Clinical Trial Result Information

Title of Study:
An open label, multicenter, efficacy and safety study of PEGASYS plus ribavirin in patients with chronic HCV infection who are unable to tolerate or who do not respond to 12 weeks of therapy with PEG-Intron plus ribavirin

Fast Facts:

Protocol number:	ML16965
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:	12/1/2006

Clinical study summary:
This was an open-label single arm study to evaluate the efficacy and safety of treatment with PEGASYS plus ribavirin on patients with chronic hepatitis C who have previously been intolerant of or unresponsive to PEG-Intron plus ribavirin therapy. PEGASYS plus ribavirin was administered for 36 weeks to non-tolerators, and for 60 weeks to non-responders.

Study center(s) :
14 centers in the United States.

Objectives:
To investigate if patients with chronic hepatitis C genotype-1 infection who were unable to tolerate or did not respond to 12 weeks of PEG-Intron plus ribavirin therapy could be safely initiated on PEGASYS plus ribavirin therapy and tolerate and complete a full course of treatment (36 to 60 weeks).

Methodology:
Patients were enrolled after receiving 12 weeks of PEG-Intron plus ribavirin therapy. After screening, eligible patients were switched to PEGASYS plus ribavirin. Patients who had positive HCV RNA tests after 12 weeks of study treatment were discontinued from the study. Patients who completed the planned study treatment period continued in a 24-week treatment-free follow-up period.
Assessments were performed during screening, at baseline, at Weeks 1, 2, 4, 6, and 8, and then every 4 weeks thereafter throughout the treatment and treatment-free follow-up periods. Safety assessments at each scheduled clinic visit included BDI-II, FSS, local injection-site reaction survey, flu-like symptom questionnaire, clinical laboratory tests, vital signs and symptom-directed physical examinations. Urinalysis, thyroid function tests, and serum serotonin were assessed periodically. Adverse events and concomitant medications were continually monitored and the reasons for premature withdrawal recorded.

Number of patients (planned/analyzed):
Planned: 80 patients. Enrolled: 57 patients.

Diagnosis and main criteria for inclusion:
Male and female patients ≥18 years old with serologic evidence of chronic hepatitis C genotype-1 infection who were unable to tolerate treatment with PEG-Intron plus ribavirin or who did not respond virologically after 12 weeks of treatment.

Test product, dose and mode of administration or test procedure:
PEGASYS (peginterferon alfa-2a) 180μg was administered subcutaneously once weekly for 36 weeks (non-tolerators) or 60 weeks (non-responders). Copegus (ribavirin) was taken twice daily, orally, at a daily dose of 1000 or 1200mg based on body weight (< or ≥75kg, respectively) for the duration of PEGASYS treatment.

Duration of treatment:
36 weeks/60 weeks

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

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: This was primarily a safety study. All efficacy endpoints were secondary endpoints, and data were analyzed for each time point assessed.
Secondary: Proportions of patients with a ≥2-log₁₀ decrease from baseline or undetectable HCV RNA (<60 IU/mL); proportions of patients with undetectable HCV RNA (<60 IU/mL); proportions of patients with normal serum alanine aminotransferase (ALT).

Safety: Primary endpoint: Proportion of patients who were able to complete the prescribed length of PEGASYS plus ribavirin therapy (i.e. patients who remained viremic at Week 12 and were discontinued for lack of efficacy, non-tolerators who completed 36 weeks of study treatment, and non-responders who completed 60 weeks of study treatment).
Secondary endpoints: Sum scores of Beck Depression Inventory, second edition (BDI-II) and Fatigue Severity Scale (FSS); mean overall local injection-site reaction score; proportions of patients with each flu-like symptom (headache, fever, myalgia, chills) and with any such symptom.
Standard safety analyses: Adverse events, clinical laboratory test results, vital signs, and reasons for discontinuation.

Statistical methods:
With the assumption that 60% of patients would complete the prescribed therapy, the half width of the 95% confidence interval for the completion rate would be 11% for a sample size of 80 patients.
All data were summarized descriptively using frequency counts and proportions for categorical variables and location and scale statistics for continuous variables. Responders were summarized at each time point assessed and presented with a 95% confidence interval. No statistical comparisons were planned or performed.

Summary (efficacy, safety, other results):
A total of 57 patients (32 non-responders and 25 non-tolerators) were enrolled into the study. Of these, 2 non-responders and 23 non-tolerators completed the planned treatment period and the treatment-free follow-up.

Safety: On study entry (following PEG-Intron plus ribavirin treatment), treatment tolerability was a greater problem among non-tolerators than non-responders. Fatigue and flu-like symptoms were more frequent problems than depression or injection-site reactions in both patient groups. During treatment with PEGASYS plus ribavirin, fatigue did not worsen and improvements were seen in the other tolerability indices in both patient groups. None of these adverse reactions led to the discontinuation of PEGASYS plus ribavirin treatment. A total of 24/32 patients in the non-responder group were discontinued due to the stringent definition of non-response after 12 weeks of PEGASYS plus ribavirin treatment.
Overall, 91% of patients experienced an adverse event, with fatigue and insomnia the most frequently reported (30% each). The majority of events were mild or moderate in intensity, with 17.5% of events classified as severe. There were no life-threatening adverse events or deaths. Two serious adverse events (abdominal pain, pelvic fracture) were reported, and resolved without sequelae, and only four patients were discontinued due to an adverse event (cough, pelvic fracture, thrombocytopenia, blurred vision). An adverse event led to a dose modification of PEGASYS or ribavirin in 10.5% and 22.8% of non-responders and non-tolerators, respectively. In general, adverse events were not more frequent in non-tolerators than in non-responders. A total of 10 patients had a hemoglobin concentration <10 g/dL (17.5% overall) and 11 had a lymphocyte count <10 x 10⁹ cells/L (19.3%) at some time during the study, but only 2 patients had a platelet count <50 x 10⁹ cells/L. In most cases, these laboratory abnormalities could be managed with a dose modification of one or both of the study drugs and/or other treatments, and only one patient with thrombocytopenia required premature discontinuation of study treatment. No meaningful effect on vital signs was observed in either of the patient groups.

Efficacy: Secondary efficacy endpoints showed an early virological response (≥ 2-log₁₀ decrease or undetectable [<60 IU/mL] HCV RNA at Week 12) among 96% of non-tolerators and 12.5% of non-responders. Among non-tolerators, 84% had a virological response (undetectable HCV RNA [<60 IU/mL]) at the end of the 36-week treatment period, and 56% had a sustained virological response at the end of the 24-week treatment-free follow-up. Due to the low virological response rate in non-responders at Week 12, 75.0% of non-responders (24 patients) had treatment discontinued per protocol due to insufficient therapeutic response. The two non-responders who completed the planned course of treatment (60 weeks) had a virological response, and one had a sustained virological response at the end of the treatment-free follow-up. A normal serum ALT concentration was observed in most non-tolerators (84.0% at baseline, 60.0% after 36 weeks of study treatment) and in smaller proportions of non-responders (65.6% at baseline, 28.1% at Week 12).

Conclusions:
The majority of patients with chronic hepatitis C genotype-1 infection who could not tolerate PEG-Intron plus ribavirin after 12 weeks of treatment were able to complete the full course of therapy with PEGASYS plus ribavirin. Only 2 patients from the non-responder group completed the planned course of treatment with PEGASYS plus ribavirin, and both had a virological response. Few patients had treatment discontinued because of an adverse effect.

Publications (references, if available):
Rustigi VK et al. Interim analysis of the efficacy and safety of peginterferon alfa-2a plus ribavirin in chronic hepatitis C patients unable to tolerate or nonresponsive to treatment with peginterferon alfa-2b plus ribavirin. 56th Annual Meeting of the American Association for the Study of Liver Diseases. (2005). Poster #1255.

Rustgi V, Esposito S, Hamzeh F, Shiffman M. Peginterferon a-2a/Ribavirin in HCV Patients Non-Tolerant or Nonresponsive to Peginterferon a-2b/Ribavirin Peginterferon . Aliment Pharmacol Ther. 2008 Mar;433-440.

Click here for the protocol registry listing of this trial.