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Pegylated Intron a-2b + ribavirin: 72 weeks

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  • claudine intexas
    Pegylated Intron a-2b + Ribivarin: 72 Weeks reported by Jules Levin, NATAP see NATAP web site for AASLD coverage Michael Mans from the Dept of
    Message 1 of 1 , Nov 25, 2000
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      Pegylated Intron a-2b + Ribivarin: 72 Weeks
      reported by Jules Levin, NATAP <www.natap.org>
      see NATAP web site for AASLD coverage

      Michael Mans from the Dept of GI & Hepatology at
      Hannover Medical
      School in
      Hannover Germany reported 72 weeks data comparing
      regular interferon
      a-2b +
      ribivarin to Pegylated Intron (Schering Plough brand
      as opposed to
      Pegasys
      the Roche brand) + ribivarin. The study objective was
      to evaluate the
      safety
      & efficacy of two regimens of Peg interferon a-2b +
      Ribivarin compared
      with a
      standard regimen of Interferon a-2b + Ribivarin.

      The trial enrolled 1530 treatment-na�ve chronic HCV
      patients with
      elevated
      ALT and compensated liver disease. The primary
      endpoint was sustained
      loss of
      serum HCV-RNA at the end of 24 weeks follow-up after
      48 weeks treatment
      (National Genetics Institute LLQ 100 copie/ml). The
      study was
      randomized and
      open label with an active control parallel group.
      Stratification was by
      genotype and cirrhosis.

      The three study arms were:

      (1) Peg IFN a-2b (1.5 ug/kg once weekly for 4 weeks) +
      Ribivarin
      1000-1200
      mg/daily and 0.5 Peg IFN ug/kg for the next 44 weeks;
      Peg IFN was
      administered by subcutaneous injection once per week
      (n=514)

      (2) Peg IFN a-2b + Ribivarin 800 mg/daily (1.5 ug/kg
      once weekly for 48
      weeks
      (n=511)

      (3) IFN a-2b + Ribivarin 1000-1200 mg/daily (IFN 3 MIU
      3 times per week
      subcutaneous injections (n=505)

      There was 24 weeks follow-up after the end of
      treatment at week 48.
      Biopsies
      were performed 6 months before treatment and 6 months
      after treatment
      but
      they have not been evaluated yet.

      DEMOGRAPHICS

      --Mean age was about the same in each treatment group-
      about 43 years
      (range
      was 22-67 years).
      --There were about 67% men in each treatment group
      --About 90% caucasians were in each group
      --The mean weight was about 82 kg in each group (range
      43-163 IFN,
      38-181 Peg
      0.5, 43-159 Peg 1.5)

      GENOTYPES

      --Geno 1- about 68% in all 3 groups
      --Geno - 2/3 - about 30% in each group
      --Geno 4/5/6 - 2-3% in each group

      VIRAL LOAD

      >2 million - 67-69% in each group

      CIRRHOSIS
      10% in each group and it was determined by local
      pathologist.

      RESULTS

      Sustained Virologic Response

      Peg 1.5/R Peg 0.5/R
      IFN/R A vs
      C
      Overall 54% 47%
      47%
      p=0.01
      SVR Geno 1 42% 34%
      33% p=0.02
      SVR Geno 2/3 82% 80% 79%

      Opimized Weight Based Dosing (>10.6 mg/kg/daily
      Ribivarin*)

      SVR (overall) 61% 48%
      47% (slide said
      57%)
      SVR Geno 1 48% 34% 34%

      SVR Geno 2 88% 80% 80%

      *10.6 mg/kg/daily Ribivarin is about 800 mg/daily for
      patient weighing
      75 kg.

      According to a logistic regression analysis Manns
      reported that 10.6
      mg/kg
      /daily is the optimal dosing. For those receiving
      <10.6 mg/kg daily in
      the 3
      arms the SVR rates were 27% IFN 3 MU, 41% Peg 0.5, and
      50% Peg 1.5. For
      those
      receiving >10.6 RBV mg/kg the SVR was 47%, 48%, and
      61% in the standard
      IFN,
      Peg 0.5 and Peg 1.5 arms, respectively.

      In the Peg 1.5 ug/kg arm the SVR by weight was 62% in
      patients with <65
      kg
      body weight, 55% with 65-85 kg, and 49% when weight
      was >85 kg. In the
      standard IFN arm where patients received 1000/1200
      mg/day RBV: 57% <65
      kg,
      48% 65-85 kg, and 41 >85 kg, had SVR, respectively.
      This suggests that
      weight
      based dosing of RBV affected the response because all
      patients were
      receiving
      the same dosing for Peg IFN.

      Therefore, Schering recommended the optimum Ribivarin
      dosing with Peg
      IFN
      a-2b 1.5 ug/kg:

      <65 kg in weight ribivarin dose should be 800 mg/day
      65-85 kg = 1000 mg/day
      >85 kg = 1200 mg/day

      ADVERSE EFFECTS: Hematology

      IFN Peg 0.5 Peg
      1.5
      <10g hemoglobin 11% 13% 9%
      Dc'd for Anemia 0.2% 0.6% 0.8%

      Neutropenia
      Grade 3 7% 11% 18%
      Grade 4 2% 2% 4%
      Dc'd for Neutr. 0.2% 0.4% 1%

      DISCONTINUATIONS and DOSE MODIFICATIONS

      Disct. IFN Peg 0.5 Peg 1.5
      Due to AEs 13% 13% 14%
      Dose Mod. 34% 36% 42%

      Discontinuations were 21% in the large US study of
      IFN+RBV. Dose
      modifications were 9% for anemia and 17% for adverse
      events.

      WARNING ABOUT PREGNANCY from Schering.
      IFN+RBV must not be used by women, or male partners of
      women who are or
      may
      become pregnant during therapy and during the 6 months
      after stopping
      therapy. Women of childbearing potential and men must
      use effective
      contraception (two reliable forms) during treatment
      and during the 6
      month
      post-treatment follow-up period. Significant
      teratogenic and/or
      embriocidal
      effects have been demonstrated for ribivarin in all
      animal species in
      which
      adequate studies have been conducted. These effects
      occurred at doses
      as low
      as 1/20th of the recommended human dose of RBV. If
      pregnancy occurs in
      a
      patient or partner of a patient during treatment or
      during the 6 months
      after
      treatment stops, physicians are encouraged to report
      such cases by
      calling
      800 727-7064.


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