Coronary Artery Bypass Grafting, Low Cardiac Output Syndrome, Mitral Valve Surgery
Conditions
Keywords
coronary artery bypass grafting, CABG, mitral valve, LCOS, low cardiac output syndrome, levosimendan
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.
Interventions
DRUGPlacebo
matching placebo
DRUGLevosimendan
Sponsors
Tenax Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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 |
Other
| Measure | Time frame |
|---|---|
| Occurrence of All-cause Mortality From Randomization Through Day 90 | 90 days |
| Rehospitalization for Any Cause Through Day 30 | 30 days |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levosimendan levosimendan 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours
Levosimendan | 428 |
| Placebo placebo 0.2 µg/kg/min for first hour, followed by 0.1 µg/kg/min for an additional 23 hours
Placebo: matching placebo | 421 |
| Total | 849 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | No longer eligible | 10 | 15 |
| Overall Study | Surgery initiated before infusion | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Levosimendan | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65 years | 65 years | 65 years |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 10 Participants | 19 Participants |
| Race/Ethnicity, Customized Black | 21 Participants | 23 Participants | 44 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not given | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 7 Participants | 12 Participants |
| Race/Ethnicity, Customized White/Caucasian | 385 Participants | 375 Participants | 760 Participants |
| Region of Enrollment Canada | 71 participants | 88 participants | 159 participants |
| Region of Enrollment United States | 357 participants | 333 participants | 690 participants |
| Sex: Female, Male Female | 81 Participants | 89 Participants | 170 Participants |
| Sex: Female, Male Male | 347 Participants | 332 Participants | 679 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 20 / 428 | 30 / 421 |
| other Total, other adverse events | 238 / 428 | 232 / 421 |
| serious Total, serious adverse events | 34 / 428 | 37 / 421 |
Outcome results
Primary
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
Time frame: 30 days
Population: mITT; population receiving any study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levosimendan | Number of Dual Efficacy Endpoint Events | 56 events |
| Placebo | Number of Dual Efficacy Endpoint Events | 48 events |
Primary
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)
Time frame: 30 days
Population: mITT; population receiving any study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levosimendan | Number of Quad Efficacy Endpoint Events | 105 events |
| Placebo | Number of Quad Efficacy Endpoint Events | 103 events |
Secondary
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
Time frame: participants will be followed for during the participant's hospital stay up to 30 days
Population: mITT; patients that received any study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levosimendan | Duration of Intensive Care Unit/Critical or Coronary Care Unit (ICU/CCU) (Days) | 2.8 days |
| Placebo | Duration of Intensive Care Unit/Critical or Coronary Care Unit (ICU/CCU) (Days) | 2.9 days |
Secondary
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.
Time frame: 5 days
Population: mITT; patients receiving any study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levosimendan | Incidence of Low Cardiac Output Syndrome (LCOS) | 78 Participants |
| Placebo | Incidence of Low Cardiac Output Syndrome (LCOS) | 108 Participants |
Secondary
Postoperative Use of Secondary Inotrope
Use of (dobutamine, milrinone, epinephrine, dopamine) associated with index surgical procedure at 24 hours after initiation of surgery
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levosimendan | Postoperative Use of Secondary Inotrope | 235 Participants |
| Placebo | Postoperative Use of Secondary Inotrope | 264 Participants |
Other Pre-specified
Occurrence of All-cause Mortality From Randomization Through Day 90
Time frame: 90 days
Population: all patients receiving study drug, according to the drug actually received
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levosimendan | Occurrence of All-cause Mortality From Randomization Through Day 90 | 20 Participants |
| Placebo | Occurrence of All-cause Mortality From Randomization Through Day 90 | 30 Participants |
Other Pre-specified
Rehospitalization for Any Cause Through Day 30
Time frame: 30 days
Population: patients receiving study drug, by study drug received
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levosimendan | Rehospitalization for Any Cause Through Day 30 | 54 Participants |
| Placebo | Rehospitalization for Any Cause Through Day 30 | 48 Participants |