Circadian Variation in QT Interval Demonstrating Assay Sensitivity in a Phase 1 Clinical Trial
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Circadian Variation in QT Interval Demonstrating Assay Sensitivity in a Phase 1 Clinical Trial Background. This study investigates whether
Peter 1. Bourdillou, MBBS, FRCP Honorary Senior Lecturer, Imperial College, London
phD Statistical Consultant, Imperial College, London
Key Words QT interval; Circadian variation; Phase I clinical trial Correspondence Address Dr Peter]. Bourdillon. ECG Department. Hammersmith Hospital, Imperial College Healthcare N H S Trust, London W12 OHS UK (email: pbourdillonOmsn.com).
exploitation of circadian variation in heart mte-adpsted QT interval (QTc) is an alternative to the inclusion of a positive confrd as a methodfor demonstmting assay sensitivity in a phase 1 clinical trial. Methods. EZ-dogmms (ECGs) j h a dose-escalating placebo-controlled phase 1 clinical trial were anafyzed. The trial incMed 63 healthy young males in 7 cohorts; each had 17 ECGs recorded. The 21 subjects receiving svlacebo were studied: hiemrchical linear model analysis was conducted with the measurements a m s a 43-hour time period nested within subjects. Sepamte analyses were conducted with QTckett, QTcFridericia, QTcFmmingharn,
INTRODUCTION Drug-induced prolongation of the QT interval on the electrocardiogram (ECG) increases the risk of serious rhythm disturbances of the heart (1).Guidance from the Food and Drug Administration ( 2 ) proposes that all drugs that are to be licensed should undergo a thorough QT study. The thorough QT study is designed to demonstrate that a drug does not prolong the QT interval corrected for a heart rate of 60 beats per minute (QTc) on average by more than 5 ms. Measurement error and the normal day-to-day variability in QTc make it difficult to demonstrate a significant change of 5 ms. To ensure that a thorough QT study is capable of detecting a 5 ms change in QTc, the guidance recommends that a positive control, such as moxifloxacin, which is known to lengthen QTc but is not proarrhythmic, is included as one of the treatments in a thorough QT study. This study presents an alternative to including a positive control as a way of demonstrating the assay sensitivity of a thorough QT study: the variation in the QT-heart rate relationship that occurs throughout the 24 hours of the day (3,4)
and a QT-heart mte z score as the dependent variable. Results. Painvise contmsts between the time points 6 and 10 h m after the administmtion of the placebo showed a difference of 15.97 ms (CI 9.58-22.37), 8.17 ms (CZ 3.47-12.88), 10.77 ms (CZ5.70-l5.84), and 0.39 (equivalent to 8 m~ CZ 0.16-0.62) for QTchett, QTcFridericia, QTcFmingham, and QT heart mte z score respectively ConcZusim. By recording sufficientECGs thmghout the dq, circadian variation in QT interval has the potential to allow the detection of changes of more than 5 ms in phase I clinical trials and to obviate the need to indude a positive contrd.
in subjects in the placebo arm of a phase 1 trial is exploited. Should one of the time points show a significant change, either increase or decrease, in QTc of more than 5 ms com
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