Abstract
AIMS: Within the framework of the clinical development of BX471, this study was intended to provide experience in conducting 'thorough QT(c) studies' according to ICH E14. A broad range of QT correction methods and analysis strategies was employed. METHODS A double-blind, placebo- and positive-controlled, single-centre, three-way cross-over study was conducted in 74 healthy volunteers. Electrocardiograms were read by blinded experts. QT correction methods included Bazett's (QT(c)B), Fridericia's (QT(c)F) and several regression-based corrections. RESULTS: There was a significant QT(c)F prolongation of 10.26 ms by the positive control compared with placebo [95% confidence interval (7.83, 12.70)]. BX471 at therapeutic doses did not cause substantial QT(c) prolongation [QT(c)F estimate 2.93 ms, 95% confidence interval (1.00, 4.86); QT(c)B estimate 3.30 ms, 95% confidence interval (0.85, 5.74)]. Regression-based QT correction methods yielded similar results to Fridericia's correction [e.g. using a linear regression across the study population, QT(c) estimate 2.39 ms, 95% confidence interval (0.55, 4.23)]. Differences between the various regression-based correction methods were small. Results were not affected by whether the QT corrections were performed per ECG or per beat. CONCLUSIONS: BX471 does not cause meaningful QT(c) prolongation. Three QT correction methods may be sufficient in future studies: Bazett's (required by regulatory authorities), Fridericia's (as the most reliable fixed formula) and a regression-based correction (individually or population-based), each performed per ECG (i.e. applied to the means of several beats of one ECG recording).