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| ID | Type | Description | Link |
|---|---|---|---|
| 1U01AG089040-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| NMN (MIB-626) for 7 days preoperatively, on day of surgery, and for 4 days postoperatively | Experimental | NMN (MIB-626) 1000 mg PO daily, for 7 days preoperatively, on day of surgery, and for 4 days postoperatively |
|
| NMN administered for 2 days preoperatively, on the day of surgery, and for 4 days postoperatively | Experimental | NMN (MIB-626) 1,000 mg PO twice daily, administered for 2 days preoperatively, on the day of surgery, and for 4 days postoperatively |
|
| Placebo | Placebo Comparator | Placebo administered for 7 days preoperatively, on the day of surgery, and for 4 days postoperatively |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MIB-626 | Drug | An orally-administered stable crystalline tablet formulation of NMN |
|
| Measure | Description | Time Frame |
|---|---|---|
| NAD+ concentration in the myocardial tissue | NAD+ concentration in the myocardial tissue (right atrial appendage) obtained intraoperatively, measured using the validated NADome Quant assay | Intraoperatively (single time point) |
| Measure | Description | Time Frame |
|---|---|---|
| Intracellular levels of NAD+ and related metabolites | NAD+, NADH, and related metabolite concentrations in discarded tissue collected intraoperatively, including right atrial appendage, internal mammary artery, sternal muscle, and fat | Intraoperatively (single time point) |
| Circulating levels of NAD+ and related metabolites |
| Measure | Description | Time Frame |
|---|---|---|
| Left ventricular ejection fraction (LVEF) | Left ventricular ejection fraction (LVEF) measured by a transesophageal echocardiogram (TEE) | change from immediately preoperative to immediate postoperative |
| Atrial fibrillation |
Inclusion Criteria:
Age ≥18 years
Scheduled to undergo elective isolated CABG surgery with cardiopulmonary bypass (CPB)
At increased risk of postoperative complications based on ≥1 of the following:
Exclusion Criteria:
Any of the following laboratory abnormalities at the time of screening:
History of gastric bypass or malabsorption
Active alcohol or illicit substance use in the prior 6 months
Participation in an investigational trial to evaluate pharmaceuticals or biologics within the past 3 months or 5 half-lives, whichever is shorter
Pregnant or breast-feeding
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
Current use of niacin >100 mg/day or NMN, nicotinamide, or nicotinamide riboside at any dose
Conflict with other research studies
Any condition which, in the judgement of the investigator, might increase the risk to the participant
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Shalender Bhasin, MB,BS | Contact | 617-525-9150 | sbhasin@bwh.harvard.edu | |
| David E Leaf, MD | Contact | 617-732-5951 | deleaf@bwh.harvard.edu |
| Name | Affiliation | Role |
|---|---|---|
| Shalender Bhasin, MB, BS | Brigham and Women's Hosptial | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Recruiting | Boston | Massachusetts | 02115 | United States |
In accordance with the NIH Policy for Data Management and Sharing, as well as the NIH Genomic Data Sharing Policy, deidentified data generated from this research will be shared with the research community by depositing it in the Harvard Dataverse. This will include any large-scale genomic data generated.
Within 1 year of the end date of the study
Only de-identified data will be available for scientific research upon review of specific request and provision of IRB-approval.
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| ID | Term |
|---|---|
| D058186 | Acute Kidney Injury |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
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| Placebo | Other | matching placebo tablets |
|
NAD+, NADH, and related metabolite concentrations in the circulation and in peripheral blood mononuclear cells |
| Baseline to day 90 |
| Markers of cardiac injury/dysfunction | Circulating levels of cardiac troponin I, creatine kinase MB fraction (CKMB), and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
| Acute kidney injury (AKI) | 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 | 7 days post-operatively |
| Serum creatinine (SCr) | Maximum baseline-adjusted changes in SCr | Immediately pre-operative to 7 days post-operative |
| Cystatin C | Circulating levels of cystatin C | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
| Neutrophil gelatinase-associated lipocalin (NGAL) | Circulating levels of measured neutrophil gelatinase-associated lipocalin (NGAL) | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
| Kidney Injury Molecule-1 (KIM-1) | Circulating levels of KIM-1 | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
| NMN level | Plasma concentrations of NMN | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
| 2PY Level | Plasma concentrations of 2PY | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
| N-Methylnicotinamide level | Plasma N-methylynicotinamide level | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
| nicotinamide level | Plasma nicotinamide concentrations | Preoperatively, on ICU arrival, and on postoperative days 1-4 |
Frequency of new-onset atrial fibrillation. Atrial fibrillation must be confirmed on a 12-lead ECG or a rhythm strip, confirmed by a healthcare provider, or treated (either medically [e.g., amiodarone] or with electrical cardioversion)
| First seven days postoperatively |
| Vasoactive-inotropic score | The vasoactive-inotropic score is a validated method for integrating all vasoactive medications and their doses on an hourly basis into a single measure. The score ranges from 0 to 100, with higher scores indicating greater cardiovascular support needs. | Immediately preoperatively to 24-hours post-incision |
| Time-to-liberation from vasoactive medications | Time (in hours) from end of cardiopulmonary bypass (CPB) to liberation from all vasopressors and inotropes. | End of cardiopulmonary bypass to 24 hours post surgery |
| ICU length of stay | time to release from the ICU post-operatively | Time in days in the ICU post-operatively, from the day of admission to the ICU postoperatively after the coronary artery bypass surgery to the time of release from ICU or date of death from any cause, up to 90 days |
| D005261 |
| Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |