Interdependence of Baseline Correction Method and Covariance Structure for Crossover TQT Studies

Abstract

Thorough QT/QTc (TQT) trials are conducted to assess a drug's risk potential for prolonging the QT interval. In a randomized crossover, multiple postdose electrocardiograph (ECG) readings are collected over time, within each period leading to a repeated-measures scenario. Additionally, baseline readings at single or multiple time points are collected prior to treatment. Two active, yet seemingly separate, areas of statistical research for TQT crossover studies concern the method of baseline correction and the specified covariance structure for repeated measures analysis. Due to interdependence of the covariance structure of baseline-corrected QTc values and the definition of baseline, these two research areas cannot be considered separately. We illustrate how the covariance structure for baseline-corrected QTc values differs under various definitions of baseline and provide recommendations on the choice of baseline: Time-matched baseline averaged over periods and time-matched baseline from the first period only are preferable in terms of efficiency; in case a period-specific correction is required to account for the treatment carryover effect, period-specific time-averaged baseline with multiple measurements taken predose in each period offers greater efficiency than a single predose baseline. This research on the interdependence of baseline correction method and covariance structure enables statisticians to use observed data from previous TQT studies to plan design and analysis for future studies.

Key Words:

• Baseline correction
• Covariance structure
• Crossover study
• Repeated-measures analysis
• TQT trials

ACKNOWLEDGMENT

The authors thank the referees for their helpful and valuable comments.