Nab-Paclitaxel and Gemcitabine As First-Line Treatment of Advanced Or Metastatic Cholangiocarcinoma - DocsLib

sign in sign up

<<

Home , Gemcitabine

3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

3U(&2*3URWRFRO1XPEHU3U( $0XOWL,QVWLWXWLRQDO6LQJOH$UP7ZR6WDJH3KDVH,,7ULDORI1DE 3DFOLWD[HODQG*HPFLWDELQHIRU)LUVW/LQH7UHDWPHQWRI3DWLHQWVZLWK $GYDQFHGRU0HWDVWDWLF&KRODQJLRFDUFLQRPD

678'<&+$,5 9DLEKDY6DKDL0'

678'<&2&+$,5 +LGD\DWXOODK*0XQVKL0' +DOOD1LPHLUL0' $O%%HQVRQ,,,0')$&3 3HWHU2¶'Z\HU0'

67$7,67,&,$1 3DXO-&DWDODQR6F'

35(&2*678'<6,7(&217$&7 &DURO\Q$QGUHZV51

0(',&$/021,725 .DWKHULQH06PLWK0'

,QWHUQDO8VH2QO\ &HOJHQH 865HI,'1XPEHU$;&/27+(53U(&2*

,1' ([HPSW

(XGUD&7

9HUVLRQ1XPEHU

9HUVLRQ'DWH

5HOHDVH5HYLVLRQ+LVWRU\ 9HUVLRQ 5HOHDVHGWR6LWHV 9HUVLRQ 5HOHDVHGWR6LWHV 9HUVLRQ 5HOHDVHGWR6LWHV

This protocol contains information that is confidential and proprietary

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

7DEOHRI&RQWHQWV 6WXG\6FKHPD /LVWRI$EEUHYLDWLRQV ,QWURGXFWLRQ %DFNJURXQGDQG5DWLRQDOH &KRODQJLRFDUFLQRPD±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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

+DQGOLQJRI6HULRXV$GYHUVH(YHQWV 6$(V 6$(5HSRUWLQJ5HTXLUHPHQWV 5HSRUWLQJRI2WKHU6HFRQG3ULPDU\&DQFHUV 3URFHGXUHVLQ&DVHRI3UHJQDQF\ 0HDVXUHPHQWRI(IIHFW 3ULPDU\(QGSRLQW$VVHVVPHQW 6HFRQGDU\(QGSRLQW$VVHVVPHQW ([SORUDWRU\(QGSRLQW$VVHVVPHQW 6ROLG7XPRU5HVSRQVH&ULWHULD 5(&,679HUVLRQ (YDOXDWLRQRI3DWLHQW¶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¶V6WDWHPHQW

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

PrECOG STUDY SITE CONTACT MEDICAL MONITOR

&DURO\Q$QGUHZV51 .DWKHULQH06PLWK0' 3URMHFW0DQDJHU &RQWLQHQWDO'ULYH 3U(&2*//& 6XLWH 0DUNHW6WUHHW .LQJRI3UXVVLD3$ 6XLWH 'XULQJQRUPDOEXVLQHVVKRXUV 3KLODGHOSKLD3$ DPSP(67 3KRQH 3KRQH (PDLOFDQGUHZV#SUHFRJOOFRUJ $IWHUQRUPDOEXVLQHVVKRXUV 3KRQH (PDLONVPLWK#SUHFRJOOFRUJ 6$()D[

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH %ULHI3URWRFRO6\QRSVLV See Protocol Document Sections for complete details 6WXG\6FKHPD

)LUVW/LQH7UHDWPHQW RI3DWLHQWVZLWK $GYDQFHGRU0HWDVWDWLF &KRODQJLRFDUFLQRPD 1

6WDJH, 1 1DE3DFOLWD[HOPJP *HPFLWDELQHPJP 'D\VHYHU\GD\V

3DWLHQWV$OLYH 3DWLHQWV$OLYH 3URJUHVVLRQ)UHH 3URJUHVVLRQ)UHHDW DW0RQWKV 0RQWKV

7HUPLQDWH6WXG\ 6WDJH,, 1 1DE3DFOLWD[HOPJP *HPFLWDELQHPJP 'D\VHYHU\GD\V

3DWLHQWV$OLYH 3DWLHQWV$OLYH 3URJUHVVLRQ)UHHDW 3URJUHVVLRQ)UHHDW 0RQWKV 0RQWKV

0RQWK3)6OHVV 0RQWK 3)6 DW WKDQ OHDVW

7UHDWPHQWVKRXOGEHJLQZLWKLQ ZRUNLQJGD\VRIUHJLVWUDWLRQ

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

/LVWRI$EEUHYLDWLRQV

$'& $SSDUHQW'LIIXVLRQ&RHIILFLHQW $( $GYHUVH(YHQW $-&& $PHULFDQ-RLQW&RPPLWWHHRQ&DQFHU $/7 $ODQLQH$PLQRWUDQVDPLQDVH 6*37 $1& $EVROXWH1HXWURSKLO&RXQW $67 $VSDUWDWH$PLQRWUDQVDPLQDVH 6*27 %6$ %RG\6XUIDFH$UHD %81 %ORRG8UHD1LWURJHQ & &HOVLXV &$ &DUERK\GUDWH$QWLJHQ &%& &RPSOHWH%ORRG&RXQW &&$ &KRODQJLRFDUFLQRPD &'$ 'HR[\F\WLGLQH'HDPLQDVH &($ &DUFLQRHPEU\RQLF$QWLJHQ &(&V &LUFXODWLQJ (QGRWKHOLDO&HOOV &)5 &RGHRI)HGHUDO5HJXODWLRQV &, &RQILGHQFH,QWHUYDO &. &\WRNHUDWLQ &5 &RPSOHWH5HVSRQVH &U(/ &UHPDSKRU(/ &7 &RPSXWHG7RPRJUDSK\ &7& &LUFXODWLQJ7XPRU&HOO &7&$( &RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV &7(3 &DQFHU7KHUDS\(YDOXDWLRQ3URJUDP '&5 'LVHDVH&RQWURO5DWH G)G8 'LÀXRURGHR[\XULGLQH '1$ 'HR[\ULERQXFOHLF$FLG '60% 'DWDDQG6DIHW\0RQLWRULQJ%RDUG (&& ([WUD+HSDWLF&KRODQJLRFDUFLQRPD (&0 ([WUD&HOOXODU0DWUL[ (&2* (DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS H&5) (OHFWURQLF&DVH5HSRUW)RUP H'& (OHFWURQLF'DWD&DSWXUH (*)5 (SLGHUPDO*URZWK)DFWRU5HFHSWRU (S&$0 (SLWKHOLDO&HOO$GKHVLRQ0ROHFXOH (9&70 (XGUDYLJLODQFH&OLQLFDO7ULDOV0RGXOH ) )DKUHQKHLW )'$ )RRGDQG'UXJ$GPLQLVWUDWLRQ

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

SO SLFROLWHU 35 3DUWLDO5HVSRQVH 36 3HUIRUPDQFH6WDWXV 37 3URWKURPELQ7LPH 5(&,67 5HVSRQVH (YDOXDWLRQ&ULWHULDLQ6ROLG7XPRUV 55 5HVSRQVH5DWH 573&5 5HYHUVH7UDQVFULSWDVH3RO\PHUDVH&KDLQ5HDFWLRQ 6$( 6HULRXV$GYHUVH(YHQW 6' 6WDEOH'LVHDVH VL51$ 6PDOO,QWHUIHULQJ5LERQXFOHLF$FLG 63$5& 6HFUHWHG3URWHLQ$FLGLFDQG5LFKLQ&\VWHLQH 650 6WXG\5HIHUHQFH0DQXDO 686$5 6XVSHFWHG8QH[SHFWHG6HULRXV$GYHUVH5HDFWLRQ 7*)ȕ 7UDQVIRUPLQJ*URZWK)DFWRUȕ 70$ 7LVVXH0LFURDUUD\ 773 7LPHWR3URJUHVVLRQ 8/1 8SSHU/LPLWRI1RUPDO 86 8OWUDVRQRJUDSK\ :%& :KLWH%ORRG&RXQW :2&%3 :RPHQRI&KLOGEHDULQJ3RWHQWLDO

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

,QWURGXFWLRQ %DFNJURXQGDQG5DWLRQDOH &KRODQJLRFDUFLQRPD ± 'LVHDVH2YHUYLHZ &KRODQJLRFDUFLQRPDV &&$V GHYHORSDVDUHVXOWRIPDOLJQDQWWUDQVIRUPDWLRQRIWKHELOLDU\ WUDFW PXFRVD DQG DUH DQDWRPLFDOO\ FODVVLILHG DV LQWUDKHSDWLF SHULKLODU RU H[WUDKHSDWLF &&$VDFFRXQWVIRURIDOOSULPDU\OLYHUFDQFHUFDVHVZRUOGZLGHDQGLWVLQFLGHQFHLV ULVLQJ>@ $GYDQFHG&&$VDUHDJJUHVVLYHWXPRUVZLWKPHGLDQVXUYLYDOWLPHDIWHUGLDJQRVLV RI OHVV WKDQ PRQWKV >@ DQG ILYH\HDU RYHUDOO VXUYLYDO 26 RIa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¶¶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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

)LEURVLVLQ&KRODQJLRFDUFLQRPD 7KH PDMRULW\ RI WKH &&$V ! DUH DGHQRFDUFLQRPDV DQG DUH IXUWKHUFODVVLILHGDV VFOHURVLQJQRGXODUDQGSDSLOODU\VXEW\SHV6FOHURVLQJRUVFLUUKRXV&&$VDUHFKDUDFWHUL]HG E\DQLQWHQVHGHVPRSODVWLFUHDFWLRQ>@ )LJXUH DQGDUHDVVRFLDWHGZLWKORZUHVHFWDELOLW\ DQGFXUHUDWHV>@7KHPDMRULW\RIWKH&&$VDUHVFLUUKRXVZLWKRXWRI UHSRUWHG WR EH VFOHURVLQJ RU VFLUUKRXV VXEW\SH LQ D UHWURVSHFWLYHVWXG\>@7KLV GHVPRSODVWLFUHDFWLRQLVFRPSRVHGRIEDQGVRIILEURXVVWURPDRUFROODJHQVXUURXQGLQJWKH PDOLJQDQWFHOOVDQGLVDFKDUDFWHULVWLFIHDWXUHRIWKHPDMRULW\RI&&$WXPRUV&ROODJHQW\SH , DQG ,,, DUH WKH PRVW FRPPRQ H[WUDFHOOXODU PDWUL[ (&0 FRPSRQHQWV WKDW KDYH EHHQ GHVFULEHGLQ&&$>@

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ȕ >@ 7*)ȕ LV NQRZQ WR VWLPXODWH FROODJHQ V\QWKHVLV DQG WKHUHIRUH 63$5& KDV WKH FDSDFLW\WRUHJXODWHILEURVLVWKURXJKWKH7*)ȕSDWKZD\,QWHUHVWLQJO\7*)ȕLVDOVRNQRZQ WR VWLPXODWH 63$5& SURGXFWLRQ DQG VLOHQFLQJ RI 63$5& WKURXJK VPDOO LQWHUIHULQJ ULERQXFOHLFDFLG VL51$ KDVEHHQVKRZQ WRGHFUHDVH7*)ȕLQGXFHGILEURWLFUHVSRQVH>@ 7KHXSUHJXODWLRQRI63$5&H[SUHVVLRQLQILEURWLFKXPDQOLYHUKDVEHHQDVVRFLDWHGZLWK LQFUHDVHGOHYHOVRIW\SH,FROODJHQ>@$UHGXFWLRQLQ63$5&H[SUHVVLRQWKURXJKVL51$ VKRZHGFRUUHVSRQGLQJGHFUHDVHLQERWK7*)ȕ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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

)LJXUH 63$5& ([SUHVVLRQ LQ &&$ 70$ ZLWK UHSUHVHQWD WLYH LPDJHV VKRZLQJ 63$5& VWDLQLQJ LQ WXPRU DQG VWURPDO FHOOV ZLWK YDU\LQJ GHJUHH RI H[SUHVVLRQ ,+& ,PPXQRKLVWR FKHPLVWU\ VWDLQ 1W 1V QXPEHU RIVHFWLRQVZLWK63$5&VWDLQLQJ LQ WXPRUFHOOV DQG VWURPDO FHOOV UHVSHFWLYHO\

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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±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µGUXJJDEOH¶WDUJHWV)XUWKHU GHYHORSPHQWDQGDVVHVVPHQWRIWKLVQRQLQYDVLYHPDUNHUVKRXOGOHDGWRPRUHHIIHFWLYHDQG EHWWHUWDLORUHGDQWLFDQFHUWUHDWPHQWVIRULQGLYLGXDOSDWLHQWVWKXVUHVXOWLQJLQLPSURYHGOLIH H[SHFWDQF\LQWKLVUDUHFDQFHU 5ROHRI&'$LQ&&$ ,QWUDFHOOXODUJHPFLWDELQHLVLUUHYHUVLEO\GHDPLQDWHGE\GHR[\F\WLGLQHGHDPLQDVH &'$ WR LQDFWLYDWHG GLÀXRURGHR[\XULGLQH G)G8 7XYHVRQ HW DO VKRZHG LQ D SDQFUHDWLF GXFWDO DGHQRFDUFLQRPD 3'$& PRXVH PRGHO WKDW WKH FRPELQDWLRQ RI QDESDFOLWD[HO DQG JHPFLWDELQHLQFUHDVHVLQWUDWXPRUDOJHPFLWDELQHOHYHOVE\GHFUHDVLQJWKHOHYHOVRI SULPDU\ JHPFLWDELQH PHWDEROL]LQJ HQ]\PH &'$ WKURXJK SRVWWUDQVODWLRQDO PHFKDQLVP >@ &'$ PHWDEROL]HVJHPFLWDELQHWRDQLQDFWLYHPHWDEROLWH¶¶GLIOXRURGHR[\XULGLQH/RZSODVPD &'$DFWLYLW\DQG&'$PXWDWLRQ*!$KDYHEHHQVLJQLILFDQWO\DVVRFLDWHGZLWKSURORQJHG 26LQSDWLHQWVZLWKDGYDQFHGSDQFUHDWLFDGHQRFDUFLQRPD>@+RZHYHUWRGDWHUROHRI &'$KDVQRWEHHQVWXGLHGLQ&&$2XUSUHFOLQLFDOGDWDVKRZVWKDWWKHUHLVUREXVW&'$ VWDLQLQJLQWKHWXPRUDOFHOOVRI&&$ Q VSHFLPHQV )LJXUH

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

)LJXUH &'$ ([SUHVVLRQ LQ &&$ +XPDQ &&$ 70$ Q VSHFLPHQV ZLWK UHSUHVHQWDWLYH LPDJHV VKRZLQJ &'$ ,+& VWDLQLQJLQWXPRUDQGVWURPDOFHOOV ZLWK YDU\LQJ GHJUHH RI H[SUHVVLRQ

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

)LJXUH K(17 H[SUHVVLRQ LQ &&$ +XPDQ &&$ 70$ Q VSHFLPHQV ZLWK UHSUHVHQWDWLYH LPDJHV VKRZLQJ K(17 ,+& VWDLQLQJLQWXPRUDQGVWURPDOFHOOV ZLWKYDU\LQJGHJUHHRIH[SUHVVLRQ

6XPPDU\RI5DWLRQDOHIRU3URSRVHG6WXG\ 3UHFOLQLFDO PXULQH GDWD VXJJHVWV WKDW FRQFXUUHQW QDESDFOLWD[HO WUHDWPHQW OHDGV WR LQFUHDVHGLQWUDWXPRUDOFRQFHQWUDWLRQRIJHPFLWDELQH0RUHRYHULQKLELWLRQRI&'$HQ]\PH E\ QDESDFOLWD[HO IXUWKHU LQFUHDVHV WKH LQWUDFHOOXODU FRQFHQWUDWLRQ RI JHPFLWDELQH 6LJQLILFDQWO\ D 3KDVH ,,, FOLQLFDO WULDO ZLWK JHPFLWDELQH DQG QDESDFOLWD[HO FRPELQDWLRQ VKRZHGDVLJQLILFDQWLPSURYHPHQWLQ26,QWHUHVWLQJO\WKHELRPDUNHUDQDO\VLVRIWKHHDUOLHU

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

6HOHFWLRQRI3DWLHQWV (DFKRIWKHFULWHULDLQWKHFKHFNOLVWWKDWIROORZVPXVWEHPHWLQRUGHUIRUDSDWLHQWWREHFRQVLGHUHG HOLJLEOH IRU WKLV VWXG\ 8VH WKH FKHFNOLVW WR FRQILUP D SDWLHQW¶V HOLJLELOLW\ )RU HDFK SDWLHQW WKLV FKHFNOLVWPXVWEHSKRWRFRSLHGFRPSOHWHGDQGPDLQWDLQHGLQWKHSDWLHQW¶VFKDUW ,QFDOFXODWLQJGD\VRIWHVWVDQGPHDVXUHPHQWVWKHGD\DWHVWRUPHDVXUHPHQWLVGRQHLV FRQVLGHUHG'D\ 7KHUHIRUHLI DWHVWLVGRQHRQ D0RQGD\WKH0RQGD\IRXUZHHNVODWHU ZRXOGEHFRQVLGHUHG'D\

3U(&2*3DWLHQW1R

3DWLHQW¶V,QLWLDOV )0/

3K\VLFLDQ6LJQDWXUHDQG'DWH

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x $EVROXWH1HXWURSKLO&RXQW $1& PP $1&BBBBBBBBBBBBBBBBBB 'DWHRI7HVWBBBBBBBBBBBB

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

x +HPRJORELQ ޓ JG/ +HPRJORELQBBBBBBBBBBBB 'DWHRI7HVWBBBBBBBBBBBB x 3ODWHOHWV ޓPP 3ODWHOHWVBBBBBBBBBBBBBBB 'DWHRI 7HVWBBBBBBBBBBBB x 6HUXP&UHDWLQLQH [8SSHU/LPLW1RUPDO 8/1 6HUXP&UHDWLQLQH BBBBBBBB 8/1BBBBBBBB 'DWHRI7HVW BBBBBBBBBBB x &UHDWLQLQH&OHDUDQFH POPLQ &UHDWLQLQH&OHDUDQFHBBBBBB 'DWHRI7HVW BBBBBBBBBBBB x $OEXPLQJG/ $OEXPLQBBBBBBBBBBBBBBBBB 'DWHRI7HVWBBBBBBBBBBBB x 7RWDO%LOLUXELQ PJG/RU[ 8/1 7RWDO%LOLUXELQBBBBBBBBBBB 8/1BBBBBBBB 'DWHRI7HVWBBBBBBBBBBB x $67$/7 [8/1 [8/1LQSDWLHQWVZLWKOLYHUPHWDVWDVHV $67$/7BBBBBBBBBBBBBB 8/1BBBBBBB 'DWHRI7HVWBBBBBBBBBBB x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for this cancer 127( 3ULRU V\VWHPLF F\WRWR[LF WKHUDS\IRURWKHUGLDJQRVHVLVSHUPLWWHGLIWKHODVWGRVHZDV ! PRQWKV SULRU DQ\ SULRU WR[LFLW\ KDV UHFRYHUHG WR JUDGH DQG WUHDWPHQW ZDV QRW GLVFRQWLQXHGIRUWR[LFLW\ BBBBB 0XVW QRW EH UHFHLYLQJ WUHDWPHQW ZLWK RWKHU LQYHVWLJDWLRQDO DJHQWV DQG PXVW QRW KDYH UHFHLYHGDQ\RWKHULQYHVWLJDWLRQDODJHQW¶V ZHHNVSULRUWRUHJLVWUDWLRQ BBBBB 0XVWQRWKDYHDSUHH[LVWLQJ>JUDGHSHULSKHUDOQHXURSDWK\

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

_____ 0XVWQRWKDYH SRVVLEOHKLVWRULHVRISQHXPRQLWLVRUSQHXPRQLWLVULVNIDFWRUV 6HFWLRQ BBBBB 0XVW QRW KDYH DQ DFWLYH VHFRQG PDOLJQDQF\ RWKHU WKDQ QRQPHODQRPD VNLQ FDQFHU RU FHUYLFDOFDUFLQRPDLQVLWX 127( 3DWLHQWVZLWKKLVWRU\RIPDOLJQDQF\DUHQRWFRQVLGHUHGWRKDYHD³FXUUHQWO\DFWLYH´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¶V RSLQLRQ ZRXOG OLPLW FRPSOLDQFH RU DELOLW\ WR FRPSO\ ZLWK VWXG\ UHTXLUHPHQWV

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

5HJLVWUDWLRQ3URFHGXUHV (WKLFV 7KLVVWXG\ZLOOEHFRQGXFWHGLQDFFRUGDQFHZLWKWKHHWKLFDOSULQFLSOHVWKDWKDYHWKHLURULJLQ LQWKHFXUUHQW'HFODUDWLRQRI+HOVLQNLDQGZLOOEHFRQVLVWHQWZLWKDSSOLFDEOH86UHJXODWRU\ UHTXLUHPHQWV DQG ,QWHUQDWLRQDO &RQIHUHQFH RQ +DUPRQL]DWLRQ*RRG &OLQLFDO 3UDFWLFH ,&+*&3 7KH VWXG\ ZLOO EH FRQGXFWHG LQ FRPSOLDQFH ZLWK WKH SURWRFRO 7KH SURWRFRO DQG DQ\ DPHQGPHQWVDQGWKHSDWLHQWLQIRUPHGFRQVHQWZLOOUHFHLYH,QVWLWXWLRQDO5HYLHZ%RDUG ,5% DSSURYDOSULRUWRLQLWLDWLRQRIWKHVWXG\ )UHHO\JLYHQZULWWHQLQIRUPHGFRQVHQWPXVWEHREWDLQHGIURPHYHU\SDWLHQWRUWKHLUOHJDOO\ DFFHSWDEOHUHSUHVHQWDWLYHSULRUWRFOLQLFDOWULDOSDUWLFLSDWLRQLQFOXGLQJLQIRUPHGFRQVHQWIRU DQ\VFUHHQLQJSURFHGXUHVFRQGXFWHGWRHVWDEOLVKSDWLHQWHOLJLELOLW\IRUWKHWULDO 6WXG\SHUVRQQHOLQYROYHGLQFRQGXFWLQJWKLVWULDOZLOOEHTXDOLILHGE\HGXFDWLRQWUDLQLQJDQG H[SHULHQFH WR SHUIRUP WKHLU UHVSHFWLYH WDVN V 7KLV WULDO ZLOOQRWXVHWKHVHUYLFHVRI LQYHVWLJDWRUVRUVWXG\SHUVRQQHOZKHUHVDQFWLRQVKDYHEHHQLQYRNHGRUZKHUHWKHUHKDV EHHQ VFLHQWLILF PLVFRQGXFW RU IUDXG HJ ORVV RI PHGLFDO OLFHQVXUH GHEDUPHQW ,QYHVWLJDWRUVDUHUHVSRQVLEOHIRUWKHFRQGXFWRIWKHVWXG\DWWKHLUVWXG\VLWH 5HJXODWRU\5HTXLUHPHQWV %HIRUHDVLWHPD\HQWHUSDWLHQWVSURWRFROVSHFLILFUHJXODWRU\DQGRWKHUGRFXPHQWVPXVWEH VXEPLWWHGWR3U(&2*DVQRWHGLQVWXG\PDWHULDOV'HWDLOHGLQIRUPDWLRQUHJDUGLQJGRFXPHQW VXEPLVVLRQDQGFRQWUROLVSURYLGHGWRHDFKVLWHLQVHSDUDWHVWXG\PDWHULDOV 2QFH UHTXLUHG GRFXPHQWV DUH UHFHLYHG UHYLHZHG DQG DSSURYHG E\ 3U(&2* RU WKHLU UHSUHVHQWDWLYHD6WXG\5HIHUHQFH0DQXDO 650 ZLOOEHIRUZDUGHGWRWKHVLWH$Q\FKDQJHV WRVLWHUHJXODWRU\GRFXPHQWVPXVWEHVXEPLWWHGE\WKHLQYHVWLJDWRUWRWKHUHVSRQVLEOH SDUW\ LQDWLPHO\PDQQHU,QLWLDOVWXG\GUXJVKLSPHQWZLOOQRWRFFXUXQWLOWKHUHJXODWRU\SDFNHWLV FRPSOHWH 1R SDWLHQWV ZLOO EHJLQ SURWRFRO WKHUDS\ ZLWKRXW IRUPDO UHJLVWUDWLRQ DV SHU WKH SURFHVVEHORZ 3DWLHQW5HJLVWUDWLRQ 3DWLHQWVPXVWQRWVWDUWSURWRFROWUHDWPHQWSULRUWRUHJLVWUDWLRQ 3DWLHQWVPXVWPHHWDOORIWKHHOLJLELOLW\UHTXLUHPHQWVOLVWHGLQ6HFWLRQSULRUWRUHJLVWUDWLRQ 7UHDWPHQWVKRXOGEHJLQ ZRUNLQJGD\VIURPVWXG\HQWU\ GDWHRIUHJLVWUDWLRQ $QHOLJLELOLW\FKHFNOLVWLVLQFOXGHG LQ6HFWLRQ$FRQILUPDWLRQRIHOLJLELOLW\DVVHVVPHQWE\ WKHLQYHVWLJDWRUDQGRUVLWHZLOOEHSHUIRUPHGGXULQJWKHUHJLVWUDWLRQSURFHVV 8SRQGHWHUPLQDWLRQWKDWDVXEMHFWPHHWVHOLJLELOLW\FULWHULDWKHVXEMHFWZLOOEHUHJLVWHUHGLQ WKHVWXG\E\VLWHSHUVRQQHOYLDDQHOHFWURQLFGDWDFDSWXUH H'& V\VWHP &RQILUPDWLRQRI UHJLVWUDWLRQZLOOEHGLVSOD\HGLQWKHH'&V\VWHP )XOOLQIRUPDWLRQUHJDUGLQJUHJLVWUDWLRQSURFHGXUHVDQGJXLGHOLQHVFDQEHIRXQGLQWKH650 SURYLGHGWR \RXUVLWH&RUUHVSRQGHQFH UHJDUGLQJSDWLHQWUHJLVWUDWLRQ PXVWEHNHSWLQWKH VWXG\UHFRUGV 5HVHDUFK%ORRGDQG7LVVXH6DPSOHV 0DQGDWRU\ ELRORJLF VDPSOHV IRU FRUUHODWLYH VWXGLHV 3URFXUHPHQW RI DUFKLYHG WLVVXH LI DYDLODEOHIURPDSUHYLRXVGLDJQRVWLFELRSV\LVPDQGDWRU\IRUHQUROOPHQW,IQRWDYDLODEOH WKLVZLOOQRWSUHFOXGHSDUWLFLSDWLRQLQWKHWULDOQRUZLOODGGLWLRQDOELRSVLHVEHSHUIRUPHGIRU UHVHDUFKSXUSRVHVRQO\ 2SWLRQDO EORRG VDPSOHV ZKROH EORRG ZLOO EH UHTXHVWHG IURP WKH SDWLHQW WR WHVW IRU &LUFXODWLQJ7XPRU&HOOV &7&V

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

,QDGGLWLRQ EORRG VDPSOHV LQFOXGLQJVHUXP SODVPD DQGEXII\FRDW DQGIL[HGOHIWRYHUWLVVXH VSHFLPHQV ZLOO EH EDQNHG ZKHQ DYDLODEOH IURP DOO HQUROOHG SDWLHQWV IRU SRVVLEOH IXWXUH PROHFXODUSKDUPDFRJHQRPLFDQGRUSURWHRPLFWHVWLQJ7KHVHVSHFLPHQV DUHRSWLRQDO 6HH 6HFWLRQ IRUPRUHLQIRUPDWLRQ

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

7UHDWPHQW3ODQ 2YHUYLHZ 7KLVLVDQRSHQODEHOVLQJOHDUPWZRVWDJHPXOWLLQVWLWXWLRQDO3KDVH,,WULDOWRHYDOXDWHWKH HIILFDF\DQGVDIHW\RIWKHFRPELQDWLRQRIQDESDFOLWD[HODQGJHPFLWDELQHDVILUVWOLQHWKHUDS\ IRU SDWLHQWV GLDJQRVHG ZLWK KLVWRORJLFDOO\FRQILUPHG DGYDQFHG &&$ LQWUD H[WUDKHSDWLF DQGSHULKLODU $OOSDWLHQWVZLOOUHFHLYHQDESDFOLWD[HODWDGRVHRIPJP ,9RYHU PLQXWHVIROORZHGE\JHPFLWDELQHDWDGRVHRIPJP ,9RYHUPLQXWHVRQGD\V DQGRIHDFKF\FOH F\FOH GD\V 5DGLRJUDSKLFDVVHVVPHQWZLOOEHSHUIRUPHGDW EDVHOLQH DQG HYHU\ ZHHNV WR HYDOXDWH UHVSRQVH WR WUHDWPHQW E\ 5(&,67 9HUVLRQ JXLGHOLQHV 3DWLHQWV PD\ FRQWLQXH WR UHFHLYH WUHDWPHQW XQWLO GLVHDVH SURJUHVVLRQ RU GHYHORSPHQWRIXQDFFHSWDEOHWR[LFLW\7KH SULPDU\HQGSRLQW ZLOO EH 3)6DW PRQWKV$ PD[LPXPRI SDWLHQWVZLOOEHHQUROOHG 7UHDWPHQW$GPLQLVWUDWLRQ 3DWLHQWVZLOOUHFHLYHERWKVWXG\GUXJVE\,9LQIXVLRQRQGD\VDQGRIHDFKF\FOH F\FOH GD\V 3DWLHQWVPD\ UHFHLYHSUHPHGLFDWLRQZLWKGLSKHQK\GUDPLQH PJ,9 PLQXWHVSULRUWRQDESDFOLWD[HORUSHULQVWLWXWLRQDOVWDQGDUGV 3UHPHGLFDWLRQWRSUHYHQW K\SHUVHQVLWLYLW\UHDFWLRQLVJHQHUDOO\QRWQHHGHGSULRUWRWKHDGPLQLVWUDWLRQ RIQDESDFOLWD[HO EXW PD\ EH QHHGHG LQ SDWLHQWV ZKR KDYH KDG SULRU K\SHUVHQVLWLYLW\ UHDFWLRQV WR QDE SDFOLWD[HO 1DESDFOLWD[HOZLOOEHDGPLQLVWHUHGILUVWDWDGRVHRIPJP ,9RYHUDSHULRG RIPLQXWHVJHPFLWDELQHZLOOEH DGPLQLVWHUHGVHFRQGDW DGRVHRIPJP RYHUD SHULRGRIPLQXWHV &DOFXODWHWKHSDWLHQW¶VERG\VXUIDFHDUHD %6$ DFFRUGLQJWRVWDQGDUGLQVWLWXWLRQDOPHWKRGV %6$ZLOOEHFDOFXODWHGRQ&\FOH'D\DQGUHFDOFXODWHGSHUWKHVLWH¶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

3DWLHQWVZLOOEHPRQLWRUHGE\LQIXVLRQFHQWHUQXUVLQJVWDIIHYHU\PLQXWHVGXULQJLQIXVLRQ RU SHU LQVWLWXWLRQDO VWDQGDUGV DQG WUHDWPHQW ZLOO EH LQWHUUXSWHG IRU DQ\ HYLGHQFH RI DQ LQIXVLRQ UHDFWLRQ ,I K\SHUVHQVLWLYLW\ V\PSWRPV GHYHORS WKH LQIXVLRQ ZLOO EH VWRSSHG 3DWLHQWVZLOOEHWUHDWHGZLWKDGGLWLRQDO+DQWDJRQLVWDVZHOODVDQ+DQWDJRQLVW VXFKDV IDPRWLGLQH PJ RU UDQLWLGLQH PJ ,9 DW WKH GLVFUHWLRQ RI WKH WUHDWLQJ LQYHVWLJDWRU ,I K\SHUVHQVLWLYLW\ V\PSWRPV DUH PLOG JUDGH RU DQG UHVROYH RYHU PLQXWHV RI REVHUYDWLRQZLWKDGPLQLVWUDWLRQRIDGGLWLRQDO+DQG+EORFNHUVWKHVWXG\GUXJLQIXVLRQ PD\ UHVXPH ZLWK FDXWLRQ DW D UHGXFHG UDWH RYHU DSSUR[LPDWHO\ PLQXWHV DW WKH GLVFUHWLRQ RI WKH WUHDWLQJ LQYHVWLJDWRU $GGLWLRQDO VXSSRUWLYH FDUH PHDVXUHV VKRXOG EH DYDLODEOH DW HDFK VWXG\ VLWH LQIXVLRQ FHQWHU LQ FDVH RI VHYHUH K\SHUVHQVLWLYLW\ UHDFWLRQ 3DWLHQWVZKRKDYHKDG VHYHUHK\SHUVHQVLWLYLW\UHDFWLRQVVKRXOGQRWEHUHFKDOOHQJHG

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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¶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¶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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

7DEOH 'RVH0RGLILFDWLRQ6FKHGXOH 1DE3DFOLWD[HO &XUUHQW'RVH 3HUFHQWDJH'HFUHDVH 0RGLILHG'RVH PJP PJP PJP PJP PJP PJP PJP 'LVFRQWLQXH *HPFLWDELQH &XUUHQW'RVH 3HUFHQWDJH'HFUHDVH 0RGLILHG'RVH PJP PJP PJP PJP PJP 'LVFRQWLQXH 'D\ RI1HZ&\FOH%DVHGRQ:RUVW7\SHRI7R[LFLW\2EVHUYHGLQWKH3ULRU&\FOH )RUDQ\WR[LFLW\QRWPHQWLRQHGLQWKHWDEOHEHORZHVSHFLDOO\ODERUDWRU\YDOXHVRI OLWWOHRUQRFOLQLFDOVLJQLILFDQFHGRVHUHGXFWLRQVQHHGQRWEHGRQHDQGZLOOEHDW WUHDWLQJLQYHVWLJDWRUV¶GLVFUHWLRQRUSHULQVWLWXWLRQDOVWDQGDUGV ,IPRUHWKDQRQHJUDGHWR[LFLW\LVVHHQFRQFXUUHQWO\DVDUHVXOWRIWKHUDS\ HJ GLDUUKHDDQGFRQFXUUHQWQHXWURSHQLFIHYHU SDWLHQWVVKRXOGEHWDNHQRIIWUHDWPHQW XQOHVVFRQWLQXDWLRQLVDSSURYHGE\WKH3,

7DEOH'D\'RVH0RGLILFDWLRQVIRU +HPDWRORJLF DQG1RQ+HPDWRORJLF 7R[LFLW\IRU 1DE3DFOLWD[HODQG*HPFLWDELQH

+HPDWRORJLF7R[LFLW\ 'RVH$GMXVWPHQWIRU1DE3DFOLWD[HODQGRU*HPFLWDELQH $1& PP 7UHDWDVVFKHGXOHG $1' 3ODWHOHWV PP

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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ޓ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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

7DEOH 'D\DQG'D\'RVH0RGLILFDWLRQVIRU+HPDWRORJLF7R[LFLW\IRU1DE3DFOLWD[HODQG*HPFLWDELQH 1RWH 8VHWDEOHEHORZE\FRUUHODWLQJ'D\FRXQWVRIFXUUHQWF\FOHWKHQFKRRVH'D\UHVXOWVIURPWKDWURZ '$< '$< 'RVH $GMXVWPHQW 'RVH $GMXVWPHQW 'RVH $GMXVWPHQW IRU 'RVH $GMXVWPHQW IRU %ORRG&RXQWV %ORRG&RXQWV IRU1DE3DFOLWD[HO IRU*HPFLWDELQH 1DE3DFOLWD[HO *HPFLWDELQH

$1&!PP $1' 1RFKDQJH 1RFKDQJH 3ODWHOHWVPP

$1&PP 'HFUHDVH GRVH JLYHQ 'HFUHDVH GRVH JLYHQ $1&!PP 25 RQ 'D\ E\OHYHO RQ'D\ E\OHYHO $1' 1RFKDQJHLQGRVH 1RFKDQJHLQGRVH 3ODWHOHWV FRQVLGHU *&6) FRQVLGHU *&6) 3ODWHOHWVPP ±PP ILOJUDVWLP D ILOJUDVWLP D

$1& PP +ROGWUHDWPHQW +ROGWUHDWPHQW 25 FRQVLGHU*&6) FRQVLGHU *&6) 3ODWHOHWV PP ILOJUDVWLP D ILOJUDVWLP D

$1&!PP $1' 1RFKDQJH 5HWXUQWRSULRUIXOOGRVH 3ODWHOHWVPP

$1&PP 'HFUHDVH GRVH JLYHQ $1&!PP 6DPH GRVH DV JLYHQ 25 RQ 'D\E\OHYHO $1' 'HFUHDVH GRVH E\ RQ 'D\ FRQVLGHU 1RFKDQJHLQGRVH 3ODWHOHWV FRQVLGHU *&6) 3ODWHOHWV OHYHO *&6) ILOJUDVWLP D ±PP ILOJUDVWLP D PP

$1& PP +ROGWUHDWPHQW +ROGWUHDWPHQW 25 FRQVLGHU*&6) FRQVLGHU *&6) 3ODWHOHWV PP ILOJUDVWLP D ILOJUDVWLP D

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

7DEOH 'D\DQG'D\'RVH0RGLILFDWLRQVIRU+HPDWRORJLF7R[LFLW\IRU1DE3DFOLWD[HODQG*HPFLWDELQH 1RWH 8VHWDEOHEHORZE\FRUUHODWLQJ'D\FRXQWVRIFXUUHQWF\FOHWKHQFKRRVH'D\UHVXOWVIURPWKDWURZ '$< '$< 'RVH $GMXVWPHQW 'RVH $GMXVWPHQW 'RVH $GMXVWPHQW IRU 'RVH $GMXVWPHQW IRU %ORRG&RXQWV %ORRG&RXQWV IRU1DE3DFOLWD[HO IRU*HPFLWDELQH 1DE3DFOLWD[HO *HPFLWDELQH $1&!PP 5HWXUQ WR SULRU IXOO 5HWXUQ WR SULRU IXOO $1' GRVHD GRVHD 3ODWHOHWVPP

$1&PP $1&PP 6DPH GRVH DV JLYHQ 6DPH GRVH DV JLYHQ 'HFUHDVHGRVHE\ 'HFUHDVH GRVH E\ 25 $1'25 RQ 'D\ FRQVLGHU RQ 'D\ FRQVLGHU OHYHO OHYHO 3ODWHOHWV 3ODWHOHWV!PP *&6) ILOJUDVWLP D *&6) ILOJUDVWLP D ±PP $1& PP +ROGWUHDWPHQW +ROGWUHDWPHQW 25 FRQVLGHU*&6) FRQVLGHU *&6) 3ODWHOHWV PP ILOJUDVWLP D ILOJUDVWLP D $1&!PP 'HFUHDVH GRVH JLYHQ 'HFUHDVH GRVH JLYHQ $1' RQ 'D\ E\OHYHOD RQ 'D\ E\OHYHOD 3ODWHOHWVPP $1&PP 'HFUHDVH GRVH JLYHQ 'HFUHDVH GRVH JLYHQ $1& PP 25 RQ 'D\ E\OHYHO RQ 'D\ E\OHYHO $1'25 +ROG7UHDWPHQW +ROG7UHDWPHQW 3ODWHOHWV FRQVLGHU *&6) FRQVLGHU *&6) 3ODWHOHWV PP ±PP ILOJUDVWLP D ILOJUDVWLP D $1& PP +ROGFRQVLGHU*&6) +ROGFRQVLGHU*&6) 25 ILOJUDVWLP D ILOJUDVWLP D 3ODWHOHWV PP

$Q\'D\'XULQJ&\FOH7UHDWPHQW'RVH0RGLILFDWLRQ 1DE3DFOLWD[HO *HPFLWDELQH +ROGWUHDWPHQW IRUDPD[LPXPGD\V2Q +ROGWUHDWPHQW IRUDPD[LPXPGD\V2QUHVXPLQJWUHDWPHQW )HEULOH1HXWURSHQLD UHVXPLQJWUHDWPHQWGHFUHDVHWRQH[WORZHU GHFUHDVH WR QH[W ORZHU GRVH DQG GR QRW UHHVFDODWH GXULQJ *UDGHRU GRVH DQG GR QRW UHHVFDODWH GXULQJ WUHDWPHQW WUHDWPHQW

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

7DEOH'D\DQG 'D\'RVH0RGLILFDWLRQVIRU1RQ+HPDWRORJLF7R[LFLW\IRU1DE3DFOLWD[HODQG*HPFLWDELQH

1RQ+HPDWRORJLF7R[LFLW\ 'RVH$GMXVWPHQWIRU1DE3DFOLWD[HODQGRU*HPFLWDELQH

*UDGH LQFOXGHVSHULSKHUDOQHXURSDWK\ 7UHDWDVVFKHGXOHGRUDWQH[WORZHUGRVHOHYHODVGHWDLOHGLQ7DEOH

*UDGH+\SHUELOLUXELQHPLD +ROGERWKQDESDFOLWD[HODQGJHPFLWDELQHXSWRDPD[LPXPRIGD\VXQWLO WR[LFLW\ LPSURYHV WR *UDGH WKHQ UHVXPH DW VDPH GRVH DV EHIRUH ,I WR[LFLW\KDVQRWLPSURYHGWKHQGLVFRQWLQXHDOOWUHDWPHQW

*UDGH3HULSKHUDO1HXURSDWK\ +ROGQDESDFOLWD[HOGRVHXQWLOWR[LFLW\LPSURYHVWR*UDGH XQWLODPD[LPXP RIGD\VWKHQUHVXPHWUHDWPHQWDWVDPHGRVHRUQH[WORZHUGRVHOHYHODV GHWDLOHGLQ7DEOH&RQWLQXHJHPFLWDELQHGRVLQJDVVFKHGXOHG

2WKHU1RQ+HPDWRORJLF7R[LFLWLHV 'RVHUHGXFH,) WKHLQYHVWLJDWRUGHHPVDSSURSULDWHDQGFOLQLFDOO\QHFHVVDU\

$OORWKHU*UDGH H[FHSWDORSHFLD QDXVHDRUYRPLWLQJ >XQOHVV +ROGERWKQDESDFOLWD[HODQGJHPFLWDELQHXQWLOWR[LFLW\LPSURYHVWR*UDGH PD[LPDOO\ WUHDWHG LQFOXGLQJ SURSK\OD[LV@ SXOPRQDU\ XQWLO D PD[LPXP RI GD\V WKHQ UHVXPH DW QH[W ORZHU GRVH OHYHO DV HPEROLVPDQGGHHSYHLQWKURPERVLV>6HFWLRQ@ GHWDLOHGLQ7DEOH

*UDGH H[FHSW K\SHUELOLUXELQHPLD DV DERYH LI FRQVLGHUHG 'LVFRQWLQXHDOOWUHDWPHQW 6XEMHFWVPD\RQO\FRQWLQXHWUHDWPHQWIRUWUDQVLHQW UHYHUVLEOHWKURXJKLQWHUYHQWLRQ *UDGHWR[LFLW\DIWHUGLVFXVVLRQZLWK6SRQVRU

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

VKRXOGEHDGYLVHGWKDWWKHUHFRXOGEHDQLQFUHDVHGULVNRIVHULRXVLQIHFWLRQDQG WKH\VKRXOGFRQWDFWWKHLUSK\VLFLDQIRUHYDOXDWLRQZKHQWKH\GHYHORSDIHYHU)HYHU RUVLPLODUV\PSWRPVVKRXOGEHIXOO\HYDOXDWHGDVDQHDUO\VLJQRIDVHULRXVLQIHFWLRQ %URDGVSHFWUXPDQWLELRWLFVVXFKDVIOXRURTXLQRORQHVPD\EHSURYLGHGWRVXEMHFWV WRWUHDWRUDVSURSK\OD[LVIRULQIHFWLRQDWWKHGLVFUHWLRQRIWKHWUHDWLQJSK\VLFLDQ +\SHUVHQVLWLYLW\5HDFWLRQV +\SHUVHQVLWLYLW\UHDFWLRQVDUHLQIUHTXHQWZLWKQDESDFOLWD[HO,IWKH\GRRFFXUPLQRU V\PSWRPVVXFKDVIOXVKLQJVNLQUHDFWLRQVG\VSQHDK\SRWHQVLRQRUWDFK\FDUGLD PD\UHTXLUHWHPSRUDU\LQWHUUXSWLRQRIWKHLQIXVLRQ+RZHYHUVHYHUHUHDFWLRQVVXFK DV K\SRWHQVLRQ UHTXLULQJ WUHDWPHQW G\VSQHD UHTXLULQJ EURQFKRGLODWRUV DQJLRHGHPD RU JHQHUDOL]HG XUWLFDULD UHTXLUH LPPHGLDWH GLVFRQWLQXDWLRQ RI QDE SDFOLWD[HO DGPLQLVWUDWLRQDQGDJJUHVVLYHV\PSWRPDWLFWKHUDS\ 6XEMHFWVZKRGHYHORSDVHYHUHK\SHUVHQVLWLYLW\UHDFWLRQWRQDESDFOLWD[HOVKRXOG QRWEHUHFKDOOHQJHG &RQFXUUHQW7KHUDSLHV 5HTXLUHGDQGRU3HUPLWWHG 7KHIROORZLQJFRQFRPLWDQWPHGLFDWLRQVRUWUHDWPHQWVDUHUHTXLUHGDQGRUSHUPLWWHG DVQRWHG x +RUPRQDOELUWKFRQWUROLVSHUPLWWHGZKLOHRQVWXG\ x 7UHDWPHQWZLWKORZPROHFXODUZHLJKWKHSDULQ XQIUDFWLRQDWHGKHSDULQ RURWKHU QHZHU DQWLFRDJXODQWV is permitted LI SDWLHQWV DUH RQ D VWDEOH GRVH ZLWKRXW HYLGHQFH RI FOLQLFDOO\ VLJQLILFDQW EOHHGLQJ IRU DW OHDVW ZHHNV SULRU WR UHJLVWUDWLRQ x 3DWLHQWV RQ &RXPDGLQ VKRXOG EH FDUHIXOO\ PRQLWRUHG DQG GRVH DGMXVWHG LI QHHGHGIRUWKHLUDQWLFRDJXODWLRQ x 3UHPHGLFDWLRQZLWKGLSKHQK\GUDPLQHPJ,9SULRUWRVWXG\GUXJLQIXVLRQ LVSHUPLWWHG x 7UHDWPHQW ZLWK DGGLWLRQDO + DQWDJRQLVW DQG DQ + DQWDJRQLVW VXFK DV IDPRWLGLQHRUUDQLWLGLQH LVSHUPLWWHGLIK\SHUVHQVLWLYLW\V\PSWRPVGHYHORSDW WKHGLVFUHWLRQRIWKHWUHDWLQJLQYHVWLJDWRU o 3DWLHQWVZKRDUHUHFHLYLQJDQ\PHGLFDWLRQVRUVXEVWDQFHVknown to affect RUZLWKpotential to affect WKHDFWLYLW\RUSKDUPDFRNLQHWLFVRIQDESDFOLWD[HO DQGRU JHPFLWDELQHDUHGLVFRXUDJHGEXWPD\EHHOLJLEOHSHUWKHGLVFUHWLRQ RIWKHORFDOLQYHVWLJDWRU 127( (IIRUWVVKRXOGEHPDGHWRVZLWFKSDWLHQWVZKRDUHWDNLQJPHGLFDWLRQV RUVXEVWDQFHVWKDWDUHNQRZQWRinhibit HJ NHWRFRQD]ROHDQGRWKHULPLGD]ROH DQWLIXQJDOV HU\WKURP\FLQ IOXR[HWLQH JHPILEUR]LO FLPHWLGLQH ULWRQDYLU VDTXLQDYLULQGLQDYLUDQGQHOILQDYLU RUinduce HJ ULIDPSLFLQFDUEDPD]HSLQH SKHQ\WRLQHIDYLUHQ]QHYLUDSLQH HLWKHU&<3&RU&<3$LVRHQ]\PHV 1RW3HUPLWWHG x 2WKHULQYHVWLJDWLRQDODJHQWV x ,PPXQRVXSSUHVVLYH PHGLFDWLRQV LQFOXGLQJ V\VWHPLF FRUWLFRVWHURLGV XQOHVV XVHG IRU DGUHQDO UHSODFHPHQW DSSHWLWH VWLPXODWLRQ WKHUDS\ IRU DVWKPD EURQFKLWLVH[DFHUEDWLRQ ZHHNV WRPDQDJHVLGHHIIHFWVRI FKHPRWKHUDS\RU SUHPHGLFDWLRQIRUSURFHGXUHV>LH&7VFDQ@ x 1RFRQFXUUHQWUDGLDWLRQ

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

6XSSRUWLYH&DUH $OO VXSSRUWLYH PHDVXUHV FRQVLVWHQW ZLWK RSWLPDO SDWLHQW FDUH ZLOO EH JLYHQ WKURXJKRXWWKHVWXG\ 7KHDGPLQLVWUDWLRQRIKHPDWRSRLHWLFFRORQ\VWLPXODWLQJ IDFWRUV DQGWUDQVIXVLRQRI EORRG SURGXFWV DFFRUGLQJ WR LQVWLWXWLRQDO SUDFWLFH LV DW WKH GLVFUHWLRQ RI WKH LQYHVWLJDWRU 'XUDWLRQRI7KHUDS\ 3DWLHQWVZLOOUHFHLYHSURWRFROWKHUDS\XQOHVV 'LVHDVHSURJUHVVLRQSHU5(&,679HUVLRQJXLGHOLQHV RUFOLQLFDOSURJUHVVLRQ 7R[LFLWLHV FRQVLGHUHG XQDFFHSWDEOH E\ HLWKHU WKH SDWLHQW RU WKH LQYHVWLJDWRU GHVSLWH RSWLPDOVXSSRUWLYHFDUHDQGGRVHPRGLILFDWLRQV 'HYHORSPHQW RI DQ LQWHUFXUUHQW LOOQHVV WKDW SUHYHQWV IXUWKHU DGPLQLVWUDWLRQ RI VWXG\ WUHDWPHQW ([WUDRUGLQDU\0HGLFDO&LUFXPVWDQFHV,IDWDQ\WLPHWKHFRQVWUDLQWVRIWKLVSURWRFRODUH GHWULPHQWDOWRWKHSDWLHQW VKHDOWKSURWRFROWUHDWPHQWVKRXOGEHGLVFRQWLQXHG 3DWLHQWZLWKGUDZVFRQVHQW RULVXQDEOHWRFRPSO\ZLWKVWXG\SURFHGXUHV 'XUDWLRQRI)ROORZ8S 3DWLHQWV ZLOO EH IROORZHG IRU DGYHUVH HYHQWV IRU GD\V DIWHU WKHLU ODVW GRVH RI VWXG\ PHGLFDWLRQ $IWHUWUHDWPHQWGLVFRQWLQXDWLRQIROORZXSIRUVXUYLYDO DQGLQLWLDWLRQRIDQ\RWKHUDQWLFDQFHU WKHUDSLHV ZLOO EH GRFXPHQWHG HYHU\ PRQWKV IRU XS WR \HDUV IURP WUHDWPHQW GLVFRQWLQXDWLRQRUXQWLOGHDWKZKLFKHYHUFRPHVILUVW RU\HDUVDIWHUILUVWGDWHRIWUHDWPHQW LQLWLDWLRQIRUWKRVHWKDWUHPDLQRQWUHDWPHQW7KHVWXG\ZLOOHQG\HDUVDIWHUWKHILQDO SDWLHQW GLVFRQWLQXHVWUHDWPHQW RUDIWHUDOOSDWLHQWVDUHGHFHDVHGZKLFKHYHUFRPHVILUVW ,IDSDWLHQW FRQWLQXHVWRGRZHOORQWKHVWXG\GUXJFRPELQDWLRQIROORZXSZLOOFHDVH\HDUVDIWHUILUVW GDWH RIWUHDWPHQWEXWSDWLHQWPD\FRQWLQXHWRUHFHLYHWKHFRPELQDWLRQWUHDWPHQWIURPWKH ORFDOLQYHVWLJDWRU ,I D SDWLHQW LV UHPRYHG IURP WUHDWPHQW IRU UHDVRQ V RWKHU WKDQ SURJUHVVLRQ IROORZ ZLWK UHJXODUWXPRUDVVHVVPHQWVSHUVWDQGDUGRIFDUHXQWLOSURJUHVVLRQ )RUSDWLHQWVZKRDUHUHJLVWHUHGEXWGRQRWUHFHLYHDQ\SURWRFROWKHUDS\EDVHOLQHDQGIROORZ XSLQIRUPDWLRQSHU6HFWLRQ ZLOOEHFROOHFWHG &ULWHULDIRU5HPRYDOIURP6WXG\7UHDWPHQW $JHQXLQHHIIRUWZLOOEHPDGHWRGHWHUPLQHWKHUHDVRQ V ZK\DSDWLHQWIDLOVWRUHWXUQIRUWKH QHFHVVDU\YLVLWVRULVGLVFRQWLQXHGIURPWKHWULDOVKRXOGWKLVRFFXU,WZLOOEHGRFXPHQWHG ZKHWKHURUQRWHDFKSDWLHQWFRPSOHWHGWKHFOLQLFDOVWXG\,IIRUDQ\SDWLHQWVWXG\WUHDWPHQW RUREVHUYDWLRQVZHUHGLVFRQWLQXHG WKHUHDVRQZLOOEHUHFRUGHGRQWKHDSSURSULDWHHOHFWURQLF FDVHUHSRUWIRUP 5HDVRQVWKDWDSDWLHQWPD\GLVFRQWLQXHWUHDWPHQW LQDFOLQLFDOVWXG\DUH FRQVLGHUHGWRFRQVWLWXWHRQHRIWKHIROORZLQJ 5HFXUUHQFH RI GLVHDVH RU GRFXPHQWHG SURJUHVVLRQ RI GLVHDVH XQOHVV FRQWLQXHG WUHDWPHQWZLWKVWXG\GUXJLVGHHPHGDSSURSULDWHDWWKHGLVFUHWLRQRIWKHLQYHVWLJDWRU ,QWHUFXUUHQW LOOQHVV WKDW SUHYHQWV IXUWKHU DGPLQLVWUDWLRQ RI WUHDWPHQW SHU LQYHVWLJDWRU GLVFUHWLRQ 8QDFFHSWDEOHDGYHUVHHYHQWV 7UHDWPHQWLQWHUUXSWLRQRIPRUHWKDQ ZHHNV

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

$GYHUVH(YHQW5HSRUWLQJ &ROOHFWLRQRI6DIHW\,QIRUPDWLRQ Adverse Event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¶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³K\SHUNDOHPLD´ 2EVHUYDWLRQV RI WKH VDPH FOLQLFDOO\ VLJQLILFDQW ODERUDWRU\ DEQRUPDOLW\ IURP YLVLW WR YLVLW VKRXOG QRW EH UHSHDWHGO\ UHFRUGHG DV $(V RU 6$(V RQ WKH H&5) XQOHVV WKHLU VHYHULW\ VHULRXVQHVVRUHWLRORJ\FKDQJHV 6HYHULW\ 7KHFDWHJRULHVDQGGHILQLWLRQVRIVHYHULW\XVHGIRUFOLQLFDOWULDOV$(VDUHGHILQHGLQWKH1&,¶V &RPPRQ7HUPLQRORJ\&ULWHULD &7&$( 9 KWWSZZZFWHSFDQFHUJRY . $WWULEXWLRQ 7KHIROORZLQJFDWHJRULHVDQGGHILQLWLRQVRIFDXVDOUHODWLRQVKLSRUDWWULEXWLRQWRVWXG\GUXJ VKRXOGEHXVHGWRDVVHVV$GYHUVH(YHQWV x 'HILQLWH7KHUHLVDUHDVRQDEOHFDXVDOUHODWLRQVKLSEHWZHHQWKHVWXG\GUXJDQGWKHHYHQW 7KH HYHQW UHVSRQVH WR ZLWKGUDZDO RI VWXG\ GUXJ GHFKDOOHQJH DQG UHFXUV ZLWK UH FKDOOHQJHLIFOLQLFDOO\IHDVLEOH x 3UREDEOH7KHUHLVDUHDVRQDEOHFDXVDOUHODWLRQVKLS EHWZHHQWKHVWXG\GUXJDQGWKH HYHQW7KHHYHQWUHVSRQGVWRGHFKDOOHQJH5HFKDOOHQJHLVQRWUHTXLUHG x 3RVVLEOH 7KHUH LV D UHDVRQDEOH FDXVDO UHODWLRQVKLS EHWZHHQ WKH VWXG\ GUXJ DQG WKH HYHQW'HFKDOOHQJHLQIRUPDWLRQLVODFNLQJRUXQFOHDU

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

x 8QOLNHO\7KHUHLVGRXEWIXOFDXVDOUHODWLRQVKLSEHWZHHQWKHVWXG\GUXJDQGWKHHYHQW x 8QUHODWHG7KHUHLVFOHDUO\QRW DFDXVDOUHODWLRQVKLS EHWZHHQWKHVWXG\GUXJDQGWKH HYHQW RU WKHUH LV D FDXVDO UHODWLRQVKLS EHWZHHQ DQRWKHU GUXJ FRQFXUUHQW GLVHDVH RU FLUFXPVWDQFHVDQGWKHHYHQW &DWHJRULHVµGHILQLWH¶µSUREDEOH¶DQGµSRVVLEOH¶DUHFRQVLGHUHGVWXG\GUXJUHODWHG&DWHJRULHV µXQOLNHO\¶DQGµXQUHODWHG¶DUHFRQVLGHUHGQRWVWXG\GUXJUHODWHG 7KHGHYHORSPHQWRIDQHZFDQFHUVKRXOGEHUHJDUGHGDVDQ$(1HZFDQFHUVDUHWKRVH WKDW DUH QRW WKH SULPDU\ UHDVRQ IRU DGPLQLVWUDWLRQ RI VWXG\ WUHDWPHQW DQG KDYH EHHQ LGHQWLILHGDIWHULQFOXVLRQRIWKHSDWLHQWLQWRWKHFOLQLFDOVWXG\ $(VUHODWHGWRQDESDFOLWD[HODQGRUJHPFLWDELQHVKRXOGEHIROORZHGIRUGD\VDIWHU ODVWGRVHRIVWXG\WKHUDS\ QDESDFOLWD[HO DQGRU JHPFLWDELQH XQWLO JUDGH RU VWDELOL]DWLRQDQGUHSRUWHGDV6$(VLIWKH\EHFRPHVHULRXV +DQGOLQJRI6HULRXV$GYHUVH(YHQWV 6$(V 6$('HILQLWLRQV $ serious AE LVDQ\XQWRZDUGPHGLFDORFFXUUHQFHRFFXUULQJDIWHULQLWLDWLRQRIVWXG\ WUHDWPHQW RUWKDWDWDQ\GRVH x UHVXOWVLQGHDWK x LVOLIHWKUHDWHQLQJ GHILQHGDVDQHYHQWLQZKLFKWKHVWXG\SDWLHQWZDVDWULVNRI GHDWKDWWKHWLPHRIWKHHYHQWLWGRHVQRWUHIHUWRDQHYHQWZKLFKK\SRWKHWLFDOO\ PLJKWKDYHFDXVHGGHDWKLILWZHUHPRUHVHYHUH x UHTXLUHV LQSDWLHQW KRVSLWDOL]DWLRQ RU FDXVHV SURORQJDWLRQ RI H[LVWLQJ KRVSLWDOL]DWLRQ x UHVXOWVLQSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\ x LVDFRQJHQLWDODQRPDO\ELUWKGHIHFW x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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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µ&7¶JXLGDQFH $QDQQXDOGHYHORSPHQWVDIHW\XSGDWHUHSRUWZLOOEHSUHSDUHGE\,UHODQG&RRSHUDWLYH 2QFRORJ\5HVHDUFK*URXS ,&25* DQGVXEPLWWHGWRWKHFRPSHWHQWDXWKRULWLHVDQG FRQFHUQHG HWKLFV FRPPLWWHHV RI WKH (XURSHDQ FRXQWULHV ZKHUH WKH WULDO KDV EHHQ DSSURYHG $OO(XURSHDQ6$(VVKRXOGEHID[HGWR 0DU\6WDSOHWRQ 3KDUPDFRYLJLODQFH0DQDJHU ,&25* 3KDUPDFRYLJLODQFH8QLW ,&25* ZLOO DFNQRZOHGJH UHFHLSW RI WKH 6$( ZLWKLQ RQH EXVLQHVV GD\E\HPDLOWRWKH ,QYHVWLJDWRU DQGZLOOIRUZDUG6$(VWR3U(&2*ZLWKLQKRXUVRI,&25*¶V$ZDUHQHVV'DWH 3U(&2* ZLOO QRWLI\ WKH &HOJHQH &RUSRUDWLRQ RI DOO 6$(¶V ZLWKLQ KRXUV RI 3U(&2*¶V $ZDUHQHVV'DWHDV GLVFXVVHGDERYH5HOHYDQWIROORZXSLQIRUPDWLRQZLOOEHSURYLGHGWR &HOJHQHDVVRRQDVLWEHFRPHVDYDLODEOH ,QYHVWLJDWRUVVKRXOGDOVRUHSRUWHYHQW V WRWKHLU,5%DVUHTXLUHG &ROOHFWLRQ RI FRPSOHWH LQIRUPDWLRQ FRQFHUQLQJ 6$(V LV H[WUHPHO\ LPSRUWDQW )XOO GHVFULSWLRQV RI HDFK HYHQW ZLOO EH IROORZHG 7KXV IROORZXS LQIRUPDWLRQ ZKLFK EHFRPHV DYDLODEOHDVWKH6$(HYROYHVDVZHOODVVXSSRUWLQJGRFXPHQWDWLRQ HJKRVSLWDOGLVFKDUJH VXPPDULHV DQGDXWRSV\UHSRUWV VKRXOGEHFROOHFWHGVXEVHTXHQWO\LIQRWDYDLODEOHDWWKH WLPHRIWKHLQLWLDOUHSRUWDQGLPPHGLDWHO\VHQWXVLQJWKHVDPHSURFHGXUHDVWKHLQLWLDO6$( UHSRUW $OO6$(VUHJDUGOHVVRIFDXVDOLW\PXVWEHFROOHFWHGZKLFKRFFXUZLWKLQGD\VRIODVWGRVH RIVWXG\WUHDWPHQW7KLVLQFOXGHVDOOGHDWKVZLWKLQGD\VRI ODVWGRVHRIQDESDFOLWD[HO DQGRU JHPFLWDELQH UHJDUGOHVV RI DWWULEXWLRQ ,Q DGGLWLRQ WKH ,QYHVWLJDWRU VKRXOG QRWLI\ 3U(&2*RUGHVLJQHHRIDQ\6$(WKDWPD\RFFXUDIWHUWKLVWLPHSHULRG ZKLFKWKH\EHOLHYH WREHGHILQLWHO\SUREDEO\RUSRVVLEO\UHODWHGWRLQYHVWLJDWLRQDOSURGXFW 127( $IWHUVWXG\FORVXUHVWXG\GUXJUHODWHG6$(VVKRXOGEHUHSRUWHGYROXQWDULO\E\WKH WUHDWLQJSK\VLFLDQWRWKHPDQXIDFWXUHU

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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¶VODVWGRVHRIVWXG\GUXJ ZLOO EH UHSRUWHG WR 3U(&2* RQ D 3UHJQDQF\ )RUP ZLWKLQ KRXUV RI WKH LQYHVWLJDWRU¶V NQRZOHGJHRIWKHSUHJQDQF\ $OOUHSRUWVRIFRQJHQLWDODEQRUPDOLWLHVELUWKGHIHFWVDQGVSRQWDQHRXVPLVFDUULDJHVVKRXOG DOVREHUHSRUWHGDQGKDQGOHGDV6$(V(OHFWLYHDERUWLRQVZLWKRXWFRPSOLFDWLRQVVKRXOGQRW EHKDQGOHGDV$(V 7KH RXWFRPH RI DOO SUHJQDQFLHV VSRQWDQHRXV PLVFDUULDJH HOHFWLYH WHUPLQDWLRQ QRUPDO ELUWK LQFOXGLQJ KHDOWK RI WKH QHZERUQ RU FRQJHQLWDO DEQRUPDOLW\ PXVW EH IROORZHG DQG GRFXPHQWHGRQWKH3UHJQDQF\)RUPHYHQLIWKHVXEMHFWZDVGLVFRQWLQXHGIURPWKHVWXG\ WUHDWPHQW 6KRXOG SUHJQDQF\ RFFXU GXULQJ D VXEMHFW¶V SDUWLFLSDWLRQ WKH VXEMHFW ZLOO LPPHGLDWHO\EHGLVFRQWLQXHGIURPWKHWUHDWPHQWDQGIROORZHGSHUSURWRFRO 7KHVWXG\VSHFLILF3UHJQDQF\)RUPFDQEHIRXQGLQWKH6WXG\5HIHUHQFH0DQXDO

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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µDQWLJHQ¶ JURXSV ZLOO EH DVVHVVHG E\ WKH ORJUDQN WHVW DQG D PXOWLYDULDWH&R[UHJUHVVLRQ PRGHOZLOOEHXVHGWRDVVHVVWKHLQGHSHQGHQWSUHGLFWLYHSRZHURIWKHDQWLJHQOHYHOV ,I WKHUH LV OLPLWHG WLVVXH VSHFLPHQ DYDLODELOLW\ WKHQ ZH ZRXOG SULRULWL]H LPPXQRKLVWRFKHPLFDO VWDLQLQJDV 63$5& ILEURVLV &'$DQG K(17

7DEOH 63$5&K(17&'$6FRULQJ

63$5&DQDO\VLVE\,+& >@ XVLQJDQWL63$5&DQWLERG\21 ,QYLWURJHQ&DPDULOOR&$

Scoring Criteria for Expression in Stromal Fibroblasts

DEVHQW ZHDN ,QWHQVLW\ PRGHUDWH VWURQJ

([WHQW

Scoring Guide

1RVWDLQLQJRU /RZ 2QO\VHHQDW[ PDJQLILFDWLRQLQ RIVWURPD

+LJK 6WDLQLQJVHHQDW[ PDJQLILFDWLRQLQޓRIVWURPD

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

+LJK 6WDLQLQJVHHQDW[ PDJQLILFDWLRQLQޓRIVWURPD

K(17DQDO\VLVE\,+& PHWKRG >@ XVLQJDQWLK(17DQWLERG\63 9HQWDQD7XFVRQ$=

Scoring Guide for Expression in Tumoral Cells (membranous staining for hENT1)

ޓRIWXPRULVQHJDWLYHIRUVWDLQRU /RZ 8QHTXLYRFDOPHPEUDQHVWDLQLQJYLVLEOHRQO\DW[[ ޓRIWXPRULVVWDLQHGDQG +LJK 8QHTXLYRFDOPHPEUDQHVWDLQLQJDW[

K(17DQDO\VLVE\,+& PHWKRG >@ XVLQJDQWLK(17DQWLERG\63 9HQWDQD7XFVRQ$=

Scoring Guide for Expression in Tumoral Cells (membranous staining for hENT1)

DEVHQW ZHDN ,QWHQVLW\ PRGHUDWH VWURQJ

([WHQWRI6WDLQLQJ 3HUFHQWDJHRIWXPRUFHOOVVWDLQHG

Scoring Guide using H score (= intensity * extent of staining)

/RZ 0HDQ+VFRUH 0HGLDQ+VFRUH

+LJK 0HDQ+VFRUHޓ 0HGLDQ+VFRUH

&'$DQDO\VLVE\,+& > ` XVLQJDQWL&'$DQWLERG\

Scoring Criteria for Expression in Tumoral Cells (cytosolic staining for CDA)

DEVHQW ZHDN ,QWHQVLW\ PRGHUDWH VWURQJ

([WHQWRI6WDLQLQJ 3HUFHQWDJHRIWXPRUFHOOVVWDLQHG

Scoring Guide using H score (= intensity * extent of staining)

/RZ 0HDQ+VFRUH 0HGLDQ+VFRUH

+LJK 0HDQ+VFRUHޓ 0HGLDQ+VFRUH

7XPRU)LEURVLV(YDOXDWLRQ $YDLODEOHWLVVXH DVQRWHGLQ6HFWLRQ ZLOOEHVWDLQHGZLWKWULFKURPHWRHYDOXDWH IRUILEURVLV 7KH GHJUHH RI ILEURVLV ZLOO EH YLVXDOO\ HVWLPDWHG E\ D EOLQGHG JDVWURLQWHVWLQDO SDWKRORJLVW DV SHU VWDQGDUG SUDFWLFH $ VHSDUDWH [ FRQWLQJHQF\ WDEOH ZLOO EH

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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x PPE\&7VFDQ LUUHVSHFWLYHRIVFDQQHUW\SH DQG05, no less than double the slice thickness and a minimum of 10 mm x PPFDOLSHUPHDVXUHPHQWE\FOLQLFDOH[DP ZKHQVXSHUILFLDO

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

x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µ&\VWLFOHVLRQV¶WKDWPHHWWKHFULWHULDIRUUDGLRJUDSKLFDOO\GHILQHG VLPSOH F\VWV VKRXOG QRW EH FRQVLGHUHG DV PDOLJQDQW OHVLRQV QHLWKHU PHDVXUDEOH QRU QRQPHDVXUDEOH VLQFH WKH\ DUH E\ GHILQLWLRQ VLPSOH F\VWV µ&\VWLFOHVLRQV¶WKRXJKWWRUHSUHVHQWF\VWLFPHWDVWDVHVFDQEHFRQVLGHUHG DV PHDVXUDEOH OHVLRQV LI WKH\ PHHW WKH GHILQLWLRQ RI PHDVXUDELOLW\ GHVFULEHGDERYH+RZHYHULIQRQF\VWLFOHVLRQVDUHSUHVHQWLQWKHVDPH SDWLHQWWKHVHDUHSUHIHUUHGIRUVHOHFWLRQDVWDUJHWOHVLRQV /\WLFERQHOHVLRQVZLWKDQLGHQWLILDEOHVRIWWLVVXHFRPSRQHQWHYDOXDWHG E\&7RU05,FDQEHFRQVLGHUHGDVPHDVXUDEOHOHVLRQVLIWKHVRIWWLVVXH FRPSRQHQW RWKHUZLVH PHHWV WKH GHILQLWLRQ RI PHDVXUDELOLW\ LQ 6HFWLRQ %ODVWLFERQHOHVLRQVDUHQRQPHDVXUDEOH 7XPRUOHVLRQVWKDWDUHVLWXDWHGLQDSUHYLRXVO\LUUDGLDWHGDUHDRULQDQ DUHDVXEMHFWHGWRRWKHUORFRUHJLRQDOWKHUDS\DUHXVXDOO\QRWFRQVLGHUHG PHDVXUDEOH XQOHVV WKHUH KDV EHHQ GHPRQVWUDWHG SURJUHVVLRQ LQ WKH OHVLRQ 'HILQLWLRQVRI5HVSRQVH 7DUJHW/HVLRQV $OOPHDVXUDEOHOHVLRQVXSWRDPD[LPXP RIOHVLRQVSHURUJDQDQG OHVLRQVLQWRWDOUHSUHVHQWDWLYHRIDOOLQYROYHGRUJDQVVKRXOGEHLGHQWLILHG DVWDUJHWOHVLRQVDQGUHFRUGHGDQGPHDVXUHGDWEDVHOLQH7DUJHWOHVLRQV VKRXOG EH VHOHFWHG RQ WKH EDVLV RI WKHLU VL]H WKRVH ZLWK WKH ORQJHVW GLDPHWHUV EH UHSUHVHQWDWLYH RI DOO LQYROYHG RUJDQV EXW LQ DGGLWLRQ VKRXOG EH WKRVH WKDW OHQG WKHPVHOYHV WR UHSURGXFLEOH UHSHDWHG PHDVXUHPHQWV,WPD\EHWKHFDVHWKDWRQRFFDVLRQWKHODUJHVWOHVLRQ GRHVQRWOHQGLWVHOIWRUHSURGXFLEOHPHDVXUHPHQWLQZKLFKFLUFXPVWDQFH WKHQH[WODUJHVWOHVLRQZKLFKFDQEHPHDVXUHGUHSURGXFLEO\VKRXOGEH VHOHFWHG

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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³´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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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³LQFUHDVH´ LQ WKH VL]H RI RQH RU PRUH QRQWDUJHW OHVLRQV LV XVXDOO\ QRW VXIILFLHQWWRTXDOLI\IRUXQHTXLYRFDOSURJUHVVLRQVWDWXV 7KHGHVLJQDWLRQ RIRYHUDOOSURJUHVVLRQVROHO\RQWKHEDVLVRIFKDQJHLQQRQWDUJHWGLVHDVH LQWKHIDFHRI6'RU35RIWDUJHWGLVHDVHZLOOWKHUHIRUHEHH[WUHPHO\UDUH :KHQ WKH SDWLHQW RQO\ KDV QRQPHDVXUDEOH GLVHDVH WKH LQFUHDVH LQ RYHUDOO GLVHDVH EXUGHQ VKRXOG EH FRPSDUDEOH LQ PDJQLWXGH WR WKH LQFUHDVHWKDWZRXOGEHUHTXLUHGWRGHFODUH3'IRUPHDVXUDEOHGLVHDVH LHDQLQFUHDVHLQWXPRUEXUGHQIURP³WUDFH´WR³ODUJH´DQLQFUHDVHLQ QRGDOGLVHDVHIURP³ORFDOL]HG´WR³ZLGHVSUHDG´RUDQLQFUHDVHVXIILFLHQW WRUHTXLUHDFKDQJHLQWKHUDS\ $OWKRXJKDFOHDUSURJUHVVLRQRI³QRQWDUJHW´OHVLRQVRQO\LVH[FHSWLRQDO WKHRSLQLRQRIWKHWUHDWLQJSK\VLFLDQVKRXOGSUHYDLOLQVXFKFLUFXPVWDQFHV (YDOXDWLRQRI1HZ/HVLRQV 7KHDSSHDUDQFHRIQHZOHVLRQVFRQVWLWXWHV3URJUHVVLYH'LVHDVH 3' 6\PSWRPDWLF'HWHULRUDWLRQ 3DWLHQWV ZLWK D JOREDO GHWHULRUDWLRQ RI KHDOWK VWDWXV UHTXLULQJ GLVFRQWLQXDWLRQ RI WUHDWPHQWZLWKRXWREMHFWLYHHYLGHQFHRIGLVHDVHSURJUHVVLRQDWWKDWWLPHVKRXOGEH UHSRUWHGDV³V\PSWRPDWLFGHWHULRUDWLRQ´ (YHU\HIIRUWVKRXOGEHPDGHWRGRFXPHQW WKHREMHFWLYHSURJUHVVLRQHYHQDIWHUGLVFRQWLQXDWLRQRIWUHDWPHQW (YDOXDWLRQRI3DWLHQW¶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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

8VHRI05,UHPDLQVDFRPSOH[LVVXH05,KDVH[FHOOHQWFRQWUDVWVSDWLDO DQG WHPSRUDO UHVROXWLRQ KRZHYHU WKHUH DUH PDQ\ LPDJH DFTXLVLWLRQ YDULDEOHV LQYROYHG LQ 05, ZKLFK JUHDWO\ LPSDFW LPDJH TXDOLW\ OHVLRQ FRQVSLFXLW\ DQG PHDVXUHPHQW )XUWKHUPRUH WKH DYDLODELOLW\ RI 05, LV YDULDEOH JOREDOO\ $V ZLWK &7 LI DQ 05, LV SHUIRUPHG WKH WHFKQLFDO VSHFLILFDWLRQVRIWKHVFDQQLQJVHTXHQFHVXVHGVKRXOGEHRSWLPL]HGIRU WKHHYDOXDWLRQRIWKHW\SHDQGVLWHRIGLVHDVH)XUWKHUPRUHDVZLWK&7 WKH PRGDOLW\ XVHG DW IROORZXS VKRXOG EH WKH VDPH DV ZDV XVHG DW EDVHOLQH DQG WKH OHVLRQV VKRXOG EH PHDVXUHGDVVHVVHG RQ WKH VDPH SXOVH VHTXHQFH ,W LV EH\RQG WKH VFRSH RI WKH 5(&,67 JXLGHOLQHVWR SUHVFULEHVSHFLILF05,SXOVHVHTXHQFHSDUDPHWHUVIRUDOOVFDQQHUVERG\ SDUWVDQGGLVHDVHV,GHDOO\WKHVDPHW\SHRIVFDQQHUVKRXOGEHXVHG DQG WKH LPDJH DFTXLVLWLRQ SURWRFRO VKRXOG EH IROORZHG DV FORVHO\ DV SRVVLEOHWRSULRUVFDQV%RG\VFDQVVKRXOGEHSHUIRUPHGZLWKEUHDWKKROG VFDQQLQJWHFKQLTXHVLISRVVLEOH 3(7&7 $W SUHVHQW WKH ORZ GRVH RU DWWHQXDWLRQ FRUUHFWLRQ &7 SRUWLRQ RI D FRPELQHG3(7&7LVQRWDOZD\VRIRSWLPDOGLDJQRVWLF&7TXDOLW\IRUXVH ZLWK5(&,67PHDVXUHPHQWV+RZHYHULIWKHVLWHFDQGRFXPHQWWKDWWKH &7SHUIRUPHGDVSDUWRID3(7&7LVRILGHQWLFDOGLDJQRVWLFTXDOLW\WRD GLDJQRVWLF&7 ZLWK,9DQGRUDOFRQWUDVW WKHQWKH&7SRUWLRQRIWKH3(7 &7 FDQ EH XVHG IRU 5(&,67 PHDVXUHPHQWV DQG FDQ EH XVHG LQWHUFKDQJHDEO\ ZLWK FRQYHQWLRQDO &7 LQ DFFXUDWHO\ PHDVXULQJ FDQFHU OHVLRQV RYHU WLPH 1RWH KRZHYHU WKDW WKH 3(7 SRUWLRQ RI WKH &7 LQWURGXFHV DGGLWLRQDO GDWD ZKLFK PD\ ELDV DQ LQYHVWLJDWRU LI LWLVQRW URXWLQHO\RUVHULDOO\SHUIRUPHG 8OWUDVRXQG 8OWUDVRXQGLVQRWXVHIXOLQDVVHVVPHQWRIOHVLRQVL]HDQGVKRXOGQRWEH XVHGDVDPHWKRGRIPHDVXUHPHQW8OWUDVRXQGH[DPLQDWLRQVFDQQRWEH UHSURGXFHGLQWKHLUHQWLUHW\IRULQGHSHQGHQWUHYLHZDWDODWHUGDWHDQG EHFDXVHWKH\DUHRSHUDWRUGHSHQGHQWLWFDQQRWEHJXDUDQWHHGWKDWWKH VDPHWHFKQLTXHDQGPHDVXUHPHQWVZLOOEHWDNHQIURPRQHDVVHVVPHQW WRWKHQH[W,IQHZOHVLRQVDUHLGHQWLILHGE\XOWUDVRXQGLQWKHFRXUVHRIWKH VWXG\FRQILUPDWLRQE\&7RU05,LVDGYLVHG,IWKHUHLVFRQFHUQDERXW UDGLDWLRQH[SRVXUHDW&705,PD\EHXVHGLQVWHDGRI&7LQVHOHFWHG LQVWDQFHV (QGRVFRS\/DSDURVFRS\ 7KHXWLOL]DWLRQRIWKHVHWHFKQLTXHVIRUREMHFWLYHWXPRUHYDOXDWLRQLVQRW DGYLVHG+RZHYHUVXFKWHFKQLTXHVPD\EHXVHIXOWRFRQILUPFRPSOHWH SDWKRORJLFDO UHVSRQVH ZKHQ ELRSVLHV DUH REWDLQHG RU WR GHWHUPLQH UHODSVHLQWULDOVZKHUHUHFXUUHQFHIROORZLQJFRPSOHWHUHVSRQVH &5 RU VXUJLFDOUHVHFWLRQLVDQHQGSRLQW 7XPRU0DUNHUV 7XPRUPDUNHUVDORQHFDQQRWEHXVHGWRDVVHVVUHVSRQVH,IPDUNHUVDUH LQLWLDOO\DERYHWKHXSSHUQRUPDOOLPLWWKH\PXVWQRUPDOL]HIRUDSDWLHQWWR EHFRQVLGHUHGLQFRPSOHWHFOLQLFDOUHVSRQVH &\WRORJ\+LVWRORJ\ 7KHVHWHFKQLTXHVFDQEHXVHGWRGLIIHUHQWLDWHEHWZHHQSDUWLDOUHVSRQVHV 35 DQGFRPSOHWHUHVSRQVHV &5 LQUDUHFDVHV HJUHVLGXDOOHVLRQV

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

LQWXPRUW\SHVVXFKDVJHUPFHOOWXPRUVZKHUHNQRZQUHVLGXDOEHQLJQ WXPRUVFDQUHPDLQ 7KHF\WRORJLFDOFRQILUPDWLRQRIWKHQHRSODVWLFRULJLQRIDQ\HIIXVLRQWKDW DSSHDUVRUZRUVHQVGXULQJWUHDWPHQWZKHQWKHPHDVXUDEOHWXPRUKDV PHWFULWHULDIRUUHVSRQVHRUVWDEOHGLVHDVHLVPDQGDWRU\WRGLIIHUHQWLDWH EHWZHHQUHVSRQVHRUVWDEOHGLVHDVH DQHIIXVLRQPD\EHDVLGHHIIHFWRI WKHWUHDWPHQW DQGSURJUHVVLYHGLVHDVH

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

6WXG\3DUDPHWHUV $OOSUHVWXG\ VFDQV VKRXOGEHGRQH ZHHNVSULRUWR UHJLVWUDWLRQ $OORWKHUSUHVWXG\DVVHVVPHQWV VKRXOGEHGRQH ZHHNVSULRUWR UHJLVWUDWLRQ

&\FOH &\FOHDQG6XEVHTXHQW &\FOHV F\FOH 'D\V (YHU\&\FOHV 2II 3URFHGXUHV 6FUHHQLQJ )ROORZ8S 'D\ 'D\ 'D\ 'D\ 'D\ 'D\ 'D\ HYHU\ZHHNV 7UHDWPHQW 'D\ %5($. %5($.

:ULWWHQ,QIRUPHG&RQVHQW ;

'LVHDVH&KDUDFWHULVWLFV ;

0HGLFDO6XUJLFDO+LVWRU\ ; $VVHVVPHQWRI%DVHOLQH ; 6LJQV 6\PSWRPV +HLJKW ; 3K\VLFDO([DPLQFOXGLQJ ;;; ; ; :HLJKW 9LWDO6LJQV 7HPSHUDWXUH3XOVH ;;;; ; ; %ORRG3UHVVXUH

%RG\6XUIDFH$UHD %6$ ; ; ;

3HUIRUPDQFH6WDWXV ; ; ; ;

&%&'LIIHUHQWLDO3ODWHOHWV ;;;; ;;; ;

&KHPLVWU\ ;;;; ; ;

&$ &($ ; ; ;

37,15 ;

6HUXP3UHJQDQF\7HVW ;

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

&\FOH &\FOHDQG6XEVHTXHQW &\FOHV F\FOH 'D\V (YHU\&\FOHV 2II 3URFHGXUHV 6FUHHQLQJ )ROORZ8S 'D\ 'D\ 'D\ 'D\ 'D\ 'D\ 'D\ HYHU\ZHHNV 7UHDWPHQW 'D\ %5($. %5($.

05,RU&7 $EGRPHQ ; ; ; 3HOYLF ZLWK&RQWUDVW

&KHVW&7ZLWK&RQWUDVW ; ; ;

$UFKLYHG7LVVXH 3URFXUHPHQW ; 0DQGDWRU\ 5HVHDUFK%ORRG 6SHFLPHQV ;; ; ; 2SWLRQDO

7UHDWPHQW$GPLQLVWUDWLRQ ;;; ; ;;

&RQFRPLWDQW0HGLFDWLRQ ;;;; ;;; ; 5HYLHZ $GYHUVH(YHQWV ;;; ; ;; ; $VVHVVPHQW 6XUYLYDO6WDWXV ;

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

'UXJ)RUPXODWLRQDQG3URFXUHPHQW 1DE3DFOLWD[HO 2WKHU1DPHV $EUD[DQH &ODVVLILFDWLRQ $QWLPLFURWXEXODU&\WRWR[LF 0RGHRI$FWLRQ 1DESDFOLWD[HO LVDPLFURWXEXOHLQKLELWRUWKDWSURPRWHVWKHDVVHPEO\RIPLFURWXEXOHV IURPWXEXOLQGLPHUVDQGVWDELOL]HVPLFURWXEXOHVE\SUHYHQWLQJGHSRO\PHUL]DWLRQ7KLV VWDELOLW\UHVXOWVLQWKHLQKLELWLRQRIWKHQRUPDOG\QDPLFUHRUJDQL]DWLRQRIWKHPLFURWXEXOH QHWZRUNWKDWLVHVVHQWLDOIRUYLWDOLQWHUSKDVHDQGPLWRWLFFHOOXODUIXQFWLRQV3DFOLWD[HO LQGXFHVDEQRUPDODUUD\VRU³EXQGOHV´RIPLFURWXEXOHVWKURXJKRXWWKHFHOOF\FOHDQG PXOWLSOHDVWHUVRIPLFURWXEXOHVGXULQJPLWRVLV 6WRUDJHDQG6WDELOLW\ 6WRUHWKHYLDOVLQRULJLQDOFDUWRQVDW&WR& )WR) 5HWDLQLQWKHRULJLQDO SDFNDJHWRSURWHFWIURPEULJKWOLJKW8QRSHQHGYLDOVRIQDESDFOLWD[HO DUHVWDEOHXQWLO WKHGDWHLQGLFDWHGRQWKHSDFNDJHZKHQVWRUHGEHWZHHQ&WR& )WR) >H[FXUVLRQVSHUPLWWHGEHWZHHQ&WR& )WR) @ LQWKHRULJLQDOSDFNDJH 1HLWKHUIUHH]LQJQRUUHIULJHUDWLRQDGYHUVHO\DIIHFWVWKHVWDELOLW\RIWKHSURGXFW Stability of Reconstituted Suspension in the Vial 5HFRQVWLWXWHG QDESDFOLWD[HO LQ WKH YLDO VKRXOG EH XVHG LPPHGLDWHO\EXWPD\EH UHIULJHUDWHGDW&WR& )WR) IRUDPD[LPXPRIKRXUVLIQHFHVVDU\,IQRW XVHG LPPHGLDWHO\ HDFK YLDO RI UHFRQVWLWXWHG VXVSHQVLRQ VKRXOG EH UHSODFHG LQ WKH RULJLQDOFDUWRQWRSURWHFWLWIURPEULJKWOLJKW'LVFDUGDQ\ XQXVHGSRUWLRQ Stability of Reconstituted Suspension in the Infusion Bag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econstitution of Nab-Paclitaxel o $VHSWLFDOO\UHFRQVWLWXWHHDFKYLDORIQDESDFOLWD[HO E\LQMHFWLQJ PO RI 6RGLXP&KORULGH,QMHFWLRQ863RUHTXLYDOHQWLQWRHDFKYLDO o 6ORZO\ LQMHFW WKH PO RI 6RGLXP &KORULGH ,QMHFWLRQ 863 RYHU D PLQLPXPRI PLQXWHXVLQJWKHVWHULOHV\ULQJHGLUHFWLQJWKHVROXWLRQIORZRQWR WKHLQVLGHZDOORIWKHYLDO

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

o '2127,1-(&7WKH6RGLXP&KORULGH,QMHFWLRQ863 GLUHFWO\RQWRWKH O\RSKLOL]HGFDNHDVWKLVZLOOUHVXOWLQIRDPLQJ o 2QFH WKH LQMHFWLRQ LV FRPSOHWH DOORZ WKH YLDO WR VLW IRU D PLQLPXP RI PLQXWHVWRHQVXUHSURSHUZHWWLQJRIWKHO\RSKLOL]HGFDNHSRZGHU o *HQWO\VZLUODQGRULQYHUWWKHYLDOVORZO\IRUDWOHDVWPLQXWHVXQWLOFRPSOHWH GLVVROXWLRQRIDQ\FDNHSRZGHURFFXUV$YRLGJHQHUDWLRQRIIRDP o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ȝP PXVWQRWEHXVHG )ROORZLQJDGPLQLVWUDWLRQRIQDESDFOLWD[HOWKHLQWUDYHQRXVOLQH VKRXOGEHIOXVKHGZLWK VRGLXPFKORULGHVROXWLRQIRULQMHFWLRQWRHQVXUHDGPLQLVWUDWLRQRIWKHFRPSOHWH GRVHDFFRUGLQJWRORFDOSUDFWLFH 1DESDFOLWD[HO ZLOOEHUHFRQVWLWXWHGE\DSSURSULDWHVWXG\SHUVRQQHO7KH,QYHVWLJDWRU ZLOOFDOFXODWHWKHERG\VXUIDFHDUHD %6$ RIWKHSDWLHQWLQRUGHUWRGHWHUPLQHWKHWRWDO DPRXQWRIQDESDFOLWD[HO WREHDGPLQLVWHUHG %6$ZLOOEHFDOFXODWHGRQ&\FOH'D\ DQGUHFDOFXODWHGSHUWKHVLWH¶VVWDQGDUGRIFDUHRULIERG\ZHLJKWFKDQJHVE\PRUH WKDQ$FWXDOKHLJKWVDQGZHLJKWVVKRXOGEHXVHGWRFDOFXODWHVXUIDFHDUHDV QR GRZQZDUG DGMXVWPHQWWR LGHDO ZHLJKW 7KLVSULQFLSOHDSSOLHV WRLQGLYLGXDOVZKRVH FDOFXODWHGVXUIDFHDUHDLVP RUOHVV,QWKRVHUDUHFDVHVZKHUHDSDWLHQW VVXUIDFH DUHDLVJUHDWHUWKDQPWKHDFWXDOVXUIDFHDUHDRUPD\EHXVHG'RVLQJ%6$ PD\EHFDSSHGLIWKHWUHDWLQJSK\VLFLDQEHOLHYHVLWLVLQWKHEHVWLQWHUHVWRIDQREHVH SDWLHQW ,QFRPSDWLELOLWLHV 1DESDFOLWD[HO VKRXOGEHSUHSDUHGLQQRUPDOVDOLQH21/

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

7DEOH7R[LFLW\3URILOHRI1DE3DFOLWD[HO *HPFLWDELQH

3UHIHUUHG7HUP 1DE3DFOLWD[HO*HPFLWDELQH

*UDGH+HPDWRORJLF$(V

1HXWURSHQLD /HXNRSHQLD 7KURPERF\WRSHQLD $QHPLD 3DWLHQWV ZKR UHFHLYHG JURZWK IDFWRUV )HEULOHQHXWURSHQLD *UDGH1RQ+HPDWRORJLF7UHDWPHQW5HODWHG$(VLQ!RI3DWLHQWV )DWLJXH 3HULSKHUDOQHXURSDWK\ 'LDUUKHD

,QDGGLWLRQSDWLHQWVDUHDWLQFUHDVHGULVNIRUSQHXPRQLWLVDQGVHSVLV 1DESDFOLWD[HO LVD3UHJQDQF\&DWHJRU\'GUXJ 1XUVLQJ3DWLHQW,PSOLFDWLRQV 8VH FDXWLRQ ZKHQ KDQGOLQJ F\WRWR[LF GUXJV &ORVHO\ PRQLWRU WKH LQIXVLRQ VLWH IRU H[WUDYDVDWLRQDQGLQILOWUDWLRQ *LYHQWKHSRVVLELOLW\RIH[WUDYDVDWLRQLWLVDGYLVDEOHWR FORVHO\ PRQLWRU WKH LQIXVLRQ VLWH IRU SRVVLEOH LQILOWUDWLRQ GXULQJ GUXJ DGPLQLVWUDWLRQ /LPLWLQJWKHLQIXVLRQRIQDESDFOLWD[HOWRPLQXWHVDVGLUHFWHGUHGXFHVWKHOLNHOLKRRG RI LQIXVLRQUHODWHG UHDFWLRQV 6HYHUH HYHQWV VXFK DV SKOHELWLV FHOOXOLWLV LQGXUDWLRQ QHFURVLV DQG ILEURVLV KDYH EHHQ UHSRUWHG DV SDUW RI WKH FRQWLQXLQJ VXUYHLOODQFH RI SDFOLWD[HO LQMHFWLRQ VDIHW\ ,Q VRPH FDVHV WKH RQVHW RI WKH LQMHFWLRQ VLWH UHDFWLRQ LQ SDFOLWD[HOLQMHFWLRQSDWLHQWVHLWKHURFFXUUHGGXULQJDSURORQJHGLQIXVLRQRUZDVGHOD\HG E\DZHHNWRWHQGD\V5HFXUUHQFHRIVNLQUHDFWLRQVDWDVLWHRISUHYLRXVH[WUDYDVDWLRQ IROORZLQJDGPLQLVWUDWLRQRISDFOLWD[HOLQMHFWLRQDWDGLIIHUHQWVLWHLH³UHFDOO´KDVEHHQ UHSRUWHG

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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in-vivo DQG in vitro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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

3UHSDUDWLRQ 7KHUHFRPPHQGHGGLOXHQWIRUUHFRQVWLWXWLRQRIJHPFLWDELQH LV6RGLXP&KORULGH ,QMHFWLRQZLWKRXWSUHVHUYDWLYHV 7RUHFRQVWLWXWHDGGPO RI6RGLXP&KORULGH,QMHFWLRQWRWKHPJYLDORU PO RI 6RGLXP &KORULGH ,QMHFWLRQ WR WKH J YLDO 7KHVH GLOXWLRQV HDFK \LHOG D JHPFLWDELQH FRQFHQWUDWLRQ RI PJPO ZKLFK LQFOXGHV DFFRXQWLQJ IRU WKH GLVSODFHPHQWYROXPHRI WKHO\RSKLOL]HGSRZGHU POIRUWKHPJYLDORUPO IRU WKH J YLDO 7KH WRWDO YROXPH XSRQ UHFRQVWLWXWLRQ ZLOO EH PO RU PO UHVSHFWLYHO\&RPSOHWHZLWKGUDZDORIWKHYLDOFRQWHQWVZLOOSURYLGHPJRUJRI JHPFLWDELQHUHVSHFWLYHO\7KHDSSURSULDWHDPRXQWRIGUXJPD\EHDGPLQLVWHUHGDV SUHSDUHGRUIXUWKHUGLOXWHGZLWK6RGLXP&KORULGH,QMHFWLRQWRFRQFHQWUDWLRQVDV ORZDVPJPO 5HFRQVWLWXWHGJHPFLWDELQH LVDFOHDUFRORUOHVVWROLJKWVWUDZFRORUHGVROXWLRQ,QVSHFW YLVXDOO\IRUSDUWLFXODWHPDWWHUDQGGLVFRORUDWLRQSULRUWRDGPLQLVWUDWLRQ,ISDUWLFXODWH PDWWHURUGLVFRORUDWLRQLVIRXQGGRQRWDGPLQLVWHU :KHQSUHSDUHGDVGLUHFWHGJHPFLWDELQH VROXWLRQV DUHVWDEOHIRUKRXUVDWFRQWUROOHG URRP WHPSHUDWXUH WR & WR ) 'LVFDUG XQXVHG SRUWLRQ 6ROXWLRQV RI UHFRQVWLWXWHGJHPFLWDELQH VKRXOGQRWEHUHIULJHUDWHGDVFU\VWDOOL]DWLRQPD\RFFXU 5HIHUWRFRPPHUFLDOSDFNDJHLQVHUWIRUSUHSDUDWLRQDQGIXOOSUHVFULELQJLQIRUPDWLRQ 5RXWHRI$GPLQLVWUDWLRQ 5HFRPPHQGHGGRVDJHRIJHPFLWDELQH LVPJP LQWUDYHQRXVO\RYHUPLQXWHV RQ'D\VDQGRIHDFKGD\F\FOHDQGVKRXOGIROORZDGPLQLVWUDWLRQRIQDE SDFOLWD[HO ,QFRPSDWLELOLWLHV 'UXJLQFRPSDWLELOLWLHVRIJHPFLWDELQHVKRXOGEHSHUWKHFRPPHUFLDOSDFNDJHLQVHUW 1R LQFRPSDWLELOLWLHV KDYH EHHQ REVHUYHG ZLWK LQIXVLRQ ERWWOHV RU SRO\YLQ\O FKORULGH EDJVDQGDGPLQLVWUDWLRQVHWV $YDLODELOLW\ *HPFLWDELQHLVDSSURYHGIRUWKHWUHDWPHQW RISDWLHQWVZLWKFKRODQJLRFDUFLQRPDDQG ZLOOEHREWDLQHGFRPPHUFLDOO\ *HPFLWDELQH IRU LQMHFWLRQ 863 LV DYDLODEOH LQ VWHULOH VLQJOHXVH YLDOV LQGLYLGXDOO\ SDFNDJHGLQDFDUWRQFRQWDLQLQJ o PJZKLWHWRRIIZKLWHO\RSKLOL]HGSRZGHULQ VWHULOHVLQJOHXVHYLDO o JZKLWHWRRIIZKLWHO\RSKLOL]HGSRZGHULQ VWHULOHVLQJOHXVHYLDO *HPFLWDELQHGLVSRVDOVKRXOGEH DFFRUGLQJWRWKHPDQXIDFWXUHU¶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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

6WDWLVWLFDO&RQVLGHUDWLRQV 6WXG\'HVLJQ 6DPSOH6L]H&RQVLGHUDWLRQV 8VLQJD6LPRQWZRVWDJHGHVLJQ>@DPD[LPXPRI SDWLHQWVZLOOEHHQUROOHG WRDWWDLQ HOLJLEOHHYDOXDEOHSDWLHQWV WRWDOWDUJHWVDPSOHVL]HKDVEHHQLQIODWHGE\ WRDOORZIRUSDWLHQW LQHOLJLELOLW\LQHYDOXDELOLW\>6HFWLRQ@ 3DWLHQWVZLOOEHIROORZHGXQWLOWKHPLQLPXPRIWKHWLPH WRSURJUHVVLRQWLPHWRGHDWKRUVL[PRQWKVLIQHLWKHUSURJUHVVLRQQRUGHDWKLV REVHUYHGEHIRUH WKHSDWLHQW¶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¶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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

DEHWWHUSURJQRVWLFPDUNHUJURXS XVLQJDWZRVLGHGOHYHOORJUDQNWHVWWRHYDOXDWH 3)63RZHUIRU 26ZLOOEHPRUHOLPLWHG

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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± DQWLERG\GLOXWLRQ - &'$ $EFDP&DPEULGJH0$ DQWLERG\GLOXWLRQ - K(17 63FORQH 9HQWDQD7XFVRQ$= ± DQWLERG\GLOXWLRQ 6OLGH:DVKLQJ 6OLGHVPXVWEHZDVKHGLQEHWZHHQVWHSV5LQVHVOLGHVZLWK3%6 7ZHHQ 9LVXDOL]DWLRQ 'HWHFWWKHDQWLERG\DVLQVWUXFWHGE\WKHLQVWUXFWLRQVSURYLGHGZLWKWKH VSHFLILFYLVXDOL]DWLRQV\VWHPXVHG

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

$QDO\VLV 6HH6HFWLRQ7DEOH 7KHGLIIHUHQFHLQ3)6773255'&5DQG26EHWZHHQWKHORZ DQGKLJKµDQWLJHQ¶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³FKLS´ VL]HRIDPLFURVFRSHVOLGH LQWKHODERUDWRU\XVLQJ VWDQGDUGV\ULQJHSXPSV7RFDSWXUH&7&V*(',REVWDFOHVZLOO EHFRDWHGZLWKDQDQWLERG\VSHFLILFWRHSLWKHOLDOFHOODGKHVLRQPROHFXOH (S&$0 DQ HSLWKHOLDO FHOOVSHFLILF PDUNHU $IWHU ZDVKHV FDSWXUHG FHOOV ZLOOEHVWDLQHG ZLWKWKH QXFOHDUPDUNHU'$3,DQGIOXRUHVFHQWO\ODEHOHGDQWLERGLHVWRF\WRNHUDWLQ &. DQGRU8VLQJIOXRUHVFHQFHPLFURVFRS\&.DQGRU'$3,&' (S&$0

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

FDSWXUHGFHOOV ZLWKLQWDFWFHOOXODUPRUSKRORJ\ZLOOEHFRXQWHGDV&7&VE\DEOLQGHG REVHUYHU )LJXUH LQSDQFUHDWLF FDQFHU &HOOVZLOOEHIL[HGDQGVWRUHGDW&IRU IXUWKHUDQDO\VLV

)LJXUH ,QGLYLGXDO,PDJHVRI1XFOHDWHG&HOOV&DSWXUHGRQ WKH *(', 'HYLFH &HOOV ZHUH VWDLQHG IRU &' UHG 3G[ JUHHQ DQGQXFOHL '$3,EOXH &HOOVLQLLLYLLDQG[LYFRQWDLQ QXFOHDU3G[VWDLQLQJLQGLFDWLQJSDQFUHDVRULJLQRI&LUFXODWLQJ (QGRWKHOLDO&HOOV &(&V &HOOVLQLYYLLL[LLDQG[LLLDUH&' OHXNRF\WHVFDSWXUHGE\*(',EXWZHUHH[FOXGHGIURPDQDO\VLV

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

3ODVPD 3UHSDUDWLRQ x 8VLQJ D WUDQVIHU SLSHWWH WDNH WKH WRS WZRWKLUGV RI WKH SODVPD DQG WUDQVIHU SODVPDLQWRD PO FRQLFDOFHQWULIXJHWXEHEHFDUHIXOQRWWRGLVWXUEWKHEXII\ FRDW OD\HU LQ WKH ('7$ WXEH 127( VHH EHORZ IRU EXII\ FRDW SURFHVVLQJ LQVWUXFWLRQV &HQWULIXJH WKHPO FRQLFDOWXEH DW 530IRUPLQXWHVDW & ,I D UHIULJHUDWHG FHQWULIXJH LV QRW DYDLODEOH VSLQ VDPSOHDWURRP WHPSHUDWXUH 530IRUPLQXWHV ,PPHGLDWHO\SODFHWKHFRQLFDOWXEHRQ ZHWLFHDIWHUFHQWULIXJDWLRQ x 7UDQVIHUHTXDODPRXQWVRISODVPDLQWRWZR SURSHUO\ODEHOHGSRO\SURS\OHQH WXEHVIRUFU\RSUHVHUYDWLRQ EHLQJFDUHIXOQRWWRGLVWXUEWKHVPDOO3%0&SHOOHW x 6WRUHWKHWZRDOLTXRWVRISODVPDVDPSOHVLQWKHIUHH]HUDW&RUFROGHUXQWLO WKH\DUHVKLSSHGWRFHQWUDOODEIRUEDQNLQJ %XII\&RDW 3UHSDUDWLRQ x )URP WKH ('7$ WXEH UHPRYH DQG DOLTXRW WKH ³EXII\ FRDW´ EH FDUHIXO QRW WR GLVWXUEWKHOD\HURI UHGEORRGFHOOV x 6WRUH WKH DOLTXRW RI FHOOV LQ RQH SURSHUO\ ODEHOHG SRO\SURS\OHQH WXEH IRU FU\RSUHVHUYDWLRQ x 6WRUHWKHVDPSOHLQWKHIUHH]HUDW&RUFROGHUXQWLOLWLVVKLSSHGWRFHQWUDO ODEIRUEDQNLQJ 6HUXP SODVPD DQG EXII\ FRDW VDPSOHV VKRXOG EH EDWFKHG WRJHWKHU DQG VKLSSHG DSSUR[LPDWHO\ HYHU\ PRQWKV ,QGLYLGXDO SDWLHQWV VKRXOG RQO\ EH LQFOXGHG LQ WKH VKLSPHQWLIDOORIWKHLU VDPSOHVKDYHEHHQFRPSOHWHG 6DPSOHVVKRXOGEHVKLSSHG0RQGD\7KXUVGD\ 6DPSOHVPXVWEHVKLSSHGRQGU\LFH YLDRYHUQLJKWFRXULHU 6KLSSLQJODEHOV VXSSOLHVDQGDGGUHVVZLOOEHSURYLGHG

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

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x WZR\HDUVDIWHUWKH)'$DSSURYHVWKHPDUNHWLQJDSSOLFDWLRQRU x WZR\HDUVDIWHUWKH)'$GLVDSSURYHVWKHDSSOLFDWLRQIRUWKHLQGLFDWLRQEHLQJVWXGLHGRU x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

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

5HIHUHQFHV 6KDLE<+HWDORising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? -+HSDWRO S 9DOOH-HWDOCisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. 1(QJO- 0HG S 1DWKDQ+HWDOTrends in survival after surgery for cholangiocarcinoma: a 30-year population- based SEER database analysis. -*DVWURLQWHVW6XUJ SGLVFXVVLRQ chemotherapy for unresectable biliary tract cancer. -SQ-&OLQ2QFRO S .RED\DVKL+HWDOHuman equilibrative nucleoside transporter 1 expression predicts survival of advanced cholangiocarcinoma patients treated with gemcitabine-based adjuvant chemotherapy after surgical resection. $QQ6XUJ S 3DUN.8HWDOAbstract 3705: Multicenter phase II clinical trial of gemcitabine and liposomal paclitaxel combination chemotherapy in patients with advanced biliary cancer. &DQFHU5HVHDUFK 6XSSOHPHQW S %ORRPVWRQ 0 HW DO Stromal osteonectin overexpression is associated with poor outcome in patients with ampullary cancer. $QQ6XUJ2QFRO S )UHVH..HWDOnab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. &DQFHU'LVFRY S 6SDUUHERRP$HWDOCremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. &DQFHU5HV S 'HVDL1HWDOIncreased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor- based paclitaxel. &OLQ&DQFHU5HV S 'HVDL13HWDOImproved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status. $QWLFDQFHU'UXJV S *XDUQHUL 9 HW DO Enhancing intracellular taxane delivery: current role and perspectives of nanoparticle albumin-bound paclitaxel in the treatment of advanced breast cancer. ([SHUW2SLQ 3KDUPDFRWKHU S *LDQQL / HW DO Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. -&OLQ2QFRO S $LW2XGKLD6HWDO Meta-analysis of nanoparticulate paclitaxel delivery system pharmacokinetics and model prediction of associated neutropenia. 3KDUP 5HV S *UDGLVKDU :- HW DO Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. -&OLQ2QFRO S 9RQ +RII '' HW DO Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. -&OLQ2QFRO S %XUULV +$ HW DO Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. -RXUQDO RI &OLQLFDO 2QFRORJ\ S 9RQ +RII '' HW DO Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine 1(QJO-0HG S

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

*ROGVWHLQ'HWDOUpdated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas. $6&20HHWLQJ$EVWUDFWV BVXSSO S 6RFLQVNL0$HWDOA dose finding study of weekly and every-3-week nab-Paclitaxel followed by carboplatin as first-line therapy in patients with advanced non-small cell lung cancer. -7KRUDF 2QFRO S +HUVK(0HWDOA phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy- naive patients with metastatic melanoma. &DQFHU S 'DQJL*DULPHOOD6HWDOThree-Dimensional Collagen I Promotes Gemcitabine Resistance In Vitro in Pancreatic Cancer Cells through HMGA2-Dependent Histone Acetyltransferase Expression. 3/R62QH SH /HH-HWDOPhase II trial of gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas. &DQFHU&KHPRWKHU3KDUPDFRO S 1HKOV 2 HW DO Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. %U-&DQFHU S .RHEHUOH ' HW DO Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research. -&OLQ2QFRO S .LP +- HW DO A phase II study of gemcitabine in combination with oxaliplatin as first-line chemotherapy in patients with inoperable biliary tract cancer. &DQFHU&KHPRWKHU3KDUPDFRO S 9DOOH-:HWDOGemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study. %U-&DQFHU S -DQJ-6HWDOGemcitabine and oxaliplatin in patients with unresectable biliary cancer including gall bladder cancer: a Korean Cancer Study Group phase II trial. &DQFHU&KHPRWKHU3KDUPDFRO S =KX$;HWDOEfficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. /DQFHW2QFRO S +DOLP$HWDO A phase II study of outpatient biweekly gemcitabine-oxaliplatin in advanced biliary tract carcinomas. -SQ-&OLQ2QFRO S 0DOND'HWDOGemcitabine and oxaliplatin (GEMOX) alone or in combination with cetuximab as first-line treatment for advanced biliary cancer: Final analysis of a randomized phase II trial (BINGO). $6&20HHWLQJ$EVWUDFWV BVXSSO S $QWKRQ\ 3 HG Tumours and tumour-like lesions of the liver and the biliary tract: aetiology, epidemiology and pathology 3DWKRORJ\ RI WKH /LYHU HG 5 0DF6ZHHQ HW DO &KXUFKLOO /LYLQJVWRQH/RQGRQ 1DNHHE$HWDOCholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. $QQ6XUJ SGLVFXVVLRQ 2NDPXUD1HWDOCellular and stromal characteristics in the scirrhous hepatocellular carcinoma: comparison with hepatocellular carcinomas and intrahepatic cholangiocarcinomas. 3DWKRO ,QW S 1DJDUDMX *3 DQG %) (L5D\HV SPARC and DNA methylation: possible diagnostic and therapeutic implications in Gastrointestinal Cancers. &DQFHU/HWW

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

7URPEHWWD(VLOYD-DQG$'%UDGVKDZThe Function of SPARC as a Mediator of Fibrosis. 2SHQ 5KHXPDWRO-S =KRX ; HW DO Small interfering RNA inhibition of SPARC attenuates the profibrotic effect of transforming growth factor beta1 in cultured normal human fibroblasts. $UWKULWLV 5KHXP S )UL]HOO(HWDOExpression of SPARC in normal and fibrotic livers. +HSDWRORJ\ S &DPLQR$0HWDOAdenovirus-mediated inhibition of SPARC attenuates liver fibrosis in rats. - *HQH0HG S %UDGVKDZ$'The role of SPARC in extracellular matrix assembly. -&HOO&RPPXQ6LJQDO S 5LFK-1HWDOBone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. -%LRO&KHP S /HGGD 0) HW DO Suppression of SPARC expression by antisense RNA abrogates the tumorigenicity of human melanoma cells. 1DW0HG S ,QIDQWH-5HWDOPeritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. -&OLQ2QFRO S 6DLQDQL1,HWDOCholangiocarcinoma: current and novel imaging techniques. 5DGLRJUDSKLFV S .KDQ6$HWDOGuidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. *XW6XSSOS9, /RZ51MR imaging of the liver using gadolinium chelates. 0DJQ5HVRQ,PDJLQJ&OLQ1$P SYL )RZOHU .- HW DO Magnetic resonance imaging of focal liver lesions: approach to imaging diagnosis. +HSDWRORJ\ S 9DUJD0HWDOOverexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival. &OLQ&DQFHU5HV S :HQW 37HWDO Frequent EpCam protein expression in human carcinomas. +XP3DWKRO -DQ S GH %RHU&-HWDO Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver. -3DWKRO S .LUE\ %- HW DO Functional characterization of circulating tumor cells with a prostate-cancer- specific microfluidic device. 3/R62QH H 5KLP$' HWDO Detection of Circulating Pancreas Epithelial Cells in Patients With Pancreatic Cystic Lesions. *DVWURHQWHURORJ\ S *OHJKRUQ-3 HWDOCapture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. /DE&KLS S $O 8VWZDQL2HWDO Detection of circulating tumor cells in cancers of biliary origin. - *DVWURLQWHVW 2QFRO S 8HQR + HW DO Effect of cytidine deaminase (CDA)-related biomarkers on overall survival in patients with advanced pancreatic cancer receiving gemcitabine (GEM) monotherapy. $6&2 0HHWLQJ$EVWUDFWV BVXSSO SH

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

0RUL 5 HW DO Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells. 2QFRO5HS S %RUEDWK,HWDOHuman equilibrative nucleoside transporter 1 (hENT1) expression is a potential predictive tool for response to gemcitabine in patients with advanced cholangiocarcinoma. (XU- &DQFHU S 7ULHX 9 HW DO Nanoparticle Albumin-bound (nab) technology may enhance antitumor activity via targeting of SPARC protein. In: New Targets and Delivery System for Cancer Diagnosis and Treatment (SKCC), 6DQ'LHJR&$$EVWUDFW 1HHVVH$ HWDO SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut Published Online First: >UG 6HSWHPEHU@GRLJXWMQO . Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 86'R+D+ 6HUYLFHV DQG )D' $GPLQLVWUDWLRQ (GLWRUV 2IILFH RI 7UDLQLQJ DQG &RPPXQLFDWLRQV5RFNYLOOH0' ,OOHL 3 HW DO SPARC Expression in Pancreatic Adenocarcinoma: Development of a Robust, Predictive Immunohistochemical Assay and Scoring Method. 0RG3DWKRO 3RSOLQ ( HW DO Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. -&OLQ2QFRO *UHHQKDOI : HW DO Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. -1DWO&DQFHU,QVWGMW 0F&DUW\ .6 -U HW DO Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. &DQFHU5HVVV (LVHQKDXHU ($ HW DO New response evaluation criteria in solid tumours: revised RECIST guideline (Version 1.1). (XU-&DQFHU-DQ 9RQ +RII '' HW DO Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). $6&20HHWLQJ$EVWUDFWV BVXSSO S/%$ 6LPRQ5Optimal two-stage designs for phase II clinical trials. &RQWURO&OLQ7ULDOV S .DSODQ(/DQG30HLHUNonparametric Estimation from Incomplete Observations. -RXUQDORI WKH$PHULFDQ6WDWLVWLFDO$VVRFLDWLRQ S 0DQWHO1Evaluation of survival data and two new rank order statistics arising in its consideration. &DQFHU&KHPRWKHU5HS S 0DQWHO1DQG:+DHQV]HOStatistical aspects of the analysis of data from retrospective studies of disease. -1DWO&DQFHU,QVW S 7DO\9HWDOMultiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. &OLQ&KHP S +DULVPHQG\2HWDODetection of low prevalence somatic mutations in solid tumors with ultra- deep targeted sequencing. *HQRPH%LRO S5

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

$SSHQGL[, &KLOG3XJK6FRUH

0HDVXUH SRLQW SRLQWV SRLQWV

7RWDO%LOLUXELQPJGO !

6HUXP$OEXPLQJGO !

377LPH x 7LPH ! x ,15 !

$VFLWHV $EVHQW 6OLJKW 0RGHUDWHWR6HYHUH

*UDGH *UDGH +HSDWLF(QFHSKDORSDWK\ 1RQH RUVXSSUHVVHGZLWKPHGLFDWLRQ RUUHIUDFWRU\

3RLQWV &ODVV 2QH

Source: R.N.H. Pugh, I.M. Murray-Lyon, J.L. Dawson, M.C. Pietroni, Roger Williams. Transection of the esophagus for bleeding esophageal varices. British Journal of Surgery. Volume 60. Issue 8, pages 646-649, August 1973.

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

$SSHQGL[,, (&2*3HUIRUPDQFH6WDWXV

36 )XOO\DFWLYHDEOHWRFDUU\RQDOOSUHGLVHDVHSHUIRUPDQFH ZLWKRXWUHVWULFWLRQ

36 5HVWULFWHG LQ SK\VLFDOO\ VWUHQXRXV DFWLYLW\ EXW DPEXODWRU\ DQGDEOHWRFDUU\RXWZRUNRIDOLJKWRUVHGHQWDU\QDWXUHHJ OLJKWKRXVHZRUN RIILFHZRUN

36 $PEXODWRU\DQGFDSDEOHRIDOOVHOIFDUHEXWXQDEOHWRFDUU\ RXW DQ\ ZRUN DFWLYLWLHV 8S DQG DERXWPRUH WKDQ RI ZDNLQJKRXUV

36 &DSDEOHRIRQO\OLPLWHGVHOIFDUHFRQILQHGWREHGRUFKDLU PRUHWKDQRIZDNLQJKRXUV

36 &RPSOHWHO\GLVDEOHG&DQQRWFDUU\RQDQ\VHOIFDUH7RWDOO\ FRQILQHGWREHGRUFKDLU

6RXUFH(DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS5REHUW&RPLV0'*URXS&KDLU

Downloaded From: https://jamanetwork.com/ on 09/25/2021 3U(&2*3URWRFRO1XPEHU3U( &RQILGHQWLDO 'DWH

$SSHQGL[,,, ,QYHVWLJDWRU¶V6WDWHPHQW ,KDYHFDUHIXOO\UHDGWKLVSURWRFROHQWLWOHG³$0XOWL,QVWLWXWLRQDO6LQJOH$UP7ZR6WDJH 3KDVH,,7ULDORI1DE3DFOLWD[HODQG*HPFLWDELQHIRU)LUVW/LQH7UHDWPHQWRI3DWLHQWV ZLWK $GYDQFHG RU 0HWDVWDWLF &KRODQJLRFDUFLQRPD´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

Downloaded From: https://jamanetwork.com/ on 09/25/2021

Web Analytics