Clinical trial NCT03504982: Study to Evaluate the QT / QTc Interval Prolongation Potential of Vericiguat
Official title: Study to Clinically Evaluate the QT/QTc Interval Prolongation Potential of Vericiguat in Patients With Stable Coronary Artery Disease in a 2-arm, Placebo-controlled, Randomized, Double-blind, Double-dummy Design Including a Vericiguat Multiple-dose Part With Fixed up Titration Periods and Moxifloxacin as Positive Control (for Assay Sensitivity Testing, Nested Into the Placebo Treatment)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Coronary Artery Disease
Keywords: Vericiguat
Stable CAD
QT/QTc
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2018-04-20
Enrollment: 74
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The primary objective of this study was to investigate whether there is a clinically meaningful effect on QTc change from baseline relative to placebo after administration of 10 mg at steady state in patients with stable CAD (coronary artery disease).


Eligibility criteria: Inclusion Criteria:

* Patients with stable CAD (coronary artery disease) defined by:

  * clinically stable for at least 3 months
  * coronary artery stenosis in any of the 3 main coronary vessels
  * or history of myocardial infarction
* Sinus rhythm at screening
* Interpretable echocardiographic images
* Age: 30 to 80 years
* Body mass index (BMI): above/equal 18.0 and below/equal 36.0 kg/m²

Exclusion Criteria:

* Ejection fraction (EF) below 30% at screening
* Progressive angina with symptoms of worsening of angina within the \<3 month
* History of recent myocardial infarction or unstable Angina
* Documented current relevant coronary stenosis ≥90% in any of the main 3 coronary vessels without bypass graft
* Symptomatic carotid stenosis, or transient ischemic attack or stroke within 3 months or patients with stroke at more than 3 months
* Insulin dependent diabetes mellitus
* Clinically significant and persisting cardiac ischemia
* Atrial fibrillation, pacemaker, defibrillator, second and third degree atrial-ventricular (AV) block
* Known clinically relevant ventricular arrhythmias
* Clinically relevant heart failure with reduced left ventricular ejection fraction
* Significant valvular heart disease with moderate or severe aortic stenosis or any other significant stenosis; any other moderate or severe valvular failures
* Valve replacement
* Hypertrophic obstructive cardiomyopathy (HOCM)
* Previous or imminent cardiac transplantation
* Known long QT syndrome or prolongation of the QT interval with ongoing proarrhythmic conditions
* Co-medication with drugs known to have QT prolonging effect
* Intolerance of fluoroquinolones, including moxifloxacin
* History of serious adverse effects e.g. tendinitis and tendon rupture, arthralgia and effects on the peripheral and central nervous system while taking fluoroquinolones including moxifloxacin
* History of tendon diseases or tendon injury caused by quinolones
* Treatment with fluoroquinolones, including moxifloxacin during the last 2 weeks
* Treatment with organic nitrates during the last 3 months
* Treatment with riociguat during the last 3 months
* Treatment with phosphodiesterase (PDE)-5 inhibitors during the last 14 days
* Systolic blood pressure below 110 or above 160 mmHg at screening visit
* Diastolic blood pressure below 50 or above 100 mmHg at screening visit
* Heart rate below 50 or above 100 beats/min (taken from ECG measurement) at first screening visit
* Estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73m\*2

Primary outcomes:
measure: Time-matched placebo-corrected change from baseline of the QT interval corrected according to Fridericia (QTcF) after 10 mg vericiguat at steady state.
timeFrame: Baseline, day 56 (steady state 10 mg) of vericiguat treatment
Secondary outcomes:
measure: Time-matched placebo-corrected change from baseline of QTcF after 1st dose of 2.5 mg vericiguat
timeFrame: Baseline and day 1 of vericiguat treatment
measure: Time-matched placebo-corrected change from baseline of QTcF after 1st dose of 5 mg vericiguat
timeFrame: Baseline and day 15 (+/- 3 days) of vericiguat treatment
measure: Time-matched placebo-corrected change from baseline of QTcF after 1st dose of 10 mg vericiguat
timeFrame: Baseline and day 29 (+/- 3 days) of vericiguat treatment
measure: Time-matched placebo-corrected change from baseline of QTcF after 2.5 mg vericiguat at steady state
timeFrame: Baseline and day 14 (+/- 3 days) of vericiguat treatment (steady state 2.5 mg)
measure: Time-matched placebo-corrected change from baseline of QTcF after 5 mg vericiguat at steady state
timeFrame: Baseline and day 28 (+/- 3 days) of vericiguat treatment (steady state 5 mg)
measure: Time-matched placebo-corrected change from baseline of QTcF after single dose of moxifloxacin
timeFrame: Baseline and day 8 of the moxifloxacin treatment period
measure: Maximum concentration of vericiguat in plasma after first dose (Cmax)
timeFrame: On profile day 1; Timeframe: 0 - 5 hours after dosing
measure: Time to maximum concentration of vericiguat in plasma after first dose (tmax)
timeFrame: On profile day 1; Timeframe: 0 - 5 hours after dosing
measure: Maximum concentration of vericiguat in plasma after multiple doses (Cmax, md)
timeFrame: On profile days: 8, 14, 15, 28, 29, 42, 43, 50 and 56; Timeframe: 0 - 5 hours after dosing
measure: Time to maximum concentration of vericiguat in plasma after multiple doses (tmax, md)
timeFrame: On profile days: 1, 8, 14, 15, 28, 29, 42, 43, 50 and 56; Timeframe: 0 - 5 hours after dosing
measure: Maximum concentration of moxifloxacin in plasma after single dose (Cmax)
timeFrame: On moxifloxacin profile days (day 8 and 50); Timeframe: 0 - 5 hours after dosing
measure: Time to maximum concentration of moxifloxacin in plasma after single dose (tmax)
timeFrame: On moxifloxacin profile days (day 8 and 50); Timeframe: 0 - 5 hours after dosing
measure: Number of subjects with treatment-emergent adverse events (TEAEs)
timeFrame: 12 months
Other outcomes:
Locations:
city: Bad Krozingen
country: Germany
facility: Universitätsherzzentrum Freiburg - Bad Krozingen
state: Baden-Württemberg
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Bonn
country: Germany
facility: Medizinische Einrichtungen der Universität Bonn
state: Nordrhein-Westfalen
city: Erfurt
country: Germany
facility: SocraTec R&D Clinical Ward
state: Thüringen
city: Berlin
country: Germany
facility: Charité Campus Virchow-Klinikum (CVK)
city: Berlin
country: Germany
facility: PAREXEL GmbH
city: Chisinau
country: Moldova, Republic of
facility: IMSP Republican Clinical Hospital
city: Leiden
country: Netherlands
facility: Center for Human Drug Research
Study officials:
References: