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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
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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, lowdose 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;47:610-611
b 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
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EPIC3 Program Design
Nonresponder Trial*: N = 2333
CHC with fibrosis (F2, F3, or F4 METAVIR)
Evaluation of virological response at week 12
HCV RNA negative at week 12
Continue P/R for 48 wk
F2/3
HCV-RNA
Negative
METAVIR F4 CHC subjects
HCV-RNA
Positive
DIRECT ENROLLERS
F4 n = 454
n = 172
Chronic Suppression
for Cirrhotics, n = 626
Chronic Suppression for
Noncirrhotics, n = 575
(Child-Pugh A, Compensated)
METAVIR F2 or F3 subjects
PEG-Intron 0.5 g/kg/wk vs control
Duration: 3 years
METAVIR F4 subjects
PEG-Intron 0.5 g/kg/wk vs control
Max. duration: up to 5 years
* 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
Methods

4
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
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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
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Baseline Demographics
Roll-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 (%)
155 (69)
161 (70)
58 (67)
59 (69)
213 (68)
220 (70)
116.5 (70.2)
116.8 (80.4)
102 (66.5)
108.3 (65.9)
112.4 (69.4)
114.7(77.0)
Baseline ALT U/L (SD)
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
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Time to First Clinical Event*
Probability of Failure
Liver decompensation (variceal bleed, >grade 2 enceph,
ascites requiring Rx, CPT C); HCC; death; liver transplantation
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
PEG
CONTROL
Censored
Time
6
At Risk
PEG:
296
CONTROL: 290
mean treatment duration = 32 months
mean treatment duration = 31 months
CONTROL
PEG
12
18
24
30
36
42
48
54
60
66
279
265
265
253
226
203
185
167
153
133
117
94
81
60
35
24
1
1
.
.
* All Randomized Subjects from sites
not closed for noncompliance.
*P = 0.144, HR = 1.452
vs observed controls
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
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Clinical Events by Treatment Arm
Observed Controls
PEG-IFN alfa-2b
Event, n (%)
n = 315
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
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Time to Disease Progression*
Probability of Failure
Primary events plus: Development of Child-Pugh B, Emergence of
varices, Enlargement of pre-existing varices requiring additional therapy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
HR: 1.564
(95% CI 1.130, 2.166)
P = 0.007
PEG
CONTROL
Censored
Time
6
At Risk
PEG:
284
CONTROL: 276
CONTROL
PEG
12
18
24
30
36
42
48
54
60
66
267
252
253
237
208
181
169
146
140
116
108
84
77
52
33
17
1
-
.
.
* All Randomized Subjects from sites
not closed for noncompliance.
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
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Subgroup Analyses
All Randomized Subjects
Baseline/Disease Characteristic Category
Observation
better
PEG-IFN alfa-2b
better
AFP ≤40ng/mL
No PTL HTN
PTL HTN
Albumin >4g/dL
Albumin ≤4g/dL
Child Pugh class >5
Child Pugh class ≤5
Platelet >100,000/mm3
Platelet ≤100,000/mm3
Nonresponder
Relapser
Body weight >105 kg
Body weight 85-105 kg
Body weight 65-85 kg
Body weight <65 kg
VL >600,000 IU/mL
VL ≤600,000 IU/mL
Genotype 2/3
Genotype 1
Noncaucasian
Caucasian
Direct enroller
From Retreatment phase
Female
Male
Age >50 years
Age ≤50 years
All subjects
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
AFP, alfa fetoprotein; PTL HTN, portal hypertension; VL viral load
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
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Time to First Clinical Event
Baseline Varices
No Varices at Baseline
Varices at Baseline
Probability of Failure
0.9
0.8
1.0
PEG
CONTROL
Censored
p=0.016
HR=4.028
0.7
0.9
0.6
CONTROL
0.5
0.4
0.3
0.2
PEG
0.1
0.0
Probability of Failure
1.0
0.8
PEG
p=0.963
HR=1.014
CONTROL
Censored
0.7
0.6
0.5
0.4
0.3
0.2
CONTROL
0.1
PEG
0.0
Time
6
At Risk
PEG:
39
CONTROL: 47
12
18
24
30
36
42
48
54
60
35
37
33
34
31
27
24
18
18
13
14
7
8
5
4
2
-
Time
6
At Risk
PEG:
257
CONTROL: 249
12
18
24
30
36
42
48
54
60
66
244
228
232
219
195
176
161
149
135
120
103
87
73
55
31
22
1
1
.
.
 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
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
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Clinical Events by Treatment Arm
Subjects with Portal Hypertension at Baseline
40
Observed Control (n = 43)
32.6
PEG-IFN alfa-2b (0.5 µg/kg/week) [n = 39]
Patients, %
30
20
16.3
14.0
10.3
10
7.7
4.7
2.6
2.3 2.6
4.7
2.6
0.0
2.3
2.3
0.0
0.0
0
Any Clinical
Event
Ascites
Child-Pugh
Class C
Variceal
Bleeding
HCC
HE
Liver
Transplant
Death
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
Summary of Adverse Events
Leading to Discontinuation
PEG-IFN alfa-2b
n = 311
Observed Controls
n = 315
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
0
1 (<1)
Event, n (%)
Subjects Reporting any AE
Metabolism and nutrition disorders
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.
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04/28/09
Adverse Events: More Serious
Infections in PEG-IFN alfa-2b Group
Control
Experimental
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)
14
EPIC3
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
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
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Serious Adverse Events
Infection/Infestation in Cirrhotic Subjects
N
Description
Treated Subjects (n = 25)
Bacterial
6
Pneumonia, bronchitis, bronchiectasis
3
Pyelonephritis/UTI
6
Abscess: lung, subQ, rectal, psoas, abdominal wall
6
Sepsis/bacteremia/endocarditis
4
Cellulitis/soft tissue infection
1
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
Results Summary

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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
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EPIC3 Investigators
Luis Colombato
Jose Curciarello
Hugo Fainboim
Adrian Gadano
Leonardo Pinchuk
Marcelo Silva
Hugo Tanno
Ruben Terg
Argentina
Wendy Cheng
Darrell Crawford
Jacob George
Gary Jeffrey
Barbara Leggett
Lindsay Mollison
Meng Ngu
Stuart Roberts
Douglas Routley
William Sievert
Australia
Harald Brunner
Andreas Maieron
Austria
Jean Delwaide
Yves Horsmans
H. Van Vlierberghe
Brazil
Marcos Mauad
Carlos Brandao Mello
Dominique Araujo Muzzillo
Heitor Rosa
Rosangela Teixeira
Canada
Frank Anderson
Kelly Warren Burak
Robert Enns
Victor Feinman
Klaus Siegfried Gutfreund
E. Jenny Heathcote
Nir Hilzenrat
Kelly Kaita
Paul Marotta
Kevork Peltekian
Florence Wong
Adriana Varon
Belgium
Brazil
Flair Carrilho
Henrique S. M. Coelho
Maria Lucia Gomes Ferraz
Raymundo P.F. Filho
Roberto Focaccia
Fernando Lopes Goncales
Luiz Lyra
Angelo Mattos
Columbia
Karl Barange
France
Marc Bourliere
Jean-Pierre Bronowicki
Xavier Causse
Patrick Marcellin
Raoul Poupon
Thierry Poynard
Albert Tran
Christian Trepo
Thomas Berg
Germany
Peter Buggisch
Wolfgang Caselmann
Dieter Haussinger
Holger Hinrichsen
Michael Manns
Claus Niederau
Wolfgang Schmidt
Ulrich Spengler
Reinhart Zachoval
Stefan Zeuzem
Germany
Ming-Yang Lai
Greece
Alfredo Alberti
Antonino Picciotto
Mauro Podda
Mario Rizzetto
Maria Grazia Rumi
Erica Villa
Anna Linda Zignego
Antonio Craxi
Italy
Armando Carvalho
Ana Maria Vale
Sweden
Beat Muellhaupt Switzerland
Jurg Reichen
Emanuel K. Manesis
Jorge-Luis Poo
Rolf Hultcrantz
Mexico
Portugal
Puerto Rico
Alvaro Reymunde
Jose Sanchez-Tapias
Doris Toro
Esther Torres
Spain
Ramon Perez Alvarez
Jose Luis Calleja
Miguel Angel Serra Desfilis
Moises Diago
Rafael Esteban-Mur
Ricardo Moreno-Otero
Mayra Ramos-Gomez
G. Castellanos Tortajada
Ramon Planas Vila
Geoffrey Dusheiko
William Rosenberg
Taiwan
UK
USA
Luis Balart
Henry Bodenheimer
Steven Flamm
Stuart Gordon
Ira Jacobson
Paul King
Paul Kwo
Luis Marsano
Arthur J. McCullough
Thomas McGarrity
John McHutchison
Mary Pat Pauly
Robert Perrillo
Fred Poordad
Robert Reindollar
Vinod Rustgi
Eugene Schiff
Warren Schmidt
Obaid S. Shaikh
Kenneth Sherman
Coleman Smith
Mark Sulkowski
Naoky Tsai
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