The J to T-peak interval as a biomarker in drug safety studies: A method of accuracy assessment applied to two algorithms.

OBJECTIVES: To evaluate performance of J-to-T-peak (JTP) measurements of 12-lead ECGs, in a five-arm study using drugs with various levels of electrolyte channel block. METHODS: The novel evaluation method distinguishes between different aspects of measurement. "Random noise" is the variability among repeated measurements made without changing the conditions. "Context noise" is the variability of changes in context of the measurement, e.g. T-wave morphology, autonomic nervous system state. RESULTS: The average random noise of our RR-corrected JTPc measurements in standard deviations was 3.0 ms and not dependent on the drug. The average context noise was 4.0 ms for ranolazine, verapamil, and placebo, and 8.8 ms for dofetilide and quinidine. Measurement consistency is corroborated by linear fit confidence intervals of baseline- and placebo-corrected JTPc versus drug concentration. CONCLUSIONS: Systematic differences were found in JTPc drug response between the Mortara method and published data. Residual signal component in the context noise may influence future study design.

The algorithmic performance of J-Tpeak for drug safety clinical trial.

INTRODUCTION: The interval from J-point to T-wave peak (JTp) in ECG is a new biomarker able to identify drugs that prolong the QT interval but have different ion channel effects. If JTp is not prolonged, the prolonged QT may be associated with multi ion channel block that may have low torsade de pointes risk. From the automatic ECG measurement perspective, accurate and repeatable measurement of JTp involves different challenges than QT. We evaluated algorithm performance and JTp challenges using the Philips DXL diagnostic 12/16/18-lead algorithm. Measurement of JTp represents a different use model. Standard use of corrected QT interval is clinical risk assessment on patients with cardiac disease or suspicion of heart disease. Drug safety trials involve a very different population - young healthy subjects - who commonly have J-waves, notches and slurs. Drug effects include difficult and unusual morphology such as flat T-waves, gentle notches, and multiple T-wave peaks. METHODS: The JTp initiative study provided ECGs collected from 22 young subjects (11 males and females) in randomized testing of dofetilide, quinidine, ranolazine, verapamil and placebo. We compare the JTp intervals between DXL algorithm and the FDA published measurements. The lead wise, vector-magnitude (VM), root-mean-square (RMS) and principal-component-analysis (PCA) representative beats were used to measure JTp and QT intervals. We also implemented four different methods for T peak detection for comparison. RESULTS: We found that JTp measurements were closer to the reference for combined leads RMS and PCA than individual leads. Differences in J-point location led to part of the JTp measurement difference because of the high prevalence of J-waves, notches and slurs. Larger differences were noted for drug effect causing multiple distinct T-wave peaks (Tp). The automated algorithm chooses the later peak while the reference was the earlier peak. Choosing among different algorithmic strategies in T peak measurement results in the tradeoff between stability and the accurate detection of calcium or sodium channel block. CONCLUSION: Measurement of JTp has different challenges than QT measurement. JTp measurement accuracy improved with combined leads RMS and PCA over lead II or V5.

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.

Identification of Drug-Induced Multichannel Block and Proarrhythmic Risk in Humans Using Continuous T Vector Velocity Effect Profiles Derived From Surface Electrocardiograms.

We present continuous T vector velocity (TVV) effect profiles as a new method for identifying drug effects on cardiac ventricular repolarization. TVV measures the temporal change in the myocardial action potential distribution during repolarization. The T vector dynamics were measured as the time required to reach p percent of the total T vector trajectory length, denoted as Tr(p), with p in {1, …, 100%}. The Tr(p) values were individually corrected for heart rate at each trajectory length percentage p. Drug effects were measured by evaluating the placebo corrected changes from baseline of Tr(p)c jointly for all p using functional mixed effects models. The p-dependent model parameters were implemented as cubic splines, providing continuous drug effect profiles along the entire ventricular repolarization process. The effect profile distributions were approximated by bootstrap simulations. We applied this TVV-based analysis approach to ECGs available from three published studies that were conducted in the CiPA context. These studies assessed the effect of 10 drugs and drug combinations with different ion channel blocking properties on myocardial repolarization in a total of 104 healthy volunteers. TVV analysis revealed that blockade of outward potassium currents alone presents an effect profile signature of continuous accumulation of delay throughout the entire repolarization interval. In contrast, block of inward sodium or calcium currents involves acceleration, which accumulates during early repolarization. The balance of blocking inward versus outward currents was reflected in the percentage pzero of the T vector trajectory length where accelerated repolarization transitioned to delayed repolarization. Binary classification using a threshold pzero = 43% separated predominant hERG channel blocking drugs with potentially higher proarrhythmic risk (moxifloxacin, dofetilide, quinidine, chloroquine) from multichannel blocking drugs with low proarrhythmic risk (ranolazine, verapamil, lopinavir/ritonavir) with sensitivity 0.99 and specificity 0.97. The TVV-based effect profile provides a detailed view of drug effects throughout the entire ventricular repolarization interval. It enables the evaluation of drug-induced blocks of multiple cardiac repolarization currents from clinical ECGs. The proposed pzero parameter enhances identification of the proarrhythmic risk of a drug beyond QT prolongation, and therefore constitutes an important tool for cardiac arrhythmia risk assessment.

The Cardiovascular Effects of a Meal: J-Tpeak and Tpeak -Tend Assessment and Further Insights Into the Physiological Effects.

Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown. This shortening of the myocardial action potential caused by the ingestion of food was further investigated in the present study by measuring the QRS, J-Tpeak , and Tpeak -Tend intervals in search of further clues to better understand the underlying mechanisms. A retrospective analysis was conducted based on data collected in a formal thorough QT/QTc study in which 32 subjects received a carbohydrate-rich "continental" breakfast, moxifloxacin without food, and moxifloxacin with food. We assessed the effect of food on T-wave morphology using validated algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Our findings demonstrate that a standardized meal significantly shortened J-Tpeak for 4 hours after a meal and to a much lesser extent and shorter duration (up to 1 hour) prolonged the Tpeak -Tend and QRS intervals. This suggests that the QTc shortening occurs mainly during phase 2 of the cardiac action potential. As there was no corresponding effect on Tpeak -Tend beyond the first hour, we conclude that a meal does not interfere with the outward correcting potassium channels but possibly with Ca2+ currents. An effect on mainly Ca2+ aligns well with our understanding of physiology whereby an increase in stroke volume, as observed after a meal, is associated with changes in Ca2+ cycling in and out of the sarcoplasmic reticulum during cardiac myocyte contraction.

Challenges in implementing and obtaining acceptance for J-Tpeak assessment as the clinical component of CiPA.

INTRODUCTION: This paper is based on a presentation held at the Annual Safety Pharmacology Society meeting in September 2017, at which challenges for the clinical component of CiPA were presented. FDA has published an automated algorithm for measurement of the J-Tpeak interval on a median beat from a vector magnitude lead derived from a 12-lead ECG. CiPA proposes that J-Tpeak prolongation < 10 ms can be used for drugs with a QTc effect < 20 ms to differentiate between safe and unsafe delayed repolarization and to reduce the level of ECG monitoring in late stage clinical trials. METHODS: We applied FDA's algorithm, complemented with iCOMPAS, to moxifloxacin and dolasetron data from the IQ-CSRC study with 9 subjects on active and 6 on placebo. The effect on QTcF and corrected J-Tpeak (J-Tpeak_c) was analyzed using concentration-effect modeling. RESULTS: There was a good correlation between QTcF and J-Tpeak_c prolongation after oral dosing of 400 mg moxifloxacin with placebo-adjusted, change-from-baseline (ΔΔ) J-Tpeak_c of ~12 ms at concentrations that caused ΔΔQTcF of ~20 ms. On dolasetron, J-Tpeak_c was highly variable, no prolongation was seen and an effect on ΔΔJ-Tpeak_c > 10 ms could be excluded across the observed plasma concentration range. DISCUSSION: In this limited analysis performed on the IQ-CSRC study waveforms using FDA's automated algorithm, J-Tpeak prolongation was observed on moxifloxacin, but not on dolasetron, despite clinical observations of proarrhythmias with both drugs. Challenges for the implementation of the J-Tpeak interval as a replacement or complement to the QTc interval, include to demonstrate that the proposed clinical algorithm using a J-Tpeak threshold of 10 ms, can be used to categorize drugs with a QT effect up to ~20 ms as having low pro-arrhythmic risk.