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![Page 1: Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09.](https://reader031.fdocuments.in/reader031/viewer/2022032600/56649dc95503460f94abf7d2/html5/thumbnails/1.jpg)
Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
1
Reduced Dose and Duration of Peginterferon alfa-2b and Weight-Based
Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial)
Final Analysis
M Manns1, S Zeuzem2, A Sood3, Y Lurie4, M Cornberg1, H Klinker5, I Merican6, Y Ilan7, T Mueller8, R Chen9, X Yu9, R Faruqi9, and H Wedemeyer1
44th European Association for Study of the LiverCopenhagen
12.00-13.30 Sunday, April 26, 2009.
1Medical School of Hannover, Hanover, Germany; 2J.W. Goethe University Hospital, Frankfurt. Germany3Dayanand Medical College & Hospital, Ludhiana, India4Tel-Aviv Sorasky Medical Center, Tel-Aviv, Israel5University of Würzburg Medical Center, Würzburg, Germany
6Selayang Hospital, Selangor, Malaysia 7Hadassah Hebrew University Medical Center, Jerusalem, Israel8University of Munich, Munich, Germany9Schering Plough Corp., NJ, USA
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
2
International Recruitment
Germany
Poland
Israel
India
Thailand
Indonesia
Malaysia
Singapore
International Cohort (SP sponsored, 2005-2007)HepNet Cohort (investigator-initiated, 2003-2006)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
3
AcknowledgmentsHEPNET INVESTIGATORS INTERNATIONAL INVESTIGATORS
JC Arnold S Mauss S Abu-Mauch Y Lurie
P Buggisch U Meyer D Amarapurkar V Mahachai
H Cordes J Ockenga Z Ben-Ari I Merican
W Fleig J Pausch C Choudhury T Piratvisuth
W Gickler T Pohle A Chutaputti D Reddy
J Gottberg J Riemann M Goenka S Sachithanandan
K Grungrieff M Rössle W Halota T Safadi
A Heer A Schober A Horban S Sarin
H Hinrichsen H Steffens Y Ilan O Segol
D Hüppe
T Käser
A Trein E Janczewska-Kazek PB Setiawan
H Klinker K Wiedmann A Konar A Sood
MP Manns K Wiegand L Lesmana T Tanwandee
R Markus S Zeuzem S Lim
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
4
Background
What is the optimum dose of PEG-IFN alfa-2b?
Reduced PEG-IFN dose?1,2
What is the optimum treatment duration?
24 weeks for all patients?
Reduced treatment duration for selected patients (<24 weeks2-6)?
Are separate treatment regimens required for G2 and G3 patients?
Higher SVR with G2, higher relapse with G3
Do global/ethnic aspects influence treatment outcomes?
Asian vs white?
Prolonged infection leads to high rates of cirrhosis among Asian patients7
What is the efficacy of standard antiviral treatment in a “real-life” setting
1. Manns et al. Lancet. 2001;358:958-965 2. Mangia et al. N Engl J Med. 2005;352:2609-26173. Shiffman et al. N Engl J Med. 2005;357;124-1344. Lagging et al. Hepatology. 2008;47:1837-1845
PEG-IFN alfa-2b (1.5 µg/kg/wk) + weight-based RBV for 24 weeks is a recommended treatment for patients with genotype 2/3 hepatitis C, but many important clinical questions remain unanswered:
5. Dalgard et al. Hepatology. 2008;47:35-426. von Wagner et al. Gastroenterology. 2005;129:522-5277. D’Souza et al. Clin Gastroenterol Hepatol. 2005;3:910-917.
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
5
Study Design and Aim Study Design
Open-label, multicenter, randomized, parallel-group study
Treatment-naive genotypes 2 and 3
Combination of “real-life” and industry-sponsored study
Large Asian population
Aim To evaluate the effect of reduced treatment duration or
reduced PEG-IFN alfa-2b dosing on SVR and relapse rates among treatment-naive G2/3 patients
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
6
Methods Treatment Arms
A: PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV (800-1200 mg/d) for 24 weeks
B: PEG-IFN alfa-2b (1.0 µg/kg/wk) + RBV (800-1200 mg/d) for 24 weeks
C: PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV (800-1200 mg/d) for 16 weeks
Co-primary End Points
Compare standard regimen of PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV with a lower dose PEG-IFN alfa-2b (1.0 µg/kg/wk) + RBV regimen (A vs B)
Compare 24-week vs 16-week regimen of PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV (A vs C)
Noninferiority criteria (p<0.025 required)
Period of Enrollment
HepNet cohort: July 2003 to March 2006
International cohort: January 2005 to March 2007
No Interim Analysis per Protocol
First presentation of results from REDD 2/3
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
7
Patient Population Key Inclusion Criteria
Adult patients with chronic hepatitis C and compensated liver disease (Child-Pugh score <7)
Genotype 2 or 3
Treatment-naive
At least 1 abnormal ALT level in previous 12 months
Key Exclusion Criteria
HIV or hepatitis B coinfection
Causes of liver disease other than hepatitis C
Evidence of advanced liver disease
Preexisting psychiatric condition
Alcohol/substance abuse
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
8
Patient DemographicsGroup A
PEG 1.5/R (24 wk) n = 230
Group B PEG 1.0/R
(24 wk) n = 224
Group C PEG1.5/R
(16 wk)n = 228
Total n = 682
Age, y, mean (SD) 38.8 (10.2) 39.9 (11.2) 39.7 (11.1) 39.5 (10.9)
Male, n (%) 139 (60.4) 146 (65.2) 148 (64.9) 433 (63.5)
Body weight, kg (SD) 73.7 (15.2) 72.8 (13.7) 72.5 (15.0) 73.0 (14.6)
Time since infection, y (SD) 7.3 (7.04) 7.6 (7.49) 7.3 (8.02) 7.4 (7.52)
Genotype, n (%)
2
3
38 (16.5)
192 (83.5)
49 (21.9)
175 (78.1)
48 (21.1)
180 (78.9)
135 (19.8)
547 (80.2)
Baseline HCV RNA, n (%)
≥600,000 IU/mL
<600,000 IU/mL
119 (51.7)
109 (47.4)
120 (53.6)
103 (46.0)
123 (53.9)
103 (45.2)
362 (53.1)
315 (46.2)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
9
HepNet vs International Cohort Patient Demographics
HepNet Cohortn = 347
International Cohortn = 335
Age, y, mean (SD) 38.8 (10.9) 40.2 (10.8)
Male, n (%) 207 (59.7) 226 (67.5)
Body weight, kg (SD) 74.4 (14.6) 71.6 (14.6)
Years since HCV exposure, y (SD) 4.7 (5.01) 11.4 (8.71)
HCV genotype, n (%)
2
3
84 (24.2)
263 (75.8)
51 (15.2)
284 (84.8)
Baseline HCV-RNA, n (%)
≥600,000 IU/mL
<600,000 IU/mL
171 (49.3)
171 (49.3)
191 (57.0)
144 (43.0)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
10
SVR by Treatment Regimen
Treatment differences (one-sided 95% CI): aGrp A – Grp B: -0.02 (-0.10); P = .041. bGrp A – Grp C: -0.10 (-0.17); P = .495. Noninferiority not achieved for all patients and individual cohorts.
All Randomized and Treated Patients
15
3/2
30
14
4/2
24
12
9/2
28
68
/11
6
69
/11
5
55
/11
6
85
/11
4
75
/10
9
74
/11
2
66.5 64.3a
56.6b 58.6 60.0
47.4
74.668.8 66.1
0
25
50
75
100
SV
R, %
All Patients(n = 682)
HepNet Cohort(n = 347)
InternationalCohort (n = 335)
A: PEG 1.5/R (24 weeks)
B: PEG 1.0/R (24 weeks)
C: PEG 1.5/R (16 weeks)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
11
SVR by Treatment Regimen
Treatment differences (one-sided 95% CI): aGrp A – Grp B: -0.02 (-0.10); P = .041. bGrp A – Grp C: -0.10 (-0.17); P = .495. Noninferiority not achieved for all patients and individual cohorts.
All Randomized and Treated Patients
15
3/2
30
14
4/2
24
12
9/2
28
68
/11
6
69
/11
5
55
/11
6
85
/11
4
75
/10
9
74
/11
2
66.5 64.3a
56.6b 58.6 60.0
47.4
74.668.8 66.1
0
25
50
75
100
SV
R, %
All Patients(n = 682)
HepNet Cohort(n = 347)
InternationalCohort (n = 335)
A: PEG 1.5/R (24 weeks)
B: PEG 1.0/R (24 weeks)
C: PEG 1.5/R (16 weeks)
Real-life setting67.1% completers
vs. 85.7% in clinical setting
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
12
SVR: Completers Analysis
Treatment differences (one-sided 95% CI):aGrp A – Grp B: -0.02 (-0.09); P = .024.bGrp A – Grp C: -0.14 (-0.21); P = .798. Noninferiority not achieved for all patients and individual cohorts.
Completers
13
6/1
67
13
9/1
74
12
1/1
79
56
/70
66
/82
48
/81
80
/97
73
/92
73
/98
81.5 79.9a
67.6b
80.0 80.5
59.3
82.5 79.474.5
0
25
50
75
100
SV
R, %
All Patients(N = 520)
HepNet Cohort(n = 233)
International Cohort (n = 287)
A: PEG 1.5/R (24 weeks)B: PEG 1.0/R (24 weeks)C: PEG 1.5/R (16 weeks)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
13
77.8
61.353.8
72.766.7
72.7
52.859.5
45.6
74.869.2
64.4
0
25
50
75
100
HepNet Cohort(n = 84)
InternationalCohort (n = 51)
HepNet Cohort(n = 263)
InternationalCohort (n = 284)
SVR by GenotypeS
VR
, %
Genotype 2 Genotype 3
21
/27
19
/31
14
/26
8/1
1
12
/18
16
/22
47
/89
50
/84
41
/90
77
/10
3
63
/91
58
/90
A: PEG 1.5/R (24 weeks)B: PEG 1.0/R (24 weeks)C: PEG 1.5/R (16 weeks)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
14
75.469.5
65.658.6 60.0
47.4
73.768.0 66.7
0
25
50
75
100
InternationalCohort (n = 177)
HepNet Cohort(n = 347)
InternationalCohort (n = 158)
SVR According to Race
Asian White
SV
R, %
43
/57
41
/59
40
/61
69
/11
5
68
/11
6
55
/11
6
42
/57
34
/50
34
/51
A: PEG 1.5/R (24 weeks)B: PEG 1.0/R (24 weeks)C: PEG 1.5/R (16 weeks)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
15
Lower Relapse Rates With 24 Weeks of Therapy
Rated (two-sided 95% CI): a0.18 (0.12, 0.24) b0.16 (0.11, 0.22) c0.29 (0.22, 0.36)
All Randomized and Treated Patients
29
/16
3
27
/16
6
49
/16
7
13
/69
11
/77
25
/73
16
/94
19
/89
24
/94
17.8a
16.3b
29.3c
18.8
14.3
34.2
17.0 18.0
25.5
0
25
50
SV
R, %
All Patients(N = 496)
HepNet Cohort(n = 219)
InternationalCohort (n = 277)
A: PEG 1.5/R (24 weeks)
B: PEG 1.0/R (24 weeks)
C: PEG 1.5/R (16 weeks)
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
16
Most Common Treatment-Emergent Adverse Eventsa
Adverse Event, %Group A:
PEG 1.5/R (24 wk)N = 230
Group B: PEG 1.0/R (24 wk)
N = 224
Group C: PEG1.5/R (16 wk)
N = 228Pyrexia 37.8 37.1 44.3
Fatigue 22.6 22.3 15.8
Headache 22.6 25.4 25.4
Alopecia 20.9 16.1 13.6
Asthenia 19.1 27.7 19.7
Myalgia 15.2 12.1 14.9
Influenza-like illness 12.6 9.4 10.1
Pruritus 12.6 19.6 10.1
Weight decrease 12.6 10.7 13.6
Anorexia 12.2 4.9 9.6
Nausea 11.7 11.6 14.0
Injection-site erythema 11.3 13.8 7.5
Depressed mood 11.3 7.1 8.3
Arthralgia 10.9 7.6 10.5
Anemia 10.0 4.9 11.0
Diarrhea 9.6 12.1 7.0
Dry skin 5.7 11.2 6.6
a Occurring at a frequency >10% in any treatment arm
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
17
Serious Adverse Events and Discontinuations
Group A PEG 1.5/R (24 weeks)
n = 230
Group B PEG 1.0/R (24 weeks)
n = 224
Group C PEG1.5/R (16 weeks)
n = 228
Treatment-emergent SAE, n (%) 14 (6.1) 11 (4.9) 7 (3.1)
Treatment-emergent severe/life-threatening AEs, n (%)
16 (7.0) 10 (4.5) 12 (5.3)
Deaths,a n (%) 2 (<1) 1 (<1) 0 (0)
AE causing discontinuation of treatment, n (%)
3 (1.3) 3 (1.3) 5 (2.2)
aAll 3 deaths were considered unlikely to be related to study medicationAE, adverse event; SAE, serious adverse event.
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Manns M, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark. 04/28/09
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Conclusions Statistically unable to demonstrate that lower dose PEG-IFN alfa-
2b (1.0 ug/kg/wk) regimen is noninferior to standard dose PEG-IFN alfa-2b (1.5 ug/kg/wk) regimen.
PEG-IFN alfa-2b 1.5 µg/kg/wk and 1.0 µg/kg/wk in combination with weight-based ribavirin have similar tolerability profiles
24 weeks of therapy is the appropriate treatment duration for G2/3
Higher relapse rate with shorter duration treatment
SVR rates were similar in Asian and white patients
This is the largest study to date in Asian G3 patients
Results from REDD 2/3 are similar to those reported in other large prospective clinical trials of PEG-IFN alfa plus RBV1-4
1. Manns et al. Lancet. 2001;358:958-965.2. Fried et al. N Engl J Med. 2002;347:975-982. 3. Shiffman et al. N Engl J Med. 2007;357:124-134.4. Mangia et al. N Engl J Med. 2005;352:2609-2617.