A Phase 1, Randomized, Placebo- and Active-Controlled Crossover Study to Determine the Effect of Single-Dose Ertugliflozin on QTc Interval in Healthy Volunteers

Clin Pharmacol Drug Dev. 2018 Jun;7(5):513-523. doi: 10.1002/cpdd.421. Epub 2018 Jan 18.

Abstract

Ertugliflozin, a selective sodium-glucose cotransporter-2 inhibitor, is being developed for the treatment of type 2 diabetes mellitus. This randomized, 6-sequence, 3-period crossover study assessed the effect of ertugliflozin (100 mg; supratherapeutic dose) vs placebo and moxifloxacin (400 mg; positive control) on the QT interval corrected for heart rate (QTc) in 42 male or female healthy subjects. Triplicate electrocardiograms were performed predose and serially over 48 hours postdose in each treatment period. The maximum observed least-squares mean (90% CI) difference in QTc using the Fridericia correction (QTcF) between ertugliflozin and placebo was 2.99 (1.68, 4.30) milliseconds, 24 hours postdose, below the 5-millisecond threshold of potential clinical concern. The upper limits of the 2-sided 90% CI were less than 10 milliseconds at all postdose time points. The lower 90% CIs for the least-squares mean QTcF difference between moxifloxacin and placebo were greater than 5 milliseconds at the preselected time points of 2, 3, and 4 hours postdose, establishing study sensitivity. The majority of adverse events were mild in severity. In healthy volunteers, at a supratherapeutic dose of 100 mg, ertugliflozin was not associated with QTc interval prolongation.

Keywords: QTc interval; cardiovascular; diabetes; ertugliflozin; safety.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cross-Over Studies
  • Electrocardiography
  • Female
  • Healthy Volunteers
  • Heart Rate / drug effects*
  • Humans
  • Male
  • Middle Aged
  • Moxifloxacin / administration & dosage
  • Moxifloxacin / adverse effects
  • Moxifloxacin / pharmacology*
  • Sample Size
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology*
  • Young Adult

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Sodium-Glucose Transporter 2 Inhibitors
  • ertugliflozin
  • Moxifloxacin