Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double‐blind, placebo‐ and positive‐controlled thorough QT study

Abstract

AIMSTo assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control.METHODSA double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers (NCT00903747). Volunteers were randomized to receive prucalopride 2–10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally.RESULTSEstimated mean difference in study specific corrected QT interval (QTcSS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl −0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QTcSS were all <10 ms. There were no outlying QTcSS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QTcSS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min–1), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment.CONCLUSIONPrucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.