Assessment of QT(c)-prolonging potential of BX471 in healthy volunteers. A 'thorough QT study' following ICH E14 using various QT(c) correction methods.
OBJECTIVE
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).
Vandemeulebroecke
Marc
M
Bayer Schering Pharma, Berlin, Germany.
Lembcke
Jürgen
J
Wiesinger
Herbert
H
Sittner
Wolfgang
W
Lindemann
Stefanie
S
D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D055815:Young Adult
D010671:Phenylurea Compounds; D010880:Piperidines; D019707:Receptors, Chemokine; C411885:BX 471