- Email: [email protected]
Traitement médical de la fibrose pulmonaire idiopathique : de nouvelles perspectives
5HYXHGHV0DODGLHV5HVSLUDWRLUHV$FWXDOLWpV
'LVSRQLEOH HQ OLJQH VXU
ZZZVFLHQFHGLUHFWFRP
31(8023$7+,(6,17(567,7,(//(6',))86(6
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUH LGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV ,GLRSDWKLFSXOPRQDU\ÀEURVLVPHGLFDOWUHDWPHQW 1HZLQVLJKWV '%RXYU\D 6-RXQHDXE D$VVLVWDQFHSXEOLTXH+{SLWDX[GH3DULVK{SLWDO$YLFHQQHVHUYLFHGHSQHXPRORJLH
%RELJQ\ E6HUYLFHGH3QHXPRORJLH&HQWUHGHFRPSpWHQFHVGHVPDODGLHVSXOPRQDLUHVUDUHV GH%UHWDJQH+{SLWDO3RQWFKDLOORX UXH+HQUL/H*XLOORX[5(11(6FHGH[ )UDQFH
$PpOLRUHUODGpPDUFKHGLDJQRVWLTXH HWO·pYDOXDWLRQSURQRVWLTXHGHODÀEURVH SXOPRQDLUHLGLRSDWKLTXHSRXUSURSRVHU XQWUDLWHPHQW /DÀEURVHSXOPRQDLUHLGLRSDWKLTXH )3, HVWODSOXVIUpTXHQWH GHV SQHXPRSDWKLHV LQWHUVWLWLHOOHV LGLRSDWKLTXHV 3,, >@ /HV pWXGHV pSLGpPLRORJLTXHV SURYLHQQHQW SULQFLSDOHPHQW GHVeWDWV8QLVG·(XURSHHWGX-DSRQ/·LQFLGHQFHDQQXHOOH UDSSRUWpHYDULHHQWUHHWKDELWDQWV>@/HV GLIÀFXOWpV GLDJQRVWLTXHV HW OHV YDULDWLRQV VXFFHVVLYHV GHV FULWqUHVUHQGHQWO·pSLGpPLRORJLHH[DFWHLPSUpFLVH /H FRQVHQVXV$76(56 >@ SHUPHW GH UHWHQLU FH GLDJQRVWLF HQ SUpVHQFH G·XQH SQHXPRSDWKLH LQWHUVWLWLHOOH FRPPXQH 3,& FHUWDLQH VXU OH VFDQQHU WKRUDFLTXH UpWL FXODWLRQV UD\RQ GH PLHO DYHF RX VDQV EURQFKHFWDVLHV SDU WUDFWLRQSUpGRPLQDQFHVRXVSOHXUDOHHWEDVDOHGHVOpVLRQVHW DEVHQFHGHVLJQHLQFRPSDWLEOHDYHFXQH3,& HWDSUqVDYRLU pOLPLQpXQHpWLRORJLH6LOHFRQWH[WHFOLQLTXHHWIRQFWLRQQHO OHSHUPHWHQO·DEVHQFHGH3,&FHUWDLQHVXUOHVFDQQHUOH UHFRXUVjXQHELRSVLHSXOPRQDLUHFKLUXUJLFDOHGLDJQRVWLTXH HVWUHFRPPDQGpDSUqVGLVFXVVLRQPXOWLGLVFLSOLQDLUH>@/HV UHFRPPDQGDWLRQVGHSHUPHWWHQWpJDOHPHQWGHFODVVHU OHVUpVXOWDWVDQDWRPRSDWKRORJLTXHVHQIRQFWLRQGHODSUR EDELOLWpGLDJQRVWLTXHGH3,&/DFRQIURQWDWLRQGHVUpVXOWDWV
$XWHXUFRUUHVSRQGDQW $GUHVVHHPDLO GLDQHERXYU\#DYFDSKSIU '%RXYU\
63/)3XEOLpSDU(OVHYLHU0DVVRQ6$67RXVGURLWVUpVHUYpV
DQDWRPRSDWKRORJLTXHVDYHFOHVpOpPHQWVFOLQLTXHVHW7'0HVW QpFHVVDLUHSRXUSRVHUOHGLDJQRVWLFGH)3,&HWWHGpPDUFKH HVWMXVWLÀpHSDUOHSURQRVWLFSDUWLFXOLqUHPHQWVRPEUHGHOD PDODGLHSDUFRPSDUDLVRQDX[DXWUHV3,,HQSDUWLFXOLHUOHV SQHXPRSDWKLHVLQWHUVWLWLHOOHVQRQVSpFLÀTXHV 3,16 >@ /HVFDQQHUWKRUDFLTXHDXQHSODFHFHQWUDOHGDQVOHGLDJQRV WLFGHVSQHXPRSDWKLHVLQWHUVWLWLHOOHVGLIIXVHV6LODSUpVHQFH GHUD\RQGHPLHOHVWLQGLVSHQVDEOHDXGLDJQRVWLFGH)3,HQ O·DEVHQFHGHELRSVLHSXOPRQDLUHFKLUXUJLFDOHVDSUpVHQFHQH VXIÀWSDVDXGLDJQRVWLF(QHIIHWLOSHXWrWUHSUpVHQWGDQV WRXWHVOHVÀEURVHVjXQVWDGHDYDQFp>@\FRPSULVOHV3,16>@ /DUHFRQQDLVVDQFHGXUD\RQGHPLHOQ·HVWSDVpYLGHQWH HQSDUWLFXOLHUORUVTX·LOHVWDVVRFLpjGHVEURQFKHFWDVLHVSDU WUDFWLRQHWODFRQFRUGDQFHHQWUHUDGLRORJXHVQ·HVWKDELWXHO OHPHQWSDVVDWLVIDLVDQWHDYHFGHVYDOHXUVκLQWHUREVHUYDWHXUV HQWUHHW> @'$/\QFK 'HQYHUeWDWV8QLV DXFRXUV GHODVHVVLRQ/8SGDWHIURPLGLRSDWKLFSXOPRQDU\ÀEURVLV QHWZRUN,3)1(7DSUpVHQWpXQHDQDO\VHUpWURVSHFWLYHGH SDWLHQWVLQFOXVGDQVGHVHVVDLVWKpUDSHXWLTXHVDYHFOH GLDJQRVWLFGH)3,HWSRXUOHVTXHOVXQHELRSVLHSXOPRQDLUH FKLUXUJLFDOH D pWp UpDOLVpH 7DEOHDX 'DQV FH FDGUH SDUWLFXOLHUG·HVVDLFOLQLTXHVXUOD)3,ODFRQFRUGDQFHLQWHU REVHUYDWHXUVpWDLWERQQH κ FRPPHFHODDGpMjpWp UDSSRUWp >@ 'H IDoRQ DWWHQGXH GDQV FHWWH SRSXODWLRQ VpOHFWLRQQpHGXUD\RQGHPLHOHVWSUpVHQWVXUOHVFDQQHU GDQV GHVFDVD\DQWXQHKLVWRORJLHFHUWDLQHRXSUREDEOH
'%RXYU\6-RXQHDX
7DEOHDX&RUUpODWLRQHQWUHDQDWRPRSDWKRORJLHHWVFDQQHUWKRUDFLTXH'·DSUqV'DYLG$/\QFK 'HQYHUeWDWV8QLV DX FRXUVGHODVHVVLRQ/ 3,& SQHXPRSDWKLHLQWHUVWLWLHOOHFRPPXQH 'LDJQRVWLFDQDWRPRSDWKRORJLTXH 'LDJQRVWLF7'0
3,&FHUWDLQH
3,&SUREDEOH
3,&SRVVLEOH
$XWUHGLDJQRVWLF
7RWDO
3,&
3,&SRVVLEOH
3,&LQFRPSDWLEOH
7RWDO
GH3,&'DQVHQYLURQXQTXDUWGHVFDV SDWLHQWV OH VFDQQHU HVW FODVVp HQ 3,& SRVVLEOH /·KLVWRORJLH SXOPR QDLUHGHFHVSDWLHQWVHVWXQH3,&W\SLTXHSRXUODPDMRULWp Q XQH3,&SRVVLEOHSRXU SDWLHQWVHWSUREDEOHSRXU SDWLHQWVSHUPHWWDQWGHUHWHQLUOHGLDJQRVWLFGH)3,FHUWDLQH RXSUREDEOHGDQVWRXVOHVFDV&HVUpVXOWDWVVRXOLJQHQWTXH O·DEVHQFHGHUD\RQGHPLHOVXUOHVFDQQHUWKRUDFLTXHQ·H[FOXW SDV OH GLDJQRVWLF GH )3, HW TXH FHWWH VLWXDWLRQ HVW DVVH] IUpTXHQWHGDQVFHWWHSRSXODWLRQROHGLDJQRVWLFUHWHQXHVW )3,(QÀQSDUPLOHVSDWLHQWVDYHFXQHKLVWRORJLHFHUWDLQH GH3,&SUqVG·XQWLHUV RQWXQRXSOXVLHXUV pOpPHQWV DW\SLTXHV VXU OH VFDQQHU WKRUDFLTXH XQ DVSHFW HQ PRVDwTXH HWRX GH SLpJHDJH DOYpRODLUH O·DEVHQFHGHSUpGRPLQDQFHEDVDOHXQHDWWHLQWHVDQV SUpGRPLQDQFHSpULSKpULTXH XQHSUpGRPLQDQFHSpUL EURQFKRYDVFXODLUHHWGDQVGHVFDVXQHSUpGRPLQDQFH VXSpULHXUHRXPR\HQQHGHVOpVLRQV 0DOJUpXQHGpPDUFKHGLDJQRVWLTXHFRPSOqWHXQFHUWDLQ QRPEUH GH SQHXPRSDWKLHV LQWHUVWLWLHOOHV GLIIXVHV UHVWHQW LQFODVVDEOHV>@'DQVXQHFRKRUWHGHSDWLHQWVD\DQW XQHSQHXPRSDWKLHLQWHUVWLWLHOOHGLIIXVHDXFXQGLDJQRVWLFQ·D SXrWUHUHWHQXGDQVGHVFDV/HSOXVVRXYHQWODELRSVLH SXOPRQDLUHFKLUXUJLFDOHQ·HVWSDVUpDOLVpH HQUDLVRQG·XQ ULVTXHRSpUDWRLUHWURSLPSRUWDQW HQFDVGHSDWKRORJLH SHXVpYqUHHWVWDEOHSRXUODTXHOOHOHUDSSRUWEpQpÀFHULVTXH Q·HVWSDVHQIDYHXUGXGLDJQRVWLFFKLUXUJLFDO RXELHQ ORUVTXHOHSDWLHQWODUHIXVH /RUVTX·HOOHDpWpUpDOLVpH ODTXDQWLWpGHWLVVXREWHQXHHVWLQVXIÀVDQWHGDQVGHVFDV HWFKH]GHVSDWLHQWVODGLVFXVVLRQPXOWLGLVFLSOLQDLUH Q·DERXWLWSDVjXQFRQVHQVXVGLDJQRVWLTXH>@ &HVGLIÀFXOWpVRQWIDLWSURSRVHUSDUDOOqOHPHQWjODGpPDUFKH GLDJQRVWLTXHFODVVLTXHXQHpYDOXDWLRQFRPSRUWHPHQWDOHGHV SQHXPRSDWKLHVLQWHUVWLWLHOOHVGLIIXVHVD[pHVXUOHSURÀOpYROXWLI HQSDUWLFXOLHUIRQFWLRQQHO>@'DQVOHFDVG·XQH)3,O·pYDOXDWLRQ SURQRVWLTXHHVWpJDOHPHQWLPSRUWDQWHVXUWRXWSRXUOHVSDWLHQWV pOLJLEOHVjXQHWUDQVSODQWDWLRQSXOPRQDLUH6LODVXUYLHPpGLDQH HVWGHjDQVLOH[LVWHSOXVLHXUVSURÀOVpYROXWLIV SURJUHVVLRQ OHQWHUDSLGHHWH[DFHUEDWLRQDLJXs /HVSDUDPqWUHVSK\VLR ORJLTXHVDVVRFLpVjXQHDXJPHQWDWLRQGHODPRUWDOLWpVRQWXQ GpFOLQGHPGHODGLVWDQFHSDUFRXUXHDXWHVWGHPDUFKH GHPLQXWHVHQVHPDLQHVXQHGLPLQXWLRQGHODFDSDFLWp YLWDOHIRUFpH &9) HWRXGHODFDSDFLWpGHWUDQVIHUWGX&2 '/&2 GHUHVSHFWLYHPHQWHWGHODYDOHXUSUpGLWHHQ PRLV>@&.*DUFLD 'DOODVeWDWV8QLV DSUpVHQWpDXFRXUV GHVVHVVLRQV' 8SGDWHVLQJHQRPLFDQGSUHFLVLRQPHGLFLQH HW& 7KHJROGÀQJHUSULQW PROHFXODUFKDUDFWHUL]DWLRQRI LQWHUVWLWLDOOXQJGLVHDVH XQWUDYDLOpJDOHPHQWSXEOLp>@VXU ODYDOHXUSUpGLFWLYHGHODORQJXHXUGHVWpORPqUHVGDQVOD)3,
/HVWpORPqUHVVRQWGHVSURWpLQHVSURWpJHDQWO·H[WUpPLWpGHV FKURPRVRPHV/HXUDOWpUDWLRQIUDJLOLVHO·pSLWKpOLXPDOYpRODLUH HWOHGpYHORSSHPHQWG·XQHÀEURVHSXOPRQDLUHHQSUpVHQFH G·XQIDFWHXUIDYRULVDQW>@,OHVWGpFULWGHVPXWDWLRQVGHV WpORPpUDVHV HQ]\PHSHUPHWWDQWO·DOORQJHPHQWGHVWpORPqUHV FKH]GHVSDWLHQWVD\DQWXQH)3,VSRUDGLTXHHWGDQVFHUWDLQHV ÀEURVHVIDPLOLDOHV7URLVFRKRUWHVGHSDWLHQWVVRQWpWXGLpHV /HVGXUpHVPR\HQQHVGHVXLYLYDULHQWHQWUHHWPRLV/HV UpVXOWDWVPRQWUHQWXQUDFFRXUFLVVHPHQWVLJQLÀFDWLIGHVWpOR PqUHVFKH]OHVSDWLHQWVD\DQWXQHSQHXPRSDWKLHLQWHUVWLWLHOOH GLIIXVH )3,RXQRQ SDUUDSSRUWDX[VXMHWVVDLQV S &KH]OHVSDWLHQWVD\DQWXQH)3,ODORQJXHXUGHVWpORPqUHVHVW DVVRFLpHjODVXUYLHVDQVUHFRXUVjODWUDQVSODQWDWLRQSXOPRQDLUH HWHVWXQIDFWHXUSURQRVWLFLQGpSHQGDQW )LJ /DSODFHGH O·pWXGHGHVWpORPqUHVUHVWHjGpÀQLUPDLVODPLVHHQpYLGHQFH G·XQOLHQDYHFODVXUYLHUHQIRUFHO·LPSOLFDWLRQSDWKRJpQLTXHTXL DYDLWpWpVXJJpUpHSDUO·pWXGHGHFDVIDPLOLDX['HX[DXWUHV FRPPXQLFDWLRQVRQWIDLWSDUWGHO·LQWpUrWGHELRPDUTXHXUV &&/HW003SRXUpYDOXHUOHSURQRVWLFGHVSDWLHQWVD\DQW XQH)3,'DQVO·DYHQLUODFRPELQDLVRQGHIDFWHXUVSURQRVWLTXHV FOLQLTXHVHWSK\VLRORJLTXHVDYHFGHVPDUTXHXUVELRORJLTXHVRX JpQpWLTXHVSRXUUDLWJXLGHUODSULVHHQFKDUJHWKpUDSHXWLTXH GHVSDWLHQWV
1DFpW\OF\VWpLQHQLQWHGDQLE HWSLUIpQLGRQH PROpFXOHVFDQGLGDWHV SRXUOHWUDLWHPHQWGHODÀEURVH SXOPRQDLUHLGLRSDWKLTXH /HVUHFRPPDQGDWLRQVSUDWLTXHVGHOD63/)SXEOLpHVHQ UDSSHOOHQWOHVGLIIpUHQWHVPROpFXOHVD\DQWIDLWO·REMHWG·HV VDLVWKpUDSHXWLTXHVGDQVOD)3,>@&HUWDLQHVG·HQWUHVHOOHV VRQWGpFRQVHLOOpHV DVVRFLDWLRQD]DWKLRSULQHSUHGQLVRQH1 DFpW\OF\VWpLQH DQWLYLWDPLQH . DPEULVHQWDQ HW G·DXWUHV QRQUHFRPPDQGpHV FRUWLFRWKpUDSLHFROFKLFLQHHWDQHUFHSW FLFORVSRULQHLQWHUIpURQγE '·DXWUHSDUWOHEpQpÀFHSDU H[HPSOHGHODSLUIpQLGRQHHWGHOD1DFpW\OF\VWpLQH 1$& Q·HVWSDVFHUWDLQ>@ /HVWUDLWHPHQWVSUHVFULWVHWGLVSRQLEOHVpYROXHQWDYHFOHV FRQQDLVVDQFHVSDWKRJpQLTXHV8QHGHVSUHPLqUHVK\SRWKqVHV SURSRVpHDpWpXQHLQÁDPPDWLRQjO·RULJLQHGHODÀEURVH $FWXHOOHPHQWODSDUWLFLSDWLRQLQÁDPPDWRLUHPrPHVLHOOH VHPEOHMRXHUXQU{OHFKH]OHVSDWLHQWVD\DQWXQSURÀOGHSUR JUHVVLRQUDSLGHGHODPDODGLHQ·HVWSOXVFRQVLGpUpHFRPPH SUpSRQGpUDQWH HW OHV PpFDQLVPHV FRQGXLVDQW j OD ÀEURVH SXOPRQDLUHVRQWPDLQWHQDQWPLHX[FRQQXV>@ )LJ
Transplant-free survival (%)
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
A Dallas IPF cohort (n = 135) 100
B Chicago IPF cohort (n = 135)
C San Francisco IPF cohort (n = 135)
Q1 Q2 Q3 Q4
80 60 40 20 p = 0,0048
0 0
10
Number at risk Q4 34 Q3 33 Q2 34 Q1 34
p = 0,029
p = 0,00066
20
30 40 Months
20 8 16 12
8 3 5 5
50
60 0 4 1 0 3
10
31 30 31 31
20
30 40 Months
26 22 21 18
50
17 13 8 9
60 0 10 5 3 0
10
12 12 12 13
20
30 40 Months
10 10 7 9
50
10 7 6 5
60 9 6 6 4
)LJXUH6XUYLHVDQVWUDQVSODQWDWLRQHQIRQFWLRQGHODORQJXHXUGHVWpORPqUHVFKH]OHVSDWLHQWVD\DQWXQHÀEURVHSXOPRQDLUHLGLRSDWKLTXH>@
A Ageing-related susceptible lung
Recurring microinjuries Alveolar epithelium Capillaries
B Wound clot
C Aberrant activation of epithelial cells
Caveolin 1 RAGE
EGFs MMP1, MMP7
AEC migration and proliferation Epithelial cell apoptosis
Epithelial recapitulation of developmental pathways (Wnt, Shh)
FXa D Fibroblast focus MMP2 MMP9
E Hypercoagulable milieu Fibroblast recapitulatin of developmental pathways (PTEN, gremlin, FAPα)
F
Exaggerated ECM accumulatin
PDGF CXCL12 TGFβ
Progressive lung remodelling
Local fibroblasts Fibrocytes EMT, myofibroblast differentiation
Honeycomb changes
)LJXUH3K\VLRSDWKROJLHGHOD)3,HWVLWHVG·DFWLRQGHOD1DFpW\OF\VWpLQH HQEOHX GHODSLUIpQLGRQH HQMDXQH HWGXQLQWHGDQLE HQURXJH /·pSLWKpOLXP DOYpRODLUH ($ IUDJLOLVp kJH HWRX PRGLÀFDWLRQV JpQpWLTXHV HVW VRXPLV j GHV PLFURDJUHVVLRQV UpSpWpHV UHÁX[ JDVWUR ±VRSKDJLHQWDEDFLQIHFWLRQYLUDOH« HQWUDLQDQWO·DSRSWRVHGHVFHOOXOHVpSLWKpOLDOHVDOYpRODLUHV &($ /DUpSDUDWLRQGHO·($VHIDLWGH PDQLqUH DEHUUDQWH DYHF DIÁX[ GH ÀEUREODVWHV G·RULJLQHV PXOWLSOHV GDQV OHV ]RQHV OpVpHV IRUPDQW OHV IR\HUV ÀEUREODVWLTXHV MHXQHV /D V\QWKqVHHQH[FqVGHODPDWULFHH[WUDFHOOXODLUH ÀEUHVFROODJqQHV PDMRUHO·DSRSWRVHGHVFHOOXOHVDOYpRODLUHVpSLWKpOLDOHV/HVOpVLRQVGH UD\RQGHPLHOVRQWDORUVHQJHQGUpHVSDUOHVIRUFHVGHWUDFWLRQV·H[HUoDQWVXUFHSRXPRQFLFDWULFLHO$GDSWpSDU0DUWLQ5-.ROE +DPLOWRQ &DQDGD VHVVLRQ$ ©6N\IDOO ODWHEUHDNLQJFOLQLFDOWULDOVLQLGLRSDWKLFSXOPRQDU\ÀEURVLVª G·DSUqV>@
/HFRQJUqVGHO·$76DpWpO·RFFDVLRQGHODSUpVHQWD WLRQGHHVVDLVWKpUDSHXWLTXHVUDQGRPLVpVFRQWUHSODFHER FRQFHUQDQWOD1$&OHQLQWHGDQLEHWODSLUIpQLGRQH /RUV GH OD VHVVLRQ$ 6N\IDOO ODWH EUHDNLQJ FOLQLFDO WULDOVLQLGLRSDWKLFSXOPRQDU\ÀEURVLV 0-.ROE +DPLOWRQ &DQDGD D UDSSHOp OH UDWLRQQHO SK\VLRSDWKRORJLTXH SRXU O·XWLOLVDWLRQGHFKDFXQHGHFHVPROpFXOHV )LJ /D1$& GLPLQXHODSUROLIpUDWLRQGHVÀEUREODVWHVHWODV\QWKqVHGH FROODJqQHDLQVLTXHODV\QWKqVHGHVF\WRNLQHVSURÀEURVDQWHV 3'*) SODWHOHWGHULYHGJURZWKIDFWRU )*) ÀEUREODVWJURZWK IDFWRU HW7*)βSDUVRQDFWLRQDQWLR[\GDQWH DXJPHQWDWLRQ GXJOXWDWKLRQHWGLPLQXWLRQGHVUDGLFDX[OLEUHV /HQLQWHGDQLE HVW XQ LQKLELWHXU LQWUDFHOOXODLUH GH QRPEUHX[ UpFHSWHXUV W\URVLQHNLQDVHQRWDPPHQWGHVUpFHSWHXUVDX[IDFWHXUVGH FURLVVDQFH)*)3'*)HW9(*) YDVFXODUHQGRWKHOLDOJURZWK IDFWRU &HVF\WRNLQHVVRQWLPSOLTXpHVGDQVOHGpYHORSSHPHQW GHODÀEURVH/DSLUIpQLGRQHGRQWOHPpFDQLVPHG·DFWLRQ HVWSDUWLHOOHPHQWLQFRQQXDXQHDFWLRQDQWLLQÁDPPDWRLUH DQWLR[\GDQWHHWDQWLÀEURVDQWHSDUUpJXODWLRQGHO·DFWLYLWpGH 7*)βHWGH71)αLQYLWURDYHFLQKLELWLRQGHODSUROLIpUDWLRQ GHVÀEUREODVWHVHWGHODV\QWKqVHGXFROODJqQH
/H1DFpW\OF\VWpLQHQHUDOHQWLW SDVODSURJUHVVLRQGHODÀEURVH SXOPRQDLUHLGLRSDWKLTXH (Q O·HVVDL UDQGRPLVp ,),*(1,$ LQFOXDQW SDWLHQWV D PRQWUp TX·XQ WUDLWHPHQW WULSOH DVVRFLDQW D]DWKLRSULQH SUHGQLVRQH HW 1$& j KDXWH GRVH PJ IRLV SDU MRXU SUpVHUYHPLHX[ODIRQFWLRQUHVSLUDWRLUHHQFRPSDUDLVRQG·XQ WUDLWHPHQW GH D]DWKLRSULQHSUHGQLVRQH >@ /·DVVRFLDWLRQ GRXEOHRXWULSOHHVWDORUVODUJHPHQWXWLOLVpHSDUOHVSQHXPR ORJXHV&HSHQGDQWO·HIÀFDFLWpH[DFWHGHFHWWHDVVRFLDWLRQ DLQVLTXHVDWROpUDQFHFOLQLTXHFKH]OHVSDWLHQWVD\DQWXQH)3, UHVWHFRQWURYHUVpHG·DXWDQWSOXVTXHO·HVVDLQ·DSDVXWLOLVp GHEUDVSODFHER8QQRXYHOHVVDL3$17+(5,3)>@HVWSXEOLp GDQV OH 1(-0 HQ ,O V·DJLW G·XQ HVVDL PXOWLFHQWULTXH FRPSUHQDQW EUDV DYHF XQH UDQGRPLVDWLRQ pTXLYDOHQWH HQWUHSODFHERYV1$&VHXOYV1$&D]DWKLRSULQHSUHGQLVRQH /HV SDWLHQWV LQFOXV VRQW kJpV GH j DQV SUpVHQWHQW XQHÀEURVHSXOPRQDLUHLGLRSDWKLTXHUpSRQGDQWDX[FULWqUHV $76(56>@HWGLDJQRVWLTXpHGDQVOHVDQVSUpFpGDQW O·LQFOXVLRQ/·DOWpUDWLRQIRQFWLRQQHOOHjO·LQFOXVLRQHVWOpJqUH jPRGpUpHGpÀQLHSDUXQH&9HWXQH'/&2 GHV YDOHXUV SUpGLWHV /HV SDWLHQWV SUpVHQWDQW GHV OpVLRQV G·HPSK\VqPH PRUSKRORJLTXHPHQW SOXV LPSRUWDQWHV TXH OHV OpVLRQV GH ÀEURVH HW XQ UDSSRUW 9(06&9) LQIpULHXU j HWRXXQ95VXSpULHXUjVRQWH[FOXV/·DQDO\VH LQWHUPpGLDLUH PRLV DSUqV OH GpEXW GHV LQFOXVLRQV D PRQWUpXQQRPEUHVLJQLÀFDWLYHPHQWSOXVLPSRUWDQWG·HIIHWV VHFRQGDLUHVJUDYHVHWG·KRVSLWDOLVDWLRQVRXGpFqVFKH]OHV SDWLHQWVUHFHYDQWO·DVVRFLDWLRQ1$&D]DWKLRSULQHSUHGQLVRQH SDUUDSSRUWDXJURXSHSODFHER&HVFRQVWDWDWLRQVRQWFRQGXLW jO·DUUrWSUpPDWXUpGHO·pWXGHHWjODUHFRPPDQGDWLRQGHQH SDVGpEXWHUFHWUDLWHPHQWFKH]OHVSDWLHQWVSRXUOHVTXHOVOH GLDJQRVWLFGH)3,HVWUHWHQX /·HVVDL D FHSHQGDQW pWp SRXUVXLYL DYHF EUDV SDWLHQWV UDQGRPLVpV GDQV OH EUDV 1$& HW GDQV OH JURXSHSODFHER/HVUpVXOWDWVVRQWSUpVHQWpVVXFFHVVLYHPHQW
'%RXYU\6-RXQHDX
SDU * 5DJKX 6HDWWOH eWDWV8QLV SXLV SDU )- 0DUWLQH] $QQ$UERUeWDWV8QLV ORUVGHODVHVVLRQ$ 6N\IDOO ODWH EUHDNLQJFOLQLFDOWULDOVLQLGLRSDWKLFSXOPRQDU\ÀEURVLV >@ /H FULWqUH GH MXJHPHQW SULQFLSDO HVW OH GpFOLQ GH OD &9) j VHPDLQHV /HV REMHFWLIV VHFRQGDLUHV FRPSUHQDLHQW OH QRPEUHGHGpFqVOHWHPSVpFRXOpMXVTX·DXGpFqVOHGpODL VDQVSURJUHVVLRQOD'/&2OH70HWSOXVLHXUVTXHVWLRQQDLUHV H[SORUDQWODTXDOLWpGHYLHHWODG\VSQpH$SUqVVHPDLQHV GHWUDLWHPHQWLOQ·H[LVWHSDVGHGLIIpUHQFHVLJQLÀFDWLYHHQWUH OHVJURXSHV(WFHFLFRQFHUQHDXVVLELHQOHGpFOLQPR\HQGH &9)FULWqUHSULQFLSDOGHMXJHPHQWTXHOHVDXWUHVSDUDPqWUHV IRQFWLRQQHOVUHVSLUDWRLUHVPrPHV·LOH[LVWDLWXQHWHQGDQFH j O·DPpOLRUDWLRQ GX 70 GDQV OH JURXSH 1$& S $SUqVVHPDLQHVGHVXLYLGpFqVRQWpWpFRQVWDWpVGDQV OH JURXSH 1$& HW GpFqV GDQV OH JURXSH SODFHER Oj QRQ SOXVVDQVGLIIpUHQFHVLJQLÀFDWLYH7URLVH[DFHUEDWLRQVDLJXsV VRQWVXUYHQXHVGDQVFKDTXHJURXSHSHQGDQWODSpULRGHGH VXLYL 6HXOV OHV TXHVWLRQQDLUHV GH TXDOLWpV GH YLH pWDLHQW VLJQLÀFDWLYHPHQWPHLOOHXUVGDQVOHJURXSH1$& 6)PHQWDO VFRUHS HW,&(&$3VXPPDU\VFRUHS $XWRWDO XQTXDUWGHVSDWLHQWVGXJURXSH1$&HWGHVSDWLHQWV GXJURXSHSODFHERRQWDUUrWpO·pWXGH'DQVOHVJURXSHV SOXVGH GHVSDWLHQWVGpFODUDLHQWSUHQGUHDXPRLQV GXWUDLWHPHQW'HVHIIHWVLQGpVLUDEOHVJUDYHVVRQWVXUYHQXV FKH]GHVSDWLHQWVUHFHYDQWGHOD1$&HWFKH] GHVSDWLHQWVUHFHYDQWOHSODFHER S DYHFXQQRPEUH G·HIIHWVFDUGLRYDVFXODLUHVLQGpVLUDEOHVJUDYHVVLJQLÀFDWLYH PHQWSOXVLPSRUWDQWGDQVOHJURXSH1$& FRQWUH S /HW\SHH[DFWGHVpYpQHPHQWVFDUGLRYDVFXODLUHV Q·HVW SDV GpWDLOOp 2Q UHPDUTXH TX·LO Q·H[LVWH SDV G·DXJ PHQWDWLRQGHVHIIHWVLQGpVLUDEOHVJUDYHVJDVWURLQWHVWLQDX[ GDQVOHJURXSH1$& /HVUpVXOWDWVGHFHWWHpWXGHRQWpWpEHDXFRXSGLVFXWpV ORUVGHOHXUSUpVHQWDWLRQ(QHIIHWOHPpFDQLVPHG·DFWLRQGH OD1$&GDQVOD)3,DYDLWHQWUHWHQXGHVHVSRLUVTXDQWjFHWWH PROpFXOH/HVUpVXOWDWVSHXYHQWrWUHSUpVHQWpVHQVpSDUDQW SKDVHVFKURQRORJLTXHV DYDQWHWDSUqVOHSDVVDJHGHO·pWXGH GHjEUDVHQUDLVRQGHO·DXJPHQWDWLRQGHVGpFqVHWGHV KRVSLWDOLVDWLRQVGDQVOHEUDV1$&D]DWKLRSULQHSUHGQLVRQH 'DQVODSUHPLqUHSpULRGHO·pYROXWLRQGHVSDUDPqWUHVUHVSL UDWRLUHVHVWPHLOOHXUHGDQVOHJURXSHWUDLWpSDU1$&PDLVVDQV GLIIpUHQFH VLJQLÀFDWLYH )LJ &HUWDLQV DXWHXUV SHQVHQW TXHO·REVHUYDQFHDpWpPRLQVERQQHDSUqVODSXEOLFDWLRQGH O·HIIHWGpOpWqUHGHO·DVVRFLDWLRQ1$&SUHGQLVRQHD]DWKLRSULQH HWTXHODWHQGDQFHjXQHHIÀFDFLWpGX1$&Q·DSDVSXrWUH FRQÀUPpHSDUOHVUpVXOWDWV1pDQPRLQVHQFRQFOXVLRQFKH] OHVSDWLHQWVD\DQWXQH)3,OpJqUHjPRGpUpHOD1$&jODGRVH GHPJMHQPRQRWKpUDSLHQHSHUPHWSDVG·HPSrFKHU OHGpFOLQGHOD&9)
(IÀFDFLWpGXQLQWHGDQLE %,%) pWXGHV,138/6,6 /5LFKHOGLDSUpVHQWpOHVUpVXOWDWVGHVpWXGHV,138/6,6 HWPRQWUDQWO·HIÀFDFLWpGXQLQWHGDQLE %,%) GDQVOH WUDLWHPHQWGHOD)3,>@ /·pWXGH7202552:SXEOLpHHQpWXGHGHSKDVH UDQGRPLVpHHQGRXEOHDYHXJOHDYDLWPRQWUpODVXSpULRULWp GXQLQWHGDQLEjODGRVHGHPJIRLVSDUMRXUSHQGDQW PRLVSDUUDSSRUWDX[DXWUHVGRVDJHV PJIRLVSDU
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
B
A Change from baseline in FVC
After alert
0,0
Outcome
• Placebo
• •
FVC (liters)
-0,05
-0,10
• Acetylcysteine • •
-0,15
••
-0,20
Base- 15 line No. at risk Acety|cysteine 133 Placebo 131
127 127
30
45
60
Week 118 119
113 118
102 109
All patients
Before alert
P Value for Interaction
t-Statistic
FVC
0,16
DLCO corrected
0,02
CPI
0,04
Alveolar-arterial gradient
0,70
Walk distance
0,20
Oxygen saturation AUC
0,72
Walk distance to desaturation
0,65
Minutes walked
0,76
SF-36 aggregate physical score
0,89
SF-36 aggregate mental score
0,08
EuroQoL score
0,51
EuroQoL thermometer response
0,56
St. George’s total score
0,19
St. George’s symptoms score
0,45
St. George’s activity score
0,20
St. George’s impacts score
0,29
UCSD SOBQ total score
0,10 0,10
ICECAP summary score -3
-2
-1
Placebo better
0
1
2
3
Acetylcysteine better
)LJXUHeYROXWLRQGHOD&9)GDQVOHJURXSHSODFHERHWGDQVOHJURXSH1$& JDXFKH 3UpVHQWDWLRQGHVUpVXOWDWVJOREDX[HWGHVUpVXOWDWV DYDQWHWDSUqVODPRGLÀFDWLRQGXSURWRFROH GURLWH >@
MRXUPJIRLVSDUMRXUPJXQHIRLVSDUMRXURXSOD FHER > @/HQLQWHGDQLEjPJIRLVSDUMRXUUDOHQWLVVDLW OH GpFOLQ GH OD &9) GLPLQXDLW OHV H[DFHUEDWLRQV GH )3, HW SUpVHUYDLWODTXDOLWpGHYLH /HV pWXGHV © MXPHOOHV ª GH SKDVH ,138/6,6 HW UDQGRPLVpHVHQGRXEOHDYHXJOHFRQWUHSODFHERRQWGRQF pYDOXpO·HIÀFDFLWpHWODWROpUDQFHGXQLQWHGDQLEjPJ IRLVSDUMRXUVXUPRLVGDQVOHWUDLWHPHQWGHOD)3,>@ /DUpDOLVDWLRQGHpWXGHVMXPHOOHVUpSRQGjXQHH[LJHQFH GHO·DJHQFHDPpULFDLQHGHVpFXULWpGXPpGLFDPHQW )'$ DÀQ G·REWHQLU XQH DXWRULVDWLRQ GH PLVH VXU OH PDUFKp $00 ,OV·DJLVVDLWGHGHX[pWXGHVPXOWLFHQWULTXHVLQFOXDQWGHV SDWLHQWVHQ$PpULTXHHQ(XURSHHQ$VLHHWHQ$XVWUDOLH /HVFULWqUHVG·LQFOXVLRQpWDLHQWFODVVLTXHV SDWLHQWVkJpVGH DQVHWSOXVGLDJQRVWLFGH)3,FHUWDLQH VFDQQHUWKRUDFLTXH KLVWRORJLH VXU ELRSVLH SXOPRQDLUH FKLUXUJLFDOH >%3&@ VL GLVSRQLEOH GDWDQW GH PRLQV GH DQV &9) GH OD WKpRULTXH'/&2HQWUHHW GHODWKpRULTXH/HVVFDQ QHUVWKRUDFLTXHVHWOHVpYHQWXHOOHV%3&EpQpÀFLDLHQWG·XQH UHOHFWXUHFHQWUDOLVpH/HVDXWUHVWUDLWHPHQWVDQWLÀEURVDQWV pWDLHQW LQWHUGLWV LH SLUIpQLGRQH 1$& D]DWKLRSULQH« VDXIODFRUWLFRWKpUDSLHVLODGRVHpWDLWVWDEOHHWPJM 1pDQPRLQVGHVGRVHVSOXVpOHYpHVGHFRUWLFRWKpUDSLHpWDLHQW DXWRULVpHVORUVGXWUDLWHPHQWGHVH[DFHUEDWLRQVGH)3,/H UDWLR GH UDQGRPLVDWLRQ pWDLW GH SDWLHQWV GDQV OH EUDV QLQWHGDQLEFRQWUHSDWLHQWVGDQVOHEUDVSODFHER /HFULWqUHGHMXJHPHQWSULQFLSDOpWDLWOHGpFOLQDQQXHOGH OD&9)/HVFULWqUHVGHMXJHPHQWVHFRQGDLUHVFOpVpWDLHQWOH WHPSVMXVTX·jODSUHPLqUHH[DFHUEDWLRQGH)3,HWO·DQDO\VH GHODTXDOLWpGHYLH TXHVWLRQQDLUHUHVSLUDWRLUH6W*HRUJHRX 6*54 8QFRPLWpG·DGMXGLFDWLRQHQDYHXJOHGXEUDVWLUpDX
VRUWDQDO\VDLWOHVGRVVLHUVGHVSDWLHQWVFKH]TXLXQHH[DFHU EDWLRQpWDLWUDSSRUWpHSDUOHVLQYHVWLJDWHXUVHWFRQÀUPDLWRX QRQO·H[DFHUEDWLRQVHORQODGpÀQLWLRQHQYLJXHXU>@3RXU UDSSHOOHGLDJQRVWLFG·H[DFHUEDWLRQGH)3,QpFHVVLWH OH GLDJQRVWLFSUpDODEOHRXFRQFRPLWDQWGH)3, ODSUpVHQFHGH QRXYHOOHVRSDFLWpVVXUOHVFDQQHUWKRUDFLTXH XQHG\VSQpH TXL V·DJJUDYH VXU PRLQV GH MRXUV O·H[FOXVLRQ G·XQH LQIHFWLRQSXOPRQDLUHSDUSUpOqYHPHQWLQYDVLI ODYDJHEURQ FKLRORDOYpRODLUHRXDVSLUDWLRQHQGRWUDFKpDOH O·H[FOXVLRQ G·XQH DXWUH pWLRORJLH LQVXIÀVDQFH FDUGLDTXH HPEROLH SXOPRQDLUHDXWUHV/DSUpVHQFHGHVFULWqUHVSHUPHWGH UHWHQLU OH GLDJQRVWLF G·H[DFHUEDWLRQ FHUWDLQH GH )3, V·LO PDQTXHXQFULWqUHOHGLDJQRVWLFHVWDORUVH[DFHUEDWLRQGH )3,VXVSHFWpH>@/DPRUWDOLWppWDLWpJDOHPHQWDQDO\VpH ELHQTXHO·pWXGHQ·DLWSDVpWpPRGpOLVpHSRXUPRQWUHUXQH GLIIpUHQFHGHPRUWDOLWpHQWUHOHVEUDV (QWUHPDLHWVHSWHPEUHSDWLHQWVRQW pWpLQFOXVGDQVO·pWXGH,138/6,6HWGDQVO·pWXGH ,138/6,6/HVFDUDFWpULVWLTXHVFOLQLTXHVGHVSDWLHQWVLQFOXV VRQWGpWDLOOpHVGDQVOHWDEOHDX/HVpWXGHVRQWPRQWUp XQUDOHQWLVVHPHQWVLJQLÀFDWLIGHOD&9)DSUqVVHPDLQHVGH WUDLWHPHQW )LJ POGDQVOHEUDVSODFHER Q FRQWUH POGDQVOHEUDVQLQWHGDQLE Q S GRQQpHV GHV pWXGHV UDVVHPEOpHV GLIIpUHQFH PR\HQQH HQWUHOHVEUDVGHPO ,& jPO &RQFHUQDQW OHV FULWqUHV VHFRQGDLUHV OH WHPSV MXVTX·j OD SUHPLqUH H[DFHUEDWLRQ GLDJQRVWLF GHV LQYHVWLJDWHXUV Q·pWDLWSDVGLIIpUHQWGDQVOHVEUDVGHO·pWXGH,138/6,6 5LVTXHUHODWLI>55@ ,& ² S DORUVTX·LOpWDLWDOORQJpGDQVOHEUDVQLQWHGDQLEGDQVO·pWXGH ,138/6,6 55 ,& ² S 8QHIRLVOHVGRQQpHVUDVVHPEOpHVH[DPLQpHVSDUOHFRPLWp
'%RXYU\6-RXQHDX
7DEOHDX&DUDFWpULVWLTXHVFOLQLTXHVGHVSDWLHQWVGHVpWXGHV,138/6,6HW,138/6,6$GDSWpG·DSUqV>@ ,138/6,6
,138/6,6
1LQWHGDQLE PJùM Q
3ODFHER Q
ÇJHDQQpHPR\HQQH 6'
6H[HPDVFXOLQQ
)XPHXU VHYUpRXQRQ Q
&9)WKpRPR\HQQH 6'
9(06&9)PR\HQQH 6'
'/&2WKpRPR\HQQH 6'
6*54VFRUHWRWDOPR\HQQH 6'
&9)P/PR\HQQH 6'
Mean Observed Change from Baseline in FVC (ml)
B INPULSIS-1 50
– 50 – 100 – 150
– 114,7
– 200 Difference, 125,3 (95 % CI, 77,7 – 172,8) – 250 P < 0,001 – 239,9 – 300
Nintedanib, 150 mg Twice Daily (N = 309)
Placebo (N = 204)
Adjusted Annual Rate of Change in FVC (ml/yr)
C INPULSIS-2 0
Nintedanib, 150 mg twice daily
– 50 – 100
Placebo
– 150
Adjusted mean difference, 109,9 (95 % CI, 71,3 – 148,6) P < 0,001
– 200 – 250
0 2 4 6
12
24 Week 292 194
284 192
36 274 187
52 250 165
D INPULSIS-1 50
– 50 – 100 – 150
0
No. of Patients Nintedanib 303 301 298 Placebo 202 198 200
– 113,6
Difference, 93,7 (95 % CI, 44,8 – 142,7 ) – 250 P < 0,001 – 207,3 – 200
Mean Observed Change from Baseline in FVC (ml)
Adjusted Annual Rate of Change in FVC (ml/yr)
A INPULSIS-1 0
1LQWHGDQLE 3ODFHER Q PJùM Q
0 Nintedanib, 150 mg twice daily – 50 – 100 – 150 – 200
Placebo Adjusted mean difference, 109,8 (95 % CI, 70,9 – 148,6) P < 0,001
– 250 0 2 4 6
– 300 Nintedanib, 150 mg Twice Daily (N = 329)
Placebo (N = 219)
No. of Patients Nintedanib 323 315 315 Placebo 215 210 207
12
24 Week 312 209
303 203
36 295 196
52 269 180
)LJXUH 'pFOLQ DQQXHO HW GLIIpUHQFH SDU UDSSRUW j OD YDOHXU LQLWLDOH GH OD FDSDFLWp YLWDOH IRUFpH &9) GDQV OHV pWXGHV ,138/6,6 HW ,138/6,6>@
G·DGMXGLFDWLRQ RQ UHWURXYDLW XQ DOORQJHPHQW VLJQLÀFDWLI GX WHPSV MXVTX·j OD SUHPLqUH H[DFHUEDWLRQ GDQV OH EUDV QLQWHGDQLESDUUDSSRUWDXSODFHER 55 ,& ² S )LJ ,OQ·\DYDLWSDVGHGLIIpUHQFHVLJQL ÀFDWLYHHQWHUPHVGHTXDOLWpGHYLHHQWUHOHVEUDVSODFHERRX QLQWHGDQLEVDXISRXUOHGRPDLQHG·DFWLYLWpGX6*54TXLpWDLW VWDWLVWLTXHPHQWPHLOOHXUGDQVOHEUDVQLQWHGDQLEPDLVVDQV
DWWHLQGUHODVLJQLÀFDWLYLWpFOLQLTXH GRQQpHVUDVVHPEOpHV GDQVOHEUDVQLQWHGDQLEFRQWUHGDQVOHEUDV SODFHER VRLWXQHGLIIpUHQFHGH S 'H PrPHLOQ·\DYDLWSDVGHGLIIpUHQFHVLJQLÀFDWLYHHQWHUPHV GHPRUWDOLWpHQWUHOHVEUDVQLQWHGDQLEHWSODFHER )LJ /HV HIIHWV LQGpVLUDEOHV pWDLHQW WUqV IUpTXHQWV DYHF OH QLQWHGDQLESULQFLSDOHPHQWG·RUGUHGLJHVWLI 7DEOHDX 2Q
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
Cumulative incidence of first confirmed/suspected acute exacerbation (%)
UHWURXYDLWGHGLDUUKpHV SULQFLSDOHPHQWOpJqUHjPRGp UpH GHVFDV GHQDXVpHVGHYRPLVVHPHQWV HWGHF\WRO\VHKpSDWLTXH WUDQVDPLQDVHVIRLVODOLPLWH VXSpULHXUHGHODQRUPDOH /HQLQWHGDQLEHVWGRQFHIÀFDFHGDQVOHUDOHQWLVVHPHQW GXGpFOLQGHOD&9)FKH]OHVSDWLHQWVDWWHLQWVGH)3,OpJqUHj
PRGpUpHDLQVLTXHGDQVODUpGXFWLRQGHVH[DFHUEDWLRQV DSUqV DGMXGLFDWLRQ /HV HIIHWV LQGpVLUDEOHV VRQW SULQFLSDOHPHQW GLJHVWLIVWRXWFRPPHDYHFODSLUIpQLGRQH/HGpS{WG·$00 DpWpHIIHFWXpGpEXWPDLDXSUqVGHVLQVWDQFHVHXUR SpHQQHVDLQVLTXHOHVGpPDUFKHVG·DXWRULVDWLRQWHPSRUDLUH G·XWLOLVDWLRQ $78 QRPLQDWLYHV
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
Nintedanib 150 mg × 2/j Placebo HR 0,32 (95 % Cl ; 0,16, 0,65) p = 0,0010
0
30
60
90
120
150
180
210
240
270
300
330
360 373
572 380
563 371
548 503 363 345
Time to first confirmed/suspected acute exacerbation (days) No. of patients Nintedanib 638 Placebo 423
634 419
629 416
613 409
610 408
602 404
597 396
593 393
589 390
580 384
Nintedanib 150 mg × 2/j (n = 638) Patients avec ≥ 1 exacerbatuion aigue, n (%)
Placebo (n = 423)
12 (1,9)
24 (5,7)
)LJXUH 7HPSV MXVTX·j OD SUHPLqUH H[DFHUEDWLRQ FHUWDLQH RX VXVSHFWpH DSUqV YDOLGDWLRQ SDU OH FRPLWp G·DGMXGLFDWLRQ DQDO\VH SUp VSpFLÀpH $GDSWpG·DSUqVGLDSRVLWLYHGH/5LFKHOGL$76
Kaplan-Meier estimate of death (%)
Nintedanib 150 mg × 2/j 100 99 98 97 96 95 94 93 92 91 90
Placebo
HR 0,70 (95 % Cl ; 0,43, 1,12) p = 0,1399
0 0
30
60
90
120
150
180
210
240
270
300
330
360 373
617 406
612 403
606 400
601 394
591 532 388 358
Time to death (days) No. of patients Nintedanib 638 Placebo 423
637 422
635 420
632 418
628 418
623 416
620 414
619 408
Nintedanib 150 mg × 2/j (n = 638) Patients décédés, n (%)
35 (5,5)
Placebo (n = 423) 33 (7,8)
)LJXUH0RUWDOLWpGHWRXWHVFDXVHVjVHPDLQHV GRQQpHVUDVVHPEOpHV $GDSWpG·DSUqVGLDSRVLWLYHGH/5LFKHOGL$76
'%RXYU\6-RXQHDX
7DEOHDX(IIHWVVHFRQGDLUHVDXFRXUVGHVpWXGHV,138/6,6$GDSWpG·DSUqV>@ (IIHWVLQGpVLUDEOHV
,138/6,6
,138/6,6
1LQWHGDQLE Q
3ODFHER Q
1LQWHGDQLE Q
3ODFHER Q
7RXWHIIHWLQGpVLUDEOH
7RXWHIIHWLQGpVLUDEOHj O·H[FOXVLRQGHODSURJUHVVLRQ GHOD)3,
'LDUUKpHV
1DXVpHV
5KLQRSKDU\QJLWHV
7RX[
%URQFKLWHV
,QIHFWLRQVGHVYRLHVDpULHQQHV VXSpULHXUHV
'\VSQpH
$QRUH[LH
9RPLVVHPHQWV
3HUWHGHSRLGV
(IIHWVLQGpVLUDEOHVVpYqUHV
(IIHWVLQGpVLUDEOHVPRUWHOV
(IIHWVLQGpVLUDEOHVFRQGXLVDQW jO·DUUrWGXWUDLWHPHQW
(IIHWVLQGpVLUDEOHVGLJHVWLIV FRQGXLVDQWjO·DUUrWGX WUDLWHPHQW
(IIHWVLQGpVLUDEOHVOHVSOXVIUpTXHQWV
3LUIpQLGRQH QRXYHOHVVDLUDQGRPLVp HWHIIHWVVHFRQGDLUHVjORQJWHUPH /D SLUIpQLGRQH HVW XQ WUDLWHPHQW DQWLÀEURVDQW GRQQp SDU YRLHRUDOHGRQWOHPpFDQLVPHG·DFWLRQHVWHQFRUHPDOFRP SULV>@3OXVLHXUVHVVDLVUDQGRPLVpVpYDOXHQWVRQHIÀFDFLWp GDQV OD )3, /H SUHPLHU SXEOLp SDU$]XPD HW DO >@ HVW XQ HVVDL SURVSHFWLI UDQGRPLVp FRQWUH SODFHER HQ GRXEOH DYHXJOHLQFOXDQWSDWLHQWV/DSLUIpQLGRQHHVWDGPLQLV WUpHjGRVHVSURJUHVVLYHVGHjPJM6LOHVUpVXOWDWV VRQWHQFRXUDJHDQWVHQSDUWLFXOLHUGDQVXQVRXVJURXSHGH SDWLHQWVJDUGDQWXQHVDWXUDWLRQHQR[\JqQHVXSpULHXUHj DXFRXUVG·XQWHVWG·H[HUFLFHGHPLQXWHVFHWHVVDLQ·DSDV SHUPLV GH PRQWUHU GH GLIIpUHQFH VLJQLÀFDWLYH HQWUH OHV JURXSHVFRQFHUQDQWOHGpFOLQGHOD&9)&HVUpVXOWDWVDVVRFLpV j OD GpPRQVWUDWLRQ G·XQH ERQQH WROpUDQFH RQW VXVFLWp OD UpDOLVDWLRQG·pWXGHVGHSKDVH,,,(QSDWLHQWVVRQW UDQGRPLVpVGDQVXQHVVDLFRPSUHQDQWEUDV SLUIpQLGRQH
j KDXWH GRVH PJM YV SLUIpQLGRQH j IDLEOH GRVH PJM YV SODFHER >@ /D GRVH GH SLUIpQLGRQH HVW DXJPHQWpHSDUSDOLHUVXUXQHGXUpHWRWDOHGHVHPDLQHV /HFULWqUHSULQFLSDOGHMXJHPHQWDpWpPRGLÀpDYDQWODOHYpH G·DYHXJOH,QLWLDOHPHQWODYDULDWLRQGHODSOXVEDVVH6D HQWUHGHVWHVWVG·H[HUFLFHjYLWHVVHVWDEOHHVWUHWHQXH PrPH FULWqUHSULQFLSDOTXH>@ PDLVO·pYROXWLRQGHVFRQQDLVVDQFHV GHVSDUDPqWUHVIRQFWLRQQHOVDVVRFLpVjODVXUYLHGDQVOD)3, HW OHV GLIÀFXOWpV GH UHSURGXFWLELOLWp GHV WHVWV G·H[HUFLFHV RQWIDLWSUpIpUHUODYDULDWLRQGHOD&9)HQSRXUFHQWDJHGHOD YDOHXUSUpGLWHDSUqVVHPDLQHVGHWUDLWHPHQW/HGpFOLQGH OD&9)HVWVLJQLÀFDWLYHPHQWPRLQVLPSRUWDQWGDQVOHJURXSH WUDLWpSDUSLUIpQLGRQHPJMHQFRPSDUDLVRQGXJURXSH SODFHER DYHF UpGXFWLRQ GX GpFOLQ GH GDQV OH JURXSH WUDLWpSDUUDSSRUWDXJURXSHUHFHYDQWOHSODFHER /YV / S /DVXUYLHVDQVSURJUHVVLRQpWDLWpJD OHPHQWVLJQLÀFDWLYHPHQWPHLOOHXUHGDQVOHJURXSHWUDLWp SDUWLUGHFHWWHpWXGHXQVRXVJURXSHGHSDWLHQWV &9)
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
HW6D ORUVGXWHVWG·H[HUFLFH DpWpLGHQWLÀpFRPPH EpQpÀFLDQW GDYDQWDJH GHODSLUIpQLGRQH>@O·LVVXHGH FHVHVVDLVO·DJHQFHMDSRQDLVHGXPpGLFDPHQWDDXWRULVpOD SLUIpQLGRQHSRXUOHWUDLWHPHQWGHOD)3,>@ 'HX[DXWUHVHVVDLVGHSKDVH,,, pWXGHV3,3)HW3,3) SURJUDPPH&$3$&,7< PXOWLFHQWULTXHV (XURSH$PpULTXHGX 1RUGHW$XVWUDOLH UDQGRPLVpVHQGRXEOHDYHXJOHRQWpWpUpD OLVpV/HVSDWLHQWVLQFOXVSUpVHQWHQWXQH)3,GLDJQRVWLTXpHGDQV OHVPRLVSUpFpGHQWVVRQWkJpVGHjDQVHWO·DOWpUDWLRQ IRQFWLRQQHOOHUHVSLUDWRLUHHVWGpÀQLHFRPPHOpJqUHjPRGpUpH /HFDUDFWqUHOpJHUjPRGpUpGHODPDODGLHDFWXHOOHPHQWDGPLV SRXUODSUHVFULSWLRQDpWpGpÀQLORUVGHFHVHVVDLVSDUXQH &9)HQWUHHW GHODYDOHXUSUpGLWHXQH'/&2FRPSULVH HQWUHHW GHODYDOHXUSUpGLWHHWXQHGLVWDQFHSDUFRXUXH DXWHVWGHPDUFKHGHPLQXWHV 70 P>@/HFULWqUH SULQFLSDOGHMXJHPHQWHVWODYDULDWLRQHQSRXUFHQWDJHGHOD &9) SDU UDSSRUW j OD YDOHXU SUpGLWH DSUqV VHPDLQHV GH WUDLWHPHQW'DQVO·pWXGHSDWLHQWVVRQWUDQGRPLVpV HQWUHSLUIpQLGRQH PJMYVSLUIpQLGRQHPJMYV SODFHER/·pWXGHDUDQGRPLVpSDWLHQWVHQWUHSLUIpQL GRQHPJMHWSODFHER'DQVO·pWXGHODSLUIpQLGRQH UpGXLWVLJQLÀFDWLYHPHQWOHGpFOLQGHOD&9)FKH]OHVSDWLHQWV UHFHYDQWPJM S 6RL[DQWHGHVSDWLHQWV DYDLHQWXQGpFOLQGHSOXVGHGHOD&9) SURJUHVVLRQ jVHPDLQHVGDQVOHJURXSHSLUIpQLGRQHPJMFRQWUH GDQVOHJURXSHSODFHER S /HEpQpÀFHGX WUDLWHPHQWVXUOHGpFOLQGHOD&9)HWODVXUYLHVDQVSURJUHVVLRQ HVWFRQVWDWpjSDUWLUGHVHPDLQHVGHWUDLWHPHQWHWMXVTX·DX[ VHPDLQHVG·pWXGH/HVUpVXOWDWVQHVRQWSDVVLJQLÀFDWLYHPHQW GLIIpUHQWVHQWHUPHVGHUDOHQWLVVHPHQWGXGpFOLQGHODIRQFWLRQ UHVSLUDWRLUHHQWUHOHJURXSHSODFHERHWOHJURXSHSLUIpQLGRQH PJM'DQVO·pWXGHLOQ·H[LVWHSDVGHGLIIpUHQFH VLJQLÀFDWLYHHQWUHOHJURXSHSODFHERHWOHJURXSHSLUIpQLGRQH HQWHUPHVGHGpFOLQGH&9) )LJ &HVUpVXOWDWVRQWSHUPLVO·DSSUREDWLRQGHODSLUIpQLGRQH PJM GDQVOHWUDLWHPHQWGHOD)3,SDUO·DJHQFHHXUR SpHQQHGXPpGLFDPHQWHWXQHUHFRPPDQGDWLRQG·XWLOLVDWLRQ FKH] GHV SDWLHQWV VpOHFWLRQQpV ORUV GX FRQVHQVXV$76(56
Mean change from baseline in FVC (1 % predicted)
A
>@(Q)UDQFHODSLUIpQLGRQHDpWpFRPPHUFLDOLVpHj SDUWLU G·RFWREUH VRXV OH QRP G·(VEULHW &HSHQGDQW OHVHUYLFHPpGLFDOUHQGXHVWIDLEOHVHORQOD+DXWH$XWRULWp GH6DQWpHWOLPLWpDX[SDWLHQWVD\DQWXQH)3,FHUWDLQHDYHF XQH&9)HWXQH'/&2'DQVOHPrPHWHPSV O·DJHQFHDPpULFDLQHGXPpGLFDPHQWQ·DSDVDXWRULVpVDPLVH VXUOHPDUFKpDX[eWDWV8QLV 8QTXDWULqPHHVVDLGHSKDVH,,,UDQGRPLVpHQGRXEOH DYHXJOH PXOWLFHQWULTXH QRPPp$6&(1' $VVHVVHPHQW RI SLUIHQLGRQH WR FRQÀUP HIÀFDFLW\ DQG VDIHW\ LQ LGLRSDWKLF SXOPRQDU\ÀEURVLV HVWSUpVHQWpORUVGXFRQJUqVGHO·$76 /HVUpVXOWDWVSXEOLpVOHPrPHMRXUGDQVOH1HZ(QJODQG -RXUQDORI0HGLFLQH>@RQWpWpGpWDLOOpVjQRXYHDXSDU7( .LQJ 6DQ)UDQFLVFR&DOLIRUQLDeWDWV8QLV GDQVODVHVVLRQ $ 6N\IDOO ODWHEUHDNLQJFOLQLFDOWULDOVLQLGLRSDWKLFSXO PRQDU\ ÀEURVLV /·pWXGH UpDOLVpH GDQV FHQWUHV LQFOXW SDWLHQWVGRQWOHVGHX[WLHUVUDQGRPLVpVDX[eWDWV8QLV GHIDoRQpTXLYDOHQWHHQWUHSODFHERHWSLUIpQLGRQHjODGRVH GHPJM /HVFULWqUHVG·LQFOXVLRQFRQFHUQDQWODIRQFWLRQUHVSLUD WRLUHVRQWXQSHXGLIIpUHQWVGHFHX[XWLOLVpVSRXUOHVpWXGHV 3,3)(QHIIHWOD&9)GRLWrWUHHQWUHHW GHODYDOHXU SUpGLWHHWOHUDSSRUW9(06&9)GRLWrWUHVXSpULHXURXpJDOj /DOLPLWHLQIpULHXUHGH'/&2HVWSOXVEDVVHjGHOD YDOHXUSUpGLWHFRQWUHGDQVOHVHVVDLVSUpFpGHQWV/HEXW GHFHVPRGLÀFDWLRQVHVWGHVpOHFWLRQQHUGHVSDWLHQWVD\DQWXQ ULVTXHGHSURJUHVVLRQGHODPDODGLHSOXVLPSRUWDQW(QÀQOH FULWqUHSULQFLSDOGHMXJHPHQWHVWOHPrPHVRLWODYDULDWLRQ GHOD&9)HQSRXUFHQWDJHGHODYDOHXUSUpGLWH FHWWHYDULD WLRQHVWPHVXUpHjVHPDLQHVGHWUDLWHPHQWYVVHPDLQHV GDQVOHVHVVDLVSUpFpGHQWV'HUQLqUHGLIIpUHQFH ODUHYXH FHQWUDOLVpHGHVpOpPHQWVGLDJQRVWLTXHVGHOD)3, VFDQQHU WKRUDFLTXHHWELRSVLHSXOPRQDLUHFKLUXUJLFDOH GHVGRQQpHV SHUPHWWDQWG·pWDEOLUXQOLHQGHFDXVDOLWpHQWUHOHGpFqVHW ODÀEURVHSXOPRQDLUHHWGHVSDUDPqWUHVGHVSLURPpWULH /HVFDUDFWpULVWLTXHVGpPRJUDSKLTXHVIRQFWLRQQHOOHVHW G·REVHUYDQFH VRQW FRPSDUDEOHV GDQV OHV JURXSHV$SUqV VHPDLQHVGHWUDLWHPHQWOHGpFOLQGHOD&9)GDQVOHJURXSH
B
C
0 –2 –4 –6 –8 – 10 Pirfenidone 2 403 mg/day (n = 174) Pirfenidone 1 197 mg/day (n = 87) Placebo (n = 174)
– 12 – 14 0
Absolute difference* Relative difference* p value†
12
24
36
48
60
1,4 % 2,5 % 4,6 % 4,8 % 4,1 % 53,5 % 65,2 % 63,7 % 52,3 % 38,3 % 0,061 0,014 0,0001 0,0009 0,0002
72
Pirfenidone 2 403 mg/day (n = 171) Placebo (n = 173) 0
12
24
36
48
60
72
– 4,4 % 2,8 % 2,4 % 1,9 % 0,6 % 0,6 % 4,4 % – 31,5 % 62,1 % 48,2 % 27,3 % 7,6 % 6,5 % 35,3 % 0,021 0,001 0,011 0,005 0,172 0,501 0,001
Pirfenidone 2 403 mg/day (n = 345) Placebo (n = 347) 0
12
24
36
48
60
72
0,5 % 2,7 % 3,5 % 3,3 % 2,4 % 2,5 % 28,5 % 63,6 % 57,5 % 41,6 % 25,1 % 22,8 % 0,003 < 0,0001 < 0,0001 < 0,0001 0,0003 0,005
)LJXUH9DULDWLRQPR\HQQHGXSRXUFHQWDJHGHOD&9)SDUUDSSRUWjODYDOHXUSUpGLWH GHJDXFKHjGURLWHpWXGHpWXGH3,3)HW SRSXODWLRQUHJURXSpHGHVpWXGHVHW >@
'%RXYU\6-RXQHDX
WUDLWpHVWVLJQLÀFDWLYHPHQWPRLQVLPSRUWDQWSDUUDSSRUWDX JURXSHSODFHER S /HVHUYLFHUHQGXSDUOHWUDLWH PHQWHVWTXDQWLÀpSDUSDUDPqWUHV SURSRUWLRQGHVSDWLHQWV D\DQWXQGpFOLQGH&9)HWRXGpFpGpVjVHPDLQHV UpGXLWHGH GDQVOHJURXSHWUDLWp SDWLHQWV>@ YV SDWLHQWV > @ HW OD SURSRUWLRQ GH SDWLHQWV SRXU OHVTXHOVOD&9)Q·DSDVGpFOLQpGDQVOHJURXSHSLUIp QLGRQHHW GDQVOHJURXSHSODFHER/DGLIIpUHQFHHQWUH OHVJURXSHVDSSDUDvWjSDUWLUGHVHPDLQHVGHWUDLWHPHQW &RQFHUQDQWOHVFULWqUHVGHMXJHPHQWVHFRQGDLUHV²YDULDWLRQ GHODGLVWDQFHSDUFRXUXHDXWHVWGHPDUFKHGHPLQXWHVj VHPDLQHVHWVXUYLHVDQVSURJUHVVLRQ²LOVVRQWpJDOHPHQW VLJQLÀFDWLYHPHQWGLIIpUHQWVHQWUHOHVJURXSHVHQIDYHXU GHODSLUIpQLGRQH )LJ /H GpFOLQ PR\HQ GH OD &9) HQ YDOHXU DEVROXH )LJ HVW GH PO VHPDLQHV GDQV OH JURXSH WUDLWp HW GH PO VHPDLQHV GDQV OH JURXSH SODFHER &HV YDOHXUV VRQWVXSpULHXUHVjFHOOHVFRQVWDWpHVGDQVOHVDXWUHVHVVDLV WKpUDSHXWLTXHV TX·LO V·DJLVVH GX JURXSH SODFHER RX GX JURXSH WUDLWp /·H[SOLFDWLRQ HVW G·XQH SDUW O·DWWULEXWLRQ G·XQH&9)jDX[SDWLHQWVGpFpGpVHQFRXUVG·HVVDLORUVGX FDOFXOGHODYDULDWLRQPR\HQQHGHOD&9)PpWKRGHTXLDYDLW pWpSUpVSpFLÀpHSRXUFDOFXOHUODYDULDWLRQGH&9)FULWqUHGH MXJHPHQWSULQFLSDOGHO·pWXGH G·DXWUHSDUWODVpOHFWLRQGHV SDWLHQWVVXUOHSODQGLDJQRVWLTXH UHYXHFHQWUDOLVpHSOXVGH
A Decreased FVC or Death 35 Pirfenidone (N = 278)
P < 0,001
Placebo (N = 277)
Pirfenidone (N = 278)
25
P < 0,001
20 P < 0,001
15 10 5
P < 0,001
0 26
39 Week
– 200 – 300 – 400
13
26 Week
39
52
D Progression-free Survival
Pirfenidone (N = 278) P = 0,04 Placebo (N = 277)
30
P = 0,12
P = 0,04 Patients (%)
35
25 20 P = 0,40 15
100 90 80 70 60 50 40 30
Pirfenidone (N = 278)
Placebo (N = 277) Hazard ratio, 0,57 (95 %, 0,43 –0,77) P < 0,001
20 10
10 5 0
Placebo (N = 277) 0
52
C Decreased Walk Distance or Death
Patients (%)
– 100
– 500 13
40
B Change in FVC 0 Mean Change (ml)
Patients (%)
30
DYHFGHVVFDQQHUVW\SLTXHVGH3,& HWIRQFWLRQQHO OLPLWH LQIpULHXUHGHOD'/&2SOXVEDVVH /DFRXUEHG·H[WUDSRODWLRQ OLQpDLUH FODVVLTXH SUpVHQWpH GDQV OHV UpVXOWDWV DQQH[HV PRQWUHXQHGLPLQXWLRQPR\HQQHGH&9)GHPOGDQVOH JURXSHWUDLWpHWGHPOGDQVOHJURXSHSODFHER GLIIpUHQFH PR\HQQHDEVROXHGHPOGLIIpUHQFHPR\HQQHUHODWLYHGH S /DPRUWDOLWpQ·HVWSDVVLJQLÀFDWLYHPHQW GLIIpUHQWHHQWUHOHVJURXSHV GDQVOHJURXSHSLUIpQLGRQH YVGDQVOHJURXSHSODFHER+5 &,j S /·HIIHWGXWUDLWHPHQWVXUO·LQFLGHQFHG·H[DFHUED WLRQDLJXsQ·HVWSDVGLVFXWp /·HQVHPEOHGHVGRQQpHVGHVSDWLHQWVGH&$3$&,7< HW$6&(1'DIDLWO·REMHWG·DQDO\VHVVWDWLVWLTXHVVXSSOpPHQ WDLUHV SUpYXHV ORUV GH O·pODERUDWLRQ GX GHUQLHU HVVDL >@ /HVFULWqUHVG·LQFOXVLRQQHVRQWSDVVWULFWHPHQWLGHQWLTXHV PDLVOHVSRSXODWLRQVGHFHVHVVDLVUHVWHQWFRPSDUDEOHVHQ WHUPHVGHGpPRJUDSKLHHWGHIRQFWLRQ/·DQDO\VHPRQWUHXQH GLPLQXWLRQGHODPRUWDOLWpjDQTXHOOHTXHVRLWODFDXVH GLPLQXWLRQGH HWGHODPRUWDOLWpOLpHjODÀEURVH GLPL QXWLRQGH FKH]OHVSDWLHQWVUHFHYDQWGHODSLUIpQLGRQH SDUUDSSRUWDXJURXSHSODFHER 7DEOHDX &HSHQGDQWFHV UpVXOWDWVQHVRQWSDVLVVXVG·XQHVHXOHpWXGHUDQGRPLVpHPDLV G·XQHDQDO\VHVWDWLVWLTXHSUpVSpFLÀpHFRQFHUQDQWSOXVLHXUV SRSXODWLRQVGHSDWLHQWV&HUWDLQVDXWHXUVFRQVLGqUHQWTXH O·pYDOXDWLRQGXWDX[GHPRUWDOLWpFRPPHFULWqUHSULQFLSDO
0 13
26
39 Week
)LJXUH5pVXOWDWVGHO·pWXGH$6&(1'>@
0
13
52
26
39
52
219 192
144 113
Week no. at Risk Pirfenidone Placebo
276 273
269 262
243 225
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
GHMXJHPHQWGDQVGHVHVVDLVFRQFHUQDQWGHVSDWLHQWVDYHF XQH)3,OpJqUHjPRGpUpHHVWGLIÀFLOHjUpDOLVHUHQWHUPH G·HIIHFWLIHWGHGXUpH> @ 3DUDOOqOHPHQWjFHVGRQQpHVVXUO·HIÀFDFLWpGXPpGLFD PHQWDXFRXUVGXFRQJUqVVRQWUDSSRUWpVOHVHIIHWVLQGpVL UDEOHVUHFHQVpVFKH] SDWLHQWVD\DQWUHoXGHODSLUIpQLGRQH jPJM>@TXLRQWpJDOHPHQWpWpSXEOLpV>@,OV·DJLW GHVSDWLHQWVLQFOXVGDQVOHVpWXGHVHWHWGHSDWLHQWV D\DQWSDUWLFLSpjGHVpWXGHVRXYHUWHV7URLVSRSXODWLRQVVRQW GRQFDQDO\VpHV ODSRSXODWLRQLQWpJUpH SDWLHQWVD\DQWUHoX SLUIpQLGRQHPJGDQV3,3)HWpWXGHVRXYHUWHV SRSXODWLRQ GHV pWXGHV HW D\DQW UHoX SLUIpQLGRQH PJMHWHQVHPEOHGHVSDWLHQWVVRXVSODFHERGDQVOHV pWXGHV HW /D GXUpH PR\HQQH GH WUDLWHPHQW HVW GHDQV VHPDLQHjDQV HW GHVSDWLHQWVRQW UHoXODSLUIpQLGRQHSHQGDQWXQHGXUpHVXSpULHXUHRXpJDOH jDQV&RPPHGDQVOHVUHFRPPDQGDWLRQVGHSUHVFULSWLRQ
GH O·(VEULHW OHV SURWRFROHV DXWRULVHQW GHV UpGXFWLRQV GH GRVHVHQIRQFWLRQGHVHIIHWVVHFRQGDLUHV /HVSULQFLSDX[HIIHWVVHFRQGDLUHVVRQWJDVWURLQWHVWLQDX[ HWFXWDQpVHWUpVXPpVGDQVOHWDEOHDX,OVVRQWGDQVOD PDMRULWp GHV FDV OpJHUV j PRGpUpV HW QH QpFHVVLWHQW TXH UDUHPHQW O·DUUrW GH OD SULVH PpGLFDPHQWHXVH ,OV VXUYLHQ QHQW OH SOXV VRXYHQW GDQV OHV SUHPLHUV PRLV UDUHPHQW DSUqVOHGRX]LqPHPRLVGHWUDLWHPHQW8QHpOpYDWLRQGHV WUDQVDPLQDVHVVXSpULHXUHjIRLVODQRUPDOHHVWFRQVWDWpH SOXV IUpTXHPPHQW FKH] OHV SDWLHQWV UHFHYDQW GH OD SLUIp QLGRQH DYHF GDQV WRXV OHV FDV XQH UpYHUVLELOLWp VDQVVpTXHOOHFOLQLTXHDSSX\DQWDLQVLOHVUHFRPPDQGDWLRQV HXURSpHQQHVHWFDQDGLHQQHVGHVXUYHLOODQFHPHQVXHOOHGHV WUDQVDPLQDVHVSHQGDQWOHVSUHPLHUVPRLVGHWUDLWHPHQW SXLVWULPHVWULHOOH'HVLQVRPQLHVHWGHVYHUWLJHVVRQWGpFODUpV FKH]UHVSHFWLYHPHQWHWGHVSDWLHQWVUHFHYDQWOD SLUIpQLGRQHGDQVOHVpWXGHVHWVRLWSOXVGHXQHIRLV
7DEOHDX0RUWDOLWpWRXWHVFDXVHVFRQIRQGXHVGDQVO·HVVDL$6&(1'OHVHVVDLV&$3$&,7<HWHQDQDO\VDQWODSRSXODWLRQ JOREDOH 3DWLHQWVQ
3LUIpQLGRQH PJM
3ODFHER
+5 ,& Â
S
$6&(1' 1
3RROHG 1
&$3$&,7< 1
'·DSUqV.LQJ7(%UDGIRUG:=&DVWUR%HUQDUGLQL6)DJDQ($*ODVSROH,*ODVVEHUJ0.HWDO$SKDVHWULDORISLUIHQLGRQHLQSDWLHQWV ZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV1(QJO-0HG0D\ ² DSSHQGL[
3UHVSHFLÀHGVHFRQGDU\HQGSRLQWLQ$6&(1' 'DWDLQWKH&$3$&,7<VWXGLHVFHQVRUHGDWRQH\HDU Â&R[SURSRUWLRQDOKD]DUGVPRGHO /RJUDQNWHVW
7DEOHDX(IIHWVVHFRQGDLUHVGHODSLUIpQLGRQHjORQJWHUPH$GDSWpG·DSUqV>@ 3RSXODWLRQLQWpJUpH Q
&$3$&,7<SLUIpQLGRQHPJM Q
&$3$&,7<SODFHER Q
5DVKFXWDQp
$UUrWGXWUDLWHPHQW
1DXVpHV $UUrWGXWUDLWHPHQW
'LDUUKpH $UUrWGXWUDLWHPHQW
'\VSHSVLH $UUrWGXWUDLWHPHQW
9RPLVVHPHQWV $UUrWGXWUDLWHPHQW
3KRWRVHQVLELOLWp $UUrWGXWUDLWHPHQW
HWGHPLHSOXVIUpTXHPPHQWTXHFKH]OHVSDWLHQWVUHFHYDQW OHSODFHERGDQVFHVPrPHVpWXGHVVDQVHQWUDvQHUWRXWHIRLV O·LQWHUUXSWLRQ GX WUDLWHPHQW /D IDWLJXH HW O·DQRUH[LH QH VHPEOHQWSDVSOXVIUpTXHQWHVFKH]OHVSDWLHQWVUHFHYDQWOD SLUIpQLGRQH'HVpYpQHPHQWVLQGpVLUDEOHVJUDYHVVRQWVLJQDOpV FKH]GHVSDWLHQWVGHODSRSXODWLRQLQWpJUpHFKH] GHVSDWLHQWVGHVpWXGHVHWUHFHYDQWODSLUIpQLGRQH HW GHV SDWLHQWV LQFOXV GDQV OH EUDV SODFHER GH FHV pWXGHV5DSSRUWpVDXWHPSVGHWUDLWHPHQWFHVpYpQHPHQWV QHVRQWSDVSOXVIUpTXHQWVGDQVFHWWHSRSXODWLRQTXHGDQV OHVDXWUHVJURXSHV/·pYpQHPHQWLQGpVLUDEOHJUDYHOHSOXV IUpTXHQWSRXUOHVSRSXODWLRQVHVWO·DJJUDYDWLRQGHOD)3, GDQVODSRSXODWLRQLQWpJUpHHWGDQVOHVHVVDLV HW FHWWHGLIIpUHQFHpWDQWH[SOLTXpHSDUXQWHPSV GHVXLYLSOXVORQJFKH]OHVSDWLHQWVGHODSRSXODWLRQLQWpJUpH 0DOJUp GHV OLPLWDWLRQV pYLGHQWHV OLpHV DX IDLW TXH OHV SDWLHQWVpWXGLpVSURYLHQQHQWG·pWXGHVGLIIpUHQWHVLOH[LVWH XQHJOREDOHVpFXULWpG·HPSORLGXPpGLFDPHQWFKH]XQQRPEUH LPSRUWDQWGHSDWLHQWVHWSHQGDQWXQWHPSVG·H[SRVLWLRQDVVH] ORQJ&HWWHLQIRUPDWLRQHVWLQWpUHVVDQWHFDUDFWXHOOHPHQW ODGXUpHGXWUDLWHPHQWHQFDVGHVWDELOLVDWLRQGHODIRQF WLRQUHVSLUDWRLUHQ·HVWSDVGpÀQLH&HSHQGDQWVLOHVHIIHWV LQGpVLUDEOHVRQWUDUHPHQWHQWUDLQpO·DUUrWGXPpGLFDPHQWLO IDXWUDSSHOHUTX·LOV·DJLWGHSDWLHQWVSDUWLFLSDQWjGHVHVVDLV H[FOXDQWFHX[SUpVHQWDQWGHVFRPRUELGLWpVLPSRUWDQWHVHW FHUWDLQHV WKpUDSHXWLTXHV PpGLFDPHQWHXVHV DVVRFLpHV HW UHFHYDQWGHVFRQVHLOVV\VWpPDWLTXHVGHSKRWRSURWHFWLRQHW GHSULVHPpGLFDPHQWHXVHDXFRXUVGHVUHSDV 'HV pWXGHV FRPSOpPHQWDLUHV VHURQW QpFHVVDLUHV SRXU pYDOXHUODVpFXULWpGXPpGLFDPHQWHQSDUWLFXOLHUFKH]OHV VRXVJURXSHVGHSDWLHQWVOHVSOXVVpYqUHV'DQVODSRSXODWLRQ LQWpJUpHGHVSDWLHQWVDYDLHQWXQH'/&2LQIpULHXUH j HW DYDLHQW XQH &9) LQIpULHXUH j GH OD YDOHXUSUpGLWH OHVUpVXOWDWVSRXUFHVRXVJURXSHQHVRQW SDVGpWDLOOpV 'HVSUpVHQWDWLRQVVHVRQWLQWpUHVVpHVjFHVSDWLHQWVSOXV JUDYHV'·DERUGXQWUDYDLOUpWURVSHFWLIpYDOXDQWSDWLHQWV VRXV SLUIpQLGRQH GRQW DYHF XQH DWWHLQWH VpYqUH '/&2 PR\HQQHj PRQWUHXQHWHQGDQFHjXQHSOXVJUDQGH IUpTXHQFHGHVHIIHWVVHFRQGDLUHVGDQVFHVRXVJURXSH YV TXLQ·HVWFHSHQGDQWSDVVLJQLÀFDWLYH S >@ (QVXLWHGDQVO·K\SRWKqVHG·XQHV\QHUJLHG·DFWLRQHQWUH1$& HWODSLUIpQLGRQHGHVSDWLHQWVD\DQWXQHDOWpUDWLRQIRQFWLRQ QHOOHVpYqUH 3DDXUHSRVLQIpULHXUHjPP+J RQWUHoX VRLWO·DVVRFLDWLRQGHSLUIpQLGRQHHW1$&LQKDOp Q VRLW GH OD SLUIpQLGRQH HQ PRQRWKpUDSLH >@ /·DQDO\VH UpWURV SHFWLYHGHVVRXVJURXSHVPRQWUHXQHPHLOOHXUHVXUYLHVDQV SURJUHVVLRQGDQVOHJURXSHELWKpUDSLH'DQVFHJURXSHOH WUDLWHPHQWDpWpDUUrWpFKH]SDWLHQWVSRXUGHVHIIHWV VHFRQGDLUHV LOQ·\DSDVHXG·LQWHUUXSWLRQGHWUDLWHPHQW FKH]OHVSDWLHQWVSUHQDQWODSLUIpQLGRQHVHXOH&HVpWXGHV UpWURVSHFWLYHVQHSHXYHQWSDVJXLGHUODWKpUDSHXWLTXHPDLV VRXOqYHQWODTXHVWLRQGHODSULVHHQFKDUJHG·XQHFDWpJRULH GHSDWLHQWVQRQUHSUpVHQWpHGDQVOHVJUDQGVHVVDLVUDQGR PLVpV'DQVO·HVVDL$6&(1'>@GHVSDWLHQWVRQWXQH '/&2HQWUHHWGHODYDOHXUSUpGLWHjO·LQFOXVLRQFH TXLSRXUUDLWIDLUHPRGLÀHUOHVLQGLFDWLRQVGHSUHVFULSWLRQ DFWXHOOHPHQWOLPLWpHjXQH'/&2
'%RXYU\6-RXQHDX
&RQFOXVLRQ /HGLDJQRVWLFGHÀEURVHSXOPRQDLUHLGLRSDWKLTXHUHVWHGLIÀFLOH HW OD PLVH HQ pYLGHQFH G·XQH FDXVH GRLW UHVWHU O·REMHFWLI SUHPLHUPrPHGHYDQWXQDVSHFWFHUWDLQGH3,&VXUOD7'0 WKRUDFLTXH/HVQRXYHDX[WUDLWHPHQWVGLVSRQLEOHVHWjYHQLU UHQGHQWODGLVFXVVLRQPXOWLGLVFLSOLQDLUHFHQWUDOHOHGLDJQRV WLF UHWHQX SHUPHWWDQW RX QRQ GH SURSRVHU XQ WUDLWHPHQW DQWLÀEURVDQW /HV PRGDOLWpV GH FH WUDLWHPHQW QH VRQW SDV HQFRUHFODLUHPHQWGpÀQLHV3DUUDSSRUWDX[UHFRPPDQGDWLRQV IUDQoDLVHV>@OD1$&HQPRQRWKpUDSLHQHGHYUDLWSOXVrWUH SUHVFULWHHQSUHPLqUHLQWHQWLRQGDQVOD)3,(Q)UDQFHVHXOH OD SLUIpQLGRQH D XQH DXWRULVDWLRQ GH PLVH VXU OH PDUFKp $00 SRXUOHVSDWLHQWVD\DQWXQH)3,OpJqUHjPRGpUpH /HQLQWHGDQLEGRQWOHVLQGLFDWLRQVHWOHVEpQpÀFHVDWWHQGXV VRQW VLPLODLUHV SRXUUDLW rWUH REWHQX HQ$78 DXWRULVDWLRQ WHPSRUDLUHG·XWLOLVDWLRQ DYDQWO·REWHQWLRQpYHQWXHOOHG·XQH $00/DSODFHG·DVVRFLDWLRQGHWUDLWHPHQWDQWLÀEURVDQWQ·HVW SDVFRQQXHHWVHUDjGpÀQLU3DUDLOOHXUVFHVUpVXOWDWVGRLYHQW IDLUHUHPHWWUHHQFDXVHODUpDOLVDWLRQG·HVVDLWKpUDSHXWLTXH FRQWUHSODFHERTXDQGO·DWWHLQWHIRQFWLRQQHOOHHVWOpJqUHj PRGpUHH ,OIDXWUDSSHOHUTXHOHVUpVXOWDWVSUpVHQWpVORUVGXFRQJUqV GHO·$76QHSHUPHWWHQWSDVGHGRQQHUXQWUDLWHPHQW DQWLÀEURVDQWDX[SDWLHQWVOHVSOXVVpYqUHVjTXLGHVHVVDLV WKpUDSHXWLTXHVSHXYHQWrWUHSURSRVpV 'DQV WRXV OHV FDV OH SDWLHQW GRLW rWUH LQIRUPp TXH OH EpQpÀFHDWWHQGXGHVWKpUDSHXWLTXHVHVWXQUDOHQWLVVHPHQW GXGpFOLQGHODFDSDFLWpIRQFWLRQQHOOHUHVSLUDWRLUH(QÀQV·LO H[LVWHXQHLQGLFDWLRQOHELODQHQYXHG·XQHWUDQVSODQWDWLRQ SXOPRQDLUH QH GRLW SDV rWUH UHWDUGp SDU OD PLVH HQ URXWH GHVWUDLWHPHQWV
/LHQVG·LQWpUrWV $XFRXUVGHVGHUQLqUHVDQQpHV'%RXYU\DSHUoXGHV KRQRUDLUHVSRXUDFWLRQVGHIRUPDWLRQGHODSDUWGXODERUDWRLUH ,QWHUPXQHHWDpWpFRLQYHVWLJDWHXUGDQVGHVSURWRFROHVGH UHFKHUFKHFOLQLTXHVXUODÀEURVHSXOPRQDLUHLGLRSDWKLTXH ODERUDWRLUH,QWHUPXQHHW%RHUKLQJHU
5pIpUHQFHV >@ 7UDYLV:'&RVWDEHO8+DQVHOO'0.LQJ7(/\QFK'$1LFKRO VRQ$*HWDO$QRIÀFLDO$PHULFDQ7KRUDFLF6RFLHW\(XURSHDQ 5HVSLUDWRU\ 6RFLHW\ VWDWHPHQW 8SGDWH RI WKH LQWHUQDWLRQDO PXOWLGLVFLSOLQDU\ FODVVLÀFDWLRQ RI WKH LGLRSDWKLF LQWHUVWLWLDO SQHXPRQLDV$P-5HVSLU&ULW&DUH0HG ² >@ /H\%&ROODUG+5(SLGHPLRORJ\RILGLRSDWKLFSXOPRQDU\ÀEUR VLV&OLQ(SLGHPLRO ² >@ 5DJKX*&ROODUG+5(JDQ--0DUWLQH])-%HKU-%URZQ.. HWDO$QRIÀFLDO$76(56-56$/$7VWDWHPHQW LGLRSDWKLFSXO PRQDU\ÀEURVLV HYLGHQFHEDVHGJXLGHOLQHVIRUGLDJQRVLVDQG PDQDJHPHQW$P-5HVSLU&ULW&DUH0HG ² >@ &RWWLQ9&UHVWDQL%9DOH\UH':DOODHUW%&DGUDQHO-'DO SKLQ-&HWDO5HFRPPDQGDWLRQVSUDWLTXHVSRXUOHGLDJQRVWLF HWODSULVHHQFKDUJHGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH eODERUpHVSDUOHFHQWUHQDWLRQDOGHUpIpUHQFHHWOHVFHQWUHVGH
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
>@
>@
>@
>@
> @
>@
>@
>@
>@
>@ >@
>@
>@
>@
FRPSpWHQFHSRXUOHVPDODGLHVSXOPRQDLUHVUDUHVVRXVO·pJLGH GH OD 6RFLpWp GH SQHXPRORJLH GH ODQJXH IUDQoDLVH 5HY 0DO 5HVSLU ² %MRUDNHU-$5\X-+(GZLQ0.0\HUV-/7D]HODDU+'6FKUR HGHU'5HWDO3URJQRVWLFVLJQLÀFDQFHRIKLVWRSDWKRORJLFVXE VHWV LQ LGLRSDWKLF SXOPRQDU\ ÀEURVLV$P - 5HVSLU &ULW &DUH 0HG ² 1LFKROVRQ$*&ROE\79GX%RLV50+DQVHOO'0:HOOV$87KH SURJQRVWLF VLJQLÀFDQFH RI WKH KLVWRORJLF SDWWHUQ RI LQWHUVWL WLDOSQHXPRQLDLQSDWLHQWVSUHVHQWLQJZLWKWKHFOLQLFDOHQWLW\ RIFU\SWRJHQLFÀEURVLQJDOYHROLWLV$P-5HVSLU&ULW&DUH0HG ² -RKNRK76DNDL)1RPD6$NLUD0)XMLPRWR.:DWDGDQL7 HW DO +RQH\FRPELQJ RQ &7 LWV GHÀQLWLRQ SDWKRORJLF FRU UHODWLRQ DQG IXWXUH GLUHFWLRQ RI LWV GLDJQRVLV (XU - 5DGLRO ² 6LOYD &,6 0OOHU 1/ +DQVHOO '0 /HH .6 1LFKROVRQ $* :HOOV$8 1RQVSHFLÀF LQWHUVWLWLDO SQHXPRQLD DQG LGLRSDWKLF SXOPRQDU\ÀEURVLV FKDQJHVLQSDWWHUQDQGGLVWULEXWLRQRIGLV HDVHRYHUWLPH5DGLRORJ\ ² :DWDGDQL76DNDL)-RKNRK71RPD6$NLUD0)XMLPRWR. HWDO,QWHUREVHUYHUYDULDELOLW\LQWKH&7DVVHVVPHQWRIKRQH\ FRPELQJLQWKHOXQJV5DGLRORJ\ ² $]XPD$1XNLZD77VXERL(6XJD0$EH61DNDWD.HWDO 'RXEOHEOLQG SODFHERFRQWUROOHG WULDO RI SLUIHQLGRQH LQ SDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV$P-5HVSLU&ULW &DUH0HG ² 5\HUVRQ &- 8UEDQLD 7+ 5LFKHOGL / 0RRQH\ -- /HH -6 -RQHV .' HW DO 3UHYDOHQFH DQG SURJQRVLV RI XQFODVVLÀDEOH LQWHUVWLWLDOOXQJGLVHDVH(XU5HVSLU- ² /H\%&ROODUG+5.LQJ7(&OLQLFDOFRXUVHDQGSUHGLFWLRQRI VXUYLYDOLQLGLRSDWKLFSXOPRQDU\ÀEURVLV$P-5HVSLU&ULW&DUH 0HG ² 6WXDUW %' /HH -6 .R]OLWLQD - 1RWK , 'HYLQH 06 *OD]HU &6HWDO(IIHFWRIWHORPHUHOHQJWKRQVXUYLYDOLQSDWLHQWV ZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV DQREVHUYDWLRQDOFRKRUW VWXG\ZLWKLQGHSHQGHQWYDOLGDWLRQ/DQFHW5HVSLU0HG .LQJ7(3DUGR$6HOPDQ0,GLRSDWKLFSXOPRQDU\ÀEURVLV/DQ FHW ² 'HPHGWV0%HKU-%XKO5&RVWDEHO8'HNKXLM]HQ5-DQ VHQ+0HWDO+LJKGRVHDFHW\OF\VWHLQHLQLGLRSDWKLFSXOPR QDU\ÀEURVLV1(QJO-0HG ² ,GLRSDWKLF 3XOPRQDU\ )LEURVLV &OLQLFDO 5HVHDUFK 1HWZRUN 5DJKX*$QVWURP.-.LQJ7(/DVN\-$0DUWLQH])-3UHGQL VRQHD]DWKLRSULQHDQG1DFHW\OF\VWHLQHIRUSXOPRQDU\ÀEUR VLV1(QJO-0HG ² ,GLRSDWKLF3XOPRQDU\)LEURVLV&OLQLFDO5HVHDUFK1HWZRUN0DU WLQH])-GH$QGUDGH-$$QVWURP.-.LQJ7(5DJKX*5DQ GRPL]HGWULDORIDFHW\OF\VWHLQHLQLGLRSDWKLFSXOPRQDU\ÀEURVLV 1(QJO-0HG ² 5LFKHOGL/GX%RLV505DJKX*$]XPD$%URZQ..&RVWD EHO8HWDO(IÀFDF\DQGVDIHW\RIQLQWHGDQLELQLGLRSDWKLFSXO PRQDU\ÀEURVLV 5HVXOWVRIWZRZHHNSKDVH,,,UDGRPL]HG SODFHERFRQWUROOHGWULDOV ,138/6,6 $
> @ 5LFKHOGL/&RVWDEHO86HOPDQ0.LP'6+DQVHOO'01LFK ROVRQ$*HWDO(IÀFDF\RIDW\URVLQHNLQDVHLQKLELWRULQLGLR SDWKLFSXOPRQDU\ÀEURVLV1(QJO-0HG ² >@ 5LFKHOGL/GX%RLV505DJKX*$]XPD$%URZQ..&RVWD EHO8HWDO(IÀFDF\DQGVDIHW\RIQLQWHGDQLELQLGLRSDWKLFSXO PRQDU\ÀEURVLV1(QJO-0HG ² >@ &ROODUG +5 0RRUH %% )ODKHUW\ .5 %URZQ .. .DQHU 5- .LQJ7(HWDO$FXWHH[DFHUEDWLRQVRILGLRSDWKLFSXOPRQDU\ ÀEURVLV$P-5HVSLU&ULW&DUH0HG ² >@ 6FKDHIHU&-5XKUPXQG':3DQ/6HLZHUW6'.RVVHQ.$QWL ÀEURWLFDFWLYLWLHVRISLUIHQLGRQHLQDQLPDOPRGHOV(XU5HVSLU 5HY2II-(XU5HVSLU6RF ² >@ 7DQLJXFKL+(ELQD0.RQGRK<2JXUD7$]XPD$6XJD0 HWDO3LUIHQLGRQHLQLGLRSDWKLFSXOPRQDU\ÀEURVLV(XU5HVSLU - ² >@ $]XPD$7DJXFKL<2JXUD7(ELQD07DQLJXFKL+.RQGRK< HWDO([SORUDWRU\DQDO\VLVRIDSKDVH,,,WULDORISLUIHQLGRQH LGHQWLÀHVDVXESRSXODWLRQRISDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ ÀEURVLVDVEHQHÀWLQJIURPWUHDWPHQW5HVSLU5HV >@ &RWWLQ97KHUROHRISLUIHQLGRQHLQWKHWUHDWPHQWRILGLRSDWKLF SXOPRQDU\ÀEURVLV5HVSLU5HV 6 >@ 1REOH3:$OEHUD&%UDGIRUG:=&RVWDEHO8*ODVVEHUJ0. .DUGDW]NH ' HW DO 3LUIHQLGRQH LQ SDWLHQWV ZLWK LGLRSDWKLF SXOPRQDU\ ÀEURVLV &$3$&,7< WZR UDQGRPLVHG WULDOV /DQ FHW ² >@ .LQJ7( %UDGIRUG := &DVWUR%HUQDUGLQL 6 )DJDQ ($ *OD VSROH , *ODVVEHUJ 0. HW DO$ SKDVH WULDO RI SLUIHQLGRQH LQSDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV1(QJO-0HG ² >@ 1REOH 3:$OEHUD & %UDGIRUG := &RVWDEHO 8 GX %RLV 50 )DJDQ($HWDO$QDO\VLVRISRROHGGDWDIURPSKDVHPXO WLQDWLRQDOUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGWULDOV HYDOXDWLQJSLUIHQLGRQHLQSDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ ÀEURVLV ,3) $P-5HVSLU&ULW&DUH0HG $ > @ .LQJ7($OEHUD&%UDGIRUG:=&RVWDEHO8GX%RLV50/HII-$ HWDO$OOFDXVHPRUWDOLW\UDWHLQSDWLHQWVZLWKLGLRSDWKLFSXO PRQDU\ÀEURVLV,PSOLFDWLRQVIRUWKHGHVLJQDQGH[HFXWLRQRI FOLQLFDOWULDOV$P-5HVSLU&ULW&DUH0HG ² >@ 1DWKDQ6'$OEHUD&%UDGIRUG:=&RVWDEHO8GX%RLV50 )DJDQ($HWDO/RQJWHUPVDIHW\RISLUIHQLGRQHLQSDWLHQWV ZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV LQWHJUDWHGDQDO\VLVRIGDWD IURPFOLQLFDOWULDOV$P-5HVSLU&ULW&DUH0HG $ >@ 9DOH\UH'$OEHUD&%UDGIRUG:=&RVWDEHO8.LQJ7(/HII-$ HWDO&RPSUHKHQVLYHDVVHVVPHQWRIWKHORQJWHUPVDIHW\RI SLUIHQLGRQHLQSDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV5HV SLURORJ\ ² >@ .DJDPL 5 .DZDPXUD7 0RFKL]XNL< 1DNDKDUD< 6DVDNL 6 0RULPRWR$ HW DO (IÀFDFLW\ DQG VDIHW\ RI SLUIHQLGRQH LQ SDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV FRPSDUDLVRQRI PLOGPRGHUDWHFDVHVDQGVHYHUHFDVHV$P-5HVSLU&ULW&DUH 0HG $ >@ +RPPD6$6DNDPRWR66XJLQR.0XUDPDWVX<.D]XWRVKL, 7DNDL<(IÀFDF\RISLUIHQLGRQHFRPELQHGZLWK1DFHW\OF\VWH LQHWKHUDS\LQSDWLHQWVZLWKDGYDQFHGLGLRSDWKLFSXOPRQDU\ ÀEURVLV$P-5HVSLU&ULW&DUH0HG $
'LVSRQLEOH HQ OLJQH VXU
ZZZVFLHQFHGLUHFWFRP
31(8023$7+,(6,17(567,7,(//(6',))86(6
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUH LGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV ,GLRSDWKLFSXOPRQDU\ÀEURVLVPHGLFDOWUHDWPHQW 1HZLQVLJKWV '%RXYU\D 6-RXQHDXE D$VVLVWDQFHSXEOLTXH+{SLWDX[GH3DULVK{SLWDO$YLFHQQHVHUYLFHGHSQHXPRORJLH
%RELJQ\ E6HUYLFHGH3QHXPRORJLH&HQWUHGHFRPSpWHQFHVGHVPDODGLHVSXOPRQDLUHVUDUHV GH%UHWDJQH+{SLWDO3RQWFKDLOORX UXH+HQUL/H*XLOORX[5(11(6FHGH[ )UDQFH
$PpOLRUHUODGpPDUFKHGLDJQRVWLTXH HWO·pYDOXDWLRQSURQRVWLTXHGHODÀEURVH SXOPRQDLUHLGLRSDWKLTXHSRXUSURSRVHU XQWUDLWHPHQW /DÀEURVHSXOPRQDLUHLGLRSDWKLTXH )3, HVWODSOXVIUpTXHQWH GHV SQHXPRSDWKLHV LQWHUVWLWLHOOHV LGLRSDWKLTXHV 3,, >@ /HV pWXGHV pSLGpPLRORJLTXHV SURYLHQQHQW SULQFLSDOHPHQW GHVeWDWV8QLVG·(XURSHHWGX-DSRQ/·LQFLGHQFHDQQXHOOH UDSSRUWpHYDULHHQWUHHWKDELWDQWV>@/HV GLIÀFXOWpV GLDJQRVWLTXHV HW OHV YDULDWLRQV VXFFHVVLYHV GHV FULWqUHVUHQGHQWO·pSLGpPLRORJLHH[DFWHLPSUpFLVH /H FRQVHQVXV$76(56 >@ SHUPHW GH UHWHQLU FH GLDJQRVWLF HQ SUpVHQFH G·XQH SQHXPRSDWKLH LQWHUVWLWLHOOH FRPPXQH 3,& FHUWDLQH VXU OH VFDQQHU WKRUDFLTXH UpWL FXODWLRQV UD\RQ GH PLHO DYHF RX VDQV EURQFKHFWDVLHV SDU WUDFWLRQSUpGRPLQDQFHVRXVSOHXUDOHHWEDVDOHGHVOpVLRQVHW DEVHQFHGHVLJQHLQFRPSDWLEOHDYHFXQH3,& HWDSUqVDYRLU pOLPLQpXQHpWLRORJLH6LOHFRQWH[WHFOLQLTXHHWIRQFWLRQQHO OHSHUPHWHQO·DEVHQFHGH3,&FHUWDLQHVXUOHVFDQQHUOH UHFRXUVjXQHELRSVLHSXOPRQDLUHFKLUXUJLFDOHGLDJQRVWLTXH HVWUHFRPPDQGpDSUqVGLVFXVVLRQPXOWLGLVFLSOLQDLUH>@/HV UHFRPPDQGDWLRQVGHSHUPHWWHQWpJDOHPHQWGHFODVVHU OHVUpVXOWDWVDQDWRPRSDWKRORJLTXHVHQIRQFWLRQGHODSUR EDELOLWpGLDJQRVWLTXHGH3,&/DFRQIURQWDWLRQGHVUpVXOWDWV
$XWHXUFRUUHVSRQGDQW $GUHVVHHPDLO GLDQHERXYU\#DYFDSKSIU '%RXYU\
63/)3XEOLpSDU(OVHYLHU0DVVRQ6$67RXVGURLWVUpVHUYpV
DQDWRPRSDWKRORJLTXHVDYHFOHVpOpPHQWVFOLQLTXHVHW7'0HVW QpFHVVDLUHSRXUSRVHUOHGLDJQRVWLFGH)3,&HWWHGpPDUFKH HVWMXVWLÀpHSDUOHSURQRVWLFSDUWLFXOLqUHPHQWVRPEUHGHOD PDODGLHSDUFRPSDUDLVRQDX[DXWUHV3,,HQSDUWLFXOLHUOHV SQHXPRSDWKLHVLQWHUVWLWLHOOHVQRQVSpFLÀTXHV 3,16 >@ /HVFDQQHUWKRUDFLTXHDXQHSODFHFHQWUDOHGDQVOHGLDJQRV WLFGHVSQHXPRSDWKLHVLQWHUVWLWLHOOHVGLIIXVHV6LODSUpVHQFH GHUD\RQGHPLHOHVWLQGLVSHQVDEOHDXGLDJQRVWLFGH)3,HQ O·DEVHQFHGHELRSVLHSXOPRQDLUHFKLUXUJLFDOHVDSUpVHQFHQH VXIÀWSDVDXGLDJQRVWLF(QHIIHWLOSHXWrWUHSUpVHQWGDQV WRXWHVOHVÀEURVHVjXQVWDGHDYDQFp>@\FRPSULVOHV3,16>@ /DUHFRQQDLVVDQFHGXUD\RQGHPLHOQ·HVWSDVpYLGHQWH HQSDUWLFXOLHUORUVTX·LOHVWDVVRFLpjGHVEURQFKHFWDVLHVSDU WUDFWLRQHWODFRQFRUGDQFHHQWUHUDGLRORJXHVQ·HVWKDELWXHO OHPHQWSDVVDWLVIDLVDQWHDYHFGHVYDOHXUVκLQWHUREVHUYDWHXUV HQWUHHW> @'$/\QFK 'HQYHUeWDWV8QLV DXFRXUV GHODVHVVLRQ/8SGDWHIURPLGLRSDWKLFSXOPRQDU\ÀEURVLV QHWZRUN,3)1(7DSUpVHQWpXQHDQDO\VHUpWURVSHFWLYHGH SDWLHQWVLQFOXVGDQVGHVHVVDLVWKpUDSHXWLTXHVDYHFOH GLDJQRVWLFGH)3,HWSRXUOHVTXHOVXQHELRSVLHSXOPRQDLUH FKLUXUJLFDOH D pWp UpDOLVpH 7DEOHDX 'DQV FH FDGUH SDUWLFXOLHUG·HVVDLFOLQLTXHVXUOD)3,ODFRQFRUGDQFHLQWHU REVHUYDWHXUVpWDLWERQQH κ FRPPHFHODDGpMjpWp UDSSRUWp >@ 'H IDoRQ DWWHQGXH GDQV FHWWH SRSXODWLRQ VpOHFWLRQQpHGXUD\RQGHPLHOHVWSUpVHQWVXUOHVFDQQHU GDQV GHVFDVD\DQWXQHKLVWRORJLHFHUWDLQHRXSUREDEOH
'%RXYU\6-RXQHDX
7DEOHDX&RUUpODWLRQHQWUHDQDWRPRSDWKRORJLHHWVFDQQHUWKRUDFLTXH'·DSUqV'DYLG$/\QFK 'HQYHUeWDWV8QLV DX FRXUVGHODVHVVLRQ/ 3,& SQHXPRSDWKLHLQWHUVWLWLHOOHFRPPXQH 'LDJQRVWLFDQDWRPRSDWKRORJLTXH 'LDJQRVWLF7'0
3,&FHUWDLQH
3,&SUREDEOH
3,&SRVVLEOH
$XWUHGLDJQRVWLF
7RWDO
3,&
3,&SRVVLEOH
3,&LQFRPSDWLEOH
7RWDO
GH3,&'DQVHQYLURQXQTXDUWGHVFDV SDWLHQWV OH VFDQQHU HVW FODVVp HQ 3,& SRVVLEOH /·KLVWRORJLH SXOPR QDLUHGHFHVSDWLHQWVHVWXQH3,&W\SLTXHSRXUODPDMRULWp Q XQH3,&SRVVLEOHSRXU SDWLHQWVHWSUREDEOHSRXU SDWLHQWVSHUPHWWDQWGHUHWHQLUOHGLDJQRVWLFGH)3,FHUWDLQH RXSUREDEOHGDQVWRXVOHVFDV&HVUpVXOWDWVVRXOLJQHQWTXH O·DEVHQFHGHUD\RQGHPLHOVXUOHVFDQQHUWKRUDFLTXHQ·H[FOXW SDV OH GLDJQRVWLF GH )3, HW TXH FHWWH VLWXDWLRQ HVW DVVH] IUpTXHQWHGDQVFHWWHSRSXODWLRQROHGLDJQRVWLFUHWHQXHVW )3,(QÀQSDUPLOHVSDWLHQWVDYHFXQHKLVWRORJLHFHUWDLQH GH3,&SUqVG·XQWLHUV RQWXQRXSOXVLHXUV pOpPHQWV DW\SLTXHV VXU OH VFDQQHU WKRUDFLTXH XQ DVSHFW HQ PRVDwTXH HWRX GH SLpJHDJH DOYpRODLUH O·DEVHQFHGHSUpGRPLQDQFHEDVDOHXQHDWWHLQWHVDQV SUpGRPLQDQFHSpULSKpULTXH XQHSUpGRPLQDQFHSpUL EURQFKRYDVFXODLUHHWGDQVGHVFDVXQHSUpGRPLQDQFH VXSpULHXUHRXPR\HQQHGHVOpVLRQV 0DOJUpXQHGpPDUFKHGLDJQRVWLTXHFRPSOqWHXQFHUWDLQ QRPEUH GH SQHXPRSDWKLHV LQWHUVWLWLHOOHV GLIIXVHV UHVWHQW LQFODVVDEOHV>@'DQVXQHFRKRUWHGHSDWLHQWVD\DQW XQHSQHXPRSDWKLHLQWHUVWLWLHOOHGLIIXVHDXFXQGLDJQRVWLFQ·D SXrWUHUHWHQXGDQVGHVFDV/HSOXVVRXYHQWODELRSVLH SXOPRQDLUHFKLUXUJLFDOHQ·HVWSDVUpDOLVpH HQUDLVRQG·XQ ULVTXHRSpUDWRLUHWURSLPSRUWDQW HQFDVGHSDWKRORJLH SHXVpYqUHHWVWDEOHSRXUODTXHOOHOHUDSSRUWEpQpÀFHULVTXH Q·HVWSDVHQIDYHXUGXGLDJQRVWLFFKLUXUJLFDO RXELHQ ORUVTXHOHSDWLHQWODUHIXVH /RUVTX·HOOHDpWpUpDOLVpH ODTXDQWLWpGHWLVVXREWHQXHHVWLQVXIÀVDQWHGDQVGHVFDV HWFKH]GHVSDWLHQWVODGLVFXVVLRQPXOWLGLVFLSOLQDLUH Q·DERXWLWSDVjXQFRQVHQVXVGLDJQRVWLTXH>@ &HVGLIÀFXOWpVRQWIDLWSURSRVHUSDUDOOqOHPHQWjODGpPDUFKH GLDJQRVWLTXHFODVVLTXHXQHpYDOXDWLRQFRPSRUWHPHQWDOHGHV SQHXPRSDWKLHVLQWHUVWLWLHOOHVGLIIXVHVD[pHVXUOHSURÀOpYROXWLI HQSDUWLFXOLHUIRQFWLRQQHO>@'DQVOHFDVG·XQH)3,O·pYDOXDWLRQ SURQRVWLTXHHVWpJDOHPHQWLPSRUWDQWHVXUWRXWSRXUOHVSDWLHQWV pOLJLEOHVjXQHWUDQVSODQWDWLRQSXOPRQDLUH6LODVXUYLHPpGLDQH HVWGHjDQVLOH[LVWHSOXVLHXUVSURÀOVpYROXWLIV SURJUHVVLRQ OHQWHUDSLGHHWH[DFHUEDWLRQDLJXs /HVSDUDPqWUHVSK\VLR ORJLTXHVDVVRFLpVjXQHDXJPHQWDWLRQGHODPRUWDOLWpVRQWXQ GpFOLQGHPGHODGLVWDQFHSDUFRXUXHDXWHVWGHPDUFKH GHPLQXWHVHQVHPDLQHVXQHGLPLQXWLRQGHODFDSDFLWp YLWDOHIRUFpH &9) HWRXGHODFDSDFLWpGHWUDQVIHUWGX&2 '/&2 GHUHVSHFWLYHPHQWHWGHODYDOHXUSUpGLWHHQ PRLV>@&.*DUFLD 'DOODVeWDWV8QLV DSUpVHQWpDXFRXUV GHVVHVVLRQV' 8SGDWHVLQJHQRPLFDQGSUHFLVLRQPHGLFLQH HW& 7KHJROGÀQJHUSULQW PROHFXODUFKDUDFWHUL]DWLRQRI LQWHUVWLWLDOOXQJGLVHDVH XQWUDYDLOpJDOHPHQWSXEOLp>@VXU ODYDOHXUSUpGLFWLYHGHODORQJXHXUGHVWpORPqUHVGDQVOD)3,
/HVWpORPqUHVVRQWGHVSURWpLQHVSURWpJHDQWO·H[WUpPLWpGHV FKURPRVRPHV/HXUDOWpUDWLRQIUDJLOLVHO·pSLWKpOLXPDOYpRODLUH HWOHGpYHORSSHPHQWG·XQHÀEURVHSXOPRQDLUHHQSUpVHQFH G·XQIDFWHXUIDYRULVDQW>@,OHVWGpFULWGHVPXWDWLRQVGHV WpORPpUDVHV HQ]\PHSHUPHWWDQWO·DOORQJHPHQWGHVWpORPqUHV FKH]GHVSDWLHQWVD\DQWXQH)3,VSRUDGLTXHHWGDQVFHUWDLQHV ÀEURVHVIDPLOLDOHV7URLVFRKRUWHVGHSDWLHQWVVRQWpWXGLpHV /HVGXUpHVPR\HQQHVGHVXLYLYDULHQWHQWUHHWPRLV/HV UpVXOWDWVPRQWUHQWXQUDFFRXUFLVVHPHQWVLJQLÀFDWLIGHVWpOR PqUHVFKH]OHVSDWLHQWVD\DQWXQHSQHXPRSDWKLHLQWHUVWLWLHOOH GLIIXVH )3,RXQRQ SDUUDSSRUWDX[VXMHWVVDLQV S &KH]OHVSDWLHQWVD\DQWXQH)3,ODORQJXHXUGHVWpORPqUHVHVW DVVRFLpHjODVXUYLHVDQVUHFRXUVjODWUDQVSODQWDWLRQSXOPRQDLUH HWHVWXQIDFWHXUSURQRVWLFLQGpSHQGDQW )LJ /DSODFHGH O·pWXGHGHVWpORPqUHVUHVWHjGpÀQLUPDLVODPLVHHQpYLGHQFH G·XQOLHQDYHFODVXUYLHUHQIRUFHO·LPSOLFDWLRQSDWKRJpQLTXHTXL DYDLWpWpVXJJpUpHSDUO·pWXGHGHFDVIDPLOLDX['HX[DXWUHV FRPPXQLFDWLRQVRQWIDLWSDUWGHO·LQWpUrWGHELRPDUTXHXUV &&/HW003SRXUpYDOXHUOHSURQRVWLFGHVSDWLHQWVD\DQW XQH)3,'DQVO·DYHQLUODFRPELQDLVRQGHIDFWHXUVSURQRVWLTXHV FOLQLTXHVHWSK\VLRORJLTXHVDYHFGHVPDUTXHXUVELRORJLTXHVRX JpQpWLTXHVSRXUUDLWJXLGHUODSULVHHQFKDUJHWKpUDSHXWLTXH GHVSDWLHQWV
1DFpW\OF\VWpLQHQLQWHGDQLE HWSLUIpQLGRQH PROpFXOHVFDQGLGDWHV SRXUOHWUDLWHPHQWGHODÀEURVH SXOPRQDLUHLGLRSDWKLTXH /HVUHFRPPDQGDWLRQVSUDWLTXHVGHOD63/)SXEOLpHVHQ UDSSHOOHQWOHVGLIIpUHQWHVPROpFXOHVD\DQWIDLWO·REMHWG·HV VDLVWKpUDSHXWLTXHVGDQVOD)3,>@&HUWDLQHVG·HQWUHVHOOHV VRQWGpFRQVHLOOpHV DVVRFLDWLRQD]DWKLRSULQHSUHGQLVRQH1 DFpW\OF\VWpLQH DQWLYLWDPLQH . DPEULVHQWDQ HW G·DXWUHV QRQUHFRPPDQGpHV FRUWLFRWKpUDSLHFROFKLFLQHHWDQHUFHSW FLFORVSRULQHLQWHUIpURQγE '·DXWUHSDUWOHEpQpÀFHSDU H[HPSOHGHODSLUIpQLGRQHHWGHOD1DFpW\OF\VWpLQH 1$& Q·HVWSDVFHUWDLQ>@ /HVWUDLWHPHQWVSUHVFULWVHWGLVSRQLEOHVpYROXHQWDYHFOHV FRQQDLVVDQFHVSDWKRJpQLTXHV8QHGHVSUHPLqUHVK\SRWKqVHV SURSRVpHDpWpXQHLQÁDPPDWLRQjO·RULJLQHGHODÀEURVH $FWXHOOHPHQWODSDUWLFLSDWLRQLQÁDPPDWRLUHPrPHVLHOOH VHPEOHMRXHUXQU{OHFKH]OHVSDWLHQWVD\DQWXQSURÀOGHSUR JUHVVLRQUDSLGHGHODPDODGLHQ·HVWSOXVFRQVLGpUpHFRPPH SUpSRQGpUDQWH HW OHV PpFDQLVPHV FRQGXLVDQW j OD ÀEURVH SXOPRQDLUHVRQWPDLQWHQDQWPLHX[FRQQXV>@ )LJ
Transplant-free survival (%)
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
A Dallas IPF cohort (n = 135) 100
B Chicago IPF cohort (n = 135)
C San Francisco IPF cohort (n = 135)
Q1 Q2 Q3 Q4
80 60 40 20 p = 0,0048
0 0
10
Number at risk Q4 34 Q3 33 Q2 34 Q1 34
p = 0,029
p = 0,00066
20
30 40 Months
20 8 16 12
8 3 5 5
50
60 0 4 1 0 3
10
31 30 31 31
20
30 40 Months
26 22 21 18
50
17 13 8 9
60 0 10 5 3 0
10
12 12 12 13
20
30 40 Months
10 10 7 9
50
10 7 6 5
60 9 6 6 4
)LJXUH6XUYLHVDQVWUDQVSODQWDWLRQHQIRQFWLRQGHODORQJXHXUGHVWpORPqUHVFKH]OHVSDWLHQWVD\DQWXQHÀEURVHSXOPRQDLUHLGLRSDWKLTXH>@
A Ageing-related susceptible lung
Recurring microinjuries Alveolar epithelium Capillaries
B Wound clot
C Aberrant activation of epithelial cells
Caveolin 1 RAGE
EGFs MMP1, MMP7
AEC migration and proliferation Epithelial cell apoptosis
Epithelial recapitulation of developmental pathways (Wnt, Shh)
FXa D Fibroblast focus MMP2 MMP9
E Hypercoagulable milieu Fibroblast recapitulatin of developmental pathways (PTEN, gremlin, FAPα)
F
Exaggerated ECM accumulatin
PDGF CXCL12 TGFβ
Progressive lung remodelling
Local fibroblasts Fibrocytes EMT, myofibroblast differentiation
Honeycomb changes
)LJXUH3K\VLRSDWKROJLHGHOD)3,HWVLWHVG·DFWLRQGHOD1DFpW\OF\VWpLQH HQEOHX GHODSLUIpQLGRQH HQMDXQH HWGXQLQWHGDQLE HQURXJH /·pSLWKpOLXP DOYpRODLUH ($ IUDJLOLVp kJH HWRX PRGLÀFDWLRQV JpQpWLTXHV HVW VRXPLV j GHV PLFURDJUHVVLRQV UpSpWpHV UHÁX[ JDVWUR ±VRSKDJLHQWDEDFLQIHFWLRQYLUDOH« HQWUDLQDQWO·DSRSWRVHGHVFHOOXOHVpSLWKpOLDOHVDOYpRODLUHV &($ /DUpSDUDWLRQGHO·($VHIDLWGH PDQLqUH DEHUUDQWH DYHF DIÁX[ GH ÀEUREODVWHV G·RULJLQHV PXOWLSOHV GDQV OHV ]RQHV OpVpHV IRUPDQW OHV IR\HUV ÀEUREODVWLTXHV MHXQHV /D V\QWKqVHHQH[FqVGHODPDWULFHH[WUDFHOOXODLUH ÀEUHVFROODJqQHV PDMRUHO·DSRSWRVHGHVFHOOXOHVDOYpRODLUHVpSLWKpOLDOHV/HVOpVLRQVGH UD\RQGHPLHOVRQWDORUVHQJHQGUpHVSDUOHVIRUFHVGHWUDFWLRQV·H[HUoDQWVXUFHSRXPRQFLFDWULFLHO$GDSWpSDU0DUWLQ5-.ROE +DPLOWRQ &DQDGD VHVVLRQ$ ©6N\IDOO ODWHEUHDNLQJFOLQLFDOWULDOVLQLGLRSDWKLFSXOPRQDU\ÀEURVLVª G·DSUqV>@
/HFRQJUqVGHO·$76DpWpO·RFFDVLRQGHODSUpVHQWD WLRQGHHVVDLVWKpUDSHXWLTXHVUDQGRPLVpVFRQWUHSODFHER FRQFHUQDQWOD1$&OHQLQWHGDQLEHWODSLUIpQLGRQH /RUV GH OD VHVVLRQ$ 6N\IDOO ODWH EUHDNLQJ FOLQLFDO WULDOVLQLGLRSDWKLFSXOPRQDU\ÀEURVLV 0-.ROE +DPLOWRQ &DQDGD D UDSSHOp OH UDWLRQQHO SK\VLRSDWKRORJLTXH SRXU O·XWLOLVDWLRQGHFKDFXQHGHFHVPROpFXOHV )LJ /D1$& GLPLQXHODSUROLIpUDWLRQGHVÀEUREODVWHVHWODV\QWKqVHGH FROODJqQHDLQVLTXHODV\QWKqVHGHVF\WRNLQHVSURÀEURVDQWHV 3'*) SODWHOHWGHULYHGJURZWKIDFWRU )*) ÀEUREODVWJURZWK IDFWRU HW7*)βSDUVRQDFWLRQDQWLR[\GDQWH DXJPHQWDWLRQ GXJOXWDWKLRQHWGLPLQXWLRQGHVUDGLFDX[OLEUHV /HQLQWHGDQLE HVW XQ LQKLELWHXU LQWUDFHOOXODLUH GH QRPEUHX[ UpFHSWHXUV W\URVLQHNLQDVHQRWDPPHQWGHVUpFHSWHXUVDX[IDFWHXUVGH FURLVVDQFH)*)3'*)HW9(*) YDVFXODUHQGRWKHOLDOJURZWK IDFWRU &HVF\WRNLQHVVRQWLPSOLTXpHVGDQVOHGpYHORSSHPHQW GHODÀEURVH/DSLUIpQLGRQHGRQWOHPpFDQLVPHG·DFWLRQ HVWSDUWLHOOHPHQWLQFRQQXDXQHDFWLRQDQWLLQÁDPPDWRLUH DQWLR[\GDQWHHWDQWLÀEURVDQWHSDUUpJXODWLRQGHO·DFWLYLWpGH 7*)βHWGH71)αLQYLWURDYHFLQKLELWLRQGHODSUROLIpUDWLRQ GHVÀEUREODVWHVHWGHODV\QWKqVHGXFROODJqQH
/H1DFpW\OF\VWpLQHQHUDOHQWLW SDVODSURJUHVVLRQGHODÀEURVH SXOPRQDLUHLGLRSDWKLTXH (Q O·HVVDL UDQGRPLVp ,),*(1,$ LQFOXDQW SDWLHQWV D PRQWUp TX·XQ WUDLWHPHQW WULSOH DVVRFLDQW D]DWKLRSULQH SUHGQLVRQH HW 1$& j KDXWH GRVH PJ IRLV SDU MRXU SUpVHUYHPLHX[ODIRQFWLRQUHVSLUDWRLUHHQFRPSDUDLVRQG·XQ WUDLWHPHQW GH D]DWKLRSULQHSUHGQLVRQH >@ /·DVVRFLDWLRQ GRXEOHRXWULSOHHVWDORUVODUJHPHQWXWLOLVpHSDUOHVSQHXPR ORJXHV&HSHQGDQWO·HIÀFDFLWpH[DFWHGHFHWWHDVVRFLDWLRQ DLQVLTXHVDWROpUDQFHFOLQLTXHFKH]OHVSDWLHQWVD\DQWXQH)3, UHVWHFRQWURYHUVpHG·DXWDQWSOXVTXHO·HVVDLQ·DSDVXWLOLVp GHEUDVSODFHER8QQRXYHOHVVDL3$17+(5,3)>@HVWSXEOLp GDQV OH 1(-0 HQ ,O V·DJLW G·XQ HVVDL PXOWLFHQWULTXH FRPSUHQDQW EUDV DYHF XQH UDQGRPLVDWLRQ pTXLYDOHQWH HQWUHSODFHERYV1$&VHXOYV1$&D]DWKLRSULQHSUHGQLVRQH /HV SDWLHQWV LQFOXV VRQW kJpV GH j DQV SUpVHQWHQW XQHÀEURVHSXOPRQDLUHLGLRSDWKLTXHUpSRQGDQWDX[FULWqUHV $76(56>@HWGLDJQRVWLTXpHGDQVOHVDQVSUpFpGDQW O·LQFOXVLRQ/·DOWpUDWLRQIRQFWLRQQHOOHjO·LQFOXVLRQHVWOpJqUH jPRGpUpHGpÀQLHSDUXQH&9HWXQH'/&2 GHV YDOHXUV SUpGLWHV /HV SDWLHQWV SUpVHQWDQW GHV OpVLRQV G·HPSK\VqPH PRUSKRORJLTXHPHQW SOXV LPSRUWDQWHV TXH OHV OpVLRQV GH ÀEURVH HW XQ UDSSRUW 9(06&9) LQIpULHXU j HWRXXQ95VXSpULHXUjVRQWH[FOXV/·DQDO\VH LQWHUPpGLDLUH PRLV DSUqV OH GpEXW GHV LQFOXVLRQV D PRQWUpXQQRPEUHVLJQLÀFDWLYHPHQWSOXVLPSRUWDQWG·HIIHWV VHFRQGDLUHVJUDYHVHWG·KRVSLWDOLVDWLRQVRXGpFqVFKH]OHV SDWLHQWVUHFHYDQWO·DVVRFLDWLRQ1$&D]DWKLRSULQHSUHGQLVRQH SDUUDSSRUWDXJURXSHSODFHER&HVFRQVWDWDWLRQVRQWFRQGXLW jO·DUUrWSUpPDWXUpGHO·pWXGHHWjODUHFRPPDQGDWLRQGHQH SDVGpEXWHUFHWUDLWHPHQWFKH]OHVSDWLHQWVSRXUOHVTXHOVOH GLDJQRVWLFGH)3,HVWUHWHQX /·HVVDL D FHSHQGDQW pWp SRXUVXLYL DYHF EUDV SDWLHQWV UDQGRPLVpV GDQV OH EUDV 1$& HW GDQV OH JURXSHSODFHER/HVUpVXOWDWVVRQWSUpVHQWpVVXFFHVVLYHPHQW
'%RXYU\6-RXQHDX
SDU * 5DJKX 6HDWWOH eWDWV8QLV SXLV SDU )- 0DUWLQH] $QQ$UERUeWDWV8QLV ORUVGHODVHVVLRQ$ 6N\IDOO ODWH EUHDNLQJFOLQLFDOWULDOVLQLGLRSDWKLFSXOPRQDU\ÀEURVLV >@ /H FULWqUH GH MXJHPHQW SULQFLSDO HVW OH GpFOLQ GH OD &9) j VHPDLQHV /HV REMHFWLIV VHFRQGDLUHV FRPSUHQDLHQW OH QRPEUHGHGpFqVOHWHPSVpFRXOpMXVTX·DXGpFqVOHGpODL VDQVSURJUHVVLRQOD'/&2OH70HWSOXVLHXUVTXHVWLRQQDLUHV H[SORUDQWODTXDOLWpGHYLHHWODG\VSQpH$SUqVVHPDLQHV GHWUDLWHPHQWLOQ·H[LVWHSDVGHGLIIpUHQFHVLJQLÀFDWLYHHQWUH OHVJURXSHV(WFHFLFRQFHUQHDXVVLELHQOHGpFOLQPR\HQGH &9)FULWqUHSULQFLSDOGHMXJHPHQWTXHOHVDXWUHVSDUDPqWUHV IRQFWLRQQHOVUHVSLUDWRLUHVPrPHV·LOH[LVWDLWXQHWHQGDQFH j O·DPpOLRUDWLRQ GX 70 GDQV OH JURXSH 1$& S $SUqVVHPDLQHVGHVXLYLGpFqVRQWpWpFRQVWDWpVGDQV OH JURXSH 1$& HW GpFqV GDQV OH JURXSH SODFHER Oj QRQ SOXVVDQVGLIIpUHQFHVLJQLÀFDWLYH7URLVH[DFHUEDWLRQVDLJXsV VRQWVXUYHQXHVGDQVFKDTXHJURXSHSHQGDQWODSpULRGHGH VXLYL 6HXOV OHV TXHVWLRQQDLUHV GH TXDOLWpV GH YLH pWDLHQW VLJQLÀFDWLYHPHQWPHLOOHXUVGDQVOHJURXSH1$& 6)PHQWDO VFRUHS HW,&(&$3VXPPDU\VFRUHS $XWRWDO XQTXDUWGHVSDWLHQWVGXJURXSH1$&HWGHVSDWLHQWV GXJURXSHSODFHERRQWDUUrWpO·pWXGH'DQVOHVJURXSHV SOXVGH GHVSDWLHQWVGpFODUDLHQWSUHQGUHDXPRLQV GXWUDLWHPHQW'HVHIIHWVLQGpVLUDEOHVJUDYHVVRQWVXUYHQXV FKH]GHVSDWLHQWVUHFHYDQWGHOD1$&HWFKH] GHVSDWLHQWVUHFHYDQWOHSODFHER S DYHFXQQRPEUH G·HIIHWVFDUGLRYDVFXODLUHVLQGpVLUDEOHVJUDYHVVLJQLÀFDWLYH PHQWSOXVLPSRUWDQWGDQVOHJURXSH1$& FRQWUH S /HW\SHH[DFWGHVpYpQHPHQWVFDUGLRYDVFXODLUHV Q·HVW SDV GpWDLOOp 2Q UHPDUTXH TX·LO Q·H[LVWH SDV G·DXJ PHQWDWLRQGHVHIIHWVLQGpVLUDEOHVJUDYHVJDVWURLQWHVWLQDX[ GDQVOHJURXSH1$& /HVUpVXOWDWVGHFHWWHpWXGHRQWpWpEHDXFRXSGLVFXWpV ORUVGHOHXUSUpVHQWDWLRQ(QHIIHWOHPpFDQLVPHG·DFWLRQGH OD1$&GDQVOD)3,DYDLWHQWUHWHQXGHVHVSRLUVTXDQWjFHWWH PROpFXOH/HVUpVXOWDWVSHXYHQWrWUHSUpVHQWpVHQVpSDUDQW SKDVHVFKURQRORJLTXHV DYDQWHWDSUqVOHSDVVDJHGHO·pWXGH GHjEUDVHQUDLVRQGHO·DXJPHQWDWLRQGHVGpFqVHWGHV KRVSLWDOLVDWLRQVGDQVOHEUDV1$&D]DWKLRSULQHSUHGQLVRQH 'DQVODSUHPLqUHSpULRGHO·pYROXWLRQGHVSDUDPqWUHVUHVSL UDWRLUHVHVWPHLOOHXUHGDQVOHJURXSHWUDLWpSDU1$&PDLVVDQV GLIIpUHQFH VLJQLÀFDWLYH )LJ &HUWDLQV DXWHXUV SHQVHQW TXHO·REVHUYDQFHDpWpPRLQVERQQHDSUqVODSXEOLFDWLRQGH O·HIIHWGpOpWqUHGHO·DVVRFLDWLRQ1$&SUHGQLVRQHD]DWKLRSULQH HWTXHODWHQGDQFHjXQHHIÀFDFLWpGX1$&Q·DSDVSXrWUH FRQÀUPpHSDUOHVUpVXOWDWV1pDQPRLQVHQFRQFOXVLRQFKH] OHVSDWLHQWVD\DQWXQH)3,OpJqUHjPRGpUpHOD1$&jODGRVH GHPJMHQPRQRWKpUDSLHQHSHUPHWSDVG·HPSrFKHU OHGpFOLQGHOD&9)
(IÀFDFLWpGXQLQWHGDQLE %,%) pWXGHV,138/6,6 /5LFKHOGLDSUpVHQWpOHVUpVXOWDWVGHVpWXGHV,138/6,6 HWPRQWUDQWO·HIÀFDFLWpGXQLQWHGDQLE %,%) GDQVOH WUDLWHPHQWGHOD)3,>@ /·pWXGH7202552:SXEOLpHHQpWXGHGHSKDVH UDQGRPLVpHHQGRXEOHDYHXJOHDYDLWPRQWUpODVXSpULRULWp GXQLQWHGDQLEjODGRVHGHPJIRLVSDUMRXUSHQGDQW PRLVSDUUDSSRUWDX[DXWUHVGRVDJHV PJIRLVSDU
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
B
A Change from baseline in FVC
After alert
0,0
Outcome
• Placebo
• •
FVC (liters)
-0,05
-0,10
• Acetylcysteine • •
-0,15
••
-0,20
Base- 15 line No. at risk Acety|cysteine 133 Placebo 131
127 127
30
45
60
Week 118 119
113 118
102 109
All patients
Before alert
P Value for Interaction
t-Statistic
FVC
0,16
DLCO corrected
0,02
CPI
0,04
Alveolar-arterial gradient
0,70
Walk distance
0,20
Oxygen saturation AUC
0,72
Walk distance to desaturation
0,65
Minutes walked
0,76
SF-36 aggregate physical score
0,89
SF-36 aggregate mental score
0,08
EuroQoL score
0,51
EuroQoL thermometer response
0,56
St. George’s total score
0,19
St. George’s symptoms score
0,45
St. George’s activity score
0,20
St. George’s impacts score
0,29
UCSD SOBQ total score
0,10 0,10
ICECAP summary score -3
-2
-1
Placebo better
0
1
2
3
Acetylcysteine better
)LJXUHeYROXWLRQGHOD&9)GDQVOHJURXSHSODFHERHWGDQVOHJURXSH1$& JDXFKH 3UpVHQWDWLRQGHVUpVXOWDWVJOREDX[HWGHVUpVXOWDWV DYDQWHWDSUqVODPRGLÀFDWLRQGXSURWRFROH GURLWH >@
MRXUPJIRLVSDUMRXUPJXQHIRLVSDUMRXURXSOD FHER > @/HQLQWHGDQLEjPJIRLVSDUMRXUUDOHQWLVVDLW OH GpFOLQ GH OD &9) GLPLQXDLW OHV H[DFHUEDWLRQV GH )3, HW SUpVHUYDLWODTXDOLWpGHYLH /HV pWXGHV © MXPHOOHV ª GH SKDVH ,138/6,6 HW UDQGRPLVpHVHQGRXEOHDYHXJOHFRQWUHSODFHERRQWGRQF pYDOXpO·HIÀFDFLWpHWODWROpUDQFHGXQLQWHGDQLEjPJ IRLVSDUMRXUVXUPRLVGDQVOHWUDLWHPHQWGHOD)3,>@ /DUpDOLVDWLRQGHpWXGHVMXPHOOHVUpSRQGjXQHH[LJHQFH GHO·DJHQFHDPpULFDLQHGHVpFXULWpGXPpGLFDPHQW )'$ DÀQ G·REWHQLU XQH DXWRULVDWLRQ GH PLVH VXU OH PDUFKp $00 ,OV·DJLVVDLWGHGHX[pWXGHVPXOWLFHQWULTXHVLQFOXDQWGHV SDWLHQWVHQ$PpULTXHHQ(XURSHHQ$VLHHWHQ$XVWUDOLH /HVFULWqUHVG·LQFOXVLRQpWDLHQWFODVVLTXHV SDWLHQWVkJpVGH DQVHWSOXVGLDJQRVWLFGH)3,FHUWDLQH VFDQQHUWKRUDFLTXH KLVWRORJLH VXU ELRSVLH SXOPRQDLUH FKLUXUJLFDOH >%3&@ VL GLVSRQLEOH GDWDQW GH PRLQV GH DQV &9) GH OD WKpRULTXH'/&2HQWUHHW GHODWKpRULTXH/HVVFDQ QHUVWKRUDFLTXHVHWOHVpYHQWXHOOHV%3&EpQpÀFLDLHQWG·XQH UHOHFWXUHFHQWUDOLVpH/HVDXWUHVWUDLWHPHQWVDQWLÀEURVDQWV pWDLHQW LQWHUGLWV LH SLUIpQLGRQH 1$& D]DWKLRSULQH« VDXIODFRUWLFRWKpUDSLHVLODGRVHpWDLWVWDEOHHWPJM 1pDQPRLQVGHVGRVHVSOXVpOHYpHVGHFRUWLFRWKpUDSLHpWDLHQW DXWRULVpHVORUVGXWUDLWHPHQWGHVH[DFHUEDWLRQVGH)3,/H UDWLR GH UDQGRPLVDWLRQ pWDLW GH SDWLHQWV GDQV OH EUDV QLQWHGDQLEFRQWUHSDWLHQWVGDQVOHEUDVSODFHER /HFULWqUHGHMXJHPHQWSULQFLSDOpWDLWOHGpFOLQDQQXHOGH OD&9)/HVFULWqUHVGHMXJHPHQWVHFRQGDLUHVFOpVpWDLHQWOH WHPSVMXVTX·jODSUHPLqUHH[DFHUEDWLRQGH)3,HWO·DQDO\VH GHODTXDOLWpGHYLH TXHVWLRQQDLUHUHVSLUDWRLUH6W*HRUJHRX 6*54 8QFRPLWpG·DGMXGLFDWLRQHQDYHXJOHGXEUDVWLUpDX
VRUWDQDO\VDLWOHVGRVVLHUVGHVSDWLHQWVFKH]TXLXQHH[DFHU EDWLRQpWDLWUDSSRUWpHSDUOHVLQYHVWLJDWHXUVHWFRQÀUPDLWRX QRQO·H[DFHUEDWLRQVHORQODGpÀQLWLRQHQYLJXHXU>@3RXU UDSSHOOHGLDJQRVWLFG·H[DFHUEDWLRQGH)3,QpFHVVLWH OH GLDJQRVWLFSUpDODEOHRXFRQFRPLWDQWGH)3, ODSUpVHQFHGH QRXYHOOHVRSDFLWpVVXUOHVFDQQHUWKRUDFLTXH XQHG\VSQpH TXL V·DJJUDYH VXU PRLQV GH MRXUV O·H[FOXVLRQ G·XQH LQIHFWLRQSXOPRQDLUHSDUSUpOqYHPHQWLQYDVLI ODYDJHEURQ FKLRORDOYpRODLUHRXDVSLUDWLRQHQGRWUDFKpDOH O·H[FOXVLRQ G·XQH DXWUH pWLRORJLH LQVXIÀVDQFH FDUGLDTXH HPEROLH SXOPRQDLUHDXWUHV/DSUpVHQFHGHVFULWqUHVSHUPHWGH UHWHQLU OH GLDJQRVWLF G·H[DFHUEDWLRQ FHUWDLQH GH )3, V·LO PDQTXHXQFULWqUHOHGLDJQRVWLFHVWDORUVH[DFHUEDWLRQGH )3,VXVSHFWpH>@/DPRUWDOLWppWDLWpJDOHPHQWDQDO\VpH ELHQTXHO·pWXGHQ·DLWSDVpWpPRGpOLVpHSRXUPRQWUHUXQH GLIIpUHQFHGHPRUWDOLWpHQWUHOHVEUDV (QWUHPDLHWVHSWHPEUHSDWLHQWVRQW pWpLQFOXVGDQVO·pWXGH,138/6,6HWGDQVO·pWXGH ,138/6,6/HVFDUDFWpULVWLTXHVFOLQLTXHVGHVSDWLHQWVLQFOXV VRQWGpWDLOOpHVGDQVOHWDEOHDX/HVpWXGHVRQWPRQWUp XQUDOHQWLVVHPHQWVLJQLÀFDWLIGHOD&9)DSUqVVHPDLQHVGH WUDLWHPHQW )LJ POGDQVOHEUDVSODFHER Q FRQWUH POGDQVOHEUDVQLQWHGDQLE Q S GRQQpHV GHV pWXGHV UDVVHPEOpHV GLIIpUHQFH PR\HQQH HQWUHOHVEUDVGHPO ,& jPO &RQFHUQDQW OHV FULWqUHV VHFRQGDLUHV OH WHPSV MXVTX·j OD SUHPLqUH H[DFHUEDWLRQ GLDJQRVWLF GHV LQYHVWLJDWHXUV Q·pWDLWSDVGLIIpUHQWGDQVOHVEUDVGHO·pWXGH,138/6,6 5LVTXHUHODWLI>55@ ,& ² S DORUVTX·LOpWDLWDOORQJpGDQVOHEUDVQLQWHGDQLEGDQVO·pWXGH ,138/6,6 55 ,& ² S 8QHIRLVOHVGRQQpHVUDVVHPEOpHVH[DPLQpHVSDUOHFRPLWp
'%RXYU\6-RXQHDX
7DEOHDX&DUDFWpULVWLTXHVFOLQLTXHVGHVSDWLHQWVGHVpWXGHV,138/6,6HW,138/6,6$GDSWpG·DSUqV>@ ,138/6,6
,138/6,6
1LQWHGDQLE PJùM Q
3ODFHER Q
ÇJHDQQpHPR\HQQH 6'
6H[HPDVFXOLQQ
)XPHXU VHYUpRXQRQ Q
&9)WKpRPR\HQQH 6'
9(06&9)PR\HQQH 6'
'/&2WKpRPR\HQQH 6'
6*54VFRUHWRWDOPR\HQQH 6'
&9)P/PR\HQQH 6'
Mean Observed Change from Baseline in FVC (ml)
B INPULSIS-1 50
– 50 – 100 – 150
– 114,7
– 200 Difference, 125,3 (95 % CI, 77,7 – 172,8) – 250 P < 0,001 – 239,9 – 300
Nintedanib, 150 mg Twice Daily (N = 309)
Placebo (N = 204)
Adjusted Annual Rate of Change in FVC (ml/yr)
C INPULSIS-2 0
Nintedanib, 150 mg twice daily
– 50 – 100
Placebo
– 150
Adjusted mean difference, 109,9 (95 % CI, 71,3 – 148,6) P < 0,001
– 200 – 250
0 2 4 6
12
24 Week 292 194
284 192
36 274 187
52 250 165
D INPULSIS-1 50
– 50 – 100 – 150
0
No. of Patients Nintedanib 303 301 298 Placebo 202 198 200
– 113,6
Difference, 93,7 (95 % CI, 44,8 – 142,7 ) – 250 P < 0,001 – 207,3 – 200
Mean Observed Change from Baseline in FVC (ml)
Adjusted Annual Rate of Change in FVC (ml/yr)
A INPULSIS-1 0
1LQWHGDQLE 3ODFHER Q PJùM Q
0 Nintedanib, 150 mg twice daily – 50 – 100 – 150 – 200
Placebo Adjusted mean difference, 109,8 (95 % CI, 70,9 – 148,6) P < 0,001
– 250 0 2 4 6
– 300 Nintedanib, 150 mg Twice Daily (N = 329)
Placebo (N = 219)
No. of Patients Nintedanib 323 315 315 Placebo 215 210 207
12
24 Week 312 209
303 203
36 295 196
52 269 180
)LJXUH 'pFOLQ DQQXHO HW GLIIpUHQFH SDU UDSSRUW j OD YDOHXU LQLWLDOH GH OD FDSDFLWp YLWDOH IRUFpH &9) GDQV OHV pWXGHV ,138/6,6 HW ,138/6,6>@
G·DGMXGLFDWLRQ RQ UHWURXYDLW XQ DOORQJHPHQW VLJQLÀFDWLI GX WHPSV MXVTX·j OD SUHPLqUH H[DFHUEDWLRQ GDQV OH EUDV QLQWHGDQLESDUUDSSRUWDXSODFHER 55 ,& ² S )LJ ,OQ·\DYDLWSDVGHGLIIpUHQFHVLJQL ÀFDWLYHHQWHUPHVGHTXDOLWpGHYLHHQWUHOHVEUDVSODFHERRX QLQWHGDQLEVDXISRXUOHGRPDLQHG·DFWLYLWpGX6*54TXLpWDLW VWDWLVWLTXHPHQWPHLOOHXUGDQVOHEUDVQLQWHGDQLEPDLVVDQV
DWWHLQGUHODVLJQLÀFDWLYLWpFOLQLTXH GRQQpHVUDVVHPEOpHV GDQVOHEUDVQLQWHGDQLEFRQWUHGDQVOHEUDV SODFHER VRLWXQHGLIIpUHQFHGH S 'H PrPHLOQ·\DYDLWSDVGHGLIIpUHQFHVLJQLÀFDWLYHHQWHUPHV GHPRUWDOLWpHQWUHOHVEUDVQLQWHGDQLEHWSODFHER )LJ /HV HIIHWV LQGpVLUDEOHV pWDLHQW WUqV IUpTXHQWV DYHF OH QLQWHGDQLESULQFLSDOHPHQWG·RUGUHGLJHVWLI 7DEOHDX 2Q
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
Cumulative incidence of first confirmed/suspected acute exacerbation (%)
UHWURXYDLWGHGLDUUKpHV SULQFLSDOHPHQWOpJqUHjPRGp UpH GHVFDV GHQDXVpHVGHYRPLVVHPHQWV HWGHF\WRO\VHKpSDWLTXH WUDQVDPLQDVHVIRLVODOLPLWH VXSpULHXUHGHODQRUPDOH /HQLQWHGDQLEHVWGRQFHIÀFDFHGDQVOHUDOHQWLVVHPHQW GXGpFOLQGHOD&9)FKH]OHVSDWLHQWVDWWHLQWVGH)3,OpJqUHj
PRGpUpHDLQVLTXHGDQVODUpGXFWLRQGHVH[DFHUEDWLRQV DSUqV DGMXGLFDWLRQ /HV HIIHWV LQGpVLUDEOHV VRQW SULQFLSDOHPHQW GLJHVWLIVWRXWFRPPHDYHFODSLUIpQLGRQH/HGpS{WG·$00 DpWpHIIHFWXpGpEXWPDLDXSUqVGHVLQVWDQFHVHXUR SpHQQHVDLQVLTXHOHVGpPDUFKHVG·DXWRULVDWLRQWHPSRUDLUH G·XWLOLVDWLRQ $78 QRPLQDWLYHV
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
Nintedanib 150 mg × 2/j Placebo HR 0,32 (95 % Cl ; 0,16, 0,65) p = 0,0010
0
30
60
90
120
150
180
210
240
270
300
330
360 373
572 380
563 371
548 503 363 345
Time to first confirmed/suspected acute exacerbation (days) No. of patients Nintedanib 638 Placebo 423
634 419
629 416
613 409
610 408
602 404
597 396
593 393
589 390
580 384
Nintedanib 150 mg × 2/j (n = 638) Patients avec ≥ 1 exacerbatuion aigue, n (%)
Placebo (n = 423)
12 (1,9)
24 (5,7)
)LJXUH 7HPSV MXVTX·j OD SUHPLqUH H[DFHUEDWLRQ FHUWDLQH RX VXVSHFWpH DSUqV YDOLGDWLRQ SDU OH FRPLWp G·DGMXGLFDWLRQ DQDO\VH SUp VSpFLÀpH $GDSWpG·DSUqVGLDSRVLWLYHGH/5LFKHOGL$76
Kaplan-Meier estimate of death (%)
Nintedanib 150 mg × 2/j 100 99 98 97 96 95 94 93 92 91 90
Placebo
HR 0,70 (95 % Cl ; 0,43, 1,12) p = 0,1399
0 0
30
60
90
120
150
180
210
240
270
300
330
360 373
617 406
612 403
606 400
601 394
591 532 388 358
Time to death (days) No. of patients Nintedanib 638 Placebo 423
637 422
635 420
632 418
628 418
623 416
620 414
619 408
Nintedanib 150 mg × 2/j (n = 638) Patients décédés, n (%)
35 (5,5)
Placebo (n = 423) 33 (7,8)
)LJXUH0RUWDOLWpGHWRXWHVFDXVHVjVHPDLQHV GRQQpHVUDVVHPEOpHV $GDSWpG·DSUqVGLDSRVLWLYHGH/5LFKHOGL$76
'%RXYU\6-RXQHDX
7DEOHDX(IIHWVVHFRQGDLUHVDXFRXUVGHVpWXGHV,138/6,6$GDSWpG·DSUqV>@ (IIHWVLQGpVLUDEOHV
,138/6,6
,138/6,6
1LQWHGDQLE Q
3ODFHER Q
1LQWHGDQLE Q
3ODFHER Q
7RXWHIIHWLQGpVLUDEOH
7RXWHIIHWLQGpVLUDEOHj O·H[FOXVLRQGHODSURJUHVVLRQ GHOD)3,
'LDUUKpHV
1DXVpHV
5KLQRSKDU\QJLWHV
7RX[
%URQFKLWHV
,QIHFWLRQVGHVYRLHVDpULHQQHV VXSpULHXUHV
'\VSQpH
$QRUH[LH
9RPLVVHPHQWV
3HUWHGHSRLGV
(IIHWVLQGpVLUDEOHVVpYqUHV
(IIHWVLQGpVLUDEOHVPRUWHOV
(IIHWVLQGpVLUDEOHVFRQGXLVDQW jO·DUUrWGXWUDLWHPHQW
(IIHWVLQGpVLUDEOHVGLJHVWLIV FRQGXLVDQWjO·DUUrWGX WUDLWHPHQW
(IIHWVLQGpVLUDEOHVOHVSOXVIUpTXHQWV
3LUIpQLGRQH QRXYHOHVVDLUDQGRPLVp HWHIIHWVVHFRQGDLUHVjORQJWHUPH /D SLUIpQLGRQH HVW XQ WUDLWHPHQW DQWLÀEURVDQW GRQQp SDU YRLHRUDOHGRQWOHPpFDQLVPHG·DFWLRQHVWHQFRUHPDOFRP SULV>@3OXVLHXUVHVVDLVUDQGRPLVpVpYDOXHQWVRQHIÀFDFLWp GDQV OD )3, /H SUHPLHU SXEOLp SDU$]XPD HW DO >@ HVW XQ HVVDL SURVSHFWLI UDQGRPLVp FRQWUH SODFHER HQ GRXEOH DYHXJOHLQFOXDQWSDWLHQWV/DSLUIpQLGRQHHVWDGPLQLV WUpHjGRVHVSURJUHVVLYHVGHjPJM6LOHVUpVXOWDWV VRQWHQFRXUDJHDQWVHQSDUWLFXOLHUGDQVXQVRXVJURXSHGH SDWLHQWVJDUGDQWXQHVDWXUDWLRQHQR[\JqQHVXSpULHXUHj DXFRXUVG·XQWHVWG·H[HUFLFHGHPLQXWHVFHWHVVDLQ·DSDV SHUPLV GH PRQWUHU GH GLIIpUHQFH VLJQLÀFDWLYH HQWUH OHV JURXSHVFRQFHUQDQWOHGpFOLQGHOD&9)&HVUpVXOWDWVDVVRFLpV j OD GpPRQVWUDWLRQ G·XQH ERQQH WROpUDQFH RQW VXVFLWp OD UpDOLVDWLRQG·pWXGHVGHSKDVH,,,(QSDWLHQWVVRQW UDQGRPLVpVGDQVXQHVVDLFRPSUHQDQWEUDV SLUIpQLGRQH
j KDXWH GRVH PJM YV SLUIpQLGRQH j IDLEOH GRVH PJM YV SODFHER >@ /D GRVH GH SLUIpQLGRQH HVW DXJPHQWpHSDUSDOLHUVXUXQHGXUpHWRWDOHGHVHPDLQHV /HFULWqUHSULQFLSDOGHMXJHPHQWDpWpPRGLÀpDYDQWODOHYpH G·DYHXJOH,QLWLDOHPHQWODYDULDWLRQGHODSOXVEDVVH6D HQWUHGHVWHVWVG·H[HUFLFHjYLWHVVHVWDEOHHVWUHWHQXH PrPH FULWqUHSULQFLSDOTXH>@ PDLVO·pYROXWLRQGHVFRQQDLVVDQFHV GHVSDUDPqWUHVIRQFWLRQQHOVDVVRFLpVjODVXUYLHGDQVOD)3, HW OHV GLIÀFXOWpV GH UHSURGXFWLELOLWp GHV WHVWV G·H[HUFLFHV RQWIDLWSUpIpUHUODYDULDWLRQGHOD&9)HQSRXUFHQWDJHGHOD YDOHXUSUpGLWHDSUqVVHPDLQHVGHWUDLWHPHQW/HGpFOLQGH OD&9)HVWVLJQLÀFDWLYHPHQWPRLQVLPSRUWDQWGDQVOHJURXSH WUDLWpSDUSLUIpQLGRQHPJMHQFRPSDUDLVRQGXJURXSH SODFHER DYHF UpGXFWLRQ GX GpFOLQ GH GDQV OH JURXSH WUDLWpSDUUDSSRUWDXJURXSHUHFHYDQWOHSODFHER /YV / S /DVXUYLHVDQVSURJUHVVLRQpWDLWpJD OHPHQWVLJQLÀFDWLYHPHQWPHLOOHXUHGDQVOHJURXSHWUDLWp SDUWLUGHFHWWHpWXGHXQVRXVJURXSHGHSDWLHQWV &9)
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
HW6D ORUVGXWHVWG·H[HUFLFH DpWpLGHQWLÀpFRPPH EpQpÀFLDQW GDYDQWDJH GHODSLUIpQLGRQH>@O·LVVXHGH FHVHVVDLVO·DJHQFHMDSRQDLVHGXPpGLFDPHQWDDXWRULVpOD SLUIpQLGRQHSRXUOHWUDLWHPHQWGHOD)3,>@ 'HX[DXWUHVHVVDLVGHSKDVH,,, pWXGHV3,3)HW3,3) SURJUDPPH&$3$&,7< PXOWLFHQWULTXHV (XURSH$PpULTXHGX 1RUGHW$XVWUDOLH UDQGRPLVpVHQGRXEOHDYHXJOHRQWpWpUpD OLVpV/HVSDWLHQWVLQFOXVSUpVHQWHQWXQH)3,GLDJQRVWLTXpHGDQV OHVPRLVSUpFpGHQWVVRQWkJpVGHjDQVHWO·DOWpUDWLRQ IRQFWLRQQHOOHUHVSLUDWRLUHHVWGpÀQLHFRPPHOpJqUHjPRGpUpH /HFDUDFWqUHOpJHUjPRGpUpGHODPDODGLHDFWXHOOHPHQWDGPLV SRXUODSUHVFULSWLRQDpWpGpÀQLORUVGHFHVHVVDLVSDUXQH &9)HQWUHHW GHODYDOHXUSUpGLWHXQH'/&2FRPSULVH HQWUHHW GHODYDOHXUSUpGLWHHWXQHGLVWDQFHSDUFRXUXH DXWHVWGHPDUFKHGHPLQXWHV 70 P>@/HFULWqUH SULQFLSDOGHMXJHPHQWHVWODYDULDWLRQHQSRXUFHQWDJHGHOD &9) SDU UDSSRUW j OD YDOHXU SUpGLWH DSUqV VHPDLQHV GH WUDLWHPHQW'DQVO·pWXGHSDWLHQWVVRQWUDQGRPLVpV HQWUHSLUIpQLGRQH PJMYVSLUIpQLGRQHPJMYV SODFHER/·pWXGHDUDQGRPLVpSDWLHQWVHQWUHSLUIpQL GRQHPJMHWSODFHER'DQVO·pWXGHODSLUIpQLGRQH UpGXLWVLJQLÀFDWLYHPHQWOHGpFOLQGHOD&9)FKH]OHVSDWLHQWV UHFHYDQWPJM S 6RL[DQWHGHVSDWLHQWV DYDLHQWXQGpFOLQGHSOXVGHGHOD&9) SURJUHVVLRQ jVHPDLQHVGDQVOHJURXSHSLUIpQLGRQHPJMFRQWUH GDQVOHJURXSHSODFHER S /HEpQpÀFHGX WUDLWHPHQWVXUOHGpFOLQGHOD&9)HWODVXUYLHVDQVSURJUHVVLRQ HVWFRQVWDWpjSDUWLUGHVHPDLQHVGHWUDLWHPHQWHWMXVTX·DX[ VHPDLQHVG·pWXGH/HVUpVXOWDWVQHVRQWSDVVLJQLÀFDWLYHPHQW GLIIpUHQWVHQWHUPHVGHUDOHQWLVVHPHQWGXGpFOLQGHODIRQFWLRQ UHVSLUDWRLUHHQWUHOHJURXSHSODFHERHWOHJURXSHSLUIpQLGRQH PJM'DQVO·pWXGHLOQ·H[LVWHSDVGHGLIIpUHQFH VLJQLÀFDWLYHHQWUHOHJURXSHSODFHERHWOHJURXSHSLUIpQLGRQH HQWHUPHVGHGpFOLQGH&9) )LJ &HVUpVXOWDWVRQWSHUPLVO·DSSUREDWLRQGHODSLUIpQLGRQH PJM GDQVOHWUDLWHPHQWGHOD)3,SDUO·DJHQFHHXUR SpHQQHGXPpGLFDPHQWHWXQHUHFRPPDQGDWLRQG·XWLOLVDWLRQ FKH] GHV SDWLHQWV VpOHFWLRQQpV ORUV GX FRQVHQVXV$76(56
Mean change from baseline in FVC (1 % predicted)
A
>@(Q)UDQFHODSLUIpQLGRQHDpWpFRPPHUFLDOLVpHj SDUWLU G·RFWREUH VRXV OH QRP G·(VEULHW &HSHQGDQW OHVHUYLFHPpGLFDOUHQGXHVWIDLEOHVHORQOD+DXWH$XWRULWp GH6DQWpHWOLPLWpDX[SDWLHQWVD\DQWXQH)3,FHUWDLQHDYHF XQH&9)HWXQH'/&2'DQVOHPrPHWHPSV O·DJHQFHDPpULFDLQHGXPpGLFDPHQWQ·DSDVDXWRULVpVDPLVH VXUOHPDUFKpDX[eWDWV8QLV 8QTXDWULqPHHVVDLGHSKDVH,,,UDQGRPLVpHQGRXEOH DYHXJOH PXOWLFHQWULTXH QRPPp$6&(1' $VVHVVHPHQW RI SLUIHQLGRQH WR FRQÀUP HIÀFDFLW\ DQG VDIHW\ LQ LGLRSDWKLF SXOPRQDU\ÀEURVLV HVWSUpVHQWpORUVGXFRQJUqVGHO·$76 /HVUpVXOWDWVSXEOLpVOHPrPHMRXUGDQVOH1HZ(QJODQG -RXUQDORI0HGLFLQH>@RQWpWpGpWDLOOpVjQRXYHDXSDU7( .LQJ 6DQ)UDQFLVFR&DOLIRUQLDeWDWV8QLV GDQVODVHVVLRQ $ 6N\IDOO ODWHEUHDNLQJFOLQLFDOWULDOVLQLGLRSDWKLFSXO PRQDU\ ÀEURVLV /·pWXGH UpDOLVpH GDQV FHQWUHV LQFOXW SDWLHQWVGRQWOHVGHX[WLHUVUDQGRPLVpVDX[eWDWV8QLV GHIDoRQpTXLYDOHQWHHQWUHSODFHERHWSLUIpQLGRQHjODGRVH GHPJM /HVFULWqUHVG·LQFOXVLRQFRQFHUQDQWODIRQFWLRQUHVSLUD WRLUHVRQWXQSHXGLIIpUHQWVGHFHX[XWLOLVpVSRXUOHVpWXGHV 3,3)(QHIIHWOD&9)GRLWrWUHHQWUHHW GHODYDOHXU SUpGLWHHWOHUDSSRUW9(06&9)GRLWrWUHVXSpULHXURXpJDOj /DOLPLWHLQIpULHXUHGH'/&2HVWSOXVEDVVHjGHOD YDOHXUSUpGLWHFRQWUHGDQVOHVHVVDLVSUpFpGHQWV/HEXW GHFHVPRGLÀFDWLRQVHVWGHVpOHFWLRQQHUGHVSDWLHQWVD\DQWXQ ULVTXHGHSURJUHVVLRQGHODPDODGLHSOXVLPSRUWDQW(QÀQOH FULWqUHSULQFLSDOGHMXJHPHQWHVWOHPrPHVRLWODYDULDWLRQ GHOD&9)HQSRXUFHQWDJHGHODYDOHXUSUpGLWH FHWWHYDULD WLRQHVWPHVXUpHjVHPDLQHVGHWUDLWHPHQWYVVHPDLQHV GDQVOHVHVVDLVSUpFpGHQWV'HUQLqUHGLIIpUHQFH ODUHYXH FHQWUDOLVpHGHVpOpPHQWVGLDJQRVWLTXHVGHOD)3, VFDQQHU WKRUDFLTXHHWELRSVLHSXOPRQDLUHFKLUXUJLFDOH GHVGRQQpHV SHUPHWWDQWG·pWDEOLUXQOLHQGHFDXVDOLWpHQWUHOHGpFqVHW ODÀEURVHSXOPRQDLUHHWGHVSDUDPqWUHVGHVSLURPpWULH /HVFDUDFWpULVWLTXHVGpPRJUDSKLTXHVIRQFWLRQQHOOHVHW G·REVHUYDQFH VRQW FRPSDUDEOHV GDQV OHV JURXSHV$SUqV VHPDLQHVGHWUDLWHPHQWOHGpFOLQGHOD&9)GDQVOHJURXSH
B
C
0 –2 –4 –6 –8 – 10 Pirfenidone 2 403 mg/day (n = 174) Pirfenidone 1 197 mg/day (n = 87) Placebo (n = 174)
– 12 – 14 0
Absolute difference* Relative difference* p value†
12
24
36
48
60
1,4 % 2,5 % 4,6 % 4,8 % 4,1 % 53,5 % 65,2 % 63,7 % 52,3 % 38,3 % 0,061 0,014 0,0001 0,0009 0,0002
72
Pirfenidone 2 403 mg/day (n = 171) Placebo (n = 173) 0
12
24
36
48
60
72
– 4,4 % 2,8 % 2,4 % 1,9 % 0,6 % 0,6 % 4,4 % – 31,5 % 62,1 % 48,2 % 27,3 % 7,6 % 6,5 % 35,3 % 0,021 0,001 0,011 0,005 0,172 0,501 0,001
Pirfenidone 2 403 mg/day (n = 345) Placebo (n = 347) 0
12
24
36
48
60
72
0,5 % 2,7 % 3,5 % 3,3 % 2,4 % 2,5 % 28,5 % 63,6 % 57,5 % 41,6 % 25,1 % 22,8 % 0,003 < 0,0001 < 0,0001 < 0,0001 0,0003 0,005
)LJXUH9DULDWLRQPR\HQQHGXSRXUFHQWDJHGHOD&9)SDUUDSSRUWjODYDOHXUSUpGLWH GHJDXFKHjGURLWHpWXGHpWXGH3,3)HW SRSXODWLRQUHJURXSpHGHVpWXGHVHW >@
'%RXYU\6-RXQHDX
WUDLWpHVWVLJQLÀFDWLYHPHQWPRLQVLPSRUWDQWSDUUDSSRUWDX JURXSHSODFHER S /HVHUYLFHUHQGXSDUOHWUDLWH PHQWHVWTXDQWLÀpSDUSDUDPqWUHV SURSRUWLRQGHVSDWLHQWV D\DQWXQGpFOLQGH&9)HWRXGpFpGpVjVHPDLQHV UpGXLWHGH GDQVOHJURXSHWUDLWp SDWLHQWV>@ YV SDWLHQWV > @ HW OD SURSRUWLRQ GH SDWLHQWV SRXU OHVTXHOVOD&9)Q·DSDVGpFOLQpGDQVOHJURXSHSLUIp QLGRQHHW GDQVOHJURXSHSODFHER/DGLIIpUHQFHHQWUH OHVJURXSHVDSSDUDvWjSDUWLUGHVHPDLQHVGHWUDLWHPHQW &RQFHUQDQWOHVFULWqUHVGHMXJHPHQWVHFRQGDLUHV²YDULDWLRQ GHODGLVWDQFHSDUFRXUXHDXWHVWGHPDUFKHGHPLQXWHVj VHPDLQHVHWVXUYLHVDQVSURJUHVVLRQ²LOVVRQWpJDOHPHQW VLJQLÀFDWLYHPHQWGLIIpUHQWVHQWUHOHVJURXSHVHQIDYHXU GHODSLUIpQLGRQH )LJ /H GpFOLQ PR\HQ GH OD &9) HQ YDOHXU DEVROXH )LJ HVW GH PO VHPDLQHV GDQV OH JURXSH WUDLWp HW GH PO VHPDLQHV GDQV OH JURXSH SODFHER &HV YDOHXUV VRQWVXSpULHXUHVjFHOOHVFRQVWDWpHVGDQVOHVDXWUHVHVVDLV WKpUDSHXWLTXHV TX·LO V·DJLVVH GX JURXSH SODFHER RX GX JURXSH WUDLWp /·H[SOLFDWLRQ HVW G·XQH SDUW O·DWWULEXWLRQ G·XQH&9)jDX[SDWLHQWVGpFpGpVHQFRXUVG·HVVDLORUVGX FDOFXOGHODYDULDWLRQPR\HQQHGHOD&9)PpWKRGHTXLDYDLW pWpSUpVSpFLÀpHSRXUFDOFXOHUODYDULDWLRQGH&9)FULWqUHGH MXJHPHQWSULQFLSDOGHO·pWXGH G·DXWUHSDUWODVpOHFWLRQGHV SDWLHQWVVXUOHSODQGLDJQRVWLTXH UHYXHFHQWUDOLVpHSOXVGH
A Decreased FVC or Death 35 Pirfenidone (N = 278)
P < 0,001
Placebo (N = 277)
Pirfenidone (N = 278)
25
P < 0,001
20 P < 0,001
15 10 5
P < 0,001
0 26
39 Week
– 200 – 300 – 400
13
26 Week
39
52
D Progression-free Survival
Pirfenidone (N = 278) P = 0,04 Placebo (N = 277)
30
P = 0,12
P = 0,04 Patients (%)
35
25 20 P = 0,40 15
100 90 80 70 60 50 40 30
Pirfenidone (N = 278)
Placebo (N = 277) Hazard ratio, 0,57 (95 %, 0,43 –0,77) P < 0,001
20 10
10 5 0
Placebo (N = 277) 0
52
C Decreased Walk Distance or Death
Patients (%)
– 100
– 500 13
40
B Change in FVC 0 Mean Change (ml)
Patients (%)
30
DYHFGHVVFDQQHUVW\SLTXHVGH3,& HWIRQFWLRQQHO OLPLWH LQIpULHXUHGHOD'/&2SOXVEDVVH /DFRXUEHG·H[WUDSRODWLRQ OLQpDLUH FODVVLTXH SUpVHQWpH GDQV OHV UpVXOWDWV DQQH[HV PRQWUHXQHGLPLQXWLRQPR\HQQHGH&9)GHPOGDQVOH JURXSHWUDLWpHWGHPOGDQVOHJURXSHSODFHER GLIIpUHQFH PR\HQQHDEVROXHGHPOGLIIpUHQFHPR\HQQHUHODWLYHGH S /DPRUWDOLWpQ·HVWSDVVLJQLÀFDWLYHPHQW GLIIpUHQWHHQWUHOHVJURXSHV GDQVOHJURXSHSLUIpQLGRQH YVGDQVOHJURXSHSODFHER+5 &,j S /·HIIHWGXWUDLWHPHQWVXUO·LQFLGHQFHG·H[DFHUED WLRQDLJXsQ·HVWSDVGLVFXWp /·HQVHPEOHGHVGRQQpHVGHVSDWLHQWVGH&$3$&,7< HW$6&(1'DIDLWO·REMHWG·DQDO\VHVVWDWLVWLTXHVVXSSOpPHQ WDLUHV SUpYXHV ORUV GH O·pODERUDWLRQ GX GHUQLHU HVVDL >@ /HVFULWqUHVG·LQFOXVLRQQHVRQWSDVVWULFWHPHQWLGHQWLTXHV PDLVOHVSRSXODWLRQVGHFHVHVVDLVUHVWHQWFRPSDUDEOHVHQ WHUPHVGHGpPRJUDSKLHHWGHIRQFWLRQ/·DQDO\VHPRQWUHXQH GLPLQXWLRQGHODPRUWDOLWpjDQTXHOOHTXHVRLWODFDXVH GLPLQXWLRQGH HWGHODPRUWDOLWpOLpHjODÀEURVH GLPL QXWLRQGH FKH]OHVSDWLHQWVUHFHYDQWGHODSLUIpQLGRQH SDUUDSSRUWDXJURXSHSODFHER 7DEOHDX &HSHQGDQWFHV UpVXOWDWVQHVRQWSDVLVVXVG·XQHVHXOHpWXGHUDQGRPLVpHPDLV G·XQHDQDO\VHVWDWLVWLTXHSUpVSpFLÀpHFRQFHUQDQWSOXVLHXUV SRSXODWLRQVGHSDWLHQWV&HUWDLQVDXWHXUVFRQVLGqUHQWTXH O·pYDOXDWLRQGXWDX[GHPRUWDOLWpFRPPHFULWqUHSULQFLSDO
0 13
26
39 Week
)LJXUH5pVXOWDWVGHO·pWXGH$6&(1'>@
0
13
52
26
39
52
219 192
144 113
Week no. at Risk Pirfenidone Placebo
276 273
269 262
243 225
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
GHMXJHPHQWGDQVGHVHVVDLVFRQFHUQDQWGHVSDWLHQWVDYHF XQH)3,OpJqUHjPRGpUpHHVWGLIÀFLOHjUpDOLVHUHQWHUPH G·HIIHFWLIHWGHGXUpH> @ 3DUDOOqOHPHQWjFHVGRQQpHVVXUO·HIÀFDFLWpGXPpGLFD PHQWDXFRXUVGXFRQJUqVVRQWUDSSRUWpVOHVHIIHWVLQGpVL UDEOHVUHFHQVpVFKH] SDWLHQWVD\DQWUHoXGHODSLUIpQLGRQH jPJM>@TXLRQWpJDOHPHQWpWpSXEOLpV>@,OV·DJLW GHVSDWLHQWVLQFOXVGDQVOHVpWXGHVHWHWGHSDWLHQWV D\DQWSDUWLFLSpjGHVpWXGHVRXYHUWHV7URLVSRSXODWLRQVVRQW GRQFDQDO\VpHV ODSRSXODWLRQLQWpJUpH SDWLHQWVD\DQWUHoX SLUIpQLGRQHPJGDQV3,3)HWpWXGHVRXYHUWHV SRSXODWLRQ GHV pWXGHV HW D\DQW UHoX SLUIpQLGRQH PJMHWHQVHPEOHGHVSDWLHQWVVRXVSODFHERGDQVOHV pWXGHV HW /D GXUpH PR\HQQH GH WUDLWHPHQW HVW GHDQV VHPDLQHjDQV HW GHVSDWLHQWVRQW UHoXODSLUIpQLGRQHSHQGDQWXQHGXUpHVXSpULHXUHRXpJDOH jDQV&RPPHGDQVOHVUHFRPPDQGDWLRQVGHSUHVFULSWLRQ
GH O·(VEULHW OHV SURWRFROHV DXWRULVHQW GHV UpGXFWLRQV GH GRVHVHQIRQFWLRQGHVHIIHWVVHFRQGDLUHV /HVSULQFLSDX[HIIHWVVHFRQGDLUHVVRQWJDVWURLQWHVWLQDX[ HWFXWDQpVHWUpVXPpVGDQVOHWDEOHDX,OVVRQWGDQVOD PDMRULWp GHV FDV OpJHUV j PRGpUpV HW QH QpFHVVLWHQW TXH UDUHPHQW O·DUUrW GH OD SULVH PpGLFDPHQWHXVH ,OV VXUYLHQ QHQW OH SOXV VRXYHQW GDQV OHV SUHPLHUV PRLV UDUHPHQW DSUqVOHGRX]LqPHPRLVGHWUDLWHPHQW8QHpOpYDWLRQGHV WUDQVDPLQDVHVVXSpULHXUHjIRLVODQRUPDOHHVWFRQVWDWpH SOXV IUpTXHPPHQW FKH] OHV SDWLHQWV UHFHYDQW GH OD SLUIp QLGRQH DYHF GDQV WRXV OHV FDV XQH UpYHUVLELOLWp VDQVVpTXHOOHFOLQLTXHDSSX\DQWDLQVLOHVUHFRPPDQGDWLRQV HXURSpHQQHVHWFDQDGLHQQHVGHVXUYHLOODQFHPHQVXHOOHGHV WUDQVDPLQDVHVSHQGDQWOHVSUHPLHUVPRLVGHWUDLWHPHQW SXLVWULPHVWULHOOH'HVLQVRPQLHVHWGHVYHUWLJHVVRQWGpFODUpV FKH]UHVSHFWLYHPHQWHWGHVSDWLHQWVUHFHYDQWOD SLUIpQLGRQHGDQVOHVpWXGHVHWVRLWSOXVGHXQHIRLV
7DEOHDX0RUWDOLWpWRXWHVFDXVHVFRQIRQGXHVGDQVO·HVVDL$6&(1'OHVHVVDLV&$3$&,7<HWHQDQDO\VDQWODSRSXODWLRQ JOREDOH 3DWLHQWVQ
3LUIpQLGRQH PJM
3ODFHER
+5 ,& Â
S
$6&(1' 1
3RROHG 1
&$3$&,7< 1
'·DSUqV.LQJ7(%UDGIRUG:=&DVWUR%HUQDUGLQL6)DJDQ($*ODVSROH,*ODVVEHUJ0.HWDO$SKDVHWULDORISLUIHQLGRQHLQSDWLHQWV ZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV1(QJO-0HG0D\ ² DSSHQGL[
3UHVSHFLÀHGVHFRQGDU\HQGSRLQWLQ$6&(1' 'DWDLQWKH&$3$&,7<VWXGLHVFHQVRUHGDWRQH\HDU Â&R[SURSRUWLRQDOKD]DUGVPRGHO /RJUDQNWHVW
7DEOHDX(IIHWVVHFRQGDLUHVGHODSLUIpQLGRQHjORQJWHUPH$GDSWpG·DSUqV>@ 3RSXODWLRQLQWpJUpH Q
&$3$&,7<SLUIpQLGRQHPJM Q
&$3$&,7<SODFHER Q
5DVKFXWDQp
$UUrWGXWUDLWHPHQW
1DXVpHV $UUrWGXWUDLWHPHQW
'LDUUKpH $UUrWGXWUDLWHPHQW
'\VSHSVLH $UUrWGXWUDLWHPHQW
9RPLVVHPHQWV $UUrWGXWUDLWHPHQW
3KRWRVHQVLELOLWp $UUrWGXWUDLWHPHQW
HWGHPLHSOXVIUpTXHPPHQWTXHFKH]OHVSDWLHQWVUHFHYDQW OHSODFHERGDQVFHVPrPHVpWXGHVVDQVHQWUDvQHUWRXWHIRLV O·LQWHUUXSWLRQ GX WUDLWHPHQW /D IDWLJXH HW O·DQRUH[LH QH VHPEOHQWSDVSOXVIUpTXHQWHVFKH]OHVSDWLHQWVUHFHYDQWOD SLUIpQLGRQH'HVpYpQHPHQWVLQGpVLUDEOHVJUDYHVVRQWVLJQDOpV FKH]GHVSDWLHQWVGHODSRSXODWLRQLQWpJUpHFKH] GHVSDWLHQWVGHVpWXGHVHWUHFHYDQWODSLUIpQLGRQH HW GHV SDWLHQWV LQFOXV GDQV OH EUDV SODFHER GH FHV pWXGHV5DSSRUWpVDXWHPSVGHWUDLWHPHQWFHVpYpQHPHQWV QHVRQWSDVSOXVIUpTXHQWVGDQVFHWWHSRSXODWLRQTXHGDQV OHVDXWUHVJURXSHV/·pYpQHPHQWLQGpVLUDEOHJUDYHOHSOXV IUpTXHQWSRXUOHVSRSXODWLRQVHVWO·DJJUDYDWLRQGHOD)3, GDQVODSRSXODWLRQLQWpJUpHHWGDQVOHVHVVDLV HW FHWWHGLIIpUHQFHpWDQWH[SOLTXpHSDUXQWHPSV GHVXLYLSOXVORQJFKH]OHVSDWLHQWVGHODSRSXODWLRQLQWpJUpH 0DOJUp GHV OLPLWDWLRQV pYLGHQWHV OLpHV DX IDLW TXH OHV SDWLHQWVpWXGLpVSURYLHQQHQWG·pWXGHVGLIIpUHQWHVLOH[LVWH XQHJOREDOHVpFXULWpG·HPSORLGXPpGLFDPHQWFKH]XQQRPEUH LPSRUWDQWGHSDWLHQWVHWSHQGDQWXQWHPSVG·H[SRVLWLRQDVVH] ORQJ&HWWHLQIRUPDWLRQHVWLQWpUHVVDQWHFDUDFWXHOOHPHQW ODGXUpHGXWUDLWHPHQWHQFDVGHVWDELOLVDWLRQGHODIRQF WLRQUHVSLUDWRLUHQ·HVWSDVGpÀQLH&HSHQGDQWVLOHVHIIHWV LQGpVLUDEOHVRQWUDUHPHQWHQWUDLQpO·DUUrWGXPpGLFDPHQWLO IDXWUDSSHOHUTX·LOV·DJLWGHSDWLHQWVSDUWLFLSDQWjGHVHVVDLV H[FOXDQWFHX[SUpVHQWDQWGHVFRPRUELGLWpVLPSRUWDQWHVHW FHUWDLQHV WKpUDSHXWLTXHV PpGLFDPHQWHXVHV DVVRFLpHV HW UHFHYDQWGHVFRQVHLOVV\VWpPDWLTXHVGHSKRWRSURWHFWLRQHW GHSULVHPpGLFDPHQWHXVHDXFRXUVGHVUHSDV 'HV pWXGHV FRPSOpPHQWDLUHV VHURQW QpFHVVDLUHV SRXU pYDOXHUODVpFXULWpGXPpGLFDPHQWHQSDUWLFXOLHUFKH]OHV VRXVJURXSHVGHSDWLHQWVOHVSOXVVpYqUHV'DQVODSRSXODWLRQ LQWpJUpHGHVSDWLHQWVDYDLHQWXQH'/&2LQIpULHXUH j HW DYDLHQW XQH &9) LQIpULHXUH j GH OD YDOHXUSUpGLWH OHVUpVXOWDWVSRXUFHVRXVJURXSHQHVRQW SDVGpWDLOOpV 'HVSUpVHQWDWLRQVVHVRQWLQWpUHVVpHVjFHVSDWLHQWVSOXV JUDYHV'·DERUGXQWUDYDLOUpWURVSHFWLIpYDOXDQWSDWLHQWV VRXV SLUIpQLGRQH GRQW DYHF XQH DWWHLQWH VpYqUH '/&2 PR\HQQHj PRQWUHXQHWHQGDQFHjXQHSOXVJUDQGH IUpTXHQFHGHVHIIHWVVHFRQGDLUHVGDQVFHVRXVJURXSH YV TXLQ·HVWFHSHQGDQWSDVVLJQLÀFDWLYH S >@ (QVXLWHGDQVO·K\SRWKqVHG·XQHV\QHUJLHG·DFWLRQHQWUH1$& HWODSLUIpQLGRQHGHVSDWLHQWVD\DQWXQHDOWpUDWLRQIRQFWLRQ QHOOHVpYqUH 3DDXUHSRVLQIpULHXUHjPP+J RQWUHoX VRLWO·DVVRFLDWLRQGHSLUIpQLGRQHHW1$&LQKDOp Q VRLW GH OD SLUIpQLGRQH HQ PRQRWKpUDSLH >@ /·DQDO\VH UpWURV SHFWLYHGHVVRXVJURXSHVPRQWUHXQHPHLOOHXUHVXUYLHVDQV SURJUHVVLRQGDQVOHJURXSHELWKpUDSLH'DQVFHJURXSHOH WUDLWHPHQWDpWpDUUrWpFKH]SDWLHQWVSRXUGHVHIIHWV VHFRQGDLUHV LOQ·\DSDVHXG·LQWHUUXSWLRQGHWUDLWHPHQW FKH]OHVSDWLHQWVSUHQDQWODSLUIpQLGRQHVHXOH&HVpWXGHV UpWURVSHFWLYHVQHSHXYHQWSDVJXLGHUODWKpUDSHXWLTXHPDLV VRXOqYHQWODTXHVWLRQGHODSULVHHQFKDUJHG·XQHFDWpJRULH GHSDWLHQWVQRQUHSUpVHQWpHGDQVOHVJUDQGVHVVDLVUDQGR PLVpV'DQVO·HVVDL$6&(1'>@GHVSDWLHQWVRQWXQH '/&2HQWUHHWGHODYDOHXUSUpGLWHjO·LQFOXVLRQFH TXLSRXUUDLWIDLUHPRGLÀHUOHVLQGLFDWLRQVGHSUHVFULSWLRQ DFWXHOOHPHQWOLPLWpHjXQH'/&2
'%RXYU\6-RXQHDX
&RQFOXVLRQ /HGLDJQRVWLFGHÀEURVHSXOPRQDLUHLGLRSDWKLTXHUHVWHGLIÀFLOH HW OD PLVH HQ pYLGHQFH G·XQH FDXVH GRLW UHVWHU O·REMHFWLI SUHPLHUPrPHGHYDQWXQDVSHFWFHUWDLQGH3,&VXUOD7'0 WKRUDFLTXH/HVQRXYHDX[WUDLWHPHQWVGLVSRQLEOHVHWjYHQLU UHQGHQWODGLVFXVVLRQPXOWLGLVFLSOLQDLUHFHQWUDOHOHGLDJQRV WLF UHWHQX SHUPHWWDQW RX QRQ GH SURSRVHU XQ WUDLWHPHQW DQWLÀEURVDQW /HV PRGDOLWpV GH FH WUDLWHPHQW QH VRQW SDV HQFRUHFODLUHPHQWGpÀQLHV3DUUDSSRUWDX[UHFRPPDQGDWLRQV IUDQoDLVHV>@OD1$&HQPRQRWKpUDSLHQHGHYUDLWSOXVrWUH SUHVFULWHHQSUHPLqUHLQWHQWLRQGDQVOD)3,(Q)UDQFHVHXOH OD SLUIpQLGRQH D XQH DXWRULVDWLRQ GH PLVH VXU OH PDUFKp $00 SRXUOHVSDWLHQWVD\DQWXQH)3,OpJqUHjPRGpUpH /HQLQWHGDQLEGRQWOHVLQGLFDWLRQVHWOHVEpQpÀFHVDWWHQGXV VRQW VLPLODLUHV SRXUUDLW rWUH REWHQX HQ$78 DXWRULVDWLRQ WHPSRUDLUHG·XWLOLVDWLRQ DYDQWO·REWHQWLRQpYHQWXHOOHG·XQH $00/DSODFHG·DVVRFLDWLRQGHWUDLWHPHQWDQWLÀEURVDQWQ·HVW SDVFRQQXHHWVHUDjGpÀQLU3DUDLOOHXUVFHVUpVXOWDWVGRLYHQW IDLUHUHPHWWUHHQFDXVHODUpDOLVDWLRQG·HVVDLWKpUDSHXWLTXH FRQWUHSODFHERTXDQGO·DWWHLQWHIRQFWLRQQHOOHHVWOpJqUHj PRGpUHH ,OIDXWUDSSHOHUTXHOHVUpVXOWDWVSUpVHQWpVORUVGXFRQJUqV GHO·$76QHSHUPHWWHQWSDVGHGRQQHUXQWUDLWHPHQW DQWLÀEURVDQWDX[SDWLHQWVOHVSOXVVpYqUHVjTXLGHVHVVDLV WKpUDSHXWLTXHVSHXYHQWrWUHSURSRVpV 'DQV WRXV OHV FDV OH SDWLHQW GRLW rWUH LQIRUPp TXH OH EpQpÀFHDWWHQGXGHVWKpUDSHXWLTXHVHVWXQUDOHQWLVVHPHQW GXGpFOLQGHODFDSDFLWpIRQFWLRQQHOOHUHVSLUDWRLUH(QÀQV·LO H[LVWHXQHLQGLFDWLRQOHELODQHQYXHG·XQHWUDQVSODQWDWLRQ SXOPRQDLUH QH GRLW SDV rWUH UHWDUGp SDU OD PLVH HQ URXWH GHVWUDLWHPHQWV
/LHQVG·LQWpUrWV $XFRXUVGHVGHUQLqUHVDQQpHV'%RXYU\DSHUoXGHV KRQRUDLUHVSRXUDFWLRQVGHIRUPDWLRQGHODSDUWGXODERUDWRLUH ,QWHUPXQHHWDpWpFRLQYHVWLJDWHXUGDQVGHVSURWRFROHVGH UHFKHUFKHFOLQLTXHVXUODÀEURVHSXOPRQDLUHLGLRSDWKLTXH ODERUDWRLUH,QWHUPXQHHW%RHUKLQJHU
5pIpUHQFHV >@ 7UDYLV:'&RVWDEHO8+DQVHOO'0.LQJ7(/\QFK'$1LFKRO VRQ$*HWDO$QRIÀFLDO$PHULFDQ7KRUDFLF6RFLHW\(XURSHDQ 5HVSLUDWRU\ 6RFLHW\ VWDWHPHQW 8SGDWH RI WKH LQWHUQDWLRQDO PXOWLGLVFLSOLQDU\ FODVVLÀFDWLRQ RI WKH LGLRSDWKLF LQWHUVWLWLDO SQHXPRQLDV$P-5HVSLU&ULW&DUH0HG ² >@ /H\%&ROODUG+5(SLGHPLRORJ\RILGLRSDWKLFSXOPRQDU\ÀEUR VLV&OLQ(SLGHPLRO ² >@ 5DJKX*&ROODUG+5(JDQ--0DUWLQH])-%HKU-%URZQ.. HWDO$QRIÀFLDO$76(56-56$/$7VWDWHPHQW LGLRSDWKLFSXO PRQDU\ÀEURVLV HYLGHQFHEDVHGJXLGHOLQHVIRUGLDJQRVLVDQG PDQDJHPHQW$P-5HVSLU&ULW&DUH0HG ² >@ &RWWLQ9&UHVWDQL%9DOH\UH':DOODHUW%&DGUDQHO-'DO SKLQ-&HWDO5HFRPPDQGDWLRQVSUDWLTXHVSRXUOHGLDJQRVWLF HWODSULVHHQFKDUJHGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH eODERUpHVSDUOHFHQWUHQDWLRQDOGHUpIpUHQFHHWOHVFHQWUHVGH
7UDLWHPHQWPpGLFDOGHODÀEURVHSXOPRQDLUHLGLRSDWKLTXH GHQRXYHOOHVSHUVSHFWLYHV
>@
>@
>@
>@
> @
>@
>@
>@
>@
>@ >@
>@
>@
>@
FRPSpWHQFHSRXUOHVPDODGLHVSXOPRQDLUHVUDUHVVRXVO·pJLGH GH OD 6RFLpWp GH SQHXPRORJLH GH ODQJXH IUDQoDLVH 5HY 0DO 5HVSLU ² %MRUDNHU-$5\X-+(GZLQ0.0\HUV-/7D]HODDU+'6FKUR HGHU'5HWDO3URJQRVWLFVLJQLÀFDQFHRIKLVWRSDWKRORJLFVXE VHWV LQ LGLRSDWKLF SXOPRQDU\ ÀEURVLV$P - 5HVSLU &ULW &DUH 0HG ² 1LFKROVRQ$*&ROE\79GX%RLV50+DQVHOO'0:HOOV$87KH SURJQRVWLF VLJQLÀFDQFH RI WKH KLVWRORJLF SDWWHUQ RI LQWHUVWL WLDOSQHXPRQLDLQSDWLHQWVSUHVHQWLQJZLWKWKHFOLQLFDOHQWLW\ RIFU\SWRJHQLFÀEURVLQJDOYHROLWLV$P-5HVSLU&ULW&DUH0HG ² -RKNRK76DNDL)1RPD6$NLUD0)XMLPRWR.:DWDGDQL7 HW DO +RQH\FRPELQJ RQ &7 LWV GHÀQLWLRQ SDWKRORJLF FRU UHODWLRQ DQG IXWXUH GLUHFWLRQ RI LWV GLDJQRVLV (XU - 5DGLRO ² 6LOYD &,6 0OOHU 1/ +DQVHOO '0 /HH .6 1LFKROVRQ $* :HOOV$8 1RQVSHFLÀF LQWHUVWLWLDO SQHXPRQLD DQG LGLRSDWKLF SXOPRQDU\ÀEURVLV FKDQJHVLQSDWWHUQDQGGLVWULEXWLRQRIGLV HDVHRYHUWLPH5DGLRORJ\ ² :DWDGDQL76DNDL)-RKNRK71RPD6$NLUD0)XMLPRWR. HWDO,QWHUREVHUYHUYDULDELOLW\LQWKH&7DVVHVVPHQWRIKRQH\ FRPELQJLQWKHOXQJV5DGLRORJ\ ² $]XPD$1XNLZD77VXERL(6XJD0$EH61DNDWD.HWDO 'RXEOHEOLQG SODFHERFRQWUROOHG WULDO RI SLUIHQLGRQH LQ SDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV$P-5HVSLU&ULW &DUH0HG ² 5\HUVRQ &- 8UEDQLD 7+ 5LFKHOGL / 0RRQH\ -- /HH -6 -RQHV .' HW DO 3UHYDOHQFH DQG SURJQRVLV RI XQFODVVLÀDEOH LQWHUVWLWLDOOXQJGLVHDVH(XU5HVSLU- ² /H\%&ROODUG+5.LQJ7(&OLQLFDOFRXUVHDQGSUHGLFWLRQRI VXUYLYDOLQLGLRSDWKLFSXOPRQDU\ÀEURVLV$P-5HVSLU&ULW&DUH 0HG ² 6WXDUW %' /HH -6 .R]OLWLQD - 1RWK , 'HYLQH 06 *OD]HU &6HWDO(IIHFWRIWHORPHUHOHQJWKRQVXUYLYDOLQSDWLHQWV ZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV DQREVHUYDWLRQDOFRKRUW VWXG\ZLWKLQGHSHQGHQWYDOLGDWLRQ/DQFHW5HVSLU0HG .LQJ7(3DUGR$6HOPDQ0,GLRSDWKLFSXOPRQDU\ÀEURVLV/DQ FHW ² 'HPHGWV0%HKU-%XKO5&RVWDEHO8'HNKXLM]HQ5-DQ VHQ+0HWDO+LJKGRVHDFHW\OF\VWHLQHLQLGLRSDWKLFSXOPR QDU\ÀEURVLV1(QJO-0HG ² ,GLRSDWKLF 3XOPRQDU\ )LEURVLV &OLQLFDO 5HVHDUFK 1HWZRUN 5DJKX*$QVWURP.-.LQJ7(/DVN\-$0DUWLQH])-3UHGQL VRQHD]DWKLRSULQHDQG1DFHW\OF\VWHLQHIRUSXOPRQDU\ÀEUR VLV1(QJO-0HG ² ,GLRSDWKLF3XOPRQDU\)LEURVLV&OLQLFDO5HVHDUFK1HWZRUN0DU WLQH])-GH$QGUDGH-$$QVWURP.-.LQJ7(5DJKX*5DQ GRPL]HGWULDORIDFHW\OF\VWHLQHLQLGLRSDWKLFSXOPRQDU\ÀEURVLV 1(QJO-0HG ² 5LFKHOGL/GX%RLV505DJKX*$]XPD$%URZQ..&RVWD EHO8HWDO(IÀFDF\DQGVDIHW\RIQLQWHGDQLELQLGLRSDWKLFSXO PRQDU\ÀEURVLV 5HVXOWVRIWZRZHHNSKDVH,,,UDGRPL]HG SODFHERFRQWUROOHGWULDOV ,138/6,6 $
> @ 5LFKHOGL/&RVWDEHO86HOPDQ0.LP'6+DQVHOO'01LFK ROVRQ$*HWDO(IÀFDF\RIDW\URVLQHNLQDVHLQKLELWRULQLGLR SDWKLFSXOPRQDU\ÀEURVLV1(QJO-0HG ² >@ 5LFKHOGL/GX%RLV505DJKX*$]XPD$%URZQ..&RVWD EHO8HWDO(IÀFDF\DQGVDIHW\RIQLQWHGDQLELQLGLRSDWKLFSXO PRQDU\ÀEURVLV1(QJO-0HG ² >@ &ROODUG +5 0RRUH %% )ODKHUW\ .5 %URZQ .. .DQHU 5- .LQJ7(HWDO$FXWHH[DFHUEDWLRQVRILGLRSDWKLFSXOPRQDU\ ÀEURVLV$P-5HVSLU&ULW&DUH0HG ² >@ 6FKDHIHU&-5XKUPXQG':3DQ/6HLZHUW6'.RVVHQ.$QWL ÀEURWLFDFWLYLWLHVRISLUIHQLGRQHLQDQLPDOPRGHOV(XU5HVSLU 5HY2II-(XU5HVSLU6RF ² >@ 7DQLJXFKL+(ELQD0.RQGRK<2JXUD7$]XPD$6XJD0 HWDO3LUIHQLGRQHLQLGLRSDWKLFSXOPRQDU\ÀEURVLV(XU5HVSLU - ² >@ $]XPD$7DJXFKL<2JXUD7(ELQD07DQLJXFKL+.RQGRK< HWDO([SORUDWRU\DQDO\VLVRIDSKDVH,,,WULDORISLUIHQLGRQH LGHQWLÀHVDVXESRSXODWLRQRISDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ ÀEURVLVDVEHQHÀWLQJIURPWUHDWPHQW5HVSLU5HV >@ &RWWLQ97KHUROHRISLUIHQLGRQHLQWKHWUHDWPHQWRILGLRSDWKLF SXOPRQDU\ÀEURVLV5HVSLU5HV 6 >@ 1REOH3:$OEHUD&%UDGIRUG:=&RVWDEHO8*ODVVEHUJ0. .DUGDW]NH ' HW DO 3LUIHQLGRQH LQ SDWLHQWV ZLWK LGLRSDWKLF SXOPRQDU\ ÀEURVLV &$3$&,7< WZR UDQGRPLVHG WULDOV /DQ FHW ² >@ .LQJ7( %UDGIRUG := &DVWUR%HUQDUGLQL 6 )DJDQ ($ *OD VSROH , *ODVVEHUJ 0. HW DO$ SKDVH WULDO RI SLUIHQLGRQH LQSDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV1(QJO-0HG ² >@ 1REOH 3:$OEHUD & %UDGIRUG := &RVWDEHO 8 GX %RLV 50 )DJDQ($HWDO$QDO\VLVRISRROHGGDWDIURPSKDVHPXO WLQDWLRQDOUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHGWULDOV HYDOXDWLQJSLUIHQLGRQHLQSDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ ÀEURVLV ,3) $P-5HVSLU&ULW&DUH0HG $ > @ .LQJ7($OEHUD&%UDGIRUG:=&RVWDEHO8GX%RLV50/HII-$ HWDO$OOFDXVHPRUWDOLW\UDWHLQSDWLHQWVZLWKLGLRSDWKLFSXO PRQDU\ÀEURVLV,PSOLFDWLRQVIRUWKHGHVLJQDQGH[HFXWLRQRI FOLQLFDOWULDOV$P-5HVSLU&ULW&DUH0HG ² >@ 1DWKDQ6'$OEHUD&%UDGIRUG:=&RVWDEHO8GX%RLV50 )DJDQ($HWDO/RQJWHUPVDIHW\RISLUIHQLGRQHLQSDWLHQWV ZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV LQWHJUDWHGDQDO\VLVRIGDWD IURPFOLQLFDOWULDOV$P-5HVSLU&ULW&DUH0HG $ >@ 9DOH\UH'$OEHUD&%UDGIRUG:=&RVWDEHO8.LQJ7(/HII-$ HWDO&RPSUHKHQVLYHDVVHVVPHQWRIWKHORQJWHUPVDIHW\RI SLUIHQLGRQHLQSDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV5HV SLURORJ\ ² >@ .DJDPL 5 .DZDPXUD7 0RFKL]XNL< 1DNDKDUD< 6DVDNL 6 0RULPRWR$ HW DO (IÀFDFLW\ DQG VDIHW\ RI SLUIHQLGRQH LQ SDWLHQWVZLWKLGLRSDWKLFSXOPRQDU\ÀEURVLV FRPSDUDLVRQRI PLOGPRGHUDWHFDVHVDQGVHYHUHFDVHV$P-5HVSLU&ULW&DUH 0HG $ >@ +RPPD6$6DNDPRWR66XJLQR.0XUDPDWVX<.D]XWRVKL, 7DNDL<(IÀFDF\RISLUIHQLGRQHFRPELQHGZLWK1DFHW\OF\VWH LQHWKHUDS\LQSDWLHQWVZLWKDGYDQFHGLGLRSDWKLFSXOPRQDU\ ÀEURVLV$P-5HVSLU&ULW&DUH0HG $