Clinical trial NCT02025621: Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery On Cardiopulmonary Bypass
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
Overall status: COMPLETED
Phase: PHASE3
Conditions: 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
Lead sponsor: Tenax Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2014-01-01
Enrollment: 882
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Number of Dual Efficacy Endpoint Events
timeFrame: 30 days
measure: Number of Quad Efficacy Endpoint Events
timeFrame: 30 days
Secondary outcomes:
measure: Duration of Intensive Care Unit/Critical or Coronary Care Unit (ICU/CCU) (Days)
timeFrame: participants will be followed for during the participant's hospital stay up to 30 days
measure: Incidence of Low Cardiac Output Syndrome (LCOS)
timeFrame: 5 days
measure: Postoperative Use of Secondary Inotrope
timeFrame: 24 hours
Other outcomes:
measure: Occurrence of All-cause Mortality From Randomization Through Day 90
timeFrame: 90 days
measure: Rehospitalization for Any Cause Through Day 30
timeFrame: 30 days
Locations:
city: Burlington
country: United States
facility: University of Alabama at Burlington Hospital
state: Alabama
city: Huntsville
country: United States
facility: Huntsville Hospital
state: Alabama
city: Sacramento
country: United States
facility: Mercy General Hospital
state: California
city: San Diego
country: United States
facility: University of California San Diego Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale-New Haven Hospital
state: Connecticut
city: Boca Raton
country: United States
facility: Boca Raton Community Hospital
state: Florida
city: Gainesville
country: United States
facility: Shands Hospital at the University of Florida
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Rome
country: United States
facility: Redmond Regional Medical Center
state: Georgia
city: Evanston
country: United States
facility: Northwestern University Hospital
state: Illinois
city: Fort Wayne
country: United States
facility: Lutheran Hospital of Indiana
state: Indiana
city: Indianapolis
country: United States
facility: Franciscan St. Francis Health
state: Indiana
city: West Des Moines
country: United States
facility: Iowa Heart Center/ Mercy Medical Center
state: Iowa
city: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: St. Joseph's Mercy Hospital
state: Michigan
city: Dearborn
country: United States
facility: Oakwood Hospital and Medical Center
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health
state: Michigan
city: Kansas City
country: United States
facility: St. Luke's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: Lincoln
country: United States
facility: Nebraska Heart Institute
state: Nebraska
city: Omaha
country: United States
facility: Nebraska Medical Center
state: Nebraska
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Albany
country: United States
facility: St. Peter's Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Roslyn
country: United States
facility: Saint Francis Hospital/The Heart Center
state: New York
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Greensboro
country: United States
facility: Moses H. Cone Memorial Hospital
state: North Carolina
city: Raleigh
country: United States
facility: Duke University Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: The Christ's Hospital; Lindner Clinical Trial Center
state: Ohio
city: Cleveland
country: United States
facility: Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Hospital
state: Ohio
city: Toledo
country: United States
facility: ProMedica Toledo Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Heart Hospital
state: Oklahoma
city: Allentown
country: United States
facility: Lehigh Valley Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: St. Thomas Heart
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Hospital
state: Texas
city: Plano
country: United States
facility: The Heart Hospital Baylor Plano
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Tacoma
country: United States
facility: Franciscan Health System Res. Center
state: Washington
city: Milwaukee
country: United States
facility: Aurora Saint Luke's Medical Center
state: Wisconsin
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Victoria
country: Canada
facility: Royal Jubilee Hospital (Vancouver Island Health Authority)
state: British Columbia
city: Victoria
country: Canada
facility: Victoria Heart Institute Foundation
state: British Columbia
city: Winnepeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: London Health Sciences Center, University Hospital
state: Ontario
city: Newmarket
country: Canada
facility: Southlake Regional Health Center
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre-Royal Victoria Hospital
state: Quebec
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Quebec
country: Canada
facility: Institute universitaire de cardiologie et pneumologie de Quebec
Study officials:
affiliation: Duke Clinical Research Institute
name: Rajendra Mehta, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke Clinical Research Institute
name: John Alexander, MD
role: STUDY_CHAIR
References:
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.
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.
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.
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.
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.