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Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
1
PegIntron Maintenance Therapy in Cirrhotic (METAVIR F4) HCV Patients Who Failed to
Respond to Interferon/Ribavirin (IR) Therapy: Final Results of the EPIC3 Cirrhosis
Maintenance Trial
J Bruix, T Poynard, M Colombo, E Schiff, J Reichen, K Burak, EJL Heathcote, T Berg, J-L Poo, C Brandao Mello, R Guenther,
C Niederau, R Terg, N Boparai, J Harvey, LH Griffel, M Burroughs, CA Brass, JK Albrecht for the EPIC3 Study Group
44th Annual Meeting of the European Association for the Study of the Liver Friday, April 24, 2009
Copenhagen, Denmark
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
2
Background and Aims A large proportion of HCV patients are nonresponders
to previous treatment HCV-related cirrhosis is associated with hepatocellular
carcinoma (HCC) and end-stage liver disease (ESLD) Interferon therapy has been associated with reduction
in rates of HCCa and ESLD-related eventsb
The aim of this study was to compare long-term, low-dose PEG-IFN alfa-2b with observed controls regarding the occurrence of HCC and ESLD-related events in cirrhotic patients (F4)
Similar trials COPILOT: 548 cirrhotics; primary end-point negativeb
HALT- C: included 428 cirrhotics; all endpoints negativec
a Yohsida et al., Gut 2000;47:610-611b Afdhal et al., J. Hepatol, 2008; 48, S2, A3 c DiBiesgelie et al., NEJM, 2008;359:2429-41
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
3
HCV RNA negative at week 12HCV RNA negative at week 12
Continue P/R for 48 wkContinue P/R for 48 wk
EPIC3 Program Design
Nonresponder Trial*Nonresponder Trial*: N = 2333: N = 2333CHC with fibrosis (F2, F3, or F4 METAVIR) CHC with fibrosis (F2, F3, or F4 METAVIR)
Evaluation of virological response at week 12Evaluation of virological response at week 12
Chronic Suppression for Chronic Suppression for NoncirrhoticsNoncirrhotics, n = 575, n = 575
METAVIR F2 or F3 subjects METAVIR F2 or F3 subjects PEG-Intron 0.5 PEG-Intron 0.5 g/kg/wk vs controlg/kg/wk vs control
Duration: 3 yearsDuration: 3 years
Chronic Suppression for Cirrhotics, n = 626
(Child-Pugh A, Compensated)
METAVIR F4 subjects PEG-Intron 0.5 g/kg/wk vs control
Max. duration: up to 5 years
METAVIR F4 CHC subjects
DIRECT ENROLLERS
n = 172n = 454
HCV-RNA
Negative
HCV-RNA
Positive
F2/3 F4
* Poynard et al., Gastro 2009:136:1618-1628
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
4
Methods Study duration
Up to 5 years from time first subject was randomized or occurrence of 98 clinical events
Statistical plan: 90% power for 98 events and hazard ratio of 2
Study completed based upon 5-year rule
Primary objective – time to first clinical event Liver decompensation (variceal bleed, >grade 2 enceph,
ascites requiring Rx, CPT C); HCC; death; liver transplantation.
Clinical evaluation/3 months, US every 6 months
Clinical events, with the exception of death and liver transplantation, were adjudicated by an external adjudication committee
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
5
Methods (cont) Secondary objective – time to disease progression
Includes all clinical events and
Development of Child-Pugh B
Emergence of varices
Enlargement of pre-existing varices requiring additional therapy
Additional prospective analyses in subjects with baseline portal hypertension Prospectively planned based upon results of COPILOT study
Defined as the existence of esophageal varices
Sensitivity analysis performed using definition of splenomegaly and platelet count <100K
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
6
Baseline DemographicsRoll-over Subjects
From Treatment Phase Direct Enrollers All Randomized
PEG (n = 224)
Control (n = 230)
PEG (n = 87)
Control (n = 85)
PEG (n = 311)
Control (n = 315)
Male, n (%) 155 (69) 156 (68) 51 (59) 59 (69) 206 (66) 216 (68)
Caucasian, n (%) 189 (84) 197 (86) 69 (79) 68 (80) 258 (83) 265 (84)
Age, years (SD) 52.2 (7.6) 51.7 (8.0) 52.3 (7.3) 53.0 (6.4) 52.3 (7.5) 52.0 (7.6)
Weight, kg (SD) 78.08 (14.35) 77.48 (14.36)
83.09 (17.62)
83.08 (16.26) 79.48 (15.47)
78.99 (15.08)
BMI, kg/m2 (SD) 26.72 (4.07) 26.78 (4.25) 28.55 (5.09)
28.13 (4.38) 27.24 (4.45) 27.13 (4.32)
Genotype 1, n (%) 207 (92) 217 (94) 71 (82) 68 (80) 278 (89) 285 (90)
Viral Load >600,000 IU/mL, n (%)
Baseline ALT U/L (SD)
155 (69)
116.5 (70.2)
161 (70)
116.8 (80.4)
58 (67)
102 (66.5)
59 (69)
108.3 (65.9)
213 (68)
112.4 (69.4)
220 (70)
114.7(77.0)
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
7
Time to First Clinical Event* Liver decompensation (variceal bleed, >grade 2 enceph,
ascites requiring Rx, CPT C); HCC; death; liver transplantation
* All Randomized Subjects from sites
not closed for noncompliance.*P = 0.144, HR = 1.452 vs observed controls
Pro
bab
ility
of
Fai
lure
1.00.9
0.80.7
0.60.50.40.3
0.20.1
0.0
TimeAt RiskPEG:
CONTROL:
6
296290
12
279265
18
265253
24
226203
30
185167
36
153133
42
11794
48
8160
54
3524
60
11
66
.
.
CONTROL
PEG
PEGCONTROLCensored
mean treatment duration = 32 months
mean treatment duration = 31 months
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
8
Clinical Events by Treatment Arm
Event, n (%)
Observed Controls
n = 315
PEG-IFN alfa-2b
n = 311
Subjects With Clinical Eventa 36 (11) 27 (9)*
Ascitesb 13 (4) 10 (3)
Childs Pugh Class Cb 1 (<1) 4 (1)
Variceal bleedingb 10 (3) 1 (<1)
HCCb 13 (4) 12 (4)
≥Grade 2 hepatic encephalopathyb 3 (1) 4 (1)
Liver transplantation 4 (1) 2 (<1)
Death 6 (2) 7 (2)aEarliest event counted in case of multiple events.
bEvents were adjudicated.cBased on Cox proportional Hazards model with age (≤50, >50 years)
and participation in retreatment phase (yes, no) as stratification factors.
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
9
Time to Disease Progression* Primary events plus: Development of Child-Pugh B, Emergence of
varices, Enlargement of pre-existing varices requiring additional therapy
* All Randomized Subjects from sites not closed for noncompliance.
Pro
bab
ility
of
Fai
lure
TimeAt RiskPEG:
CONTROL:
6
284276
12
267252
18
253237
24
208181
30
169146
36
140116
42
10884
48
7752
54
3317
60
1-
66
.
.
PEG
1.00.9
0.80.7
0.60.50.40.3
0.20.1
0.0
PEGCONTROLCensored
HR: 1.564 (95% CI 1.130, 2.166)P = 0.007 CONTROL
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
10
Subgroup AnalysesAll Randomized Subjects
AFP, alfa fetoprotein; PTL HTN, portal hypertension; VL viral load
Observation better
PEG-IFN alfa-2bbetter
Bas
elin
e/D
ise
ase
Ch
arac
teri
stic
Cat
ego
ry
AFP ≤40ng/mLNo PTL HTN
PTL HTNAlbumin >4g/dL
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Albumin ≤4g/dLChild Pugh class >5Child Pugh class ≤5
Platelet >100,000/mm3
Platelet ≤100,000/mm3
NonresponderRelapser
All subjects
Body weight >105 kgBody weight 85-105 kg
Body weight 65-85 kgBody weight <65 kg
VL >600,000 IU/mLVL ≤600,000 IU/mL
Genotype 2/3Genotype 1
NoncaucasianCaucasian
Direct enrollerFrom Retreatment phase
FemaleMale
Age >50 yearsAge ≤50 years
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
11
Time to First Clinical Event Baseline Varices
Portal hypertension defined as esophageal varices at baseline EGD performed at baseline, EOT and when clinically indicated Findings confirmed by exploratory analysis when portal hypertension defined
as platelet <100 and presence of splenomegaly
Pro
bab
ility
of
Fai
lure
TimeAt RiskPEG:
CONTROL:
6
3947
12
3537
18
3334
24
3127
30
2418
36
1813
42
147
48
85
54
42
60
--
CONTROL
PEG
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
PEG
CONTROLCensored
Pro
bab
ility
of
Fai
lure
TimeAt RiskPEG:
CONTROL:
6
257249
12
244228
18
232219
24
195176
30
161149
36
135120
42
10387
48
7355
54
3122
60
11
66
.
.
CONTROL
PEG
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
PEG
CONTROLCensored
Varices at Baseline No Varices at Baseline
p=0.963HR=1.014
p=0.016HR=4.028
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
12
Clinical Events by Treatment ArmSubjects with Portal Hypertension at Baseline
32.6
16.3
2.3
14.0
4.7 4.72.3 2.3
10.3
2.6 2.6
0.0
7.7
2.6
0.0 0.00
10
20
30
40
Any ClinicalEvent
Ascites Child-PughClass C
VaricealBleeding
HCC HE LiverTransplant
Death
Pa
tie
nts
, %
Observed Control (n = 43)
PEG-IFN alfa-2b (0.5 µg/kg/week) [n = 39]
Subjects may have multiple events.
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
13
Summary of Adverse Events Leading to Discontinuation
Event, n (%)PEG-IFN alfa-2b
n = 311Observed Controls
n = 315
Subjects Reporting any AE 53 (17) 12 (4)
Psychiatric disorders 8 (3) 1 (<1)
Investigations 8 (3) 0
Infections (all) 7 (2) 0
Blood and lymphatic disorders 5 (2) 0
Neoplasms 5 (2) 4 (1)
Nervous system disorders 4 (1) 1 (<1)
Gastrointestinal disorders 4 (1) 4 (1)
Respiratory disorders 3 (1) 0
Hepatobiliary disorders 2 (1) 0
General disorders 2 (1) 0
Cardiac disorders 1 (<1) 0
Endocrine disorders 1 (<1) 0
Eye disorders 1 (<1) 0
Musculoskeletal disorders 1 (<1) 1 (<1)
Renal and urinary disorders 1 (<1) 0
Vascular disorders 1 (<1) 0
Metabolism and nutrition disorders 0 1 (<1)
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
14
Adverse Events: More Serious Infections in PEG-IFN alfa-2b Group
Expert Review Conclusions from review by 2 infectious disease specialists
Predominance of events in PEG-IFN alfa-2b-treated patients
No pattern that suggests relationship to Rx in timing, type of infection, WBC count
Events seem random
Control Experimental
EPIC3
All patients 1% (3/315) 8% (25/311)
Baseline portal hypertension 0% (0/52) 7% (3/46)
HALT-C 8.5% (44/517) 8% (44/533)
COPILOT 6.3% (17/269) 2.8 % (8/286)
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
15
Serious Adverse Events Infection/Infestation in Cirrhotic Subjects
N Description
Treated Subjects (n = 25)
Bacterial 6
3
6
6
4
1
Pneumonia, bronchitis, bronchiectasis
Pyelonephritis/UTI
Abscess: lung, subQ, rectal, psoas, abdominal wall
Sepsis/bacteremia/endocarditis
Cellulitis/soft tissue infection
Discitis
Tuberculosis 1
Fungal 1 Esophageal candidiasis
Viral 3 Viral meningitis, gastroenteritis, febrile infection
Procedure 2 Appendicitis
Observed Subjects (n = 3)
Bacterial 3 Pneumonia, bronchitis, E. coli UTI
Treated subjects: 3 deaths (pneumonia, septic shock, sepsis).
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
16
Results Summary
Mean treatment duration PEG-IFN alfa-2b: 32 months, 14 subjects for 5 yrs
Observed controls: 31 months, 10 subjects for 5 yrs
Primary end point failed: Time to clinical event (adjudicated events + death/liver transplant) Treatment has no effect on occurrence of HCC
Significant treatment effect in Disease Progression
Portal hypertension Treatment benefit suggested in subjects with baseline portal
hypertension
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
17
Conclusions Long-term therapy with low-dose PEG-IFN
alfa-2b has no effect on incidence of HCC in HCV-infected cirrhotics
Long-term therapy with low-dose PEG-IFN alfa-2b may be beneficial for cirrhotic patients with chronic HCV and portal hypertension
Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09
18
SwitzerlandSwitzerland
EPICEPIC33 Investigators InvestigatorsMichael Manns Michael Manns Claus NiederauClaus NiederauWolfgang SchmidtWolfgang SchmidtUlrich SpenglerUlrich SpenglerReinhart Zachoval Reinhart Zachoval Stefan ZeuzemStefan Zeuzem
Emanuel K. Manesis Emanuel K. Manesis
Alfredo Alberti Alfredo Alberti Antonino Picciotto Antonino Picciotto Mauro PoddaMauro PoddaMario RizzettoMario RizzettoMaria Grazia Rumi Maria Grazia Rumi Erica Villa Erica Villa Anna Linda Zignego Anna Linda Zignego Antonio Craxi Antonio Craxi
Jorge-Luis Poo Jorge-Luis Poo
Armando Carvalho Armando Carvalho Ana Maria ValeAna Maria Vale
Alvaro ReymundeAlvaro ReymundeJose Sanchez-Tapias Jose Sanchez-Tapias Doris ToroDoris ToroEsther TorresEsther Torres
Ramon Perez Alvarez Ramon Perez Alvarez Jose Luis CallejaJose Luis CallejaMiguel Angel Serra Desfilis Miguel Angel Serra Desfilis Moises Diago Moises Diago Rafael Esteban-MurRafael Esteban-MurRicardo Moreno-OteroRicardo Moreno-OteroMayra Ramos-GomezMayra Ramos-GomezG. Castellanos TortajadaG. Castellanos TortajadaRamon Planas VilaRamon Planas Vila
Luis Colombato Luis Colombato Jose Curciarello Jose Curciarello Hugo Fainboim Hugo Fainboim Adrian GadanoAdrian GadanoLeonardo PinchukLeonardo PinchukMarcelo SilvaMarcelo SilvaHugo TannoHugo TannoRuben Terg Ruben Terg
Wendy Cheng Wendy Cheng Darrell Crawford Darrell Crawford Jacob GeorgeJacob GeorgeGary JeffreyGary JeffreyBarbara LeggettBarbara LeggettLindsay MollisonLindsay MollisonMeng NguMeng NguStuart Roberts Stuart Roberts Douglas Routley Douglas Routley William SievertWilliam Sievert
Harald BrunnerHarald BrunnerAndreas Maieron Andreas Maieron
Jean Delwaide Jean Delwaide Yves Horsmans Yves Horsmans H. Van VlierbergheH. Van Vlierberghe
Flair CarrilhoFlair CarrilhoHenrique S. M. CoelhoHenrique S. M. CoelhoMaria Lucia Gomes FerrazMaria Lucia Gomes FerrazRaymundo P.F. FilhoRaymundo P.F. FilhoRoberto FocacciaRoberto FocacciaFernando Lopes Goncales Fernando Lopes Goncales Luiz Lyra Luiz Lyra
Angelo MattosAngelo Mattos
Marcos MauadMarcos MauadCarlos Brandao MelloCarlos Brandao MelloDominique Araujo MuzzilloDominique Araujo MuzzilloHeitor RosaHeitor RosaRosangela Teixeira Rosangela Teixeira
Frank AndersonFrank AndersonKelly Warren Burak Kelly Warren Burak Robert Enns Robert Enns Victor Feinman Victor Feinman Klaus Siegfried Gutfreund Klaus Siegfried Gutfreund E. Jenny HeathcoteE. Jenny HeathcoteNir HilzenratNir HilzenratKelly KaitaKelly KaitaPaul MarottaPaul MarottaKevork PeltekianKevork PeltekianFlorence WongFlorence Wong
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Rolf Hultcrantz Rolf Hultcrantz
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