On the Relationship Between Baseline Correction Method and Covariance Structure for Analysis of a Thorough QT Crossover Study

• Activity Number: 240
• Type: Contributed
• Date/Time: Monday, August 1, 2011 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Wenqing Li*+ and Andrea Lynn Maes and Michelle Quinlan and Suraj Anand
• Companies: Novartis Oncology Biometrics and Data Management and Novartis Oncology Biometrics and Data Management and Novartis Oncology Biometrics and Data Management and Novartis Oncology Biometrics and Data Management
• Keywords: Through QT (TQT) ; cross over ; baseline correction ; variance covariance ; repeated measures

Abstract

Thorough QT/QTc (TQT) trials are conducted to assess a drug's risk potential for prolonging the QT interval. A randomized crossover with therapeutic and supra-therapeutic doses of a test drug, placebo and an active control is a frequently used TQT study design for drugs with a short half-life. Within each period, multiple postdose ECG readings are collected over time leading to a repeated measures scenario. In addition, baseline readings at single or multiple timepoints are collected prior to treatment. Two active, yet seemingly separate, areas of statistical research for TQT crossovers concern the method of baseline correction and the specified covariance structure for repeated measures analysis. Due to the fact that the correlation among baseline-corrected QTc values is dependent upon the definition of baseline, these two research areas cannot be considered separately. Assuming reasonable correlation patterns for the marginal baseline and postdose QTc values, we illustrate how the covariance structure for baseline -corrected QTc differs under various definitions of baseline, thereby providing guidance on suitable covariance structures given any baseline specification.