Baseline and new‐onset morphologic ECG abnormalities in healthy volunteers in phase I studies receiving placebo: Changes over a 6‐week follow‐up period

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.

Who is a ‘healthy subject’?—consensus results on pivotal eligibility criteria for clinical trials

“…During 24-h ambulatory ECG recordings, Stinson et al observed normal sinus rhythm in only 13% of 156 healthy volunteers throughout the entire observation period [14] . In one striking example from a case report, an idiosyncratic ventricular rhythm was found under placebo medication during a double-blind phase I study [15] .…”

Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials

“…Whether these arrhythmias are due to the investigational new drug or are a normal occurrence can be interpreted only if the background prevalence of the arrhythmia in healthy individuals is well documented. Some previous studies have documented prevalence of arrhythmias in 10‐second ECGs from healthy volunteers in clinical trials . However, there are very sparse data in literature on the prevalence of arrhythmias on 24‐hour continuous ECGs in healthy volunteers from clinical trials .…”

“…Some previous studies have documented prevalence of arrhythmias in 10-second ECGs from healthy volunteers in clinical trials. [11][12][13][14] However, there are very sparse data in literature on the prevalence of arrhythmias on 24-hour continuous ECGs in healthy volunteers from clinical trials. [7][8][9] We therefore studied the prevalence of various cardiac arrhythmias in 24-hour continuous ECG recordings in a large number of healthy subjects participating in phase 1 clinical trials.…”

The Prevalence and Clinical Significance of Cardiac Arrhythmias

“…при записи ЭКГ у 420 здоровых волонтеров. Частота ЖЭ в этом исследовании составила 1%, наджелудочковая экстрасистолия (НЖЭ) была выявлена в 3,8% случаев [14]. Аналогичные результаты были получены и в ряде других исследований [20,21].…”

“…Интерес к этой проблеме сохраняется на протяжении длительного времени, однако отсутствие единых методологических подходов, а также использование в большинстве исследований однократной регистрации электрокардиограммы (ЭКГ), малоинформативного метода выявления аритмий делают результаты исследований посвященных изучению распространенности НРС весьма противоречивыми [13,14].…”