No abstract

No abstract

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.