title: Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study.
abstract: OBJECTIVE
  To 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.
  
  
  METHODS
  A 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.
  
  
  RESULTS
  Estimated mean difference in study specific corrected QT interval (QT(c)SS) 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 QT(c)SS were all <10 ms. There were no outlying QT(c)SS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT(c)SS (>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.
  
  
  CONCLUSIONS
  Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.
authors.affiliation: CoreLab Partners Inc, London, UK.
authors.forename: Boaz
authors.initials: B
authors.lastname: Mendzelevski
authors.forename: Jannie
authors.initials: J
authors.lastname: Ausma
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Chanter
authors.forename: Patricia
authors.initials: P
authors.lastname: Robinson
authors.forename: Rene
authors.initials: R
authors.lastname: Kerstens
authors.forename: Lieve
authors.initials: L
authors.lastname: Vandeplassche
authors.forename: John
authors.initials: J
authors.lastname: Camm
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001572:Benzofurans / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058828:Serotonin 5-HT4 Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001572:Benzofurans; D058828:Serotonin 5-HT4 Receptor Agonists; C406662:prucalopride