Pharmacokinetics of Inhaled Levosimendan (Symbiov)

Determination of biological availability, time-to-peak and elimination half-life of inhaled levosimendan by administration of an inhaled- and intravenous dose of levosimendan.

Study Overview

• Status: Recruiting
• Conditions: Left Ventricular Dysfunction
• Intervention / Treatment: Drug: Levosimendan 2.5 milligram/milliliter Injectable Solutiondose Inhaled; Drug: Levosimendan 2.5 milligram/milliliter Injectable Solutiondose Intravenous

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Matthias Raes, MD; Phone Number: 024749872; Email: matthias.raes@uzbrussel.be
• Study Contact Backup: Name: Marie-Claire Van Malderen, SC; Phone Number: 024763110; Email: marieclaire.vanmalderen@uzbrussel.be

Study Locations

• Belgium
  • Brussel, Belgium, 1090
    • Recruiting
    • UZ Brussel
    • Contact: Matthias Raes, MD; Phone Number: 024749872; Email: matthias.raes@uzbrussel.be
    • Contact: Marie-Claire Van Malderen, SC; Phone Number: 024763110; Email: marieclaire.vanmalderen@uzbrussel.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject >18 years of age
• Scheduled for elective coronary artery bypass grafting (CABG)
• Provided written informed consent
• Impaired left ventricular function (LVEF <40%)

Exclusion Criteria:

• Known allergy for levosimendan or solutes
• Persistent angina, defined as Canadian Cardiovascular Society score > I
• History of valvular intervention or uncorrected primary stenotic valve disease
• Uncorrected thyroid disease
• Infiltrative, hypertrophic or restrictive cardiomyopathy
• Pericardial disease
• Active myocarditis
• Chronic obstructive pulmonary disease requiring long-term treatment with β-agonists, Theophylline, or corticosteroids (FEV1 < 80%; Tiffeneau-index <0.7)
• History of serious arrhythmias, defined as a history of ventricular tachycardia or fibrillation other than that occurring within 24 hours after acute myocardial infarction (MI)
• resting heart rate > 115 bpm for at least 10 minutes on repeated measurements
• Supine systolic blood pressure < 85 mm Hg or >200 mm Hg
• patients with implanted pacemaker/defibrillator or cardiac resynchronisation therapy (CRT-device)
• primary renal or hepatic impairment (creatinine > 2.5 mg/dL or aspartate aminotransferase/alanine aminotransferase >2 times upper limit of normal and/or increased level of bilirubin (> 2 times the upper limit of normal and increase of international normalised ratio (INR) above the upper limit of normal, respectively)
• Uncorrected hypokalemia or hyperkalemia (potassium <3.5 mmol/L or >5.5 mmol/L)
• Uncorrected hypomagnesemia (magnesium <0.65mmol/L)
• Treatment with another investigational agent within 30 days before study entry
• Intubated and mechanically ventilated at the time of study entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levosimendan inhalation; Levosimendan 12µg/kg inhalation over 10 minutes, once	Drug: Levosimendan 2.5 milligram/milliliter Injectable Solutiondose Inhaled; Each patient will receive 12µg/kg of levosimendan by inhalation over 10 min. During 10h following inhaled dose, plasma concentrations will be measured.
Active Comparator: Levosimendan intravenous; Levosimendan 12µg/kg intravenous over 10 minutes, once	Drug: Levosimendan 2.5 milligram/milliliter Injectable Solutiondose Intravenous; Each patient will receive 12µg/kg of levosimendan by intravenous (IV) administration over 10 min and at the same timepoints plasma samples will be measured

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bioavailability of inhaled levosimendan	Assessment of bioavailability of inhaled levosimendan in spontaneous breathing patients,	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Time-to-peak of inhaled levosimendan	Assessment of time-to-peak plasma concentration of inhaled levosimendan in spontaneous breathing patients	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Elimination half-life of inhaled levosimenan	Assessment of elimination half-life of inhaled levosimendan in spontaneous breathing patients	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of inhaled levosimendan on MAP	Assessment of effect of inhaled levosimendan on invasively-measured hemodynamic parameter mean arterial blood pressure (MAP)	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Effect of inhaled levosimendan on TVR	Assessment of effect of inhaled levosimendan on invasively-measured hemodynamic parameter total vascular resistance (TVR)	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Effect of inhaled levosimendan on CO	Assessment of effect of inhaled levosimendan on invasively-measured hemodynamic parameter Cardiac Output (CO)	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Effect of inhaled levosimendan on LVOT VTI	Assessment of effect of inhaled levosimendan on echocardiography-derived parameter left -ventricular-outflow-tract (LVOT) velocity-time-integral (VTI) as marker for cardiac output	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Effect of inhaled levosimendan on FAC of the right vetricle	Assessment of effect of inhaled levosimendan on echocardiography-derived parameter Fractional-Area-Change (FAC) of the right ventricle as marker of right ventricular function	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Effect of inhaled levosimendan on S'	Assessment of effect of inhaled levosimendan on echocardiography-derived parameter S' wave velocity as marker of right ventricular function	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation
Effect of inhaled levosimendan on SPAP	Assessment of effect of inhaled levosimendan on echocardiography-derived parameter (SPAP) systolic pulmonary artery pressure	Baseline, plasma samples at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1hour 30 minutes, 2 hours , 3 hours , 6 hours, 10 hours after end of infusion/inhalation

Collaborators and Investigators

• Sponsor: Universitair Ziekenhuis Brussel
• Investigators: Principal Investigator: Matthias Raes, MD, Universitair Ziekenhuis Brussel

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: January 9, 2024
• First Submitted That Met QC Criteria: April 23, 2024
• First Posted (Actual): April 29, 2024

Study Record Updates

• Last Update Posted (Estimated): May 20, 2024
• Last Update Submitted That Met QC Criteria: May 17, 2024
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: levosimendan; inhalation; pharmakokinetic
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Ventricular Dysfunction; Ventricular Dysfunction, Left; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: 2022SIMBIOV

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No