Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure

NCT04528004 | Active Not Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY000074321R01HL144937-01A1
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

Preliminary animal studies by ourselves and others suggest that the dietary supplement, nicotinamide riboside (NR), may improve cardiac function in heart failure (HF) by increasing cellular levels of its metabolite, nicotinamide adenine dinucleotide (NAD+, NADH). This Study will address a key gap in current knowledge by assessing the mechanisms through which raising blood and myocardial NAD+ levels in humans mediates changes in mitochondrial function, protein and epigenetic modifications, as well as inflammation. Human myocardium will be obtained after 4-14 days of oral NR supplementation from advanced heart failure patients undergoing elective left ventricular assist device (LVAD) implantation. Positive results would provide evidence to proceed with further studies of NR as a mitochondria-targeted metabolic therapy in heart failure.

Conditions

Heart Failure, Systolic; Heart Failure NYHA Class IV; Metabolic Disturbance

Outcome Measures

Primary Outcomes (1)

• Between-group comparisons of whole blood NAD+ levels

  Comparisons of whole blood NAD+ levels on the Day of LVAD Surgery in participants randomized to NR vs. placebo

  Up to 14 days

Secondary Outcomes (7)

• Between-group comparisons of myocardial NAD(H) levels

  Up to 14 days

• Between-group comparisons of myocardial mitochondrial respiratory function.

  Up to 14 days

• Between-group comparisons of myocardial mitochondrial morphology.

  Up to 14 days

• Between-group comparisons of myocardial protein acetylation

  Up to 14 days

• Between-group comparisons of myocardial gene expression by RNA-seq and the myocardial epigenome by ATAC-seq

  Up to 14 days

Other Outcomes (2)

• Correlations of whole blood NAD+ levels with secondary outcome measures

  Up to 14 days

• Correlations of myocardial NAD(H) levels with secondary outcome measures

  Up to 14 days

Study Arms (2)

Nicotinamide riboside

EXPERIMENTAL

Participants randomized to Nicotinamide Riboside (NR) and scheduled to receive an LVAD will receive nicotinamide riboside (NR) capsules according to the following administration schedule: Dose Escalation Day 1: 250 mg (1 capsule) twice daily (total daily intake = 500 mg) Day 2: 500 mg (2 capsules) twice daily (total daily intake = 1000 mg) Day 3: 1000 mg (4 capsules) twice daily (total daily intake = 2000 mg) Dose Maintenance Day 4: 1000 mg (4 capsules) twice daily Day 5-14 as applicable thru Day Before Surgery: 1000 mg (4 capsules) twice daily Washout Day of LVAD Surgery and/or Day 15: None

Drug: Nicotinamide riboside

Placebo

PLACEBO COMPARATOR

Participants randomized to Placebo and scheduled to receive an LVAD will receive Placebo capsules according to the following administration schedule: Dose Escalation Day 1: 250 mg (1 capsule) twice daily (total daily intake = 500 mg) Day 2: 500 mg (2 capsules) twice daily (total daily intake = 1000 mg) Day 3: 1000 mg (4 capsules) twice daily (total daily intake = 2000 mg) Dose Maintenance Day 4: 1000 mg (4 capsules) twice daily Day 5-14 as applicable thru Day Before Surgery: 1000 mg (4 capsules) twice daily Washout Day of LVAD Surgery and/or Day 15: None

Other: Placebo

Interventions

Nicotinamide riboside DRUG

Nicotinamide riboside 250mg capsules

Nicotinamide riboside

Placebo OTHER

Matching placebo 250mg capsules

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• End-stage heart failure due to ischemic or non-ischemic cardiomyopathy
• a. If implanted for destination therapy indication, must have New Your Heart Association (NYHA) Class IV Heart Failure AND left ventricular ejection fraction (LVEF) \<25% OR maximum minute consumption of oxygen (VO2) \<14 OR on requirement for continuous intravenous inotropes
• Meet clinical and socioeconomic screening criteria for elective LVAD implantation by the University of Washington Mechanical Circulatory Support Program
• Scheduled (or soon to be scheduled) for elective LVAD implantation
• Age \>18 years

You may not qualify if:

• End-stage heart failure due to causes other than ischemic or non-ischemic cardiomyopathy (e.g., valvular, hypertrophic or infiltrative cardiomyopathies).
• Disease that disqualifies from consideration for LVAD implantation by the University of Washington program:
• Cirrhosis as evidenced by liver biopsy
• Irreversible, severe renal disease (estimated glomerular filtration rate (eGFR) \<30) or on chronic dialysis
• Untreated thyroid disease (hyper- or hypo-thyroidism)
• Severe complications of diabetes, such as diabetes-related amputation, severe retinopathy, peripheral neuropathy or diabetic renal disease (eGFR \<30)
• Tissue physiology or other factors that, in the opinion of the Cardiac Surgeons, make the patient at unacceptably high risk for adverse outcomes.
• Non-compliance with current treatments, including failure to follow prescribed therapies, such as medications, clinic visits, diagnostic testing and behavioral contracts
• Active use/abuse of illicit substances
• Lack of adequate caregiver support to help patient manage LVAD
• Known allergies to niacin, nicotinamide or warfarin
• Inability to perform Study visits or procedures
• Unwillingness/inability to provide informed consent.
• Participants considered by the attending cardiologist and/or the investigator to be unsuitable for the study

Sponsors & Collaborators

• University of Washington: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of Washington

Seattle, Washington, 98195, United States

Location

MeSH Terms

Conditions

Heart Failure, Systolic

Interventions

nicotinamide-beta-riboside

Condition Hierarchy (Ancestors)

Heart Failure; Heart Diseases; Cardiovascular Diseases

Study Officials

• Kevin D O'Brien, MD

  University of Washington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomization with a 2:1 nicotinamide riboside:matching placebo allocation ratio. Dispensing of nicotinamide riboside and matching placebo will be performed by the University of Washington Investigational Drug Services.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, School of Medicine

Model Details: Randomized, interventional trial

Study Record Dates

• First Submitted: August 18, 2020
• First Posted: August 27, 2020
• Study Start: September 26, 2020
• Primary Completion: November 30, 2024
• Study Completion: July 31, 2025
• Last Updated: March 25, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: Data will be deposited no later than three years after the final study dataset is locked or two years after the core manuscript from the trial has been published, whichever comes first.
• Access Criteria: It is the explicit intention of the Investigators that these data will be placed in a readily accessible public database. The Investigators anticipate placing de-identified study results into the NHLBI data repository at the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) (biolincc.nhlbi.nih.gov/home/).

Locations

US (1)