manns m, et al. presented at the 44 th annual meeting of the european association for the study of...

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


2

International Recruitment

Germany

Poland

Israel

India

Thailand

Indonesia

Malaysia

Singapore

International Cohort (SP sponsored, 2005-2007)HepNet Cohort (investigator-initiated, 2003-2006)


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


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.


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


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


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


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)


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)


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)


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.


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


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)


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)


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





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



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)


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)







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


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.


18

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.

manns m, et al. presented at the 44 th annual meeting of the european association for the study of...

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