Clinical Trial Result Information

Title of Study:
An open-label, multicenter study evaluating the end of the follow up response predicatability at week 12 of treatment with peginterferon alfa-2a (40KD) in combination with ribavirin in patients with Chronic Hepatitis C, Genotype 1 under daily clinical practice conditions.

Fast Facts:

Protocol number:	ML16713
Sponsor:	Roche Farma S.A.
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:	12/28/2005

Clinical study summary:
This was a multicenter, open-label, health outcomes research study. Patients with chronic hepatitis C (CHC) were treated with PEGASYS (peginterferon alfa-2a (40KD)) by subcutaneous (sc) injection once weekly and oral ribavirin administered in split daily doses.

Study center(s) :
33 centers in Spain.

Objectives:
Primary: To prove SVR negative predictive value of HCV-PCR performed at week 12 of active treatment with PEGASYS 180μg once weekly in combination with ribavirin (RBV) 1000/1200mg per day according to body weight (<75/≥75kg) in patients with chronic hepatitis C (CHC), Genotype 1 under daily clinical practice conditions.
Secondary: 1)To evaluate the effectiveness of PEGASYS in combination with ribavirin (RBV) given for 48 weeks on the clearance of HCV viremia 24 weeks after treatment end (sustained virological response), taking into account the predictability of the quantitative HCV-PCR determination at week 12. 2)To describe the daily clinical practice management of CHC patients in Spain. 3)To evaluate the safety of PEGASYS plus RBV in patients with CHC.

Methodology:
All patients were treated with combined therapy PEGASYS 180μg administered sc once weekly, and ribavirin 1000/1200mg according to body weight (<75/≥75kg) administered in split daily doses for a 48 week period, followed by 24 weeks of treatment-free follow-up.

Number of patients (planned/analyzed):
490 enrolled. 481 in safety population. 475 in efficacy population.

Diagnosis and main criteria for inclusion:
Male and female patients ≥18 years of age with serologic evidence of chronic hepatitis C infection by an anti-HCV antibody test or serum HCV-RNA quantifiable at >1000 IU/mL by the Roche AMPLICOR HCV MONITOR™ Test, v2.0. Persistently elevated serum ALT activity within the past 6 months (at least one determination). Chronic compensated liver disease consistent with chronic hepatitis C infection on a biopsy as judged by a pathologist. Genotype 1 HCV. Patients who had received interferon and/or ribavirin in the past were excluded.

Test product, dose and mode of administration or test procedure:
PEGASYS 180μg in 0.5ml solution, administered sc once weekly, plus Ribavirin 1000 or 1200mg/day (<75 or >75kg body weight) (200mg bid).

Duration of treatment:
48 weeks

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

Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: Sustained virological response rate defined as percentage of patients with non-detectable HCV-RNA as measured by Roche AMPLICOR® qualitative HCV Test (<100 copies/mL;<50 UI/mL) at the end of the 24 weeks follow-up period after a treatment period of 48 weeks (ie at week 72).
Secondary efficacy parameters: (1) Percentage of patients with non-detectable HCV-RNA after 12 weeks of treatment as measured by Roche AMPLICOR® qualitative HCV Test. (2) Percentage of patients with non-detectable HCV-RNA after 48 weeks of treatment as measured by Roche AMPLICOR® qualitative HCV Test. (3) Sustained virological response rate at 24 weeks post-completion of the treatment period of 48 weeks (week 72), with good compliance assessments (>80%) and positive predictive  test at week 12 of treatment.

Safety parameters: Adverse Events (frequency, intensity) and withdrawal/drop out rate.

Statistical methods:
All data captured electronically were included. Comparisons between patients who had an Early Virological Response (EVR) and those who did not have an EVR were made by chi-square test. The effect of baseline variables on EVR were analysed using a Mann-Whitney U-test.

Summary (efficacy, safety, other results):
Efficacy: (ITT population): Sustained Virologic Response (SVR) rate at the end of follow-up was 47.8% (N=475) (CI 95% 43.3%-52.3%). The SVR was significantly higher in patients with a low basal viral load (≤800000 UI/mL or ≤2000000 copies/mL) than those with higher basal viral load (>800000 UI/ML or >2000000 copies/mL)-- 54.4% vs 36.3% respectively.
Efficacy (PP population) was also evaluated after 12 and 24 weeks of treatment. A total of 82.6% of the patients whose week 12 response was documented (EVR) were responders. EVR was defined as negative qualitative HCV-PCR; patients with ≥2 logs decrease in viral load were also considered as responders. It is important to point out that 23.8% of the patients did not have their EVR (12 week +2) documented. A total of 78.8% of the patients with a documented week 24 response were responders; however, 46.3% of patients had no documented response at week 24.

Predictability (PP population): This analysis was performed on the population with a documented EVR and SVR. The Probability of success of positive predictability (PSPP) was 61.4%. It was defined as the total number of patients with EVR and sustained virological response, divided by the total number of patients with EVR. The Probability of success of negative predictability (PSNP) was higher, at 93.3%. It was defined as the total number of patients without EVR and sustained virological response, divided by the total number of patients without EVR.
The analysis was also performed on the population with a documented 24 week response and SVR. The PSPP was 66.7% and the PSNP was 89.1%.

Safety: A total of 84% of patients suffered from ≥ 1 AE probably related to PEGASYS and 46.6% probably related to ribavirin.
The AEs most frequently reported were asthenia (50.7%), flulike symptoms (24.1%), insomnia (23.9%), pruritus (19.3%), headache (18.7%) and anemia (17.1%). The AEs were classified as mild (55%), severe (3.5%), life-threatening (0.1%). In 10.7% of the AEs the PEGASYS/ribavirin treatment was modified (including dose modification and temporary or permanent withdrawal of treatment).
A total of 66 patients were withdrawn during the trial. Most of the withdrawals (60%) were due to adverse events. In 58 patients the treatment was stopped prematurely, at weeks 12 and 24 of treatment, due to the rules for stopping treatment included in the Summary of Product Characteristics.

Conclusions:
The Spanish daily clinical practice security and effectiveness outcomes study, identifying a 47.8% SVR in the ITT population, confirmed what had been previously published. In this population higher basal viral load (> 800000 UI/mL or >2000000 copies/mL) and also a high level of ALT at week 12 were negative predictors of subsequent clinical response.

Publications (references, if available):
Planas R, Solá R, Diago M et al : Preliminary health outcome results of peginterferon alpha-2a (40 kDa) plus ribavirin treatment for chronic hepatitis C genotype 1 in daily routine clinical practice: The Heracles Project. Journal of Hepatology 42 (Suppl 2), 2005.

Diago M, Olveira A, Solá R et al: Preliminary health outcome results of treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) for chronic hepatitis C genotype 1 in routine daily clinical practice: the Heracles project. Presented at the 40th Annual Meeting of the European Association for the Study of the Liver. April 13-17, 2005.
Paris, France.

Diago M, Olveira A, Solá R et al: Treatment of chronic hepatitis C genotype 1 with peginterferon-α2a (40 kDa) plus ribavirin under routine clinical practice in Spain: early prediction of sustained virological response rate. Alimentary Pharmacology and Therapeutics 25; 899-906, 2007.