Levosimendan Versus Placebo Before Tricuspid Valve Surgery in Patients With Right Ventricular Dysfunction (LEONARD)

A Prospective, multicenter, randomized (two arms, parallel groups); double-blind, placebo-controlled in order to assess the ability of preoperative levosimendan to prevent post-operative low cardiac output in high-risk patients referred to cardiac surgery for correcting functional tricuspid regurgitation. The primary end point is a composite element that includes peri-operative mortality and low cardiac output syndrome at day-90: 1) catecholamine infusion persisting beyond 48 hours after cardiac surgery, 2) the need for circulatory mechanical assist devices in the postoperative period, 3) or the need for renal replacement therapy at any time during intensive care unit stay. If a patient had at least 1 of these criteria, he or she was considered as meeting the primary end point.The secondary end points were 1) each component of the primary end point, and 2) the study drug safety defined as refractory hypotension.

Study Overview

• Status: Recruiting
• Conditions: Patients Referred for an Isolated or a Combined Surgical Correction of Functional Moderate to Severe Tricuspid
• Intervention / Treatment: Drug: Levosimendan; Drug: PLACEBO

Detailed Description

Patients referred for an isolated or a combined surgical correction of functional moderate to severe tricuspid are randomized in 2 arms, the levosimendan group or to the placebo group.

In the experimental group, levosimendan is administered as a continuous infusion over a 24-hour period at the rate of 0.2μg/kg/min, with no bolus administration. The infusion will begin 24H to 48H before anesthetic induction.

In the comparator group, Placebo (isotonic sodium) administered as a continuous infusion over a 24-hour period at the rate of 0.2μg/kg/min, with no bolus administration. The infusion will begin <48H before anesthetic induction

• Study Type: Interventional
• Enrollment (Anticipated): 230
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pascal LIM, MD, PhD; Phone Number: 33 (0)1.49.81.45.84; Email: pascal.lim@aphp.fr
• Study Contact Backup: Name: Akim SOUAG; Phone Number: 33 (0)1 44 84 17 15; Email: akim.souag@aphp.fr

Study Locations

• France
  • Créteil, France, 94000
    • Recruiting
    • Assistance Publique Hôpitaux de Paris-Hôpital Henri Mondor
    • Contact: Pascal LIM, Pr; Phone Number: 33 0033-149812111; Email: lim.pascal.hmn@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients referred for an isolated or a combined surgical correction of functional moderate to severe tricuspid regurgitation [effective regurgitant orifice (ERO)>20mm², or systolic hepatic vein flow blunting or reversal]
• Written signed informed consent
• Affiliation to the French health care system (Sécurité Sociale)

Exclusion Criteria:

• Age < 18 years
• Severe organic renal dysfunction defined by creatinine clearance <30mL/min
• Recent endocarditis (<3 months)
• Recent myocardial infarction (<3 months)
• Tricuspid valve perforation or prolapse
• Cardiogenic shock requiring dobutamine support or cardiac assistance
• Severe liver injury (CHILD C)
• Left ventricular obstruction
• Allergy to levosimedan
• Current participation in other investigational drug or device studies or being in the exclusion period at the end of a previous study involving human participants, if applicable
• Pregnant or breastfeeding women
• Females of childbearing potential without effective method of birth control
• Patient on AME (state medical aid) unless exemption from affiliation
• Hypotension with SBP<90mmHg
• Severe tachycardia
• History of torsade de pointe

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LEVOSIMEDAN; Levosimendan administered as a continuous infusion over a 24-hour period at the rate of 0.2μg/kg/min, with no bolus administration. The infusion will begin 24H to 48H before anesthetic induction.	Drug: Levosimendan; Levosimendan administered as a continuous infusion over a 24-hour period at the rate of 0.2μg/kg/min, with no bolus administration. The infusion will begin 24H to 48H before anesthetic induction.; Other Names: Experimental arm
Placebo Comparator: PLACEBO; Placebo (isotonic sodium) administered as a continuous infusion over a 24-hour period at the rate of 0.2μg/kg/min, with no bolus administration. The infusion will begin <48H before anesthetic induction.	Drug: PLACEBO; Placebo (isotonic sodium) administered as a continuous infusion over a 24-hour period at the rate of 0.2μg/kg/min, with no bolus administration. The infusion will begin <48H before anesthetic induction.; Other Names: Control arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the effects of CTAC on ventilation/perfusion ratios during a moderate to severe ARDS	The primary end point is a composite element that includes peri-operative mortality and low cardiac output syndrome at day-90: 1) catecholamine infusion persisting beyond 48 hours after cardiac surgery, 2) the need for circulatory mechanical assist devices in the postoperative period, 3) or the need for renal replacement therapy at any time during intensive care unit stay. If a patient had at least 1 of these criteria, he or she was considered as meeting the primary end point.	day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
incidence of Refractory Hypotension (Drug safety)	the study drug safety is defined as a refractory hypotension.	day 90
Number of catecholamine infusion	persistence of infusion beyond 48 hours after cardiac surgery	during 90 days
Number of circulatory mechanical assist devices	the need of circulatory mechanical assist devices in the postoperative period	during 90 days
Number of renal replacement therapy	Need for renal replacement therapy at any time during intensive care unit stay	during 90 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2023
• Primary Completion (Anticipated): January 23, 2025
• Study Completion (Anticipated): January 23, 2025

Study Registration Dates

• First Submitted: February 9, 2022
• First Submitted That Met QC Criteria: February 9, 2022
• First Posted (Actual): February 10, 2022

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Ventricular Dysfunction; Ventricular Dysfunction, Right; 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: APHP200072

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