Absence of QTc prolongation in a thorough QT study with imeglimin, a first in class oral agent for type 2 diabetes mellitus

Abstract

Purpose

Imeglimin is the first in a new class of oral antidiabetic agents, the glimins, currently in development to improve glycemic control in patients with type 2 diabetes mellitus. A thorough QT study was conducted to establish electrophysiological effects of therapeutic and supratherapeutic doses of imeglimin on cardiac repolarization.

Methods

In this randomized, double-blind, four-period, placebo and active controlled crossover study, healthy subjects were administered a single dose of imeglimin 2250 mg, imeglimin 6000 mg, moxifloxacin 400 mg, and placebo. 12-Lead Holter ECGs were recorded from 1 h before dosing until at least 24 h after each dose. This study was performed at a single-center inpatient clinical pharmacology unit.

Results

The upper bound of the two-sided 90% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTc intervals (ΔΔQTcF) did not exceed the regulatory threshold of 10 ms in any of the imeglimin dose groups. There were no QTcF values above 500 ms nor changes from pre-dose in QTcF above 60 ms in the imeglimin groups. Imeglimin did not exert a relevant effect on heart rate and PR or QRS intervals. Assay sensitivity was demonstrated by the effect of moxifloxacin 400 mg, with a lower bound two-sided 90% confidence interval for ΔΔQTcF of 10.6 ms.

Conclusion

This thorough QT study demonstrated that therapeutic and supratherapeutic exposures of imeglimin did not induce a QT/QTc prolongation with a strong confidence as evidenced by the assay sensitivity.

Trial registration number/date

NCT02924337/ October 5, 2016

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Funding

This study was sponsored by Poxel. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.

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Authors

Contributions

JD contributed to the interpretation of data and drafted and edited the report. SP, MF, SB, PV, and PF contributed to the study design and interpretation of data and reviewed the report. All authors read the manuscript critically and approved the submitted version.

Corresponding author

Correspondence to Julie Dubourg.

Ethics declarations

This clinical trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines [15] and was approved by an Independent Ethics Committee/Institutional Review Board (Office for Research Ethics Committees Northern Ireland - ORECNI). All participants provided written informed consent prior to any trial-related activities.

Conflict of interest

JD, SP, SB, and PF are employees of Poxel. MF is an employee of Phinc development. PV is an employee of Banook Group.

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Dubourg, J., Perrimond-Dauchy, S., Felices, M. et al. Absence of QTc prolongation in a thorough QT study with imeglimin, a first in class oral agent for type 2 diabetes mellitus. Eur J Clin Pharmacol (2020). https://doi.org/10.1007/s00228-020-02929-6

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Keywords

  • Imeglimin
  • QT interval
  • Thorough QT study
  • Type 2 diabetes mellitus