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Morphological ECG abnormalities occur in 5-12% healthy adults participating in early phase clinical trials. We retrospectively analyzed 16,472 12-lead ECGs recorded at multiple time points in 420 volunteers (282 males, 138 females; aged 18-76 years) randomized to receive placebo from 19 Phase I studies to see if some baseline ECG abnormalities may disappear or new abnormalities may appear during the study. One hundred forty-four (34.3%) subjects had abnormal baseline ECGs, of which 66 (44.8%) reverted to normal during follow-up. Of 276 (65.7%) subjects with normal baseline ECGs, 118 (42.8%) developed ECG abnormalities over the next 6 weeks. Common baseline abnormalities included sinus bradycardia, R wave transition abnormalities, right axis deviation, non-specific T wave changes and atrial premature complexes. On follow-up ECGs, prolonged QT interval, first-degree AV block, sinus bradycardia, short PR interval, and R wave transition abnormalities reverted to normal. Common new-onset abnormalities in subjects with normal baseline ECGs included sinus bradycardia, prolonged QT interval, non-specific T wave changes, R wave transition abnormalities, and sinus tachycardia. Thus, transient morphological ECG changes may occur in healthy volunteers possibly due to diurnal variation, effect of food, hormones, or autonomic changes. This should be considered when interpreting "treatment-emergent" ECG changes in clinical trials.

In a "thorough QT/QTc" (TQT) study, several replicate electrocardiograms (ECGs) are recorded at each time point to reduce within-subject variability. This decreases the sample size but increases the cost of ECG analysis. To determine the most cost-effective number of ECG replicates, the authors retrospectively analyzed data from the placebo and moxifloxacin arms of a TQT study with crossover design. Six replicate ECGs were recorded at 7 time points on day -1 (baseline day), day 1, and day 3 in 124 normal healthy volunteers who were randomized to receive moxifloxacin or placebo on day 1 and the other treatment on day 3. QT interval was corrected for heart rate by the Fridericia (QTcF) and individual subject-specific (QTcI) formulas. Within-subject and between-subject standard deviations for QTcF obtained by repeated-measures analysis of covariance were 9.5 and 13.3 milliseconds with 1 replicate; 7.8 and 12.7 milliseconds with 2 replicates; 7.3 and 12.3 milliseconds with 3 replicates; 6.9 and 12.2 milliseconds with 4 replicates; 6.8 and 11.9 milliseconds with 5 replicates; and 6.6 and 11.8 milliseconds with 6 replicates. Within- and between-subject variance with QTcI also declined with increasing replicates. Sample size benefit based on these estimates was negligible beyond 4 replicates. The study cost was least with 3 or 4 replicates, depending on per-ECG and per-subject costs.

When QT interval cannot be measured in Lead II, the best alternative leads are aVR, aVF, V5, V6 and V4 in that sequence. It differs maximally from that in Lead II in Lead aVL.

We compared heart rate-corrected QT interval (QTc) and its within- and between-subject variability, in ECGs recorded several days apart for 207 patients with schizophrenia (age range 19-60 yr) with age- and gender-matched healthy controls. Patients had higher heart rates (mean±s.d.) than controls [75±15 beats per minute (bpm) vs. 63±10 bpm; p<0.0001]. QTc by Bazett's formula (QTcB) overestimated QTc interval at high heart rates; consequently QTcB was longer in patients (412±24 ms) than in controls (404±24 ms; p=0.0003). QTc by Fridericia's method (QTcF), which was not influenced by heart rate, was comparable (398±22 ms in patients vs. 401±19 ms in controls; p=0.17). Between-subject variability in QTcF was similar in patients (17 ms) and controls (16.2 ms) but within-subject variability was larger (13.1 ms vs. 10 ms, respectively). Thus, a larger sample size is required when thorough QTc studies with a cross-over design are performed in patients with schizophrenia than in healthy subjects; sample size is not increased for studies with a parallel design. Last, QTcF is preferred over QTcB in schizophrenia patients with higher heart rates.

Background: Two methods of estimating reader variability (RV) in QT measurements between 12 readers were compared.Methods: Using data from 500 electrocardiograms (ECGs) analyzed twice by 12 readers, we bootstrapped 1000 datasets each for both methods. In grouped analysis design (GAD), the same 40 ECGs were read twice by all readers. In pairwise analysis design (PAD), 40 ECGs analyzed by each reader in a clinical trial were reanalyzed by the same reader (intra-RV) and also by another reader (inter-RV); thus, variability between each pair of readers was estimated using different ECGs.Results: Inter-RV (mean [95% CI]) between pairs of readers by GAD and PAD was 3.9 ms (2.1-5.5 ms) and 4.1 ms (2.6-5.4 ms), respectively, using ANOVA, 0 ms (-0.0 to 0.4 ms), and 0 ms (-0.7 to 0.6 ms), respectively, by actual difference between readers and 7.7 ms (6.2-9.8 ms) and 7.7 ms (6.6-9.1 ms), respectively, by absolute difference between readers. Intra-RV too was comparable.Conclusions: RV estimates by the grouped-and pairwise analysis designs are comparable.

The E14 guidelines of the International Conference on Harmonization require that all new drugs that have systemic bioavailability be subjected to a thorough QT/QTc study to look for possible effects on cardiac repolarization. Recent publications have discussed various aspects of thorough QTc studies. The thorough QTc study is designed to detect a mean drug-induced QTc prolongation of >5 ms with an upper bound of the 95% one-sided confidence limits of >10 ms. The E14 guideline has spelled out the procedures to be followed in a thorough QT/QTc study, including choice of subjects, methods of electrocardiogram (ECG) acquisition, details of ECG analysis, and statistical analysis of the study data. Since the measurement of the QT interval is a relatively subjective assessment, the ECGs must be analyzed in a central ECG laboratory by "a few skilled readers." In order to maintain quality in ECG interpretation, the E14 guidelines have two requirements. First, as a measure of the assay sensitivity, the study must include an active control known to prolong the QTc interval. Second, a certain percentage of ECGs must be subjected to an inter- and intra-reader variability analysis; these data are submitted to the regulatory authorities along with the study results.