Cardiopulmonary Bypass, Coronary Artery Bypass, Myocardial Infarction, Stroke, Ventricular Dysfunction, Left
Conditions
Brief summary
The purpose of this study is to determine whether acadesine is effective in reducing the cardiovascular and cerebrovascular adverse events in high-risk participants undergoing CABG surgery.
Interventions
DRUGAcadesine
Acadesine 42 mg/kg diluted in normal saline to a total of 500 mL, delivered as an IV infusion over approximately 7 hours commencing within approximately 30 minutes before induction of anesthesia at a rate of 0.1 mg/kg/min (translating into 1.2 mL/min for a 500 mL solution). In addition, a 5 µg/mL cardioplegia solution of acadesine will be administered, and acadesine will be added to the priming solution (5 µg/mL) in the heart lung machine during CPB.
DRUGNormal Saline
Normal saline, 500 mL delivered as an IV infusion over approximately 7 hours commencing within approximately 30 minutes before induction of anesthesia at a rate of 1.2 mL/min for a 500 mL solution. In addition, standard cardioplegia solution with added normal saline will be administered, and placebo (normal saline) will also be added to the heart lung machine priming solution.
Sponsors
Duke Clinical Research Institute
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A high risk participant undergoing non emergency CABG surgery requiring CPB and cardioplegia. * Age: \>=50 years * At least one of the following risk factors: * Female (but not pregnant or lactating), or * History of prior CABG, or * History of myocardial infarction (MI), or * History of ischemic stroke, or * Left ventricular ejection fraction \<=30%, or * Diabetes mellitus requiring insulin and/or antidiabetic agents. * Significant coronary artery stenosis
Exclusion criteria
* Planned valve replacement, carotid artery or aortic surgery, distal coronary endarterectomy,surgical ablation for cardiac arrhythmia, or ventricular aneurysmectomy, alone or with CABG surgery (repair for mild to moderate mitral valve disease with concomitant CABG is not excluded). * Planned or staged major surgery within 30 days of CABG surgery * CABG surgery using intermittent aortic cross clamping without cardioplegia. * Minimally invasive surgery (ie, without use of CPB). * MI within 5 days prior to surgery. * Pre-operative or planned intra operative/postoperative use of intra-aortic balloon pump (IABP), ventricular assist device (VAD), extra-corporeal membrane oxygenator (ECMO), or other mechanical hemodynamic assist device. * History or presence of gout or uric acid nephrolithiasis. * Serum creatinine \>2 mg/dL (180 µmol/L). * Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2 x Upper Limit of Normal (ULN). * Adenosine, aminophylline, nicotinic acid, pentoxifylline, theophylline, and any cardioplegia solution containing adenosine, dipyridamole or lidoflazine within 24 hours before surgery: * Dipyridamole within 2 days and allopurinol or febuxostat within 4 days before surgery * Food and drinks containing caffeine, theobromines or methylxanthines (such as coffee, tea, colas, some 'energy' drinks or chocolate) within 12 hours before surgery. * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | Up to Post-Operative Day 28 | Incidence of all-cause death, non-fatal stroke, or need for mechanical support for SLVD (any component and composite) through post-operative Day 28 during and following CABG and administration of acadesine or placebo. Components defined as follows: All-cause death: Death from any cause, Non-fatal Stoke: occurrence of a stoke that was confirmed and adjudicated by Clinical Endpoints Committee that did not result in death, and Mechanical Support for SLVD: New use of any mechanical support for ≥1 hour for treatment of low cardiac output. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Up to Post-Operative Day 28 | Incidence of cardiovascular death, non-fatal stroke, and need for mechanical support for SLVD (any component and composite) through post-operative Day 28 during and following CABG and administration of acadesine or placebo. Components defined as follows: Cardiovascular death: Death due to cardiovascular causes, Non-fatal Stroke: occurrence of a stroke that was confirmed and adjudicated by Clinical Endpoints Committee that did not result in death, and Mechanical Support for SLVD: New use of any mechanical support for ≥1 hour for treatment of low cardiac output. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acadesine Acadesine IV infusion, plus cardioplegia solution with acadesine, and priming solution with acadesine in the heart lung machine during cardiopulmonary bypass (CPB) | 1,536 |
| Placebo (Normal Saline) Placebo (normal saline) IV infusion, plus cardioplegia solution with added normal saline, and priming solution with added normal saline in the heart lung machine during CPB | 1,544 |
| Total | 3,080 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative | 23 | 15 |
| Overall Study | Adverse Event | 34 | 23 |
| Overall Study | Did Not Meet Protocol Eligibility | 38 | 36 |
| Overall Study | Lost to Follow-up | 13 | 12 |
| Overall Study | Protocol Defined Clinical Event | 5 | 7 |
| Overall Study | Protocol Violation | 5 | 8 |
| Overall Study | Withdrawal by Subject | 18 | 30 |
Baseline characteristics
| Characteristic | Acadesine | Placebo (Normal Saline) | Total |
|---|---|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 8.5 | 66.7 years STANDARD_DEVIATION 8.7 | 66.5 years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 519 Participants | 523 Participants | 1042 Participants |
| Sex: Female, Male Male | 1017 Participants | 1021 Participants | 2038 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,154 / 1,442 | 1,189 / 1,457 |
| serious Total, serious adverse events | 327 / 1,442 | 329 / 1,457 |
Outcome results
Primary
Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population)
Incidence of all-cause death, non-fatal stroke, or need for mechanical support for SLVD (any component and composite) through post-operative Day 28 during and following CABG and administration of acadesine or placebo. Components defined as follows: All-cause death: Death from any cause, Non-fatal Stoke: occurrence of a stoke that was confirmed and adjudicated by Clinical Endpoints Committee that did not result in death, and Mechanical Support for SLVD: New use of any mechanical support for ≥1 hour for treatment of low cardiac output.
Time frame: Up to Post-Operative Day 28
Population: The Intent-to-Treat Population included all participants randomly assigned to a treatment group and did not have to receive study drug. Each participant contributed to no more than one efficacy endpoint in any composite, i.e., a participant who experienced multiple components of an endpoint composite was counted only once in that composite.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acadesine | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | Composite of All Events | 4.9 Percentage of Participants |
| Acadesine | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | All-Cause Death | 1.9 Percentage of Participants |
| Acadesine | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | Non-Fatal Stroke | 1.7 Percentage of Participants |
| Acadesine | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | Need for Mechanical Support for SLVD | 2.2 Percentage of Participants |
| Placebo | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | Need for Mechanical Support for SLVD | 2.3 Percentage of Participants |
| Placebo | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | Composite of All Events | 4.9 Percentage of Participants |
| Placebo | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | Non-Fatal Stroke | 1.7 Percentage of Participants |
| Placebo | Incidence of All-cause Death, Non-fatal Stroke, and Need for Mechanical Support for Severe Left Ventricular Dysfunction (SLVD) (Intent-to-Treat Population) | All-Cause Death | 1.7 Percentage of Participants |
Secondary
Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population)
Incidence of cardiovascular death, non-fatal stroke, and need for mechanical support for SLVD (any component and composite) through post-operative Day 28 during and following CABG and administration of acadesine or placebo. Components defined as follows: Cardiovascular death: Death due to cardiovascular causes, Non-fatal Stroke: occurrence of a stroke that was confirmed and adjudicated by Clinical Endpoints Committee that did not result in death, and Mechanical Support for SLVD: New use of any mechanical support for ≥1 hour for treatment of low cardiac output.
Time frame: Up to Post-Operative Day 28
Population: The Intent-to-Treat Population included all participants randomly assigned to a treatment group and did not have to receive study drug. Each participant contributed to no more than one efficacy endpoint in any composite, i.e., a participant who experienced multiple components of an endpoint composite was counted only once in that composite.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acadesine | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Composite of All Events | 4.8 Percentage of Participants |
| Acadesine | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Cardiovascular Death | 1.7 Percentage of Participants |
| Acadesine | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Non-Fatal Stroke | 1.7 Percentage of Participants |
| Acadesine | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Need for Mechanical Support for SLVD | 2.2 Percentage of Participants |
| Placebo | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Need for Mechanical Support for SLVD | 2.3 Percentage of Participants |
| Placebo | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Composite of All Events | 4.7 Percentage of Participants |
| Placebo | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Non-Fatal Stroke | 1.7 Percentage of Participants |
| Placebo | Incidence of Cardiovascular Death, Non-fatal Stroke, and Need for Mechanical Support for SLVD (Intent-to-Treat Population) | Cardiovascular Death | 1.6 Percentage of Participants |