title: QT effect of semagacestat at therapeutic and supratherapeutic doses.
abstract: OBJECTIVE
  This thorough QT/ QT interval corrected for heart rate (QTc) study was designed to assess the potential of semagacestat, a functional gamma-secretase inhibitor, to delay cardiac repolarization.
  
  
  METHODS
  In this Phase I, single-dose, randomized, 4-period crossover study, semagacestat was compared with placebo in 54 healthy male and female subjects between the ages of 19 and 63 years, inclusive. Each study period included single oral-dose administrations of semagacestat 140 mg, semagacestat 280 mg, moxifloxacin 400 mg, or placebo. Study subjects and the investigator were blinded to the identity of semagacestat and placebo; however, moxifloxacin was administered as open-label. Moxifloxacin was compared with placebo for assay sensitivity analysis. Pharmacokinetic parameters were also assessed.
  
  
  RESULTS
  For each QTc, the upper bound of the 2-sided 90% confidence interval (CI) for the least squares mean difference between semagacestat (at both the 140- and 280-mg dose levels) and placebo was < 10 msec at all time points, and thus, within the limits set for clinical relevance in regulatory guidelines.
  
  
  CONCLUSIONS
  The results of this study indicate that single doses of 140 and 280 mg semagacestat did not prolong QTc to a clinically significant degree.
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. zhangweiwz@lilly.com
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Mosun
authors.initials: M
authors.lastname: Ayan-Oshodi
authors.forename: Brian A
authors.initials: BA
authors.lastname: Willis
authors.forename: William
authors.initials: W
authors.lastname: Annes
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hall
authors.forename: Joseph
authors.initials: J
authors.lastname: Chiesa
authors.forename: Mary
authors.initials: M
authors.lastname: Seger
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology; D001372:Aza Compounds / Q000008:administration & dosage / Q000009:adverse effects; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004562:Electrocardiography; D004739:England; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D001372:Aza Compounds; D001381:Azepines; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D011804:Quinolines; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine; D000077266:Moxifloxacin