Comparison of Pegasys Versus Peg-Intron for Treatment of Chronic Hepatitis C Genotype 4

Hepatitis C Clinical Trial

Official title: Phase 4 Comparative Study of Pegasys vs Peg-Intron for Treatment of Chronic Hepatitis C Genotype 4

Status Completed

Clinical Trial Summary

Genotype 4 hepatitis C virus is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world. Although rare in western nations, genotype 4 is the most common variant of the hepatitis C virus in Egypt and is also found throughout Africa and the Middle East. Early reports on the treatment of patients with genotype 4 chronic hepatitis C with interferon-alfa (IFN)-alfa monotherapy indicate poor rates of sustained viral response (SVR). With the introduction of ribavirin combination therapy and with pegylation of the IFN alfa molecule, however, response rates have improved dramatically, and current clinical trial data indicate that SVR rates between 43 and 79% are attainable in genotype 4 patients who are receiving pegylated IFN alfa plus ribavirin for 48 weeks. Clinical advances to optimize treatment for each patient have also been made, and tailored treatment options are now being developed that are comparable to the treatment approaches for genotype 1, 2, and 3 patients. A treatment duration of between 36 and 48 weeks appears to be optimal for most patients with chronic hepatitis C genotype 4.The aim of this study is to assess the efficacy and safety of pegylated interferon alpha 2a in patients with chronic hepatitis C genotype 4 in comparison to a historical cohort of patients treated with pegylated interferon alpha 2b

Clinical Trial Description

The treatment of chronic hepatitis C with interferon (IFN)-based medicines has advanced steadily since publication of the first clinical trials in the late 1980s.Initial interventions using IFN-alfa monotherapy achieved limited success, but the introduction of IFN-alfa plus ribavirin combination therapy and the pegylation of the IFN alfa molecule, which improved pharmacokinetics and simplified dosing regimens, resulted in a steady improvement in overall treatment outcomes. Sustained virologic responses (SVR, defined as undetectable HCV RNA 24 weeks after completing treatment) have increased from 6% with IFN alfa monotherapy to more than 50% with pegylated interferon alfa (PEG-IFN alfa) plus ribavirin regimensObservations specific to genotype 4 chronic hepatitis C have followed a similar path, with initial investigations of IFN-alfa monotherapy producing limited success .These studies found that IFN-alfa monotherapy, which is usually administered at a dose of 3-5 MIU three times a week for six months, resulted in an SVR in only 5-25% of treated patients.[24-26] The subsequent inclusion of ribavirin in treatment regimens had a dramatic improvement on SVR attainment, with rates of 8 and 42% reported for patients receiving IFN-alfa alone and in combination with ribavirin (1000-1200 mg/day), respectively.

Pegylation of the IFN alfa molecule was the next major advance in the treatment of genotype 4 chronic hepatitis C.Although two early studies failed to demonstrate a significant difference in SVR rates between PEG-IFN alfa-2b plus ribavirin and native IFN alfa-2b plus ribavirin (e.g., 42.9% vs. 32.3%, p = 0.43)[27], subsequent investigations reported SVR rates of 50 to 79% in patients receiving PEG-IFN alfa-2b plus ribavirin (800-1,200 mg/day) for 48 weeks.[ Overall, meta-analysis of clinical trial data shows that SVR rates are significantly higher among genotype 4 patients receiving PEG-IFN alfa plus ribavirin than in those receiving IFN-alfa plus ribavirin (55% vs. 30%, p = 0.0088).[33] This analysis also confirms the importance of adequate ribavirin dosing with higher SVR rates in patients receiving PEG-IFN alfa in combination with high-dose (1000¬-1200 mg/day) and low-dose (800 mg/day) ribavirin (72.0 and 45.8%, respectively; p value not presented). The importance of ribavirin dosing in genotype 4 patients with chronic hepatitis C is also demonstrated in an analysis of the genotype 4 patients included in the registration studies for PEG-IFN alfa-2a.[22, 34] In this analysis, SVR rates were 79% among patients receiving PEG-IFN alfa-2a (180 mcg/week) plus ribavirin (1000-1200 mg/day) for 48 weeks compared with 63% in those receiving the same regimen plus a lower dose of ribavirin (800 mg/day).The optimization of treatment duration is critical in ensuring that SVR rates are maximized without exposing the patient to an unnecessarily long treatment regimen that may have unfavorable implications in terms of cost and tolerability. The question of optimal treatment duration for genotype 4 chronic hepatitis C was addressed in a prospective randomized study in which patients received PEG-IFN alfa-2b (1.5 mcg/kg/week) plus ribavirin (1000-1200 mg/day) for 24, 36, or 48 weeks.Overall, SVR rates were significantly higher in patients receiving treatment for 36 or 48 weeks than in those treated for 24 weeks (66 and 69% vs. 29%; p = 0.001 for each comparison) (Fig. 2). Relapse appeared to be a major factor in determining treatment outcomes: virologic relapse during follow-up was highest among patients treated for 24 weeks (20 of 45, 44%) but relatively rare among the longer treatment arms.

There was no significant difference between the 36-week and 48-week treatment regimens for the overall cohort. However, among patients with baseline viral load >2 million copies/mL who attained SVR, 65% were treated for 48 weeks and 35% were treated for 36 weeks: all patients with high baseline viral load treated for 24 weeks failed to attain SVR. This suggests that the 48-week treatment regimen may be better suited to patients with high baseline viremia. The efficacy and safety of pegylated interferon 2a has not be adequately evaluated in chronic hepatitis C genotype 4 patients in well conducted clinical trials involving well characterized cohorts and long follow up. ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

• NCT number: NCT00502099
• Study type: Interventional
• Source: Ain Shams University
• Status: Completed
• Phase: Phase 4
• Start date: January 2006
• Completion date: May 2009