Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery On Cardiopulmonary Bypass

Phase 3

Completed

• Conditions: Coronary Artery Bypass Grafting; Mitral Valve Surgery; Low Cardiac Output Syndrome
• Interventions: Drug: Levosimendan; Drug: Placebo

• Registration Number: NCT02025621
• Lead Sponsor: Tenax Therapeutics, Inc.

Brief Summary

A study to evaluate levosimendan compared with placebo in reducing the composite event rate of all-cause death, perioperative MI, need for new dialysis, or use of mechanical assist (IABP, LVAD or ECMO) in subjects with reduced ejection fraction undergoing cardiac surgery on cardiopulmonary bypass (CPB).

Detailed Description

This study is being done to evaluate the efficacy of levosimendan compared with placebo in reducing the co-primary endpoints of 30-day composite of all-cause death or use of mechanical assist device (IABP, LVAD or ECMO) or the composite event rate of all-cause death, perioperative MI, need for dialysis, or use of mechanical assist (IABP, LVAD or ECMO) in subjects with reduced ejection fraction undergoing cardiac surgery on CPB.

Study Timeline

• Study First Submitted: 2013-12-18
• Study First Submitted QC: 2013-12-30
• Study First Posted: 2014-01-01
• Study Start: 2014-07
• Primary Completion: 2016-11
• Study Completion: 2016-11
• Results First Submitted: 2017-11-02
• Results First Submitted QC: 2018-04-25
• Status Verified: 2018-05
• Results First Posted: 2018-05-22
• Last Update Submitted: 2018-05-22
• Last Update Posted: 2018-06-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 882

Inclusion Criteria

• Documented LVEF ≤35% measured by ventriculogram, echocardiogram (ECHO), nuclear scan, or MRI within 60 days before surgery.
• Scheduled or urgent 1) CABG surgery, 2)CABG with aortic valve surgery, 3) CABG with mitral valve surgery, or 4) mitral valve surgery with or without other valves
• Surgery will employ CPB pump
• Signed (by the subjects or their legally acceptable representatives) informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study

Exclusion Criteria

• Restrictive or obstructive cardiomyopathy, constrictive pericarditis, restrictive pericarditis, pericardial tamponade, or other conditions in which cardiac output is dependent on venous return.
• Evidence of systemic bacterial, systemic fungal, or viral infection within 72 hours before surgery.
• Dialysis at randomization (either hemodialysis, peritoneal dialysis, continuous venovenous hemofiltration, or ultrafiltration).
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2.
• Weight ≥ 170 kg.
• Patients whose SBP cannot be managed to ensure SBP > 90 mmHg at initiation of study drug.
• Heart rate ≥ 120 bpm, persistent for at least 10 minutes screening and unresponsive to treatment.
• Hemoglobin < 80 g/L.
• Serum potassium < 3.5 mmol/L and > 5.5 mmol/L at baseline.
• A history of Torsades de Pointes.
• Mechanical assist device (IABP, LVAD, ECMO) in the patient at the start of surgery or pre-planned to be inserted during surgery before coming off CPB.
• Patients with aortal femoral occlusive disease that would prohibit use of IABP unless VAD or ECMO not available.
• Liver dysfunction Child Pugh Class B or C
• Patients having severely compromised immune function
• Pregnant, suspected to be pregnant, or breast-feeding.
• Received an experimental drug or used an experimental medical device in previous 30 days.
• Known allergic reaction or sensitivity to Levosimendan or excipients.
• Received commercial Levosimendan within 30 days before the planned start of study drug.
• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Levosimendan	Levosimendan	levosimendan 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours
Placebo	Placebo	placebo 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours

Primary Outcome Measures

Name	Time	Method
Number of Dual Efficacy Endpoint Events	30 days	The all-cause death at 30 days or use of mechanical assist device (IABP, LVAD or ECMO) following the start of surgery for poor cardiac function despite inotropic support and adequate fluid replacement) through Day 5
Number of Quad Efficacy Endpoint Events	30 days	Composite of all-cause death (at 30 days), or perioperative nonfatal MI \[CK-MB \>10xULN or \>100 ng/mL, CK-MB \>5xULN or 50 ng/mL with new Q wave (\>0.04 seconds wide in two contiguous leads) or new left bundle branch block)\] (through Day 5), or need for renal dialysis (through Day 30), or use of mechanical assist device (IABP, LVAD or ECMO) following the start of surgery for poor cardiac function despite inotropic support and adequate fluid replacement) (through Day 5)

Secondary Outcome Measures

Name	Time	Method
Duration of Intensive Care Unit/Critical or Coronary Care Unit (ICU/CCU) (Days)	participants will be followed for during the participant's hospital stay up to 30 days	Duration of intensive care unit/critical or coronary care unit (ICU/CCU) length of stay (LOS) in days
Incidence of Low Cardiac Output Syndrome (LCOS)	5 days	Use of a mechanical cardiac assist device within 5 days after surgery, two consecutive measurements of low cardiac output (defined as a cardiac output of ≤2.0 liters per minute per square meter of bodysurface area), one measurement of low cardiac output plus the use of two or more inotropes at or beyond 24 hours after surgery, or the use of two or more inotropes at or beyond 24 hours after surgery with the indicated reason being low cardiac output.
Postoperative Use of Secondary Inotrope	24 hours	Use of (dobutamine, milrinone, epinephrine, dopamine) associated with index surgical procedure at 24 hours after initiation of surgery

Trial Locations

Locations (60)

University of Alabama at Burlington Hospital; 🇺🇸 Burlington, Alabama, United States

Huntsville Hospital; 🇺🇸 Huntsville, Alabama, United States

Mercy General Hospital; 🇺🇸 Sacramento, California, United States

University of California San Diego Medical Center; 🇺🇸 San Diego, California, United States

Stanford University School of Medicine; 🇺🇸 Stanford, California, United States

Hartford Hospital; 🇺🇸 Hartford, Connecticut, United States

Yale-New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States

Boca Raton Community Hospital; 🇺🇸 Boca Raton, Florida, United States

Shands Hospital at the University of Florida; 🇺🇸 Gainesville, Florida, United States

Tampa General Hospital; 🇺🇸 Tampa, Florida, United States

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