Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development

Min, Sherene; Turner, J. Rick; Nada, A. A.; DiMino, Tara; Hynie, I; Kleiman, Robert B.; Kowey, Peter R.; Krucoff, Mitchell W.; Mason, Jay W.; Phipps, Alex; Newton‐Cheh, Christopher; Pordy, Robert; Strnadova, Colette; Targum, Shari L.; Uhl, Kathleen; Finkle, John K.

doi:10.1016/j.ahj.2010.02.004

Cited by 17 publications

(37 citation statements)

References 55 publications

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“…Ambulatory ECG recording offers several advantages that include the ability to study ECG intervals at specified time points when the heart rate has been steady and also the ability to detect transient and infrequent cardiac arrhythmias. It has been estimated that the prevalence of cardiac arrhythmias in a 24‐hour ambulatory ECG recording could exceed that detected in a 10‐second ECG by a factor of more than 100 . Our findings confirm this estimate.…”

Section: Discussionsupporting

confidence: 87%

“…Regulatory agencies too are encouraging sponsors to submit ambulatory ECG data to the FDA ECG warehouse because this would increase the ability to detect infrequently occurring arrhythmias . As a result, rare arrhythmias such as nonsustained ventricular and supraventricular tachycardia are occasionally being encountered in Holter recordings in a few studies . 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.…”

mentioning

confidence: 99%

“…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 . 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.…”

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confidence: 99%

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

Hingorani

Karnad

Rohekar

et al. 2016

The Journal of Clinical Pharmacology

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Regulatory agencies encourage sponsors to submit 24-hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early-phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24-hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug-free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18-65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs. Supraventricular arrhythmias such as supraventricular premature complexes were observed in 60.8% of healthy volunteers, supraventricular tachycardia in 2.2%, and atrial fibrillation in 0.1%. Ventricular arrhythmias included premature ventricular complexes (PVCs) in 43.4%, >200 PVCs per 24 hours in 3.3%, multifocal PVCs in 5.3%, nonsustained ventricular tachycardia in 0.7%, and accelerated idioventricular rhythm in 0.3%. Bradyarrhythmias included sinus pause >3 seconds in 0.3%, and second-degree AV block in 2.4%. Complete heart block and torsades de pointes were not seen in any subject. Based on the observed incidence, we estimated the maximum number of healthy subjects in whom these arrhythmias may be seen as a matter of chance in studies with smaller sample sizes if the study drug has no arrhythmogenic effect. Our results and these estimates could help interpret whether cardiac arrhythmias observed in early-phase studies are due to chance or possibly are a drug effect.

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Section: Discussionsupporting

confidence: 87%

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confidence: 99%

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confidence: 99%

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

Hingorani

Karnad

Rohekar

et al. 2016

The Journal of Clinical Pharmacology

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“…Studies using 24‐hour ambulatory Holter ECG recordings have shown that occasional APCs may occur in 56–100% of healthy subjects . It is estimated that a ten second recording of a 12‐lead ECG may underestimate the prevalence of premature complexes by a factor of up to 100 times due to their infrequency . It is therefore remarkable that of the nine subjects with APCs at baseline, they persisted in all post‐baseline ECGs in five individuals.…”

Section: Discussionmentioning

confidence: 99%

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

Hingorani

Karnad

Natekar

et al. 2014

The Journal of Clinical Pharma

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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.

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“…potassium channel binding assays) are one of the greatest factors leading to the loss of promising therapies from the drug development pipeline. 33,34 There has been an increased call for awareness of medications that prolong the QTc and/or predispose to TdP which has led to development of consensus-based lists of implicated drugs including an online registry located at www.qtdrugs.org. 35,36 …”

Section: Epidemiology Of Tdpmentioning

confidence: 99%

Clinical and Genetic Determinants of Torsade de Pointes Risk

Sauer

Newton‐Cheh

2012

Circulation

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Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development

Cited by 17 publications

References 55 publications

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

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

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

Clinical and Genetic Determinants of Torsade de Pointes Risk

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