Assessment of QT_c‐prolonging potential of BX471 in healthy volunteers. A ‘thorough QT_c study’ following ICH E14 using various QT correction methods

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • A prolongation of the QT interval in the ECG is a sign of delayed cardiac repolarization, a condition that increases the risk of potentially fatal arrhythmias. • Since the QT interval depends on heart rate, some correction is indicated to obtain a less heart rate dependent ‘QT c interval’. • Building on the recently issued ICH E14 guideline, the most appropriate methods to evaluate the QT/QT c prolonging potential of novel drugs are yet to be found. WHAT THIS STUDY ADDS • This study gives a detailed account of different analysis strategies and QT correction methods consistent with ICH E14. • Regression‐based QT correction methods, applied to average intervals of each ECG recording, yielded results comparable with those obtained by Fridericia's formula; using one representative of such methods may be sufficient in practice. • BX471 does not cause meaningful QT c prolongation. 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).