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Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery On Cardiopulmonary Bypass (LEVO-CTS)

Primary Purpose

Coronary Artery Bypass Grafting, Mitral Valve Surgery, Low Cardiac Output Syndrome

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Levosimendan
Placebo
Sponsored by
Tenax Therapeutics, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Coronary Artery Bypass Grafting focused on measuring coronary artery bypass grafting, CABG, mitral valve, LCOS, low cardiac output syndrome, levosimendan

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama at Burlington Hospital
  • Huntsville Hospital
  • Mercy General Hospital
  • University of California San Diego Medical Center
  • Stanford University School of Medicine
  • Hartford Hospital
  • Yale-New Haven Hospital
  • Boca Raton Community Hospital
  • Shands Hospital at the University of Florida
  • Tampa General Hospital
  • Redmond Regional Medical Center
  • Northwestern University Hospital
  • Lutheran Hospital of Indiana
  • Franciscan St. Francis Health
  • Iowa Heart Center/ Mercy Medical Center
  • University of Louisville Hospital
  • Maine Medical Center
  • Brigham and Women's Hospital
  • Tufts Medical Center
  • St. Joseph's Mercy Hospital
  • Oakwood Hospital and Medical Center
  • Spectrum Health
  • St. Luke's Hospital
  • Barnes Jewish Hospital
  • Nebraska Heart Institute
  • Nebraska Medical Center
  • Morristown Medical Center
  • St. Peter's Hospital
  • Columbia University Medical Center
  • Lenox Hill Hospital
  • Mount Sinai Medical Center
  • Saint Francis Hospital/The Heart Center
  • Mission Hospital
  • Moses H. Cone Memorial Hospital
  • Duke University Hospital
  • The Christ's Hospital; Lindner Clinical Trial Center
  • Case Medical Center
  • Cleveland Clinic
  • Ohio State University Hospital
  • ProMedica Toledo Hospital
  • Oklahoma Heart Hospital
  • Lehigh Valley Hospital
  • St. Thomas Heart
  • Vanderbilt University Medical Center
  • Baylor Hospital
  • The Heart Hospital Baylor Plano
  • University of Virginia Health System
  • Franciscan Health System Res. Center
  • Aurora Saint Luke's Medical Center
  • University of Alberta Hospital
  • Royal Jubilee Hospital (Vancouver Island Health Authority)
  • Victoria Heart Institute Foundation
  • St. Boniface Hospital
  • Hamilton Health Sciences
  • London Health Sciences Center, University Hospital
  • Southlake Regional Health Center
  • St. Michael's Hospital
  • McGill University Health Centre-Royal Victoria Hospital
  • Montreal Heart Institute
  • Institute universitaire de cardiologie et pneumologie de Quebec

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Levosimendan

Placebo

Arm Description

levosimendan 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours

placebo 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours

Outcomes

Primary Outcome Measures

Number of Dual Efficacy Endpoint Events
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
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

Duration of Intensive Care Unit/Critical or Coronary Care Unit (ICU/CCU) (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)
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
Use of (dobutamine, milrinone, epinephrine, dopamine) associated with index surgical procedure at 24 hours after initiation of surgery

Full Information

First Posted
December 18, 2013
Last Updated
May 22, 2018
Sponsor
Tenax Therapeutics, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02025621
Brief Title
Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery On Cardiopulmonary Bypass
Acronym
LEVO-CTS
Official Title
A Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
July 2014 (undefined)
Primary Completion Date
November 2016 (Actual)
Study Completion Date
November 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tenax Therapeutics, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Artery Bypass Grafting, Mitral Valve Surgery, Low Cardiac Output Syndrome
Keywords
coronary artery bypass grafting, CABG, mitral valve, LCOS, low cardiac output syndrome, levosimendan

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
882 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Levosimendan
Arm Type
Experimental
Arm Description
levosimendan 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
placebo 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours
Intervention Type
Drug
Intervention Name(s)
Levosimendan
Other Intervention Name(s)
Simdax
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
matching placebo
Primary Outcome Measure Information:
Title
Number of Dual Efficacy Endpoint Events
Description
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
Time Frame
30 days
Title
Number of Quad Efficacy Endpoint Events
Description
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)
Time Frame
30 days
Secondary Outcome Measure Information:
Title
Duration of Intensive Care Unit/Critical or Coronary Care Unit (ICU/CCU) (Days)
Description
Duration of intensive care unit/critical or coronary care unit (ICU/CCU) length of stay (LOS) in days
Time Frame
participants will be followed for during the participant's hospital stay up to 30 days
Title
Incidence of Low Cardiac Output Syndrome (LCOS)
Description
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.
Time Frame
5 days
Title
Postoperative Use of Secondary Inotrope
Description
Use of (dobutamine, milrinone, epinephrine, dopamine) associated with index surgical procedure at 24 hours after initiation of surgery
Time Frame
24 hours
Other Pre-specified Outcome Measures:
Title
Occurrence of All-cause Mortality From Randomization Through Day 90
Time Frame
90 days
Title
Rehospitalization for Any Cause Through Day 30
Time Frame
30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rajendra Mehta, MD
Organizational Affiliation
Duke Clinical Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
John Alexander, MD
Organizational Affiliation
Duke Clinical Research Institute
Official's Role
Study Chair
Facility Information:
Facility Name
University of Alabama at Burlington Hospital
City
Burlington
State/Province
Alabama
Country
United States
Facility Name
Huntsville Hospital
City
Huntsville
State/Province
Alabama
Country
United States
Facility Name
Mercy General Hospital
City
Sacramento
State/Province
California
Country
United States
Facility Name
University of California San Diego Medical Center
City
San Diego
State/Province
California
Country
United States
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
Country
United States
Facility Name
Hartford Hospital
City
Hartford
State/Province
Connecticut
Country
United States
Facility Name
Yale-New Haven Hospital
City
New Haven
State/Province
Connecticut
Country
United States
Facility Name
Boca Raton Community Hospital
City
Boca Raton
State/Province
Florida
Country
United States
Facility Name
Shands Hospital at the University of Florida
City
Gainesville
State/Province
Florida
Country
United States
Facility Name
Tampa General Hospital
City
Tampa
State/Province
Florida
Country
United States
Facility Name
Redmond Regional Medical Center
City
Rome
State/Province
Georgia
Country
United States
Facility Name
Northwestern University Hospital
City
Evanston
State/Province
Illinois
Country
United States
Facility Name
Lutheran Hospital of Indiana
City
Fort Wayne
State/Province
Indiana
Country
United States
Facility Name
Franciscan St. Francis Health
City
Indianapolis
State/Province
Indiana
Country
United States
Facility Name
Iowa Heart Center/ Mercy Medical Center
City
West Des Moines
State/Province
Iowa
Country
United States
Facility Name
University of Louisville Hospital
City
Louisville
State/Province
Kentucky
Country
United States
Facility Name
Maine Medical Center
City
Portland
State/Province
Maine
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
Tufts Medical Center
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
St. Joseph's Mercy Hospital
City
Ann Arbor
State/Province
Michigan
Country
United States
Facility Name
Oakwood Hospital and Medical Center
City
Dearborn
State/Province
Michigan
Country
United States
Facility Name
Spectrum Health
City
Grand Rapids
State/Province
Michigan
Country
United States
Facility Name
St. Luke's Hospital
City
Kansas City
State/Province
Missouri
Country
United States
Facility Name
Barnes Jewish Hospital
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
Nebraska Heart Institute
City
Lincoln
State/Province
Nebraska
Country
United States
Facility Name
Nebraska Medical Center
City
Omaha
State/Province
Nebraska
Country
United States
Facility Name
Morristown Medical Center
City
Morristown
State/Province
New Jersey
Country
United States
Facility Name
St. Peter's Hospital
City
Albany
State/Province
New York
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
Country
United States
Facility Name
Lenox Hill Hospital
City
New York
State/Province
New York
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
Country
United States
Facility Name
Saint Francis Hospital/The Heart Center
City
Roslyn
State/Province
New York
Country
United States
Facility Name
Mission Hospital
City
Asheville
State/Province
North Carolina
Country
United States
Facility Name
Moses H. Cone Memorial Hospital
City
Greensboro
State/Province
North Carolina
Country
United States
Facility Name
Duke University Hospital
City
Raleigh
State/Province
North Carolina
Country
United States
Facility Name
The Christ's Hospital; Lindner Clinical Trial Center
City
Cincinnati
State/Province
Ohio
Country
United States
Facility Name
Case Medical Center
City
Cleveland
State/Province
Ohio
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
Country
United States
Facility Name
Ohio State University Hospital
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
ProMedica Toledo Hospital
City
Toledo
State/Province
Ohio
Country
United States
Facility Name
Oklahoma Heart Hospital
City
Oklahoma City
State/Province
Oklahoma
Country
United States
Facility Name
Lehigh Valley Hospital
City
Allentown
State/Province
Pennsylvania
Country
United States
Facility Name
St. Thomas Heart
City
Nashville
State/Province
Tennessee
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
Country
United States
Facility Name
Baylor Hospital
City
Dallas
State/Province
Texas
Country
United States
Facility Name
The Heart Hospital Baylor Plano
City
Plano
State/Province
Texas
Country
United States
Facility Name
University of Virginia Health System
City
Charlottesville
State/Province
Virginia
Country
United States
Facility Name
Franciscan Health System Res. Center
City
Tacoma
State/Province
Washington
Country
United States
Facility Name
Aurora Saint Luke's Medical Center
City
Milwaukee
State/Province
Wisconsin
Country
United States
Facility Name
University of Alberta Hospital
City
Edmonton
State/Province
Alberta
Country
Canada
Facility Name
Royal Jubilee Hospital (Vancouver Island Health Authority)
City
Victoria
State/Province
British Columbia
Country
Canada
Facility Name
Victoria Heart Institute Foundation
City
Victoria
State/Province
British Columbia
Country
Canada
Facility Name
St. Boniface Hospital
City
Winnepeg
State/Province
Manitoba
Country
Canada
Facility Name
Hamilton Health Sciences
City
Hamilton
State/Province
Ontario
Country
Canada
Facility Name
London Health Sciences Center, University Hospital
City
London
State/Province
Ontario
Country
Canada
Facility Name
Southlake Regional Health Center
City
Newmarket
State/Province
Ontario
Country
Canada
Facility Name
St. Michael's Hospital
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
McGill University Health Centre-Royal Victoria Hospital
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
Montreal Heart Institute
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
Institute universitaire de cardiologie et pneumologie de Quebec
City
Quebec
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
35263653
Citation
Verma S, Rathwell S, Fremes S, Zheng Y, Mehta R, Lopes RD, Alexander JH, Goodman SG, Diepen SV; LEVO-CTS investigators. Associated factors and clinical outcomes in mechanical circulatory support use in patients undergoing high risk on-pump cardiac surgery: Insights from the LEVO-CTS trial. Am Heart J. 2022 Jun;248:35-41. doi: 10.1016/j.ahj.2022.02.013. Epub 2022 Mar 7.
Results Reference
derived
PubMed Identifier
28316276
Citation
Mehta RH, Leimberger JD, van Diepen S, Meza J, Wang A, Jankowich R, Harrison RW, Hay D, Fremes S, Duncan A, Soltesz EG, Luber J, Park S, Argenziano M, Murphy E, Marcel R, Kalavrouziotis D, Nagpal D, Bozinovski J, Toller W, Heringlake M, Goodman SG, Levy JH, Harrington RA, Anstrom KJ, Alexander JH; LEVO-CTS Investigators. Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery. N Engl J Med. 2017 May 25;376(21):2032-2042. doi: 10.1056/NEJMoa1616218. Epub 2017 Mar 19.
Results Reference
derived
PubMed Identifier
27914501
Citation
Mehta RH, Van Diepen S, Meza J, Bokesch P, Leimberger JD, Tourt-Uhlig S, Swartz M, Parrotta J, Jankowich R, Hay D, Harrison RW, Fremes S, Goodman SG, Luber J, Toller W, Heringlake M, Anstrom KJ, Levy JH, Harrington RA, Alexander JH; LEVO-CTS Investigators. Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial. Am Heart J. 2016 Dec;182:62-71. doi: 10.1016/j.ahj.2016.09.001. Epub 2016 Sep 9.
Results Reference
derived
PubMed Identifier
25989324
Citation
Lim JY, Deo SV, Rababa'h A, Altarabsheh SE, Cho YH, Hang D, McGraw M, Avery EG, Markowitz AH, Park SJ. Levosimendan Reduces Mortality in Adults with Left Ventricular Dysfunction Undergoing Cardiac Surgery: A Systematic Review and Meta-analysis. J Card Surg. 2015 Jul;30(7):547-54. doi: 10.1111/jocs.12562. Epub 2015 May 19.
Results Reference
derived
PubMed Identifier
25734940
Citation
Toller W, Heringlake M, Guarracino F, Algotsson L, Alvarez J, Argyriadou H, Ben-Gal T, Cerny V, Cholley B, Eremenko A, Guerrero-Orriach JL, Jarvela K, Karanovic N, Kivikko M, Lahtinen P, Lomivorotov V, Mehta RH, Music S, Pollesello P, Rex S, Riha H, Rudiger A, Salmenpera M, Szudi L, Tritapepe L, Wyncoll D, Owall A. Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion. Int J Cardiol. 2015 Apr 1;184:323-336. doi: 10.1016/j.ijcard.2015.02.022. Epub 2015 Feb 24.
Results Reference
derived

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

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