Comparison of QTinno, a fully automated electrocardiographic analysis program, to semiautomated electrocardiographic analysis methods in a drug safety study in healthy subjects

Sarapa, Nenad; Gussak, Ihor; Vajdic, Branislav; George, Samuel; Hadžievski, Ljupčo; Francom, Steven F.; Kowey, Peter R.

doi:10.1016/j.jelectrocard.2009.02.001

Cited by 15 publications

(12 citation statements)

References 18 publications

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“…Using these data sets, emerging, methods have been shown to reproduce the moxifloxacin QTc effect in a way that is consistent with the E14 requirements (Couderc and Zareba, 2009). Some methods also support the reader to determine which QT inter-val should be overread, through 'confidence scores', which identifies T-waves that fall outside templates that are produced on baseline recordings (Sarapa et al, 2009b;Strachan et al, 2009). This is a highly dynamic area and it can be foreseen that the role of automated QT algorithms will dramatically increase during the next coming years, not only to replace manual QT measurements but also to improve the detection of subtle T-wave changes.…”

Section: Emerging Methods For Qt Interval Measurementsmentioning

confidence: 99%

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

Darpö

2010

British J Pharmacology

136

148

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The ICH E14 guidance on how to clinically assess a new drug's liability to prolong the QT interval was adopted in May 2005. A centre-piece of the guidance was the establishment of one single trial, the 'thorough QT/QTcstudy', intended to confidently identify drugs that may cause QT prolongation. Initially perceived as a great challenge, this study has rapidly become a standard component of all clinical development programs for new molecular entities. The study is normally conducted in healthy volunteers, includes both a positive and a negative (placebo) control and is stringently powered to exclude an effect on the QTc interval exceeding 10 ms. The E14 guidance was intentionally not very prescriptive and allowed sponsors and service providers to explore new methodologies. This has allowed for a rapid development of new methods during the first years after the guidance's implementation, such as computer-assisted algorithms for QT measurements. Regulators have worked in close collaboration with pharmaceutical industry to set standards for the design and conduct of the 'thorough QT/QTc study', which therefore has evolved as a key component of cardiac safety assessment of new drugs. This paper summarizes the requirements on the 'thorough QT/QTc study' with emphasis on the standard that has evolved based on interactions between regulators and sponsors and the experience from a large number of completed studies.

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Section: Emerging Methods For Qt Interval Measurementsmentioning

confidence: 99%

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

Darpö

2010

British J Pharmacology

136

148

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“…(12) Briefly, the QTinno algorithm uses the full 12-lead ECG input to generate a vector magnitude (VM) lead, and then uses the VM lead for all interval duration measurements. Fiducial point placements are made primarily by curve-fitting to a third-order polynomial, an approach that was chosen because it is relatively noise-resistant and does not require location of an isoelectric baseline.…”

Section: Methodsmentioning

confidence: 99%

Detection of QT prolongation using a novel electrocardiographic analysis algorithm applying intelligent automation: Prospective blinded evaluation using the Cardiac Safety Research Consortium electrocardiographic database

Green

Kligfield

George³

et al. 2012

American Heart Journal

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Background The Cardiac Safety Research Consortium (CSRC) provides both “learning” and blinded “testing” digital ECG datasets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This manuscript reports the first results from a blinded “testing” dataset that examines Developer re-analysis of original Sponsor-reported core laboratory data. Methods 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel-group TQT in 191 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. Results Developer and Sponsor-reported baseline-adjusted data were similar with average differences less than 1 millisecond (ms) for all intervals. Both Developer and Sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject standard deviation for triplicate QTcF measurements was significantly lower for Developer than Sponsor-reported data (5.4 ms and 7.2 ms, respectively; p<0.001). Conclusion The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared to the Sponsor-reported study, without the use of a manual core laboratory. These findings indicate CSRC ECG datasets can be useful for evaluating novel methods and algorithms for determining QT/QTc prolongation by drugs. While the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to provide prospective, blinded comparisons of ECG technologies applied for QT/QTc measurement is illustrated.

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“…The feasibility of reliable automated QT interval measurements has been previously demonstrated. 23,24 To more fully characterize the current machine-read LSS technology, we compared the core laboratory semiautomated raw QT values with corresponding machine-read values by Bland-Altman analysis, which demonstrated good agreement between the 2 methods. To confirm the accurate clinical translation of distribution-based analysis, we compared the effects of moxifloxacin assessed by both the core laboratory semiautomated QTcS and machine-read QTca methods ( Figure 5A).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Human QT Interval: Novel Distribution‐Based Assessment of the Repolarization Effects of Moxifloxacin

Holzgrefe

Ferber

Morrison

et al. 2012

The Journal of Clinical Pharma

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The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer. Distribution-based analysis was applied to the placebo and moxifloxacin (400 mg) arms to characterize the nature of the QT interval and to assess the efficacy of distribution-based analysis for QTc determination. Novel statistics using continuous means and bootstrapped 95% confidence intervals were developed to facilitate QT analysis. Machine-read QT values were compared with core laboratory semiautomated values for verification. RR intervals demonstrated repetitive protocol-dependent variations (50-250 milliseconds); QT intervals were normally distributed, spanning 60 to 100 milliseconds for each RR interval. Distribution-based analysis detected a moxifloxacin response identical to semiautomated analysis, but with reduced variability and improved statistical power, where n = 12 satisfied the ICH E14 criteria for a positive control. Distribution-based analysis has the potential to provide a universal method for clinical QT heart rate correction, enabling accurate detection of QT changes when limited numbers of volunteers are exposed to drug.

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Comparison of QTinno, a fully automated electrocardiographic analysis program, to semiautomated electrocardiographic analysis methods in a drug safety study in healthy subjects

Cited by 15 publications

References 18 publications

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

Detection of QT prolongation using a novel electrocardiographic analysis algorithm applying intelligent automation: Prospective blinded evaluation using the Cardiac Safety Research Consortium electrocardiographic database

Characterization of the Human QT Interval: Novel Distribution‐Based Assessment of the Repolarization Effects of Moxifloxacin

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