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Clinical Trial
. 2023 Mar;23(2):145-155.
doi: 10.1007/s40256-022-00557-2. Epub 2023 Jan 12.

Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes

Michael Böttcher  1 , Hans-Dirk Düngen  2 , Vasile Corcea  3 , Frank Donath  4 , Rainard Fuhr  5 , Pim Gal  6   7 , Gerd Mikus  8 , Dietmar Trenk  9 , Martin Coenen  10 , Philippe Vieira Pires  11 , Claudia Maschke  12 , Antonios Othon Aliprantis  13   14 , Nina Besche  15 , Corina Becker  16
Affiliations
Clinical Trial

Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes

Michael Böttcher et al. Am J Cardiovasc Drugs. 2023 Mar.

Abstract

Background: Vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event.

Objective: To investigate the effects of vericiguat on QT interval in patients with chronic coronary syndromes (CCS).

Methods: This was a randomized, phase Ib, placebo-controlled, double-blind, double-dummy, multicenter study. Vericiguat once daily was up-titrated from 2.5 mg to 5 mg and then to 10 mg (treatments A, B, and C) at 14-day intervals. Positive control was moxifloxacin 400 mg (single dose on day 8 or day 50; placebo on other days [treatment D]). We evaluated the placebo-adjusted change from baseline of the Frederica-corrected QTc interval (QTcF), pharmacokinetics, safety, and tolerability of vericiguat.

Results: In total, 74 patients with CCS, with mean (standard deviation) age 63.4 (8.0) years, were included and 72 patients completed the study. At each timepoint up to 7 h after administration, mean placebo-corrected change in QTcF from baseline was < 6 ms and the upper limit of the two-sided 90% confidence interval of the mean was below the 10-ms threshold for clinical relevance. Moxifloxacin confirmed the assay sensitivity. Median time of maximum concentration of vericiguat was 4.5 h post-dose. The adverse event profile of vericiguat was consistent with its mechanism of action, and the findings did not indicate any safety concerns.

Conclusions: As part of an integrative risk assessment, this study demonstrated no clinically relevant corrected QT prolongation with vericiguat 10 mg once daily at steady state.

Clinical trial registration: ClinicalTrials.gov number, NCT03504982.

Plain language summary

Vericiguat is approved for treating worsening heart failure with reduced ejection fraction. As part of the safety evaluation of vericiguat, this study assessed its effect on the QT interval of the electrocardiogram. An electrocardiogram measures electrical activity of the heart. The QT interval is the time from the start of the Q wave to the end of the T wave. A longer than normal QT interval indicates an increased chance for abnormal heart rhythms. Usually, a QT study is conducted at high doses in healthy volunteers. Previous studies indicated that high doses of vericiguat may cause increased changes in blood pressure in healthy volunteers. Therefore, this study was performed in patients at a normal therapeutic dose. Patients with chronic coronary syndromes were enrolled rather than patients with heart failure with reduced ejection fraction, because they have fewer electrocardiogram abnormalities. The starting dose of vericiguat was 2.5 mg once daily, and the dose was increased to 5 mg and then to 10 mg at 14-day intervals. Placebo was tested for comparison and moxifloxacin (400 mg), a drug known to increase the QT interval, was tested to confirm that the study could detect a change in the QT interval. An increase in the QT interval of more than 10 ms was considered clinically relevant. Of 74 patients included, 72 completed the study. At each timepoint (up to 7 h after dosing), the difference between the QT change for vericiguat and placebo was less than 10 ms; therefore, vericiguat does not prolong the QT interval to a clinically relevant extent.

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Conflict of interest statement

Corina Becker and Claudia Maschke are employees of Bayer AG. Philippe Vieira Pires was previously an employee of Bayer AG at the time of the study. Michael Böttcher is a former employee of Bayer AG, and has received within the last 36 months, salary, pension, and payment for writing and reviewing vericiguat manuscripts from Bayer AG and for lectures, exercises, and awarding and supporting bachelor and master theses. Dietmar Trenk received within the last 36 months through to the foreseeable future consulting fees/payment for lectures including service on speakers’ bureaus by Amgen, AstraZeneca, Atriva, Bayer, Berlin Chemie, Bristol-Myers Squibb, Böhringer Ingelheim, Daiichi Sankyo, Ferrer, Pfizer, and Sanofi. Hans-Dirk Düngen has received institutional payment as an investigator and personal honoraria for advisory boards from Bayer. Antonios Othon Aliprantis was an employee of Merck & Co., Inc., Rahway, NJ, USA, at the time the study was conducted and held stock in the company. Rainard Fuhr is an employee of Parexel, the Clinical Research Organization that received funding from Bayer AG for the conduct of the study. Nina Besche is an employee of Chrestos Concept GmbH & Co. KG, which received funding for this analysis from Bayer AG. Martin Coenen received travel costs from Bayer AG to attend an investigator meeting related to the conduct of the study. Frank Donath, Pim Gal, Gerd Mikus, and Vasile Corcea declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Corrected QT study design. Blinding concept: vericiguat 2.5-mg and 5.0-mg tablets were the same size and shape; therefore, the same matching placebo tablet was administered. The vericiguat 10-mg tablet was larger in size than the 2.5-mg and 5.0-mg tablets; thus, a different matching placebo tablet was administered. Therefore, two tablets (one small and one larger) containing placebo or vericiguat were always administered to maintain blinding to the respective sequence. *Moxifloxacin placebo was administered on day 8 or day 50
Fig. 2
Fig. 2
Geometric mean (standard deviation) for concentration of a vericiguat in plasma after administration of first and multiple doses of vericiguat 10 mg and b moxifloxacin (pharmacokinetic analysis set, N = 73). *Denotes the timepoints of the electrocardiogram recordings
See this image and copyright information in PMC

References

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