Clinical Trial Result Information

Title of Study:
A prospective randomized, open-label study evaluating the viral kinetics and pharmacokinetics of PEGASYS plus COPEGUS and PEG-Intron plus Rebetol in interferon-naïve patients with chronic hepatitis C

Fast Facts:

Protocol number:	ML17756
Sponsor:	Roche Laboratories Inc.
Company division:	Pharmaceutical
Product name:	PEGASYS
Generic name:	peginterferon alfa-2a (40KD)
Phase of development:	IV
Therapeutic area, approved indication:	Hepatitis C, Chronic
Date of report:	2/1/2007

Clinical study summary:
This was a prospective, multicenter, randomized, open-label, parallel-group study in interferon-naïve HCV genotype 1 patients with high viral load, comparing treatment for 12 weeks with PEGASYS plus Copegus, and Peg-Intron plus Rebetol.

Study center(s) :
The study was conducted at 41 centers in the United States.

Objectives:
Primary: To compare the change from baseline in serum hepatitis C virus (HCV) RNA levels among interferon-naïve patients chronically infected with hepatitis C virus genotype 1 and having a high serum viral load (HCV1-HVL) after 12 weeks of treatment with either PEGASYS plus Copegus or PEG-Intron plus Rebetol combination therapy.
Secondary: To compare the changes from baseline in serum HCV RNA levels after 4 and 8 weeks of treatment; to evaluate the pharmacokinetics of PEGASYS and PEG-Intron when administered with Copegus and Rebetol, respectively, during 12 weeks of treatment; to evaluate the viral kinetic profile during 12 weeks of treatment; to evaluate the safety of 12 weeks of treatment with PEGASYS plus Copegus and PEG-Intron plus Rebetol therapies.

Methodology:
After screening, eligible patients were randomized 1:1 to 12 weeks of treatment with PEGASYS plus Copegus or PEG-Intron plus Rebetol. Serum sampling for measurement of HCV RNA and PEG-IFN, clinical laboratory tests, symptom-directed physical examinations, and measurement of vital signs were performed weekly. Adverse events and concomitant medications were continually monitored and reasons for premature withdrawal recorded.
Patients who completed the 12-week randomized treatment period and who wished to continue therapy were offered PEGASYS plus Copegus combination therapy for an additional 36 weeks. After treatment completion, patients were followed-up for safety for 24 weeks. During continued treatment and safety follow-up periods, only limited safety data (including deaths, serious adverse events, dose modifications, and withdrawals) were recorded.

Number of patients (planned/analyzed):
385 were randomized, and 380 received study medication

Diagnosis and main criteria for inclusion:
Male and female patients ≥18 years old with serologic evidence of chronic HCV infection, evidence of HCV genotype 1 infection, and serum HCV RNA at >800,000 IU/mL.

Test product, dose and mode of administration or test procedure:
PEGASYS (peginterferon alfa-2a (40KD)) 180µg was administered subcutaneously once weekly at the clinic visit for 12 weeks, Copegus was taken twice daily, orally, with food, as a daily dose of 1000 or 1200 mg based on body weight (< or ≥75 kg, respectively) for the duration of PEGASYS treatment.
After Week 12, patients who wished to continue treatment received PEGASYS plus Copegus at the dosages above for an additional 36 weeks to complete a full 48-week treatment course.
PEG-Intron (peginterferon alfa-2b) 1.5µg/kg was administered subcutaneously once weekly for 12 weeks. Rebetol (ribavirin) was administered orally, twice daily at a dose of 1000 or 1200 mg based on body weight (< or ≥75kg, respectively) for the duration of PEG-Intron treatment.
After Week 12, patients who wished to continue treatment received PEGASYS plus Copegus at the dosages in the above treatment arm for an additional 36 weeks to complete a full 48 week treatment course.

Duration of treatment:
48 weeks (12 weeks core study duration).

Reference therapy, dose and mode of administration or reference procedure:
N/A.

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: Change from baseline in viral load (log₁₀ reduction) at Week 12 with PEGASYS plus Copegus compared with PEG-Intron plus Rebetol therapies.
Secondary: Viral load reduction at Weeks 4 and 8; weekly viral load reductions; weekly HCV area under the curve (AUC) and cumulative HCV absolute AUC minus baseline (AUCMB) over 12 weeks; percent of patients with a ≥2-log₁₀ decrease or undetectable (<60 IU/mL) HCV RNA at each visit; percent of patients with undetectable HCV RNA (<60 IU/mL) at each visit.

Pharmacokinetic: Weekly trough interferon (IFN) concentrations with PEGASYS and PEG-Intron over 12 weeks of combination treatment; weekly IFN AUC with PEGASYS and PEG-Intron.

Safety: Adverse events, clinical laboratory test results, vital signs, and reasons for discontinuation.

Statistical methods:
Mean treatment difference for the primary endpoint (viral load reduction at Week 12) was tested using the two-sided t-test (main analysis), and median reductions were evaluated using the Wilcoxon test. The main analysis was on the Intent-to-treat (ITT) population, with supporting analyses on the per-protocol and 12-week completer populations. Viral load reductions at other time points were analyzed in the same manner as for the primary endpoint.
Patients with a viral or biochemical response at each week were summarized and presented with a 95% confidence interval (CI); treatment effect was evaluated using the chi-square test. The times to initial response were analyzed using the Kaplan-Meier procedure; overall treatment differences were assessed using the log-rank test.
The weekly AUCs and AUCMBs for viral load and IFN concentrations were calculated using the trapezoidal rule, and results were summarized descriptively and presented with 95% CI. The cumulative AUCMB over 4-week intervals was compared between treatments using an analysis of variance with treatment as the only factor. Weekly HCV RNA profiles were analyzed using a repeated measures mixed model with terms for baseline, treatment, patient, week and week-by-treatment interaction.

Summary (efficacy, safety, other results):
Efficacy: A total of 380 patients were included in the ITT population. After 12 weeks of treatment with PEGASYS plus Copegus or PEG-Intron plus Rebetol, mean (± standard error) viral load reductions (log₁₀) were -3.26 ± 0.12 and -3.27 ± 0.14, respectively, with no significant difference between treatments (p=0.978, primary endpoint). Similar results were observed in the per-protocol and 12-week completer analyses and at all other time points. The median HCV RNA level was below the limit of quantification by Week 9 in both treatment groups. Weekly viral AUCs were similar in the two treatment groups, and comparison between treatments in the cumulative viral load AUCMB at Weeks 4, 8, and 12 showed no difference. Similar proportions of patients in each treatment group had >2-Log drop or undetectable HCV RNA at weeks 4, 8 and 12 (39.2% and 44.0% at Week 12).

Pharmacokinetic: Mean trough IFN concentrations increased from Week 1 and plateaued in both treatment groups. At Week 1, trough IFN concentrations were already significantly different between the two treatment groups, with 3.6% vs 78.2% of patients having IFN concentrations below the limit of quantification. After Week 1, <3% of patients on PEGASYS and ~50%-70% of patients on PEG-Intron had IFN concentrations below the respective limit of quantification.

Safety: The most frequent adverse events were fatigue, headache, nausea, and insomnia, each of which had a similar incidence in the two treatment groups. Patients on PEG-Intron plus Rebetol had more severe events (21% vs. 16%, mainly due to more severe headache and fatigue). Patients on PEG-Intron were more frequently withdrawn due to an adverse event (6% vs. 1%). There were no deaths, few serious adverse events (3% and 1%) and no life-threatening events. Similar decreases in hemoglobin concentration, neutrophils, platelets, lymphocytes and total cholesterol, and an increase in serum triglycerides, were observed with both treatments. Most of the laboratory changes could be managed with a decrease in the dose of one or both of the study drugs and/or other treatments. No meaningful effect on vital signs was observed in either treatment group.
Of the 293 patients who continued treatment after Week 12, 64% completed the full 48 weeks of study treatment, and 48% completed the treatment-free follow-up. Most discontinuations of treatment after Week 12 were due to insufficient therapeutic response (20% of continuing patients), and only 9% were discontinued because of an adverse event. These events were most often a psychiatric disorder (2%), but depression, fatigue, and rash (1% each) were the most frequent individual events that led to early treatment discontinuation. A total of 7% of patients experienced serious adverse events after Week 12. Gastrointestinal disorders accounted for 2% of the serious adverse events, but chest pain (1%) was the most frequent individual serious adverse event. Most serious adverse events resolved and were considered by the investigator to be unrelated to study treatment. The one death in the study occurred 166 days after the end of study treatment (the patient received PEG-Intron plus Rebetol until Week 12 and did not switch to PEGASYS plus Copegus); death was due to cardiomyopathy and was considered unrelated to study treatment. No differences between patient groups defined by original randomized treatment were apparent in the proportions of deaths, serious adverse events, dose modifications, or withdrawals.

Conclusions:
Early efficacy of PEGASYS plus Copegus and PEG-Intron plus Rebetol, as measured by the change from baseline in HCV RNA at Week 12, was similar in patients infected with HCV genotype 1 and a high viral load. A higher exposure to interferon was obtained with administration of PEGASYS plus Copegus than with PEG-Intron plus Rebetol. The higher exposure did not appear to influence overall viral response within the first 12 weeks. The safety profiles of the two treatment regimens were generally similar and typical of interferon and ribavirin therapy, but patients on PEG-Intron plus Rebetol more often required treatment discontinuation for safety reasons and experienced more types of adverse events overall and more severe events.
Post-Week-12 data on deaths, other serious adverse events, dose modifications, and withdrawals revealed no unexpected safety findings overall. No apparant differences were observed between the two patient groups as originally assigned, indicating that patients were able to safely switch to PEGASYS plus Copegus treatment. The better pharmacokinetic and safety profiles of PEGASYS plus Copegus compared to PEG-Intron plus Rebetol may provide a superior risk/benefit balance in the treatment of chronic hepatitis C due to HCV genotype 1 infection.

Publications (references, if available):
Di Bisceglie AM, Ghalib RH, Hamzeh FM et al. Early virologic response after peginterferon alfa-2a plus ribavirin or peginterferon alfa-2b plus ribavirin treatment in patients with chronic hepatitis. J Viral Hepat. doi:10.1111/j.1365-2893.2007.00862.x (2007).

DiBisceglie AM, Ghalib RH, Hamzeh FM, Rustgi VK. Early Virologic Response after Peginterferon Alfa-2a plus Ribavirin or Peginterferon Alfa-2b plus Ribavirin Treatment in Patients with Chronic Hepatitis C. J Viral Hepat. 2007;14:721-729.

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