Clinical Trial Result Information
Protocol number
NR16141
Title of Study
The safety, viral kinetics, and pharmacokinetics of Pegasys after multiple doses in young children with chronic hepatitis C infection.
Sponsor
Roche Laboratories Inc
Company division
Pharmaceutical
Product name
PEGASYS
Generic name
peginterferon alfa-2a (40KD)
Therapeutic area
Hepatitis C, Chronic
Clinical study summary
This was an open-label, multiple-dose, viral kinetics, pharmacokinetics, and safety study of weekly subcutaneous (sc) pegylated interferon alfa-2a (PEGASYS; 90 µg and 135 µg, 180 µg x BSA/1.73 m2) in children 2–8 years of age with chronic hepatitis C (CHC).
Study center(s)
5 centers in the United States.
Phase of development
II
Objectives
Primary: To investigate the viral kinetic and pharmacokinetic characteristics of PEGASYS in children 2–8 years of age with CHC.
Secondary: To investigate the safety of PEGASYS in children 2–8 years of age with CHC.
Methodology
After screening, patients received weekly subcutaneous (sc) injections of PEGASYS (180 µg x body surface area [BSA]/1.73 m2, with dose modifications as needed for safety reasons) for 48 weeks. Blood samples were collected pre-dose and at 24, 96, and 168 hours after the first dose of Pegasys, and pre-dose at Weeks 4, 8, 12, 40, 48, and 60 for pharmacokinetic analysis of serum concentrations of PEGASYS and for measurement of HCV-RNA. In addition, blood samples were collected pre-dose and at 24, 96, and 168 hours after the Week-24 dose of PEGASYS for pharmacokinetic analysis. After completing 48 weeks of treatment, patients were assessed for an additional 24 weeks for sustained viral response and for safety. Clinical adverse events, laboratory results, and vital signs were monitored throughout the study.
Number of patients (planned/analyzed)
14.
Diagnosis and main criteria for inclusion
Male or female patients 2–8 years of age with the following: serologic and histological evidence of CHC, compensated liver disease without cirrhosis, and detectable HCV-RNA. Excluded were patients with human immunodeficiency virus infection, other forms of hepatitis, or previous treatment with an interferon.
Test product, dose and mode of administration or test procedure
PEGASYS 90 µg and 135 µg, 180 µg x BSA/1.73 m2/sc.
Duration of treatment
48 weeks.
Reference therapy, dose and mode of administration or reference procedure
Not applicable.
Criteria for evaluation (efficacy, safety)
Viral kinetic parameters: (1) Sustained viral response; and (2) Viral response over time.
Pharmacokinetic parameters: (1) Apparent total body clearance (CL/F); (2) Volume of distribution (V1/F); (3) Area under the concentration versus time curve over the dosing interval at steady state (AUCτ); (4) Pre-dose concentration (C0h); and (5) Trough concentration (Ctrough) over time.
Safety parameters: (1) Premature withdrawals for safety reasons; (2) Clinical adverse events; (3) Laboratory values; and (4) Vital signs.
Statistical methods
Sustained viral response was presented as a percentage with 95% confidence interval (CI). HCV-RNA concentrations were listed and displayed graphically. Apparent CL/F and V1/F were estimated by population analysis. Individual patients’ values of AUCτ and C0h at Week 24 were then predicted using the individual post hoc parameters from the population analysis. Descriptive statistics for Ctrough at Weeks 4–48 were calculated.
Summary (efficacy, safety, other results)
The sustained viral response rate was 43% (95% CI, 18%–71%). HCV-RNA was undetectable in 8 of the 14 patients (57%) at Week 24, 7 patients (50%) at Week 48, and 6 patients (43%) at Week 72.
Pharmacokinetics – The final population pharmacokinetic model developed to describe the pharmacokinetics of peginterferon alfa-2a (40KD) in young children was a 2-compartment model with a 0-order resorption process. A linear influence of BSA on CL/F and a linear influence of body weight on V1/F were demonstrated. The mean Ctrough increased over time from Week 4 to Week 12 and remained relatively stable thereafter.
Safety – The most frequently reported adverse events (those reported by ≥5 patients, 36%) were pyrexia, headache, vomiting, cough, upper abdominal pain, decreased appetite, dermatitis, and rhinorrhea. The majority of adverse events were mild in intensity. No serious adverse events occurred. Three patients were withdrawn from therapy for safety reasons (2 because of elevated alanine aminotransferase levels, 1 because of exacerbation of baseline hypertriglyceridemia). Six patients had dose reductions because of laboratory abnormalities, the most common reason being neutropenia. Transient elevations in blood pressure were seen frequently during the study. The investigators attributed the sporadic elevations in blood pressure to anxiety.
Conclusions
PEGASYS at a dose of 180 µg x BSA/1.73 m2 sc once weekly appears to be of benefit in treating CHC in children 2–8 years of age. The population pharmacokinetic analysis indicated a linear influence of BSA on steady state clearance (CL/F) and a linear influence of body weight on V1/F. With a dose of 180 µg x BSA/1.73 m2, AUCt in children tended to be at the high end of the range of exposures found in adults treated with 180 µg of PEGASYS. In addition, children appeared to take longer to reach steady state. Despite the slightly higher exposure in children, PEGASYS was well tolerated, with adverse events and effects on clinical laboratory parameters resembling those seen in adults. The percentage of children having a sustained viral response to PEGASYS monotherapy (6 of 14 patients, 43%) was comparable with results from studies of PEGASYS monotherapy in adults with CHC.
Publications (references, if available)
Safety, efficacy and pharmacokinetics of peginterferon alfa-2a (40KD) in children with chronic hepatitis C. Manuscript accepted by Journal of Pediatric Gastroenterology and Nutrition.
Date of report
10/3/2003
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