Download - 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.

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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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


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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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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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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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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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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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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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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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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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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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.


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)






Real-life setting67.1% completers

vs. 85.7% in clinical setting


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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)


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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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





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



14

75.469.5

65.658.6 60.0

47.4

73.768.0 66.7

0

25

50

75

100




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



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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)


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)







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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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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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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.