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Near-Thorough QT Study as Part of a First-In-Man Study

From St Paul's Cardiac Electrophysiology, London, England (Dr Malik, Dr Hnatkova) and Xention Ltd, Cambridge, England (Dr Ford, Dr Madge).

Detailed electrocardiographic (ECG) support was provided to a first-in-man, single-ascending-dose study that included 6 cohorts of 8 male volunteers each. In each cohort, 6 and 2 subjects received active compound and placebo, respectively. Long-term 12-lead ECGs were obtained on baseline day –1, dosing day 1, and day 2. Automatic QT-interval measurements were made at 63 time points (28 at baseline and 35 on treatment). Based on QT/RR distribution, 20% of measurements were visually verified. Baseline-corrected time-matched QTc values were obtained at 35 postdose time points. Placebo subjects of all cohorts were pooled. When 2 cohorts of the lowest, middle, and highest doses were pooled (12 subjects per active treatment group), the spreads of placebo-corrected QTc values were within the regulatory requirements (single-sided 95% confidence interval <10 milliseconds) at all time points. Thus, this ECG support of the first-in-man study provided data of regulatory acceptable accuracy at a small fraction of the cost of a full thorough QT study.

Key Words: Electrocardiography • QT interval • first-in-man study

Address for reprints: Marek Malik, PhD, MD, St Paul's Cardiac Electrophysiology, London, England; e-mail: marek.malik{at}btinternet.com.

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