Compliance as an Explanatory Variable in Hepatitis-C
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Copyright 0 2001 Drug Information Association Inc.
COMPLIANCE AS AN EXPLANATORY VARIABLE IN HEPATITIS-C* CARMEN MAK,PHD, SAMUELM. HEFT, PHD, HAROLDAMKRAUT, PHD, AND MEI-HSIULING,PHD Schering-Plough Research Institute, Kenilworth, New Jersey
A Hepatitis C clinical trial program forpatients infected with Hepatitis C virus of genotype
I demonstrated that the sustained virologic response rate is higher with 48 weeks of Ribavirin in combination with Interferon (I/R) than with 48 weeks of Interferon and placebo (UP). The intent-to-treat (ITT)response rate for the I/R group is 29%. versus 9% for the I/P group. However; since not all patients completed their treatment, it is likely that the benefit would have been greater if all the patients had taken their full dose for 48 weeks. Assessing the impact of taking the full dose is not trivial: clearly the ITT approach underestimates the response, whereas subsetting the patients who took a large majority of their full dose (eg, 80% of the total dose) likely overestimates the response. Using methodology developed by Efron and Feldman (I), we develop a statistical model that incorporates compliance as a covariate, thereby allowing for an estimate of tlw fully compliant response rate. It is estimated that the treatment benefit as measured b y the difference in sustained virologic response rates of I/R versus I/P atfull compliance ranged from 23% to 26% compared to 20% for the I’IT analysis and 27% for the 80% compliant subgroup.. Key Words: Compliance; Dose-response; Hepatitis C; Interferon; Ribavirin
INTRODUCTION HEPATITIS C IS A CHRONIC infection, which is estimated to affect 170 million people worldwide and 4 million in the United States alone (2). Until recently, Interferon alpha was the only available treatment for patients infected with Hepatitis C Virus (HCV). However, Interferon is effective in the long-term eradication of HCV in only 15% to 20% (3) of patients. For patients infected with HCV of genotype I, the response rate is less than 10%. Recently, in a clinical trial program of two studies ( 4 3 , the combi*Presented at the FDMndustry Workshop “Statistically Sound Decision Making,” September 14-15, 2000. Bethesda, Maryland. Reprint address: Carmen Mak, Statistics, ScheringPlough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539.
nation of Ribavirin and Interferon for 48 weeks was shown to be more effective than Interferon and placebo for 48 weeks as an initial treatment for Hepatitis C patients. Details and results of the clinical trial can be found in the referenced papers. This paper focuses on a subgroup of patients infected with HCV of genotype I, to address a particular research question. From these 2 studies, 325 patients infected with HCV of genotype I were randomized to undergo 48 weeks of the combination therapy of Interferon and Ribavirin (I/R) and 330 patients were randomized to receive the control treatment of 48 weeks of Interferon and placebo (UP).The primary efficacy parameter was the sustained virologic res
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