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Background: Heart rate-corrected QT interval (QTc) prolongation, whether secondary to drugs, genetics including congenital long QT syndrome, and/or systemic diseases including SARS-CoV-2-mediated coronavirus disease 2019 (COVID-19), can predispose to ventricular arrhythmias and sudden cardiac death. Currently, QTc assessment and monitoring relies largely on 12-lead electrocardiography. As such, we sought to train and validate an artificial intelligence (AI)-enabled 12-lead ECG algorithm to determine the QTc, and then prospectively test this algorithm on tracings acquired from a mobile ECG (mECG) device in a population enriched for repolarization abnormalities.Methods: Using >1.6 million 12-lead ECGs from 538 200 patients, a deep neural network (DNN) was derived (patients for training, n = 250 767; patients for testing, n = 107 920) and validated (n = 179 513 patients) to predict the QTc using cardiologist-overread QTc values as the "gold standard". The ability of this DNN to detect clinically-relevant QTc prolongation (eg, QTc ≥500 ms) was then tested prospectively on 686 patients with genetic heart disease (50% with long QT syndrome) with QTc values obtained from both a 12-lead ECG and a prototype mECG device equivalent to the commercially-available AliveCor KardiaMobile 6L.Results: In the validation sample, strong agreement was observed between human over-read and DNN-predicted QTc values (-1.76±23.14 ms). Similarly, within the prospective, genetic heart disease-enriched dataset, the difference between DNN-predicted QTc values derived from mECG tracings and those annotated from 12-lead ECGs by a QT expert (-0.45±24.73 ms) and a commercial core ECG laboratory [10.52±25.64 ms] was nominal. When applied to mECG tracings, the DNN's ability to detect a QTc value ≥500 ms yielded an area under the curve, sensitivity, and specificity of 0.97, 80.0%, and 94.4%, respectively.Conclusions: Using smartphone-enabled electrodes, an AI DNN can predict accurately the QTc of a standard 12-lead ECG. QTc estimation from an AI-enabled mECG device may provide a cost-effective means of screening for both acquired and congenital long QT syndrome in a variety of clinical settings where standard 12-lead electrocardiography is not accessible or cost-effective. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors.Methods: Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2-4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration-QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data.Results: Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration-QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as - 0.00269 ms/(ng/mL) and - 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was < 10 ms at the upper bound of the two-sided 90% confidence interval.Conclusions: ECG data and the concentration-QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters. Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34. [ABSTRACT FROM AUTHOR]

The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a "double negative" nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical "double negative" data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&As guideline (Q&As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the safety pharmacology cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation. [ABSTRACT FROM AUTHOR]

Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e. , demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g. , supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g. , the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal). [ABSTRACT FROM AUTHOR]

The human voltage-gated sodium channel Na v 1.5 (hNa v 1.5/SCN5A) plays a critical role in the initiation and propagation of action potentials in cardiac myocytes, and its modulation by various drugs has significant implications for cardiac safety. Drug-dependent block of Na v 1.5 current (I Na ) can lead to significant alterations in cardiac electrophysiology, potentially resulting in conduction slowing and an increased risk of proarrhythmic events. This review aims to provide a comprehensive overview of the mechanisms by which various pharmacological agents interact with Na v 1.5, focusing on the molecular determinants of drug binding and the resultant electrophysiological effects. We discuss the structural features of Na v 1.5 that influence drug affinity and specificity. Special attention is given to the concept of state-dependent block, where drug binding is influenced by the conformational state of the channel, and its relevance to therapeutic efficacy and safety. The review also examines the clinical implications of I Na block, highlighting case studies of drugs that have been associated with adverse cardiac events, and how the Vaughan-Williams Classification system has been employed to qualify "unsafe" sodium channel block. Furthermore, we explore the methodologies currently used to assess I Na block in nonclinical and clinical settings, with the hope of providing a weight of evidence approach including in silico modeling, in vitro electrophysiological assays and in vivo cardiac safety studies for mitigating proarrhythmic risk early in drug discovery. This review underscores the importance of understanding Na v 1.5 pharmacology in the context of drug development and cardiac risk assessment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Sites participating in clinical trials may not have the expertise and infrastructure to accurately measure cardiac intervals on 12-lead ECGs and rely heavily on the automated ECG device generated results for clinical decision-making., Methods: Using a dataset of over 260,000 ECGs collected in clinical oncology studies, we investigated the mean difference and the rate of false negative results between the digital ECG machine QTc and QRS measurements compared to those obtained by a centralized ECG core lab., Results: The mean differences between the core lab and the automated algorithm QTcF and QRS measurements were + 1.8 ± 16.0 ms and - 1.0 ± 8.8 ms, respectively. Among the ECGs with a centralized QTcF value > 450 or > 470 ms, 39.5% and 47.8% respectively had a device reported QTcF value ≤ 450 ms or ≤ 470 ms. Among the ECGs with a centrally measured QTcF > 500 ms, 55.8% had a device reported value ≤ 500 ms. Automated QTcF measurements failed to detect a QTcF increase > 60 ms for 53.9% of the ECGs identified by the core lab. Automated measurements also failed to detect QRS prolongation, though to a lesser extent than failures to detect QTc prolongation. Among the ECGs with a centrally measured QRS > 110 or 120 ms, 7.9% and 7.3% respectively had a device reported QRS value ≤ 110 ms or ≤ 120 ms., Conclusion: Relying on automated measurements from ECG devices for patient inclusion and treatment (dis)continuation decisions poses a potential risk to patients participating in oncology studies., (© 2022. The Author(s).)

Background: Oliceridine is a biased ligand at the μ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter., Objective: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval., Methods: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control., Results: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 μM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure., Conclusion: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Interval duration measurements (IDMs) were compared between standard 12-lead electrocardiograms (ECGs) and 6-lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand-held mobile device designed for use by patients at home., Methods: Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12-lead and 6-lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi-automated technique., Results: Despite differences in patient position (supine for 12-lead ECGs and sitting for 6-lead ECGs), mean IDMs were comparable, with mean values for the 12-lead and 6-lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, -5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities., Conclusions: The 6-lead hand-held device is potentially useful for a clinical follow-up of remote patients, and for a safety follow-up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12-lead ECG recordings during the current COVID-19 pandemic as remote patient monitoring becomes more common in virtual or hybrid-design clinical studies., (© 2021 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Introduction: Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling., Methods: Patients had intermediate- or high-risk smoldering multiple myeloma. Patients with QT interval corrected by Fridericia's formula (QTcF) > 470 ms, QRS interval ≥ 110 ms, or PR interval ≥ 200 ms were excluded. Triplicate ECGs were collected at screening, Dose 1, and Dose 8. Analyses of on-treatment ECGs were conducted with a time-matched baseline (primary analysis). By time-point, pharmacokinetic-pharmacodynamic (PK/PD), and outlier analyses were conducted., Results: Of 123 patients in CENTAURUS, 31 were enrolled in the QTc substudy. Daratumumab produced a small increase in heart rate (5-12 beats per minute) of unclear significance. There was a small but clinically insignificant effect on QTc, as measured by both time-matched time-point and PK/PD analyses. The primary analysis demonstrated a maximum mean increase in QTcF of 9.1 ms (90% 2-sided upper confidence interval [CI], 14.1 ms). The primary PK/PD analysis predicted a maximum QTcF increase of 8.5 ms (90% 2-sided upper CI, 13.5 ms). No patient had an abnormal U wave, a new QTcF > 500 ms, or > 60 ms change from baseline for QTcF., Conclusion: Analysis of ECG intervals and concentration-QTc relationships showed a small but clinically insignificant effect of daratumumab., Trial Registration: ClinicalTrials.gov Identifier: NCT02316106.

Objective: To assess the effects of a supratherapeutic dose of SPN-812, a drug currently under investigation as a treatment for attention-deficit/hyperactivity disorder, on cardiac repolarization (QTc) in healthy adults., Methods: The study was conducted from June 27, 2018, to July 10, 2018. It had a double-blind, randomized, crossover design in which subjects received a 3-treatment sequence-placebo, 400 mg moxifloxacin, and 1,800 mg SPN-812 for 2 consecutive days (separated by at least a 3-day washout). The primary endpoint was the correlation between the change from baseline (CFB) in individual heart rate corrected QT interval (QTcI) (ΔQTcI) and viloxazine and 5-hydroxyviloxazine glucuronide (5-OH-VLX-gluc) plasma concentrations (Cps). The secondary endpoint was the time point placebo-adjusted CFB in QTcI (ΔΔQTcI) for viloxazine. For assay sensitivity, the correlations between moxifloxacin Cp and the ΔQTcI, and moxifloxacin and time point ΔΔQTcI were evaluated. Additional evaluations included Fridericia's formula QT correction, heart rate, and the PR and QRS intervals. Changes in electrocardiogram (ECG) morphology along with other safety parameters were also analyzed and reported., Results: The correlation between ΔQTcI and viloxazine Cp demonstrated a statistically significant negative slope (P = .0012). 5-OH-VLX-gluc Cp and ΔQTcI also demonstrated a statistically significant negative slope (P = .0007). Secondary time point analyses showed no effect of SPN-812 on QTcI. Assay sensitivity with moxifloxacin was confirmed. Safety parameters were acceptable., Conclusions: This study demonstrated that SPN-812 had no effect on cardiac repolarization or other ECG parameters in healthy adults, suggesting that it is not associated with a risk for cardiac arrhythmias or other electrocardiographic parameters., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Aims: Remimazolam is a new, ultra-short-acting benzodiazepine developed for intravenous (IV) use during procedural sedation and in general anaesthesia. Two trials were conducted to characterize its effects on cardiac repolarization., Methods: A thorough QT/QTc (TQT) study assessed electrocardiography effects of therapeutic and supratherapeutic doses of remimazolam and midazolam. To investigate whether RR-QT hysteresis effects due to rapid heart rate changes might have confounded the QTc assessments in the TQT trial, a second trial used continuous IV remimazolam infusion to achieve stable heart rates during periods of stable remimazolam plasma concentration., Results: During the TQT, both compounds produced a 10-20-beats/min increase in heart rate within 30 seconds, persisting for 5-10 minutes. Within 30 seconds, the upper bound of the 2-sided 90% confidence interval for the placebo-corrected change from baseline for QTcI (ΔΔQTcI) exceeded 10 ms for both doses of remimazolam (ΔΔQTcI 7.2 [3.2, 11.2] ms for the 10 mg dose and 10.4 [6.5, 14.3] ms for the 20 mg dose) as well as for the 7.5-mg dose of midazolam (8.2 [4.4, 12.1] ms). At 2 minutes after IV bolus, the upper bound of the 2-sided 90% confidence interval for ΔΔQTcI exceeded 10 ms only for the remimazolam 20-mg dose (6.3 [2.3, 10.2] ms). During the second study, during periods of stable heart rate, remimazolam had no clinically significant effect on QTc (peak ΔΔQTcI 3.4 [-1.1, 7.6] ms)., Conclusion: Remimazolam does not prolong cardiac repolarization (QTc). The methods reported here may allow assessment of the QTc effects of other drugs given by IV bolus., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses important issues regarding sudden cardiac death in the young (SCDY), a problem that does not discriminate by gender, race, ethnicity, education, socioeconomic level, or athletic status. The occurrence of SCDY has devastating impact on families and communities. Sudden cardiac death in the young is a matter of national and international public health, and its prevention has generated deep interest from multiple stakeholders, including families who have lost children, advocacy groups, academicians, regulators, and the medical industry. To promote scientific and clinical discussion of SCDY prevention and to germinate future initiatives to move this field forward, a Cardiac Safety Research Consortium-sponsored Think Tank was held on February 21, 2015 at the US Food and Drug Administration's White Oak facilities, Silver Spring, MD. The ultimate goal of the Think Tank was to spark initiatives that lead to the development of a rational, reliable, and sustainable national health care resource focused on SCDY prevention. This article provides a detailed summary of discussions at the Think Tank and descriptions of related multistakeholder initiatives now underway: it does not represent regulatory guidance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This white paper, prepared by members of the Cardiac Safety Research Consortium (CSRC), discusses important issues regarding scientific and clinical aspects of long-term electrocardiographic safety monitoring during clinical drug development. To promote multistakeholder discussion of this topic, a Cardiac Safety Research Consortium-sponsored Think Tank was held on 2 December 2015 at the American College of Cardiology's Heart House in Washington, DC. The goal of the Think Tank was to explore how and under what circumstances new and evolving ambulatory monitoring technologies could be used to improve and streamline drug development. This paper provides a detailed summary of discussions at the Think Tank: it does not represent regulatory guidance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Many clinical trials of investigational oncologic agents utilize electrocardiogram (ECG) machine measurements of QTc, for inclusion/exclusion and dosing decisions, though their reliability in this setting has not been established., Methods: We compared the digital ECG machine QTc measurements with those obtained by a centralized ECG core lab on more than 270,000 consecutive ECGs collected from 299 clinical oncology trials., Results: The mean difference between the ECG machine measurements and the central measured QTcF was 1.8 ± 15.7 milliseconds. In addition, 29.7% of ECGs with an ECG machine-measured QTcF >450 milliseconds had a centrally measured QTcF <450 milliseconds, 44.6% of ECGs with an ECG machine-measured QTcF >470 milliseconds had a centrally measured QTcF <470 milliseconds, and 77.2% of ECGs with an ECG machine-measured QTcF >500 milliseconds had a centrally measured QTcF <500 milliseconds. The likelihood of a large discrepancy between the ECG machine- and centrally measured value for QTcF increased at both the high and low ends of the range of ECG machine QTcF measurements., Conclusions: While on average ECG machine-measured QTcF values were very similar to the central core lab measurements; there were very significant discrepancies which will have important implications for patient recruitment for clinical oncology trials as well as for patient safety during dosing with new oncologic agents. Reliance on ECG machine QTc measurements during clinical oncology trials may lead to unnecessary exclusion of patients as well as unneeded treatment interruptions.

Aim: We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different., Methods: A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQTc F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2., Results: There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml(-1) ), ΔΔQTc F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml(-1) ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml(-1) ). The difference in the two ΔΔQTc F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits., Conclusions: Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study., (© 2015 The British Pharmacological Society.)

Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development., (Copyright © 2013 Mosby, Inc. All rights reserved.)

This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question., (2010 Mosby, Inc. All rights reserved.)