Highly Automated QT Measurement Techniques in 7 Thorough QT Studies Implemented under ICH E14 Guidelines

Couderc, Jean‐Philippe; Garnett, Christine; Li, Mike; Handzel, Robert; McNitt, Scott; Xia, Xiajuan; Polonsky, Slava; Zaręba, Wojciech

doi:10.1111/j.1542-474x.2010.00402.x

Cited by 33 publications

(22 citation statements)

References 44 publications

(38 reference statements)

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“…The magnitude of the moxifloxacin-induced delta-delta change in QT RMS was 11.5 ms compared to 9.5 ms for the RT PK value. Similar drug-induced delta-delta QT changes were reported in published TQT studies [7]–[9]. Based on these observations, we conclude that QT RMS and RT PK intervals lengthen in response to moxifloxacin administration and that these values track changes in ventricular repolarization comparable to findings using QT II .…”

Section: Resultssupporting

confidence: 88%

The Application of Root Mean Square Electrocardiography (RMS ECG) for the Detection of Acquired and Congenital Long QT Syndrome

et al. 2014

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BackgroundPrecise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS).MethodsRMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II.ResultsAll measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3.ConclusionThese data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements.

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Section: Resultssupporting

confidence: 88%

The Application of Root Mean Square Electrocardiography (RMS ECG) for the Detection of Acquired and Congenital Long QT Syndrome

et al. 2014

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“…These studies include a positive arm to demonstrate that the QT measurement method employed in the study is sensitive enough to detect a drug-induced prolongation of 5 to 10 msec. 3 Consequently, TQT studies provide a highly sensitive test for drug-induced QT prolongation. Unfortunately, the risk of drug-induced arrhythmias is not a linear function of the QT interval, nor of the extent of the QT-interval prolongation during drug therapy 4 so there is a need for ECG markers that would complement QT/QTc prolongation in assessing the propensity of a new drug to trigger life-threatening arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

T-wave morphology abnormalities in benign, potent, and arrhythmogenic Ikr inhibition

et al. 2011

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Background There is a consensus on the limited value of QT/QTc prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited LQTS patients. Objective We investigated the interest of repolarization morphology in the acquired and the inherited LQTS. Methods We analyzed two retrospective ECG datasets from healthy on/off moxifloxacin, and from genotyped KCNH2 patients. We measured QT, RR and T peak to T end intervals, early (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart-rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 ECGs from 143 LQT2 carriers and 150 non-carrier family members were analyzed. Results In the moxifloxacin model, ERD was associated with the presence of the drug (OR=1.15 per ms increase, CI:1.04-1.26, p=0.0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (OR=0.38 per 1.5microV/ms decrease, CI:0.23-0.64, p=0.0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2. Conclusions These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface ECG are specific. Future research should investigate if this phenomenon is linked to different level/form of loss functions of Ikr channels, and if they could result in different arrhythmogenic mechanisms.

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“…At each time, the QTcF value was calculated from 12‐lead ECGs extracted from the 5‐minute time window preceding the protocol‐defined nominal time from a continuous (Holter) recording. For the purposes of this study, the results from the ECG technique employed by the core lab (iCardiac's High Precision QT Technique [HPQT]) were compared with the results from a fully automated, computer‐based algorithm, COMPAS . All QT/RR measurements with COMPAS were made in lead II.…”

Section: Methodsmentioning

confidence: 99%

Can Bias Evaluation Provide Protection Against False‐Negative Results in QT Studies Without a Positive Control Using Exposure‐Response Analysis?

Ferber

Zhou²,

Dota

et al. 2016

The Journal of Clinical Pharma

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The revised ICH E14 document allows the use of exposure-response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant levels is achieved, a positive control is not required. In cases when this cannot be achieved, there may be a need for metrics to protect against false-negative results. The objectives of this study were to create bias in electrocardiogram laboratory QT-interval measurements and define a metric that can be used to detect bias severe enough to cause false-negative results using exposure-response analysis. Data from the IQ-CSRC study, which evaluated the QT effect of 5 QT-prolonging drugs, were used. Negative bias using 3 deterministic and 2 random methods was introduced into the reported QTc values and compared with fully automated data from the underlying electrocardiogram algorithm (COMPAS). The slope estimate of the Bland-Altman plot was used as a bias metric. With the deterministic bias methods, negative bias, measured between electrocardiogram laboratory values and COMPAS, had to be larger than approximately -20 milliseconds over a QTcF range of 100 milliseconds to cause failures to predict the QT effect of ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. With the random methods, the rate of false-negatives was ≤5% with bias severity < -10 milliseconds for all 5 drugs when plasma levels exceeded those of interest. Severe and therefore detectable bias has to be introduced into reported QTc values to cause false-negative predictions with exposure-response analysis.

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Highly Automated QT Measurement Techniques in 7 Thorough QT Studies Implemented under ICH E14 Guidelines

Cited by 33 publications

References 44 publications

The Application of Root Mean Square Electrocardiography (RMS ECG) for the Detection of Acquired and Congenital Long QT Syndrome

The Application of Root Mean Square Electrocardiography (RMS ECG) for the Detection of Acquired and Congenital Long QT Syndrome

T-wave morphology abnormalities in benign, potent, and arrhythmogenic Ikr inhibition

Can Bias Evaluation Provide Protection Against False‐Negative Results in QT Studies Without a Positive Control Using Exposure‐Response Analysis?

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