title: Thorough QT study of the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor, on cardiac repolarization and conduction in healthy volunteers.
abstract: OBJECTIVE
  This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction.
  
  
  METHODS
  Healthy volunteers (n = 101) were randomized (1:1:1:1 ratio) to vildagliptin 100 or 400 mg, moxifloxacin 400 mg (active control), or placebo once daily for 5 days. Electrocardiograms were recorded at baseline and day 5 for 24 hours post-dose. Placebo-adjusted mean change from baseline in QT interval, heart-rate-corrected QT intervals by Fridericia's (QTcF) or Bazett's (QTcB) formula, and PR and QRS intervals were compared at each time-point (time-matched analysis) and for values averaged across the dosing period (time-averaged analysis).
  
  
  RESULTS
  For time-matched analysis, mean changes in QTcF with vildagliptin were below predefined limits for QTc prolongation (mean increase <5 ms; upper 90% confidence interval [CI] < 10 ms), except for vildagliptin 100 mg at 1 and 8 hours post-dose (upper 90% CI > 10 ms). With moxifloxacin, significant QTcF prolongation occurred at most time-points, demonstrating assay sensitivity. No vildagliptin- or placebo-treated volunteer had QTcF > 450 ms. Incidences of QTcF increases ≥30 ms with vildagliptin (100 and 400 mg) and placebo were similar (4-8%) and were much lower than with moxifloxacin (39%). No QTcF increase ≥60 ms was observed with vildagliptin or placebo (versus one with moxifloxacin). Time-averaged, time-matched, and categorical analyses of QT/QTcF/QTcB showed similar results. Drug exposure analysis showed no correlation between vildagliptin plasma levels and QTc changes. Vildagliptin had no effect on PR or QRS intervals. Although this study, completed before publication of current ICH E14 guidelines, was underpowered for time-matched analysis, the results are consistent with lack of effect of vildagliptin on QTc.
  
  
  CONCLUSIONS
  Vildagliptin did not prolong QT interval or affect cardiac conduction at the highest daily therapeutic dose or a fourfold higher dose.
authors: Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA.
authors: Y-L
authors: YL
authors: He
authors: Y
authors: Y
authors: Zhang
authors: D
authors: D
authors: Serra
authors: Y
authors: Y
authors: Wang
authors: M
authors: M
authors: Ligueros-Saylan
authors: W P
authors: WP
authors: Dole