Roche trials database

Protocol number:

ML18562

Title of Study:

A randomized, multicenter, phase IIIB, two arm study evaluating the tolerability of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C genotype 1 infection co-infected with human immunodeficiency virus receiving HAART versus not receiving HAART.

Sponsor:

Hoffmann-La Roche Inc

Company division:

Pharmaceutical

Product name:

PEGASYS

Generic name:

peginterferon alfa-2a (40KD)

Therapeutic area:

• Hepatitis C, Chronic

Clinical study summary:

This was a randomized, multicenter, open-label, prospective, phase IIIb clinical trial investigating the effect of peginterferon alfa-2a (PEG-IFN) plus ribavirin in patients with chronic hepatitis C genotype 1 infection co-infected with human immunodeficiency virus receiving HAART versus not receiving HAART. Eligible patients were randomized to receive PEG-IFN 180 μg in 0.5 mL solution administered subcutaneously (SC) once weekly plus 1000 mg or 1200 mg of ribavirin (5-6 tablets of 200 mg administered orally in two divided doses with food) for 48 weeks. Ribavirin 1000 mg/day was administered to patients 75 kg. Due to poor enrolment, the study was prematurely discontinued after four patients were randomized.

Study center(s):

5 centers in Canada

Phase of development:

III

Objectives:

The primary objective of the study was to compare the safety and tolerability of the combination therapy of PEG-IFN with ribavirin in HIV/HCV co-infected patients who continued HAART therapy compared to those who were randomized to discontinue HAART therapy in the first 12 weeks of initiating HCV treatment.
Secondary objectives included the following: to compare the SVR of the combination therapy of PEG-IFN with ribavirin in HIV/HCV co-infected patients who continued HAART compared with those who were randomized to discontinue HAART during HCV treatment; to compare the safety and tolerability of the combination therapy of PEG-IFN with ribavirin with HAART versus combination therapy without HAART in the first 24 and 48 weeks of initiating HCV therapy; to compare the efficacy of PEG-IFN and ribavirin in patients receiving HAART compared to those not receiving HAART on the reduction of HCV viremia after 4, 12, 24 and 48 weeks of treatment; to compare the effect of PEG-IFN and ribavirin in patients receiving HAART compared to those not receiving HAART; to compare the treatment arms regarding Quality of Life (QoL) and fatigue severity as measured by the Health Utilities Index Mark 2 and Mark 3 Survey and the Fatigue Severity Scale (FSS); to monitor serum ALT during and after therapy with PEG-IFN and ribavirin and compared in patients who continued HAART versus those who were randomized to discontinue HAART therapy; to compare treatment arms with respect to the development of opportunistic infections during treatment and the untreated follow-up period; and to determine the predictors of dose reduction and toxicity.

Methodology:

A total of 100 patients were to be enrolled into one of two treatment arms. A total of six patients were enrolled into the study prior to premature discontinuation of the study, due to slow enrollment. Of these six patients, only five were randomized, two into Group 1 (continued HAART therapy) and three were randomized to Group 2 (discontinued HAART therapy). A total of three patients provided data up to study Week 24, one up to study Week 4, and one patient provided only partial screening data. So a total of four patients were randomized and initiated treatment prior to the premature discontinuation of the study.

Number of patients (planned/analyzed):

100 planned; 4 enrolled and treated

Diagnosis and main criteria for inclusion:

Subjects who were coinfected with both stable HIV disease and HCV genotype 1, had compensated liver disease (Child-Pugh Grade A clinical classification only), a CD4 cell count ≥ 350 cells/μL, receiving stable HAART for at least 12 weeks prior to baseline with the most recent HIV-1 RNA < 5000 copies/mL while on prestudy HAART regimen.

Test product, dose and mode of administration or test procedure:

Peginterferon-alfa-2a: 180 μg per 0.5 mL, 0.5 mL solution in prefilled syringes for single dose SC injection once weekly
Ribavirin: 1000 mg or 1200 mg (200 mg tablets) orally once weekly

Duration of treatment:

48 weeks

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Efficacy: The primary efficacy parameter was the safety and tolerability of the first 12 weeks of treatment as measured by the difference between number of doses of PEG-IFN and ribavirin prescribed versus the number of doses of PEG-IFN and ribavirin received.
Secondary efficacy parameters were:
• Sustained virological response, defined as the percentage of patients with undetectable HCV-RNA as measured by the Roche AMPLICOR™ HCV Test (< 100 copies/mL; <50 IU/mL) at 24 weeks post-completion of the 48 week treatment period (two consecutive HCV-RNA PCR < 100 copies/mL, < 50 IU/mL ≥ 21 days apart, measured ≥ study Day 408, the lower end of the time window for Week 60). • Safety and tolerability of the first 24 and 48 weeks of treatment as measured by the difference between number of doses of PEG-IFN and ribavirin prescribed versus number of doses of PEG-IFN and ribavirin received
• Percentage of patients with undetectable HCV-RNA after 4, 12, 24, 36 and 48 weeks of treatment as measured by Roche AMPLICOR™ HCV Test (<100 copies/mL; <50 IU/mL)
• HIV-1 RNA levels after 4, 8, 12, 24, 36, 48, 52, 60 and 72 weeks by Roche AMPLICOR HIV-1 MONITOR® Test, version 1.5
• CD4 and CD8 cell counts after 4, 8, 12, 24, 36, 48, 52, 60 and 72 weeks
• Quality of Life and Fatigue Severity scores after 2, 4, 8, 12, 24, 48 and 72 weeks as determined by the Health Utilities Index Mark 2 and 3 survey (HUI2/3) and the FSS
• Serum ALT levels after 4, 12, 24, 36, 48, 60 and 72 weeks
• Percentage of patients able to continue with optimal dose regimens of ribavirin during treatment with the use of colony stimulating factor agents such as erythropoetin (Epoetin alfa®) or darbepoietin (Aranesp®) to elevate hemoglobin laboratory parameters

Safety parameters were blood pressure, heart rate, body temperature, hematology, clinical chemistry, Child-Pugh score, urinalysis, thyroid function tests, HCG pregnancy test, concomitant medications, AIDS defining adverse events, general adverse events.

Statistical methods:

The primary outcome was the proportion of patients able to achieve 80% adherence with PEG-IFN and ribavirin. It was estimated that 60% of patients who continued with their HAART therapy were able to achieve 80% adherence. With a sample size of 50 patients per group, it was estimated that an increase in the proportion of patients who discontinued their HAART therapy who were able to achieve 80% adherence to 85% or greater, assuming 80% power and a significance level of 0.05. The primary analysis was a two sample test of the proportions of patients able to achieve 80% adherence between the two groups.

Summary (efficacy, safety, other results):

The primary objective of this study was to compare the safety and tolerability of the combination of PEG-IFN with ribavirin in HIV/HCV co-infected patients who continued HAART therapy compared to those who were randomized to discontinue HAART therapy in the first 12 weeks of initiating HCV treatment. In the very few subjects who were randomized to treatment, no new safety or tolerability concerns were noted in this patient population.

Conclusions:

Due to the early termination of the study and very small enrolment (4 patients initiated HCV treatment), no overall conclusions can be made on the safety and tolerability of these two treatment strategies. All four of the patients who provided follow-up information beyond baseline had drug compliance assessments in the range between 80% to 100% for both PEG-IFN and ribavirin. None of the patients reached study week 48, therefore, no data on SVR is available.

Date of report:

01.01.2009

Click here for the protocol registry listing of this trial.