New Waves

In the past few years, the ICH E14 Guideline ‘Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs’ has provided the industry with standards for the design and implementation of thorough QT (TQT) and intensive QT trials.

Even protocols that are not designed primarily with a focus on the QT often use recommendations taken from the ICH E14. The authors of the ICH E14 understood that the measurement of the QT interval presented certain issues, and set out to clarify them in Section 2.2.1 of the document:

“An important problem in the measurement of the QT/QTc interval is its intrinsic variability. This variability results from many factors including activity level, postural changes, circadian patterns, and food ingestion. It is critical to address intrinsic variability in the conduct of the ‘thorough QT/QTc study.’ This can be accomplished in several ways, including the collection of multiple ECGs at baseline and during the study.”

Variability falls into one of two categories, either physiologic or technical. Physiologic variability includes changes in the QT interval due to heart rate (including hysteresis), autonomic system, physical activity, electrolyte balance, circadian rhythms and the kinetics of the drug under study. The second source of QT measurement variability – technical factors – includes noise in the signal called high-frequency artifact (from multiple sources), baseline wander (also known as lowfrequency artifact), sampling and filtering of the ECG signal, reproducibility factors measured by inter- and intra-reader variability and errors introduced by rate correction formulae.

In an effort to reduce or eliminate intrinsic variability, the collection of multiple ECGs at a single time-point has become an essential part of the TQT trial. The purpose of multiple collections is to reduce the standard deviations associated with the QT interval, thus reducing sample size and, ultimately, the cost of the study. The majority of TQT trials collect triplicate ECGs at each time-point, which has been shown to be most efficient in terms of both standard deviation and cost-effectiveness.

ACQUIRING ECGs FOR TQT TRIALS – STANDARD 12-LEAD VERSUS CONTINUOUS

The usual protocol of ECG collection for a TQT trial is with a ‘resting’ 12-lead ECG machine. Industry standard machines will allow sites to collect 10 seconds of all 12-leads as a digital waveform and provide them with an immediate bedside printout with an unconfirmed interpretation. The printout allows sites to check on the safety of the subject, as well as ensuring that they have taken a clean, high quality ECG.