PROTON

PROTON Study: SOF + PEG- IFNα-2a + RBV for genotypes 1, 2 and 3
Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial
Lawitz E. Lancet Infect Dis 2013;13:401-8

Anti-HCV
Sofosbuvir
PEG-IFNα 2a
Ribavirin
Genotype
1
1a
1b
2
3
Treatment history
Naive
Cirrhosis
No

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Design


* Randomisation was stratified on IL28 genotype (CC or non-CC) and HCV RNA (< or = 800,000 IU/ml)
** If eRVR (HCV RNA < 15 IU/ml from W4-12) : 12 additional weeks of PEG-IFN + RBV ; if not, or if in placebo groups, 36 additional weeks

Treatment regimens

  • SOF in genotype 1 (double-blind); PEG-IFNα-2a : 180 mg SC once weekly
  • RBV weight based (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

Objective

  • Superiority of SOF vs placebo, in combination with PEG-IFN + RBV, in genotype 1 : eRVR (HCV RNA < 15 IU/ml from W4 to W12) > 55% in SOF group (vs 15% in placebo group), 95% power with a 2-sided significance level of 5%
  • Safety and tolerability
  • Efficacy endpoints
    • RVR at week 4
    • eRVR (W4-12)
    • Response at end of treatment
    • SVR12
    • SVR24

Baseline characteristics and patient disposition

SVR24 (HCV RNA < 15 IU /ml) % (95% CI)

  • Virologic failures in Genotype 1
    • Virologic rebound or breakthrough
      • 3 in SOF 200 (on PEG-IFN + RBV)
      • 2 in placebo
    • Post-treatment relapse
      • 1 in SOF 200
      • 1 in SOF 400
    • No resistance emergence at failure
      • No S282T mutation by population sequencing
  • Difference in SVR24 in Genotype 1
    • SOF 200 vs placebo : 28%; 95% CI; 9 to 46, p = 0.0017
    • SOF 400 vs placebo : 30% ; 95% CI : 11 to 49, p = 0.0006

Treatment-emergent adverse events (until W12 of SOF)

Grade 3-4 laboratory abnormalities (until W12 of SOF)

Discontinuation for adverse events in Genotype 1, N = 8 ; in Genotype 2-3, N = 0

  • 6 in the first 12 weeks
    • 3 in the placebo group
    • 3 in the SOF 400 group

Summary

  • In this phase II trial, patients receiving SOF plus PEG-IFN + RBV had adverse events that were similar in both type and severity to those seen in patients receiving placebo plus PEG-IFN + RBV
    • No additional or new adverse events attributable to SOF
    • Fatigue, rash, fever, and diarrhea were more commonly seen in patients with HCV genotype-1 receiving SOF than in patients receiving placebo
  • During the SOF phase of treatment, response in patients with HCV genotype-1 receiving SOF was much the same, irrespective of dose (200 mg or 400 mg)
    • During the PEG-IFN + RBV extension phase of dosing, there were 3 breakthrough post SOF in the 200 mg group vs 0 in the 400 mg group
  • In genotype 1 naïve patients, SOF 400 mg 12 weeks (+ PEG-IFN + RBV 24-48 weeks) provided a SVR24 rate 30% higher than placebo
  • In patients with HCV genotypes 2 and 3, SVR24 was 92%