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 semiautomated 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.
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late‐stage electrocardiogram (ECG) monitoring for mildly QT‐prolonging drugs. ECG waveforms from the IQ‐CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT‐prolonging drugs — moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine — and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12‐lead ECGs, and measurements were made on a median beat from three 10‐second replicates. Data were analyzed using a linear concentration‐response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)‐QTcF and C‐JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C‐ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C‐ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (−0.3 and −7.5 milliseconds per ng/mL). Pure hERG‐blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.
Nonclinical assays with JNJ-54861911, a β-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo-corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9-18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure-response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ-54861911 peak plasma concentrations (C ) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; C , 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ-54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.
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