Study to Evaluate the QT / QTc Interval Prolongation Potential of Vericiguat

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Vericiguat (BAY1021189)
* Drug: Moxifloxacin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment 1<br>Treatment sequences: A*-B-C-D | Drug: Vericiguat (BAY1021189)<br>* A : 2.5 mg vericiguat A*: 2.5 mg vericiguat B : 5 mg vericiguat C : 10 mg vericiguat C*: 10 mg vericiguat<br>Drug: Moxifloxacin<br>* D: 400 mg moxifloxacin<br>Drug: Placebo<br>* A : vericiguat placebo 10 mg A*: vericiguat placebo 10 mg + moxifloxacin placebo B : vericiguat placebo 10 mg C : vericiguat placebo 2.5 mg C*: vericiguat placebo 2.5 mg + moxifloxacin placebo D : vericiguat placebo 2.5 mg + vericiguat placebo 10 mg<br>|
| Experimental: Treatment 2<br>Treatment sequences: D-A-B-C* | Drug: Vericiguat (BAY1021189)<br>* A : 2.5 mg vericiguat A*: 2.5 mg vericiguat B : 5 mg vericiguat C : 10 mg vericiguat C*: 10 mg vericiguat<br>Drug: Moxifloxacin<br>* D: 400 mg moxifloxacin<br>Drug: Placebo<br>* A : vericiguat placebo 10 mg A*: vericiguat placebo 10 mg + moxifloxacin placebo B : vericiguat placebo 10 mg C : vericiguat placebo 2.5 mg C*: vericiguat placebo 2.5 mg + moxifloxacin placebo D : vericiguat placebo 2.5 mg + vericiguat placebo 10 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-matched placebo-corrected change from baseline of the QT interval corrected according to Fridericia (QTcF) after 10 mg vericiguat at steady state. |  | Baseline, day 56 (steady state 10 mg) of vericiguat treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-matched placebo-corrected change from baseline of QTcF after 1st dose of 2.5 mg vericiguat |  | Baseline and day 1 of vericiguat treatment | 
| Time-matched placebo-corrected change from baseline of QTcF after 1st dose of 5 mg vericiguat |  | Baseline and day 15 (+/- 3 days) of vericiguat treatment | 
| Time-matched placebo-corrected change from baseline of QTcF after 1st dose of 10 mg vericiguat |  | Baseline and day 29 (+/- 3 days) of vericiguat treatment | 
| Time-matched placebo-corrected change from baseline of QTcF after 2.5 mg vericiguat at steady state |  | Baseline and day 14 (+/- 3 days) of vericiguat treatment (steady state 2.5 mg) | 
| Time-matched placebo-corrected change from baseline of QTcF after 5 mg vericiguat at steady state |  | Baseline and day 28 (+/- 3 days) of vericiguat treatment (steady state 5 mg) | 
| Time-matched placebo-corrected change from baseline of QTcF after single dose of moxifloxacin |  | Baseline and day 8 of the moxifloxacin treatment period | 
| Maximum concentration of vericiguat in plasma after first dose (Cmax) |  | On profile day 1; Timeframe: 0 - 5 hours after dosing | 
| Time to maximum concentration of vericiguat in plasma after first dose (tmax) |  | On profile day 1; Timeframe: 0 - 5 hours after dosing | 
| Maximum concentration of vericiguat in plasma after multiple doses (Cmax, md) |  | On profile days: 8, 14, 15, 28, 29, 42, 43, 50 and 56; Timeframe: 0 - 5 hours after dosing | 
| Time to maximum concentration of vericiguat in plasma after multiple doses (tmax, md) |  | On profile days: 1, 8, 14, 15, 28, 29, 42, 43, 50 and 56; Timeframe: 0 - 5 hours after dosing | 
| Maximum concentration of moxifloxacin in plasma after single dose (Cmax) |  | On moxifloxacin profile days (day 8 and 50); Timeframe: 0 - 5 hours after dosing | 
| Time to maximum concentration of moxifloxacin in plasma after single dose (tmax) |  | On moxifloxacin profile days (day 8 and 50); Timeframe: 0 - 5 hours after dosing | 
| Number of subjects with treatment-emergent adverse events (TEAEs) |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vericiguat, Stable CAD, QT/QTc