Database Open Access

ECG Effects of Dofetilide, Moxifloxacin, Dofetilide+Mexiletine, Dofetilide+Lidocaine and Moxifloxacin+Diltiazem

Published: Sept. 15, 2016. Version: 1.0.0


When using this resource, please cite the original publication:

Johannesen L, Vicente J, Mason JW, Erato C, Sanabria C, Waite-Labott K, Hong M, Lin J, Guo P, Mutlib A, Wang J, Crumb WJ, Blinova K, Chan D, Stohlman J, Florian J, Ugander M, Stockbridge N, Strauss DG. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial. Clin Pharmacol Ther. 2016 Feb;99(2):214-23. doi: 10.1002/cpt.205. Epub 2015 Nov 28.

Please include the standard citation for PhysioNet:

Goldberger AL, Amaral LAN, Glass L, Hausdorff JM, Ivanov PCh, Mark RG, Mietus JE, Moody GB, Peng C-K, Stanley HE. PhysioBank, PhysioToolkit, and PhysioNet: Components of a New Research Resource for Complex Physiologic Signals (2003). Circulation. 101(23):e215-e220.

Abstract

The ECGDMMLD database contains data from a randomized, double-blind, 5-period crossover clinical trial in 22 healthy male and female subjects, 18 to 35 years of age, to compare the electrophysiological response of hERG potassium channel blocking drugs with and without the addition of late sodium or calcium channel blocking drugs. The 5 treatment periods are 1) dofetilide alone, 2) mexiletine with and without dofetilide, 3) lidocaine with and without dofetilide, 4) moxifloxacin with and without diltiazem and 5) placebo. During each treatment period, 12 blood samples for pharmacokinetic measurements are obtained with matched 12-lead ECG recordings.

Experimental Method

In each of the five treatment periods, the subjects were dosed three times during the day [Johannesen et al, Clin Pharmacol Ther. 2016]. Dofetilide (Tikosyn, Pfizer, New York, NY) and mexiletine (Teva Pharmaceuticals USA, North Wales, PA) were administered orally immediately after meals, whereas lidocaine (B. Braun Medical, Bethlehem, PA), moxifloxacin and diltiazem were administered intravenously. Intravenous infusions were split into a 60-minute loading dose followed by a 30-minute maintenance dose.

The primary pharmacokinetic samples were taken at the start and end of each of the three maintenance doses during the day (morning, afternoon and evening), as these were expected to be associated with highest plasma concentrations of both the oral and intravenously administered drugs. Additional pharmacokinetic samples were taken at 30 and 120 minutes poststart of intravenous dosing during each of the three dosing periods during the day. There was one week between treatment periods.

During each period, continuous ECGs were recorded at 500 Hz with an amplitude resolution of 2.5 μV using the Mortara Surveyor system (Mortara, Milwaukee, WI). From the continuous recording, triplicate 10‐second ECGs were extracted before the draw of each pharmacokinetic sample at 14 predefined time‐points: 1 point pre-dose (-0.5 h) and 13 points post‐dose (1.5, 2, 2.5, 3, 6.5, 7, 7.5, 8, 12, 12.5, 13, 13.5 and 24 h), during which the subjects were resting in a supine position for 10 minutes.

At each of the 14 time‐points, 3 optimal 10‐second 12‐lead ECGs were extracted with stable heart rates and maximum signal quality using Antares software (AMPS‐LLC, New York City, NY). The resulting ECGs were up‐sampled from 500 to 1000 Hz.

Files

The raw directory contains the 4211 original extracted 10-second standard 12 lead ECG segments organized in subdirectories named after the subject number or randomization number RANDID in the second column of the SCR-003.Clinical.Data.csv file. The ECGs are stored in standard MIT format, with a signal .dat file and corresponding header .hea file for each segment

The medians directory contains derived representative median beats for the raw ECG segments. Median beats were obtained as follows: the median PQRST waveform (median cardiac beat) for each lead was calculated by sample-by-sample synchronization of the QRS complex, and beats of a nonsinus origin were excluded based on a cross-correlation coefficient and RR interval history [1].

There are also semi-automatic annotations of each median beat based on the vector magnitude lead, containing P onset, QRS onset, QRS offset, T peak, secondary T peak (if present) and T offset. The annotations are stored in standard MIT annotation format, with annotator extension .atr.

The SCR-003.Clinical.Data.csv file contains demographic information about the subjects, and important metadata about each ECG recording including their time-point, dosing period, associated drug, various beat intervals, and morphology measurements. The spreadsheet column headings are described in the SCR-003.Clinical.Data.Description.txt file.

References

  1. Improving the assessment of heart toxicity for all new drugs through translational regulatory science

Additional Information

ClinicalTrials.gov identifier: NCT02308748

 


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Total uncompressed size: 1.1 GB.Download Zip (1.1 GB)

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