUKHDKDYHUHTXLUHGLQWUDYHQRXVIOXLG
DGPLQLVWUDWLRQ5HYLHZRISRVWPDUNHWLQJFDVHVRISUHFLSLWDWHGRSLRLGZLWKGUDZDOLQDVVRFLDWLRQ
ZLWKQDOWUH[RQHWUHDWPHQWKDVLGHQWLILHGFDVHVZLWKV\PSWRPVRIZLWKGUDZDOVHYHUHHQRXJKWR
UHTXLUHKRVSLWDODGPLVVLRQDQGLQVRPHFDVHVPDQDJHPHQWLQWKHLQWHQVLYHFDUHXQLW ³
6.6
Depression and Suicidality
7KHQDOWUH[RQHSDFNDJLQJLQVHUWFDUULHVDZDUQLQJIRU'HSUHVVLRQDQG6XLFLGDOLW\³'HSUHVVLRQ
VXLFLGHDWWHPSWHGVXLFLGHDQGVXLFLGDOLGHDWLRQKDYHEHHQUHSRUWHGLQWKHSRVWPDUNHWLQJ
H[SHULHQFHZLWKQDOWUH[RQHK\GURFKORULGHXVHGLQWKHWUHDWPHQWRIRSLRLGGHSHQGHQFH1RFDXVDO
 &2175$9(QDOWUH[RQH+&ODQGEXSURSLRQ+&O([WHQGHG5HOHDVH7DEOHWVSDFNDJHLQVHUW,QLWLDO86
$SSURYDOKWWSZZZDFFHVVGDWDIGDJRYGUXJVDWIGDBGRFVODEHOVOEOSGI

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
UHODWLRQVKLSKDVEHHQGHPRQVWUDWHG,QWKHOLWHUDWXUHHQGRJHQRXVRSLRLGVKDYHEHHQWKHRUL]HGWR
FRQWULEXWHWRDYDULHW\RIFRQGLWLRQV´
6.7
Potential Hepatotoxicity Risks of the Investigational Drug
+HSDWRWR[LFLW\DQGSRWHQWLDO'UXJ,QGXFHG/LYHU,QMXU\',/,KDYHEHHQDVVRFLDWHGZLWKERWK
FRPSRQHQWVRIWKHLQYHVWLJDWLRQDOGUXJDQGPD\EHDQDQWLFLSDWHGULVN $FHWDPLQRSKHQKDV
DQDUURZVDIHW\PDUJLQH[FHHGLQJIRXUJUDPVSHUGD\FDQFDXVHVHULRXVOLYHULQMXU\HYHQGHDWK
+RZHYHUOLYHUWR[LFLW\GXHWRERWKDFHWDPLQRSKHQDQG QDOWUH[RQHLVFOHDUO\GRVHGHSHQGHQW
7KHGRVHRI
PJRIDFHWDPLQRSKHQFRQWDLQHGLQWKHLQYHVWLJDWLRQDOGUXJFRQVWLWXWHVRIWKH
GDLO\PD[LPXPGRVHRIPJ7KHGRVHRI
PJRIQDOWUH[RQHFRQWDLQHGLQWKH
,QYHVWLJDWLRQDOGUXJLVRIWKHPJGDLO\DSSURYHGGRVDJHXVHGIRUWUHDWPHQWRIRSLRLG
DQGDOFRKROGHSHQGHQFH
,QWKLVVWXG\WKHVWXG\GUXJZLOOEHDGPLQLVWHUHGWZLFHDGD\IRUDZHHN7UHDWPHQW3HULRG
7KHORZGRVDJHRIERWKFRQVWLWXHQWVLQ$//2'VLJQLILFDQWO\GLPLQLVKHVWKHOLNHOLKRRGRI
KHSDWRWR[LFLW\
7KH2),50(9DFHWDPLQRSKHQIRULQMHFWLRQSDFNDJHLQVHUWLQGLFDWHV³8VHFDXWLRQZKHQ
DGPLQLVWHULQJDFHWDPLQRSKHQLQSDWLHQWVZLWKWKHIROORZLQJFRQGLWLRQVKHSDWLFLPSDLUPHQWRU
DFWLYHKHSDWLFGLVHDVHDOFRKROLVPFKURQLFPDOQXWULWLRQVHYHUHK\SRYROHPLDHJGXHWR
GHK\GUDWLRQRUEORRGORVVRUVHYHUHUHQDOLPSDLUPHQWFUHDWLQLQHFOHDUDQFHP/PLQ´
7KHPHFKDQLVPRIOLYHULQMXU\FDXVHGE\DFHWDPLQRSKHQLVGXHWRVPDOODPRXQWRI
DFHWDPLQRSKHQFRQYHUWHGWRDWR[LFPHWDEROLWH1$34,1DFHW\OSEHQ]RTXLQRQHLPLQH7KH
WR[LFPHWDEROLWHELQGVZLWKOLYHUSURWHLQVWRFDXVHFHOOXODULQMXU\7KHDPRXQWRIWR[LFPHWDEROLWH
SURGXFHGDQGWKHDELOLW\RIWKHOLYHUWRUHPRYHWKLVPHWDEROLWHEHIRUHLWELQGVWROLYHUSURWHLQ
LQIOXHQFHWKHH[WHQWRIOLYHULQMXU\ 
6.8
Hepatotoxicity Stopping Rules 
'XHWRKHSDWRWR[LFLW\FRQFHUQVZLWKERWKFRPSRQHQWVRIWKH,QYHVWLJDWLRQDOGUXJWRHYDOXDWHIRU
SRWHQWLDOGUXJLQGXFHGOLYHULQMXU\',/,ODERUDWRU\HYDOXDWLRQRIOLYHUIXQFWLRQWHVWZLOOEH
FRQGXFWHGDWEDVHOLQHDQGGD\VDIWHUWDNLQJWKHVWXG\GUXJ
,QWKHHYHQWRIDEQRUPDOOLYHUIXQFWLRQWHVWVWKHIROORZLQJFDQEHFRQVLGHUHGDEDVLFJXLGHIRU
GLVFRQWLQXDWLRQRIWUHDWPHQW,UUHOHYDQW IRUWKLVVLQJOHGRVHVWXG\,QWKHHYHQWRIDEQRUPDO
/)7¶VZLWKOLPLWVEHORZSDWLHQWVZLOOEHIROORZHGXQWLODEQRUPDOLWLHVUHWXUQVWRQRUPDORUWRWKH
EDVHOLQHVWDWH
 )'$ $FHWDPLQRSKHQ%DFNJURXQGDQG2YHUYLHZ$YDLODEOHDW
KWWSZZZIGDJRYGRZQORDGV$GYLVRU8&0SGI
 $FHWDPLQRSKHQ2YHUGRVHDQG/LYHU,QMXU\%DFNJURXQGDQG2SWLRQVIRU5HGXFLQJ,QMXU\0D\
KWWSZZZIGDJRYGRZQORDGV$GYLVRU\&RPPLWWHHV&RPPLWWHHV0HHWLQJ0DWHULDOV'UXJV'UXJ6DIHW\DQG5LVN0DQDJHPHQW$GYLV
RU\&RPPLWWHH8&0
)'$$FHWDPLQRSKHQ2YHUGRVHDQG/LYHU,QMXU\²%DFNJURXQGDQG2SWLRQVIRU5HGXFLQJ,QMXU\0D\
KWWSZZZIGDJRYGRZQORDGV$GYLVRU\&RPPLWWHHV&RPPLWWHHV0HHWLQJ0DWHULDOV'UXJV'UXJ6DIHW\DQG5LVN0DQDJHPHQW$GYLV
RU\&RPPLWWHH8&0

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
x
$/7RU$67![8/1
x
$/7RU$67![8/1IRUPRUHWKDQZHHNV
x
$/7RU$67![8/1DQG7%/![8/1RU,15!
x
$/7RU$67![8/1ZLWKWKHDSSHDUDQFHRIIDWLJXHQDXVHDYRPLWLQJULJKWXSSHU
TXDGUDQWSDLQRUWHQGHUQHVVIHYHUUDVKDQGRUHRVLQRSKLOLD!´
',/,PD\GHYHORSRUSURJUHVVHYHQDIWHUWKHFDXVDWLYHGUXJKDVEHHQVWRSSHG5HVXOWVVKRXOGEH
UHFRUGHGRQWKHFDVHUHSRUWIRUP1RWHWKDWORQJHUIROORZXSFDQVRPHWLPHVUHYHDODQRIIGUXJ
UHSHWLWLRQRIZKDWKDGDSSHDUHGWREH',/,LQGLFDWLQJWKDWOLYHULQMXU\ZDVUHODWHGWRXQGHUO\LQJ
OLYHUGLVHDVH
2QHRIWKHFULWLFDOSXUSRVHVRIFORVHREVHUYDWLRQLVWRJDWKHUDGGLWLRQDOFOLQLFDOLQIRUPDWLRQWR
GHWHUPLQHWKHPRVWOLNHO\FDXVHRUFDXVHVRIWKHREVHUYHGDEQRUPDOLWLHVDQGVSHFLILFDOO\
ZKHWKHUWKHUHLVDFDXVHRWKHUWKDQWKHVWXG\GUXJVXFKDVRQHRIWKHIROORZLQJFRPPRQFDXVHV
2WKHUOHVVFRPPRQFDXVHVDOVRPD\QHHGWREHFRQVLGHUHG
([FOXVLRQRIWKHWZR$%&VLHYLUDOKHSDWLWLV$%RU&DOFRKROLFRUDXWRLPPXQHKHSDWLWLV
ELOLDU\GLVRUGHUVDQGFLUFXODWRU\GLVRUGHUVDVFDXVHVRIOLYHULQMXU\VKRXOGEHDWWHPSWHGLQDOO
FDVHVRIVXVSHFWHG',/,DQGWKHUHVXOWVVKRXOGEHUHFRUGHG7KHUHLVDSUDFWLFDOOLPLWDVWRKRZ
PXFKWHVWLQJVKRXOGEHGRQHWRH[FOXGHOHVVFRPPRQOLYHUGLVHDVHVVXFKDVDFXWH:LOVRQ¶V
GLVHDVHRUDOSKDDQWLWU\SVLQGHILFLHQF\
3DWLHQWGLVFRQWLQXHGIURPWKHVWXG\EDVHGRQDEQRUPDO/)7VPXVWEHUHSRUWHGDVDQ$(RU6$(
7KHVSRQVRUZLOOEHUHVSRQVLEOHIRUUHSRUWLQJWRWKH)'$
6.9
Management of Liver Transaminase Elevation 
,QJHQHUDODQLQFUHDVHRIVHUXPOLYHUHQ]\PHVWR![8/1VKRXOGEHIROORZHGE\UHSHDWWHVWLQJ
ZLWKLQWRKRXUVRIDOOIRXURIWKHXVXDOVHUXPPHDVXUHV$/7$67$/3DQG7%/WR
FRQILUPWKHDEQRUPDOLWLHVDQGWRGHWHUPLQHLIWKH\DUHLQFUHDVLQJRUGHFUHDVLQJ7KHUHDOVR
VKRXOGEHLQTXLU\DERXWV\PSWRPVLHLQFOXGLQJWKHDSSHDUDQFHRIIDWLJXHQDXVHDYRPLWLQJ
ULJKWXSSHUTXDGUDQWSDLQRUWHQGHUQHVVIHYHUUDVKDQGRUHRVLQRSKLOLD3DWLHQWVPXVWEH
FORVHO\REVHUYHGDFFRUGLQJWRWKHIROORZLQJ
5HSHDWLQJOLYHUWHVWVWZRRUWKUHHWLPHVZHHNO\)UHTXHQF\RIUHWHVWLQJFDQGHFUHDVHWRRQFHD
ZHHNRUOHVVLIDEQRUPDOLWLHVVWDELOL]HRUVWXG\GUXJKDVEHHQGLVFRQWLQXHGDQGWKHSDWLHQWLV
DV\PSWRPDWLF
x
2EWDLQLQJDPRUHGHWDLOHGKLVWRU\RIV\PSWRPVDQGSULRURUFRQFXUUHQWGLVHDVHV
x
2EWDLQLQJDKLVWRU\RIFRQFRPLWDQWGUXJXVHLQFOXGLQJQRQSUHVFULSWLRQPHGLFDWLRQV
KHUEDODQGGLHWDU\VXSSOHPHQWSUHSDUDWLRQVDOFRKROXVHUHFUHDWLRQDOGUXJXVHDQG
VSHFLDOGLHWV
x
2EWDLQLQJDKLVWRU\RIH[SRVXUHWRHQYLURQPHQWDOFKHPLFDODJHQWV
x
2EWDLQLQJDGGLWLRQDOWHVWVWRHYDOXDWHOLYHUIXQFWLRQDVDSSURSULDWHHJ,QWHUQDWLRQDO
1RUPDOL]HG5DWLR,15
x
&RQVLGHULQJJDVWURHQWHURORJ\RUKHSDWRORJ\FRQVXOWDWLRQ

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7KHREVHUYDWLRQRIWKHFULWLFDOLPSRUWDQFHRIDOWHUHGOLYHUIXQFWLRQKDVEHHQUHIHUUHGWR
LQIRUPDOO\DV+\¶V/DZ
%ULHIO\+\¶V/DZFDVHVKDYHWKHIROORZLQJWKUHHFRPSRQHQWV
 7KHGUXJFDXVHVKHSDWRFHOOXODULQMXU\JHQHUDOO\VKRZQE\PRUHIUHTXHQWIROGRU
JUHDWHUHOHYDWLRQVDERYHWKH8/1RI$/7RU$67WKDQWKHQRQKHSDWRWR[LFFRQWURO
DJHQWRUSODFHER
 $PRQJSDWLHQWVVKRZLQJVXFKDPLQRWUDQVIHUDVHHOHYDWLRQVRIWHQZLWKDPLQRWUDQVIHUDVHV
PXFKJUHDWHUWKDQ[8/1VRPHSDWLHQWVDOVRVKRZHOHYDWLRQRIVHUXP7%/WR![8/1
ZLWKRXWLQLWLDOILQGLQJVRIFKROHVWDVLVVHUXPDONDOLQHSKRVSKDWDVH$/3DFWLYLW\
![8/1
1RRWKHUUHDVRQFDQEHIRXQGWRH[SODLQWKHFRPELQDWLRQRILQFUHDVHG$7DQG7%/VXFKDVYLUDO
KHSDWLWLV$%RU&SUHH[LVWLQJRUDFXWHOLYHUGLVHDVHRUDQRWKHUGUXJFDSDEOHRIFDXVLQJWKH
REVHUYHGLQMXU\
7
MANAGEMENT OF THE INVESTIGATIONAL DRUG  
7.1
Investigational Drug Allocation, Dispensation, Labeling and Packaging 
7KHVWXG\SKDUPDFLVWZLOOFRQWUROWKHUDQGRPL]DWLRQVFKHPH7KHUDQGRPL]DWLRQFRGHZLOOQRWEH
UHYHDOHGXQWLODIWHUWKHGDWDORFNRXW
7KHVWXG\GUXJ LVSODFHGLQVHTXHQWLDOO\QXPEHUHGYLDOV(DFKYLDOFRQWDLQVWZRSXUSOHFDSVXOHV
DVL]HVPDOOFDSVXOHDQGDVL]HFDSVXOHODUJH3DWLHQWVZLOOEHLQVWUXFWHGWRWDNHWKHWZR
FDSVXOHVWRJHWKHU7KHYLDOV KDYHLGHQWLFDOODEHOLQJDQGDSSHDUDQFH7KHFDSVXOHVKDYHWKHVDPH
DSSHDUDQFHZHLJKWFRORUDQGVRXQGWKHVDPHZKHQVKDNHQ7KHVLWHZLOODGPLQLVWHUWKHVWXG\
GUXJYLDOVVHTXHQWLDOO\
7KHLQYHVWLJDWLRQDOGUXJYLDOV ZHUHODEHOHGDFFRUGLQJWR*RRG0DQXIDFWXULQJ3URFHGXUH
JXLGHOLQHV7KHPHGLFDWLRQYLDOV ODEHOLQFOXGHVWKHIROORZLQJLWHPVSDWLHQWLGHQWLILHUVWXG\GUXJ
QDPHGRVDJHVWUHQJWKORWQXPEHUSURWRFROQXPEHUQXPEHURIWDEOHWVFDXWLRQVWDWHPHQWIRU
,QYHVWLJDWLRQDO3URGXFWVVWRUDJHLQVWUXFWLRQVDQGVSRQVRULGHQWLILFDWLRQ
7KHVWXG\GUXJ ZLOOEHNHSWLQWKHVLWHXQGHUSURSHUFRQGLWLRQVLQDORFNHGFDELQHWLQD
WHPSHUDWXUHFRQWUROOHGURRP7KHYLDOQXPEHUDGPLQLVWHUHGWRHDFKSDWLHQWZLOOEHGRFXPHQWHG
LQDPHGLFDWLRQORJ
7KHVLWHVPXVWVDYHDOOHPSW\SDFNDJLQJRUSDFNDJLQJFRQWDLQLQJXQXVHGWDEOHWVIRUILQDO
GLVSRVLWLRQE\WKHVSRQVRURUVSRQVRUUHSUHVHQWDWLYH
$FXWHPLJUDLQHUHVFXHPHGLFDWLRQVZLOOQRWEHSURYLGHGE\WKHVWXG\
7.2
Receipt of Investigational Drug Supplies 
7KHVWXG\GUXJ ZLOOEHGHOLYHUHGWRWKHVLWHDQGDFKDLQRIFXVWRG\ZLOOEHPDLQWDLQHG
8SRQUHFHLSWRIVWXG\SURGXFWWKHLQYHVWLJDWRURUGHVLJQHHVKRXOGHQVXUHWKDWWKHLQIRUPDWLRQRQ
WKHSDFNLQJVOLSPDWFKHVWKHVWXG\SURGXFWUHFHLYHG$WDPLQLPXPWKHUHFLSLHQWVKRXOGYHULI\
WKHIROORZLQJSURGXFWLGHQWLILFDWLRQDPRXQWRISURGXFWUHFHLYHGORWQXPEHUVH[SLUDWLRQGDWHV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
SK\VLFDOSURGXFWLVLQJRRGFRQGLWLRQDQGSURSHUPDLQWHQDQFHRIVWRUDJHFRQGLWLRQVGXULQJ
WUDQVSRUW$FRS\RIVKLSSLQJPDQLIHVWVZLOOEHNHSWLQWKHUHJXODWRU\IROGHU
(YLGHQFHRIEUHDNDJHFRPSURPLVHGVWRUDJHRUSURGXFWWDPSHULQJVKRXOGEHUHSRUWHGWRWKH
VSRQVRULPPHGLDWHO\ DQGWKHVWXG\SURGXFWVKRXOGEHTXDUDQWLQHGDQGPDLQWDLQHGXQGHUWKH
FRUUHFWVWRUDJHFRQGLWLRQVXQWLOIXUWKHULQVWUXFWLRQVDUHJLYHQ,QYHVWLJDWLRQDOGUXJVZLOOQRWEH
GLVSHQVHGXQWLOSURSHUDXWKRUL]DWLRQWKDWWKHHQUROOPHQWSURFHVVFDQEHJLQ
7.3
Investigational drug Dispensation 
$PHFKDQLVPPXVWEHHVWDEOLVKHGWRHQVXUHWKDWWKHLQYHVWLJDWLRQDOGUXJLVGLVSHQVHGRQO\XSRQ
WKHRUGHURIWKH&OLQLFDO,QYHVWLJDWRUDVVWDWHGRQ)'$IRUP)'$)RUPLVDELQGLQJ
GRFXPHQWZKHUHE\E\FRPSOHWLQJDQGVLJQLQJWKH)'$IRUPWKH,QYHVWLJDWRUKDVFHUWLILHG
WKDWWKHVWXG\SURGXFWLVDGPLQLVWHUHGRQO\WRSDWLHQWVXQGHUKLVKHUSHUVRQDOVXSHUYLVLRQRU
XQGHUWKHVXSHUYLVLRQRIFRLQYHVWLJDWRUVUHVSRQVLEOHWRKLPKHU
$WUDQGRPL]DWLRQ7KH,QYHVWLJDWRU ZLOODVVLJQWKHVHTXHQWLDOYLDOQXPEHUIURPWKHVWXG\GUXJ
FRQWDLQHUWRDSDWLHQWXVLQJGRXEOHFKHFNLQJPHGLFDWLRQGLVSHQVDWLRQSURFHGXUHGLVFXVVHG
EHORZLQPRUHGHWDLOVDQGGRFXPHQWWKHYLDOQXPEHUDGPLQLVWHUHGLQWKHDSSURSULDWHORJV3RVW
UDQGRPL]DWLRQWKHYLDO,'QXPEHUEHFRPHVWKHSDWLHQW¶VVWXG\,'7KH,QYHVWLJDWRUZLOOODEHO
HDFKRIWKHYLDOV ZLWKWKHSDWLHQW¶VELUWK\HDU
7.4
Double-Checking Procedure during Dispensation of the Study Drug
'RXEOHFKHFNLQJPHGLFDWLRQGLVSHQVDWLRQLVDPHDQVRIUHGXFLQJPHGLFDWLRQHUURUV0HGLFDWLRQ
GLVSHQVDWLRQHUURUVSRVHDWKUHDWWRSDWLHQW VDIHW\DQGDULVNWRGDWDLQWHJULW\'RXEOHFKHFNLQJ
PHGLFDWLRQGLVSHQVDWLRQSURFHGXUHLQYROYHVWZRVWDIIPHPEHUVWKHUHVSRQVLELOLW\RIWKHVHFRQG
VWDIIPHPEHULVWRFRQGXFWDYHULILFDWLRQRIWKHZRUNSHUIRUPHGE\WKHILUVW
'RXEOHFKHFNLQJLVUHTXLUHGGXULQJWZRVWHSVRIWKHPHGLFDWLRQGLVSHQVDWLRQSURFHVV)LUVWZKHQ
UHPRYLQJWKHLQYHVWLJDWLRQDOGUXJYLDO IURPWKH PHGLFDWLRQFRQWDLQHUDQGVHFRQGZKHQWKH
PHGLFDWLRQYLDO LVGLVSHQVHGWRWKHSDWLHQW7ZRVWDIIPHPEHUVVLGHE\VLGHPXVWHQVXUHWKDWDOO
LQIRUPDWLRQRQWKHPHGLFDWLRQYLDO LVDFFXUDWHZLWKUHJDUGWRSDWLHQWDQGHQVXULQJWKDWWKH
LQYHVWLJDWLRQDOGUXJ YLDOLVGHOLYHUHGLQSHUVRQWRWKHSRVLWLYHO\LGHQWLILHGSDWLHQW2QFHWKHWZR
VWHSVDUHFRPSOHWHWKHVWDIIPHPEHUVZLOOFRLQLWLDOWKHPHGLFDWLRQORJ
7.5
Ensuring Compliance with the Investigational Drug and Reconciliation
7KHLQYHVWLJDWRULVUHVSRQVLEOHIRUPDLQWDLQLQJVWULFWFRQWURORYHUWKHLQYHVWLJDWLRQDOGUXJDQG
PDLQWDLQVRIDQLQYHQWRU\ORJGXULQJWKHVWXG\DQ\GLVFUHSDQFLHVPXVWEHLQYHVWLJDWHGUHVROYHG
DQGGRFXPHQWHG7KH&OLQLFDO,QYHVWLJDWRUPXVWDOVRHQVXUHSURSHUVHFXULW\DQGVWRUDJHRIWKH
LQYHVWLJDWLRQDOGUXJ
(DFKWLPHDQLQYHVWLJDWLRQDOGUXJYLDOLVGLVSHQVHGRUUHWXUQHGWKHHYHQWZLOOEHGRFXPHQWHGLQ
WKHPHGLFDWLRQORJ7KHPHGLFDWLRQYLDOV UHWXUQHGE\WKHSDWLHQWZLOOEHUHWXUQHGWRWKHFRQWDLQHU
$WVWXG\FRPSOHWLRQWKHLQYHVWLJDWLRQDOGUXJ FRQWDLQHU ZLOOEH UHWDLQHGDWWKHVWXG\VLWHV DVSDUW
RIWKHUHFRUG

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7.6
Drug Accountability Monitoring
'XULQJURXWLQHYLVLWVWKHWULDOPRQLWRUZLOODVVHVVWKHFOLQLF¶VGLVSHQVLQJSURFHGXUHVWKH SDWLHQW
FRPSOLDQFHDQGHQVXUHSURSHUGUXJVWRUDJHDQGWHPSHUDWXUHORJPDLQWHQDQFH7KHPRQLWRUZLOO
DOVRYHULI\WKDWWKH&OLQLFDO,QYHVWLJDWRU RUDQDXWKRUL]HGUHSUHVHQWDWLYHLVWKHSHUVRQGLVSHQVLQJ
WKHPHGLFDWLRQ)XUWKHUWKHPRQLWRUZLOO FRQILUPWKDWDOOLQYHVWLJDWLRQDOGUXJVDUHDFFRXQWHGIRU
LQYHVWLJDWHDQ\GLVFUHSDQFLHVDQGUHVROYHDOOLWHPVEHIRUHVLWHFORVXUH7KHUHVKRXOGEHHYLGHQFH
WKDWHQWULHVLQWRWKHORJVZHUHPDGHLQUHDOWLPHDWWKHWLPHWKHDFWLRQWRRNSODFH $Q\
LGHQWLILHGLQDSSURSULDWHSUDFWLFHVZLOOSURPSWUHWUDLQLQJRIVLWHVWDIIDVQHHGHG$QDXGLWRUPD\
FRQGXFWVLPLODUGRFXPHQWUHYLHZVDWDQ\WLPH'RFXPHQWDWLRQVKRXOGVXSSRUWSURSHUVWRUDJH
DQGVHFXULW\RIWKHGUXJ,QDOOWKHGRFXPHQWDWLRQVKRXOGSURYLGHDIXOODQGDFFXUDWHH[SODQDWLRQ
RIGUXJKDQGOLQJIURPUHFHLSWWKURXJKILQDOGLVSRVLWLRQ
7.7
Investigational Drug Storage
7KHVXSSO\RILQYHVWLJDWLRQDOGUXJZLOOEHVWRUHGLQDORFNHGFDELQHWLQDURRPZLWKFOLPDWH
FRQWUROPDLQWDLQLQJWKHWHPSHUDWXUHZLWKLQDUDQJHRI&)$WHPSHUDWXUHORJ
PXVWEHPDLQWDLQHGLQWKHVWRUDJHURRPDQGWKHWHPSHUDWXUHZLOOEH UHFRUGHGRQFHHYHU\ZRUNLQJ
GD\$FFHVVWRWULDO GUXJZLOOEH OLPLWHGWRWKH&OLQLFDO,QYHVWLJDWRUDQGKLVKHUGHVLJQHHV7KH
&OLQLFDO,QYHVWLJDWRUPXVWPDLQWDLQDQLQYHQWRU\UHFRUGRIWKHLQYHVWLJDWLRQDOGUXJUHFHLYHG
GLVSHQVHGDQGUHWXUQHG
7.8
Emergency Preparedness Measures for Investigational drug
6LWH623VZLOOGLFWDWHSUHSDUHGQHVVIRUHPHUJHQFLHVVXFKDVSRZHURXWDJHVIORRGVKXUULFDQHV
HWFWRSURWHFWWKHLQWHJULW\RIWKHLQYHVWLJDWLRQDOGUXJDQGWRPLQLPL]HWKHLPSDFWRISRWHQWLDO
LQWHUUXSWLRQVWRWKHFOLQLFDOWULDO
7.9
Blinding and Emergency Un-Blinding 
$OOVWXG\VWDIIZLOOEHEOLQGWRWUHDWPHQWDVVLJQPHQWV6SRQVRU¶VVWDIILQYROYHGLQGDWD
PDQDJHPHQWGDWDDQDO\VLVDQGWULDOPRQLWRULQJZLOOQRWKDYHDFFHVVWRWKHUDQGRPL]DWLRQFRGH
GXULQJWKHWULDO
,QHPHUJHQFLHVWKDWLQYROYHSDWLHQW VDIHW\WKHLGHQWLW\RIWKHLQYHVWLJDWLRQDOGUXJDVVLJQPHQWFDQ
EHUHYHDOHG3KDUPDF\VWDIIFKDUJHGZLWKSDFNDJLQJWKHLQYHVWLJDWLRQDOGUXJZLOOKDYHDFFHVVWR
WKHUDQGRPL]DWLRQ,QWKHHYHQWRIDQ6$(WKHUDQGRPL]DWLRQDVVLJQPHQWFDQEHXQEOLQGHGE\
WKHVWXG\SKDUPDFLVWLQDFRPPXQLFDWLRQQRWVKDUHGZLWKWKHVSRQVRUWKHVWXG\SKDUPDFLVWZLOO
LQIRUPWKHQHFHVVDU\SDUWLHVRIWKHLQGLYLGXDO¶VQDPHSDWLHQW,'QXPEHUDQGUDQGRPL]DWLRQ
FRGHDVVLJQPHQW7KHVSRQVRUZLOOUHSRUWDOOUHOHYDQWDQGUHTXLUHGLQIRUPDWLRQWRWKH)'$,5%
DQGDOORWKHUUHTXLUHGUHJXODWRU\DJHQFLHV7KH&OLQLFDO,QYHVWLJDWRU LVHQFRXUDJHGWRFRQWDFWWKH
VSRQVRUWRGLVFXVVWKHLUUDWLRQDOHIRUXQEOLQGLQJDOWKRXJKVSRQVRUDSSURYDOLVQRWUHTXLUHGSULRU
WRXQEOLQGLQJ7KH&OLQLFDO,QYHVWLJDWRU ZLOOEH DEOHWRREWDLQWKHFRGHEUHDNLQIRUPDWLRQ
LQGHSHQGHQWRIWKHVSRQVRU:KHQEUHDNLQJWKHEOLQGLQJFRGHWKH&OLQLFDO,QYHVWLJDWRU ZLOO IXOO\
GRFXPHQWWKHGDWHWLPHWKHVLWHVWDIILQYROYHGDQGWKHUHDVRQIRUWKHXQEOLQGLQJLQWKHVRXUFH
GRFXPHQWDWLRQ7KH&OLQLFDO,QYHVWLJDWRU PXVWQRWLI\WKHVSRQVRURIWKHXQEOLQGLQJZLWKLQ
KRXUV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7.10
Drug Product Quality Complaints (PQC) Reporting
3URGXFWTXDOLW\FRPSODLQWVFDQEHLVVXHGE\WKHVWXG\VLWHVWDIISDWLHQWUHJXODWRU\DJHQF\RU
RWKHUWKLUGSDUW\WKDWDOOHJHVGHILFLHQFLHVRUGLVVDWLVIDFWLRQUHODWHGWRLGHQWLW\TXDOLW\ODEHOLQJ
SDFNDJLQJUHOLDELOLW\VDIHW\GXUDELOLW\WDPSHULQJFRXQWHUIHLWLQJWKHIWHIIHFWLYHQHVV RU
SHUIRUPDQFHRIDGUXJSURGXFWDIWHULWLVUHOHDVHGIRUGLVWULEXWLRQ5HOHYDQWH[DPSOHVLQFOXGH
x
,QFRUUHFWRUPLVVLQJODEHOLQJ
x
3DFNDJLQJLVVXHVHJGDPDJHGGLUW\FUXVKHGPLVVLQJSURGXFW
x
9LDOGHIHFWVHJXQGHUILOORURYHUILOOQRVDIHW\VHDO
x
3URGXFWGHIHFWHJRGRUFKLSSHGEURNHQHPERVVLQJLOOHJLEOH
x
/RVVRUWKHIWRISURGXFW
7KH&OLQLFDO,QYHVWLJDWRU PXVWQRWLI\WKHVSRQVRUZLWKLQKRXUVRIEHFRPLQJDZDUHRIWKH
SURGXFWTXDOLW\FRPSODLQWV
7.11
Investigational Drug Return
$WWKHHQGRIWKHVWXG\RUDVGLUHFWHGE\WKHVSRQVRUDOO LQYHVWLJDWLRQDOGUXJLQFOXGLQJXQXVHG
SDUWLDOO\XVHGRUHPSW\YLDOVZLOOEHUHWXUQHGWRDGHVLJQHHDVLQVWUXFWHGE\WKHVSRQVRU
,QYHVWLJDWLRQDOGUXJ ZLOOEHUHWXUQHGRQO\DIWHUWKH WULDOPRQLWRUKDVFRPSOHWHGDILQDOLQYHQWRU\WR
YHULI\WKHTXDQWLW\WREHUHWXUQHG7KHUHWXUQ RILQYHVWLJDWLRQDOGUXJPXVWEHGRFXPHQWHGDQGWKH
GRFXPHQWDWLRQLQFOXGHGLQWKHVKLSPHQW$WWKHHQGRIWKHVWXG\DILQDO,QYHVWLJDWLRQDOGUXJ
UHFRQFLOLDWLRQVWDWHPHQWPXVWEHFRPSOHWHGE\WKHLQYHVWLJDWRURUGHVLJQHHDQGSURYLGHGWRWKH
VSRQVRU
$OO,QYHVWLJDWLRQDOGUXJLQYHQWRU\IRUPVPXVWEHPDGHDYDLODEOHIRULQVSHFWLRQWRWKHVSRQVRU¶V
UHSUHVHQWDWLYHHJVLWHPRQLWRUDQGDQ\DXWKRUL]HGLQVSHFWRUIURPDUHJXODWRU\DJHQF\7KH
LQYHVWLJDWRULVUHVSRQVLEOHIRUWKHDFFRXQWDELOLW\RIDOOXVHGDQGXQXVHGVWXG\VXSSOLHVDWWKH
FOLQLF
8
SAFETY AND ADVERSE EVENTS MANAGEMENT
8.1
Adverse Event Definition
8QDQWLFLSDWHGSUREOHPVLQYROYLQJULVNWRSDWLHQWVRURWKHUVDQ\LQFLGHQWH[SHULHQFHRURXWFRPH
WKDWPHHWVDOORIWKHIROORZLQJFULWHULD
x
8QH[SHFWHGLQQDWXUHVHYHULW\RUIUHTXHQF\LHQRWGHVFULEHGLQVWXG\UHODWHG
GRFXPHQWVVXFKDVWKH,5%DSSURYHGSURWRFRORUFRQVHQWIRUPWKH,QYHVWLJDWRU¶V
EURFKXUHHWF
x
5HODWHGRUSRVVLEO\UHODWHGWRSDUWLFLSDWLRQLQWKHUHVHDUFKLHSRVVLEO\UHODWHGPHDQV
WKHUHLVDUHDVRQDEOHSRVVLELOLW\WKDWWKHLQFLGHQWH[SHULHQFHRURXWFRPHPD\KDYHEHHQ
FDXVHGE\WKHSURFHGXUHVLQYROYHGLQWKHUHVHDUFK
x
6XJJHVWVWKDWWKHUHVHDUFKSODFHVSDWLHQWVRURWKHUVDWJUHDWHUULVNRIKDUPLQFOXGLQJ
SK\VLFDOSV\FKRORJLFDOHFRQRPLFRUVRFLDOKDUP

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
$QDGYHUVHHYHQW$(LVDQ\V\PSWRPVLJQLOOQHVVRUH[SHULHQFHWKDWGHYHORSVRUZRUVHQVLQ
VHYHULW\GXULQJWKHFRXUVHRIWKHVWXG\([DPSOHVRI$(VLQFOXGHV\PSWRPVRIGL]]LQHVVRU
QDXVHDRUVLJQVRIEUDG\FDUGLDRUK\SRWHQVLRQ,QWHUFXUUHQWLOOQHVVHVRULQMXULHVVKRXOGEH
UHJDUGHGDVDGYHUVHHYHQWV$EQRUPDOUHVXOWVRIGLDJQRVWLFSURFHGXUHVDUHFRQVLGHUHGWREH
DGYHUVHHYHQWVLIWKHDEQRUPDOLW\
x
UHVXOWVLQVWXG\ZLWKGUDZDO
x
LVDVVRFLDWHGZLWKDVHULRXVDGYHUVHHYHQW
x
LVDVVRFLDWHGZLWKFOLQLFDOVLJQVRUV\PSWRPV
x
OHDGVWRDGGLWLRQDOWUHDWPHQWRUWRIXUWKHUGLDJQRVWLFWHVWV
x
LVFRQVLGHUHGE\WKH&OLQLFDO,QYHVWLJDWRU WREHRIFOLQLFDOVLJQLILFDQFH
x
VHULRXVDGYHUVHHYHQW6$(V
$QDGYHUVHHYHQWLVFODVVLILHGDV³VHULRXV´LILWUHVXOWVLQDQ\RIWKHIROORZLQJRXWFRPHV
x
GHDWK
x
LVOLIHWKUHDWHQLQJDQHYHQWLQZKLFKWKHSDWLHQWZDVDWULVNRIGHDWK
x
LQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ
x
SHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\
x
DFRQJHQLWDODEQRUPDOLW\ELUWKGHIHFW
x
LVDQLPSRUWDQWPHGLFDOHYHQW
x
QRWH6$(VLQFOXGHVFRQGLWLRQVWKDWGRQRWUHTXLUHKRVSLWDOL]DWLRQEXWUHTXLUHLQWHQVLYH
WUHDWPHQWDWKRPHRULQWKHHPHUJHQF\URRPHJVHYHUHDOOHUJLFUHDFWLRQDVHL]XUHWKDW
GLGQRWUHVXOWLQLQSDWLHQWKRVSLWDOL]DWLRQ(OHFWLYHRUSUHYLRXVO\VFKHGXOHGVXUJHU\IRU
SUHH[LVWLQJFRQGLWLRQVZKLFKKDYHQRWZRUVHQHGDIWHULQLWLDWLRQRIWUHDWPHQWVKRXOGQRW
EHFODVVLILHGDV6$(
V
$OODGYHUVHHYHQWVWKDWGRQRWPHHWDQ\RIWKHFULWHULDIRUVHULRXVVKRXOGEHUHJDUGHGDV
QRQVHULRXVDGYHUVHHYHQWV
8.2
Adverse Event Prompting Procedure
$WHDFKYLVLWLQFOXGLQJWHOHSKRQHYLVLWVWKH&OLQLFDO,QYHVWLJDWRU PXVWSDVVLYHO\FDSWXUH
VSRQWDQHRXVO\UHSRUWHGDGYHUVHHYHQWVDQGVHHNLQIRUPDWLRQIURPWKHSDWLHQWUHJDUGLQJ DGYHUVH
HYHQWVZLWKXVHRIDQRSHQHQGHGSURPSWE\GLUHFWO\DVNLQJ ³+DYH\RXKDGDQ\KHDOWKFRQFHUQV
VLQFHWKHODVWWLPH\RXZHUHVHHQ"´7KHSDWLHQWVKRXOGEHTXHVWLRQHGUHJDUGLQJ$(V LQDJHQHUDO
ZD\ZLWKRXWDVNLQJDERXWH[LVWHQFHRIVSHFLILFV\PSWRPV$GGLWLRQDOO\$(VZLOOEHFDSWXUHG
ZKHQSDWLHQWV FDOOWKHVLWHIURPKRPHUHSRUWLQJDQ$(,IDSSURSULDWHRUQHFHVVDU\IXUWKHU
HYDOXDWLRQVVKDOO EHFRQGXFWHG
8.3
Recording of Adverse Events  
,QIRUPDWLRQRQDOODGYHUVHHYHQWVVKRXOGEHUHFRUGHGLQWKHVRXUFHGRFXPHQWLPPHGLDWHO\DQG
LQWKHDGYHUVHHYHQW&5)$OOFOHDUO\UHODWHGVLJQVV\PSWRPVDQGDEQRUPDOGLDJQRVWLF

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
SURFHGXUHVUHVXOWVVKRXOGEHUHFRUGHGLQWKHVRXUFHGRFXPHQWWKRXJKWKH\VKRXOGEHJURXSHG
XQGHURQHGLDJQRVLV$OODGYHUVHHYHQWVRFFXUULQJGXULQJWKHVWXG\SHULRGPXVWEHUHFRUGHG7KH
FOLQLFDOFRXUVHRIHDFKHYHQWVKRXOGEHIROORZHGXQWLOUHVROXWLRQVWDELOL]DWLRQRUXQWLOLWKDVEHHQ
GHWHUPLQHGWKDWWKHVWXG\WUHDWPHQWRUSDUWLFLSDWLRQLVQRWWKHFDXVH6HULRXVDGYHUVHHYHQWVWKDW
DUHVWLOORQJRLQJDWWKHHQGRIWKHVWXG\SHULRGPXVWEHIROORZHGXSWRGHWHUPLQHWKHRXWFRPH
$Q\VHULRXVDGYHUVHHYHQWWKDWRFFXUVDIWHUWKHVWXG\SHULRGDQGLVFRQVLGHUHGWREHSRVVLEO\
UHODWHGWRWKHVWXG\WUHDWPHQWRUVWXG\SDUWLFLSDWLRQVKRXOGEHUHFRUGHGDQGUHSRUWHG
LPPHGLDWHO\
8.4
Adverse Event Reporting Period 
7KHVWXG\SHULRGGXULQJZKLFKDGYHUVHHYHQWVPXVWEHUHSRUWHGLVQRUPDOO\GHILQHGDVWKHSHULRG
IURPWKHLQLWLDWLRQRIDQ\VWXG\SURFHGXUHVWRWKHHQGRIWKHVWXG\WUHDWPHQWIROORZXS)RUWKLV
VWXG\WKHVWXG\WUHDWPHQWIROORZXSLVGHILQHGDVGD\VIROORZLQJWKHODVWDGPLQLVWUDWLRQRI
LQYHVWLJDWLRQDOGUXJ
8.5
Preexisting Conditions 
$SUHH[LVWLQJFRQGLWLRQ LVRQHWKDWLVSUHVHQWDWWKHVWDUWRIWKHVWXG\$SUHH[LVWLQJFRQGLWLRQ
VKRXOGEHUHFRUGHGDVDQDGYHUVHHYHQWLIWKHIUHTXHQF\LQWHQVLW\RUWKHFKDUDFWHURIWKH
FRQGLWLRQZRUVHQVGXULQJWKHVWXG\SHULRG$WVFUHHQLQJDQ\FOLQLFDOO\VLJQLILFDQWDEQRUPDOLW\
VKRXOGEHUHFRUGHGDVDSUHH[LVWLQJFRQGLWLRQ$WWKHHQGRIWKHVWXG\DQ\QHZFOLQLFDOO\
VLJQLILFDQWILQGLQJVDEQRUPDOLWLHVWKDWPHHWWKHGHILQLWLRQRIDQDGYHUVHHYHQWPXVWDOVREH
UHFRUGHGDQGGRFXPHQWHGDVDQDGYHUVHHYHQW
8.6
Post-study Adverse Event 
$OOXQUHVROYHGDGYHUVHHYHQWVVKRXOGEHIROORZHGE\WKH&OLQLFDO,QYHVWLJDWRUXQWLOWKHHYHQWV
KDYHUHVROYHG$WWKHODVWVFKHGXOHGYLVLWWKH&OLQLFDO,QYHVWLJDWRUVKRXOGLQVWUXFWHDFKSDWLHQWWR
UHSRUWDQ\VXEVHTXHQWHYHQWVWKDWWKHSDWLHQWRUWKHSDWLHQW¶V SHUVRQDOSK\VLFLDQEHOLHYHV
PLJKWUHDVRQDEO\EHUHODWHGWRSDUWLFLSDWLRQLQWKLVVWXG\7KH&OLQLFDO,QYHVWLJDWRUVKRXOGQRWLI\
WKHVWXG\VSRQVRURIDQ\GHDWKRUDGYHUVHHYHQWRFFXUULQJDWDQ\WLPHDIWHUDSDWLHQW KDV
GLVFRQWLQXHGRUWHUPLQDWHGVWXG\SDUWLFLSDWLRQWKDWPD\UHDVRQDEO\EHUHODWHGWRWKLVVWXG\7KH
VSRQVRUVKRXOGDOVREHQRWLILHGLIWKH&OLQLFDO,QYHVWLJDWRUVKRXOGEHFRPHDZDUHRIWKH
GHYHORSPHQWRIFDQFHURURIDFRQJHQLWDODQRPDO\LQDVXEVHTXHQWO\FRQFHLYHGRIIVSULQJRID
SDWLHQW WKDWKDVSDUWLFLSDWHGLQWKLVVWXG\
8.7
Determination of Abnormal Laboratory Values as Adverse Events
$FOLQLFDOODERUDWRU\DEQRUPDOLW\VKRXOGEHGRFXPHQWHGDVDQDGYHUVHHYHQWLIDQ\RQHRIWKH
IROORZLQJFRQGLWLRQVLVPHW
x
7KHODERUDWRU\DEQRUPDOLW\LVQRWRWKHUZLVHUHIXWHGE\DUHSHDWWHVWWRFRQILUPWKH
DEQRUPDOLW\
x
7KHDEQRUPDOLW\VXJJHVWVDGLVHDVHDQGRURUJDQWR[LFLW\
x
7KHDEQRUPDOLW\LVRIDGHJUHHWKDWUHTXLUHVDFWLYHPDQDJHPHQWHJFKDQJHRIGRVH
GLVFRQWLQXDWLRQRIWKHGUXJPRUHIUHTXHQWIROORZXSDVVHVVPHQWVIXUWKHUGLDJQRVWLF

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
LQYHVWLJDWLRQHWF
7KHLQYHVWLJDWRUVKRXOGHYDOXDWHWKHODERUDWRU\YLWDOVLJQRU(&*DEQRUPDOLWLHV IRU FOLQLFDO
VLJQLILFDQFHWKH\VKRXOGEHUHSRUWHGDV$(VLIWKH\DUHV\PSWRPDWLFOHDGWRVWXG\GUXJ
GLVFRQWLQXDWLRQRUUHTXLUHFRUUHFWLYHWUHDWPHQW
8.8
Hospitalization, Prolonged Hospitalization or Surgery 
$Q\DGYHUVHHYHQWWKDWUHVXOWVLQKRVSLWDOL]DWLRQRUSURORQJHGKRVSLWDOL]DWLRQVKRXOGEH
GRFXPHQWHGDQGUHSRUWHGDVDVHULRXVDGYHUVHHYHQWXQOHVVVSHFLILFDOO\LQVWUXFWHGRWKHUZLVHLQ
WKLVSURWRFRO$Q\FRQGLWLRQUHVSRQVLEOHIRUVXUJHU\VKRXOGEHGRFXPHQWHGDVDQDGYHUVHHYHQWLI
WKHFRQGLWLRQPHHWVWKHFULWHULDIRUDQGDGYHUVHHYHQW1HLWKHUWKHFRQGLWLRQKRVSLWDOL]DWLRQ
SURORQJHGKRVSLWDOL]DWLRQQRUVXUJHU\DUHUHSRUWHGDVDQDGYHUVHHYHQWLQWKHIROORZLQJ
FLUFXPVWDQFHV
x
+RVSLWDOL]DWLRQRUSURORQJHGKRVSLWDOL]DWLRQIRUGLDJQRVWLFRUHOHFWLYHVXUJLFDO
SURFHGXUHVIRUDSUHH[LVWLQJFRQGLWLRQ
x
6XUJHU\VKRXOGQRWEHUHSRUWHGDVDQRXWFRPHRIDQDGYHUVHHYHQWLIWKHSXUSRVHRIWKH
VXUJHU\ZDVHOHFWLYHRUGLDJQRVWLFDQGWKHRXWFRPHZDVXQHYHQWIXO
x
+RVSLWDOL]DWLRQRUSURORQJHGKRVSLWDOL]DWLRQUHTXLUHGWRDOORZHIILFDF\PHDVXUHPHQWIRU
WKHVWXG\
x
+RVSLWDOL]DWLRQRUSURORQJHGKRVSLWDOL]DWLRQIRUWKHUDS\RIWKHWDUJHWGLVHDVHRIWKHVWXG\
XQOHVVLWLVDZRUVHQLQJRULQFUHDVHLQIUHTXHQF\RIKRVSLWDODGPLVVLRQVDVMXGJHGE\WKH
FOLQLFDO,QYHVWLJDWRU
8.9
Reporting of Serious Adverse Events and Unanticipated Problems
,QYHVWLJDWRUVDQGWKHVSRQVRUPXVWFRQIRUPWRWKHDGYHUVHHYHQWUHSRUWLQJWLPHOLQHVIRUPDWVDQG
UHTXLUHPHQWVRIWKHYDULRXVHQWLWLHVWRZKLFKWKH\DUHUHVSRQVLEOHEXWDWDPLQLPXPWKRVH
HYHQWVWKDWPXVWEHUHSRUWHGDUHWKRVHWKDWDUH
x
5HODWHGWRVWXG\SDUWLFLSDWLRQ
x
8QH[SHFWHGDQG
x
6HULRXVRULQYROYHULVNVWRSDWLHQWVRURWKHUVUHIHUWRGHILQLWLRQVVHFWLRQ
8.10
Clinical Investigator reporting and notifying the study sponsor
$Q\VWXG\UHODWHGXQDQWLFLSDWHGSUREOHPSRVLQJULVNRIKDUPWRSDWLHQWVRURWKHUVDQGDQ\W\SH
RIVHULRXVDGYHUVHHYHQWPXVWEHUHSRUWHGWRWKHVWXG\VSRQVRUE\WHOHSKRQHZLWKLQKRXUVRI
WKHHYHQW7RUHSRUWVXFKHYHQWVD6HULRXV$GYHUVH(YHQW6$(IRUPPXVWEHFRPSOHWHGE\WKH
LQYHVWLJDWRUDQGID[HGWRWKHVWXG\VSRQVRUZLWKLQKRXUV7KH&OLQLFDO,QYHVWLJDWRU ZLOONHHSD
FRS\RIWKLV6$(IRUPRQILOHDWWKHVWXG\FOLQLF:LWKLQWKHIROORZLQJKRXUVWKH&OLQLFDO
,QYHVWLJDWRUPXVWSURYLGHIXUWKHULQIRUPDWLRQRQWKHVHULRXVDGYHUVHHYHQWRUWKHXQDQWLFLSDWHG
SUREOHPLQWKHIRUPRIDZULWWHQQDUUDWLYH7KLVVKRXOGLQFOXGHDFRS\RIWKHFRPSOHWHG6HULRXV
$GYHUVH(YHQWIRUPDQGDQ\RWKHUGLDJQRVWLFLQIRUPDWLRQWKDWZLOODVVLVWWKHXQGHUVWDQGLQJRI
WKHHYHQW6LJQLILFDQWQHZLQIRUPDWLRQRQRQJRLQJVHULRXVDGYHUVHHYHQWVVKRXOGEHSURYLGHG

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
SURPSWO\WRWKHVWXG\VSRQVRU
8.11
Categorizing Relationship of AE’s to Investigational drug  
,QYHVWLJDWRUVZLOOGHWHUPLQHWKHUHODWLRQVKLSEHWZHHQHDFK$(DQGWKH,QYHVWLJDWLRQDOGUXJ7KH
GHWHUPLQDWLRQZLOOUHIOHFWZKHWKHULQWKHRSLQLRQRI WKH,QYHVWLJDWRUV
x
$UHODWLRQVKLSH[LVWV
x
3RVVLEO\H[LVWVRU
x
'RHVQRWH[LVW
7KHRXWFRPHRI$(VPXVWEHUHFRUGHGRQ&5)VRXWFRPHFDWHJRULHVDUHDVIROORZV
x
5HVROYHGQRVHTXHODH
x
6WLOOSUHVHQWQRWEHLQJWUHDWHG
x
6WLOOSUHVHQWDQGEHLQJWUHDWHG
x
5HVLGXDOHIIHFWVSUHVHQWEXWQRWWUHDWHG
x
5HVLGXDO HIIHFWVEXWEHLQJWUHDWHG
x
'HDWK
x
8QNQRZQ
6\PSWRPVRIWKHGLVHDVHXQGHUVWXG\PLJUDLQHVKRXOGQRWEHUHSRUWHGDV$(VDVORQJDVWKH\
DUHZLWKLQWKHQRUPDOGD\WRGD\IOXFWXDWLRQRUH[SHFWHGSURJUHVVLRQRIWKHGLVHDVH+RZHYHU
VLJQLILFDQWZRUVHQLQJRIWKHV\PSWRPVVKRXOGEHUHFRUGHGDVDQ$(
8.12
Non-Serious Adverse Events
$OODGYHUVHHYHQWVWKDWDUHQRWLGHQWLILHGDVVHULRXVRUOLIHWKUHDWHQLQJLVFRQVLGHUHGQRQVHULRXV
DGYHUVHHYHQWV1RQVHULRXVDGYHUVHHYHQWVZLOOEH LGHQWLILHGE\VHYHULW\DQGLVUHFRUGHGLQWKH
&5)SDWLHQW WRWKHSHUWLQHQWVHYHULW\VFDOH$QHZ$(LVUHFRUGHGLIDQGZKHQDSUHH[LVWLQJ$(
ZRUVHQV
7KHPHGLFDODVVHVVPHQWRIVHYHULW\LVGHWHUPLQHGE\XVLQJWKHIROORZLQJGHILQLWLRQV
x
0LOG$(WKDWLVWUDQVLHQWUHTXLULQJRQO\PLQLPDOWUHDWPHQW
x
0RGHUDWHDQ$(WKDWXVXDOO\UHTXLUHVWUHDWPHQWEXWSRVHVQRVLJQLILFDQWRUSHUPDQHQW
KDUPWRWKHSDWLHQW
x
6HYHUH$(WKDWLQWHUUXSWVDFWLYLWLHVRIGDLO\OLYLQJDQGPD\UHTXLUHLQWHQVLYHWUHDWPHQW
1RQVHULRXVDGYHUVHHYHQWVPXVWEHUHSRUWHGWRVSRQVRUE\WKHFRPSOHWLRQRIWKH$GYHUVH(YHQW
)RUP1RQVHULRXVDGYHUVHHYHQWVDQGQRQVHULRXVVXVSHFWHGDGYHUVHUHDFWLRQVDUHUHSRUWHGWR
WKHVSRQVRUSHULRGLFDOO\WKURXJKRXWWKHGXUDWLRQRIWKHVWXG\7KH&OLQLFDO,QYHVWLJDWRU PXVW
UHSRUWWKLVLQIRUPDWLRQWRWKHVSRQVRUZLWKLQDPD[LPXPRIGD\VRIWKHUHFRUGLQJRIWKHQRQ
VHULRXVVXVSHFWHGDGYHUVHHYHQW
8.13
Other Reportable Events
7KHIROORZLQJHYHQWVDUHDOVRUHSRUWDEOHWRWKHVSRQVRU

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
x
$Q\DGYHUVHH[SHULHQFHGHILQHGDVDQXQWRZDUGRUXQIDYRUDEOHPHGLFDORFFXUUHQFHLQD
KXPDQSDWLHQWLQFOXGLQJDQ\DEQRUPDOVLJQIRUH[DPSOHDEQRUPDOSK\VLFDOH[DPRU
ODERUDWRU\ILQGLQJV\PSWRPRUGLVHDVHWHPSRUDOO\DVVRFLDWHGZLWKWKHSDWLHQW¶V
SDUWLFLSDWLRQLQUHVHDUFKZKHWKHURUQRWFRQVLGHUHGUHODWHGWRWKHSDWLHQW¶V SDUWLFLSDWLRQLQ
WKHUHVHDUFKWKDWLVFRQVLGHUHG
x
6HULRXV'HDWKDOLIHWKUHDWHQLQJDGYHUVHGUXJH[SHULHQFHLQSDWLHQWKRVSLWDOL]DWLRQRU
SURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQDSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\RU
LQFDSDFLW\RUDFRQJHQLWDODQRPDO\RUELUWKGHIHFWDQG
x
8QH[SHFWHG$Q\DGYHUVHH[SHULHQFHWKHVSHFLILFLW\RUVHYHULW\RIZKLFKLVQRW
FRQVLVWHQWZLWKWKHFXUUHQW&OLQLFDO,QYHVWLJDWRUEURFKXUHRUFRQVHQWIRUPDQG
x
3RVVLEO\UHODWHG7KHUHLVDUHDVRQDEOHSRVVLELOLW\WKDWWKHLQFLGHQWH[SHULHQFHRU
RXWFRPHPD\KDYHEHHQDVVRFLDWHGZLWKWKHSURFHGXUHVLQYROYHGLQWKHUHVHDUFKDQG
x
,VH[SHULHQFHGE\DSDUWLFLSDQWLQDWULDO
x
,QIRUPDWLRQWKDWLQGLFDWHVDFKDQJHWRWKHULVNVRUSRWHQWLDOEHQHILWVRIWKHUHVHDUFKLQWHUPV
RIVHYHULW\RUIUHTXHQF\)RUH[DPSOH
x
$QLQWHULPDQDO\VLVLQGLFDWHVWKDWSDWLHQWV KDYHDORZHUUDWHRIUHVSRQVHWRWUHDWPHQW
WKDQLQLWLDOO\H[SHFWHG
x
6DIHW\PRQLWRULQJLQGLFDWHVWKDWDSDUWLFXODUVLGHHIIHFWLVPRUHVHYHUHRUPRUH
IUHTXHQWWKDQLQLWLDOO\H[SHFWHG
x
$SDSHULVSXEOLVKHGIURPDQRWKHUVWXG\WKDWVKRZVWKDWDQJURXSRI\RXUUHVHDUFK
VWXG\LVRIQRWKHUDSHXWLFYDOXH
x
&KDQJHLQ)'$VDIHW\ODEHOLQJRUZLWKGUDZDOIURPPDUNHWLQJRIDGUXJGHYLFHRUELRORJLF
XVHGLQDUHVHDUFKSURWRFRO
x
%UHDFKRIFRQILGHQWLDOLW\
x
&KDQJHWRWKHSURWRFROWDNHQZLWKRXWSULRU,5%UHYLHZWRHOLPLQDWHDSSDUHQWLPPHGLDWH
KD]DUGWRDUHVHDUFKSDUWLFLSDQW
x
&RPSODLQWRIDSDUWLFLSDQWZKHQWKHFRPSODLQWLQGLFDWHVXQH[SHFWHGULVNVRUWKHFRPSODLQW
FDQQRWEHUHVROYHGE\WKHUHVHDUFKWHDP
x
3URWRFROYLRODWLRQ PHDQLQJDQDFFLGHQWDORUXQLQWHQWLRQDOYLRODWLRQIURPWKH,5%DSSURYHG
SURWRFROWKDWLQWKHRSLQLRQRIWKH&OLQLFDO,QYHVWLJDWRUSODFHGRQHRUPRUHSDWLHQWV DW
LQFUHDVHGULVNRUDIIHFWVWKHULJKWVRUZHOIDUHRISDWLHQWV
8.14
Sponsor Reporting and Notifying the FDA
7KHVWXG\VSRQVRULVUHTXLUHGWRUHSRUWFHUWDLQVWXG\HYHQWVLQDQH[SHGLWHGIDVKLRQWRWKH)'$
7KHVHZULWWHQQRWLILFDWLRQVRI$(V DUHUHIHUUHGWRDV,1'VDIHW\UHSRUWV7KHIROORZLQJGHVFULEHV
WKHVDIHW\UHSRUWLQJUHTXLUHPHQWVE\WLPHOLQHIRUUHSRUWLQJDQGDVVRFLDWHGW\SHRIHYHQW
x
:LWKLQFDOHQGDUGD\V

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
$Q\VWXG\HYHQWDVVRFLDWHGZLWKWKHXVHRIWKHVWXG\GUXJWKDWLV
x
8QH[SHFWHG
x
)DWDORUOLIHWKUHDWHQLQJDQG
x
:LWKLQFDOHQGDUGD\V$Q\VWXG\HYHQWDVVRFLDWHGZLWKWKHXVHRIWKHVWXG\GUXJWKDWLV
x
8QH[SHFWHGDQG
x
6HULRXVEXWQRWIDWDORUOLIHWKUHDWHQLQJ
2U
x
$SUHYLRXVDGYHUVHHYHQWWKDWZDVQRWLQLWLDOO\GHHPHGUHSRUWDEOHEXWLVODWHUIRXQGWRILW
WKHFULWHULDIRUUHSRUWLQJUHSRUWLQJZLWKLQFDOHQGDUGD\VIURPZKHQHYHQWZDVGHHPHG
UHSRUWDEOH
8.15
FDA Reporting Process and Sponsor Notifying Participating Investigators
$GYHUVHHYHQWVPD\EHVXEPLWWHGRQ)'$)RUP$RULQDQDUUDWLYHIRUPDW
7KHVSRQVRULVUHVSRQVLEOHRIQRWLI\LQJDOOWKHLQYHVWLJDWRUVRIDQ\VHULRXVDQGRUXQH[SHFWHG
DGYHUVHHYHQWDVVRFLDWHGZLWKWKHXVHRIWKHGUXJ$GGLWLRQDOO\WKHVSRQVRULVUHTXLUHGWR
LGHQWLI\LQWKH,1'VDIHW\UHSRUWVDOOSUHYLRXVUHSRUWVFRQFHUQLQJVLPLODUDGYHUVHHYHQWVDQGWR
DQDO\]HWKHVLJQLILFDQFHRIFXUUHQWHYHQWLQOLJKWRIWKHSUHYLRXVUHSRUWV
8.16
Pregnancy Prevention and Counseling
:RPHQRIFKLOGEHDULQJSRWHQWLDODUHGHILQHGDVDQ\IHPDOHZKRKDVH[SHULHQFHGPHQDUFKHDQG
ZKRLV127SHUPDQHQWO\VWHULOHRUSRVWPHQRSDXVDO3RVWPHQRSDXVDOLVGHILQHGDV
FRQVHFXWLYHPRQWKVZLWKQRPHQVHVZLWKRXWDQDOWHUQDWLYHPHGLFDOFDXVH
7KHIHPDOHSDWLHQWZKRLVSUHPHQRSDXVDORUSRVWPHQRSDXVDOOHVVWKDQ\HDURUKDYHQRWKDG
VXUJLFDOVWHULOL]DWLRQLHWXEDOOLJDWLRQSDUWLDORUFRPSOHWHK\VWHUHFWRP\PXVWKDYHD QHJDWLYH
XULQHSUHJQDQF\WHVWEHQRQODFWDWLQJDQGFRPPLWWRXVLQJPHWKRGVRIDGHTXDWHDQGUHOLDEOH
FRQWUDFHSWLRQWKURXJKRXWWKHVWXG\DQGIRUGD\VDIWHUWDNLQJWKHODVWGRVHRIWKHVWXG\GUXJ
HJEDUULHUZLWKDGGLWLRQDOVSHUPLFLGDOLQWUDXWHULQHGHYLFHKRUPRQDOFRQWUDFHSWLRQ
7KH&OLQLFDO,QYHVWLJDWRU ZLOOGLVFXVVZLWKZRPHQRIFKLOGEHDULQJDJHEHIRUHHQUROOPHQWWKH
LPSRUWDQFHRIDYRLGLQJSUHJQDQF\GXULQJWULDOSDUWLFLSDWLRQDQGWKHSRWHQWLDOULVNIDFWRUVIRUDQ
XQLQWHQWLRQDOSUHJQDQF\SUHJQDQF\SUHYHQWLRQLQIRUPDWLRQFRQWUDFHSWLYHVLQFXUUHQWXVHDQG
JXLGHOLQHVIRUWKHIROORZXSRIDUHSRUWHGSUHJQDQF\7KHSDWLHQW PXVWVLJQDQ,QIRUPHG&RQVHQW
VWDWLQJWKDWWKHDERYHPHQWLRQHGULVNIDFWRUVDQGWKHFRQVHTXHQFHVZHUHGLVFXVVHGZLWKKHU
'XULQJWKHWULDODOOZRPHQRIFKLOGEHDULQJSRWHQWLDOVKRXOGEHLQVWUXFWHGWRFRQWDFWWKH&OLQLFDO
,QYHVWLJDWRULPPHGLDWHO\LIWKH\VXVSHFWWKH\PLJKWEHSUHJQDQW,ISUHJQDQF\LVFRQILUPHGWKH
LQYHVWLJDWLRQDOGUXJ ZLOOEHGLVFRQWLQXHGDQGWKHSDWLHQW ZLOOEHZLWKGUDZQIURPWKHWULDO
$Q\SUHJQDQF\RIDVWXG\SDUWLFLSDQWPXVWEHUHSRUWHGWRWKHVSRQVRUZLWKLQRQHEXVLQHVVGD\
7KHVWXG\SDUWLFLSDQWPXVWEHZLWKGUDZQIURPWKHVWXG\(YHU\HIIRUWVKRXOGEHPDGHWRJDWKHU
LQIRUPDWLRQUHJDUGLQJWKHSUHJQDQF\RXWFRPHDQGFRQGLWLRQRIWKHLQIDQW,WLVWKHGXW\RIWKH
&OLQLFDO,QYHVWLJDWRU WRREWDLQWKLVLQIRUPDWLRQZLWKLQFDOHQGDUGD\VDIWHUWKHLQLWLDO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
QRWLILFDWLRQDQGDSSUR[LPDWHO\FDOHQGDU GD\VSRVWSDUWXP
3UHJQDQF\FRPSOLFDWLRQVVXFKDVVSRQWDQHRXVDERUWLRQPLVFDUULDJHRUFRQJHQLWDODEQRUPDOLW\
DUHFRQVLGHUHG6$(VDQGPXVWEHUHSRUWHGXVLQJWKH6HULRXV$GYHUVH(YHQW)RUP$QHOHFWLYH
DERUWLRQLVQRWFRQVLGHUHGDVHULRXVDGYHUVHHYHQW6$(
8.17
Abuse, Misuse, Overdose and Medication Error of Investigational Drug
$EXVHPLVXVHRYHUGRVHRUPHGLFDWLRQHUURUUHJDUGLQJWKLVVWXG\¶V,QYHVWLJDWLRQDOGUXJPXVWEH
UHSRUWHGWRWKHVSRQVRUIROORZLQJWKH6$(UHSRUWLQJSURFHGXUHZKHWKHURUQRWWKH\UHVXOWLQDQ
$(6$(KRZHYHUWKHRQHEXVLQHVVGD\UHSRUWLQJUHTXLUHPHQWIRU6$(VGRHVQRWDSSO\WR
UHSRUWVRIDEXVHPLVXVHRYHUGRVHRUPHGLFDWLRQHUURUVXQOHVVWKHVHUHVXOWLQDQ6$(
$PHGLFDWLRQHUURUPDGHUHJDUGLQJSUHVFULELQJGLVSHQVLQJDGPLQLVWUDWLRQDQGRUXVHRIDQ
,QYHVWLJDWLRQDOGUXJ ZLOOEHUHSRUWHGDVDPDMRUSURWRFROYLRODWLRQ0HGLFDWLRQHUURUVVKRXOGEH
FROOHFWHGDQGUHSRUWHGRQO\IRUWKH,QYHVWLJDWLRQDOGUXJ7KHDGPLQLVWUDWLRQDQGRUXVHRIDQ
H[SLUHGSURGXFWVKRXOGEHFRQVLGHUHGDVDUHSRUWDEOHPHGLFDWLRQHUURUPLVVLQJGRVHVDUHQRW
UHSRUWDEOHDVPHGLFDWLRQHUURUV
7KHSRWHQWLDOIRUPLVXVHRUDEXVHRIQDOWUH[RQHRUDFHWDPLQRSKHQLVORZ
7KHGHILQLWLRQRIDQRYHUGRVHZLWKWKHLQYHVWLJDWLRQDOGUXJIRUWKHSXUSRVHRIWKLVVWXG\LVLQWDNH
RIPRUHWKDQWDEOHWVSHUGD\LQWHQWLRQDORUXQLQWHQWLRQDO7KLVFRUUHVSRQGVWRFRQVXPSWLRQ
RIPRUHWKDQPJRIDFHWDPLQRSKHQ7ZHOYH WDEOHWVRIWKHLQYHVWLJDWLRQDOGUXJFRQWDLQ
PJRIQDOWUH[RQHZKLFKLVORZHUWKDQWKHPJGD\DSSURYHGGRVH7KHRFFXUUHQFHRIDQ
RYHUGRVHZLWKWKHLQYHVWLJDWLRQDOGUXJZLOOPDQDJHG DVDQHPHUJHQF\
9
DATA HANDLING AND RECORD KEEPING
9.1
Data Management Responsibilities
'DWDFROOHFWLRQDQGDFFXUDWHGRFXPHQWDWLRQDUHWKHUHVSRQVLELOLW\RIWKHVLWHVWXG\VWDIIXQGHUWKH
VXSHUYLVLRQRIWKH,QYHVWLJDWRU7KH,QYHVWLJDWRUPXVWUHYLHZDOOVRXUFHGRFXPHQWVDQG
ODERUDWRU\UHSRUWVIRUDFFXUDF\DQGFRPSOHWHQHVV7KHLQYHVWLJDWRURUGHVLJQHHPXVWDGGUHVV DQ\
XQDQWLFLSDWHGSUREOHPVWKDWPLJKWRFFXU
9.2
Source Documentation Requirements
'DWDVKRXOGEHKDQGOHGLQDFFRUGDQFHZLWK*&386IHGHUDOUHJXODWLRQVDQGORFDOUHJXODWLRQV
LIDSSOLFDEOH$OOVRXUFHGRFXPHQWVVKRXOGEHILOOHGRXWFRPSOHWHO\E\WKH&OLQLFDO,QYHVWLJDWRU
RUWKHVWXG\FRRUGLQDWRUDQGVKRXOGEHVLJQHGE\WKHSHUVRQFROOHFWLQJWKHGDWDRQWKDWIRUP7KH
&OLQLFDO,QYHVWLJDWRUZLOOUHYLHZVLJQDQGGDWHGWKHVRXUFHGRFXPHQWV:KHQHYHUSRVVLEOH
VRXUFHGRFXPHQWVVKRXOGQRWLGHQWLI\SDWLHQWVE\QDPHEXWE\VWXG\,'VXFKLGHQWLILHUV
IDFLOLWDWHFURVVLQGH[LQJRIWKHSDUWLFLSDQW¶VGDWDZKLOHSURWHFWLQJWKHSDWLHQW¶VSULYDF\
'DWDHQWULHVLQWRVRXUFH&5)GRFXPHQWVVKRXOGEHPDGHLQEOXHRUEODFNLQN&RUUHFWLRQVVKRXOG
EHPDGHZLWKDVLQJOHOLQHWKURXJKWKHHQWU\DQGWKHFKDQJHLQLWLDOHGDQGGDWHGRULJLQDOHQWULHV
VKRXOGUHPDLQOHJLEOHLHWKH\VKRXOGQHYHUEHHUDVHGRUFRYHUHGZLWKFRUUHFWLRQIOXLGWR
REVFXUHWKHRULJLQDOHQWU\ODWHHQWULHVVKRXOGEHLQLWLDOHGDQGGDWHGDWWKHWLPHHQWHUHG

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
6RXUFHGRFXPHQWVIRUSDWLHQWVZKRDUHVFUHHQHGEXWQRWHQUROOHGPXVWEHUHWDLQHGIROORZLQJWKH
VDPHJXLGHOLQHVDVRWKHUVWXG\VRXUFHGRFXPHQWV
9.3
Data collection into Case Report Forms (CRF)
7KHVSRQVRUZLOOSURYLGHGXSOLFDWHFDUERQOHVVSDSHU&5)VWRFROOHFWWKHVSHFLILFGDWDQHHGHGWR
DQVZHUWKLVVWXG\¶VUHVHDUFKTXHVWLRQV
7KHLQYHVWLJDWRUVZLOOHQWHUWKHGDWDRQGXSOLFDWH&DVH5HSRUW)RUPV&5)VDQGWKHILHOGVWXG\
PRQLWRUVZLOOUHYLHZWKH&5)VIRUFRPSOHWHQHVVDQGDFFXUDF\7KHILHOGVWXG\PRQLWRUVZLOO
FROOHFWDQGIRUZDUGWKHRULJLQDOFRS\RIWKH&5)IRUPVWRWKHVSRQVRUWKHVHFRQGFRS\ZLOO
UHPDLQDWWKHVWXG\VLWH7KHRULJLQDOFRS\RIWKH&5)ZLOOEHIRUZDUGHGWRWKH6SRQVRU¶V'DWD
0DQDJHPHQWWHDPRQFHWKH6SRQVRU¶V'DWD0DQDJHPHQWWHDPUHFHLYHVWKH&5)VUHFHLSWZLOO
EHUHFRUGHGWKHRULJLQDOFRS\ZLOOEHSODFHGLQ&HQWUDO)LOHVDQGDZRUNLQJFRS\ZLOOEHPDGH
DQGIRUZDUGHGWRWKHUHVSRQVLEOHGDWDPDQDJHPHQWVWDIIIRUSURFHVVLQJ'DWDLWHPVIURPWKH
&5)VZLOOEHHQWHUHGLQWRWKHVWXG\GDWDEDVHXVLQJGRXEOHGDWDHQWU\ZLWKYHULILFDWLRQXSRQ
VHFRQGHQWU\
6FUHHQHGSDWLHQWVDUHGHILQHGDVSDWLHQWVZKRVLJQHGWKH,QIRUPHG&RQVHQW6FUHHQHGSDWLHQWV
ZKRGLVFRQWLQXHGSULRUWRUDQGRPL]DWLRQZLOOEHUHFRUGHGDVVFUHHQIDLOXUHV$OOVFUHHQHG
SDWLHQWVLQFOXGLQJVFUHHQHGIDLOXUHVZLOOEH HQWHUHGLQWRDVFUHHQLQJORJDVHSDUDWH&5)OLNH
GRFXPHQW,WZLOOEHSURFHVVHGOLNHDQ\RWKHU&5)SDJH
9.4
Data Entry Errors
$Q\FKDQJHWRD&5) HQWU\RQFHWKHGDWDKDVEHHQVXEPLWWHGUHTXLUHVWKH,QYHVWLJDWRU¶V
VLJQDWXUHDFRPPHQWH[SODLQLQJWKHUHDVRQWKHGDWDZDVFKDQJHGDQGFRPSOHWLRQRID'DWD
&RUUHFWLRQ)RUP'&)
10 STATISTICAL METHODS
10.1
Management of the Statistical Analysis Plan
$OOVWDIILQYROYHGZLWKWKHDQDO\VLVRIWKHVWXG\ZLOOUHPDLQEOLQGHGXQWLOSURWRFROYLRODWRUVDUH
LGHQWLILHG DQGWKHGDWDEDVHLVORFNHG$FRPSUHKHQVLYH6WDWLVWLFDO$QDO\VLV3ODQ6$3ZLOOEH
SUHSDUHGEHIRUHWKHILUVWSDWLHQWLVUDQGRPL]DWLRQ3ULRUWRWKHXQEOLQGLQJRIWKHGDWDWKH6$3LV
ILQDOL]HGWRUHIOHFWWKHSURWRFRODQGDQ\DPHQGPHQWV7KHVSRQVRURUGHVLJQHHZLOOSHUIRUPWKH
GDWDDQDO\VLV
10.2
Sample Size Determination
7RGHWHUPLQHWKHVDPSOHVL]HIRUWKHPLJUDLQHSUHYHQWLRQVWXG\WKHUHVXOWVRIWZRSUHYLRXV
VWXGLHVZHUHFRQVLGHUHG
$Q,1'GRXEOHEOLQGFOLQLFDOWULDOIRUEDFNSDLQZLWKQDOWUH[RQH
PJFORQLGLQH
PJELG
FDSWXUHGGDWDIRUFRQFRPLWDQWKHDGDFKHPLJUDLQH7KHWDEOHEHORZVKRZVWKHFKDQJHLQ
KHDGDFKHGD\IUHTXHQF\IURPEDVHOLQHWRZHHNODVWZHHNRIWUHDWPHQW7KHUHVXOWVIRU
KHDGDFKHGD\VZHUHVWDWLVWLFDOO\VLJQLILFDQWZLWKQDOWUH[RQH
PJFORQLGLQH
PJJURXSRI
VXEMHFWVDQGSODFHERRIVXEMHFWV:HEHOLHYHQDOWUH[RQHDFHWDPLQRSKHQLVHYHQPRUH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
SRWHQWWKDQQDOWUH[RQHFORQLGLQH
7KH)'$JUDQWHGQDOWUH[RQHFORQLGLQHDEUHDNWKURXJKGHVLJQDWLRQEDVHGRQWKH,1'VWXG\
ANALYSIS OF CHANGE FROM BASELINE IN WEEKLY FREQUENCY TO WEEK 3 IN MIGRAINE SUBJECTS
Treatment
N
Weekly Frequency of Migraine Days
Baseline
WK3
Change (Standard Error)
p-value
Placebo
10
2.60
1.50
1.10 (0.85)
0.04284
ATNC05
13
3.85
0.00
3.85 (0.90)
Groups 
All Migraine Subjects
Method
t-Test, 2-sided
P Value
0.04284
Mean Difference
-2.75
Standard Error
± 0.88
95% Confidence Interval
(-0.050 to 5.550)
7KHVHFRQGVWXG\ZDVDQDFXWHPLJUDLQHSLORWVWXG\ZKHUHQDOWUH[RQH
PJDFHWDPLQRSKHQ
PJ1 YVQDOWUH[RQH
PJ
PJ1 KHDGDFKHSDLQIUHHDWPLQXWHZDV
YV&DOFXODWLQJ WKHVDPSOHVL]HEDVHGRQRGGVUDWLRRI\LHOGVSDWLHQWV
SHUJURXS
7KHVWXG\SODQVWRHQUROO SDWLHQWVSHUJURXSWRDOORZIRUJUHDWHUSRZHU
7KHPLJUDLQHSUHYHQWLRQ VWXG\LVDSURRIRIFRQFHSWVWXG\7KHLQYHVWLJDWRUK\SRWKHVL]HVD
UHGXFWLRQLQPLJUDLQHKHDGDFKHGD\VLQWKH$//2'JURXSYHUVXVWKHSODFHERJURXSIRU
ZKLFKSDWLHQWVLQHDFKJURXSFDQSURYLGHVWDWLVWLFDOVLJQLILFDQFH 
10.3
Analysis Populations 
7KHDQDO\VLVSRSXODWLRQVZLOOEHDVIROORZV
6FUHHQHGSDWLHQWVWKHVFUHHQHGSDWLHQW¶VSRSXODWLRQFRQVLVWVRIDOOWKHSDWLHQWVZKRVLJQHGWKH
,QIRUPHG&RQVHQW6FUHHQ)DLOXUHVDUHVFUHHQHGSDWLHQWVZKRZHUHQRWUDQGRPL]HG7KHVFUHHQHG
SRSXODWLRQLQFOXGHVVFUHHQIDLOXUHVDQGUDQGRPL]HGSDWLHQWV
,QWHQWWRWUHDW,77SRSXODWLRQFRQVLVWVRIDOOSDWLHQWV ZKRZHUHUDQGRPL]HGZKRWRRNWKHVWXG\
GUXJUHFRUGHGEDVHOLQHSDLQDVPRGHUDWHRUVHYHUHDQGKDGDWOHDVWSRVWEDVHOLQHHIILFDF\
HYDOXDWLRQ$OOHIILFDF\DQDO\VHVDUHFRQGXFWHGRQWKH,77SRSXODWLRQ
6DIHW\SDWLHQWSRSXODWLRQFRQVLVWVRIDOOSDWLHQWVZKRKDYHUHFHLYHG WKHLQYHVWLJDWLRQDOGUXJ
3HU3URWRFROSRSXODWLRQFRQVLVWVRIDOOSDWLHQWV ZKRGLGQRWSUHVHQWZLWKDQ\PDMRUSURWRFRO
GHYLDWLRQVLQDFFRUGDQFHZLWKWKHVWXG\VSHFLILFLQFOXVLRQH[FOXVLRQFULWHULD 'HWHUPLQDWLRQRI
WKHSHUSURWRFRODQDO\VLVVHWLVPDGHEHIRUHXQELQGLQJRIWKHWULDO3URWRFROGHYLDWLRQVZLOOQRW
QHFHVVDULO\UHVXOWLQGLVFRQWLQXDWLRQRIWKHWULDO7KHSHUSURWRFRODQDO\VLVSRSXODWLRQZLOOEH
 KWWSSRZHUDQGVDPSOHVL]HFRP

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
XVHG IRUVHQVLWLYLW\DQDO\VHVRIWKHSULPDU\HQGSRLQW
10.4
Statistical Analyses
$OOVWDWLVWLFDODQDO\VLVZLOOVXPPDUL]HWKHQXPEHUDQGSHUFHQWRISDWLHQWV'HVFULSWLYH
VWDWLVWLFVE\WUHDWPHQWJURXSPHDQVWDQGDUGGHYLDWLRQPHGLDQPLQLPXPPD[LPXPDQG
FRQILGHQFHLQWHUYDOVZLOOEHSURYLGHG
$KHDGDFKHGD\LVGHILQHGDVDFDOHQGDUGD\GXULQJZKLFKDSDWLHQWKDGDPLJUDLQHKHDGDFKH
ODVWLQJPLQXWHVDPLJUDLQHKHDGDFKHLVGHILQHGDVPRGHUDWHWRVHYHUHKHDGDFKHZLWKDW
OHDVWRQHPLJUDLQHDVVRFLDWHGV\PSWRPLHOLJKWVHQVLWLYLW\QRLVHVHQVLWLYLW\QDXVHD
6WDWLVWLFDODQDO\VLVZLOOEHSHUIRUPHGRQSDWLHQWUHSRUWHGGDWDIURPWKHPLJUDLQHGLDU\
SDWLHQWUHSRUWHGGDWDIURPVLWHYLVLWVDQGGDWDFROOHFWHGGXULQJVLWHYLVLWV
$QDO\VLVZLOOEHSHUIRUPHGIRUWKHFRPSDULVRQRIWKHUHGXFWLRQLQWKHPHDQ PLJUDLQH
KHDGDFKHGD\VKHDGDFKHGD\VRUPRUHUHGXFWLRQLQPRQWKO\PLJUDLQHIUHTXHQF\
VHYHULW\GXUDWLRQQDXVHDVHYHULW\OLJKWVHQVLWLYLW\QRLVHVHQVLWLYLW\DQGGD\VRIUHVFXH
PHGLFDWLRQLQWDNHIURPEDVHOLQHWRWKHODVWGD\VRIWKHZHHN7UHDWPHQW3HULRG
$QDO\VLVZLOOEHSHUIRUPHGIRUWKHFRPSDULVRQRIWKHUHGXFWLRQLQ0,'$6+,7DQG
3,56IURPEDVHOLQHWR(QGRIWUHDWPHQW9LVLW
10.5
Missing Data Imputation
0LVVLQJGDWDLPSXWDWLRQZLOOEHGHWHUPLQHGSULRUWRGDWDORFNRXW
10.6
Analysis of Patients Background Data 
7KHDQDO\VLVRIWKHEDFNJURXQGGDWDZLOOLQFOXGHSDWLHQWGHPRJUDSKLFVKLVWRU\RIPLJUDLQH
EDVHOLQHPLJUDLQHGXUDWLRQDQGFKDUDFWHULVWLFVEDVHOLQHFRQFRPLWDQWPHGLFDWLRQVDQGEDVHOLQH
FRQFRPLWDQWLOOQHVVHVSUHVHQWHGE\WUHDWPHQWJURXS
10.7
Statistical Analysis of the Study Endpoints
3ULPDU\(QGSRLQW

&KDQJHIURPEDVHOLQHLQWKHPHDQ QXPEHURIPLJUDLQHSUREDEOHPLJUDLQHKHDGDFKH
GD\V
'HVFULSWLRQ 3UREDEOHPLJUDLQHLV GHILQHGE\,&+'±EHWDYHUVLRQFULWHULDLVDQ
DWWDFNIXOILOOLQJDOOEXWRQHRIFULWHULD$'IRUPLJUDLQHZLWKRUZLWKRXW DXUD
KHDGDFKHVPXVWEHPRGHUDWHRU VHYHUHDQGODVWLQJPLQXWHV
7LPH)UDPH )URPWKHGD\EDVHOLQHSHULRGWRWKHODVWGD\VRIWKH ZHHN
7UHDWPHQW3HULRG
6HFRQGDU\(QGSRLQWV

&KDQJHIURPEDVHOLQHLQWKHPHDQ QXPEHURIKHDGDFKHGD\V
'HVFULSWLRQ +HDGDFKHGD\VDUHGHILQHGDVQRQHPLJUDLQHKHDGDFKHGD\VSOXV
PLJUDLQHKHDGDFKHGD\V
7LPH)UDPH )URPWKHGD\ EDVHOLQH SHULRGWRWKHODVWGD\VRIWKHZHHN
7UHDWPHQW3HULRG

3URSRUWLRQRISDWLHQWVZLWKRUPRUHUHGXFWLRQLQPLJUDLQHSUREDEOHPLJUDLQH
KHDGDFKHGD\V
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\VRIWKHZHHN

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ PLJUDLQHVHYHULW\
'HVFULSWLRQ0HDVXUHGRQDSRLQWUDWLQJ VFDOH QRQH PLOG PRGHUDWH
 VHYHUH
7LPH)UDPH)URPWKHGD\EDVHOLQHSHULRGWRWKHODVWGD\VRIWKHZHHN
7UHDWPHQW3HULRG

&KDQJH IURPEDVHOLQH LQWKHPHDQ PLJUDLQHGXUDWLRQ
7LPH)UDPH)URPWKHGD\EDVHOLQHSHULRGWRWKHODVWGD\VRIWKHZHHN
7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ QDXVHDVHYHULW\
'HVFULSWLRQ0HDVXUHGRQDSRLQWUDWLQJ VFDOH QRQH PLOG PRGHUDWH
 VHYHUH
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\VRIWKHZHHN
7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ QXPEHURIDFXWHPLJUDLQHPHGLFDWLRQVLQWDNH
GD\V
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\VRIWKHZHHN
7UHDWPHQW3HULRG

3URSRUWLRQRISDWLHQWVVDWLVILHGRUH[WUHPHO\VDWLVILHGZLWKPLJUDLQHSUHYHQWLRQ
7LPH)UDPH ZHHN

&KDQJHIURPEDVHOLQHLQWKHPHDQPLJUDLQHGLVDELOLW\DVVHVVPHQWVFDOH0,'$6
7LPH)UDPH )URPEDVHOLQHWRZHHN RIWKH 7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ KHDGDFKHLPSDFWWHVW+,7
7LPH)UDPH )URPWKHGD\ EDVHOLQHSHULRGWRWKHODVWGD\VRIWKHZHHN
7UHDWPHQW3HULRG

&KDQJHIURPEDVHOLQHLQWKHPHDQ 3LWWVEXUJK,QVRPQLD5DWLQJ6FDOH3,56
7LPH)UDPH )URPEDVHOLQHWRZHHN RIWKH 7UHDWPHQW3HULRG
6DIHW\(QGSRLQWV

&RPSDULVRQRIWKHSURSRUWLRQRISDWLHQWVZKRH[SHULHQFHGDGYHUVHHYHQWVGHILQHG
DVDQ\XQWRZDUGPHGLFDORFFXUUHQFHVUHJDUGOHVVRIWKHLUVXVSHFWHGFDXVH
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG

&RPSDULVRQRIWKHSURSRUWLRQRISDWLHQWVZKRH[SHULHQFHGWUHDWPHQWHPHUJHQW
DGYHUVHHYHQWV
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG

&RPSDULVRQRIWKHFKDQJHIURPVFUHHQLQJLQWKHPHDQ EORRGFRXQWVKHSDWLFDQG
UHQDOIXQFWLRQ
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG

&RPSDULVRQRIWKHFKDQJHIURPVFUHHQLQJ LQWKHPHDQ V\VWROLFEORRGSUHVVXUH
GLDVWROLFEORRGSUHVVXUHDQGSXOVH
7LPH)UDPH $ ZHHN7UHDWPHQW3HULRG
10.8
Safety Analysis Considerations
9LWDOVLJQVDQGODERUDWRU\GDWDKHPDWRORJLFKHSDWLFDQGUHQDOIXQFWLRQZLOOEHREWDLQHGDW
EDVHOLQHDQGGD\VSRVWGRVH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
10.9
Adverse Event Classification
7KH0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV0HG'5$&ODVVLILFDWLRQV\VWHPZLOOEHXVHG
WRFODVVLI\$(V7($(LVGHILQHGDVDQ$(WKDWHPHUJHGRUZRUVHQHGGXULQJWUHDWPHQW7KH
7($(ZLOOEH FODVVLILHGE\WUHDWPHQWVHULRXVQHVV VHYHULW\V\VWHPRUJDQFODVVDQGUHODWLRQVKLS
WRWKHVWXG\GUXJ$QHYHQWRFFXUULQJPRUHWKDQRQFHLQWKHVDPHSDWLHQWZLOOEHFRXQWHGRQO\
RQFH'HDWKV6$(VDQGWUHDWPHQWGLVFRQWLQXDWLRQGXHWR$(VZLOOEHWDEXODWHG
10.10 Interim Analysis
,QWHULPDQDO\VLVZLOOQRWEHSHUIRUPHG
11 STUDY ADMINISTRATION
11.1
Study Oversight
7KH,QYHVWLJDWRULVUHVSRQVLEOHIRUVWXG\RYHUVLJKWLQFOXGLQJPRQLWRULQJVDIHW\HQVXULQJWKDWWKH
VWXG\LVFRQGXFWHGDFFRUGLQJWRWKHSURWRFRODQGHQVXULQJGDWDLQWHJULW\7KH,QYHVWLJDWRUZLOO
UHYLHZWKHGDWDIRUVDIHW\FRQFHUQVDQGGDWDWUHQGVDWUHJXODULQWHUYDOVDQGZLOOSURPSWO\UHSRUW
WRWKHVSRQVRUDQGWKH,5%DQ\XQDQWLFLSDWHGSUREOHPSURWRFROYLRODWLRQRUDQ\RWKHU
VLJQLILFDQWHYHQWWKDWDULVHVGXULQJWKHFRQGXFWRIWKHVWXG\
11.2
Responsibilities of the Study Sites
(DFKVWXG\VLWHLVUHVSRQVLEOHIRUHQUROOLQJWULDOSDWLHQWVH[HFXWLQJWKHWULDOSURWRFROFROOHFWLQJ
WULDOGDWDFRPSO\LQJZLWKUHJXODWRU\UHTXLUHPHQWVDQGSURYLGLQJFOLQLFDORYHUVLJKW7KHVSRQVRU
ZLOOVXSSRUWWKHVLWHVWKURXJKWKLVSURFHVVDQGIDFLOLWDWHWUDLQLQJDQGLPSOHPHQWDWLRQRIWULDO
6LWHV VHOHFWHGIRUWKLVWULDODUHUHTXLUHGWRKDYHSULRUH[SHULHQFHZLWKSDLQVWXGLHVIDPLOLDULW\
ZLWKSDLQDVVHVVPHQWLQVWUXPHQWVDQGGHGLFDWHGUHVHDUFKVWDII
7KHVWXG\VLWHVWDIIPXVWLQFOXGHDGHVLJQDWHG,QYHVWLJDWRU0HGLFDO'RFWRURU'RFWRURI
2VWHRSDWK\DFOLQLFDOUHVHDUFKFRRUGLQDWRU&5&DQGDQRQVLWHSKOHERWRPLVW7KHVLWHLV
UHTXLUHGWRKDYHDQHOHFWURFDUGLRJUDPPDFKLQHDFFHVVLELOLW\WR/DE&RUSEORRGVDPSOH
VXEPLVVLRQKLJKVSHHGLQWHUQHW DQGDORFNHGVWRUDJHDUHDDVGHVFULEHGEHORZ
7KH&OLQLFDO,QYHVWLJDWRULVUHTXLUHGWRGLVFORVHDQ\ILQDQFLDODUUDQJHPHQWGXULQJWKHWULDODQGIRU
\HDUDIWHUSHUWDLQLQJWRDQ\VLJQLILFDQWHTXLW\LQWHUHVWLQWKHVSRQVRUDVGHILQHGLQ&)5
E$VFRPSHQVDWLRQIRUSDUWLFLSDWLRQLQWKHWULDOWKHVSRQVRUSD\VWKH&OLQLFDO,QYHVWLJDWRU WKH
VXPVVHWRXWLQWKHSD\PHQWVFKHGXOHDWWDFKHGWRWKH&OLQLFDO,QYHVWLJDWRU DJUHHPHQW
11.3
Investigator Responsibilities
7KH,QYHVWLJDWRUKDVWKHRYHUDOOUHVSRQVLELOLW\IRUDOODVSHFWVRIWKHVWXG\FOLQLF7KH,QYHVWLJDWRU
KDVWKHIROORZLQJDGPLQLVWUDWLYHDQGFOLQLFDOUHVSRQVLELOLWLHV
x
3URYLGLQJSDWLHQWVLQIRUPDWLRQDERXWWKHWULDODQGREWDLQLQJWKH,QIRUPHG&RQVHQWIURP
WKHWULDO SDWLHQWV
x
&RPSOLDQFHRIWKHVWXG\VLWHZLWKUHJXODWRU\UHTXLUHPHQWVDQGWULDOGRFXPHQWDWLRQ
LQFOXGLQJWKLV3URWRFRO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
x
3HUIRUPDQFHRIWULDOSURFHGXUHVLQDFFRUGDQFHZLWKWKLV3URWRFRO
x
&RPSOHWLRQRIUHTXLUHGWUDLQLQJLQFOXGLQJDWWHQGLQJDQ\WULDOLQYHVWLJDWRU¶V PHHWLQJV
DQGKXPDQSDWLHQWSURWHFWLRQWUDLQLQJ
x
3URYLVLRQRIVXIILFLHQWWUDLQLQJDQGVXSSRUWIRUVWXG\VLWHVWDII
x
5HSRUWLQJRIDOO6HULRXV$GYHUVH(YHQWV6$(VZLWKLQKRXUVRIORFDOHYHQW
DZDUHQHVVEXWQRODWHUWKDQWKHQH[WEXVLQHVVGD\WRWKHVSRQVRUZLWKIXOOZULWWHQ
UHSRUWWRIROORZ
x
5HYLHZRIDQGWLPHO\UHVSRQVHWRDOORIWKHVSRQVRU¶VFRPPXQLFDWLRQV
x
5HYLHZRIDOO&5)VDQGVLJQDWXUHZKHUHUHTXLUHG
x
5HYLHZRIDQGWLPHO\UHVSRQVHWRDOORIVSRQVRU¶VFRPPXQLFDWLRQV
11.4
Responsibilities of the Clinical Research Coordinator (CRC) 
7KH&5& KDVWKHSULPDU\UHVSRQVLELOLW\RILPSOHPHQWLQJWKHSURWRFRO7KLVLQFOXGHVWKH
IROORZLQJDGPLQLVWUDWLYHDQGFOLQLFDOUHVSRQVLELOLWLHV
x
0DLQWDLQLQJXSGDWHGFRQWDFWLQIRUPDWLRQIRUHDFKWULDO SDWLHQW
x
&RPSOHWHXSGDWH&5)V
x
3HUIRUPDQFHRIWULDOSURFHGXUHVDFFRUGLQJWRWKHSURWRFRO
x
0DLQWDLQLQJFRQWDFWZLWKSDWLHQWVDQGIROORZLQJXSRQPLVVHGODEVRUYLVLWV
x
&RPSOHWLRQRIUHTXLUHGWUDLQLQJLQFOXGLQJKXPDQSDWLHQW SURWHFWLRQWUDLQLQJ
x
5HYLHZRIDQGWLPHO\UHVSRQVHWRDOORIVSRQVRU¶VFRPPXQLFDWLRQV
x
PRQLWRULQJRILQYHVWLJDWLRQDOGUXJLQYHQWRU\
11.5
Regulatory Requirements, Essential Document and Archiving
7KLVWULDOLVVXEMHFWWRUHJXODWRU\UHTXLUHPHQWVERWKIRUWKHSURWHFWLRQRIKXPDQSDWLHQWVWKURXJK
WKH,QVWLWXWLRQDO5HYLHZ%RDUGVWUXFWXUHDQGIRUWKHUHJXODWLRQRILQYHVWLJDWLRQDOGUXJVWKURXJK
WKH)RRGDQG'UXJ$GPLQLVWUDWLRQ
$OONH\GDWDPXVWEHUHFRUGHGLQWKHSDWLHQW¶V PHGLFDOUHFRUGV7KH&OLQLFDO,QYHVWLJDWRU PXVW
SHUPLWDXWKRUL]HGUHSUHVHQWDWLYHVRIWKHVSRQVRUUHVSHFWLYHQDWLRQDORUORFDOUHJXODWRU\
DXWKRULWLHVWKH,5%DQGDXGLWRUVWRLQVSHFWIDFLOLWLHVDQGWRKDYHGLUHFWDFFHVVWRRULJLQDOVRXUFH
UHFRUGVUHOHYDQWWRWKLVWULDOUHJDUGOHVVRIPHGLD 2ULJLQDOVRXUFHGDWDZLOOLQFOXGHDQGDUHQRW
OLPLWHGWRSDWLHQW¶V PHGLFDOILOHDQGRULJLQDOFOLQLFDOODERUDWRU\UHSRUWVDQG(&*UHSRUWV
,WLVWKH,QYHVWLJDWRU¶VUHVSRQVLELOLW\WRUHWDLQHVVHQWLDOVWXG\GRFXPHQWVIRUDWOHDVW\HDUVDIWHU
WKHODVWDSSURYDORIDPDUNHWLQJDSSOLFDWLRQLQWKHLUFRXQWU\DQGXQWLOWKHUHDUHQRSHQGLQJRU
FRQWHPSODWHG PDUNHWLQJDSSOLFDWLRQVLQWKHLUFRXQWU\RUDWOHDVW\HDUVKDYHHODSVHGVLQFHWKH
IRUPDOGLVFRQWLQXDWLRQRIFOLQLFDOGHYHORSPHQWRIWKH,QYHVWLJDWLRQDOGUXJLQDFFRUGDQFHZLWK
&)5F7KHVHGRFXPHQWVVKRXOGEHUHWDLQHGIRUDORQJHUSHULRGLIUHTXLUHGE\DQ
DJUHHPHQWZLWKWKHVSRQVRU,QVXFKDQLQVWDQFHLWLVWKHUHVSRQVLELOLW\RIWKHVSRQVRUWRLQIRUP
WKH&OLQLFDO,QYHVWLJDWRUDVWRZKHQWKHVHGRFXPHQWVQRORQJHUQHHGWREHUHWDLQHG,QDGGLWLRQLI

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
DSSOLFDEOHWKHVSRQVRURUGHVLJQHHZLOOVHQGDOLVWRIWUHDWPHQWFRGHVE\WULDO SDWLHQWWRWKH
&OLQLFDO,QYHVWLJDWRU DIWHUWKHFOLQLFDOGDWDEDVHIRUWKLVWULDOKDVEHHQXQEOLQGHG
11.6
Emergency Preparedness Measures for Study Records
6LWH623VZLOOGLFWDWHSUHSDUHGQHVVIRUHPHUJHQFLHVVXFKDVSRZHURXWDJHVIORRGVKXUULFDQHV
HWFWRSURWHFWWKHLQWHJULW\RIWKHVWXG\UHFRUGVDQGWRPLQLPL]HWKHLPSDFWRISRWHQWLDO
LQWHUUXSWLRQVWRWKHFOLQLFDOWULDO
11.7
Institutional Review Board
(DFKVWXG\VLWHLVUHTXLUHGWRREWDLQDSSURYDOIURPWKH6FKXOPDQ,5%RUORFDO,5%LIDSSOLFDEOH
SULRUWRLQLWLDWLRQRIDQ\FROOHFWLRQRISDWLHQW GDWD7KH,QVWLWXWLRQDO5HYLHZ%RDUGIRUWKLVWULDOLV
6FKXOPDQ,5%/DNH)RUHVW'ULYH6XLWH&LQFLQQDWL2+
,QDGGLWLRQWRDSSURYDOIRUSODQQHGWULDO DFWLYLWLHVWKH,5%DQGWKHVSRQVRUPXVWEHLQIRUPHGRI
DOOSURWRFROGHYLDWLRQVYLRODWLRQVDQGDGYHUVHHYHQWV7KLVSURWRFRODQGWKH,QIRUPHG&RQVHQW
GRFXPHQWDQGDQ\VXEVHTXHQWDPHQGPHQWVLVUHYLHZHGDQGDSSURYHGE\WKHWULDO¶V,5%RUORFDO
,5%LIDSSOLFDEOH7KH,QYHVWLJDWRUVZLOOVXEPLWSHULRGLFUHSRUWVDQGLQIRUPWKH,5%RIDQ\
UHSRUWDEOHDGYHUVHHYHQWVSHU,&+JXLGHOLQHVDQGORFDO,5%VWDQGDUGVRISUDFWLFH
11.8
Essential Documents 
7KHIROORZLQJHVVHQWLDOGRFXPHQWV PXVWEHUHWDLQHGDWWKHVWXG\VLWHPXVWEHDFFXUDWHO\
PDLQWDLQHGDQGPD\EHYHULILHGGXULQJWULDOPRQLWRULQJYLVLWV
&OLQLFVSHFLILFGRFXPHQWV
x
7KHSURWRFRODQGDOOSURWRFRO
DPHQGPHQWV
x
'RFXPHQWDWLRQRIFOLQLFDOUHVHDUFKDQG VWXG\
WUDLQLQJ
x
$OOYHUVLRQVRI,5%DSSURYHG
FRQVHQWGRFXPHQWV
x
6FUHHQLQJDQGHQUROOPHQWORJ
x
,5%GRFXPHQWDWLRQDSSURYDOV
DQGFRUUHVSRQGHQFH
x
6WXG\SURGXFWUHFRUGVHJSKDUPDF\ORJV
x
,QYHVWLJDWRUEURFKXUHSURGXFW
ODEHORUGUXJLQIRUPDWLRQVKHHW
x
*&3 FHUWLILFDWHIRUWKHLQYHVWLJDWRUV
x
)'$)RUP
x
0HGLFDOOLFHQVH
x
)LQDQFLDOGLVFORVXUHIRUPV
x
6HULRXV$GYHUVH(YHQWV6$(V8QDQWLFLSDWHG
3UREOHPV
x
6WXG\FRPPXQLFDWLRQ
x
3URWRFROGHYLDWLRQV
x
'HOHJDWLRQRIUHVSRQVLELOLWLHVORJ
x
'RFXPHQWDWLRQRIFOLQLFDOVLWHPRQLWRULQJYLVLWV
3DWLHQWVSHFLILFGRFXPHQWV
x &RPSOHWHGFDVHUHSRUWIRUPV
x 6RXUFHGRFXPHQWVHJODEUHSRUWV(&*WUDFLQJV
[UD\VUDGLRORJ\UHSRUWVHWF
x 'DWDFRUUHFWLRQIRUPV
x 6LJQHGFRQVHQWGRFXPHQWV
x 3URJUHVVQRWHV
x 0LJUDLQH'LDU\ IRUPVFRPSOHWHGE\WKHSDUWLFLSDQW
,QWKHFDVHRIDQ\VHULRXVDGYHUVHHYHQWVWKHVWXG\VLWHVZLOOUHSRUWVXFKRFFXUUHQFHVWRWKH
VSRQVRUZLWKLQKRXUV7KHVSRQVRULVUHVSRQVLEOHIRUDOOUHSRUWLQJWRWKH)RRGDQG'UXJ

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
$GPLQLVWUDWLRQ
11.9
 Investigator Meetings
$IDFHWRIDFHLQYHVWLJDWRU¶VPHHWLQJZLOOEH KHOGVLWH3,VDQGRQHVWXG\FRRUGLQDWRUDUHLQYLWHG
DQGVWURQJO\HQFRXUDJHGWRDWWHQG7KHVSRQVRUZLOOIDFLOLWDWHWUDYHODQGZLOOFRYHUWKHDVVRFLDWHG
FRVWV
$WWKHPHHWLQJVNH\FRPSRQHQWVRIWKHWULDOGHVLJQDQGLPSOHPHQWDWLRQZLOOEHSUHVHQWHGDQG
VLWHVWDIIZLOOKDYHWKHRSSRUWXQLW\WRPHHWDQGDVNTXHVWLRQVRIVSRQVRUVWXG\WHDP
11.10 Training of Study Site Staff and Routine Contact with the Sponsor’s Study Team
7KH,QYHVWLJDWRUZLOO HQVXUHWKDWDOOVWXG\VLWHVWDIIDUHIDPLOLDUZLWKWKHWULDO3URWRFRODQG
RSHUDWLQJSURFHGXUHV$OOWULDO VWDIIPXVWDOVRPDLQWDLQXSWRGDWHKXPDQSDWLHQWV WUDLQLQJ $VLWH
LQLWLDWLRQYLVLWE\WKHVSRQVRUZLOOWDNHSODFHDIWHUWKHDSSURYDOE\,5%DQGSULRUWRWKHILUVW
SDWLHQW¶V HQUROOPHQWLQWRWKHWULDO7KHYLVLWZLOOHQVXUHLQYHVWLJDWRUVIXOO\XQGHUVWDQGWKHLU
UHVSRQVLELOLWLHVDQG WKHUHVSRQVLELOLWLHVRIWKH VWDII,WLVWKH3,
VGXW\WRHQVXUHWKDWDOOVWDII
LQYROYHGLQWKLVWULDO LVDSSURSULDWHO\WUDLQHGWRHQVXUHFRPSOLDQFHZLWKWKLVSURWRFRO7KH
,QYHVWLJDWRUZLOOPDLQWDLQUHFRUGVRIDOOVLWHVWDIIWUDLQLQJVDQG UHFRUGVUHJDUGLQJWKH
TXDOLILFDWLRQVRIVLWHVWDII
7KURXJKRXWWKHWULDOGXUDWLRQVWXG\VLWHVWDIIZLOOEHLQFORVHFRPPXQLFDWLRQZLWKWKHVSRQVRU,Q
DGGLWLRQWRWKHUHSRUWLQJUHTXLUHPHQWVVWXG\VLWHV DUHHQFRXUDJHGWRFRQWDFWWKHVSRQVRUZLWK
SUREOHPVTXHVWLRQVVXJJHVWLRQVRUFRQFHUQV7KHVSRQVRUZLOODOVREHFRQWDFWLQJ WKHVWXG\VLWHV
WRFKHFNRQUHFUXLWPHQWDQGUHWHQWLRQRISDWLHQWVUHVROYHTXHVWLRQVRQDQ\ WULDO GDWD LVVXHVDQG
LQIRUPVLWHVRIXSGDWHGSDUWLFLSDQWLQIRUPDWLRQ
11.11 Trial Monitoring Plan 
7KHRYHUDOOJRDORIWKHPRQLWRULQJSODQLVWRSURYLGHRYHUVLJKWWRHQVXUHDGHTXDWHSURWHFWLRQRI
WKHULJKWV ZHOIDUHDQGVDIHW\RIKXPDQSDWLHQWVDQGWKHTXDOLW\RIWKHFOLQLFDOWULDOGDWD
VXEPLWWHGWR WKH)'$7KHPRQLWRULQJSODQZLOOHPSOR\ULVNEDVHGPRQLWRULQJVWUDWHJLHVZKLFK
IRFXVWKHVSRQVRU¶VRYHUVLJKWDFWLYLWLHVRQSUHYHQWLQJRUPLWLJDWLQJLPSRUWDQWDQGOLNHO\ULVNVWR
GDWDTXDOLW\WRSURFHVVHVFULWLFDOWRKXPDQSDWLHQW SURWHFWLRQDQGWULDOLQWHJULW\
0RQLWRULQJVWUDWHJLHVZLOOLQFOXGHWKHDSSURSULDWHXVHRIWHFKQRORJLFDOWRPHHWVWDWXWRU\DQG
UHJXODWRU\UHTXLUHPHQWV
7KHVSRQVRU¶VPRQLWRULQJDFWLYLWLHVZLOOIRFXVRQWKHIROORZLQJFULWLFDOGDWDHOHPHQWVDQG
SURFHVVHV
x
9HULILFDWLRQWKDW,QIRUPHG&RQVHQWZDVREWDLQHGDSSURSULDWHO\
x
$GKHUHQFHWRSURWRFROHOLJLELOLW\FULWHULDGHVLJQHGWRH[FOXGHLQGLYLGXDOVIRUZKRP
WKHLQYHVWLJDWLRQDOGUXJPD\EHOHVVVDIHWKDQWKHSURWRFROLQWHQGHGDQGWRLQFOXGH
 *XLGDQFHIRU,QGXVWU\2YHUVLJKWRI&OLQLFDO,QYHVWLJDWLRQV$5LVN%DVHG$SSURDFKWRPRQLWRULQJ$YDLODEOHDW
KWWSZZZIGDJRYGRZQORDGV'UXJV*XLGDQFV8&0$FFHVVHG0DUFK

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
RQO\SDWLHQWV IURPWKHWDUJHWHGVWXG\SRSXODWLRQIRUZKRPWKHWHVWDUWLFOHLVPRVW
DSSURSULDWH
x
3URFHGXUHVIRUGRFXPHQWLQJDSSURSULDWHDFFRXQWDELOLW\DQGDGPLQLVWUDWLRQRIWKH
,QYHVWLJDWLRQDOGUXJHJHQVXULQJWKHLQWHJULW\RIUDQGRPL]DWLRQDWWKHVLWHOHYHO

&RQGXFWDQGGRFXPHQWDWLRQRISURFHGXUHVDQGDVVHVVPHQWVUHODWHGWR VWXG\
HQGSRLQWV

3URWRFROUHTXLUHGVDIHW\DVVHVVPHQWV

(YDOXDWLQJGRFXPHQWLQJDQGUHSRUWLQJVHULRXVDGYHUVHHYHQWVSDWLHQW GHDWKV
DQGZLWKGUDZDOVHVSHFLDOO\ZKHQDZLWKGUDZDOPD\EHUHODWHGWRDQ DGYHUVH
HYHQW
x
&RQGXFWDQGGRFXPHQWDWLRQRISURFHGXUHVHVVHQWLDOWRWULDOLQWHJULW\VXFKDV
HQVXULQJWKHVWXG\EOLQGLVPDLQWDLQHGERWKDWWKHVLWHOHYHODQGDWWKHVSRQVRUOHYHO
DVDSSURSULDWH
7KHPRQLWRUZLOOYLVLWWKHVLWHDWUHJXODULQWHUYDOV WKURXJKRXWWKH VWXG\DFFRUGLQJWRWKHFOLQLFDO
PRQLWRULQJSODQWRYHULI\DGKHUHQFHWRWKHSURWRFROFRPSOHWHQHVVDFFXUDF\DQGFRQVLVWHQF\RI
WKHGDWDDQGDGKHUHQFHWR,&+*&3DQGORFDOUHJXODWLRQV
7KH&5&DQG,QYHVWLJDWRUPXVWEHDYDLODEOHWRWKHWULDOPRQLWRUGXULQJWKHPRQLWRULQJYLVLW$Q\
HJUHJLRXVDFWLYLW\LQYROYLQJSDWLHQW VDIHW\RUODFNRIDGKHUHQFHWR*RRG&OLQLFDO3UDFWLFH*&3
DVUHTXLUHGE\IHGHUDOJXLGHOLQHVPD\UHTXLUHUHSRUWLQJWRWKHUHOHYDQW,5%VDQGJRYHUQPHQWDO
UHJXODWRU\DJHQFLHV$UHSRUWRIDQ\ILQGLQJVZLOOEHSURYLGHGWRWKHVLWHIRUDOOPRQLWRULQJ
HQFRXQWHUV
'XULQJWKHWULDOWKHVSRQVRUZLOOKDYHUHJXODUFRQWDFWZLWKWKHVLWHWRHQVXUHSURWRFRODGKHUHQFH
DQGWRSURYLGHDGGLWLRQDOVXSSRUWDQGWUDLQLQJ7KHVSRQVRUZLOODOVRHQVXUHWKHWLPHO\UHFRUGLQJ
RI&5)V
7KH&OLQLFDO,QYHVWLJDWRU ZLOODOORZWKHWULDOPRQLWRUWRLQVSHFWWKHFOLQLFDOODERUDWRU\DQG
SKDUPDF\IDFLOLWLHV7KH&OLQLFDO,QYHVWLJDWRU DQGVWDIIDUHH[SHFWHGWRFRRSHUDWHZLWKWKH7ULDO
PRQLWRUWREHDYDLODEOHGXULQJDSRUWLRQRIWKHPRQLWRULQJYLVLWWRDQVZHUTXHVWLRQVDQG WR DOORZ
WKHWULDOPRQLWRUWRFRQGXFWLQVSHFWLRQV,WLVHVVHQWLDOWKDWWKHWULDOPRQLWRUKDYHDFFHVVWRDOOWULDO
DQGSDWLHQWUHODWHGGRFXPHQWVDWDQ\WLPHWKHVHDUHUHTXHVWHG7KH&5)VDQGFRUUHVSRQGLQJ
RULJLQDOSDWLHQWVRXUFHGRFXPHQWVPXVWEHIXOO\DYDLODEOHIRUUHYLHZ E\WKHWULDOPRQLWRUWRYHULI\
GDWDDFFXUDF\DQGDGKHUHQFHWRWULDOSURWRFRO7KHWULDOPRQLWRUZLOODGKHUHWRDOOUHTXLUHPHQWV
IRUSDWLHQW FRQILGHQWLDOLW\
11.12 Auditing and Inspecting 
7KHLQYHVWLJDWRUZLOOSHUPLWVWXG\UHODWHGPRQLWRULQJDXGLWVDQGLQVSHFWLRQVE\WKH,5%WKH
VSRQVRURUJRYHUQPHQWUHJXODWRU\ERGLHVGLUHFWDFFHVVWRDOOVWXG\UHODWHGGRFXPHQWVHJVRXUFH
GRFXPHQWVUHJXODWRU\GRFXPHQWVGDWDFROOHFWLRQLQVWUXPHQWVVWXG\GDWDHWF7KHLQYHVWLJDWRU
ZLOOHQVXUHWKHFDSDELOLW\IRULQVSHFWLRQVRIDSSOLFDEOHVWXG\UHODWHGIDFLOLWLHVHJSKDUPDF\
GLDJQRVWLFODERUDWRU\HWF7KHLQYHVWLJDWRUZLOOJLYHKLVKHUSHUPLVVLRQWRH[DPLQHDQDO\]H

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
YHULI\DQGUHSURGXFHDQ\UHFRUGVDQGUHSRUWVWKDWDUHLPSRUWDQWWRWKHHYDOXDWLRQRIDFOLQLFDO
VWXG\3DUWLFLSDWLRQDVDQLQYHVWLJDWRULQWKLVVWXG\LPSOLHVDFFHSWDQFHRISRWHQWLDOLQVSHFWLRQE\
JRYHUQPHQWUHJXODWRU\DXWKRULWLHV
11.13 Clinical Trial Agreement 
7KH,QYHVWLJDWRUDWHDFKVWXG\VLWHZLOOFRPSO\ZLWKDOOWKHWHUPVFRQGLWLRQVDQGREOLJDWLRQVRI
WKHFOLQLFDOWULDODJUHHPHQW6KRXOGDQ\GLVFUHSDQF\DULVHEHWZHHQWKLVFOLQLFDOWULDOSURWRFRODQG
WKHFOLQLFDOWULDODJUHHPHQWWKHWHUPVRIWKHFOLQLFDOWULDOSURWRFROVKDOOSUHYDLOUHJDUGLQJWKH
FRQGXFWRIWKHWULDODQGWKHWUHDWPHQWRISDWLHQWV,QDOORWKHUUHVSHFWVQRWUHODWLQJWRWULDOFRQGXFW
RUWUHDWPHQWRISDWLHQWVWKHWHUPVRIWKHFOLQLFDOWULDODJUHHPHQWVKDOOSUHYDLO6WXG\VLWHV ZLOOEH
UHLPEXUVHGIRUVXFFHVVIXOFRPSOHWLRQRIPLOHVWRQHVDVRXWOLQHGLQWKHFOLQLFDOWULDODJUHHPHQW
11.14 Confidentiality of the Protocol
7KHFRQWHQWVRIWKLVSURWRFRODUHFRQILGHQWLDO7KH,QYHVWLJDWRU,QYHVWLJDWRU¶VVWDIIDQGWKH,5%
ZLOOQRWGLVFORVHRUXVHLQZKROHRULQSDUWDQ\RIWKHFRQWHQWVDPHQGPHQWVRIWKLVSURWRFRORU
UHVXOWVRIWKLVVWXG\WRRWKHUVIRUDQ\SXUSRVHRWKHUWKDQUHYLHZLQJRUSHUIRUPLQJWKHVWXG\
DEVHQWSULRUZULWWHQDXWKRUL]DWLRQIURPWKHVSRQVRU
11.15 HIPAA, Disclosure and Confidentiality
$OOVLWHVODERUDWRULHVDQGRWKHUHQWLWLHVLQYROYHGLQWKLVVWXG\PXVWLIDSSOLFDEOHFRPSO\ZLWK
WKH+HDOWK,QVXUDQFH3RUWDELOLW\DQG$FFRXQWDELOLW\$FWRI+,3$$7KHFRQILGHQWLDOLW\RI
UHFRUGVWKDWPD\EHDEOHWRLGHQWLI\SDWLHQWV LVSURWHFWHGLQDFFRUGDQFHZLWKDSSOLFDEOHODZV
UHJXODWLRQVDQGJXLGHOLQHV$IWHUSDWLHQWVKDYHFRQVHQWHGWRWDNHSDUWLQWKHWULDOWKHVSRQVRU
DQGRULWVUHSUHVHQWDWLYHV¶UHYLHZ WKHLUPHGLFDOUHFRUGVDQGGDWDFROOHFWHGGXULQJWKHWULDO2WKHUV
LQFOXGLQJWKHIROORZLQJPD\LQDGGLWLRQUHYLHZWKHVHUHFRUGVDQGGDWDLQGHSHQGHQWDXGLWRUVZKR
YDOLGDWHWKHGDWDRQEHKDOIRIWKHVSRQVRUWKLUGSDUWLHVZLWKZKRPWKHVSRQVRUPD\GHYHORS
UHJLVWHURUPDUNHWWKHLQYHVWLJDWLRQDOGUXJQDWLRQDORUORFDOUHJXODWRU\DXWKRULWLHVDQGWKH
,5%V 7KHVSRQVRUDQGRULWVUHSUHVHQWDWLYHVDFFHVVLQJWKHUHFRUGVDQGGDWDZLOOWDNHDOO
UHDVRQDEOHSUHFDXWLRQVLQDFFRUGDQFHZLWKDSSOLFDEOHODZVUHJXODWLRQVDQGJXLGHOLQHVWR
PDLQWDLQWKHFRQILGHQWLDOLW\RISDWLHQWV
LGHQWLWLHV
3DWLHQWV DUHLGHQWLILHGXVLQJDXQLTXHLGHQWLI\LQJQXPEHU+RZHYHUODERUDWRU\EORRGSURFHGXUHV
ZLOOUHTXLUHLGHQWLI\LQJLQIRUPDWLRQVXFKDVQDPHLQLWLDOVJHQGHUDQGGDWHRIELUWK7KHQDPH
LQLWLDOVDQGGDWHRIELUWK ZLOOQRWEHWUDQVIHUUHGWRWKHFDVHUHSRUWIRUP$IWHUSDWLHQWV DUH HQUROOHG
LQWKHWULDODOOODERUDWRU\VSHFLPHQVHYDOXDWLRQIRUPVDQGUHSRUWVWKDWOHDYHWKHVLWHZLOOEH
LGHQWLILHGRQO\E\VWXG\,GHQWLILFDWLRQ1XPEHU,'WRPDLQWDLQSDWLHQWFRQILGHQWLDOLW\
$OOUHFRUGVZLOOEHNHSWLQDORFNHGILOHFDELQHW'DWDHQWHUHGLQWRRQOLQHIRUPVDUH LGHQWLILHG
XVLQJSDWLHQW,'QXPEHUV&OLQLFDOLQIRUPDWLRQZLOOQRWEHUHOHDVHGZLWKRXWZULWWHQSHUPLVVLRQ
IURP WKHSDWLHQWH[FHSWDVQHFHVVDU\IRUPRQLWRULQJE\WKH)'$WKH2IILFHIRU+XPDQ5HVHDUFK
3URWHFWLRQV2+53WKHVSRQVRURUWKHVSRQVRU¶VGHVLJQHH
,QIRUPDWLRQDERXWVWXG\SDWLHQWV ZLOOEHNHSWFRQILGHQWLDODQGPDQDJHGDFFRUGLQJWRWKH
UHTXLUHPHQWVRIWKH+HDOWK,QIRUPDWLRQ3RUWDELOLW\DQG$FFRXQWDELOLW\$FW+,3$$7KRVH
UHJXODWLRQVUHTXLUHDVLJQHGSDWLHQWDXWKRUL]DWLRQLQIRUPLQJWKHSDWLHQWRIWKHIROORZLQJ

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
x
7KHSHUVRQDOKHDOWKLQIRUPDWLRQ3+,WREHFROOHFWHGIURPSDWLHQWV LQWKLVVWXG\
x
:KRZLOOKDYHDFFHVVWRWKDWLQIRUPDWLRQDQGZK\
x
:KRZLOOXVHRUGLVFORVHWKDWLQIRUPDWLRQ
x
7RZKRPWKHGDWDPD\EHGLVFORVHGDQGWKHUHDVRQVIRUWKLVGLVFORVXUH
x
7KHULJKWVRIDUHVHDUFKSDWLHQWWRUHYRNHWKHLUDXWKRUL]DWLRQIRUXVHRIWKHLU3+,
,QWKHHYHQWWKDWDSDWLHQWUHYRNHVDXWKRUL]DWLRQWRFROOHFWRUXVH3+,WKH,QYHVWLJDWRUE\
UHJXODWLRQUHWDLQVWKHDELOLW\WRXVHDOOLQIRUPDWLRQFROOHFWHGSULRUWRWKHUHYRFDWLRQRISDWLHQW
DXWKRUL]DWLRQ
)RUSDWLHQWV ZKRKDYHUHYRNHGDXWKRUL]DWLRQWRFROOHFWRUXVH3+,DWWHPSWVVKRXOGEHPDGHWR
REWDLQSHUPLVVLRQWRFROOHFWDWOHDVWYLWDOVWDWXVLHWKDWWKHSDWLHQW LVDOLYHDWWKHHQGRIWKHLU
VFKHGXOHGVWXG\SHULRG
11.16 Inspection Procedures, Study Timetable and End of Study 
$JRYHUQPHQWUHJXODWRU\DXWKRULW\PD\FRQGXFWDQLQVSHFWLRQGXULQJWKHVWXG\RUDIWHULWV
FRPSOHWLRQ,IDQLQVSHFWLRQLVUHTXHVWHGE\DUHJXODWRU\DXWKRULW\WKH&OLQLFDO,QYHVWLJDWRU PXVW
LPPHGLDWHO\LQIRUPWKHVSRQVRUWKDWDUHTXHVW KDVEHHQPDGH
7KHVSRQVRUZLOOQRWLI\WKHLQYHVWLJDWRUVZKHQWKHVWXG\UHFUXLWPHQWLVFRPSOHWH7KHVWXG\PD\
EHWHUPLQDWHGDWLQGLYLGXDOVLWHV LIWKHVWXG\SURFHGXUHVDUHQRWEHLQJSHUIRUPHGDFFRUGLQJWR
*&3 RULIUHFUXLWPHQWLVVORZ7KHVSRQVRUPD\DOVRWHUPLQDWHWKHHQWLUHVWXG\SUHPDWXUHO\LI
FRQFHUQVIRUVDIHW\DULVHZLWKLQWKLVWULDO
12 DUTIES OF THE SPONSOR AND THE INVESTIGATORS  
12.1
Recruitment/Retention and GCP Compliance by the Investigator 
(DFKFRLQYHVWLJDWRULVIXOO\UHVSRQVLEOHIRUIXOILOOLQJDOORIWKHREOLJDWLRQVRIDQLQYHVWLJDWRUDV
LGHQWLILHGLQ&)57KXVXQGHU&)5EHDFKFRLQYHVWLJDWRULVDQ
LQYHVWLJDWRUDQGDVVXFKPXVWVLJQDVHSDUDWH
7KH&OLQLFDO,QYHVWLJDWRU LVUHTXLUHGWRFRQGXFWWKHVWXG\LQDFFRUGDQFHZLWKWKH,QWHUQDWLRQDO
&RQIHUHQFHRQ+DUPRQL]DWLRQ,&+JRRGFOLQLFDOSUDFWLFH*&3JXLGHOLQHV7KH&OLQLFDO
,QYHVWLJDWRULVUHVSRQVLEOHIRUSURYLGLQJDSSURSULDWHIDFLOLWLHVWUDLQHGVWDIIDQGWR GHPRQVWUDWH
DELOLW\WRUHFUXLWWKHUHTXLUHGQXPEHURIVXLWDEOHSDWLHQWVZLWKLQWKHDJUHHGUHFUXLWPHQWSHULRG
SULRUWRFRPPLWWLQJ WRSDUWLFLSDWHLQWKH WULDO7KH&OLQLFDO,QYHVWLJDWRU ZLOOPDLQWDLQDOLVWRI
DSSURSULDWHO\TXDOLILHGSHUVRQVWRZKRPKHVKHKDVGHOHJDWHGVLJQLILFDQWWULDOUHODWHGWDVNV
12.2
Study Staff Training
$OOVWXG\VWDIIZLOOUHFHLYHWUDLQLQJRQDOODVSHFWVRIWKHSURWRFROWRLQFOXGH
x
6WXG\REMHFWLYHV
x
3DWLHQWYLVLWVFKHGXOH
x
,QFOXVLRQH[FOXVLRQFULWHULD
x
6FUHHQLQJWUHDWPHQWDQGHQGRI
VWXG\HDUO\WHUPLQDWLRQYLVLWV
x
3URWRFROGHYLDWLRQV
x
/DERUDWRU\HYDOXDWLRQV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
x
,QYHVWLJDWLRQDOGUXJ
x
6DIHW\PRQLWRULQJDQGVWRSSLQJUXOHV
x
7UHDWPHQWWLPHOLQHV
x
7UHDWPHQWLQWHUUXSWLRQVRUGLVFRQWLQXDWLRQ
$OOVWXG\VWDIIZLOOUHFHLYHWUDLQLQJLQWKHIROORZLQJDUHDVRIFOLQLFDORSHUDWLRQV
x
&RPPXQLFDWLRQ
x
(VVHQWLDOGRFXPHQWFROOHFWLRQDQGVWRUDJH
x
6LWHYLVLWV
x
,5%UHSRUWLQJUHTXLUHPHQWV
x
,QYHVWLJDWRUUHVSRQVLELOLWLHV
x
$XGLWV
x
*RRGFOLQLFDOSUDFWLFH*&3
x
,QIRUPHGFRQVHQWSURFHGXUHV
12.3
Protocol Adherence and Investigator Agreement
7KHLQYHVWLJDWRUGHVLJQHHVDUHUHTXLUHGWRDGKHUHWRWKHSURWRFRODVGHWDLOHGLQWKLVGRFXPHQW
7KH&OLQLFDO,QYHVWLJDWRULVUHVSRQVLEOHIRUHQUROOLQJRQO\WKRVHSDWLHQWVZKRKDYHPHWSURWRFRO
HOLJLELOLW\FULWHULD$FOLQLFDOVWXG\DJUHHPHQWZLOOEHVLJQHGE\WKH&OLQLFDO,QYHVWLJDWRUWR
FRQILUPZLOOLQJQHVVWRFRPSO\ZLWKWKHVWXG\SURWRFRO
,QWKHHYHQWRIDQLQYHVWLJDWRU
VGHFLVLRQWRWHUPLQDWHRUVXVSHQGWKHWULDOWKH&OLQLFDO
,QYHVWLJDWRULVUHTXLUHGWRLQIRUPWKH,5%DQGWKHVSRQVRULPPHGLDWHO\DQGSURYLGHWKHPZLWK
GHWDLOHGZULWWHQH[SODQDWLRQ7KH&OLQLFDO,QYHVWLJDWRU ZLOOUHWXUQDOO,QYHVWLJDWLRQDOGUXJDQG
RWKHUVWXG\PDWHULDOVWRWKHVSRQVRU
12.4
Reimbursement and Insurance
3ULRUWRVWDUWLQJ WKHVWXG\WKH&OLQLFDO,QYHVWLJDWRU ZLOOVLJQDFOLQLFDOVWXG\DJUHHPHQWZLWKWKH
VSRQVRU)LQDQFLDODVSHFWVDQGSDWLHQWLQVXUDQFHIRUWKHWULDOZLOOEHGRFXPHQWHGLQWKH
DJUHHPHQWEHWZHHQWKHVSRQVRUDQGWKHLQYHVWLJDWRU
12.5
Study Modification/Discontinuation or Suspension/Termination by the sponsor
7KHVWXG\PD\EHPRGLILHGRUGLVFRQWLQXHGDWDQ\WLPHE\WKH,5%WKHVSRQVRURUJRYHUQPHQW
DJHQFLHVDVSDUWRIWKHLUGXWLHVWRHQVXUHWKDWUHVHDUFKSDWLHQWV DUHSURWHFWHG
7KHVSRQVRUPD\VXVSHQGRUWHUPLQDWHWKHVWXG\RUSDUWRIWKHVWXG\DWDQ\WLPHIRUDQ\UHDVRQ
,IWKHVWXG\LVVXVSHQGHGRUWHUPLQDWHGWKHVSRQVRUZLOOHQVXUHWKDWDSSOLFDEOHUHJXODWRU\
DJHQFLHVDQG,5%V,(&VDUHQRWLILHGDVDSSURSULDWH
12.6
Public Posting of Study Information
7KLVVWXG\ZLOOEHUHJLVWHUHGDQGUHJXODUO\XSGDWHGRQWKH&OLQLFDO7ULDOVJRYUHJLVWU\LQ
DFFRUGDQFHZLWKDOOUHOHYDQWUHJXODWLRQV,QIRUPDWLRQLQFOXGHGLQWKHUHJLVWU\PD\LQFOXGH
SDUWLFLSDWLQJLQYHVWLJDWRUV¶QDPHVDQGFRQWDFWLQIRUPDWLRQ
12.7
Publication Policy
1HLWKHUWKHFRPSOHWHQRUDQ\SDUWRIWKHUHVXOWVRIWKHVWXG\FDUULHGRXWXQGHUWKLVSURWRFROQRU
DQ\RIWKHLQIRUPDWLRQSURYLGHGE\WKHVSRQVRUIRUWKHSXUSRVHVRISHUIRUPLQJWKHVWXG\ZLOOEH
SXEOLVKHGRUSDVVHGRQWRDQ\WKLUGSDUW\ZLWKRXWWKHFRQVHQWRIWKHVWXG\VSRQVRU$Q\
LQYHVWLJDWRULQYROYHGZLWKWKLVVWXG\LVREOLJDWHGWRSURYLGHWKHVSRQVRUZLWKFRPSOHWHWHVW
UHVXOWVDQGDOOGDWDGHULYHGIURPWKHVWXG\

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
$OOSXEOLFDWLRQVRUSUHVHQWDWLRQVDULVLQJIURPWKHUHVXOWVRIWKLVVWXG\PXVWEHUHYLHZHGDQG
DSSURYHGLQZULWLQJE\WKHVSRQVRUDWOHDVWEXVLQHVVGD\VLQDGYDQFHRIWKHSXEOLFDWLRQ
VXEPLVVLRQ7KHUHYLHZLVDLPHGWRSURWHFWWKHVSRQVRU¶VSURSULHWDU\LQIRUPDWLRQH[LVWLQJHLWKHU
DWWKHGDWHRIWKHEHJLQQLQJRIWKHVWXG\RUSURGXFHGGXULQJWKHVWXG\7KLVSHUPLWVWKHVSRQVRU
WRUHYLHZVXEPLWWHGSXEOLFDWLRQVIRUDFFXUDF\DQGYHULILFDWLRQWKDWSURWHFWHGLQIRUPDWLRQLVQRW
LQDGYHUWHQWO\GLVFORVHGWRDOORZIRUDGGLWLRQDOSDWHQWSURWHFWLRQHVWDEOLVKPHQWRIFRDXWKRUVKLS
DQGWRSURYLGHUHOHYDQWVXSSOHPHQWDU\LQIRUPDWLRQ
3XEOLFDWLRQRUSUHVHQWDWLRQRIGDWDFROOHFWHGDVDUHVXOWRIWKLVVWXG\GLUHFWO\RULQGLUHFWO\LV
FRQVLGHUHGDMRLQWSXEOLFDWLRQE\LQYHVWLJDWRUVLQDOOVWXG\VLWHV7KHLQLWLDOSXEOLFDWLRQLV EDVHG
RQGDWDFROOHFWHGIURPDOODQDO\]HGSDWLHQWVQRWWKHLQGLYLGXDOLQYHVWLJDWRUV$EVHQWDJUHHPHQW
E\DOORWKHULQYHVWLJDWRUVDQGWKHVSRQVRULQYHVWLJDWRUVDJUHHQRWWRSUHVHQWGDWDJDWKHUHG
LQGLYLGXDOO\SULRUWRWKHIXOOLQLWLDOSXEOLFDWLRQ
3XEOLFDWLRQE\LQYHVWLJDWRUVRIDQ\UHVXOWVRUGDWDFROOHFWHGRUREWDLQHGWKURXJKRXWWKHFRXUVHRI
WKLVVWXG\LVSURKLELWHGDEVHQWSULRUZULWWHQDXWKRUL]DWLRQIURPWKHVSRQVRU
13 ETHICS/PROTECTION OF HUMAN PATIENTS
13.1
Ethical Standard
7KHLQYHVWLJDWRUZLOOHQVXUHWKDWWKLVVWXG\LVFRQGXFWHGLQIXOOFRQIRUPLW\ZLWKWKHSULQFLSOHVVHW
IRUWKLQ7KH%HOPRQW5HSRUW$VZHOODVZLWKWKHHWKLFDOSULQFLSOHVDQGJXLGHOLQHVIRUWKH
3URWHFWLRQRI+XPDQ3DWLHQWV RI5HVHDUFKDVGUDIWHGE\WKH861DWLRQDO&RPPLVVLRQIRUWKH
3URWHFWLRQRI+XPDQ3DWLHQWVRI%LRPHGLFDODQG%HKDYLRUDO5HVHDUFK$SULODQG
FRGLILHGLQ&)53DUWDQGRUWKH,&+(
7KHUHVHDUFKSDUWLFLSDQWULJKWVDQGVDIHW\DUHSURWHFWHGWKURXJKWKH,QIRUPHG&RQVHQWDSSURYDO
RIWKHFOLQLFDOWULDOSURWRFROE\WKH,QVWLWXWLRQDO5HYLHZ%RDUG,5%RYHUVLJKWE\WKH)'$DQG
RQJRLQJPRQLWRULQJRIWKHWULDO
13.2
Institutional Review Board
7KHSURWRFRO,QIRUPHG&RQVHQW IRUPVUHFUXLWPHQWPDWHULDOVDQGDOOSDUWLFLSDQWPDWHULDOVZLOO
EHVXEPLWWHGWRWKH,5%IRUUHYLHZDQGDSSURYDO$SSURYDORIERWKWKHSURWRFRODQGWKHFRQVHQW
IRUPZLOOEHREWDLQHGEHIRUHDQ\SDUWLFLSDQWLVHQUROOHG $Q\DPHQGPHQWWRWKHSURWRFROZLOO
UHTXLUHUHYLHZDQGDSSURYDOE\WKH,5%EHIRUHWKHFKDQJHVZLOOEH LPSOHPHQWHGLQWKHVWXG\
13.3
Informed Consent Process
,QIRUPHGFRQVHQWLVDSURFHVVWKDWZLOOEH LQLWLDWHGSULRUWRWKHLQGLYLGXDODJUHHPHQWWR
SDUWLFLSDWHLQWKHVWXG\DQGFRQWLQXHVWKURXJKRXWVWXG\SDUWLFLSDWLRQ([WHQVLYHGLVFXVVLRQRI
ULVNVDQGSRVVLEOHEHQHILWVRIVWXG\SDUWLFLSDWLRQZLOOEHSURYLGHGWRSDWLHQWV DQG WKHLUIDPLOLHVLI
DSSOLFDEOH$FRQVHQWIRUPGHVFULELQJLQGHWDLOWKHVWXG\SURFHGXUHVDQGULVNVLVJLYHQWRWKH
SDUWLFLSDQW&RQVHQWIRUPVLV,5%DSSURYHGDQGWKHSDUWLFLSDQWLVUHTXLUHGWRUHDGDQGUHYLHZWKH
GRFXPHQWRUKDYHWKHGRFXPHQWUHDGWRKLPRUKHU7KHLQYHVWLJDWRURUGHVLJQHHZLOOH[SODLQWKH
UHVHDUFKVWXG\WRWKHSDUWLFLSDQWDQGDQVZHUDQ\TXHVWLRQVWKDWPD\DULVH7KHSDUWLFLSDQWZLOO
VLJQWKH,QIRUPHG&RQVHQWGRFXPHQWSULRUWRDQ\VWXG\UHODWHGDVVHVVPHQWVRUSURFHGXUHV

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
3DWLHQWV ZLOOEHJLYHQWKHRSSRUWXQLW\WRGLVFXVVWKHVWXG\ZLWKWKHLUVXUURJDWHVRUWKLQNDERXWLW
SULRUWRDJUHHLQJWRSDUWLFLSDWH7KH\PD\ZLWKGUDZFRQVHQWDWDQ\WLPHWKURXJKRXWWKHFRXUVHRI
WKHVWXG\$FRS\RIWKHVLJQHG,QIRUPHG&RQVHQWGRFXPHQWPXVWEHJLYHQWRWKHSDWLHQWV IRU
WKHLUUHFRUGV7KHULJKWVDQGZHOIDUHRIWKHSDWLHQWV DUH SURWHFWHGE\HPSKDVL]LQJWRWKHPWKDWWKH
TXDOLW\RIWKHLUFOLQLFDOFDUHZLOOQRWEHDGYHUVHO\DIIHFWHGLIWKH\GHFOLQHWRSDUWLFLSDWHLQWKLV
VWXG\7KHFRQVHQWSURFHVVZLOOEHGRFXPHQWHGLQWKHUHVHDUFKUHFRUG
13.4
Participant Confidentiality
3DUWLFLSDQWFRQILGHQWLDOLW\ZLOOEH VWULFWO\KHOGLQWUXVWE\ WKHLQYHVWLJDWRUVVWXG\VWDIIWKH
VSRQVRUDQGWKHLUDJHQWV7KLVFRQILGHQWLDOLW\LVLPPHGLDWHWRFRYHUWHVWLQJRIELRORJLFDOVDPSOHV
DQGJHQHWLFWHVWVLQDGGLWLRQWRDQ\VWXG\LQIRUPDWLRQUHODWLQJWRSDWLHQWV
7KHVWXG\SURWRFROGRFXPHQWDWLRQGDWDDQGDOORWKHULQIRUPDWLRQJHQHUDWHGZLOO KHOGLQVWULFW
FRQILGHQWLDOLW\1RLQIRUPDWLRQFRQFHUQLQJWKHVWXG\RUWKHGDWDZLOOEH UHOHDVHGWRDQ\
XQDXWKRUL]HGWKLUGSDUW\ZLWKRXWSULRUZULWWHQDSSURYDORIWKHVSRQVRU
7KHWULDOPRQLWRURURWKHUDXWKRUL]HGUHSUHVHQWDWLYHVRIWKHVSRQVRUPD\LQVSHFWDOOVWXG\
GRFXPHQWVDQGUHFRUGVUHTXLUHGWREHPDLQWDLQHGE\WKHLQYHVWLJDWRULQFOXGLQJEXWQRWOLPLWHG
WRPHGLFDOUHFRUGVRIILFHFOLQLFRUKRVSLWDOIRUWKHVWXG\SDWLHQWV7KHFOLQLFDOVWXG\VLWHZLOO
SHUPLWDFFHVVWRVXFKUHFRUGV
14 APPENDICES
14.1
Appendix 1: The International Classification Of Headache Disorders-3 (Beta version)
1.1 0LJUDLQHZLWKRXWDXUD
'LDJQRVWLFFULWHULD
$$WOHDVWILYHDWWDFNV IXOILOOLQJFULWHULD%'
%+HDGDFKHDWWDFNVODVWLQJKRXUVXQWUHDWHGRUXQVXFFHVVIXOO\WUHDWHG
&+HDGDFKHKDVDWOHDVWWZRRIWKHIROORZLQJIRXUFKDUDFWHULVWLFV
8QLODWHUDOORFDWLRQ
3XOVDWLQJTXDOLW\
0RGHUDWHRUVHYHUHSDLQLQWHQVLW\
$JJUDYDWLRQE\RUFDXVLQJDYRLGDQFHRIURXWLQHSK\VLFDODFWLYLW\HJZDONLQJRUFOLPELQJVWDLUV
''XULQJKHDGDFKHDWOHDVWRQHRIWKHIROORZLQJ
1DXVHDDQGRUYRPLWLQJ
3KRWRSKRELDDQGSKRQRSKRELD
(1RWEHWWHUDFFRXQWHGIRUE\DQRWKHU,&+'GLDJQRVLV
1.2 Migraine with aura 
'LDJQRVWLFFULWHULD
$$WOHDVWWZRDWWDFNVIXOILOOLQJFULWHULD%DQG&
%2QHRUPRUHRIWKHIROORZLQJIXOO\UHYHUVLEOHDXUDV\PSWRPV9LVXDO6HQVRU\6SHHFKDQGRU

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
ODQJXDJH0RWRU%UDLQVWHP5HWLQDO
&$WOHDVWWZRRIWKHIROORZLQJIRXUFKDUDFWHULVWLFV
$WOHDVWRQHDXUDV\PSWRPVSUHDGVJUDGXDOO\RYHUPLQDQGRUWZRRUPRUHV\PSWRPVRFFXULQ
VXFFHVVLRQ
(DFKLQGLYLGXDODXUDV\PSWRPODVWVPLQ
$WOHDVWRQHDXUDV\PSWRPLVXQLODWHUDO
7KHDXUDLVDFFRPSDQLHGRUIROORZHGZLWKLQPLQE\KHDGDFKH
'1RWEHWWHUDFFRXQWHGIRUE\DQRWKHU,&+'GLDJQRVLVDQGWUDQVLHQWLVFKDHPLFDWWDFNKDVEHHQ
H[FOXGHG
1.5 Probable migraine
3UHYLRXVO\XVHGWHUP0LJUDLQRXVGLVRUGHU
&RGHGHOVHZKHUH0LJUDLQHOLNHKHDGDFKHVHFRQGDU\WRDQRWKHUGLVRUGHUV\PSWRPDWLFPLJUDLQHLVFRGHG
DFFRUGLQJWRWKDWGLVRUGHU
'HVFULSWLRQ 0LJUDLQHOLNHDWWDFNVPLVVLQJRQHRIWKHIHDWXUHVUHTXLUHGWRIXOILODOOFULWHULDIRUDVXEW\SHRI
PLJUDLQHFRGHGDERYHDQGQRWIXOILOOLQJFULWHULDIRUDQRWKHUKHDGDFKHGLVRUGHU
'LDJQRVWLFFULWHULD
$$WWDFNVIXOILOOLQJDOOEXWRQHRIFULWHULD$'IRU0LJUDLQHZLWKRXWDXUDRUDOOEXWRQHRIFULWHULD$
&IRU0LJUDLQHZLWKDXUD
%1RWIXOILOOLQJ,&+'FULWHULDIRUDQ\RWKHUKHDGDFKHGLVRUGHU
&1RWEHWWHUDFFRXQWHGIRUE\DQRWKHU,&+'GLDJQRVLV
&RPPHQW,QPDNLQJDKHDGDFKHGLDJQRVLVDWWDFNVWKDWIXOILOFULWHULDIRUERWK7HQVLRQW\SHKHDGDFKH
DQG3UREDEOHPLJUDLQHDUHFRGHGDVWKHIRUPHULQDFFRUGDQFHZLWKWKHJHQHUDOUXOHWKDWDGHILQLWH
GLDJQRVLVDOZD\VWUXPSVDSUREDEOHGLDJQRVLV+RZHYHULQSDWLHQWVZKRDOUHDG\KDYHDPLJUDLQH
GLDJQRVLVDQGZKHUHWKHLVVXHLVWRFRXQWWKHQXPEHURIDWWDFNVWKH\DUHKDYLQJIRUH[DPSOHDVDQ
RXWFRPHPHDVXUHLQDGUXJWULDODWWDFNVIXOILOOLQJFULWHULDIRU3UREDEOHPLJUDLQHVKRXOG EHFRXQWHGDV
PLJUDLQH7KHUHDVRQIRUWKLVLVWKDWPLOGPLJUDLQHDWWDFNVRUDWWDFNVWUHDWHGHDUO\RIWHQGRQRWDFKLHYH
DOOFKDUDFWHULVWLFVQHFHVVDU\IRUDPLJUDLQHDWWDFNGLDJQRVLVEXWQHYHUWKHOHVVUHVSRQGWRVSHFLILFPLJUDLQH
WUHDWPHQWV
1.3 Chronic migraine 
'HVFULSWLRQ+HDGDFKHRFFXUULQJRQRUPRUHGD\VSHUPRQWKIRUPRUHWKDQWKUHHPRQWKVZKLFKRQDW
OHDVWGD\VSHUPRQWKKDVWKHIHDWXUHVRIPLJUDLQHKHDGDFKH
8.2 Medication-overuse headache (MOH)
'HVFULSWLRQ+HDGDFKHRFFXUULQJRQRUPRUHGD\VSHUPRQWKGHYHORSLQJDVDFRQVHTXHQFHRIUHJXODU
RYHUXVHRIDFXWHRUV\PSWRPDWLFKHDGDFKHPHGLFDWLRQRQRUPRUHRURUPRUHGD\VSHUPRQWK
GHSHQGLQJRQWKHPHGLFDWLRQIRUPRUHWKDQWKUHHPRQWKV,WXVXDOO\EXWQRWLQYDULDEO\UHVROYHVDIWHUWKH
RYHUXVHLVVWRSSHG
*HQHUDOFRPPHQW,QWKHFULWHULDVHWRXWEHORZIRUWKHYDULRXVVXEW\SHVWKHVSHFLILHGQXPEHUVRIGD\VRI
PHGLFDWLRQXVHFRQVLGHUHGWRFRQVWLWXWHRYHUXVHDUHEDVHGRQH[SHUWRSLQLRQUDWKHUWKDQRQIRUPDO
HYLGHQFH
'LDJQRVWLFFULWHULD
$+HDGDFKHRFFXUULQJRQGD\VSHUPRQWKLQDSDWLHQWZLWKDSUHH[LVWLQJKHDGDFKHGLVRUGHU
%5HJXODURYHUXVHIRU!PRQWKVRIRQHRUPRUHGUXJVWKDWFDQEHWDNHQIRUDFXWHDQGRUV\PSWRPDWLF
WUHDWPHQWRIKHDGDFKH
&1RWEHWWHUDFFRXQWHGIRUE\DQRWKHU,&+'GLDJQRVLV
1RWH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
3DWLHQWVVKRXOGEHFRGHGIRURQHRUPRUHVXEW\SHVRI0HGLFDWLRQRYHUXVHKHDGDFKHDFFRUGLQJWR
WKHVSHFLILFPHGLFDWLRQVRYHUXVHGDQGWKHFULWHULDIRUHDFKEHORZ)RUH[DPSOHDSDWLHQWZKRIXOILOVWKH
FULWHULDIRU7ULSWDQRYHUXVHKHDGDFKHDQGWKHFULWHULDIRURQHRIWKHVXEIRUPVRI6LPSOH
DQDOJHVLFRYHUXVHKHDGDFKHVKRXOGUHFHLYHERWKWKHVHFRGHV7KHH[FHSWLRQRFFXUVZKHQSDWLHQWVRYHUXVH
FRPELQDWLRQDQDOJHVLFPHGLFDWLRQVZKRDUHFRGHG&RPELQDWLRQDQDOJHVLFRYHUXVHKHDGDFKHDQG
QRWDFFRUGLQJWRHDFKFRQVWLWXHQWRIWKHFRPELQDWLRQDQDOJHVLFPHGLFDWLRQ
3DWLHQWVZKRXVHPXOWLSOHGUXJVIRUDFXWHRUV\PSWRPDWLFWUHDWPHQWRIKHDGDFKHPD\GRVRLQDPDQQHU
WKDWFRQVWLWXWHVRYHUXVHHYHQWKRXJKQRLQGLYLGXDOGUXJRUFODVVRIGUXJLVRYHUXVHGVXFKSDWLHQWVVKRXOG
EHFRGHG0HGLFDWLRQRYHUXVHKHDGDFKHDWWULEXWHGWRPXOWLSOHGUXJFODVVHVQRWLQGLYLGXDOO\
RYHUXVHG
3DWLHQWVZKRDUHFOHDUO\RYHUXVLQJPXOWLSOHGUXJVIRUDFXWHRUV\PSWRPDWLFWUHDWPHQWRIKHDGDFKHEXW
FDQQRWJLYHDQDGHTXDWHDFFRXQWRIWKHLUQDPHVDQGRUTXDQWLWLHVDUHFRGHG0HGLFDWLRQRYHUXVH
KHDGDFKHDWWULEXWHGWRXQYHULILHGRYHUXVHRIPXOWLSOHGUXJFODVVHVXQWLOEHWWHULQIRUPDWLRQLVDYDLODEOH,Q
DOPRVWDOOFDVHVWKLVQHFHVVLWDWHVGLDU\IROORZXS
&RPPHQWV
0HGLFDWLRQRYHUXVHKHDGDFKHLVDQLQWHUDFWLRQEHWZHHQDWKHUDSHXWLFDJHQWXVHGH[FHVVLYHO\DQGD
VXVFHSWLEOHSDWLHQW$PRQJWKRVHZLWKDSUHYLRXVSULPDU\KHDGDFKHGLDJQRVLVPRVWKDYH0LJUDLQHRU
7HQVLRQW\SHKHDGDFKHRUERWKRQO\DVPDOOPLQRULW\KDYHRWKHUSULPDU\KHDGDFKHGLDJQRVHVVXFKDV
&KURQLFFOXVWHUKHDGDFKHRU1HZGDLO\SHUVLVWHQWKHDGDFKH
7KHGLDJQRVLVRI0HGLFDWLRQRYHUXVHKHDGDFKHLVH[WUHPHO\LPSRUWDQWFOLQLFDOO\$SSUR[LPDWHO\KDOI
RISHRSOHZLWKKHDGDFKHRQRUPRUHGD\VSHUPRQWKIRUPRUHWKDQWKUHHPRQWKVKDYH0HGLFDWLRQ
RYHUXVHKHDGDFKH(YLGHQFHVKRZVWKDWWKHPDMRULW\RISDWLHQWVZLWKWKLVGLVRUGHULPSURYHDIWHU
GLVFRQWLQXDWLRQRIWKHRYHUXVHGPHGLFDWLRQDVGRHVWKHLUUHVSRQVLYHQHVVWRSUHYHQWDWLYHWUHDWPHQW
6LPSOHDGYLFHRQWKHFDXVHVDQGFRQVHTXHQFHVRI0HGLFDWLRQRYHUXVHKHDGDFKHLVDQHVVHQWLDOSDUWRI
LWVPDQDJHPHQW$QH[SODQDWRU\EURFKXUHLVRIWHQDOOWKDWLVQHFHVVDU\WRSUHYHQWRUGLVFRQWLQXH
PHGLFDWLRQRYHUXVH3UHYHQWLRQLVHVSHFLDOO\LPSRUWDQWLQSDWLHQWVSURQHWRIUHTXHQWKHDGDFKH
+RZHYHUWKHEHKDYLRXURIVRPHSDWLHQWVZLWK0HGLFDWLRQRYHUXVHKHDGDFKHLVVLPLODUWRWKDWVHHQ
ZLWKRWKHUGUXJDGGLFWLRQVDQGWKH6HYHULW\RI'HSHQGHQFH6FDOH6'6VFRUHLVDVLJQLILFDQWSUHGLFWRURI
PHGLFDWLRQRYHUXVHDPRQJKHDGDFKHSDWLHQWV I: The primary he
14.2
Appendix 2: Four-Point Likert Scale for Assessing Headache Pain and Nausea
5DWLQJ
3DLQ/HYHO

1RKHDGDFKHSDLQ

0LOGKHDGDFKHSDLQLQWHUIHULQJOLWWOHZLWK$FWLYLWLHVRI'DLO\/LYLQJ$'/V

0RGHUDWHKHDGDFKHSDLQ SDLQLQWHUIHULQJVLJQLILFDQWO\ZLWK$'/V

6HYHUHKHDGDFKHSDLQGLVDEOLQJXQDEOHWRSHUIRUP$'/V
14.3
Patient Global Impression of Change (PGIC)
6LQFHWKHVWDUWRIWKHWUHDWPHQWP\RYHUDOOVWDWXVLV3OHDVHFKHFNRQO\RQHFKRLFH
'DWH
'DWH
'DWH
'DWH
'DWH
9LVLW
9LVLW
9LVLW
9LVLW
9LVLW

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
9HU\PXFK
ZRUVH
0XFKZRUVH
0LQLPDOO\
ZRUVH
1RFKDQJH
0LQLPDOO\
LPSURYHG
0XFK
LPSURYHG
9HU\PXFK
LPSURYHG
9HU\PXFK
ZRUVH
0XFKZRUVH
0LQLPDOO\
ZRUVH
1RFKDQJH
0LQLPDOO\
LPSURYHG
0XFK
LPSURYHG
9HU\PXFK
LPSURYHG
9HU\PXFK
LPSURYHG
0XFK
LPSURYHG
0LQLPDOO\
LPSURYHG
1RFKDQJH
0LQLPDOO\
ZRUVH
0XFKZRUVH
9HU\PXFK
ZRUVH
9HU\PXFK
LPSURYHG
0XFK
LPSURYHG
0LQLPDOO\
LPSURYHG
1RFKDQJH
0LQLPDOO\
ZRUVH
0XFKZRUVH
9HU\PXFK
ZRUVH
9HU\PXFK
LPSURYHG
0XFK
LPSURYHG
0LQLPDOO\
LPSURYHG
1RFKDQJH
0LQLPDOO\
ZRUVH
0XFKZRUVH
9HU\PXFK
ZRUVH
14.4
Appendix 3: Criteria for Identifying Laboratory Values of Potential Clinical Relevance  
7HVW
5DQJH
5XOH
9DOXH
+HSDWLF
)XQFWLRQ
7%/PJG/
± 
!î8/1
PJG/
$/3,8/
 
![8/1
,8/
$676*27,8/
± 
![8/1
,8/
$/76*37,8/
 
![8/1
,8/
5HQDO
)XQFWLRQ
%81PJG/
 
!î8/1
PJG/
&UHDWLQLQHPJG/
± 
!î8/1
PJG/
/DE&RUS1RUPDO5DQJH
8/1 XSSHUOLPLWRIWKHODERUDWRU\UHIHUHQFHQRUPDOUDQJH
%81 EORRGXUHDQLWURJHQ
7%/ 7RWDOELOLUXELQVHUXP
$/3 DONDOLQHSKRVSKDWDVH
$676*27 DVSDUWDWHWUDQVDPLQDVHVHUXPJOXWDPLFR[DORDFHWLFWUDQVDPLQDVH
$/76*37 DODQLQHWUDQVDPLQDVHVHUXPJOXWDPLFS\UXYLFWUDQVDPLQDVH
OLPLWFULWHULDDUHQRWDSSOLFDEOHIRUSDWLHQWVGRFXPHQWHGWRKDYH*LOEHUW¶VV\QGURPH
14.5
Appendix 4: Limits for baseline vital signs values
0HDVXUH
/RZ9DOXH
+LJK9DOXH
+HDUW5DWH
ESP
!ESP
6\VWROLF%ORRG3UHVVXUH
PP+J
!PP+J
'LDVWROLF%ORRG3UHVVXUH
PP+J
!PP+J
%DVHOLQHYDOXHVPXVWEHLQWKHDERYHUDQJHV
14.6
Appendix 5: List of Narcotic Pain Medications (Painkillers)
*HQHULF
%UDQG 1DPH
%XSUHQRUSKLQH
%XSUHQH[%XWUDQVWUDQVGHUPDOSDWFK
%XWRUSKDQRO
6WDGRO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
&RGHLQH
+\GURFRGRQH
+\GURPRUSKRQH
'LODXGLG'LODXGLG'LODXGLG+3+\GURVWDW,5([DOJR(5
/HYRUSKDQRO
/HYR'URPRUDQ
0HSHULGLQH
'HPHURO
0HWKDGRQH
'RORSKLQH0HWKDGRVH
0RUSKLQH
$VWUDPRUSK3)$9,1=$'XUDPRUSK.DGLDQ
06&RQWLQ06,52UDPRUSK655HVFXGRVH5R[DQRO
1DOEXSKLQH
1XEDLQ
2[\FRGRQH
2[\&RQWLQ5R[LFRGRQH2[HFWD
2[\PRUSKRQH
1XPRUSKDQ
3HQWD]RFLQH
7DOZLQ
3URSR[\SKHQH
&RWDQDO'DUYRQ
7DSHQWDGRO
1XF\QWD
7UDPDGRO
8OWUDP
7UDPDGRODQG $FHWDPLQRSKHQ
8OWUDFHW
&RPELQDWLRQV
%XWDOELWDODFHWDPLQRSKHQ
FDIIHLQHDQGFRGHLQH
)LRULFHWZLWK&RGHLQH
+\GURFRGRQHDQG,EXSURIHQ
+\GURVWDO,59LFRSURIHQ
0RUSKLQH1DOWUH[RQH
(PEHGD
3HQWD]RFLQH1DOR[RQH
7DOZLQ1;
$FHWDPLQRSKHQDQG&RGHLQH
&DSLWDOZLWK&RGHLQH0DUJHVLF3KHQDSKHQZLWK&RGHLQH
7\OHQROZLWK&RGHLQH
'LK\GURFRGHLQH$FHWDPLQRSKHQ
DQG&DIIHLQH
'+&SOXV
+\GURFRGRQHDQG$FHWDPLQRSKHQ
$OOD\$QH[VLD$QH[VLD 'RODFHW'RODJHVLF
'XRFHW+\FRPHG+\GURFHW+\GURJHVLF+<3+(1/RUFHW
/RUFHW+'/RUWDE3DQDFHW3DQORU6WDJHVLF7
*HVLF8JHVLF9LFRGLQ=\GRQH
2[\FRGRQHDQG$FHWDPLQRSKHQ
(QGRFHW3HUFRFHW5R[LFHW5R[LOR[7\OR[;DUWHPLV;5
3HQWD]RFLQHDQG$FHWDPLQRSKHQ
7DODFHQ
3URSR[\SKHQHDQG$FHWDPLQRSKHQ
'DUYRFHW1 'DUYRFHW1(/RU3URSDFHW 
$VSLULQ&DIIHLQHDQG
'LK\GURFRGHLQH
6\QDOJRV'&
$VSLULQDQG&RGHLQH
(PSLULQZLWK&RGHLQH
+\GURFRGRQHDQG$VSLULQ
'DPDVRQ3/RUWDE$6$3DQDVDO 
2[\FRGRQHDQG$VSLULQ
(QGRGDQ3HUFRGDQ3HUFRGDQ 'HPL5R[LSULQ
3HQWD]RFLQHDQG$VSLULQ
7DOZLQ&RPSRXQG
3URSR[\SKHQH$VSLULQDQG
&DIIHLQH
'DUYRQ&RPSRXQG3&&DS3URSR[\SKHQH&RPSRXQG
14.7
Appendix 6: List Opiate Antagonists Medications 45
*HQHULF
%UDQG 1DPH
1DOPHIHQHLQMHFWDEOHVROXWLRQ
5HYH[
$OYLPRSDQ
(QWHUHJ
 /LVWRI3DLQ5HOLHI0HGLFDWLRQV16$,'V$YDLODEOHDWKWWSZZZHPHGH[SHUWFRPOLVWVSDLQPHGVVKWPO

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
1DOR[RQH
1DUFDQ
0HWK\OQDOWUH[RQHEURPLGH
5HOLVWRU
1DOWUH[RQH
9LYLWURO5H9LD
14.8
Appendix 7: List Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)  
*HQHULF
%UDQG 1DPH
%URPIHQDF
3UROHQVD%URPGD\
'LFORIHQDF
&DWDIODP9ROWDUHQ=LSVRU
'LIOXQLVDO
'RORELG
(WRGRODF
/RGLQH/RGLQH;/
)HQRSURIHQ
1DOIRQ
)OXUELSURIHQ
$QVDLG
,EXSURIHQ
$GYLO&UDPS(QG'ROJHVLF([FHGULQ,%*HQSULO
+DOWUDQ,EUHQ,EX,EXSULQ,EXSURKP,EX7DE
0HGLSUHQ0LGRO,%0RWULQ1XSULQ3DPSULQ,%4
3URIHQ5XIHQ7UHQGDU
,QGRPHWKDFLQ
,QGRFLQ,QGRFLQ657LYRUEH[
.HWRSURIHQ
$FWURQ2UXGLV2UXYDLO
.HWRURODF
7RUDGRO6SUL[
0HFORIHQDPDWH
0HFORPHQ
0HIHQDPLF$FLG
3RQVWHO
0HOR[LFDP
0RELF
1DEXPHWRQH
5HODIHQ
1DSUR[HQ
$OHYH$QDSUR[ $QDSUR['6(&1DSURV\Q1DSUHODQ
1DSURV\Q
2[DSUR]LQ
'D\SUR
3KHQ\OEXWD]RQH
&RW\OEXWD]RQH
3LUR[LFDP
)HOGHQH
6XOLQGDF
&OLQRULO
&2;,QKLELWRUV
&HOHFR[LE
&HOHEUH[
1RQ1DUFRWLF$QDOJHVLFV
$FHWDPLQRSKHQ
7\OHQRO
&RPELQDWLRQV
%XWDOELWDO$FHWDPLQRSKHQDQG
&DIIHLQH
)HPFHW)LRULFHW(VJLF(VJLF3OXV
%XWDOELWDO$VSLULQDQG&DIIHLQH
)LRULQDO
14.9
Appendix 8: List of the Study’s Clinical Laboratory Evaluations
&DWHJRU\
3DUDPHWHUV
+HPDWRORJLFWHVW
&RPSOHWHEORRGFRXQW
/LYHUIXQFWLRQWHVWV
DPLQRWUDQVIHUDVH$67>6*27@DODQLQHDPLQRWUDQVIHUDVH$/7>6*37@
DONDOLQHSKRVSKDWDVHDVSDUWDWHWRWDOELOLUXELQ
5HQDOIXQFWLRQWHVWV
EORRGXUHDRUEORRGXUHDQLWURJHQ%81FUHDWLQLQH
8ULQHGUXJVFUHHQ
FRFDLQHPDULMXDQDRSLDWHVPHWKDPSKHWDPLQHVDQGRU2[\FRGRQH

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
8ULQHSUHJQDQF\WHVW
4XDOLWDWLYHK&*
14.10 Appendix 9: Blood Collection Procedure
7KHVLWHZLOOFROOHFWD1RQIDVWLQJEORRGVDPSOHVHYHU\YLVLWH[FHSW9LVLWDQG9LVLW
%ORRGVSHFLPHQ FROOHFWLRQLQVWUXFWLRQ
 &ROOHFWEORRGLQWRRQHVHUXPVHSDUDWLQJWXEH667/DE&RUSUHGDQGEODFNWLJHUWRS
WXEHDQGRQHODYHQGHUWRSWXEH
 0L[EORRGE\JHQWO\LQYHUWLQJWKHWXEHVWLPHV
 $IIL[FRPSOHWHG,'ODEHOVWRWKHWXEHV%HVXUHODEHOVFRUUHVSRQGWRWKHUHTXLVLWLRQIRUP
 7KHEORRGWXEH,'ODEHOLQFOXGHVWKHIROORZLQJLQIRUPDWLRQVWXG\DFFRXQWQXPEHU
SURWRFROQXPEHUDQGSDWLHQW¶V LQLWLDOVYLVLWQXPEHUSDWLHQW VWXG\,'FROOHFWLRQGDWHDQG
FROOHFWLRQWLPH
 $OORZEORRGWRFORWXSULJKWDWURRPWHPSHUDWXUHIRUPLQ 81638163(&,0(160$<
1276,7/21*(57+$10,1
 &(175,)8*(DW±JIRUPLQ DWURRPWHPSHUDWXUH
 'RQRWUHPRYHWRSRI6677XEHLVWREHVHQWLQ³DVLV´DIWHUFHQWULIXJDWLRQ'RQRWVHQG
XQFHQWULIXJHGVSHFLPHQV'RQRWVXEPLWKHPRO\]HGVHUXPRFFXUUHQFHRISLQNLVKWLQJH
WRVHUXPFRPSRQHQW
 7KHSDWLHQW¶V VWXG\,'JHQGHUDQG\HDURIELUWKPXVWPDWFKWKHLQIRUPDWLRQRQWKHODE
UHTXLVLWLRQVOLS 7KLV HQVXUHVWKDWODEUHVXOWVDUHDWWDFKHGWRWKHFRUUHFWSDUWLFLSDQW
14.11 Appendix 10: Blood pressure procedure instructions 46
$SSURYHGHTXLSPHQWIRUPHDVXUHPHQWRIEORRGSUHVVXUHLQFOXGHVDQQXDOO\FDOLEUDWHG PHUFXU\
PDQXDOVSK\JPRPDQRPHWHURUFHUWLILHGFDOLEUDWHGDXWRPDWLFGHYLFHSURYLGHGE\WKHVWXG\FOLQLF
$QXPEHURIIDFWRUVUHODWHGWRWKHSDWLHQW FDQFDXVHVLJQLILFDQWYLRODWLRQVLQPHDVXUHGEORRG
SUHVVXUH7KHVHLQFOXGHURRPWHPSHUDWXUHH[HUFLVHDOFRKRORUQLFRWLQHFRQVXPSWLRQSRVLWLRQLQJ
RIWKHDUPPXVFOHWHQVLRQEODGGHUGLVWHQVLRQWDONLQJDQGEDFNJURXQGQRLVH 7KHSDWLHQWVKRXOG
EHDVNHGWRUHPRYHDOOFORWKLQJWKDWFRYHUVWKHORFDWLRQRIFXIISODFHPHQW7KHSDWLHQWVKRXOGEH
FRPIRUWDEO\VHDWHGZLWKWKHOHJVXQFURVVHGDQGWKHEDFNDQGDUPVXSSRUWHGVXFKWKDWWKH
PLGGOHRIWKHFXIIRQWKHXSSHUDUPLVDWWKHOHYHORIWKHULJKWDWULXPWKHPLGSRLQWRIWKH
VWHUQXP0HDVXUHPHQWVPDGHZKLOHWKHSDWLHQW LVRQDQH[DPLQLQJWDEOHGRQRWIXOILOOWKHVH
FULWHULDDQGVKRXOGSUHIHUDEO\EHPDGHZKLOHWKHSDWLHQW LVVHDWHGLQDFKDLU7KHSDWLHQWVKRXOG
EHLQVWUXFWHGWRUHOD[DVPXFKDVSRVVLEOHDQGWRQRWWDONGXULQJWKHPHDVXUHPHQWSURFHGXUH
 3LFNHULQJ7*+DOO-($SSHO/-HWDO5HFRPPHQGDWLRQVIRUEORRGSUHVVXUHPHDVXUHPHQWLQKXPDQVDQG
H[SHULPHQWDODQLPDOV)URPWKH6XEFRPPLWWHHRI3URIHVVLRQDODQG3XEOLF(GXFDWLRQRIWKH$PHULFDQ+HDUW
$VVRFLDWLRQ&RXQFLORQ+LJK%ORRG3UHVVXUH5HVHDUFK+\SHUWHQVLRQ

3URWRFRO$12'<1(

3DJH RI
9HUVLRQ
-XO\ , 
7KH³JROGVWDQGDUG´GHYLFHIRURIILFHEORRGSUHVVXUHPHDVXUHPHQWKDVEHHQWKHPHUFXU\
VSK\JPRPDQRPHWHULWLVUHFRPPHQGHGWKDWLIDYDLODEOHDSURSHUO\PDLQWDLQHGPHUFXU\
VSK\JPRPDQRPHWHUEHXVHGIRUURXWLQHRIILFHPHDVXUHPHQWV0HUFXU\VSK\JPRPDQRPHWHUVDUH
FULWLFDOIRUHYDOXDWLQJWKHDFFXUDF\RIDQ\W\SHRIQRQPHUFXU\GHYLFH
14.12 Appendix 11: Pulse Measurement Procedure 47
5HVWLQJKHDUWUDWHLVDQHDVLO\PHDVXUDEOHFDUGLRYDVFXODUSDUDPHWHUEXWLVVXEMHFWWRKLJK
YDULDELOLW\6WXGLHVIRFXVLQJRQKHDUWUDWHVKRXOGWDNHLQWRDFFRXQWDOOSRVVLEOHVRXUFHVRI
YDULDELOLW\LQFOXGLQJWKHUHVWLQJSHULRGEHIRUHPHDVXUHPHQWHQYLURQPHQWDOFRQGLWLRQVPHWKRG
RIPHDVXUHPHQWSXOVHSDOSDWLRQYVHOHFWURFDUGLRJUDPQXPEHURIUHDGLQJVGXUDWLRQRI
PHDVXUHPHQWSRVLWLRQRIWKHERG\DQGQDWXUHRIWKHREVHUYHU7RPLQLPL]HWKHHIIHFWVRIWKHVH
FRQIRXQGLQJIDFWRUVWKHPHDVXUHPHQWRIWKLVFOLQLFDOYDULDEOHVKRXOGEHVWULFWO\VWDQGDUGL]HG
([HUFLVHDOFRKROQLFRWLQHDQGFRIIHHVKRXOGEHDYRLGHGLQWKHKRXUVSUHFHGLQJPHDVXUHPHQW
5HDGLQJVVKRXOGSUHIHUDEO\EHWDNHQE\SXOVHSDOSDWLRQZKLOHWKHSDWLHQW LVFRPIRUWDEO\VHDWHGLQ
DFKDLUZLWKOHJVXQFURVVHG7KHURRPVKRXOGEHDWDFRPIRUWDEOHWHPSHUDWXUHDQGEDFNJURXQG
QRLVHVVKRXOGEHDYRLGHG7KHSDWLHQWVKRXOGUHIUDLQIURPWDONLQJGXULQJWKHSURFHGXUHDQGDW
OHDVWPLQVKRXOGHODSVHEHIRUHWKHILUVWUHDGLQJLVWDNHQ
15 ATTACHMENTS: STUDY FORMS
 5HFRPPHQGDWLRQVRQKRZWRPHDVXUHUHVWLQJKHDUWUDWHDYDLODEOHDW
KWWSZZZPHGLFRJUDSKLDFRPUHFRPPHQGDWLRQVRQKRZWRPHDVXUHUHVWLQJKHDUWUDWH