Peginterferon alfa-2a (40KD) (PEGASYS
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Peginterferon alfa-2a (40KD) (PEGASYS ® ) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose. Professor Stephanos J. Hadziyannis

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Professor stephanos j hadziyannis department of medicine and hepatology henry dunant hospital

Peginterferon alfa-2a (40KD) (PEGASYS®) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose

Professor Stephanos J. Hadziyannis

Department of Medicine and Hepatology

Henry Dunant Hospital

Athens, Greece


Background
Background

  • Previous clinical studies with pegylated IFNs only investigated 48 weeks

  • No prospective studies of the efficacy and safety of ribavirin doses have been conducted

  • Therefore no evidence-based recommendation could be made


Study aims
Study Aims

  • To compare the efficacy and safety of the combination of PEGASYS® and ribavirin given for 24 weeks vs. 48 weeks

  • To compare the efficacy and safety of two different daily doses of ribavirin (low dose 800 mg vs. ‘standard’ dose of 1000/1200 mg) taken with PEGASYS®


Study design 1
Study Design (1)

Total 1284 patients randomized and treated

PEGASYS® 180 µg sc qw + ribavirin 800 mg qd, 24 weeks

A :

PEGASYS® 180 µg sc qw + ribavirin 1000/1200 mg qd, 24 weeks

B :

C :

PEGASYS® 180 µg sc qw + ribavirin 800 mg qd, 48 weeks

D :

PEGASYS® 180 µg sc qw + ribavirin 1000/1200 mg qd, 48 weeks

Treatment-free follow-up of 24 weeks for all patients


Study design 2
Study Design (2)

  • Randomization stratified by HCV genotype(1 vs. non-1) and viral titre (low vs. high, defined as  or >2 million copies/mL, respectively) and by geographic region

  • Pre-planned distribution of genotypes

    • Genotype non 1 and 1 LVT 1:1:1:1

    • Genotype 1 HVT 1:1:4:4

  • Treatment duration blinded until week 24

  • Ribavirin dose blinded throughout study


Primary endpoint
Primary Endpoint

  • Undetectable serum HCV RNA at the end of a 24-week treatment-free follow-up period

  • (COBAS AMPLICOR® HCV Test v2.0, sensitivity 50 IU/mL)


Main inclusion criteria
Main Inclusion Criteria

  • Quantifiable HCV RNA in serum (AMPLICOR HCV MONITOR® Test, v2.0)

  • Elevated serum ALT levels

  • Liver biopsy consistent with chronic HCV infection

  • No previous interferon or ribavirin treatment


Main exclusion criteria
Main Exclusion Criteria

  • Decompensated liver disease

  • Coinfection with HIV or HBV

  • Anaemia or expected inability to tolerate anaemia

  • Significant co-morbid medical conditions


Patient characteristics

Male (%)

68

66

63

66

Age (mean, y)

41

42

43

43

Weight (mean, kg)

78

77

77

77

HCV RNA titre

(mean, x106 copies/mL)

5.0

5.5

7.2

6.1

Genotype 1 (%)

49

42

69

62

Cirrhosis/bridging fibrosis (%)

21

25

25

26

Patient Characteristics

24 weeks 48 weeks

800

1000/

1200

800

1000/

1200


Results svr genotype 1
Results: SVR Genotype 1

51%

41%

40%

29%

SVR (%)

n=101

n=118

n=250

n=271

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

24 weeks

48 weeks


Results svr genotype 1 low viral titre
Results: SVR Genotype 1 Low Viral Titre

61%

53%

51%

41%

SVR (%)

n=51

n=71

n=60

n=85

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

24 weeks

48 weeks


Results svr genotype 1 high viral titre
Results: SVR Genotype 1 High Viral Titre

46%

35%

26%

SVR (%)

16%

n=50

n=47

n=190

n=186

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

24 weeks

48 weeks


Results svr genotype non 1
Results: SVR Genotype Non-1

78%

78%

77%

73%

SVR (%)

n=106

n=162

n=111

n=165

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

24 weeks

48 weeks


Sustained virologic response effect of cirrhosis
Sustained Virologic Response: Effect of Cirrhosis

65%

61%

50%

SVR (%)

n=436

n=321

n=115

All patients

Non-cirrhotics

Cirrhotics

Treatment: PEGASYS® + RBV 1000/1200 mg for 48 weeks


Rate of withdrawal from treatment

PEGASYS® + RBV 800 mg, 24 weeks

PEGASYS® + RBV 1000/1200 mg, 24 weeks

PEGASYS® + RBV 800 mg, 48 weeks

PEGASYS® + RBV 1000/1200 mg, 48 weeks

Rate of Withdrawal From Treatment

30

25

20

%

14.2%

15

12.4%

10

3.5%

3.7%

2.7%

5

1.9%

1.0%

0.9%

0

Due to Adverse Event

Due to Lab Abnormality


Ribavirin discontinuations for adverse events lab abnormalities
Ribavirin Discontinuations for Adverse Events / Lab Abnormalities

19%

18%

Discontinuations (%)

7%

6%

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

24 weeks

48 weeks


Serious adverse events

Treatment-related SAEs Abnormalities

Serious Adverse Events

10%

9%

7%

%

3%

3%

4%

3%

1%

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

PEGASYS®RBV 800

PEGASYS®RBV 1000/1200

24 weeks

48 weeks


Summary 1
Summary (1) Abnormalities

  • Overall SVR of 61% in patients treated for 48 weeks with PEGASYS® and RBV 1000/1200 mg

  • Overall safety profile similar to previous studies


Summary 2
Summary (2) Abnormalities

  • Genotype 1

    • 51% SVR achieved with 48 weeks treatment, 1000/1200 mg RBV

    • Shorter duration and/or lower RBV dose leads to reduction in efficacy


Summary 3
Summary (3) Abnormalities

  • Genotype non-1

    • SVR 78% 24 weeks with 800 mg RBV

    • Increasing duration and/or dose of RBV gave no increase in efficacy

  • Shorter treatment associated with fewer SAEs and withdrawals for safety

  • Lower dose RBV associated with fewer

    • SAEs (24 weeks)

    • RBV dose modifications

    • Large decreases in haemoglobin


Study countries
Study Countries Abnormalities

Norway

UK Sweden

Canada Ireland Denmark

Belgium Finland

USA Netherlands

France

Mexico Germany Taiwan Brazil Portugal

Spain Australia

Italy New Zealand

Greece

21 Countries