A Phase 1/ Phase 2 Study Evaluating the Safety and Efficacy of the Investigational New Drug TTHX1114(NM141) on the Regeneration of Corneal Endothelial Cells in Patients With Corneal Endothelial Dystrophies Following Intracameral Delivery
Phase: PHASE1
Conditions: Corneal Endothelial Dystrophy, Fuchs Endothelial Corneal Dystrophy, Pseudophakic Bullous Keratopathy, Endothelial Dysfunction
Sponsor: Trefoil Therapeutics, Inc.

7* &OLQLFDO 6WXG\ 3URWRFRO  $
7KLV VWXG\ ZLOO EH FRQGXFWHG DFFRUGLQJ WR WKH SURWRFRO DQG LQ FRPSOLDQFH ZLWK *RRG &OLQLFDO 3UDFWLFH *&3 ZKLFK
KDYH WKHLU RULJLQV LQ WKH 'HFODUDWLRQ RI +HOVLQNL DQG ZLWK RWKHU DSSOLFDEOH UHJXODWRU\ UHTXLUHPHQWV
&OLQLFDO 6WXG\ 3URWRFRO
3URWRFRO 1R
77+;
3KDVH
3KDVH  3KDVH 
1DPH RI 6WXG\
$ 3KDVH  3KDVH  6WXG\ (YDOXDWLQJ WKH 6DIHW\ DQG (IILFDF\
RI WKH ,QYHVWLJDWLRQDO 1HZ 'UXJ 77+;10 RQ WKH
5HJHQHUDWLRQ RI &RUQHDO (QGRWKHOLDO &HOOV LQ 3DWLHQWV ZLWK
&RUQHDO (QGRWKHOLDO '\VWURSKLHV IROORZLQJ ,QWUDFDPHUDO
'HOLYHU\
6WXG\ 'UXJ 1DPH
77+;10
,1' 1XPEHU

6SRQVRU
7UHIRLO 7KHUDSHXWLFV ,QF
 1DQF\ 5LGJH 'ULYH 6XLWH 
6DQ 'LHJR &$ 
'DWH RI 3URWRFRO
$PHQGPHQW 
6HSWHPEHU  
2ULJLQDO
9HUVLRQ  -XQH  
$SSURYHG %\
7KRPDV 0 7UHPEOD\ 51 %61
93 &OLQLFDO 'HYHORSPHQW
'DWH
'DYLG (YHOHWK 3K'
&KLHI ([HFXWLYH 2IILFHU
'DWH
   

	

	


NCT 04520321

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
“The only thing worse than being blind is having sight but no vision.” 
+HOHQ .HOOHU
'2&80(17 +,6725<
9HUVLRQ
'HVFULSWLRQ RI &KDQJHV

1$
$PHQGPHQW 
x
'HILQH '/7 FULWHULD 6HFWLRQ 
x
$GGHG LQVWUXFWLRQ UHODWHG WR FRQWUDFHSWLRQ DQG SUHJQDQF\ LQ D VXEMHFW RU SDUWQHU
IROORZXS 6HH 6HFWLRQ 
x
7R FODULI\ WKDW YLVXDO DFXLW\ ZLOO EH DVVHVVHG E\ %HVW &RUUHFWHG 9LVXDO $FXLW\
%&9$ QRW %HVW 6SHFWDFOHFRUUHFWHG 9LVXDO $FXLW\ %6&9$
x
8SGDWH FODULI\ HOLJLELOLW\ LQFOXGLQJ
o
([FOXGH D KLVWRU\ RI UHSHDWHG HOHYDWHG ,23
o
([FOXGH UHIUDFWLYH VXUJHU\ LQ WKH 6WXG\ (\H
o
([FOXGH FDWDUDFW VXUJHU\ LQ WKH SULRU  PRQWKV
o
([FOXGH $QWHULRU &KDPEHU ,2/ 3ODFHPHQW LQ WKH 6WXG\ (\H
o
([FOXGH RSHQ RU DEVHQW SRVWHULRU FDSVXOH LI YLWUHRXV SUHVHQW LQ WKH DQWHULRU
FKDPEHU XQOHVV DSSURYHG E\ 0HGLFDO 0RQLWRU
o
&ODULI\ ³HLWKHU H\H´ YHUVXV ³VWXG\ H\H RQO\´ FULWHULD
o
&ODULI\ HOLJLELOLW\ UHODWHG WR SUHJQDQF\ DQG FRQWUDFHSWLRQ
x
&ODULI\ WKH SRVWLQMHFWLRQ ,23 PXVW EH PRQLWRUHG XQWLO OHVV WKDQ  PP+J JUHDWHU
WKDQ SUHLQMHFWLRQ UDWKHU WR  PP+J
x
8SGDWH 3.$'$ VDPSOH SUHSDUDWLRQ
x
&ODULI\ WKDW WKH FRPSUHKHQVLYH H\H H[DPLQDWLRQ ZLOO LQFOXGH VOLW ODPS H[DPLQDWLRQ
DQG GLODWHG H[DPLQDWLRQ RI WKH OHQV IXQGXV DQG YLWUHRXV
x
&ODULI\ WKH REVHUYDWLRQDO VXEVWXG\ HOLJLELOLW\ EDVHG RQ DYDLODELOLW\ RI RFXODU
DVVHVVPHQW UHVXOWV
,Q DGGLWLRQ WR FKDQJHV OLVWHG DERYH DGGLWLRQDO HGLWV PD\ KDYH EHHQ PDGH IRU FODULW\ DQG
FRQVLVWHQF\
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
EHIRUH WKH\ EHFRPH VH[XDOO\ DFWLYH 0HQ ZKR DUH VH[XDOO\ DFWLYH ZLWK D ZRPDQ RI
FKLOGEHDULQJ SRWHQWLDO PXVW DJUHH WR XVH D GRXEOH EDUULHU PHWKRG
([FOXVLRQ

+LVWRU\ RI DQ\ RI WKH IROORZLQJ LQ HLWKHU H\H
D
2FXODU FDQFHU LQFOXGLQJ PHODQRPD
E
+HUSHWLF NHUDWLWLV
F
&RUQHDO WUDQVSODQW IXOOWKLFNQHVV RU ODPHOODU
G
'RFXPHQWHG DQG UHSHDWHG HOHYDWHG ,23 LQ HLWKHU H\H
H
3RVWHULRU 3RO\PRUSKRXV &RUQHDO '\VWURSK\ 33&' DND 6FKOLFKWLQJ
G\VWURSK\
I
8YHLWLV
J
&DWDUDFW VXUJHU\ ZLWKLQ WKH  PRQWKV SULRU WR 6WXG\ 'D\ 

5HIUDFWLYH VXUJHU\ LQ WKH 6WXG\ (\H LQFOXGLQJ SKDNLF ,2/ FXUUHQWO\ LQ SODFH
1RWH 3RWHQWLDO VXEMHFWV ZKR KDYH KDG WKH SKDNLF ,2/ SODFHG DQG UHPRYHG DUH
DOORZHG /LPEDO UHOD[LQJ LQFLVLRQ SHUIRUPHG DW WKH WLPH RI FDWDUDFW VXUJHU\ LV
DOORZHG

$Q\ FRQGLWLRQ WKDW ZRXOG LPSDLU H[DPLQDWLRQ RI WKH DQWHULRU FKDPEHU VWUXFWXUHV LQ
WKH 6WXG\ (\H

$QWHULRU &KDPEHU ,2/ SODFHPHQW LQ WKH 6WXG\ (\H

([SHFWHG RU SODQQHG RFXODU VXUJHU\ LQFLVLRQDO RU ODVHU LQ WKH 6WXG\ (\H ZLWKLQ WKH
 PRQWKV IROORZLQJ 6WXG\ 'D\  LQFOXGLQJ HQGRWKHOLDO NHUDWRSODVW\

8VH RI V\VWHPLF RU GHUPDWRORJLFDO F\WRWR[LF FKHPRWKHUDS\ ZLWKLQ WKH  PRQWK
SULRU WR RU SODQQHG XVH ZLWKLQ WKH  PRQWKV IROORZLQJ 6WXG\ 'D\ 

8VH RI K\SHUWRQLF VDOLQH H\H SUHSDUDWLRQV HJ 0XUR  ZLWKLQ WKH  GD\V SULRU WR
6WXG\ 'D\  HLWKHU H\H

$FWLYH H[WUDRFXODU LQIODPPDWLRQ IURP DQ\ QRQLQIHFWLRXV RU LQIHFWLRXV FDXVH
EDFWHULDO YLUDO RU IXQJDO LQ WKH 6WXG\ (\H ZLWKLQ WKH  PRQWKV SULRU WR 6WXG\ 'D\

1RWH 0LOG EOHSKDULWLV DQGRU GU\ H\H UHODWHG LQIODPPDWLRQ DUH DOORZHG

7UHDWPHQW ZLWK D UKR NLQDVH LQKLELWRU ZLWKLQ WKH ODVW  PRQWKV HLWKHU H\H
 8VH RI F\FORVSRULQH RSKWKDOPLF HPXOVLRQHJ 5(67$6,6 ZLWKLQ WKH  GD\V
SULRU WR 6WXG\ 'D\  HLWKHU H\H
 8VH RI ;LLGUD OLILWHJUDVW RSKWKDOPLF VROXWLRQ ZLWKLQ WKH  GD\V SULRU WR 6WXG\
'D\  HLWKHU H\H
 6\VWHPLF QDVDO LQKDOHG RUDO SDUHQWHUDO RU WRSLFDO RU RSKWKDOPLF FRUWLFRVWHURLG
XVH LQ WKH  GD\V SULRU WR 6WXG\ 'D\  XQOHVV DSSURYHG E\ WKH 0HGLFDO 0RQLWRU
1RWH 3RWHQWLDO VXEMHFWV RQ D VWDEOH FKURQLF ORZGRVH WKDW LV QRW H[SHFWHG WR FKDQJH
LQ WKH  PRQWKV IROORZLQJ 6WXG\ 'D\  PD\ EH FRQVLGHUHG IRU WKH VWXG\ DIWHU
DSSURYDO E\ WKH 0HGLFDO 0RQLWRU
 +LVWRU\ RI VLJQLILFDQW DOOHUJ\ K\SHUVHQVLWLYLW\ RU LQWROHUDQFH WR DQ\ GUXJ
FRPSRXQG IRRG RU RWKHU VXEVWDQFH
1RWH 7KLV LQFOXGHV DOO FRPSRQHQWV DQG H[FLSLHQWV RI WKH VWXG\ GUXJ
 :RPHQ RI FKLOGEHDULQJ SRWHQWLDO ZKR DUH FXUUHQWO\ SUHJQDQW EUHDVW IHHGLQJ
SODQQLQJ WR EHFRPH SUHJQDQW GXULQJ WKH VWXG\ RU QRW ZLOOLQJ WR XVH KLJKO\ HIIHFWLYH
ELUWK FRQWURO PHDVXUHV HJ KRUPRQDO FRQWUDFHSWLYHV >RUDO LPSODQWHG WUDQVGHUPDO@
RU PHFKDQLFDO EDUULHU PHWKRGV >VSHUPLFLGH LQ FRQMXQFWLRQ ZLWK D EDUULHU VXFK DV D
FRQGRP RU GLDSKUDJP@ RU LQWUDXWHULQH GHYLFH >,8'@ GXULQJ WKH HQWLUH FRXUVH RI WKH
VWXG\
 &XUUHQW RU UHFHQW HJ WKH  GD\V SULRU WR 6WXG\ 'D\  SDUWLFLSDWLRQ LQ DQ\ RWKHU
LQWHUYHQWLRQDO FOLQLFDO UHVHDUFK VWXG\
 $Q HPSOR\HH RI WKH VLWH WKDW LV GLUHFWO\ LQYROYHG LQ WKH PDQDJHPHQW DGPLQLVWUDWLRQ
RU VXSSRUW RI WKLV VWXG\ RU EH DQ LPPHGLDWH IDPLO\ PHPEHU RI WKH VDPH
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
6XE6WXG\
6WXG\ 77+;
6FUHHQ
6WXG\ 'D\
9LVLW


            


3UH
,QIRUPHG FRQVHQW
;
;
'HPRJUDSKLFV
;
;
0HGLFDO DQG RFXODU KLVWRU\
;
;
&RPSUHKHQVLYH RFXODU H[DPLQDWLRQ
LQFOXGLQJ VOLW ODPS H[DPLQDWLRQ DQG GLODWHG H[DP RI
WKH OHQV IXQGXV DQG YLWUHRXV
28
6(I
28
8ULQH SUHJQDQF\ WHVW :2&%3
;
;
/DERUDWRU\ WHVWLQJ &KHP +HPH 8$ 	 +E$F
;
;
;
1(,9)4D
;
;
2SWLRQDO EORRG VDPSOH IRU JHQHWLF WHVWLQJ
;
$'$ DVVD\
;
;
3UHLQMHFWLRQ
;
;
3. VDPSOLQJ
;
3UHLQMHFWLRQ
;
;
 KRXUV DIWHU LQMHFWLRQ
;
;
6WXG\ 7UHDWPHQW ,& ,QMHFWLRQ 6(
;
;
;
;
5HFRUG &RQFRPLWDQW 0HGLFDWLRQV
;
;
;
;
;
;
;
;
;
;
;
;
5HFRUG $GYHUVH (YHQWV
;
;
;
;
;
;
;
;
2FXODU $VVHVVPHQWV
6SHFXODU PLFURVFRS\E
LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
28FG 28
28
28
28
28
28
28
28
28
3HQWDFDP H[DPLQDWLRQ
28
28
%HVW FRUUHFWHG YLVXDO DFXLW\E
28FG
28
6(
6(
6(
6(
6(
6(
6(
6OLW ODPS ELRPLFURVFRS\
28FG
6(
6(
6(
6(
6(
6(
,QWUDRFXODU 3UHVVXUH ,23 PHDVXUHPHQW
28FG
6( H 6( H
6( H
6( H
6( H
6(
6(
6(
28 ERWK H\HV 6( 6WXG\ (\H D 3HUIRUP SULRU WR DQ\ RWKHU DVVHVVPHQWV E ,I VXEMHFW LV WR EH GLODWHG SHUIRUP SULRU WR GLODWLRQ F 
WLPHSRLQWV  LQ WKH HDUO\ PRUQLQJ DQG  LQ WKH ODWH DIWHUQRRQ PD\ EH GLIIHUHQW GD\V G
 H ,23 SUHGRVH DQG SRVWGRVH DW OHDVW HYHU\  PLQXWHV XQWLO QRUPDOL]HG GHILQHG DV OHVV WKDQ  PP+J KLJKHU WKDQ
SUHLQMHFWLRQ ,23 I GLODWHG H[DP RQO\ LQ VXEMHFWV ZLWK YLWUHRXV LQ WKH $& DW EDVHOLQH
,QFOXGLQJ DOO RFXODU PHGLFDWLRQV
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
/,67 2) $%%5(9,$7,216
$'$
$QWL'UXJ $QWLERG\
$(
$GYHUVH (YHQW
%&9$
%HVW &RUUHFWHG 9LVXDO $FXLW\
&(&
&RUQHDO (QGRWKHOLDO &HOO
&('
&RUQHDO (QGRWKHOLDO '\VWURSKLHV
&,$5&
&RUQHD ,PDJH $QDO\VLV 5HDGLQJ &HQWHU
&5) H&5)
&DVH 5HSRUW )RUP HOHFWURQLF &DVH 5HSRUW )RUP
&52
&RQWUDFW 5HVHDUFK 2UJDQL]DWLRQ
'++6
'HSDUWPHQW RI +HDOWK DQG +XPDQ 6HUYLFHV
'/7
'RVH OLPLWLQJ WR[LFLW\
'0(.
'HVFHPHW 0HPEUDQH (QGRWKHOLDO .HUDWRSODVW\
'6(.
'HVFHPHW 6WULSSLQJ (QGRWKHOLDO .HUDWRSODVW\
(&'
(QGRWKHOLDO &HOO 'HQVLW\
('&
(OHFWURQLF 'DWD &DSWXUH
H)*)
HQJLQHHUHG )*)
(7'56
(DUO\ WUHDWPHQW GLDEHWLF UHWLQRSDWK\ VWXG\
)'$
)RRG DQG 'UXJ $GPLQLVWUDWLRQ
)(&'
)XFKV (QGRWKHOLDO &RUQHDO '\VWURSK\
)*)
)LEUREODVW *URZWK )DFWRU
*$7
*ROGPDQQ $SSODQDWLRQ 7RQRPHWU\
*&3
*RRG &OLQLFDO 3UDFWLFH
+('
+XPDQ (TXLYDOHQW 'RVH
,&
,QWUDFDPHUDO
,&)
,QIRUPHG FRQVHQW IRUP
,&+
,QWHUQDWLRQDO &RQIHUHQFH RQ +DUPRQLVDWLRQ
,23
,QWUDRFXODU SUHVVXUH
,5%
,QVWLWXWLRQDO UHYLHZ ERDUG
,77
,QWHQW WR 7UHDW
,8'
,QWUDXWHULQH GHYLFH
/2&)
/DVW 2EVHUYDWLRQ &DUULHG )RUZDUG
0050
0L[HG 0RGHO 5HSHDWHG 0HDVXUHV
056'
0D[LPXP 5HFRPPHQGHG 6WDUWLQJ 'RVH
1(,9)4
1DWLRQDO (\H ,QVWLWXWH 9LVXDO )XQFWLRQ 4XHVWLRQQDLUH
12$(/
1R 2EVHUYDEOH $GYHUVH (YHQW /HYHO
3$'
3KDUPDFRORJLFDOO\ $FWLYH 'RVH
3.
3KDUPDFRNLQHWLF
33
3HU 3URWRFRO
6$(
6HULRXV $GYHUVH (YHQW
6$5
6XVSHFWHG $GYHUVH 5HDFWLRQ
6(
6WXG\ (\H
70
7UDEHFXODU 0HVKZRUN
:2&%3
:RPHQ RI &KLOGEHDULQJ 3RWHQWLDO
ZW)*)
:LOG W\SH )*)
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
7$%/( 2) &217(176
'RFXPHQW +LVWRU\ 
6\QRSVLV 
/LVW RI $EEUHYLDWLRQV  

,QWURGXFWLRQ 

&RUQHDO (QGRWKHOLDO '\VWURSK\ 

7UHDWPHQW 2SWLRQV 

)*) IRU WKH 7UHDWPHQW RI &RUQHDO (QGRWKHOLDO '\VWURSK\  

'LXUQDO 9DULDWLRQ LQ 2FXODU )XQFWLRQ  

%DFNJURXQG ,QIRUPDWLRQ 

,QYHVWLJDWLRQDO 3URGXFW 77+;10 

6XPPDU\ RI 1RQFOLQLFDO 6WXGLHV DQG &OLQLFDO 7ULDOV 

1RQFOLQLFDO 6WXGLHV 

&OLQLFDO 7ULDOV 

3RWHQWLDO 5LVNV DQG %HQHILWV 

5DWLRQDOH IRU 'RVH 6HOHFWLRQ 

6WDWHPHQW RI &RPSOLDQFH  

6WXG\ 3RSXODWLRQ  

7ULDO 2EMHFWLYHV DQG 3XUSRVH  

7ULDO 'HVLJQ  

(IILFDF\ (QGSRLQWV 

3ULPDU\ (QGSRLQW 

6HFRQGDU\ (QGSRLQWV  

([SORUDWRU\ (QGSRLQWV  

0HDVXUHV 7DNHQ WR 0LQLPL]H $YRLG %LDV 

5DQGRPL]DWLRQ 

0DVNLQJ 

0DVNHG 0HGLFDO 0RQLWRU 

6WXG\ 7UHDWPHQW 

77+;10 'UXJ 3URGXFW 

77+;10 9HKLFOH 3DFNDJLQJ 

77+;10 9HKLFOH 6WRUDJH 

77+;10 9HKLFOH 3UHSDUDWLRQ 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 

'XUDWLRQ RI WKH 6WXG\ DQG 6WXG\ 7UHDWPHQW 

5HWUHDWPHQW &ULWHULD 

'RVH (VFDODWLRQ &RKRUW 5HYLHZ 

'RVH /LPLWLQJ 7R[LFLWLHV  

6WRSSLQJ 5XOHV  

,QYHVWLJDWLRQDO 3URGXFW $FFRXQWDELOLW\ 

,QYHVWLJDWLRQDO 3URGXFW 2UGHULQJ DQG 5HVXSSO\ 5HTXHVW  

0DLQWHQDQFH RI DQG 3URFHGXUH IRU %UHDNLQJ WKH 5DQGRPL]DWLRQ &RGH 

'DWD WR EH (QWHUHG LQWR WKH 'DWDEDVH  

6HOHFWLRQ DQG :LWKGUDZDO RI 6XEMHFWV  

,QFOXVLRQ &ULWHULD 

([FOXVLRQ &ULWHULD 

6XEMHFW :LWKGUDZDO &ULWHULD 

7UHDWPHQW RI 6XEMHFWV 

6XEMHFW 6FUHHQLQJ DQG (QUROOPHQW 

6WXG\ 7UHDWPHQW $GPLQLVWUDWLRQ ,QWUDFDPHUDO ,QMHFWLRQ  

&RQFRPLWDQW 0HGLFDWLRQV DQG 7UHDWPHQWV 

&RQFRPLWDQW 0HGLFDWLRQV 

3URKLELWHG 0HGLFDWLRQV 

3UHJQDQF\ 7HVWLQJ DQG &RQWUDFHSWLRQ  

6WXG\ 3URFHGXUHV 

,QIRUPHG &RQVHQW 

'HPRJUDSKLFV  

0HGLFDO +LVWRU\ DQG 2FXODU +LVWRU\ 

&RPSUHKHQVLYH 2FXODU ([DPLQDWLRQ 

6SHFXODU 0LFURVFRS\  

%HVW FRUUHFWHG 9LVXDO $FXLW\ %&9$  

6OLW /DPS %LRPLFURVFRS\  

3DFK\PHWU\  

,QWUDRFXODU 3UHVVXUH 0HDVXUHPHQW 

8ULQH 3UHJQDQF\ 7HVW 

&OLQLFDO /DERUDWRU\ $VVHVVPHQWV 

3ODVPD IRU 3. DQG $'$ 

1DWLRQDO (\H ,QVWLWXWH 9LVXDO )XQFWLRQ 4XHVWLRQQDLUH 1(,9)4  
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 

3HQWDFDP 7RPRJUDSK\  

2SWLRQDO %ORRG 6DPSOH IRU *HQHWLF 7HVWLQJ 

6WXG\ 9LVLWV  

6FUHHQLQJ 3HULRG%DVHOLQH $VVHVVPHQWV 

'D\  

'D\  

'D\    

'D\    

'D\    

'D\    

'D\    

'D\    

(DUO\ 7HUPLQDWLRQ 9LVLW  

8QVFKHGXOHG 9LVLW 

3UHJQDQF\ 

$VVHVVPHQW RI (IILFDF\ 

$VVHVVPHQW RI 6DIHW\ 

$GYHUVH (YHQWV 

$GYHUVH (YHQWV 'HILQLWLRQV  

$GYHUVH (YHQWV 5HSRUWLQJ 

$GYHUVH (YHQW 7HUP  

$GYHUVH (YHQW 6HYHULW\ 

$GYHUVH (YHQW 'XUDWLRQ 

$GYHUVH (YHQW &DXVDOLW\ 

$GYHUVH (YHQW 6HULRXVQHVV 

6HULRXV $GYHUVH (YHQWV DQG $GYHUVH (YHQWV RI 6SHFLDO ,QWHUHVW 5HSRUWLQJ 


4XDOLW\ &RQWURO DQG 4XDOLW\ $VVXUDQFH  

'DWD 4XDOLW\ $VVXUDQFH 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 

0RQLWRULQJ  

'DWDEDVH 0DQDJHPHQW DQG 4XDOLW\ &RQWURO 

$GPLQLVWUDWLYH 

3URWRFRO $SSURYDO DQG $PHQGPHQW 

3UHPDWXUH 7HUPLQDWLRQ RI WKH 6WXG\ 

&RQILGHQWLDOLW\ 

'DWD +DQGOLQJ DQG 5HFRUG .HHSLQJ  

&DVH 5HSRUW )RUPV DQG 6RXUFH 'RFXPHQWDWLRQ  

'DWD &ROOHFWLRQ  

$FFHVV WR 6RXUFH 'DWD 

'DWD 3URFHVVLQJ 

$UFKLYLQJ 6WXG\ 5HFRUGV  

3XEOLFDWLRQ 3ROLF\ 
5HIHUHQFHV 
3URWRFRO 6LJQDWXUH 3DJH  
/,67 2) 7$%/(6
7DEOH  6WXG\ &RKRUWV DQG 1XPEHU RI 6XEMHFWV
7DEOH  )'$$SSURYHG 0HWKRGV RI &RQWUDFHSWLRQ DQG (VWLPDWHG )DLOXUH 5DWHV
7DEOH  *UDGLQJ RI 6OLW /DPS %LRPLFURVFRS\ $VVHVVPHQWV
7DEOH  &OLQLFDO /DERUDWRU\ $VVHVVPHQWV 
7DEOH  6HYHULW\ *UDGLQJ *XLGHOLQH IRU $GYHUVH (YHQWV 
/,67 2) ),*85(6
)LJXUH  6WXG\ 6FKHPD 'RVH (VFDODWLRQ 
)LJXUH  6WXG\ 3DUWLFLSDQW 6FKHPD
)LJXUH  6XEMHFW ,' 1XPEHULQJ
)LJXUH  ,QWUDFDPHUDO ,QMHFWLRQ (QWU\ 3RLQW 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
 ,1752'8&7,21
 &RUQHDO (QGRWKHOLDO '\VWURSK\
&RUQHDO HQGRWKHOLDO K\SRFHOOXODULW\ GULYHQ E\ FRUQHDO HQGRWKHOLDO FHOO &(& ORVV GXH WR WUDXPD
VXUJLFDO GDPDJH RU FRUQHDO HQGRWKHOLDO G\VWURSKLHV &(' FDQ KDYH D VLJQLILFDQW HIIHFW RQ YLVLRQ
DQG D KLJK LPSDFW RQ TXDOLW\ RI OLIH &RUQHDO HQGRWKHOLDO FHOO ORVV RU ORZ &(& FRXQWV FRQWULEXWH
WR SRRU RXWFRPHV RI RFXODU VXUJHU\ LQFOXGLQJ FDWDUDFW VXUJHU\ )XFKV (QGRWKHOLDO &RUQHDO
'\VWURSK\ )(&' LV WKH PRVW FRPPRQ GULYHU RI FRUQHDO WUDQVSODQWDWLRQ >@ ZLWK 
HQGRWKHOLDO NHUDWRSODVW\ SURFHGXUHV SHUIRUPHG LQ WKH 86 LQ  >@ &RUQHDO HQGRWKHOLDO
G\VWURSKLHV KDYH EHHQ HVWLPDWHG WR DIIHFW DSSUR[LPDWHO\  RI WKH 86 SRSXODWLRQ RYHU WKH DJH RI
 >@ DOWKRXJK PRUH UHFHQW HVWLPDWHV XVLQJ FODLPV GDWD DQG PRUH VWULQJHQW FULWHULD SXW WKH
RYHUDOO SUHYDOHQFH RI &(' DW  DQG WKH SUHYDOHQFH RI )(&' DW  >@ &RUQHDO
HQGRWKHOLDO K\SRFHOOXODULW\ VHFRQGDU\ WR VXUJHU\ RU WUDXPD LV DQ LQIUHTXHQW EXW VLJQLILFDQW
FRPSOLFDWLRQ WKDW FDQ OHDG WR FRUQHDO WUDQVSODQWDWLRQ DQG FRQWULEXWHV WR YLVXDO LPSDLUPHQW
 7UHDWPHQW 2SWLRQV
%H\RQG V\PSWRPDWLF WUHDWPHQW XVLQJ YDULRXV SKDUPDFRORJLF WKHUDSLHV WKH RQO\ WUHDWPHQW RSWLRQ
IRU SDWLHQWV ZLWK &(' LV WKH WUDQVSODQWDWLRQ RI &(&V HLWKHU DV D ZKROH FRUQHDO WUDQVSODQW RU
WUDQVSODQWDWLRQ RI WKH HQGRWKHOLDO OD\HU YLD D YDULHW\ RI HQGRWKHOLDO NHUDWRSODVW\ SURFHGXUHV
LQFOXGLQJ 'HVFHPHW 6WULSSLQJ (QGRWKHOLDO .HUDWRSODVW\ '6(. >@ DQG 'HVFHPHW 0HPEUDQH
(QGRWKHOLDO .HUDWRSODVW\ '0(. >@ (YHQ DIWHU WUDQVSODQWDWLRQ WKH QXPEHU RI &(&V LQ WKH
WUDQVSODQW FRQWLQXHV WR GHFUHDVH >@ DQG UHSHDW WUDQVSODQWV DUH VRPHWLPHV QHHGHG &RUQHDO
WUDQVSODQWDWLRQ LV DQ RSWLRQ RI ODVW UHVRUW DV GRQRU WLVVXH LV LQ VKRUW VXSSO\ WKH VXUJHU\ UHTXLUHV D
KLJKO\ VNLOOHG VXUJHRQ DQG WKHUH LV D VLJQLILFDQW ULVN RI FRPSOLFDWLRQV WUDQVSODQW UHMHFWLRQ DQG
ORQJWHUP IDLOXUH &RUQHDO WUDQVSODQWDWLRQ LQ SDWLHQWV ZLWK &(' KDV D VLJQLILFDQWO\ KLJKHU ORQJ
WHUP IDLOXUH UDWH WKDQ WUDQVSODQWDWLRQ IRU NHUDWRFRQXV DQG DSSUR[LPDWHO\  RI WUDQVSODQWV ZLOO
IDLO LQ WKH ILUVW  \HDUV YV  IRU NHUDWRFRQXV >@
:KLOH WKH &(&V GR QRW UHSRSXODWH RU UHQHZ LQ HLWKHU QRUPDO H\HV RU LQ SDWLHQWV ZLWK )(&' WKHUH
LV HYLGHQFH VXJJHVWLQJ WKDW FHOOV IURP WKH SHULSKHUDO FRUQHDO HQGRWKHOLXP FDQ XQGHU VRPH
FRQGLWLRQV PLJUDWH FHQWUDOO\ >@ DQG WKDW FHOOV RI WKH SHULSKHUDO FRUQHDO HQGRWKHOLXP >@ RU
WUDEHFXODU PHVKZRUN 70 > @ PD\ FRQWDLQ D SURJHQLWRU SRSXODWLRQ >@ ,Q DGGLWLRQ ZKLOH
&(&V GR QRW VHHP WR UHJHQHUDWH in vivo ZKHQ H[SODQWHG WKH\ VKRZ WKH DELOLW\ WR SUROLIHUDWH LI
VWLPXODWHG E\ JURZWK IDFWRUV >@ 7KHUHIRUH WUHDWPHQWV WKDW LQFUHDVH PLJUDWLRQ DQG
SUROLIHUDWLRQ RI &(&V RU WKHLU SURJHQLWRU SRSXODWLRQ LQ VLWX PD\ UHJHQHUDWH WKH HQGRWKHOLXP DQG
LPSURYH EDUULHU IXQFWLRQ LQ WKH FHQWUDO FRUQHD 7KLV LQ WXUQ VKRXOG UHGXFH FRUQHDO HGHPD
LPSURYH YLVLRQ DQG GHOD\ RU HOLPLQDWH WKH QHHG IRU FRUQHDO WUDQVSODQWDWLRQ
 )*) IRU WKH 7UHDWPHQW RI &RUQHDO (QGRWKHOLDO '\VWURSK\
)LEUREODVW JURZWK IDFWRUV )*)V DUH D ODUJH IDPLO\ RI SURWHLQV WKDW VWLPXODWH WKH SUROLIHUDWLRQ
DQG PLJUDWLRQ RI D ZLGH YDULHW\ RI FHOOV )*)V DUH NH\ GHYHORSPHQWDO JURZWK IDFWRUV LQ PDQ\
WLVVXHV LQFOXGLQJ WKH FRUQHD )LEUREODVW JURZWK IDFWRU )*) LV WKH PRVW SRWHQW VWLPXODWRU RI
SUROLIHUDWLRQ RI &(&V NQRZQ DQG LV WKH UDWLRQDOH IRU DSSO\LQJ )*) WR &('
)*) LQ LWV QDWLYH RU ZLOG W\SH IRUP ZW)*) LV VXVFHSWLEOH WR ERWK SURWHRO\VLV DQG F\VWHLQH
R[LGDWLRQ FUHDWLQJ D YHU\ VKRUW ELRORJLFDO KDOIOLIH DQG WKXV PDNLQJ LW XQVXLWDEOH DV D WKHUDS\
7R RYHUFRPH WKHVH GHILFLHQFLHV )*) ZDV VWDELOL]HG YLD WKH VXEVWLWXWLRQ RI NH\ DPLQR DFLGV WR
GHFUHDVH WKH IOH[LELOLW\ RI WKH SURWHLQ ZLWKRXW LQWURGXFLQJ DQ\ QHZ IXQFWLRQDOLWLHV RI WKH SURWHLQ
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
RQ D TXDOLWDWLYH EDVLV 7KHVH HQJLQHHUHG )*)V H)*)V ZRXOG QRW EH H[SHFWHG WR KDYH DQ\
DFWLYLWLHV WKDW WKH ZW)*) GRHV QRW SRVVHVV DV ZHOO DV DQ LQFUHDVHG DIILQLW\ IRU WKH )*)
UHFHSWRUV DQGRU KHSDULQ VXOIDWH SURWHRJO\FDQV
 'LXUQDO 9DULDWLRQ LQ 2FXODU )XQFWLRQ
'LXUQDO YDULDWLRQ LV D FRPPRQ FRQFHUQ LQ FOLQLFDO WULDOV ZKHUH HQGSRLQW PHDVXUHPHQWV PD\
IOXFWXDWH WKURXJKRXW WKH FRXUVH RI WKH GD\ DQG DUH DVVRFLDWHG WKH WLPLQJ RI DVVHVVPHQWV 7KH
HIIHFW RI GLXUQDO YDULDWLRQ LQ LQWUDRFXODU SUHVVXUH KDV EHHQ REVHUYHG LQ SDWLHQWV ZLWK JODXFRPD
> @ DQG LQ KHDOWK\ YROXQWHHUV >@ DQG LW LV UHFRPPHQGHG WKDW FRPSDUDWLYH DVVHVVPHQWV EH
REWDLQHG LQ WKH HDUO\ PRUQLQJ WR KHOS DYRLG YDULDELOLW\ LQ LQWUDRFXODU SUHVVXUH PHDVXUHPHQWV GXH
WR GLXUQDO IOXFWXDWLRQV > @ 2WKHU RFXODU DVVHVVPHQWV VXFK DV FRUQHDO WKLFNQHVV KDYH DOVR
EHHQ VKRZQ WR EH DIIHFWHG E\ GLXUQDO YDULDWLRQ ZKHQ DVVHVVHG LQ SDWLHQWV ZLWK GU\ H\H >@ DQG LQ
KHDOWK\ YROXQWHHUV >@ 9DULDELOLW\ ZLWKLQ WKH ILUVW  KRXUV RI ZDNLQJ KDV EHHQ REVHUYHG LQ
SDWLHQWV ZLWK )(&' >@ 7KH GHJUHH RI GLXUQDO YDULDWLRQ LQ DOO WKH RFXODU DVVHVVPHQWV SODQQHG
LQ WKLV VWXG\ KDV QRW EHHQ HYDOXDWHG LQ WKLV VWXG\ SRSXODWLRQ 7KH 2EVHUYDWLRQDO 6XEVWXG\ ZLOO
FROOHFW VWXG\ HQGSRLQWV RFXODU DVVHVVPHQWV LQ WKH PRUQLQJ DQG LQ WKH HYHQLQJ DQG HYDOXDWH WKH
HIIHFW RI GLXUQDO YDULDWLRQ RQ WKH LQGLYLGXDO VWXG\ HQGSRLQWV 7KH WLPLQJ RI VWXG\ DVVHVVPHQWV LQ
WKH PDLQ VWXG\ LV FRQVLVWHQW DV HDUO\ PRUQLQJ DVVHVVPHQWV DW DOO WLPHSRLQWV LI WKH GLXUQDO
YDULDWLRQ HIIHFW LV GHWHUPLQHG WR EH PLQLPDO RU LQVLJQLILFDQW WKH WLPLQJ RI QRQEDVHOLQH DQG QRQ
SULPDU\ HQGSRLQW HYDOXDWLRQV PD\ EH UHOD[HG WR DFFRPPRGDWH VXEMHFW VFKHGXOLQJ DQG
FRQYHQLHQFH
 %$&.*5281' ,1)250$7,21
 ,QYHVWLJDWLRQDO 3URGXFW 77+;10
7UHIRLO KDV GHYHORSHG 77+;10 ZKLFK LV DQ HQJLQHHUHG )*) H)*) FRQWDLQLQJ
WKUHH VWDELOL]LQJ PXWDWLRQV LQFOXGLQJ WKH LQWURGXFWLRQ RI DQ LQWHUQDO GLVXOILGH ERQG WKDW KDV
DFWLYLW\ DW PXFK ORZHU DSSOLHG FRQFHQWUDWLRQV EXW TXDOLWDWLYHO\ KDV ELRORJLFDO DFWLYLW\ LGHQWLFDO WR
WKDW RI ZW)*) $V VXFK 77+;10 LV H[SHFWHG WR KDYH WKH VDPH
PHFKDQLVPGULYHQ HIIHFWV WKDW ZW)*) KDV ZLWK QR XQH[SHFWHG DFWLYLW\ 6LQFH ZW)*) KDV
EHHQ FOLQLFDOO\ WHVWHG LQ VHYHUDO V\VWHPV LQFOXGLQJ JHQH WKHUDS\ WKH SRWHQWLDO VDIHW\ LVVXHV ZLWK
H)*) FDQ EH DQWLFLSDWHG EDVHG RQ WKRVH VWXGLHV
3OHDVH UHIHU WR WKH 3KDUPDF\ 0DQXDO IRU VWXG\ WUHDWPHQW VWRUDJH KDQGOLQJ DQG SUHSDUDWLRQ
LQVWUXFWLRQV
 6XPPDU\ RI 1RQFOLQLFDO 6WXGLHV DQG &OLQLFDO 7ULDOV
1RQFOLQLFDO 6WXGLHV
,Q WKH UDEELW FRUQHDO FU\RLQMXU\ PRGHO D VLQJOH LQWUDFDPHUDO LQMHFWLRQ RI 77+;10
DFFHOHUDWHG WKH FOHDULQJ RI WKH FRUQHD IRU DV PXFK DV  GD\V SRVW LQMXU\
,Q DGGLWLRQ 77+;10 VWLPXODWHV WKH SUROLIHUDWLRQ RI &(&V LQ ERWK QRUPDO KXPDQ
FRUQHDV LQ RUJDQ FXOWXUH DQG LQ FRUQHDV WKDW VKRZ VLJQV RI )(&'
,Q SUHFOLQLFDO WR[LFRORJ\ WHVWLQJ LQ WKH UDEELW DQG WKH GRJ QR FKDQJHV LQ LQWUDRFXODU SUHVVXUH
,23 DQG QR QHRYDVFXODUL]DWLRQ ZDV QRWHG DW GRVHV XS WR [ WKH KLJKHVW GRVH WR EH HYDOXDWHG
LQ WKLV VWXG\ ZLWK JUHDWHU WRWDO H[SRVXUH PRUH WKDQ  LQMHFWLRQV )ROORZLQJ LQWUDFDPHUDO
LQMHFWLRQ RI [ WKH KLJKHVW GRVH WR EH HYDOXDWHG LQ WKLV WULDO GRVHGHSHQGHQW PLOG WR
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
PRGHUDWH YDFXRODWLRQ RI WKH SRVWHULRU HSLWKHOLXP RI WKH LULV ZDV QRWHG 7KLV HIIHFW ZDV UHYHUVLEOH
RQ FHVVDWLRQ RI GUXJ WUHDWPHQW
3OHDVH UHYLHZ WKH ,QYHVWLJDWRU¶V %URFKXUH IRU GHWDLOHG LQIRUPDWLRQ LQYROYLQJ WKH SUHFOLQLFDO
GHYHORSPHQW SURJUDP
&OLQLFDO 7ULDOV
7KLV LV WKH ILUVW FOLQLFDO VWXG\ RI 77+;10
 3RWHQWLDO 5LVNV DQG %HQHILWV
7KLV LV WKH ILUVW LQ PDQ FOLQLFDO VWXG\ $QWLFLSDWHG K\SRWKHWLFDO DGYHUVH HYHQWV LQFOXGH EXW DUH
QRW OLPLWHG WR
ͻ
$QWHULRU FKDPEHU IODUH
ͻ
&RQMXQFWLYDO LQIODPPDWLRQ
ͻ
(QGRSKWKDOPLWLV
ͻ
,QIODPPDWLRQ RI WKH DQWHULRU FKDPEHU HJ FRUQHD DQGRU LULV
ͻ
%UXLVLQJ RI H[WHUQDO H\H VWUXFWXUHV HVSHFLDOO\ IRU VXEMHFWV RQ DQWLFRDJXODQW WKHUDS\
 5DWLRQDOH IRU 'RVH 6HOHFWLRQ
7KLV VWXG\ LV D GRVH HVFDODWLRQ VWXG\ WKDW ZLOO DVVHVV XS  GRVH OHYHOV RI 77+;10

LQ SDWLHQWV ZLWK &(' 7KH PD[LPXP UHFRPPHQGHG VWDUWLQJ GRVH
056' IRU WKLV ILUVWLQKXPDQ WULDO ZDV EDVHG RQ WKH IROORZLQJ FRQVHUYDWLYH DVVXPSWLRQV
 7KH ORZHVW GRVH LQ FXUUHQW WR[LFRORJ\ VWXGLHV RI  QJ YLD LQWUDFDPHUDO ,& LQMHFWLRQ
UHVXOWV LQ  QJP/ &PD[ DQG ZDV D QR REVHUYDEOH DGYHUVH HYHQW OHYHO 12$(/ GRVH
 7KH SKDUPDFRORJLFDOO\ DFWLYH GRVH 3$' ZDV SUHGLFWHG EDVHG RQ WKH GRVH WKDW ZDV
DFWLYH LQ FHOO FXOWXUH WKH  HIIHFWLYH FRQFHQWUDWLRQ >(&@ RI
DSSUR[LPDWHO\  QJP/   QJ ,& LQMHFWLRQ
 *LYHQ WKH DQDWRPLFDO VLPLODULW\ RI WKH H\HV RI WKH WR[LFRORJ\ VSHFLHV UDEELWV DQG GRJV
DQG KXPDQV QR VFDOLQJ IDFWRU ZDV XVHG WR GHWHUPLQH WKH KXPDQ HTXLYDOHQW GRVH +('
 6WXG\ WUHDWPHQW ZLOO EH DGPLQLVWHUHG LQ DW  PF/ YROXPH 7KLV YROXPH ZDV FKRVHQ VR
DV WR EH PLQLPDOO\ GLVUXSWLYH DQG LV ZHOO EHORZ WKH P/ PF/ YROXPH XVHG LQ
PDQ\ LQWUDFDPHUDOO\ DGPLQLVWHUHG DQWLELRWLFV
7KH  )'$ JXLGDQFH WLWOHG “Estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers” VXJJHVWV D VDIHW\ IDFWRU IRU WKH 056' RI DW
OHDVW IROG EHORZ WKH +(' DQG WKLV VKRXOG EH DGMXVWHG WDNLQJ LQWR DFFRXQW WKH 3$' 7KH
3$' EDVHG RQ WLVVXH FXOWXUH H[SHULPHQWV LV  QJP/ $Q ,& GRVH RI  QJ  QJP/ &PD[ GXH
WR WKH OLPLWHG YROXPH RI WKH DQWHULRU FKDPEHU %DVHG RQ WKHVH GDWD WKH GRVH UDQJH IRU WKLV WULDO
LQFOXGHV WKH 3$' QJP/ DV WKH ORZ GRVH DQG D KLJK GRVH RI  QJ   QJP/ &PD[ ZKLFK
LV D IROG VDIHW\ PDUJLQ RYHU WKH 12$(/ +('
 6WDWHPHQW RI &RPSOLDQFH
7KLV VWXG\ ZLOO EH FRQGXFWHG DFFRUGLQJ WR WKH SURWRFRO DQG LQ FRPSOLDQFH ZLWK *RRG &OLQLFDO
3UDFWLFH *&3 ZKLFK KDYH WKHLU RULJLQV LQ WKH 'HFODUDWLRQ RI +HOVLQNL DQG ZLWK DOO RWKHU
DSSOLFDEOH UHJXODWRU\ UHTXLUHPHQWV
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
 6WXG\ 3RSXODWLRQ
7KH VWXG\ SRSXODWLRQ ZLOO FRQVLVW RI PHQ DQG ZRPHQ DJHG   \HDUV SUHVHQWLQJ ZLWK FRUQHDO
HQGRWKHOLDO G\VWURSK\ K\SRFHOOXODULW\ 6XEMHFWV ZLOO EH UHFUXLWHG IURP D QRQVXUJLFDO SRSXODWLRQ
RU SRVWRSHUDWLYH FDWDUDFW SRSXODWLRQ DW OHDVW  PRQWKV SRVWRS 7KH LQWHQW LV WR HQUROO VXEMHFWV
ZLWK ORZ (&' FRXQWV DQG HQGRWKHOLDO FHOO LPDJHV FOHDUO\ TXDQWLWDWDEOH XVLQJ VSHFXODU
PLFURVFRS\ LPDJLQJ 6XEMHFWV LQFOXGHG VKRXOG QRW EH H[SHFWHG WR SURJUHVV WR WUDQVSODQWDWLRQ
ZLWKLQ WKH VWXG\ SHULRG RI  PRQWKV 7KH SRSXODWLRQ LV H[SHFWHG WR LQFOXGH D PL[ RI SDWLHQWV
ZLWK FRUQHDO HGHPD DQG WKRVH WKDW GR QRW \HW KDYH HGHPD
 75,$/ 2%-(&7,9(6 $1' 385326(
7KH SULPDU\ REMHFWLYH RI WKLV 3KDVH  3KDVH  SURVSHFWLYH PDVNHG UDQGRPL]HG
SODFHERFRQWUROOHG VWXG\ LV WR HYDOXDWH WKH VDIHW\ DQG HIILFDF\ RI 77+;10 LQ SDWLHQWV
ZLWK FRUQHDO HQGRWKHOLDO G\VWURSK\
 75,$/ '(6,*1
7KLV LV D SURVSHFWLYH PXOWLFHQWHU UDQGRPL]HG PDVNHG YHKLFOHFRQWUROOHG GRVHHVFDODWLRQ
VWXG\ WKDW ZLOO LQFOXGH DQ REVHUYDWLRQDO QR LQWHUYHQWLRQ VXEVWXG\ 8S WR DSSUR[LPDWHO\ 
HOLJLEOH VXEMHFWV ZLWK PRGHUDWH WR VHYHUH FRUQHDO HQGRWKHOLDO G\VWURSK\ GHILQHG DV (&'  
PPA LQ DW OHDVW RQH H\H DW DSSUR[LPDWHO\  LQYHVWLJDWLRQDO VLWHV ZLOO EH HQUROOHG DQG
UDQGRPL]HG LQ WKH PDLQ VWXG\ DIWHU WKH ,1' KDV EHHQ DSSURYHG E\ WKH )'$ 7KH 2EVHUYDWLRQDO
6XEVWXG\ 6HH $SSHQGL[ % ZLOO HQUROO DSSUR[LPDWHO\  WR  VXEMHFWV DQG ZLOO SUHFHGH &RKRUW
 HQUROOPHQW DQG UXQ LQ SDUDOOHO WR &RKRUWV  DQG  6XEMHFWV HQUROOHG LQ DQG SDUWLFLSDWLQJ LQ WKH
2EVHUYDWLRQDO 6XEVWXG\ ZKR DUH HOLJLEOH PD\ ³UROORYHU´ LQWR WKH PDLQ VWXG\ SURYLGHG WKH\
PHHW DOO RI WKH DGGLWLRQDO HOLJLELOLW\ FULWHULD WKHUH LV DQ RSHQ FRKRUW DQG WKH\ FRQVHQW
7KH QXPEHU RI VXEMHFWV SHU FRKRUW LQ WKH PDLQ VWXG\ DQG SHU VWXG\ WUHDWPHQW LV VXPPDUL]HG
EHORZ LQ 7DEOH 
7DEOH  6WXG\ &RKRUWV DQG 1XPEHU RI 6XEMHFWV
6WXG\ 7UHDWPHQW 5DQGRPL]DWLRQ
&RKRUW
9HKLFOH
SODFHER
/RZGRVH
0LGGRVH
+LJKGRVH
7RWDO


















7RWDO





7KH VWXG\ WHDP ZLOO LQFOXGH D PDVNHG DQG DQ XQPDVNHG 0HGLFDO 0RQLWRU 7KH PDVNHG 0HGLFDO
0RQLWRU ZLOO GLVFXVV HOLJLELOLW\ TXHVWLRQV ZLWK WKH LQYHVWLJDWLRQDO VLWHV DQG RYHUVHH WKH GDLO\
UXQQLQJ RI WKH FOLQLFDO VWXG\ 7KH PDVNHG DQG XQPDVNHG 0HGLFDO 0RQLWRUV ZLOO UHYLHZ FOLQLFDO
GDWD LQFOXGLQJ DGYHUVH HYHQWV IUHTXHQF\ DQG VHYHULW\ RQ DQ RQJRLQJ EDVLV 7KH XQPDVNHG
0HGLFDO 0RQLWRU ZLOO UHYLHZ DOO GDWD DQG PDNH GHFLVLRQV UHJDUGLQJ WKH RSHQLQJ RI VXEVHTXHQW
FRKRUWV 6HH 6HFWLRQ  7KH GRVH HVFDODWLRQ VFKHPD LV SUHVHQWHG LQ )LJXUH 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
FRKRUW PD\ VWDUW ,I DW DQ\ WLPH WKH VDIHW\ SURILOH LV GHHPHG XQDFFHSWDEOH WUHDWPHQW ZLOO UHYHUW
WR WKH SULRU ORZHUGRVH OHYHO ZKLFK ZDV GHHPHG VDIH
'RVH /LPLWLQJ 7R[LFLWLHV
3RWHQWLDO GRVH OLPLWLQJ WR[LFLW\ '/7 LV GHILQHG DV DQ\ RI WKH IROORZLQJ HYHQWV
x
9LVXDO DFXLW\ ORVV RI  (7'56 OHWWHUV RU PRUH
x
!  DQWHULRU FKDPEHU FHOOV REVHUYHG RQ VOLW ODPS H[DPLQDWLRQ
x
!  YLWUHRXV FHOOV REVHUYHG RQ VOLW ODPS H[DPLQDWLRQ
x
! PLFURQ FRUQHDO WKLFNQHVV RU D  PLFURQ LQFUHDVH IURP EDVHOLQH 'D\  SUH
WUHDWPHQW
x
,QFUHDVH RI  RU PRUH JUDGHV LQ FRQMXQFWLYDO K\SHUHPLD
o
*UDGH   1R YDVRGLODWLRQ $EVHQW
o
*UDGH   6RPH YDVRGLODWLRQ
o
*UDGH   ([WHQVLYH YHVVHO YDVRGLODWLRQ
o
*UDGH   2YHUDOO YDVRGLODWLRQ
x
,23 WKDW UHPDLQV KLJKHU WKDQ  PP+J DQG QRW UHVSRQGLQJ WR WKHUDS\
,I DQ\ VXEMHFW H[SHULHQFHV DQ\ RI WKH HYHQWV OLVWHG DERYH VWXG\ WUHDWPHQW PXVW EH KHOG IRU DW
OHDVW  GD\V DQG WKH PDVNHG 0HGLFDO 0RQLWRU PXVW EH FRQWDFWHG WR GLVFXVV PHGLFDO PDQDJHPHQW
RI WKH VXEMHFW LQFOXGLQJ SRVVLEOH WUHDWPHQW DQG DGGLWLRQDO XQVFKHGXOHG VWXG\ DVVHVVPHQWV
$IWHU WKH GD\ VWXG\ WUHDWPHQW GHOD\ WKH VXEMHFW PD\ UHFHLYH DGGLWLRQDO VWXG\ WUHDWPHQW LI WKH
VXEMHFW UHPDLQV HOLJLEOH DQG DOO RI WKH SRWHQWLDO '/7V WKH VXEMHFW H[SHULHQFHG KDYH GHFUHDVHG WR
D OHYHO WKDW QR ORQJHU PHHWV WKH '/7 UHTXLUHPHQWV $Q\ RI WKH HYHQWV OLVWHG DERYH WKDW FRQWLQXH
WR PHHW WKH '/7 UHTXLUHPHQWV DIWHU WKH GD\ GHOD\ LQ VWXG\ WUHDWPHQW ZLOO EH FRQVLGHUHG '/7
DQG WKH VXEMHFW ZLOO EH GLVFRQWLQXHG IURP VWXG\ WUHDWPHQW $Q\ VWXG\ WUHDWPHQW GHOD\ RI JUHDWHU
WKDQ  GD\V PXVW EH GLVFXVVHG ZLWK DQG DSSURYHG E\ WKH PDVNHG 0HGLFDO 0RQLWRU
 6WRSSLQJ 5XOHV
6WRSSLQJ UXOHV IRU WKH VWXG\ ZLOO EH WKH LQFLGHQFH RI XQDFFHSWDEOH WR[LFLW\ ,I DW DQ\ WLPH WKH
VDIHW\ SURILOH LV GHHPHG XQDFFHSWDEOH VWXG\ WUHDWPHQW ZLOO UHYHUW WR WKH SULRU ORZHUGRVH OHYHOV
GHHPHG VDIH
 ,QYHVWLJDWLRQDO 3URGXFW $FFRXQWDELOLW\
,Q DFFRUGDQFH ZLWK  &)5  DQG  &)5 D WKH ,QYHVWLJDWRU
x
:LOO DGPLQLVWHU WKH GUXJ RQO\ WR VXEMHFWV XQGHU WKH LQYHVWLJDWRU
V SHUVRQDO VXSHUYLVLRQ RU
XQGHU WKH VXSHUYLVLRQ RI D VXELQYHVWLJDWRU UHVSRQVLEOH WR WKH LQYHVWLJDWRU
x
6KDOO QRW VXSSO\ WKH LQYHVWLJDWLRQDO GUXJ WR DQ\ SHUVRQ QRW DXWKRUL]HG XQGHU WKLV SDUW WR
UHFHLYH LW DQG
x
:LOO PDLQWDLQ DGHTXDWH UHFRUGV RI WKH GLVSRVLWLRQ RI WKH GUXJ LQFOXGLQJ GDWHV TXDQWLW\
DQG XVH E\ VXEMHFWV
,I WKH LQYHVWLJDWLRQ LV WHUPLQDWHG VXVSHQGHG GLVFRQWLQXHG RU FRPSOHWHG WKH LQYHVWLJDWRU VKDOO
UHWXUQ WKH XQXVHG VXSSOLHV RI WKH GUXJ WR WKH VSRQVRU RU RWKHUZLVH SURYLGH IRU GLVSRVLWLRQ RI WKH
XQXVHG VXSSOLHV RI WKH GUXJ XQGHU  &)5 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
$OO WKDZHG DQG SDUWLDOO\ XVHG VWXG\ WUHDWPHQW YLDOV ZLOO EH UHIUR]HQ DQG VWRUHG 8QXVHG DQG
SDUWLDOO\ XVHG VWXG\ WUHDWPHQW YLDOV ZLOO EH UHWXUQHG WR 7UHIRLO RU GHVLJQHH DW WKH HQG RI WKH
6WXG\ 7UHDWPHQW 3HULRG
 ,QYHVWLJDWLRQDO 3URGXFW 2UGHULQJ DQG 5HVXSSO\ 5HTXHVW
,QYHVWLJDWLRQDO VLWHV ZLOO EH SURYLGHG ZLWK D VXEMHFWVSHFLILF VWXG\ WUHDWPHQW NLW FRQWDLQLQJ
 YLDOV DW WKH WLPH RI UDQGRPL]DWLRQ ,Q WKH HYHQW RI ORVV RU GDPDJH WKH LQYHVWLJDWLRQDO VLWH PXVW
FRQWDFW WKH FHQWUDO VWXG\ WHDP DQG UHTXHVW UHSODFHPHQW VWXG\ WUHDWPHQW YLDOV IRU WKH VSHFLILF
VXEMHFW 7KH GUXJ GHSRW ZLOO VKLS UHSODFHPHQW PDVNHG VWXG\ WUHDWPHQW YLDOV FRUUHVSRQGLQJ ZLWK
WKH VXEMHFW¶V WUHDWPHQW DVVLJQPHQW
 0DLQWHQDQFH RI DQG 3URFHGXUH IRU %UHDNLQJ WKH 5DQGRPL]DWLRQ &RGH
7KH UDQGRPL]DWLRQ OLVW ZLOO EH PDLQWDLQHG E\ WKH VWXG\ WHDP $Q XQPDVNHG ELRVWDWLVWLFLDQ RU
GHVLJQHH ZLOO SURYLGH WKH UDQGRPL]DWLRQ OLVW DQG PDVNHG 6WXG\ 7UHDWPHQW .LW ,'V WR WKH VWXG\
WHDP
,Q WKH HYHQW WKDW XQPDVNLQJ D VXEMHFW WR WUHDWPHQW DVVLJQPHQW LV FRQVLGHUHG QHFHVVDU\ SULRU WR
WKH GDWDEDVH ORFN WKH ,QYHVWLJDWRU LV LQVWUXFWHG WR FRQWDFW WKH PDVNHG 0HGLFDO 0RQLWRU WR GLVFXVV
WKH UHDVRQV IRU UHTXHVWLQJ XQPDVNLQJ ,I WKH UHDVRQ IRU UHTXHVWLQJ XQPDVNLQJ LV IRU WKH
PDQDJHPHQW RI DGYHUVH HYHQWV RU D GHFLVLRQ WR FRQWLQXH VWXG\ WUHDWPHQW WKH DGYHUVH HYHQWV
VKRXOG EH PDQDJHG DV PHGLFDOO\ DSSURSULDWH DQG WKH VXEMHFW VKRXOG EH GLVFRQWLQXHG IURP VWXG\
WUHDWPHQW ZLWKRXW XQPDVNLQJ ,I XQPDVNLQJ LV GHWHUPLQHG WR EH UHTXLUHG WKH PDVNHG 0HGLFDO
0RQLWRU ZLOO FRQWDFW WKH XQPDVNHG 0HGLFDO 0RQLWRU DQG WKH PDVNHG 0HGLFDO 0RQLWRU ZLOO
FRPPXQLFDWH ZLWK WKH ,QYHVWLJDWRU DQG UHYHDO WKH VXEMHFW¶V VWXG\ WUHDWPHQW DVVLJQPHQW

'DWD WR EH (QWHUHG LQWR WKH 'DWDEDVH
(QGRWKHOLDO FHOO FRXQW GHQVLW\ PHDVXUHG E\ WKH FHQWUDO UHDGLQJ IDFLOLW\ LV WKH SULPDU\ HIILFDF\
HQGSRLQW IRU WKLV VWXG\ 7KH GDWD JHQHUDWHG E\ WKH FHQWUDO UHDGLQJ IDFLOLW\ ZLOO EH UHFRQFLOHG
6XEMHFW ,' GDWH WLPH WLPHSRLQW ZLWK WKH FOLQLFDO GDWDEDVH DQG WKH UHVXOWV ZLOO EH XSORDGHG LQWR
WKH GDWDEDVH XQGHU D 4XDOLW\ DQG 'DWD 7UDQVIHU 6SHFLILFDWLRQV $JUHHPHQW 8SORDGHG GDWD ZLOO
WKHQ EH  TXDOLW\ FKHFNHG HJ VRXUFHG GDWD YHULILHG ZLWK WKH GDWD DW WKH FHQWUDO UHDGLQJ
IDFLOLW\
2WKHU GDWD DQG UHVXOWV JHQHUDWHG E\ WKH LQYHVWLJDWLRQDO VLWH ZLOO EH GDWD HQWHUHG GLUHFWO\ LQWR WKH
HOHFWURQLF GDWD FDSWXUH ('& V\VWHP $OO GDWD LQ WKH ('& ZLOO EH PRQLWRUHG DQG FULWLFDO
YDULDEOHV ZLOO EH  VRXUFH GDWD YHULILHG
 6(/(&7,21 $1' :,7+'5$:$/ 2) 68%-(&76
3DWLHQWV ZLOO EH SULPDULO\ VHOHFWHG RQ WKH EDVLV RI GLDJQRVLV RI &RUQHDO (QGRWKHOLDO '\VWURSK\
DQG FRUQHDO HQGRWKHOLDO FHOO &(& K\SRFHOOXODULW\ (OLJLELOLW\ PD\ EH EDVHG RQ WKH SDWKRORJ\
QRWHG LQ RQH RU ERWK H\HV ,I ERWK H\HV PHHW RFXODU HOLJLELOLW\ FULWHULD WKH H\H ZLWK WKH ORZHU
&(& FRXQW ZLOO EH GHVLJQDWHG DV WKH VWXG\ H\H 6( LI RQO\  H\H PHHWV WKH HOLJLELOLW\ FULWHULD LW
ZLOO EH WKH 6(
 ,QFOXVLRQ &ULWHULD
 0DOH RU IHPDOH  \HDUV RI DJH RU ROGHU
 $EOH DQG ZLOOLQJ WR SURYLGH LQIRUPHG FRQVHQW
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
 )XFKV (QGRWKHOLDO &RUQHDO '\VWURSK\ SVHXGRSKDNLF EXOORXV NHUDWRSDWK\ RU HQGRWKHOLDO
G\VIXQFWLRQ LQVXIILFLHQF\ GXH WR VXUJLFDO LQWHUYHQWLRQ GLDJQRVHG PRUH WKDQ  PRQWKV
SULRU WR 6WXG\ 'D\  LQ WKH VWXG\ H\H
 ,QWDFW DQWHULRU FKDPEHU DQDWRP\ LI SRVWHULRU FDSVXOH LV RSHQ RU DEVHQW DEVHQFH RI
YLWUHRXV LQ WKH DQWHULRU FKDPEHU PXVW EH YHULILHG RU HQUROOPHQW DSSURYHG E\ WKH 0HGLFDO
0RQLWRU LQ WKH VWXG\ H\H DQG QR VWUXFWXUDO DEQRUPDOLWLHV WKDW ZRXOG PDNH LQWUDFDPHUDO
LQMHFWLRQ GLIILFXOW
 $EOH WR REWDLQ FOHDU FRUQHDO HQGRWKHOLDO FHOO &(& PRUSKRORJ\ DQG FHQWUDO &(& FRXQWV
E\ VSHFXODU PLFURVFRS\ IURP ERWK H\HV DV GHWHUPLQHG E\ WKH FHQWUDO UHDGLQJ IDFLOLW\
 &HQWUDO HQGRWKHOLDO FHOO FRXQW RI   PPA LQ DW OHDVW RQH H\H DV GHWHUPLQHG E\ WKH
FHQWUDO UHDGLQJ IDFLOLW\ GXULQJ WKH VFUHHQLQJ SHULRG
1RWH )(&' SDWLHQWV ZLWK GHQVH FHQWUDO JXWWDH PD\ QRW EH FRXQWDEOH DQG
WKHUHIRUH QRW HOLJLEOH
 %HVW &RUUHFWHG 9LVXDO $FXLW\ %&9$ RI DW OHDVW  OHWWHUV SHU (DUO\ 7UHDWPHQW RI
'LDEHWLF 5HWLQRSDWK\ 6WXG\ >(7'56@ WHVWLQJ DSSUR[LPDWHO\  LQ HDFK H\H
 ,I IHPDOH DUH QRQSUHJQDQW QRQODFWDWLQJ 6XEMHFWV ZKR DUH ZRPHQ RI FKLOGEHDULQJ
SRWHQWLDO :2&%3 PXVW EH XVLQJ DQ DFFHSWDEOH PHWKRG RI ELUWK FRQWURO >HJ DQ
,QWUDXWHULQH &RQWUDFHSWLYH 'HYLFH ,8&' KRUPRQDO FRQWUDFHSWLYHV RU GRXEOH EDUULHU
PHWKRG@ VWDUWLQJ DW OHDVW  PRQWK SULRU WR 6WXG\ 'D\  DQG IRU WKH GXUDWLRQ RI WKH VWXG\
,I D IHPDOH VXEMHFW LV FXUUHQWO\ DEVWLQHQW WKH\ PXVW DJUHH WR XVH D GRXEOH EDUULHU PHWKRG
RI ELUWK FRQWURO EHIRUH WKH\ EHFRPH VH[XDOO\ DFWLYH 0HQ ZKR DUH VH[XDOO\ DFWLYH ZLWK D
ZRPDQ RI FKLOGEHDULQJ SRWHQWLDO PXVW DJUHH WR XVH D GRXEOH EDUULHU PHWKRG
 ([FOXVLRQ &ULWHULD
 +LVWRU\ RI DQ\ RI WKH IROORZLQJ LQ HLWKHU H\H
D
2FXODU FDQFHU LQFOXGLQJ PHODQRPD
E +HUSHWLF NHUDWLWLV
F
&RUQHDO WUDQVSODQW IXOOWKLFNQHVV RU ODPHOODU
G 'RFXPHQWHG DQG UHSHDWHG HOHYDWHG ,23 LQ HLWKHU H\H
H
3RVWHULRU 3RO\PRUSKRXV &RUQHDO '\VWURSK\ 33&' DND 6FKOLFKWLQJ G\VWURSK\
I
8YHLWLV
J &DWDUDFW VXUJHU\ ZLWKLQ WKH  PRQWKV LQ SULRU WR 6WXG\ 'D\ 
 5HIUDFWLYH VXUJHU\ LQ WKH VWXG\ H\H LQFOXGLQJ SKDNLF ,2/ FXUUHQWO\ LQ SODFH
1RWH 3RWHQWLDO VXEMHFWV ZKR KDYH KDG WKH SKDNLF ,2/ SODFHG DQG UHPRYHG DUH DOORZHG
/LPEDO UHOD[LQJ LQFLVLRQ SHUIRUPHG DW WKH WLPH RI FDWDUDFW VXUJHU\ LV DOORZHG
 $Q\ FRQGLWLRQ WKDW ZRXOG LPSDLU H[DPLQDWLRQ RI WKH DQWHULRU FKDPEHU VWUXFWXUHV LQ WKH
6WXG\ (\H
 $QWHULRU &KDPEHU ,2/ SODFHPHQW LQ WKH 6WXG\ (\H
 ([SHFWHG RU SODQQHG RFXODU VXUJHU\ LQFLVLRQDO RU ODVHU LQ WKH 6WXG\ (\H ZLWKLQ WKH QH[W
 PRQWKV LQFOXGLQJ HQGRWKHOLDO NHUDWRSODVW\
 8VH RI V\VWHPLF RU GHUPDWRORJLFDO F\WRWR[LF FKHPRWKHUDS\ ZLWKLQ WKH  PRQWK SULRU WR RU
SODQQHG XVH ZLWKLQ WKH  PRQWKV IROORZLQJ 6WXG\ 'D\ 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
 8VH RI K\SHUWRQLF VDOLQH H\H SUHSDUDWLRQV HJ 0XUR  ZLWKLQ WKH  GD\V SULRU WR
6WXG\ 'D\  HLWKHU H\H
 $FWLYH H[WUDRFXODU LQIODPPDWLRQ IURP DQ\ QRQLQIHFWLRXV RU LQIHFWLRXV FDXVH EDFWHULDO
YLUDO RU IXQJDO LQ WKH 6WXG\ (\H ZLWKLQ WKH  PRQWKV SULRU WR 6WXG\ 'D\ 
1RWH 0LOG EOHSKDULWLV DQGRU GU\ H\H UHODWHG LQIODPPDWLRQ DUH DOORZHG
 7UHDWPHQW ZLWK D UKR NLQDVH LQKLELWRU ZLWKLQ WKH ODVW  PRQWKV HLWKHU H\H
 8VH RI F\FORVSRULQH RSKWKDOPLF HPXOVLRQ HJ 5(67$6,6 ZLWKLQ WKH  GD\V SULRU WR
6WXG\ 'D\  HLWKHU H\H
 8VH RI ;LLGUD OLILWHJUDVW RSKWKDOPLF VROXWLRQ ZLWKLQ WKH  GD\V SULRU WR 6WXG\ 'D\ 
HLWKHU H\H
 6\VWHPLF QDVDO LQKDOHG RUDO SDUHQWHUDO RU WRSLFDO RU RSKWKDOPLF FRUWLFRVWHURLG XVH LQ
WKH  GD\V SULRU WR 6WXG\ 'D\  XQOHVV DSSURYHG E\ WKH 0HGLFDO 0RQLWRU
1RWH 3RWHQWLDO VXEMHFWV RQ D VWDEOH FKURQLF ORZGRVH WKDW LV QRW H[SHFWHG WR
FKDQJH LQ WKH  PRQWKV IROORZLQJ 6WXG\ 'D\  PD\ EH FRQVLGHUHG IRU WKH VWXG\
DIWHU DSSURYDO E\ WKH 0HGLFDO 0RQLWRU
 +LVWRU\ RI VLJQLILFDQW DOOHUJ\ K\SHUVHQVLWLYLW\ RU LQWROHUDQFH WR DQ\ GUXJ FRPSRXQG
IRRG RU RWKHU VXEVWDQFH
1RWH 7KLV LQFOXGHV DOO FRPSRQHQWV DQG H[FLSLHQWV RI WKH VWXG\ GUXJ
 :RPHQ RI FKLOGEHDULQJ SRWHQWLDO ZKR DUH FXUUHQWO\ SUHJQDQW EUHDVW IHHGLQJ SODQQLQJ WR
EHFRPH SUHJQDQW GXULQJ WKH VWXG\ RU QRW ZLOOLQJ WR XVH KLJKO\ HIIHFWLYH ELUWK FRQWURO
PHDVXUHV HJ KRUPRQDO FRQWUDFHSWLYHV >RUDO LPSODQWHG WUDQVGHUPDO@ RU PHFKDQLFDO
EDUULHU PHWKRGV >VSHUPLFLGH LQ FRQMXQFWLRQ ZLWK D EDUULHU VXFK DV D FRQGRP RU
GLDSKUDJP@ RU LQWUDXWHULQH GHYLFH >,8'@ GXULQJ WKH HQWLUH FRXUVH RI WKH VWXG\
 &XUUHQW RU UHFHQW HJ WKH  GD\V SULRU WR 6WXG\ 'D\  SDUWLFLSDWLRQ LQ DQ\ RWKHU
LQWHUYHQWLRQDO FOLQLFDO UHVHDUFK VWXG\
 $Q HPSOR\HH RI WKH VLWH WKDW LV GLUHFWO\ LQYROYHG LQ WKH PDQDJHPHQW DGPLQLVWUDWLRQ RU
VXSSRUW RI WKLV VWXG\ RU EH DQ LPPHGLDWH IDPLO\ PHPEHU RI WKH VDPH
 $Q\ RWKHU UHDVRQ HJ VHULRXV V\VWHPLF GLVHDVH RU XQFRQWUROOHG PHGLFDO FRQGLWLRQ WKDW
LQ WKH RSLQLRQ RI WKH ,QYHVWLJDWRU FRXOG LQFUHDVH WKH VXEMHFW¶V ULVN LQWHUIHUH ZLWK WKH
LQWHUSUHWDWLRQ RI WKH VWXG\ UHVXOWV RU DIIHFW WKH VXEMHFW
V DELOLW\ WR SURYLGH LQIRUPHG
FRQVHQW RU FRPSO\ ZLWK WKH VWXG\
 6XEMHFW :LWKGUDZDO &ULWHULD
6XEMHFWV ZLOO EH GLVFRQWLQXHG IURP FRQWLQXHG VWXG\ WUHDWPHQW LI DQ\ RI WKH IROORZLQJ RFFXU
x
,QWROHUDEOH VLGH HIIHFWV
x
7KH ,QYHVWLJDWRU IHHOV LW LV LQ WKH VXEMHFW¶V EHVW LQWHUHVW
x
1RQFRPSOLDQFH
x
3UHJQDQF\
6XEMHFWV ZKR DUH GLVFRQWLQXHG IURP VWXG\ WUHDWPHQW DUH H[SHFWHG WR UHPDLQ RQ WKH VWXG\ DQG
FRPSOHWH DOO DSSURSULDWH VDIHW\ DQG HIILFDF\ DVVHVVPHQWV
6XEMHFWV PD\ ZLWKGUDZ IURP WKH WULDO DW DQ\ WLPH DQG IRU DQ\ UHDVRQ
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
,I D VXEMHFW ZLWKGUDZV IURP WKH WULDO DWWHPSWV VKRXOG EH PDGH WR FRQWDFW WKH VXEMHFW WR GHWHUPLQH
WKH UHDVRQV IRU GLVFRQWLQXDWLRQ ZKLOH UHVSHFWLQJ WKH VXEMHFW¶V SULYDF\ $OO SURFHGXUHV DQG
HYDOXDWLRQV UHTXLUHG E\ WKH ILQDO VWXG\ YLVLW VKRXOG EH FRPSOHWHG LQ WKH HYHQW RI HDUO\
ZLWKGUDZDO $OO VXEMHFWV ZKR GLVFRQWLQXH WKH WULDO GXH WR DQ DGYHUVH HYHQW PXVW EH IROORZHG
XQWLO WKH HYHQW KDV UHVROYHG UHWXUQHG WR EDVHOLQH RU VWDELOL]HG LI UHVROXWLRQ LV QRW DQWLFLSDWHG
 75($70(17 2) 68%-(&76
7KLV VWXG\ ZLOO EH FRQGXFWHG DW TXDOLILHG FOLQLFDO LQYHVWLJDWLRQDO VLWHV 6LWHV ZLOO EH VHOHFWHG
EDVHG RQ WKH DELOLW\ WR VDIHO\ FRQGXFW WKH VWXG\ DQG ZKHUH 7UHIRLO FDQ EH DVVXUHG RI SDWLHQW VDIHW\
DQG WKH DELOLW\ WR HIIHFWLYHO\ PRQLWRU ,QYHVWLJDWLRQDO VLWHV VKRXOG PRQLWRU KHDOWK ZHEVLWHV VXFK
DV KWWSVZZZFGFJRYFRURQDYLUXVQFRYLQGH[KWPO IRU XSWRGDWH LQIRUPDWLRQ DQG
UHVRXUFHV
,QYHVWLJDWLRQDO VLWH VWDII DUH LQVWUXFWHG WR IROORZ WKHLU LQVWLWXWLRQDO LQIHFWLRQ FRQWURO VWDQGDUG
SURFHGXUHV DQG WR FRQVLGHU DGGLWLRQDO PHDVXUHV GXULQJ SHULRGV RI FRPPXQLW\ WUDQVPLVVLRQ RI
FRQGLWLRQV VXFK DV &29,' 7KHVH DGGLWLRQDO PHDVXUHV PD\ LQFOXGH
x
&RQWDFWLQJ VXEMHFWV WKH GD\ EHIRUH D VFKHGXOHG DSSRLQWPHQW
o
7R GHWHUPLQH LI WKH\ DUH H[SHULHQFLQJ DQ\ VLJQV RU V\PSWRPV RI SRVVLEOH
LQIHFWLRQV VXFK DV

)HYHU

&RXJK

6KRUWQHVV RI EUHDWK

6RUH WKURDW
o
7R GHWHUPLQH LI WKH VXEMHFW KDV WHVWHG SRVLWLYH IRU &29,' EHHQ LQ FRQWDFW
ZLWK VRPHRQH ZKR LV NQRZQ RU VXVSHFWHG &29,' RU WUDYHOHG WR DQ DUHD RI
ULVN
x
5HVFKHGXOLQJ VXEMHFWV ZKR DUH H[SHULHQFLQJ UHVSLUDWRU\ V\PSWRPV DQG LQVWUXFWLQJ WKHP
WR VHHN DSSURSULDWH PHGLFDO DWWHQWLRQ
x
5HPLQGLQJ VXEMHFW WR FRQWDFW WKH LQYHVWLJDWLRQDO VLWH LI WKH\ GHYHORS UHVSLUDWRU\
V\PSWRPV RQ WKH PRUQLQJ EHIRUH D VFKHGXOHG H[DPLQDWLRQ RU LI WKH\ KDYH KDG FKDQJHV WR
WKHLU KHDOWK VWDWXV
8SRQ DUULYDO DW WKH LQYHVWLJDWLRQDO VLWH VXEMHFWV VKRXOG EH
x
$VVHVVHG IRU IHYHU
x
3URYLGHG ZLWK 33( HJ IDFH PDVNV
(TXLSPHQW WKDW LV PHDQW WR EH XVHG RQ PRUH WKDQ RQH SHUVRQ VKRXOG EH GUDSHG WR SUHYHQW
SRVVLEOH FRQWDPLQDWLRQ DQG DSSURSULDWHO\ FOHDQHG EHIRUH DQG DIWHU HDFK XVH $GGLWLRQDO
PHDVXUHV VKRXOG DOVR EH FRQVLGHUHG VXFK DV
x
3RVWLQJ JXLGHOLQHV
x
5HPLQG VXEMHFWV RI WKH QHHG IRU VRFLDO GLVWDQFLQJ FRQVLGHU KDYLQJ VXEMHFWV ZDLW RXWVLGH
RI WKH LQYHVWLJDWLRQDO VLWH HJ LQ WKHLU YHKLFOHV XQWLO UHDG\ WR EH VHHQ
x
1RQHVVHQWLDO LQGLYLGXDOV DFFRPSDQ\LQJ VWXG\ VXEMHFWV VKRXOG QRW SHUPLWWHG LQ SDWLHQW
DUHDV
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
x
3URYLGH VXSSOLHV IRU UHVSLUDWRU\ K\JLHQH DQG FRXJK HWLTXHWWH LQFOXGLQJ 
DOFRKROEDVHG KDQG VDQLWL]HU $%+6 WLVVXHV QRWRXFK UHFHSWDFOHV IRU GLVSRVDO IDFH
PDVNV DQG WLVVXHV DW KHDOWKFDUH IDFLOLW\ HQWUDQFHV ZDLWLQJ URRPV SDWLHQW FKHFNLQV HWF
x
3URYLGH UHVSLUDWRU\ K\JLHQH VXSSOLHV VXFK DV WLVVXH WR FRYHU FRXJK DQG KDQGVIUHH
UHFHSWDFOH IRU UHIXVH GLVSRVDO
x
5HPLQG VXEMHFWV WR ZDVK KDQGV DQG RU XVH KDQG VDQLWL]HU
6WXG\ YLVLWV DQG DVVHVVPHQWV VKRXOG EH UHVFKHGXOHG DW WKH GLVFUHWLRQ RI WKH ,QYHVWLJDWRU ZKHQ
WKHUH LV D SHUFHLYHG LQFUHDVHG ULVN WR VWXG\ VXEMHFWV DQGRU LQYHVWLJDWLRQDO VLWH VWDII
 6XEMHFW 6FUHHQLQJ DQG (QUROOPHQW
3RWHQWLDO VWXG\ SDUWLFLSDQWV ZLOO EH DVNHG WR VLJQ DQ ,QIRUPHG &RQVHQW )RUP ,&) SULRU WR DQ\
VWXG\ DVVHVVPHQWV 6FUHHQLQJ VKRXOG EH FRPSOHWHG ZLWKLQ  GD\V RI 6WXG\ 'D\ 
QRQTXDOLI\LQJ VFUHHQLQJ DVVHVVPHQWV HJ VSHFXODU PLFURVFRS\ DQG VFUHHQLQJ DVVHVVPHQWV
RXWVLGH WKLV ZLQGRZ PD\ EH UHSHDWHG 6FUHHQLQJ DVVHVVPHQWV ZLOO LQFOXGH
x
$VVHVVPHQW RI VWXG\ HOLJLELOLW\
x
0HGLFDO DQG RFXODU KLVWRU\
x
%&9$ DVVHVVPHQW
x
&RPSUHKHQVLYH RFXODU H[DPLQDWLRQ VOLW ODPS ELRPLFURVFRS\ DQG GLODWHG H[DPLQDWLRQ RI
OHQV IXQGXV DQG YLWUHRXV
x
6SHFXODU PLFURVFRS\ LQFOXGLQJ LPDJHV RI WKH FHQWUDO FRUQHD
,I WKH VXEMHFW LV GHHPHG SUHOLPLQDULO\ HOLJLEOH E\ WKH ,QYHVWLJDWRU VSHFXODU PLFURVFRS\ LPDJHV RI
WKH FHQWUDO FRUQHD ZLOO EH VHQW WR FHQWUDO LPDJH UHDGLQJ IDFLOLW\ ,I WKH UHDGLQJ FHQWHU FRQILUPV
WKDW (&' LV DW OHDVW RQH H\H LV   FHOOVPPA D VSDFH LV DYDLODEOH LQ D FRKRUW DQG WKH
VXEMHFW PHHWV DOO RI WKH DGGLWLRQDO HOLJLELOLW\ FULWHULD WKH VXEMHFW ZLOO EH UDQGRPL]HG DQG
DGGLWLRQDO EDVHOLQH DVVHVVPHQWV REWDLQHG
,I ERWK H\HV TXDOLI\ WKH H\H ZLWK WKH ORZHVW YLVLEOH FHOO FRXQW SHU WKH FHQWUDO UHDGLQJ IDFLOLW\
ZLOO EH GHVLJQDWHG DV WKH 6WXG\ (\H 6( ,I ERWK H\HV KDYH WKH VDPH YLVLEOH FHOO FRXQW WKH ULJKW
H\H ZLOO EH GHVLJQDWHG WKH 6(
$OO SRWHQWLDO VWXG\ VXEMHFWV ZLOO EH SURYLGHG ZLWK D XQLTXH 6XEMHFW ,' 1XPEHU 6XEMHFW ,' DW
WKH WLPH RI SURYLGLQJ ZULWWHQ LQIRUPHG FRQVHQW 7KH 6XEMHFW ,' ZLOO FRQVLVW RI D XQLTXH GLJLW
QXPEHU GLJLW VLWH QXPEHU DQG D GLJLW VXEMHFW QXPEHU VHSDUDWHG E\ D K\SKHQ >@
)LJXUH  6XEMHFW ,' 1XPEHULQJ
6XEMHFW ,' 1XPEHU
6LWH 1XPEHU
6XEMHFW 1XPEHU







)RU H[DPSOH 6XEMHFW ,'   7KH ILUVW SDUWLFLSDQW FRQVHQWHG DW 6LWH  
 7KH WKLUG SDUWLFLSDQW FRQVHQWHG DW 6LWH 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
2QFH D 6XEMHFW ,' QXPEHU KDV EHHQ LVVXHG LW FDQQRW EH UHXVHG
6XEMHFWV HQUROOHG LQ DQG SDUWLFLSDWLQJ LQ WKH 2EVHUYDWLRQDO 6XEVWXG\ ZKR DUH HOLJLEOH PD\
³UROORYHU´ LQWR WKH PDLQ VWXG\ SURYLGHG WKH\ PHHW DOO RI WKH DGGLWLRQDO HOLJLELOLW\ FULWHULD WKHUH LV
DQ RSHQ FRKRUW DQG WKH\ FRQVHQW 6XEMHFWV ZKR ³UROORYHU´ LQWR WKH PDLQ VWXG\ GR QRW QHHG WR
FRPSOHWH WKH UHPDLQLQJ YLVLWV LQ WKH 2EVHUYDWLRQDO 6XEVWXG\ DQG 2EVHUYDWLRQDO 6XEVWXG\
DVVHVVPHQWV PD\ EH XVHG DV VFUHHQLQJ DVVHVVPHQWV IRU WKH PDLQ VWXG\ DV ORQJ DV WKH\ ZHUH
SHUIRUPHG ZLWKLQ WKH SURWRFROVSHFLILHG WLPHIUDPH
3RWHQWLDO VXEMHFWV PD\ EH UHVFUHHQHG RU KDYH UHSHDW HOLJLELOLW\ DVVHVVPHQWV LI DSSURSULDWH
 6WXG\ 7UHDWPHQW $GPLQLVWUDWLRQ ,QWUDFDPHUDO ,QMHFWLRQ
7KLV SURFHGXUH FDQ EH SHUIRUPHG E\ D TXDOLILHG DQG WUDLQHG LQYHVWLJDWRU DW WKH VOLW ODPS
PLFURVFRSH RU LQ D SURFHGXUH URRP VHWWLQJ 6XEVHTXHQW LQMHFWLRQV VKRXOG EH SHUIRUPHG LQ WKH
VDPH VHWWLQJ
0DWHULDOV
3URFHGXUH
$IWHU DSSURSULDWH VWHULOH SUHSSLQJ DQG GUDSLQJ

   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
x
5KRNLQDVH LQKLELWRUV WRSLFDO RU V\VWHPLF HJ )DVXGLO 1HWDUVXGLO >5KRSUHVVD@
x
6\VWHPLF RU GHUPDWRORJLFDO F\WRWR[LF FKHPRWKHUDS\
x
+\SHUWRQLF VRGLXP FKORULGH RLQWPHQW DQG GURSV LQFOXGLQJ 0XUR 
x
6\VWHPLF QDVDO LQKDOHG RUDO SDUHQWHUDO RU WRSLFDO RU RSKWKDOPLF FRUWLFRVWHURLGV
1RWH ,QKDOHG FRUWLFRVWHURLGV DUH DFFHSWDEOH DV ORQJ DV WKH VXEMHFW LV RQ VWDEOH ORZ
GRVHV DQG WKH GRVH LV QRW H[SHFWHG WR FKDQJH IRU WKH GXUDWLRQ RI WKH VWXG\
x
&\FORVSRULQH RSKWKDOPLF HPXOVLRQ
x
;LLGUD  OLILWHJUDVW RSKWKDOPLF VROXWLRQ
6XEMHFWV UHTXLULQJ WKH XVH RI SURKLELWHG PHGLFDWLRQV PXVW EH GLVFXVVHG ZLWK WKH PDVNHG 0HGLFDO
0RQLWRU
3UHJQDQF\ 7HVWLQJ DQG &RQWUDFHSWLRQ
:RPHQ RI FKLOGEHDULQJ SRWHQWLDO :2&%3 DUH GHILQHG DV D SUHPHQRSDXVDO IHPDOH FDSDEOH RI
EHFRPLQJ SUHJQDQW :RPHQ ZKR DUH QRW :2&%3 DUH WKRVH ZKR KDYH QRW KDG D PHQVWUXDO F\FOH
IRU DW OHDVW  \HDUV RU ZKR KDYH KDG K\VWHUHFWRP\ ELODWHUDO WXEDO OLJDWLRQ RU ELODWHUDO
RRSKRUHFWRP\ 6H[XDOO\ DFWLYH IHPDOH VXEMHFWV ZKR DUH :2&%3 PXVW XVH DW OHDVW 
KLJKO\HIIHFWLYH PHWKRG RI FRQWUDFHSWLRQ RU DW OHDVW  OHVV HIIHFWLYH PHWKRGV RI FRQWUDFHSWLRQ
LQFOXGLQJ  EDUULHU PHWKRG VWDUWLQJ DW OHDVW  PRQWK SULRU WR 'D\  DQG PDOH VXEMHFWV ZKR DUH
VH[XDOO\ DFWLYH ZLWK ZRPHQ RI FKLOGEHDULQJ SRWHQWLDO PXVW DJUHH WR XVH D GRXEOHEDUULHU PHWKRG
RI FRQWUDFHSWLRQ 3HU ICH M3(R2) Non-Clinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals KLJKO\HIIHFWLYH PHWKRGV DUH GHILQHG DV
³WKRVH DORQH RU LQ FRPELQDWLRQ WKDW UHVXOW LQ D ORZ IDLOXUH UDWH LH OHVV WKDQ  SHU \HDU ZKHQ
XVHG FRQVLVWHQWO\ DQG FRUUHFWO\´ )'$DSSURYHG FRQWUDFHSWLYH PHWKRGV DQG HVWLPDWHG IDLOXUH
UDWHV DUH VXPPDUL]HG LQ 7DEOH 
7DEOH  )'$$SSURYHG 0HWKRGV RI &RQWUDFHSWLRQ DQG (VWLPDWHG )DLOXUH 5DWHV
0HWKRG
)DLOXUH 5DWH
+LJKO\(IIHFWLYH
x
6WHULOL]DWLRQ VXUJHU\ IRU ZRPHQ
/HVV WKDQ 
x
6WHULOL]DWLRQ LPSODQW IRU ZRPHQ
/HVV WKDQ 
x
6WHULOL]DWLRQ VXUJHU\ IRU PHQ
/HVV WKDQ 
x
,8' &RSSHU
/HVV WKDQ 
x
,8' ZLWK 3URJHVWLQ
/HVV WKDQ 
x
,PSODQWDEOH 5RG
/HVV WKDQ 
/HVV(IIHFWLYH
x
6KRW ,QMHFWLRQ

x
2UDO &RQWUDFHSWLYHV ³7KH 3LOO´ 

x
3DWFK

x
9DJLQDO &RQWUDFHSWLYH 5LQJ

x
'LDSKUDJP ZLWK 6SHUPLFLGH

x
&HUYLFDO &DS ZLWK 6SHUPLFLGH

x
0DOH &RQGRP

x
)HPDOH &RQGRP

x
6SHUPLFLGH $ORQH

LQFOXGLQJ &RPELQHG ([WHQGHG &RQWLQXRXV 8VH &RPELQHG 3LOO DQG WKH ³0LQL 3LOO´ 3URJHVWLQ RQO\
$GDSWHG IURP )'$ %LUWK &RQWURO *XLGH ZZZ)'$JRYELUWKFRQWURO
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
7KH FRQWUDFHSWLYH SODQ IRU HDFK VXEMHFW VKRXOG EH GLVFXVVHG ZLWK WKH ,QYHVWLJDWRU DQG ZLOO EH
GHWHUPLQHG DW WKH ,QYHVWLJDWRU¶V GLVFUHWLRQ LQFOXGLQJ WKH XVH RI D GRXEOHEDUULHU HJ PDOH
FRQGRP IHPDOH GLDSKUDJP ZLWK VSHUPLFLGH LQ PDOH VXEMHFWV
 6WXG\ 3URFHGXUHV
,QIRUPHG &RQVHQW
$ VDPSOH ,QIRUPHG &RQVHQW )RUP ,&) ZLOO EH SURYLGHG E\ 7UHIRLO DQG ZLOO EH LQ DFFRUGDQFH
ZLWK  &)5  3DUW  6XESDUW % 6HFWLRQ  7KH VDPSOH ,&) ZLOO EH UHYLVHG E\ WKH
LQYHVWLJDWLRQDO VLWH WR LQFOXGH VLWHVSHFLILF LQIRUPDWLRQ DQG UHTXLUHG ODQJXDJH DV QHHGHG 7KH
,QYHVWLJDWRU HQVXUH ,5%,(& UHYLHZ DQG DSSURYDO RI ,&)
:ULWWHQ LQIRUPHG FRQVHQW ZLOO EH REWDLQHG IURP DOO SRWHQWLDO VXEMHFWV SULRU WR DQ\ VWXG\VSHFLILF
DVVHVVPHQWV DUH FRQGXFWHG ,QIRUPHG FRQVHQW ZLOO EH REWDLQHG LQ DFFRUGDQFH ZLWK 21 CFR Part 
50 Protection of Human Subjects
$OWHUQDWLYH WKHUDSLHV ZLOO EH GLVFXVVHG ZLWK HDFK SRWHQWLDO SDUWLFLSDQW LQFOXGLQJ RWKHU
SKDUPDFRORJLF WKHUDSLHV LQYHVWLJDWLRQDO WUHDWPHQWV LI DYDLODEOH RU ZDWFKIXO ZDLWLQJ ,QIRUPHG
FRQVHQW ZLOO LQFOXGH D +,3$$ UHOHDVH ZDLYHU
'HPRJUDSKLFV
'HPRJUDSKLF LQIRUPDWLRQ ZLOO EH UHFRUGHG LQFOXGLQJ
x
$JH
x
6H[
x
5DFH
x
(WKQLFLW\
7KH VXEMHFW¶V KHLJKW DQG ZHLJKW ZLOO EH PHDVXUHG DQG UHFRUGHG +HLJKW VKRXOG EH PHDVXUHG
ZLWKRXW VKRHV DQG ZHLJKW VKRXOG EH PHDVXUHG ZLWK PLQLPDO VWUHHW FORWKLQJ ,I WKH ,QYHVWLJDWRU
IHHOV WKDW WKH VXEMHFW LV D UHOLDEOH VRXUFH VHOIUHSRUWHG KHLJKW DQG ZHLJKW PD\ EH UHFRUGHG
0HGLFDO +LVWRU\ DQG 2FXODU +LVWRU\
'XULQJ WKH 6FUHHQLQJ 3UHWUHDWPHQW 3HULRG WKH ,QYHVWLJDWRU RU GHVLJQHH ZLOO UHYLHZ WKH PHGLFDO
KLVWRU\ RI DOO SRWHQWLDO VXEMHFWV WR GRFXPHQW DOO UHOHYDQW FOLQLFDOO\ VLJQLILFDQW EDVHOLQH PHGLFDO
FRQGLWLRQV FRQFRPLWDQW PHGLFDWLRQ XVH DQG WR GHWHUPLQH VWXG\ HOLJLELOLW\ 0HGLFDO +LVWRU\
$VVHVVPHQW ZLOO LQFOXGH UHYLHZ RI DOO DYDLODEOH PHGLFDO UHFRUGV DQG SDWLHQW LQWHUYLHZ
$VVHVVPHQW RI DOO HOLJLELOLW\ FULWHULD VKRXOG EH HYLGHQFHG LQ WKH VWXG\ UHFRUGV 0HGLFDO KLVWRU\
ZLOO LQFOXGH D GHWDLOHG GLVHDVH KLVWRU\ UHJDUGLQJ RQVHW VHYHULW\ DQG KLVWRU\ RI SULRU WKHUDS\
,Q DGGLWLRQ WR WKH GDWD FROOHFWHG LQ GHPRJUDSKLFV DQG PHGLFDO KLVWRU\ VSHFLILF LQIRUPDWLRQ ZLOO
EH FROOHFWHG UHJDUGLQJ HDFK VXEMHFW¶V RFXODU KLVWRU\ LQFOXGLQJ
x
3UHVHQW FRQGLWLRQ
o
'XUDWLRQ GDWH DJH RI RQVHW
o
6LQJOH RU ERWK H\HV LQYROYHG
o
$VVRFLDWHG V\PSWRPV
x
2WKHU FRUQHDO G\VWURSKLHV
x
&RQWDFW OHQV XVH DQG KLVWRU\
x
3DVW RFXODU VXUJHU\ LQFOXGLQJ /$6,.
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
x
+LVWRU\ RI RFXODU WUDXPD
x
)DPLO\ KLVWRU\ RI RFXODU FRQGLWLRQV
x
$OOHUJLHV
x
'LDEHWHV
x
+\SHUWHQVLRQ
x
$XWRLPPXQH GLVHDVH
$GGLWLRQDO UHOHYDQW PHGLFDO KLVWRU\ ZLOO DOVR EH UHFRUGHG
&RPSUHKHQVLYH 2FXODU ([DPLQDWLRQ
$ FRPSUHKHQVLYH RFXODU H[DPLQDWLRQ ZLOO EH SHUIRUPHG DW 6FUHHQLQJ DQG 'D\  DQG ZLOO
LQFOXGH VOLWODPS ELRPLFURVFRS\ DQG D GLODWHG H[DPLQDWLRQ RI WKH OHQV IXQGXV DQG YLWUHRXV
6SHFXODU 0LFURVFRS\
6SHFXODU PLFURVFRSLF LPDJHV ZLOO EH REWDLQHG RI WKH FHQWHU RI WKH FRUQHD DW HYHU\ YLVLW 7KH
FHQWHU RI WKH FRUQHD LV GHILQHG DV WKH UHJLRQ RI WKH FRUQHD DERYH WKH SXSLO ,I D VXEMHFW LV WR EH
GLODWHG DW D YLVLW VSHFXODU PLFURVFRS\ PXVW EH SHUIRUPHG SULRU WR GLODWLRQ
(QGRWKHOLDO FHOO GHQVLW\ SHUFHQW KH[DJRQDOLW\ DQG WKH FRHIILFLHQW RI YDULDWLRQ ZLOO EH DVVHVVHG
IURP VSHFXODU PLFURVFRSH LPDJHV $ FHQWUDOL]HG UHDGLQJ FHQWHU ZLWK H[SHULHQFHG UHDGHUV
ZLOO EH UHVSRQVLEOH IRU WKH FKRLFH DQG FHUWLILFDWLRQ RI HTXLSPHQW DQG WUDLQLQJ RI
WHFKQLFLDQV DV ZHOO DV UHDGLQJ LPDJHV DQG FRQGXFWLQJ LPDJH DQDO\VLV
&RPPRQ VRXUFHV RI YDULDELOLW\ LQ VSHFXODU PLFURVFRS\ DUH
x
GLIILFXOW\ LQ UHWXUQLQJ WR VDPH ORFDWLRQ RQ WKH FRUQHD DW HDFK YLVLW
x
SRRU LPDJH TXDOLW\ OHVV WKDQ  FRXQWDEOH FHOOV
x
WHFKQLFLDQ HUURU
x
LPSURSHU UHDGHU DQDO\VLV
x
PDLQWDLQLQJ HTXLSPHQW FDOLEUDWLRQDOLJQPHQW
$OO LQGLYLGXDOV UHVSRQVLEOH IRU RQVWXG\ LPDJH FDSWXUH PXVW EH FHUWLILHG E\ WKH UHDGLQJ FHQWHU
7R DGGUHVV GLIIHUHQFHV LQ ORFDWLRQ RI WKH LPDJH ZLWKLQ D JLYHQ DUHD RI WKH FRUQHD WKUHH
DFFHSWDEOH LPDJHV VKRXOG EH WDNHQ DW HDFK ORFDWLRQ DW HDFK YLVLW 7KH GHQVLW\ IURP DW OHDVW RQH
SUHIHUUHG LPDJH VKRXOG EH GHWHUPLQHG
3ULRU WR REWDLQLQJ EDVHOLQH LPDJHV 'D\  WKH WHFKQLFLDQ ZLOO REWDLQ DQ LQLWLDO VHW RI LPDJHV IRU
DQ HYDOXDWLRQ RI LPDJH TXDOLW\ 7UDLQLQJ RU UHWUDLQLQJ ZLOO EH SHUIRUPHG DV QHFHVVDU\ DQG
LQFOXGH WKH IROORZLQJ LPSRUWDQW SRLQWV
$ SUHIHUUHG LPDJH KDV
x
'LVWLQFW FHOOV
x
$W OHDVW  LGHQWLILDEOH FRXQWDEOH FHOOV DV D PLQLPXP  FHOOV SUHIHUUHG DQG
x
&HOOV WKDW FDQ EH JURXSHG LQ D XQLIRUP DUHD
7R FDSWXUH D JRRG LPDJH
x
0DNH VXUH WKH VXEMHFW LV FRPIRUWDEOH
x
,QVWUXFW WKH VXEMHFW WR EOLQN
x
,QVWUXFW VXEMHFW QRW WR PRYH DQG WR RSHQ H\HV ZLGH
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
x
,QVWUXFW VXEMHFW WR IRFXV RQ WKH IL[DWLRQ OLJKW
x
,I QHFHVVDU\ XVH WKH PDQXDO VHWWLQJ
1RWH 8VH RI WKH PDQXDO VHWWLQJ PD\ UHTXLUH DGGLWLRQDO WUDLQLQJ
$ FDOLEUDWLRQ JULG PD\ EH REWDLQHG IURP WKH VSHFXODU PLFURVFRSH PDQXIDFWXUHU
%HVW FRUUHFWHG 9LVXDO $FXLW\ %&9$
:KHUHYHU SRVVLEOH EHVW FRUUHFWHG YLVXDO DFXLW\ %&9$ VKRXOG EH PHDVXUHG EHWZHHQ
 $0 DQG $0 ZLWK WKH H[FHSWLRQ RI WKH 2EVHUYDWLRQDO 6XE6WXG\ 9LVLW  30 YLVLW
ZKLFK LV WR EH PHDVXUHG DIWHU QRRQ 6LWH VWDII VKRXOG IROORZ WKHLU VWDQGDUG SURFHGXUHV IRU
FRQGXFWLQJ %&9$ XVLQJ (DUO\ 7UHDWPHQW 'LDEHWLF 5HWLQRSDWK\ 6WXG\ (7'56 WHVWLQJ %&9$
DW D VLQJOH VLWH VKRXOG EH GRQH FRQVLVWHQWO\ WKURXJKRXW WKH VWXG\ XVLQJ WKH VDPH HTXLSPHQW
OLJKWLQJ FRQGLWLRQV HWF
%&9$ WHVWLQJ VKRXOG SUHFHGH DQ\ H[DPLQDWLRQ UHTXLULQJ FRQWDFW ZLWK WKH H\H LQFOXGLQJ
PHDVXUHPHQW RI ,23 DQG VKRXOG EH SHUIRUPHG SULRU WR LQVWLOODWLRQ RI DQ\ RI DQ\ G\H RU GURSV WR
GLODWH RU DQHVWKHWL]H WKH H\H 5HIUDFWLRQ VKRXOG EH SHUIRUPHG SULRU WR PHDVXUHPHQW RI %&9$ DQG
WKH DSSURSULDWH FRUUHFWLRQ ZRUQ LQ D WULDO IUDPH GXULQJ YLVXDO DFXLW\ WHVWLQJ
6OLW /DPS %LRPLFURVFRS\
7KH VOLW ODPS ELRPLFURVFRS\ H[DPLQDWLRQ ZLOO EH SHUIRUPHG DW HYHU\ YLVLW ZLWK WKH VOLW ODPS XVLQJ
D EHDP RI  PP KHLJKW DQG  PP ZLGWK ZLWK WKH EHDP DW PD[LPXP OXPLQDQFH DQG XVLQJ WKH
KLJK SRZHUHG OHQV 7KH VXEMHFW ZLOO EH VHDWHG GXULQJ WKH H[DPLQDWLRQ 7KLV SURFHGXUH VKRXOG EH
FRQGXFWHG LQ WKH VDPH PDQQHU IRU DOO VXEMHFWV DQG ZLOO LQFOXGH DQ DVVHVVPHQW RI HDFK RI WKH
IROORZLQJ
x
/HQV
x
&RUQHDO (GHPD
o
$VVHVVHG LQ WKH FHQWUDO UHJLRQ
x
&RUQHDO 2SDFLW\
x
&RQMXQFWLYD  %XOEDU ,QMHFWLRQ
x
6FOHUD  &LOLDU\ )OXVK
x
$QWHULRU &KDPEHU &HOOV
x
$QWHULRU &KDPEHU )ODUH
x
(YDOXDWLRQ RI WKH LQWUDRFXODU OHQV ,2/ DQG WKH SRVWHULRU FDSVXOH IRU VXEMHFWV ZLWK
SVHXGRSKDNLF ,2/
7KHVH DVVHVVPHQWV ZLOO EH JUDGHG DFFRUGLQJ WR WKH FULWHULD GHVFULEHG LQ 7DEOH 
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
x
7KH DEQRUPDOLW\ LV RI D GHJUHH WKDW UHTXLUHV DGGLWLRQDO DFWLYH PDQDJHPHQW HJ FKDQJH
RI GRVH GLVFRQWLQXDWLRQ RI WKH GUXJ FORVH REVHUYDWLRQ PRUH IUHTXHQW IROORZXS
DVVHVVPHQWV RU IXUWKHU GLDJQRVWLF LQYHVWLJDWLRQ
7KHUHIRUH D FOLQLFDOO\ VLJQLILFDQW ODERUDWRU\ YDOXH LV RQH WKDW VXJJHVWV D QHZ GLVHDVH SURFHVV DQ
H[DFHUEDWLRQ RU ZRUVHQLQJ RI DQ H[LVWLQJ FRQGLWLRQ RU UHTXLUHV IXUWKHU DFWLRQV WR EH WDNHQ
,I D FOLQLFDOO\ VLJQLILFDQW ODERUDWRU\ UHVXOW LV IRXQG RQ D ODERUDWRU\ WHVW HJ KHPDWRORJ\ WKH
,QYHVWLJDWRU VKRXOG GHWHUPLQH LI DQ XQGHUO\LQJ FRQGLWLRQ LV WKH UHSRUWDEOH $( LQVWHDG RI WKH
LQGLYLGXDO ODERUDWRU\ SDUDPHWHUV HJ DQHPLD LQVWHDG RI GHFUHDVH LQ UHG EORRG FHOO FRXQW
KHPDWRFULW UHWLFXORF\WH DQG KHPRJORELQ OHYHOV
7DEOH  &OLQLFDO /DERUDWRU\ $VVHVVPHQWV
+HPDWRORJ\
x
+HPDWRFULW
x
+HPRJORELQ
x
:KLWH EORRG FHOO :%& FRXQW ZLWK GLIIHUHQWLDO
x
3ODWHOHW FRXQW
6HUXP &KHPLVWU\
8ULQDO\VLV
x
$OEXPLQ
x
$ONDOLQH SKRVSKDWDVH
x
$/7 DODQLQH DPLQR WUDQVIHUDVH 6*37
x
$67 DVSDUWDWH DPLQR WUDQVIHUDVH 6*27
x
%LFDUERQDWH&2
x
%LOLUXELQ
x
%ORRG XUHD QLWURJHQ
x
&DOFLXP
x
&KORULGH
x
&UHDWLQLQH
x
+E$F
x
/'+ /DFWDWH GHK\GURJHQDVH
x
3RWDVVLXP
x
6RGLXP
x
7RWDO SURWHLQ
x
8ULF DFLG
x
6SHFLILF JUDYLW\
x
.HWRQHV
x
S+
x
3URWHLQ
x
*OXFRVH
x
%ORRG
x
8URELOLQRJHQ
x
%LOLUXELQ
x
/HXNRF\WH HVWHUDVH
x
0LFURVFRSLF H[DPLQDWLRQ DV DSSOLFDEOH
3ODVPD IRU 3. DQG $'$
%ORRG VDPSOHV ZLOO EH FROOHFWHG IRU SKDUPDFRNLQHWLF 3. DQG DQWLGUXJ DQWLERG\ $'$
DQDO\VLV 6DPSOHV ZLOO EH FHQWULIXJHG DQGRU SUHSDUHG SHU LQVWUXFWLRQV IURP WKH DQDO\WLF
ODERUDWRU\ 3UHLQMHFWLRQ VDPSOHV VKRXOG EH FROOHFWHG ZLWKLQ WKH  KRXUV SULRU WR VWXG\ WUHDWPHQW
DGPLQLVWUDWLRQ 3. VDPSOHV VKRXOG EH FROOHFWHG ZLWKLQ   PLQXWHV RI WKH QRPLQDO WLPHSRLQW RU
DV VRRQ DV SUDFWLFDEOH
6HH 6WXG\ 77+; /DERUDWRU\ 0DQXDO IRU EORRG SURFHVVLQJ LQVWUXFWLRQV
1DWLRQDO (\H ,QVWLWXWH 9LVXDO )XQFWLRQ 4XHVWLRQQDLUH 1(,9)4
7KH 1(,9)4 LV D UHOLDEOH DQG YDOLGDWHG LWHP YHUVLRQ RI WKH LWHP 1(,9)4 >@ 7KH
VXEMHFW ZLOO FRPSOHWH WKH 1(,9)4 DW 'D\  SUHLQMHFWLRQ DQG 'D\  7KH 1(,9)4 LV
WR EH FRPSOHWHG SULRU WR DQ\ RWKHU SURFHGXUHV DW WKHVH YLVLWV 8SRQ FRPSOHWLRQ RI WKH
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
TXHVWLRQQDLUH WKH VWXG\ FRRUGLQDWRU ZLOO FKHFN WKH TXHVWLRQQDLUH IRU FRPSOHWHQHVV $Q\
RPLVVLRQV RU DPELJXRXV DQVZHUV ZLOO EH FODULILHG E\ WKH VXEMHFW SULRU WR OHDYLQJ WKH FOLQLF 7KH
1(,9)4 VKRXOG EH VHOIDGPLQLVWHUHG KRZHYHU WUDLQHG LQYHVWLJDWLRQDO VLWH VWDII ZLOO
DGPLQLVWHU WKH TXHVWLRQQDLUH WR VXEMHFWV ZKR DUH XQDEOH WR VHOIDGPLQLVWHU WKH TXHVWLRQQDLUH
3HQWDFDP 7RPRJUDSK\
3HQWDFDP WRPRJUDSK\ PXVW EH SHUIRUPHG GXULQJ VFUHHQLQJ DQG DW 6WXG\ 'D\  7KH
3HQWDFDP LPDJHV PXVW PHHW WKH LQWHUQDO VRIWZDUH TXDOLW\ PHWULF WR EH DFFHSWDEOH
2SWLRQDO %ORRG 6DPSOH IRU *HQHWLF 7HVWLQJ
6XEMHFWV ZLWK D GLDJQRVLV RI )(&' ZLOO EH DVNHG WR SURYLGH DQ RSWLRQDO EORRG VDPSOH IRU JHQHWLF
WHVWLQJ 6XEMHFWV ZLOO EH DVNHG WR SURYLGH VSHFLILF FRQVHQW IRU WKLV RSWLRQDO JHQHWLF WHVWLQJ 7KLV
VDPSOH ZLOO EH FRPSOHWHO\ GHLGHQWLILHG SULRU WR WUDQVPLWWDO WR WKH WHVWLQJ IDFLOLW\ 7KLV VDPSOH LV
RSWLRQDO DQG SDUWLFLSDWLRQ LQ QHLWKHU WKH 2EVHUYDWLRQDO 6XEVWXG\ QRU WKH LQWHUYHQWLRQDO SRUWLRQ LV
FRQGLWLRQDO RQ WKH FRQVHQW WR SURYLGH WKLV VDPSOH IRU JHQHWLF WHVWLQJ
 6WXG\ 9LVLWV
$OO VWXG\ YLVLWV DVVHVVPHQWV ZLOO EH FRQGXFWHG E\ TXDOLILHG LQYHVWLJDWLRQDO VLWH VWDII 6WXG\
YLVLWV DVVHVVPHQWV DUH WR EH FRQGXFWHG ZLWKLQ WKH SURWRFROVSHFLILHG ZLQGRZ IRU HDFK YLVLW
DVVHVVPHQW ,I DQ DVVHVVPHQW LV QRW DEOH WR EH FROOHFWHG ZLWKLQ WKH SURWRFROVSHFLILHG ZLQGRZ LW
VKRXOG EH FROOHFWHG DV VRRQ DV SUDFWLFDEOH DQG WKH DFWXDO GDWH WLPH UHFRUGHG &RPSDUDWLYH
DVVHVVPHQWV VKRXOG EH FROOHFWHG DW WKH VDPH WLPH DW HDFK WLPHSRLQW ZKHQ SRVVLEOH XQOHVV
RWKHUZLVH GLUHFWHG ,I DQ RQVLWH YLVLW LV QRW SRVVLEOH DV PDQ\ DVVHVVPHQWV DV IHDVLEOH FDQ EH
FRQGXFWHG UHPRWHO\
6FUHHQLQJ 3HULRG%DVHOLQH $VVHVVPHQWV
6FUHHQLQJ DVVHVVPHQWV PD\ EH SHUIRUPHG DQ\WLPH GXULQJ WKH 6FUHHQLQJ 3HULRG XQOHVV RWKHUZLVH
VSHFLILHG
6FUHHQLQJ
x
,QIRUPHG FRQVHQW
x
(OLJLELOLW\ DVVHVVPHQW
x
'HPRJUDSKLFV
x
0HGLFDO DQG 2FXODU +LVWRU\
x
5HFRUG &RQFRPLWDQW 0HGLFDWLRQ 8VH
x
%&9$
o
%RWK H\HV
o
%HWZHHQ  $0 DQG  $0
x
6SHFXODU 0LFURVFRS\ LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
o
%RWK H\HV
x
&RPSUHKHQVLYH 2FXODU ([DPLQDWLRQ
o
6OLWODPS ELRPLFURVFRS\
o
'LODWHG H[DPLQDWLRQ RI OHQV IXQGXV DQG YLWUHRXV
o
%RWK H\HV
1RWH 6XEMHFWV HQUROOHG LQ DQG SDUWLFLSDWLQJ LQ WKH 2EVHUYDWLRQDO 6XEVWXG\ ZKR DUH HOLJLEOH
PD\ ³UROORYHU´ LQWR WKH PDLQ VWXG\ SURYLGHG WKH\ PHHW DOO RI WKH DGGLWLRQDO HOLJLELOLW\ FULWHULD
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
WKHUH LV DQ RSHQ FRKRUW DQG WKH\ FRQVHQW 2EVHUYDWLRQDO 6XEVWXG\ DVVHVVPHQWV PD\ EH XVHG DV
VFUHHQLQJ DVVHVVPHQWV IRU WKH PDLQ VWXG\ DV ORQJ DV WKH\ ZHUH SHUIRUPHG ZLWKLQ WKH SURWRFRO
VSHFLILHG WLPHIUDPH
'D\ 
3UH,QMHFWLRQ
x
5HFRUG &RQFRPLWDQW 0HGLFDWLRQ 8VH
x
8ULQH SUHJQDQF\ :2&%3
x
2EWDLQ VDPSOHV IRU ODERUDWRU\ WHVWLQJ
o
&ROOHFW VDPSOHV IRU &KHPLVWU\ +HPDWRORJ\ 8ULQDO\VLV +E$F SHU WKH 77+;
 /DERUDWRU\ 0DQXDO
o
&ROOHFW RSWLRQDO EORRG VDPSOH IRU JHQHWLF WHVWLQJ LI FRQVHQWHG
x
2EWDLQ VDPSOH IRU $'$
x
2EWDLQ VDPSOH IRU 3.
x
1(,9)4
x
%HVW FRUUHFWHG YLVXDO DFXLW\ %&9$
o
6WXG\ H\H
o
%HWZHHQ  $0 DQG  $0
x
6SHFXODU 0LFURVFRS\ LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
o
%RWK H\HV
x
6OLW /DPS %LRPLFURVFRS\
o
6WXG\ H\H
x
,23
o
6WXG\ H\H
x
3HQWDFDP H[DPLQDWLRQ
o
%RWK H\HV
x
&RQILUP HOLJLELOLW\
3RVW,QMHFWLRQ
x
,23
o
6WXG\ H\H RQO\
o
$W OHDVW HYHU\  PLQXWHV DIWHU LQMHFWLRQ XQWLO QRUPDOL]HG ZLWKLQ  PP+J RI
SUHLQMHFWLRQ PHDVXUHPHQW
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH
'D\ 
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH 7KLV YLVLW PD\ EH FRQGXFWHG
E\ SKRQH
'D\   
x
%&9$
o
6WXG\ H\H RQO\
o
%HWZHHQ  $0 DQG  $0
o
3UHLQMHFWLRQ
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
x
6SHFXODU 0LFURVFRS\ LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
o
%RWK H\HV
o
3UHLQMHFWLRQ
x
6OLW /DPS %LRPLFURVFRS\
o
6WXG\ H\H RQO\
o
3UHLQMHFWLRQ
x
,23
o
6WXG\ H\H RQO\
o
3UHLQMHFWLRQ
o
$W OHDVW HYHU\  PLQXWHV DIWHU LQMHFWLRQ XQWLO QRUPDOL]HG ZLWKLQ  PP+J RI
SUHLQMHFWLRQ PHDVXUHPHQW
x
6WXG\ 7UHDWPHQW ,& ,QMHFWLRQ 6(
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH
'D\   
x
%&9$
o
6WXG\ H\H RQO\
o
%HWZHHQ  $0 DQG  $0
o
3UHLQMHFWLRQ
x
6SHFXODU 0LFURVFRS\ LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
o
%RWK H\HV
o
3UHLQMHFWLRQ
x
6OLW /DPS %LRPLFURVFRS\
o
6WXG\ H\H RQO\
o
3UHLQMHFWLRQ
x
,23
o
6WXG\ H\H RQO\
o
3UHLQMHFWLRQ
o
$W OHDVW HYHU\  PLQXWHV DIWHU LQMHFWLRQ XQWLO QRUPDOL]HG ZLWKLQ  PP+J RI
SUHLQMHFWLRQ PHDVXUHPHQW
x
6WXG\ 7UHDWPHQW ,& ,QMHFWLRQ 6(
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH
'D\   
x
2EWDLQ 6DPSOH IRU $'$
o
3UHLQMHFWLRQ
x
2EWDLQ 6DPSOH IRU 3.
o
3UHLQMHFWLRQ
o
 KRXUV DIWHU LQMHFWLRQ
x
%&9$
o
6WXG\ H\H RQO\
o
%HWZHHQ  $0 DQG  $0
o
3UHLQMHFWLRQ
x
6SHFXODU 0LFURVFRS\
o
%RWK H\HV
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
o
3UHLQMHFWLRQ
x
6OLW /DPS %LRPLFURVFRS\
o
6WXG\ H\H RQO\
o
3UHLQMHFWLRQ
x
,23
o
6WXG\ H\H RQO\
o
3UHLQMHFWLRQ
o
$W OHDVW HYHU\  PLQXWHV DIWHU LQMHFWLRQ XQWLO QRUPDOL]HG ZLWKLQ  PP+J RI
SUHLQMHFWLRQ PHDVXUHPHQW
x
6WXG\ 7UHDWPHQW ,& ,QMHFWLRQ 6(
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH
'D\   
x
2EWDLQ VDPSOHV IRU /DERUDWRU\ 7HVWLQJ &KHPLVWU\ +HPDWRORJ\ 8ULQDO\VLV +E$F
x
2EWDLQ VDPSOH IRU $'$
x
%&9$
o
6WXG\ H\H RQO\
o
%HWZHHQ  $0 DQG  $0
x
6SHFXODU 0LFURVFRS\ LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
o
%RWK H\HV
x
6OLW /DPS %LRPLFURVFRS\
o
6WXG\ H\H RQO\
x
,23
o
6WXG\ H\H RQO\
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH
'D\   
x
8ULQH SUHJQDQF\ :2&%3
x
2EWDLQ VDPSOHV IRU ODERUDWRU\ WHVWLQJ &KHPLVWU\ +HPDWRORJ\ 8ULQDO\VLV +E$F
x
2EWDLQ VDPSOH IRU $'$
x
2EWDLQ VDPSOH IRU 3.
x
1(,9)4
x
%&9$
o
6WXG\ H\H RQO\
o
%HWZHHQ  $0 DQG  $0
x
6SHFXODU 0LFURVFRS\ LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
o
%RWK H\HV
x
&RPSUHKHQVLYH 2FXODU ([DPLQDWLRQ
o
6OLWODPS ELRPLFURVFRS\
o
'LODWHG H[DPLQDWLRQ RI OHQV IXQGXV DQG YLWUHRXV 1RWH GLODWLRQ VKRXOG EH
SHUIRUPHG DIWHU %&9$ DQG PHDVXUHPHQW RI ,23
o
%RWK H\HV
x
,23
o
6WXG\ H\H RQO\
x
3HQWDFDP H[DPLQDWLRQ
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
o
%RWK H\HV
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH
'D\   
x
%&9$
o
6WXG\ H\H RQO\
o
%HWZHHQ  $0 DQG  $0
x
6SHFXODU 0LFURVFRS\ LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
o
%RWK H\HV
x
6OLW /DPS %LRPLFURVFRS\
o
6WXG\ H\H RQO\
x
,23
o
6WXG\ H\H RQO\
x
5HFRUG $GYHUVH (YHQWV DQG &RQFRPLWDQW 0HGLFDWLRQ 8VH
(DUO\ 7HUPLQDWLRQ 9LVLW
,I D VXEMHFW LV GLVFRQWLQXHG IURP VWXG\ WUHDWPHQW HDUO\ RU ZLWKGUDZV IURP WKH VWXG\ KHVKH
VKRXOG EH DVVHVVHG DSSUR[LPDWHO\  GD\V IROORZLQJ WKH ODVW VWXG\ WUHDWPHQW DGPLQLVWUDWLRQ LI
WKH VXEMHFW LV XQDEOH WR EH HYDOXDWHG DSSUR[LPDWHO\  GD\V IROORZLQJ WKH ODVW VWXG\ WUHDWPHQW
DGPLQLVWUDWLRQ KHVKH VKRXOG EH HYDOXDWHG DV VRRQ DV SUDFWLFDEOH DW OHDVW E\ WHOHSKRQH $OO
DVVHVVPHQWV VFKHGXOHG IRU 'D\  VKRXOG EH SHUIRUPHG DW WKH (DUO\ 7HUPLQDWLRQ 9LVLW
8QVFKHGXOHG 9LVLW
6WXG\ VXEMHFWV PD\ EH VHHQ DW DQ\ WLPH LQ EHWZHHQ VFKHGXOHG VWXG\ YLVLWV DW WKH GLVFUHWLRQ RI WKH
,QYHVWLJDWRU DQG DQ\ UHOHYDQW VWXG\ DVVHVVPHQWV SHUIRUPHG 7KH GDWH DQG UHDVRQ IRU WKH
XQVFKHGXOHG YLVLW ZLOO EH UHFRUGHG DV ZHOO DV WKH UHVXOWV RI WKH DVVHVVPHQWV
 3UHJQDQF\
6XEMHFWV ZLOO EH LQVWUXFWHG WR QRWLI\ WKH ,QYHVWLJDWRU DV VRRQ DV SRVVLEOH DIWHU EHFRPLQJ SUHJQDQW
RU OHDUQLQJ RI WKH SUHJQDQF\ RI D SDUWQHU ,I D VXEMHFW RU SDUWQHU RI D VXEMHFW EHFRPHV SUHJQDQW
GXULQJ WUHDWPHQW RU XS WR  GD\V IROORZLQJ WKH ODVW VWXG\ GUXJ DGPLQLVWUDWLRQ WKH ,QYHVWLJDWRU
LV LQVWUXFWHG WR QRWLI\ 7UHIRLO RU GHVLJQHH ZLWKLQ  KRXUV RI OHDUQLQJ RI WKH SUHJQDQF\
,I WKH VXEMHFW EHFRPHV SUHJQDQW ZKLOH UHFHLYLQJ LQYHVWLJDWLRQDO SURGXFW WKH LQYHVWLJDWLRQDO
SURGXFW ZLOO EH SHUPDQHQWO\ GLVFRQWLQXHG 3URWRFROUHTXLUHG SURFHGXUHV IRU VWXG\
GLVFRQWLQXDWLRQ DQG IROORZXS PXVW EH SHUIRUPHG RQ WKH VXEMHFW XQOHVV FRQWUDLQGLFDWHG E\
SUHJQDQF\ 2WKHU DSSURSULDWH SUHJQDQF\ IROORZXS SURFHGXUHV VKRXOG EH FRQVLGHUHG LI LQGLFDWHG
,I WKH SDUWQHU RI D VWXG\ SDUWLFLSDQW EHFRPHV SUHJQDQW WKH ,QYHVWLJDWRU LV LQVWUXFWHG WR REWDLQ D
3UHJQDQW 3DUWQHU 5HOHDVH )RUP DQG FROOHFW UHOHYDQW LQIRUPDWLRQ UHJDUGLQJ WKH SDUWQHU DQG WKH
SUHJQDQF\ 7KH ,QYHVWLJDWRU ZLOO GLVFXVV WKH ULVNV DQG FRQFHUQV RI LQYHVWLJDWLRQDO GUXJ H[SRVXUH
WR D GHYHORSLQJ IHWXV DQG FRXQVHO WKH VXEMHFW DQGRU SUHJQDQW SDUWQHU RU HQVXUH WKDW VXFK
FRXQVHOLQJ LV SURYLGHG
3UHJQDQFLHV ZLOO EH IROORZHG WKURXJK WKH RXWFRPH RI WKH SUHJQDQF\ 1HZERUQV VKRXOG EH
IROORZHG IRU D PLQLPXP RI  ZHHNV 7KH ,QYHVWLJDWRU ZLOO FRPSOHWH D 3UHJQDQF\ 6XUYHLOODQFH
)RUP DQG UHSRUW WKH LQIRUPDWLRQ UHJDUGLQJ WKH SUHJQDQF\ RXWFRPH DQG VWDWXV RI WKH QHZERUQ DV
DSSURSULDWH
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
 $66(660(17 2) ()),&$&<
$V GHVFULEHG DERYH WKH SULPDU\ HIILFDF\ HQGSRLQW ZLOO EH HQGRWKHOLDO FHOO FRXQW GHQVLW\ DV
PHDVXUHV E\ VSHFXODU PLFURVFRS\ 2WKHU HIILFDF\ DVVHVVPHQWV LQFOXGH
x
1(,9)4
x
%&9$
x
3HQWDFDP H[DPLQDWLRQ
x
6OLW ODPS ELRPLFURVFRS\
x
3DFK\PHWU\
x
,23
7KH SULPDF\ HIILFDF\ WLPHSRLQW LV 'D\  3OHDVH UHIHU WR $SSHQGL[ $ IRU WKH VFKHGXOH RI
HYHQWV
 $66(660(17 2) 6$)(7<
 $GYHUVH (YHQWV
,QYHVWLJDWRUV ZLOO FROOHFW LQIRUPDWLRQ UHODWHG WR DGYHUVH HYHQWV $(V WKURXJKRXW WKLV FOLQLFDO
WULDO 7KH WHUPV DQG GHILQLWLRQV DUH FRQVLVWHQW ZLWK Guidance for Industry and Investigators 
Safety Reporting Requirements for INDs and BA/BE Studies, FDA 2012
x
$OO $(V RFFXUULQJ LQ DOO VXEMHFWV IROORZLQJ H[SRVXUH WR VWXG\ WUHDWPHQW XQWLO  GD\V
DIWHU WKH ODVW VWXG\ WUHDWPHQW ZLOO EH UHSRUWHG
x
$(V ZLOO EH IROORZHG XQWLO DW OHDVW WKH HQG RI WKH VWXG\
x
$(V FRQVLGHUHG UHODWHG WR WKH VWXG\ WUHDWPHQW E\ WKH ,QYHVWLJDWRU 6$5V DQG 6$(V ZLOO
EH IROORZHG XQWLO UHVROXWLRQ UHWXUQ WR EDVHOLQH RU VWDELOL]DWLRQ LI UHVROXWLRQ LV QRW
H[SHFWHG
&KDQJHV LQ WKH VXEMHFW¶V PHGLFDO FRQGLWLRQ WKDW RFFXU SULRU WR WKH ILUVW H[SRVXUH WR VWXG\
WUHDWPHQW ZLOO EH UHSRUWHG DV PHGLFDO KLVWRU\ $W HDFK SRVWWUHDWPHQW YLVLW VXEMHFWV ZLOO EH DVNHG
DERXW DQ\ SRVVLEOH DGYHUVH HYHQWV LQ D QRQOHDGLQJ PDQQHU $Q H[DPSOH RI D QRQOHDGLQJ
PHWKRG RI HOLFLWLQJ $( LQIRUPDWLRQ LV ³Have there been any changes in your health since you 
were here last"´ 6XEMHFWV VKRXOG DOVR EH DVNHG DERXW WKH VHYHULW\ DQGRU SHUVLVWHQFH RI DQ\ $(V
WKDW ZHUH RQJRLQJ DW WKH WLPH RI WKHLU ODVW YLVLW
$GYHUVH (YHQWV 'HILQLWLRQV
 $GYHUVH (YHQWV  &)5 D
$Q DGYHUVH HYHQW $( LV GHILQHG DV DQ\ XQWRZDUG PHGLFDO RFFXUUHQFH DVVRFLDWHG ZLWK WKH XVH RI
D GUXJ LQ KXPDQV ZKHWKHU RU QRW FRQVLGHUHG GUXJ UHODWHG $Q $( DOVR UHIHUUHG WR DV DQ DGYHUVH
H[SHULHQFH FDQ EH DQ\ XQIDYRUDEOH DQG XQLQWHQGHG VLJQ HJ DQ DEQRUPDO ODERUDWRU\ ILQGLQJ
V\PSWRP RU GLVHDVH WHPSRUDOO\ DVVRFLDWHG ZLWK WKH XVH RI D GUXJ DQG GRHV QRW LPSO\ DQ\
MXGJPHQW DERXW FDXVDOLW\ $Q DGYHUVH HYHQW FDQ DULVH ZLWK DQ\ XVH RI WKH GUXJ HJ RIIODEHO
XVH XVH LQ FRPELQDWLRQ ZLWK DQRWKHU GUXJ DQG ZLWK DQ\ URXWH RI DGPLQLVWUDWLRQ IRUPXODWLRQ RU
GRVH LQFOXGLQJ DQ RYHUGRVH
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
 6XVSHFWHG $GYHUVH 5HDFWLRQ  &)5 D
6XVSHFWHG DGYHUVH UHDFWLRQ PHDQV DQ\ DGYHUVH HYHQW IRU ZKLFK WKHUH LV D UHDVRQDEOH SRVVLELOLW\
WKDW WKH GUXJ FDXVHG WKH DGYHUVH HYHQW )RU WKH SXUSRVHV RI ,1' VDIHW\ UHSRUWLQJ µUHDVRQDEOH
SRVVLELOLW\¶ PHDQV WKHUH LV HYLGHQFH WR VXJJHVW D FDXVDO UHODWLRQVKLS EHWZHHQ WKH GUXJ DQG WKH
DGYHUVH HYHQW $ VXVSHFWHG DGYHUVH UHDFWLRQ LPSOLHV D OHVVHU GHJUHH RI FHUWDLQW\ DERXW FDXVDOLW\
WKDQ DGYHUVH UHDFWLRQ ZKLFK PHDQV DQ\ DGYHUVH HYHQW FDXVHG E\ D GUXJ
 8QH[SHFWHG  &)5 D
$Q DGYHUVH HYHQW RU VXVSHFWHG DGYHUVH UHDFWLRQ LV FRQVLGHUHG ³XQH[SHFWHG´ LI LW LV QRW OLVWHG LQ
WKH LQYHVWLJDWRU EURFKXUH RU LV QRW OLVWHG DW WKH VSHFLILFLW\ RU VHYHULW\ WKDW KDV EHHQ REVHUYHG RU
LI DQ LQYHVWLJDWRU EURFKXUH LV QRW UHTXLUHG RU DYDLODEOH LV QRW FRQVLVWHQW ZLWK WKH ULVN LQIRUPDWLRQ
GHVFULEHG LQ WKH JHQHUDO LQYHVWLJDWLRQDO SODQ RU HOVHZKHUH LQ WKH FXUUHQW DSSOLFDWLRQ DV DPHQGHG
)RU H[DPSOH XQGHU WKLV GHILQLWLRQ KHSDWLF QHFURVLV ZRXOG EH XQH[SHFWHG E\ YLUWXH RI JUHDWHU
VHYHULW\ LI WKH LQYHVWLJDWRU EURFKXUH UHIHUUHG RQO\ WR HOHYDWHG KHSDWLF HQ]\PHV RU KHSDWLWLV
6LPLODUO\ FHUHEUDO WKURPERHPEROLVP DQG FHUHEUDO YDVFXOLWLV ZRXOG EH XQH[SHFWHG E\ YLUWXH RI
JUHDWHU VSHFLILFLW\ LI WKH LQYHVWLJDWRU EURFKXUH OLVWHG RQO\ FHUHEUDO YDVFXODU DFFLGHQWV
8QH[SHFWHG DV XVHG LQ WKLV GHILQLWLRQ DOVR UHIHUV WR DGYHUVH HYHQWV RU VXVSHFWHG DGYHUVH
UHDFWLRQV WKDW DUH PHQWLRQHG LQ WKH LQYHVWLJDWRU EURFKXUH DV RFFXUULQJ ZLWK D FODVV RI GUXJV RU DV
DQWLFLSDWHG IURP WKH SKDUPDFRORJLFDO SURSHUWLHV RI WKH GUXJ EXW DUH QRW VSHFLILFDOO\ PHQWLRQHG DV
RFFXUULQJ ZLWK WKH SDUWLFXODU GUXJ XQGHU LQYHVWLJDWLRQ
 6HULRXV $GYHUVH (YHQW  &)5 D
$Q DGYHUVH HYHQW RU VXVSHFWHG DGYHUVH UHDFWLRQ LV FRQVLGHUHG ³VHULRXV´ LI LQ WKH YLHZ RI HLWKHU
WKH LQYHVWLJDWRU RU VSRQVRU LW UHVXOWV LQ DQ\ RI WKH IROORZLQJ RXWFRPHV
x
'HDWK
x
D OLIHWKUHDWHQLQJ DGYHUVH HYHQW
x
LQSDWLHQW KRVSLWDOL]DWLRQ RU SURORQJDWLRQ RI H[LVWLQJ KRVSLWDOL]DWLRQ
x
D SHUVLVWHQW RU VLJQLILFDQW LQFDSDFLW\ RU VXEVWDQWLDO GLVUXSWLRQ RI WKH DELOLW\ WR FRQGXFW
QRUPDO OLIH IXQFWLRQV RU
x
D FRQJHQLWDO DQRPDO\ ELUWK GHIHFW
,PSRUWDQW PHGLFDO HYHQWV WKDW PD\ QRW UHVXOW LQ GHDWK EH OLIHWKUHDWHQLQJ RU UHTXLUH
KRVSLWDOL]DWLRQ PD\ EH FRQVLGHUHG VHULRXV ZKHQ EDVHG XSRQ DSSURSULDWH PHGLFDO MXGJPHQW WKH\
PD\ MHRSDUGL]H WKH SDWLHQW RU VXEMHFW DQG PD\ UHTXLUH PHGLFDO RU VXUJLFDO LQWHUYHQWLRQ WR SUHYHQW
RQH RI WKH RXWFRPHV OLVWHG LQ WKLV GHILQLWLRQ ([DPSOHV RI VXFK PHGLFDO HYHQWV LQFOXGH DOOHUJLF
EURQFKRVSDVP UHTXLULQJ LQWHQVLYH WUHDWPHQW LQ DQ HPHUJHQF\ URRP RU DW KRPH EORRG G\VFUDVLDV
RU FRQYXOVLRQV WKDW GR QRW UHVXOW LQ LQSDWLHQW KRVSLWDOL]DWLRQ RU WKH GHYHORSPHQW RI GUXJ
GHSHQGHQF\ RU GUXJ DEXVH
 $GYHUVH (YHQWV 5HSRUWLQJ
$GYHUVH (YHQW 7HUP
$GYHUVH HYHQWV PXVW EH UHSRUWHG XVLQJ VWDQGDUG PHGLFDO WHUPLQRORJ\ 7KH XVH RI DEEUHYLDWLRQV
VWDQGDUG DQG QRQVWDQGDUG VKRXOG EH DYRLGHG WR KHOS HQVXUH D FOHDU XQGHUVWDQGLQJ RI WKH HYHQW
$Q H[DPSOH RI D VWDQGDUG DEEUHYLDWLRQ WKDW PD\ KDYH VHYHUDO PHDQLQJV LV ³0,´ ZKLFK FRXOG
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
PHDQ ³P\RFDUGLDO LQIDUFWLRQ´ RU ³PLWUDO LQVXIILFLHQF\´ $OO $( WHUPV ZLOO EH FRGHG XVLQJ D
VWDQGDUGL]HG GLFWLRQDU\ LH 0HGLFDO 'LFWLRQDU\ IRU 5HJXODWRU\ $FWLYLWLHV >0HG'5$@
x
*HQHUDOO\ ZKHQ UHSRUWLQJ D ZHOONQRZQ DQG XQGHUVWRRG FRQGLWLRQ LW LV SUHIHUDEOH WR
UHSRUW WKH RYHUDOO GLDJQRVLV UDWKHU WKDW WKH LQGLYLGXDO VLJQV DQG V\PSWRPV WKH H[FHSWLRQ
WR WKLV UXOH LQ WKLV VWXG\ LV ZKHQ WKH VXEMHFW H[SHULHQFHV DQ LQMHFWLRQ VLWH UHDFWLRQ
x
7KH WHUP ³LQWHUPLWWHQW´ VKRXOG EH DYRLGHG DV WKH GXUDWLRQ DQG LQFLGHQFH RI HYHQWV KHOSV
LQ XQGHUVWDQGLQJ WKH VDIHW\ SURILOH RI WKH VWXG\ GUXJ
$GYHUVH (YHQW 6HYHULW\
$GYHUVH HYHQWV ZLOO EH UHSRUWHG DW WKH KLJKHVW H[SHULHQFHG $GYHUVH HYHQWV VHYHULW\ ZLOO EH
JUDGHG DFFRUGLQJ WR WKH FULWHULD GHVFULEHG LQ 7DEOH 
7DEOH  6HYHULW\ *UDGLQJ *XLGHOLQH IRU $GYHUVH (YHQWV
*UDGH
'HVFULSWLRQ

0LOG
$V\PSWRPDWLF RU PLOG V\PSWRPV
&OLQLFDO RU GLDJQRVWLF REVHUYDWLRQV RQO\
,QWHUYHQWLRQ QRW LQGLFDWHG

0RGHUDWH
0LQLPDO ORFDO RU QRQLQYDVLYH LQWHUYHQWLRQ LQGLFDWHG
/LPLWLQJ DJHDSSURSULDWH LQVWUXPHQWDO $'/

6HYHUH RU PHGLFDOO\ VLJQLILFDQW
+RVSLWDOL]DWLRQ RU SURORQJDWLRQ RI KRVSLWDOL]DWLRQ LQGLFDWHG
'LVDEOLQJ
/LPLWLQJ VHOIFDUH $'/
$GDSWHG IURP 1&,&7&$( 9
1RWH $ 6HPLFRORQ LQGLFDWHV µRU¶ ZLWKLQ WKH GHVFULSWLRQ RI WKH JUDGH
,QVWUXPHQWDO $'/ UHIHU WR SUHSDULQJ PHDOV VKRSSLQJ IRU JURFHULHV RU FORWKHV XVLQJ WKH WHOHSKRQH PDQDJLQJ
PRQH\ HWF
6HOIFDUH $'/ UHIHU WR EDWKLQJ GUHVVLQJ DQG XQGUHVVLQJ IHHGLQJ VHOI XVLQJ WKH WRLOHW WDNLQJ PHGLFDWLRQV DQG
QRW EHGULGGHQ
$GYHUVH (YHQW 'XUDWLRQ
7KH VWDUW GDWH WKH GDWH WKDW WKH HYHQW ZDV ILUVW QRWLFHG DQG WKH HQG GDWH WKH GDWH WKDW WKH HYHQW
KDG FRPSOHWHO\ UHVROYHG RU UHWXUQHG WR EDVHOLQH ZLOO EH UHFRUGHG ,I WKH H[DFW GDWH LV QRW NQRZQ
WKH EHVW HVWLPDWH VKRXOG EH UHSRUWHG
$OO 6$5V ZLOO EH IROORZHG XQWLO VWDELOL]DWLRQ RU UHVROXWLRQ
$GYHUVH (YHQW &DXVDOLW\
:KHUH WKH ,QYHVWLJDWRU DVVHVVPHQW RI WKH UHODWLRQVKLS RI WKH $( WR LQYHVWLJDWLRQDO SURGXFW UHVWV
RQ PHGLFDO MXGJPHQW WKH GHWHUPLQDWLRQ PXVW EH PDGH ZLWK WKH DSSURSULDWH LQYROYHPHQW RI WKH
,QYHVWLJDWRU RU LI WKH ,QYHVWLJDWRU LV QRW D SK\VLFLDQ D GHVLJQDWHG VXE,QYHVWLJDWRU ZKR LV D
SK\VLFLDQ $VVHVVPHQW RI FDXVDOLW\ VKRXOG EH SHUIRUPHG LQ DFFRUGDQFH ZLWK WKH GHILQLWLRQ RI
6$5 LQ 6HFWLRQ 
8VLQJ WKH IROORZLQJ FULWHULD ,QYHVWLJDWRUV ZLOO DVVHVV ZKHWKHU WKHUH LV D UHDVRQDEOH SRVVLELOLW\
WKDW WKH VWXG\ WUHDWPHQW GUXJ RU SURFHGXUH FDXVHG RU FRQWULEXWHG WR WKH $(
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
5HODWHG
7KHUH LV D UHDVRQDEOH SRVVLELOLW\ WR VXJJHVW D FDXVDO UHODWLRQVKLS EHWZHHQ WKH VWXG\ WUHDWPHQW
DQG WKH DGYHUVH HYHQW EDVHG RQ HYLGHQFH
x
7KH ,QYHVWLJDWRU VKRXOG XVH WKH IROORZLQJ FULWHULD ZKHQ DVVHVVLQJ FDXVDOLW\
x
,V WKH $( D NQRZQ VLGH HIIHFW DGYHUVH UHDFWLRQ WR WKH VWXG\ WUHDWPHQW RU RWKHU WKHUDSLHV
LQ WKLV WUHDWPHQW FODVV"
x
,V WKHUH D UHDVRQDEOH WHPSRUDO UHODWLRQVKLS EHWZHHQ WKH VWDUW RI WKH $( DQG VWXG\
WUHDWPHQW DGPLQLVWUDWLRQ"
x
'LG WKH $( LPSURYH ZKHQ WKH VWXG\ WUHDWPHQW ZDV VWRSSHG"
x
'LG WKH $( UHFXU ZKHQ WKH VWXG\ WUHDWPHQW ZDV UHVXPHG LI DSSOLFDEOH"
x
&DQ WKH $( EH HDVLO\ DWWULEXWHG WR D FRPRUELG FRQGLWLRQ RU FRQFRPLWDQW PHGLFDWLRQ
WUHDWPHQW"
1RW 5HODWHG
7KHUH LV 127 D UHDVRQDEOH SRVVLELOLW\ WR VXJJHVW D FDXVDO UHODWLRQVKLS EHWZHHQ WKH VWXG\
WUHDWPHQW DQG WKH DGYHUVH HYHQW EDVHG RQ HYLGHQFH
$GYHUVH (YHQW 6HULRXVQHVV
3OHDVH UHSRUW 6$( FULWHULD XVLQJ WKH IROORZLQJ JXLGHOLQHV
'HDWK
5HSRUW LI \RX VXVSHFW WKDW WKH GHDWK ZDV DQ RXWFRPH RI WKH DGYHUVH HYHQW DQG LQFOXGH WKH GDWH LI
NQRZQ
/LIHWKUHDWHQLQJ
5HSRUW LI VXVSHFWHG WKDW WKH SDWLHQW ZDV DW VXEVWDQWLDO ULVN RI G\LQJ DW WKH WLPH RI WKH DGYHUVH
HYHQW RU XVH RU FRQWLQXHG XVH RI WKH GHYLFH RU RWKHU PHGLFDO SURGXFW PLJKW KDYH UHVXOWHG LQ WKH
GHDWK RI WKH SDWLHQW
+RVSLWDOL]DWLRQ LQLWLDO RU SURORQJHG
5HSRUW LI DGPLVVLRQ WR WKH KRVSLWDO RU SURORQJDWLRQ RI KRVSLWDOL]DWLRQ ZDV D UHVXOW RI WKH DGYHUVH
HYHQW (PHUJHQF\ URRP YLVLWV WKDW GR QRW UHVXOW LQ DGPLVVLRQ WR WKH KRVSLWDO VKRXOG EH HYDOXDWHG
IRU RQH RI WKH RWKHU VHULRXV RXWFRPHV HJ OLIHWKUHDWHQLQJ UHTXLUHG LQWHUYHQWLRQ WR SUHYHQW
SHUPDQHQW LPSDLUPHQW RU GDPDJH RWKHU VHULRXV PHGLFDOO\ LPSRUWDQW HYHQW
'LVDELOLW\ RU 3HUPDQHQW 'DPDJH
5HSRUW LI WKH DGYHUVH HYHQW UHVXOWHG LQ D VXEVWDQWLDO GLVUXSWLRQ RI D SHUVRQ
V DELOLW\ WR FRQGXFW
QRUPDO OLIH IXQFWLRQV LH WKH DGYHUVH HYHQW UHVXOWHG LQ D VLJQLILFDQW SHUVLVWHQW RU SHUPDQHQW
FKDQJH LPSDLUPHQW GDPDJH RU GLVUXSWLRQ LQ WKH SDWLHQW
V ERG\ IXQFWLRQVWUXFWXUH SK\VLFDO
DFWLYLWLHV DQGRU TXDOLW\ RI OLIH
&RQJHQLWDO $QRPDO\%LUWK 'HIHFW
5HSRUW LI \RX VXVSHFW WKDW H[SRVXUH WR D PHGLFDO SURGXFW SULRU WR FRQFHSWLRQ RU GXULQJ SUHJQDQF\
PD\ KDYH UHVXOWHG LQ DQ DGYHUVH RXWFRPH LQ WKH FKLOG
2WKHU 6HULRXV ,PSRUWDQW 0HGLFDO (YHQWV
5HSRUW ZKHQ WKH HYHQW GRHV QRW ILW WKH RWKHU RXWFRPHV EXW WKH HYHQW PD\ MHRSDUGL]H WKH SDWLHQW
DQG PD\ UHTXLUH PHGLFDO RU VXUJLFDO LQWHUYHQWLRQ WUHDWPHQW WR SUHYHQW RQH RI WKH RWKHU
RXWFRPHV ([DPSOHV LQFOXGH DOOHUJLF EURFKRVSDVP D VHULRXV SUREOHP ZLWK EUHDWKLQJ UHTXLULQJ
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
$GGLWLRQDO LQYHVWLJDWLRQDO VLWH WUDLQLQJ ZLOO EH SURYLGHG DV QHHGHG
 $'0,1,675$7,9(

3URWRFRO $SSURYDO DQG $PHQGPHQW
7KH 7UHIRLO RU GHVLJQHH ZLOO VXEPLW DOO SURWRFROV DQG SURWRFRO DPHQGPHQWV WR WKH )'$ DQG
UHOHYDQW UHJXODWRU\ DXWKRULWLHV DV DSSOLFDEOH 7KH ,QYHVWLJDWRU ZLOO HQVXUH ORFDO ,5%,(& UHYLHZ
DQG DSSURYDO RI WKH SURWRFRO DQG SURWRFRO DPHQGPHQWV SULRU WR LPSOHPHQWDWLRQ DW KLVKHU
LQYHVWLJDWLRQDO VLWH
,I DQ DPHQGPHQW VXEVWDQWLDOO\ DOWHUV WKH VWXG\ GHVLJQ RU LQFUHDVHV WKH SRWHQWLDO ULVN WR WKH
VXEMHFW
x
7KH FRQVHQW IRUP PXVW EH UHYLVHG DQG VXEPLWWHG WR WKH ,5%,(& IRU UHYLHZ DQG DSSURYDO
IDYRUDEOH RSLQLRQ
x
7KH UHYLVHG IRUP PXVW EH XVHG WR REWDLQ FRQVHQW IURP VXEMHFWV FXUUHQWO\ HQUROOHG LQ WKH
VWXG\ LI WKH\ DUH DIIHFWHG E\ WKH DPHQGPHQW
x
7KH QHZ IRUP PXVW EH XVHG WR REWDLQ FRQVHQW IURP QHZ VXEMHFWV SULRU WR HQUROOPHQW
,I WKH UHYLVLRQ LV DQ DGPLQLVWUDWLYH OHWWHU ,QYHVWLJDWRUV PXVW LQIRUP WKHLU ,5%,(&

3UHPDWXUH 7HUPLQDWLRQ RI WKH 6WXG\
7KH VWXG\ PD\ EH SUHPDWXUHO\ WHUPLQDWHG LI WKH 7UHIRLO EHFRPHV DZDUH RI FRQGLWLRQV RU HYHQWV
WKDW VXJJHVW D SRVVLEOH KD]DUG WR VXEMHFWV RU DW WKH GLVFUHWLRQ RI 7UHIRLO 5HDVRQV IRU SUHPDWXUH
VWXG\ WHUPLQDWLRQ PD\ LQFOXGH EXW DUH QRW OLPLWHG WR
x
$Q XQDFFHSWDEOH ULVN WR WKH VXEMHFWV
x
)DLOXUH WR HQUROO VXEMHFWV DW DQ DFFHSWDEOH UDWH RU
x
7KH VWXG\ REMHFWLYHV KDYH EHHQ PHW
,I WKH VWXG\ LV SUHPDWXUHO\ WHUPLQDWHG 7UHIRLO ZLOO SURYLGH LQVWUXFWLRQV UHJDUGLQJ D ZLQGGRZQ
SODQ WKDW ZLOO LQFOXGH D QRWLILFDWLRQ WR VXEMHFWV ,5%,(& DQG UHOHYDQW UHJXODWRU\ DJHQFLHV DV
ZHOO DV D SURFHVV IRU WKH FRQWLQXDWLRQ DQGRU GLVFRQWLQXDWLRQ RI VWXG\ WUHDWPHQW DQG VDIHW\
IROORZXS IRU DOO DFWLYH VXEMHFWV 6XEMHFWV ZKR PD\ KDYH DOUHDG\ FRPSOHWHG WKH VWXG\ PD\ EH
FRQWDFWHG LI DSSOLFDEOH IRU DGGLWLRQDO VDIHW\ DVVHVVPHQWV

&RQILGHQWLDOLW\
$OO UHFRUGV LGHQWLI\LQJ WKH VXEMHFW ZLOO EH NHSW DV FRQILGHQWLDO DV SRVVLEOH ZLWKLQ WKH ODZ
6XEMHFW QDPHV DQG RWKHU SHUVRQDOO\ LGHQWLILDEOH LQIRUPDWLRQ 3,, ZLOO QRW EH VXSSOLHG WR WKH
VSRQVRU 'DWD DQGRU VDPSOHV FROOHFWHG IURP VXEMHFWV ZLOO EH LGHQWLILHG RQO\ E\ D XQLTXH 6XEMHFW
,' 1XPEHU ,I WKH VXEMHFW¶V QDPH DSSHDUV RQ DQ\ RWKHU PDWHULDO FROOHFWHG HJ SDWKRORJLVW
UHSRUW RU RWKHU VWXG\ PDWHULDOV HJ ELRSV\ WLVVXH VOLGHV DOO 3,, PXVW EH UHGDFWHG EHIRUH EHLQJ
VXSSOLHG WR WKH 7UHIRLO RU GHVLJQHH 6WXG\ GDWD VWRUHG RQ D FRPSXWHU ZLOO EH VWRUHG LQ
DFFRUGDQFH ZLWK ORFDO GDWD SURWHFWLRQ ODZV DQG UHJXODWLRQV 6XEMHFWV ZLOO EH LQIRUPHG LQ ZULWLQJ
WKDW UHSUHVHQWDWLYHV RI WKH 7UHIRLO ,5%,(& RU UHJXODWRU\ DXWKRULWLHV PD\ LQVSHFW WKHLU PHGLFDO
UHFRUGV WR YHULI\ WKH LQIRUPDWLRQ FROOHFWHG $OO SHUVRQDO LQIRUPDWLRQ PDGH DYDLODEOH IRU
LQVSHFWLRQ ZLOO EH KDQGOHG LQ VWULFWHVW FRQILGHQFH DQG LQ DFFRUGDQFH ZLWK ORFDO GDWD SURWHFWLRQ
ODZV DQG UHJXODWLRQV 7KH ,QYHVWLJDWRU ZLOO PDLQWDLQ D OLVW WR HQDEOH VXEMHFWV¶ UHFRUGV WR EH
LGHQWLILHG LQ DFFRUGDQFH ZLWK DSSOLFDEOH ODZV DQG UHJXODWLRQV
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
,I WKH UHVXOWV RI WKH VWXG\ DUH SXEOLVKHG WKH VXEMHFW¶V LGHQWLW\ ZLOO UHPDLQ FRQILGHQWLDO
 '$7$ +$1'/,1* $1' 5(&25' .((3,1*

&DVH 5HSRUW )RUPV DQG 6RXUFH 'RFXPHQWDWLRQ
3HU  &)5 E ,QYHVWLJDWRUV VKDOO UHWDLQ UHTXLUHG WR SUHSDUH DQG PDLQWDLQ DGHTXDWH DQG
DFFXUDWH FDVH KLVWRULHV WKDW UHFRUG DOO REVHUYDWLRQV DQG RWKHU GDWD SHUWLQHQW WR WKH LQYHVWLJDWLRQ RQ
HDFK LQGLYLGXDO DGPLQLVWHUHG WKH LQYHVWLJDWLRQDO GUXJ RU HPSOR\HG DV D FRQWURO LQ WKH
LQYHVWLJDWLRQ &DVH KLVWRULHV LQFOXGH WKH FDVH UHSRUW IRUPV DQG VXSSRUWLQJ GDWD LQFOXGLQJ IRU
H[DPSOH VLJQHG DQG GDWHG FRQVHQW IRUPV DQG PHGLFDO UHFRUGV LQFOXGLQJ IRU H[DPSOH SURJUHVV
QRWHV RI WKH SK\VLFLDQ WKH LQGLYLGXDO
V KRVSLWDO FKDUWV DQG WKH QXUVH¶V QRWHV 7KH FDVH KLVWRU\
IRU HDFK LQGLYLGXDO VKDOO GRFXPHQW WKDW LQIRUPHG FRQVHQW ZDV REWDLQHG SULRU WR SDUWLFLSDWLRQ LQ
WKH VWXG\ 6RXUFH GRFXPHQWV PD\ EH LQ WKH ORFDO QDWLYH ODQJXDJH EXW DOO GDWD UHSRUWHG LQ WKH GDWD
FROOHFWLRQV IRUPV ZLOO EH LQ (QJOLVK
'DWD &ROOHFWLRQ
&5)V VKRXOG EH FRPSOHWHG IRU HDFK VXEMHFW LQFOXGHG LQ WKH VWXG\ DQG VKRXOG UHIOHFW WKH ODWHVW
REVHUYDWLRQV RQ WKH VXEMHFWV SDUWLFLSDWLQJ LQ WKH VWXG\ DQG VKRXOG EH FRPSOHWHG DV VRRQ DV
SRVVLEOH GXULQJ RU DIWHU WKH DVVHVVPHQW 7KH ,QYHVWLJDWRU PXVW FRQILUP WKDW DOO GDWD HQWULHV LQ WKH
&5) DUH DFFXUDWH DQG FRUUHFW
'DWD DERXW DOO VWXG\ GUXJ GLVSHQVHG RU DGPLQLVWHUHG WR WKH VXEMHFW DQG DQ\ GRVDJH FKDQJHV ZLOO
EH UHFRUGHG

$FFHVV WR 6RXUFH 'DWD
3HU  &)5  WKH ,QYHVWLJDWRU VKDOO XSRQ UHTXHVW IURP DQ\ SURSHUO\ DXWKRUL]HG RIILFHU RU
HPSOR\HH RI )'$ DW UHDVRQDEOH WLPHV SHUPLW VXFK RIILFHU RU HPSOR\HH WR KDYH DFFHVV WR DQG
FRS\ DQG YHULI\ DQ\ UHFRUGV RU UHSRUWV PDGH E\ WKH LQYHVWLJDWRU SXUVXDQW WR  &)5  7KH
,QYHVWLJDWRU PXVW QRWLI\ WKH 7UHIRLO RU GHVLJQHH SURPSWO\ RI DQ\ LQVSHFWLRQV E\ UHJXODWRU\
DXWKRULWLHV DV VRRQ DV SRVVLEOH DQG IRUZDUG SURPSWO\ FRSLHV RI LQVSHFWLRQ UHSRUWV
$FFHVV WR VRXUFH GDWD H[WHQGV WR WKH 6SRQVRU RU GHVLJQHH ZKR ZLOO UHYLHZ VWXG\ UHFRUGV DQG
GLUHFWO\ FRPSDUH WKHP ZLWK VRXUFH GRFXPHQWV GLVFXVV WKH FRQGXFW RI WKH VWXG\ ZLWK WKH
,QYHVWLJDWRU DQG YHULI\ WKDW WKH IDFLOLWLHV UHPDLQ DFFHSWDEOH

'DWD 3URFHVVLQJ
$OO GDWD ZLOO EH HQWHUHG LQWR WKH GDWD FROOHFWLRQ IRUPV E\ WKH LQYHVWLJDWLRQDO VLWH VWDII 2QJRLQJ
GDWD UHYLHZ ZLOO EH SHUIRUPHG GXULQJ WKH FRQGXFW RI WKH VWXG\ LQFOXGLQJ FKHFNV IRU FRQVLVWHQF\
DQG ORJLF RI GDWD 4XHULHV DQG UHTXHVWV IRU FODULILFDWLRQ ZLOO EH JHQHUDWHG E\ WKH 6SRQVRU RU
GHVLJQHH DQG WUDQVPLWWHG WR WKH LQYHVWLJDWLRQDO VLWH VWDII 7KH FROOHFWLRQV IRUPV DQGRU GDWDEDVH
ZLOO EH XSGDWHG DV QHHGHG ZKLOH PDLQWDLQLQJ D FOHDU DXGLW WUDLO
$GYHUVH HYHQWV ZLOO EH FRGHG XVLQJ WKH 0HGLFDO 'LFWLRQDU\ IRU 5HJXODWRU\ $FWLYLWLHV
0HG'5$ 7KH YHUVLRQV RI WKH FRGLQJ GLFWLRQDU\ ZLOO EH SURYLGHG LQ WKH &OLQLFDO 6WXG\ 5HSRUW

$UFKLYLQJ 6WXG\ 5HFRUGV
3HU  &)5 F ,QYHVWLJDWRUV VKDOO UHWDLQ UHFRUGV UHTXLUHG WR EH PDLQWDLQHG XQGHU WKLV SDUW
IRU D SHULRG RI  \HDUV IROORZLQJ WKH GDWH D PDUNHWLQJ DSSOLFDWLRQ LV DSSURYHG IRU WKH GUXJ IRU WKH
LQGLFDWLRQ IRU ZKLFK LW LV EHLQJ LQYHVWLJDWHG RU LI QR DSSOLFDWLRQ LV WR EH ILOHG RU LI WKH
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
DSSOLFDWLRQ LV QRW DSSURYHG IRU VXFK LQGLFDWLRQ XQWLO  \HDUV DIWHU WKH LQYHVWLJDWLRQ LV
GLVFRQWLQXHG DQG )'$ LV QRWLILHG +RZHYHU GRFXPHQWV PD\ EH UHWDLQHG IRU D ORQJHU SHULRG LI
UHTXLUHG E\ WKH DSSOLFDEOH OHJDO UHTXLUHPHQWV
 38%/,&$7,21 32/,&<
%\ VLJQLQJ WKH VWXG\ SURWRFRO VLJQDWXUH SDJH WKH ,QYHVWLJDWRU DJUHHV ZLWK WKH XVH RI UHVXOWV RI
WKH VWXG\ IRU WKH SXUSRVHV RI QDWLRQDO DQG LQWHUQDWLRQDO UHJLVWUDWLRQ SXEOLFDWLRQ DQG LQIRUPDWLRQ
IRU PHGLFDO DQG SKDUPDFHXWLFDO SURIHVVLRQDOV ,I QHFHVVDU\ 5HJXODWRU\ $XWKRULWLHV ZLOO EH
QRWLILHG RI WKH ,QYHVWLJDWRU
V QDPH DGGUHVV TXDOLILFDWLRQV DQG H[WHQW RI LQYROYHPHQW
$Q ,QYHVWLJDWRU VKDOO QRW SXEOLVK DQ\ GDWD SRVWHU DEVWUDFW SDSHU HWF ZLWKRXW GLVFXVVLRQ ZLWK
DQG DSSURYDO E\ 7UHIRLO
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
5()(5(1&(6

.OLQWZRUWK *. &RUQHDO G\VWURSKLHV 2USKDQHW - 5DUH 'LV 

/L -< 0DQQLV 0- (\H EDQNLQJ DQG WKH FKDQJLQJ WUHQGV LQ FRQWHPSRUDU\ FRUQHDO VXUJHU\ ,QW
2SKWKDOPRO &OLQ 

6FKPHGW 7 6LOYD 00 =LDHL $ -XUNXQDV 8 0ROHFXODU EDVHV RI FRUQHDO HQGRWKHOLDO G\VWURSKLHV ([S
(\H 5HV 

0XVFK '& HW DO 3UHYDOHQFH RI FRUQHDO G\VWURSKLHV LQ WKH 8QLWHG 6WDWHV HVWLPDWHV IURP FODLPV GDWD
,QYHVW 2SKWKDOPRO 9LV 6FL 

$QVKX $ HW DO (QGRWKHOLDO NHUDWRSODVW\ D UHYROXWLRQ LQ HYROXWLRQ 6XUY 2SKWKDOPRO 


3ULFH 02 3ULFH ): -U 'HVFHPHW
V PHPEUDQH HQGRWKHOLDO NHUDWRSODVW\ VXUJHU\ XSGDWH RQ WKH
HYLGHQFH DQG KXUGOHV WR DFFHSWDQFH &XUU 2SLQ 2SKWKDOPRO 

3DWHO 69 *UDIW VXUYLYDO DQG HQGRWKHOLDO RXWFRPHV LQ WKH QHZ HUD RI HQGRWKHOLDO NHUDWRSODVW\ ([S (\H
5HV 

:LOOLDPV .$ /RZH 07 .HDQH 0& -RQHV 9- /RK 56 &RVWHU '- 7KH $XVWUDOLDQ &RUQHDO *UDIW
5HJLVWU\  5HSRUW  >FLWHG  0DUFK  @ $YDLODEOH IURP
KWWSGVSDFHIOLQGHUVHGXDX[POXLELWVWUHDPKDQGOH'VSDFH YHUVLRQ  5(3257
&203/(7(SGI"VHTXHQFH 

+H = HW DO 5HYLVLWHG PLFURDQDWRP\ RI WKH FRUQHDO HQGRWKHOLDO SHULSKHU\ QHZ HYLGHQFH IRU FRQWLQXRXV
FHQWULSHWDO PLJUDWLRQ RI HQGRWKHOLDO FHOOV LQ KXPDQV 6WHP &HOOV 

0LPXUD 7 HW DO &RPSDULVRQ RI UDEELW FRUQHDO HQGRWKHOLDO FHOO SUHFXUVRUV LQ WKH FHQWUDO DQG SHULSKHUDO
FRUQHD ,QYHVW 2SKWKDOPRO 9LV 6FL 

<DPDJDPL 6 HW DO 'LVWULEXWLRQ RI SUHFXUVRUV LQ KXPDQ FRUQHDO VWURPDO FHOOV DQG HQGRWKHOLDO FHOOV
2SKWKDOPRORJ\ 

<X :< HW DO 3URJHQLWRUV IRU WKH FRUQHDO HQGRWKHOLXP DQG WUDEHFXODU PHVKZRUN D SRWHQWLDO VRXUFH IRU
SHUVRQDOL]HG VWHP FHOO WKHUDS\ LQ FRUQHDO HQGRWKHOLDO GLVHDVHV DQG JODXFRPD - %LRPHG %LRWHFKQRO


:KLNHKDUW '5 HW DO (YLGHQFH VXJJHVWLQJ WKH H[LVWHQFH RI VWHP FHOOV IRU WKH KXPDQ FRUQHDO
HQGRWKHOLXP 0RO 9LV 

0F*RZDQ 6/ HW DO 6WHP FHOO PDUNHUV LQ WKH KXPDQ SRVWHULRU OLPEXV DQG FRUQHDO HQGRWKHOLXP RI
XQZRXQGHG DQG ZRXQGHG FRUQHDV 0RO 9LV 

-R\FH 1& 3UROLIHUDWLYH FDSDFLW\ RI FRUQHDO HQGRWKHOLDO FHOOV ([S (\H 5HV 

0DQJLRQH &0 /HH 33 *XWLHUUH] 35 6SULW]HU . %HUU\ 6 DQG +D\V 5' 'HYHORSPHQW RI WKH 
LWHP 1DWLRQDO (\H ,QVWLWXWH 9LVXDO )XQFWLRQ 4XHVWLRQQDLUH 9)4 $UFKLYHV RI 2SKWKDOPRORJ\
 

6\DP 33 0DYULNDNLV , /LX & ,PSRUWDQFH RI HDUO\ PRUQLQJ LQWUDRFXODU SUHVVXUH UHFRUGLQJ IRU
PHDVXUHPHQW RI GLXUQDO YDULDWLRQ RI LQWUDRFXODU SUHVVXUH %ULWLVK -RXUQDO RI
2SKWKDOPRORJ\ 

:LOHQVN\ -7 'LXUQDO YDULDWLRQV LQ LQWUDRFXODU SUHVVXUH 7UDQV $P 2SKWKDOPRO 6RF ±


:DONHU 30 /DQH .- 2XVOHU UG *: $EHOVRQ 0% 'LXUQDO YDULDWLRQ RI YLVXDO IXQFWLRQ DQG WKH
VLJQV DQG V\PSWRPV RI GU\ H\H &RUQHD H

5HDG 6 	 &ROOLQV 0 'LXUQDO 9DULDWLRQ RI &RUQHDO 6KDSH DQG 7KLFNQHVV 2SWRPHWU\ DQG YLVLRQ
VFLHQFH  RIILFLDO SXEOLFDWLRQ RI WKH $PHULFDQ $FDGHP\ RI 2SWRPHWU\  
23;EHEH

)ULW] HW DO 'LXUQDO 9DULDWLRQ LQ &RUQHDO (GHPD LQ )XFKV (QGRWKHOLDO &RUQHDO '\VWURSK\ $P -
2SKWKDOPRO  1RY GRL MDMR
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
$SSHQGL[ $ 6FKHGXOH RI (YHQWV
6XE6WXG\
6WXG\ 77+;
6FUHHQ
6WXG\ 'D\
9LVLW


 
 
 
 
 
  


3UH
,QIRUPHG FRQVHQW
;
;
'HPRJUDSKLFV
;
;
0HGLFDO DQG RFXODU KLVWRU\
;
;
&RPSUHKHQVLYH RFXODU H[DPLQDWLRQ
LQFOXGLQJ VOLW ODPS H[DPLQDWLRQ DQG GLODWHG H[DP RI WKH OHQV
IXQGXV DQG YLWUHRXV
28
6(I
28
8ULQH SUHJQDQF\ WHVW :2&%3
;
;
/DERUDWRU\ WHVWLQJ &KHP +HPH 8$ 	 +E$F
;
;
;
1(,9)4D
;
;
2SWLRQDO EORRG VDPSOH IRU JHQHWLF WHVWLQJ
;
$'$ DVVD\
;
;
3UHLQMHFWLRQ
;
;
3. VDPSOLQJ
;
3UHLQMHFWLRQ
;
;
 KRXUV DIWHU LQMHFWLRQ
;
;
6WXG\ 7UHDWPHQW ,& ,QMHFWLRQ 6(
;
;
;
;
5HFRUG &RQFRPLWDQW 0HGLFDWLRQV
;
;
;
;
;
;
;
;
;
;
;
;
5HFRUG $GYHUVH (YHQWV
;
;
;
;
;
;
;
;
2FXODU $VVHVVPHQWV
6SHFXODU PLFURVFRS\E
LQFOXGLQJ DXWRPDWHG SDFK\PHWU\
28F G
28
28
28
28
28
28
28
28
28
3HQWDFDP H[DPLQDWLRQ
28
28
%HVW FRUUHFWHG YLVXDO DFXLW\E
28F G
28
6(
6(
6(
6(
6(
6(
6(
6OLW ODPS ELRPLFURVFRS\
28F G
6(
6(
6(
6(
6(
6(
,QWUDRFXODU 3UHVVXUH ,23 PHDVXUHPHQW
28F G
6( H
6( H
6( H
6( H
6( H
6(
6(
6(
28 ERWK H\HV 6( 6WXG\ (\H D 3HUIRUP SULRU WR DQ\ RWKHU DVVHVVPHQWV E ,I VXEMHFW LV WR EH GLODWHG SHUIRUP SULRU WR GLODWLRQ F  WLPHSRLQWV  LQ WKH HDUO\ PRUQLQJ DQG  LQ WKH ODWH
DIWHUQRRQ PD\ EH GLIIHUHQW GD\V G 7KH 266 $0 DVVHVVPHQWV FDQ EH XVHG IRU VFUHHQLQJ H ,23 SUHGRVH DQG SRVWGRVH DW OHDVW HYHU\  PLQXWHV XQWLO QRUPDOL]HG GHILQHG DV OHVV
WKDQ  PP+J KLJKHU WKDQ SUHLQMHFWLRQ ,23 I GLODWHG H[DP RQO\ LQ VXEMHFWV ZLWK YLWUHRXV LQ WKH $& DW EDVHOLQH
,QFOXGLQJ DOO RFXODU PHGLFDWLRQV
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
7KLV SDJH LQWHQWLRQDOO\ OHIW EODQN
   

	

	

7UHIRLO 7KHUDSHXWLFV ,QF
&OLQLFDO 6WXG\ 3URWRFRO 77+;
&RQILGHQWLDO DQG 3URSULHWDU\
$PHQGPHQW  6HSWHPEHU  
3DJH  RI 
35272&2/ 6,*1$785( 3$*(
75()2,/ ',6&/2685( 67$7(0(17
7KLV GRFXPHQW FRQWDLQV LQIRUPDWLRQ WKDW LV FRQILGHQWLDO DQG SURSULHWDU\ WR 7UHIRLO 7KHUDSHXWLFV ,QF 7UHIRLO 7KLV
LQIRUPDWLRQ LV EHLQJ SURYLGHG WR \RX VROHO\ IRU WKH SXUSRVH RI HYDOXDWLQJ RU FRQGXFWLQJ D FOLQLFDO VWXG\ IRU 7UHIRLO
<RX PD\ GLVFORVH WKH FRQWHQWV RI WKLV GRFXPHQW RQO\ WR VWXG\ SHUVRQQHO XQGHU \RXU VXSHUYLVLRQ ZKR QHHG WR NQRZ
WKH FRQWHQWV IRU WKLV SXUSRVH DQG WR \RXU ,QVWLWXWLRQDO 5HYLHZ %RDUG ,5% RWKHUZLVH WKH FRQWHQWV RI WKLV GRFXPHQW
PD\ QRW EH GLVFORVHG ZLWKRXW WKH SULRU DXWKRUL]DWLRQ IURP 7UHIRLO 7KH IRUHJRLQJ VKDOO QRW DSSO\ WR GLVFORVXUH
UHTXLUHG E\ JRYHUQPHQWDO UHJXODWLRQV RU ODZV $Q\ VXSSOHPHQWDO LQIRUPDWLRQ WKDW PD\ EH DGGHG WR WKLV GRFXPHQW
DOVR LV FRQILGHQWLDO DQG SURSULHWDU\ WR 7UHIRLO DQG PXVW EH NHSW LQ FRQILGHQFH LQ WKH VDPH PDQQHU DV WKH FRQWHQWV RI
WKLV GRFXPHQW
$OO GRFXPHQWDWLRQ IRU WKLV VWXG\ WKDW LV VXSSOLHG WR PH DQG WKDW KDV QRW EHHQ SUHYLRXVO\ SXEOLVKHG ZLOO EH NHSW LQ WKH
VWULFWHVW FRQILGHQFH 7KLV GRFXPHQWDWLRQ LQFOXGHV WKLV VWXG\ SURWRFRO ,QYHVWLJDWRU
V %URFKXUH HOHFWURQLF GDWD
FDSWXUH V\VWHP DQG RWKHU VFLHQWLILF GDWD , KDYH UHDG DQG XQGHUVWRRG DQG DJUHH WR DELGH E\ DOO WKH FRQGLWLRQV DQG
LQVWUXFWLRQV FRQWDLQHG LQ WKLV SURWRFRO DQG DJUHH WR
x
&RQGXFW WKH VWXG\ LQ DFFRUGDQFH ZLWK WKH UHOHYDQW FXUUHQW SURWRFRO DQG ZLOO RQO\ PDNH FKDQJHV LQ D
SURWRFRO DIWHU QRWLI\LQJ WKH VSRQVRU H[FHSW ZKHQ QHFHVVDU\ WR SURWHFW WKH VDIHW\ ULJKWV RU ZHOIDUH RI
VXEMHFWV
x
3HUVRQDOO\ FRQGXFW RU VXSHUYLVH WKH GHVFULEHG LQYHVWLJDWLRQ
x
3HUVRQDOO\ DGPLQLVWHU DOO VWXG\ WUHDWPHQW LQWUDFDPHUDO LQMHFWLRQV RU RQO\ DOORZ TXDOLILHG LQGLYLGXDOV ZKR
KDYH EHHQ DSSURYHG E\ 7UHIRLO WR DGPLQLVWHU VWXG\ WUHDWPHQW LQWUDFDPHUDO LQMHFWLRQV
x
,QIRUP DQ\ SDWLHQWV RU DQ\ SHUVRQV XVHG DV FRQWUROV WKDW WKH GUXJV DUH EHLQJ XVHG IRU LQYHVWLJDWLRQDO
SXUSRVHV DQG , ZLOO HQVXUH WKDW WKH UHTXLUHPHQWV UHODWLQJ WR REWDLQLQJ LQIRUPHG FRQVHQW LQ  &)5 3DUW 
DQG LQVWLWXWLRQDO UHYLHZ ERDUG ,5% UHYLHZ DQG DSSURYDO LQ  &)5 3DUW  DUH PHW
x
5HSRUW WR WKH VSRQVRU DGYHUVH H[SHULHQFHV WKDW RFFXU LQ WKH FRXUVH RI WKH LQYHVWLJDWLRQV LQ DFFRUGDQFH
ZLWK  &)5  , KDYH UHDG DQG XQGHUVWDQG WKH LQIRUPDWLRQ LQ WKH SURWRFRO DQG LQYHVWLJDWRU¶V
EURFKXUH LQFOXGLQJ WKH SRWHQWLDO ULVNV DQG VLGH HIIHFWV RI WKH GUXJ
x
(QVXUH WKDW DOO DVVRFLDWHV FROOHDJXHV DQG HPSOR\HHV DVVLVWLQJ LQ WKH FRQGXFW RI WKH VWXG\ DUH LQIRUPHG
DERXW WKHLU REOLJDWLRQV LQ PHHWLQJ WKH DERYH FRPPLWPHQWV
x
0DLQWDLQ DGHTXDWH DQG DFFXUDWH UHFRUGV LQ DFFRUGDQFH ZLWK  &)5  DQG WR PDNH WKRVH UHFRUGV
DYDLODEOH IRU LQVSHFWLRQ LQ DFFRUGDQFH ZLWK  &)5 
x
(QVXUH WKDW DQ ,5% WKDW FRPSOLHV ZLWK WKH UHTXLUHPHQWV RI  &)5 3DUW  ZLOO EH UHVSRQVLEOH IRU WKH LQLWLDO
DQG FRQWLQXLQJ UHYLHZ DQG DSSURYDO RI WKH FOLQLFDO LQYHVWLJDWLRQ , DOVR DJUHH WR SURPSWO\ UHSRUW WR WKH ,5%
DOO FKDQJHV LQ WKH UHVHDUFK DFWLYLW\ DQG DOO XQDQWLFLSDWHG SUREOHPV LQYROYLQJ ULVNV WR KXPDQ VXEMHFWV RU
RWKHUV $GGLWLRQDOO\ , ZLOO QRW PDNH DQ\ FKDQJHV LQ WKH UHVHDUFK ZLWKRXW ,5% DSSURYDO H[FHSW ZKHUH
QHFHVVDU\ WR HOLPLQDWH DSSDUHQW LPPHGLDWH KD]DUGV WR KXPDQ VXEMHFWV
x
&RPSO\ ZLWK DOO RWKHU UHTXLUHPHQWV UHJDUGLQJ WKH REOLJDWLRQV RI FOLQLFDO LQYHVWLJDWRUV DQG DOO RWKHU
SHUWLQHQW UHTXLUHPHQWV LQ  &)5 3DUW 
5HVSRQVLEOH ,QYHVWLJDWRU
6LJQDWXUH
'DWH
1DPH 7LWOH 3ULQWHG
   

	

	