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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

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Professor Stephanos J. Hadziyannis Department of Medicine and Hepatology Henry Dunant Hospital

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  1. 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

  2. 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

  3. 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®

  4. 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

  5. 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

  6. 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)

  7. 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

  8. Main Exclusion Criteria • Decompensated liver disease • Coinfection with HIV or HBV • Anaemia or expected inability to tolerate anaemia • Significant co-morbid medical conditions

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Treatment-related SAEs 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

  18. Summary (1) • Overall SVR of 61% in patients treated for 48 weeks with PEGASYS® and RBV 1000/1200 mg • Overall safety profile similar to previous studies

  19. Summary (2) • 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

  20. Summary (3) • 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

  21. Study Countries Norway UK Sweden Canada Ireland Denmark Belgium Finland USA Netherlands France Mexico Germany Taiwan Brazil Portugal Spain Australia Italy New Zealand Greece 21 Countries

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