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Design

* Randomisation 1:2 if genotype 1a (PEARL-IV) ; 1:1 if genotype 1b (PEARL-III), stratified on IL-28B (CC or non-CC)

Treatment regimens

• Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg qd = 2 tablets
• Dasabuvir (DSV) : 250 mg bid
• RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)

Efficacy endpoints

• Sustained virologic response (HCV RNA < 25 IU/mL) 12 weeks after end of treatment, with two-sided 95% CI, modified ITT analysis
• Non-inferiority of SVR assessed vs estimated rate of SVR₂₄ with a telaprevir-based regimen
  • for genotype 1a : 72%, 95% CI: 68 to 75
  • for genotype 1b : 80%, 95% CI: 75 to 84
  • Non-inferiority (primary end-point) established if lower bound of the 95% CI for the SVR greater than the upper bound of the 95% CI for SVR of telaprevir-based therapy minus 10.5%, i.e. 65% in PEARL-IV and 73% in PEARL-III ; power 95%
  • Superiority in PEARL-IV (genotype 1a) if lower margin of the 95% CI for the SVR₁₂ > 75% ; in PEARL-III (genotype 1b) if lower margin of the 95% CI for the SVR₁₂ > 84% ; power 90%
• Non inferiority of RBV vs placebo in both studies : SVR₁₂ rate, with lower margin of the 95% CI for the difference = -10.5% ; power 95%

Trial conduct

• Hemoglobin and hematocrit results blinded to investigators, unless criteria for virologic failure or relevant predefined toxicity were met

HCV RNA : COBAS TaqMan real-time RT–PCR assay, v 2.0 (Roche)

Virologic failure :

• 2 consecutive HCV RNA > 1 log10 IU/ml above the nadir at any time during treatment,
• HCV RNA ≥ 25 UI/ml at all assessments during treatment among patients who received at least 6 weeks of treatment,
• confirmed HCV RNA ≥ 25 IU/ml after a level < 25 IU/ml during treatment

Virologic relapse : confirmed HCV RNA ≥ 25 IU/ml between the end of treatment and 12 weeks after the last dose of study drug among patients who completed treatment and had an HCV RNA < 25 IU/ml at the final visit during the treatment period

Exploratory analysis : stepwise logistic-regression model to assess the association between the rate of SVR₁₂ and continuous and categorical subgroup variables

Objective

• SVR₁₂ (HCV RNA < 25 IU /ml) by intention to treat analysis : non inferiority of both groups to historical SVR₁₂ of telaprevir + PEG-IFN + RBV (lower limit of the 95% CI > upper limit of the CI for the historical rate minus a 10.5% noninferiority margin (64%))

Baseline characteristics and patient disposition

Baseline characteristics and patient disposition

SVR₁₂ (HCV RNA < 25 IU/ml)

Multivariate analysis of factors associated with increased SVR

• IL28B CC genotype (p = 0.03)

Resistance testing (population sequencing)

• 18 virologic failures (on-treatment or relapse)
  • Resistance, N = 18/18
    • Most frequent variants :
      • D168V (NS3),
      • M28T and Q30R (NS5A),
      • S556G (NS5B)

Adverse events and laboratory abnormalities, n (%)

Adverse events and laboratory abnormalities, n (%)

Summary

• After 12 weeks of treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without RBV, 90.2% to 99.5% of previously untreated patients with HCV genotype 1 infection and no cirrhosis had a SVR₁₂
• Response rates in all treatment groups were superior to the historical response rate with a PEG-IFN-containing telaprevir-based regimen
  • In genotype 1b, SVR₁₂ was > 99% with or without RBV
  • A total of 18 patients with genotype 1a had virologic failure, and only 2/18 received RBV. The use of RBV in genotype 1a confers an additional benefit
• Regardless of whether the antiviral regimen included RBV, the rate of discontinuation of the study drugs owing to adverse events was low (<1%)