Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients

Abstract

Introduction: Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin.

Material and methods: Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa-2a (40KD) 180 or 90 µg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns.

Results: The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication.

Conclusion: Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).

Trial registration: ClinicalTrials.gov NCT00517439.

Figure 1

Study design including the planned number of patients in each treatment group. ^aTherapy was stopped at week 24 in patients with an RVR in group C, provided that their HCV RNA had remained undetectable at all visits through to week 22. ^bA protocol amendment on May 29, 2008 specified that treatment with balapiravir was to be stopped immediately in all patients in group D, and that treatment with balapiravir was to be stopped at week 12 rather than week 24 in all other treatment groups with a corresponding increase in the length of treatment with peginterferon alfa-2a (40KD) plus ribavirin from 24 to 36 weeks. Patients that had completed more than 12 weeks of treatment with balapiravir were required to stop balapiravir immediately and switch to peginterferon alfa-2a (40KD) plus ribavirin to complete 48 weeks of treatment. Balapiravir was given twice daily (bid). Peginterferon alfa-2a (40KD) was given once weekly. Ribavirin was given at a dosage of 1,000 mg/day to patients weighing < 75 kg and 1,200 mg/day to patients weighing ≥ 75 kg. The daily dosage of ribavirin was divided into two, each half was administered bid with food. RVR: undetectable HCV RNA (< 15 IU/mL) in serum at week 4. P/R: Peginterferon alfa-2a (40KD) 180 μg/week + ribavirin 1,000/1,200 mg/day.

Figure 2

Flow of patients through the trial showing the actual enrolment in each treatment group. Twelve patients were randomized but did not receive study medication because of violation of entry criteria (n = 3), withdrawal of consent (n = 7) and administrative or other reasons (n = 2).

Figure 3

Virological response during treatment defined as undetectable HCV RNA (< 15 IU/mL). Percentages are shown at the top of each bar. Vertical bars show the upper limit of the 95% confidence interval. Analyses were conducted according to the intention-to-treat principle.

Figure 4

Sustained virological response defined as undetectable HCV RNA (< 15 IU/mL) in serum at the end of untreated follow-up. Vertical bars show the upper limit of the 95% confidence interval. Analyses were conducted according to the intention-to-treat principle.

Figure 5

Mean hematological parameters during treatment and follow-up. A. White blood cells. B. Neutrophils. C. Platelets. D. Lymphocytes. E. Red blood cells. F. Hemoglobin.