Coronary Artery Bypass Graft
Conditions
Keywords
coronary artery bypass graft, cardiac surgery, cardiopulmonary bypass, nicotinamide, NMN, acute kidney injury
Brief summary
The investigators will perform a phase 2a, randomized, double-blind, placebo-controlled clinical trial in adult patients undergoing elective coronary artery bypass grafting (CABG) surgery to investigate the effects of oral nicotinamide mononucleotide (NMN) administration on myocardial NAD+ concentrations and on postoperative markers of myocardial and kidney injury.
Detailed description
This is a phase 2a, randomized, double-blind, parallel-group, placebo-controlled clinical trial in adult patients undergoing elective coronary artery bypass grafting (CABG) surgery. A total of 90 patients will be randomized 1:1:1 to placebo or to one of two dosing regimens of NMN seven days prior to surgery as follows: Arm A: NMN 1,000 mg PO twice daily, administered for 7 days preoperatively, on the day of surgery, and for 4 days postoperatively Arm B: NMN 1,000 mg PO twice daily, administered for 2 days preoperatively, on the day of surgery, and for 4 days postoperatively Arm C: Placebo PO twice daily, administered for 7 days preoperatively, on the day of surgery, and for 4 days postoperatively There are two major study aims: Aim 1: Test the effect of oral NMN administration on myocardial NAD+ concentration. Aim 2: Test the effect of oral NMN administration on postoperative myocardial and kidney injury parameters.
Interventions
DRUGMIB-626
An orally-administered stable crystalline tablet formulation of NMN
OTHERPlacebo
matching placebo tablets
Sponsors
Brigham and Women's Hospital
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years 2. Scheduled to undergo elective isolated CABG surgery with cardiopulmonary bypass (CPB) 3. At increased risk of postoperative complications based on ≥1 of the following: 1. Age ≥65 years 2. eGFR \<45 ml/min/1.73m2 3. Documented history of congestive heart failure or left ventricular ejection fraction (LVEF) ≤40% within 6 months before surgery 4. Diabetes mellitus and urine albumin-to-creatinine ratio \>30 mg/g creatinine 5. Peripheral arterial disease 6. Anemia, defined as hemoglobin \<10 g/dl 7. Prior cardiac surgery
Exclusion criteria
1. Any of the following laboratory abnormalities at the time of screening: 1. ALT \>3-fold the upper limit of normal 2. eGFR \<30 ml/min/1.73m2 or ESKD on dialysis 3. Hemoglobin \<8 g/dl 2. History of gastric bypass or malabsorption 3. Active alcohol or illicit substance use in the prior 6 months 4. Participation in an investigational trial to evaluate pharmaceuticals or biologics within the past 3 months or 5 half-lives, whichever is shorter 5. Pregnant or breast-feeding 6. Unwillingness to use contraception while taking study drug and for 8 weeks after the last dose for women of reproductive age or non-sterilized male participants who are sexually active with a female partner of childbearing potential 7. Current use of niacin \>100 mg/day or NMN, nicotinamide, or nicotinamide riboside at any dose 8. Conflict with other research studies 9. Any condition which, in the judgement of the investigator, might increase the risk to the participant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| NAD+ concentration in the myocardial tissue | Intraoperatively (single time point) | NAD+ concentration in the myocardial tissue (right atrial appendage) obtained intraoperatively, measured using the validated NADome Quant assay |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intracellular levels of NAD+ and related metabolites | Intraoperatively (single time point) | NAD+, NADH, and related metabolite concentrations in discarded tissue collected intraoperatively, including right atrial appendage, internal mammary artery, sternal muscle, and fat |
| Circulating levels of NAD+ and related metabolites | Baseline to day 90 | NAD+, NADH, and related metabolite concentrations in the circulation and in peripheral blood mononuclear cells |
| Markers of cardiac injury/dysfunction | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Circulating levels of cardiac troponin I, creatine kinase MB fraction (CKMB), and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) |
| Acute kidney injury (AKI) | 7 days post-operatively | Incidence of acute kidney injury (AKI) defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria as any of the following: 1) urine output \<0.5 ml/kg/h for ≥6 consecutive hours (assessed within the first 48h or until the Foley catheter is removed, whichever occurs first); 2) an increase in SCr ≥0.3 mg/dl within the first 48h; 3) an increase in SCr ≥50% within the first 7 days; or 4) receipt of KRT within the first 7 days |
| Serum creatinine (SCr) | Immediately pre-operative to 7 days post-operative | Maximum baseline-adjusted changes in SCr |
| Cystatin C | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Circulating levels of cystatin C |
| Neutrophil gelatinase-associated lipocalin (NGAL) | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Circulating levels of measured neutrophil gelatinase-associated lipocalin (NGAL) |
| Kidney Injury Molecule-1 (KIM-1) | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Circulating levels of KIM-1 |
| NMN level | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Plasma concentrations of NMN |
| 2PY Level | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Plasma concentrations of 2PY |
| N-Methylnicotinamide level | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Plasma N-methylynicotinamide level |
| nicotinamide level | Preoperatively, on ICU arrival, and on postoperative days 1-4 | Plasma nicotinamide concentrations |
Countries
United States
Contacts
CONTACTShalender Bhasin, MB,BS
CONTACTDavid E Leaf, MD
PRINCIPAL_INVESTIGATORShalender Bhasin, MB, BS
Brigham and Women's Hosptial
Outcome results
None listed