Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure (NRII)

March 23, 2025 updated by: Kevin O'Brien, University of Washington
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

To definitively demonstrate the effects of increasing NAD+ levels in HF patients, this randomized, placebo-controlled trial of NR in 40 participants scheduled for elective LVAD surgery with the underlying hypotheses that those randomized to NR will have higher myocardial NAD+ levels, improved mitochondrial function, restored gene expression and reduced inflammatory response as compared to participants randomized to placebo. To this end, the study has the following specific aims:

Aim 1: Randomize 40 participants undergoing elective LVAD placement into a double-blind, placebo-controlled study of NR vs. placebo at an NR:placebo ratio of 2:1.

  1. Participants will have labs (including safety panels) drawn at baseline (Day 1), with NR or placebo dose escalation to 1000mg twice daily by Day 3, and the last dose administered the evening prior to surgery.
  2. Final labs will be drawn on the day of surgery, and samples of fresh cardiac tissue removed from the left ventricular apex during LVAD implantation surgery will be collected in the operating room.

Aim 2: Determine the effect of NR vs. placebo on NAD(H) levels, mitochondrial function and its regulation through epigenetic modifications in the failing myocardium.

  1. Measure NAD+ and NADH levels in the blood and myocardium of the participants.
  2. Assess mitochondrial morphology and function in cardiac tissue using electron microscopy (EM) and isolated mitochondria.
  3. Determine changes in protein acetylation in the mitochondrial and non-mitochondrial compartments and in nuclear gene regulation.

Aim 3: Test the hypothesis that NR improves mitochondrial function and reduces inflammatory response in HF patients.

  1. Measure mitochondrial function in peripheral blood mononucleated cells (PBMC).
  2. Determine the inflammatory response in PBMC from NR-treated vs. placebo participants.
  3. Compare effects on the circulating inflammasome vs. myocardial inflammation.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
32

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

  • Name: Shannon L Yedinak
  • Phone Number: 206-221-2142
  • Email: syedinak@uw.edu

Study Locations

  • United States
    • Washington
      • Seattle, Washington, United States, 98195
        • University of Washington

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. 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

  2. Meet clinical and socioeconomic screening criteria for elective LVAD implantation by the University of Washington Mechanical Circulatory Support Program
  3. Scheduled (or soon to be scheduled) for elective LVAD implantation
  4. Age >18 years

Exclusion Criteria:

  1. End-stage heart failure due to causes other than ischemic or non-ischemic cardiomyopathy (e.g., valvular, hypertrophic or infiltrative cardiomyopathies).

  2. Disease that disqualifies from consideration for LVAD implantation by the University of Washington program:

    1. Cirrhosis as evidenced by liver biopsy
    2. Irreversible, severe renal disease (estimated glomerular filtration rate (eGFR) <30) or on chronic dialysis
    3. Untreated thyroid disease (hyper- or hypo-thyroidism)
    4. Severe complications of diabetes, such as diabetes-related amputation, severe retinopathy, peripheral neuropathy or diabetic renal disease (eGFR <30)
  3. Tissue physiology or other factors that, in the opinion of the Cardiac Surgeons, make the patient at unacceptably high risk for adverse outcomes.
  4. Non-compliance with current treatments, including failure to follow prescribed therapies, such as medications, clinic visits, diagnostic testing and behavioral contracts
  5. Active use/abuse of illicit substances
  6. Lack of adequate caregiver support to help patient manage LVAD
  7. Known allergies to niacin, nicotinamide or warfarin
  8. Inability to perform Study visits or procedures
  9. Unwillingness/inability to provide informed consent.
  10. Participants considered by the attending cardiologist and/or the investigator to be unsuitable for the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Nicotinamide riboside

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
Nicotinamide riboside 250mg capsules
Placebo Comparator: Placebo

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
Matching placebo 250mg capsules

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Between-group comparisons of whole blood NAD+ levels
Time Frame: Up to 14 days
Comparisons of whole blood NAD+ levels on the Day of LVAD Surgery in participants randomized to NR vs. placebo
Up to 14 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Between-group comparisons of myocardial NAD(H) levels
Time Frame: Up to 14 days
Comparisons of myocardial NAD(H) levels in participants randomized to NR vs. placebo
Up to 14 days
Between-group comparisons of myocardial mitochondrial respiratory function.
Time Frame: Up to 14 days
Comparisons of myocardial mitochondrial respiration in participants randomized to NR vs. placebo
Up to 14 days
Between-group comparisons of myocardial mitochondrial morphology.
Time Frame: Up to 14 days
Comparisons of myocardial mitochondrial morphology, by electron microscopy, in participants randomized to NR vs. placebo
Up to 14 days
Between-group comparisons of myocardial protein acetylation
Time Frame: Up to 14 days
Comparisons of myocardial protein acetylation in participants randomized to NR vs. placebo
Up to 14 days
Between-group comparisons of myocardial gene expression by RNA-seq and the myocardial epigenome by ATAC-seq
Time Frame: Up to 14 days
Comparisons, NR vs. placebo-treated participants, of myocardial gene expression by RNA sequencing (RNA-seq) and the myocardial epigenome by the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq)
Up to 14 days
Between-group comparisons of inflammatory markers in blood
Time Frame: Up to 14 days
Comparisons, in patients randomized to NR vs. placebo of: 1) plasma levels of highly-sensitive C-reactive protein, interleukin-1beta, interleukin-6, interleukin-18, tumor necrosis factor-alpha, and NLR family pyrin domain containing 3 (NLRP3), as well as 2) mRNA expression of these cytokines in isolated peripheral blood mononuclear cells
Up to 14 days
Between-group comparisons of inflammatory markers in myocardium
Time Frame: Up to 14 days
Comparisons by quantitative morphometry of immunohistochemical staining of macrophages (including M1 and M2 phenotypes) in myocardium in participants randomized to NR vs. placebo
Up to 14 days

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Correlations of whole blood NAD+ levels with secondary outcome measures
Time Frame: Up to 14 days
Analyses of correlations of whole blood NAD+ levels and their changes with each of the secondary outcome measures in the NR-treated group
Up to 14 days
Correlations of myocardial NAD(H) levels with secondary outcome measures
Time Frame: Up to 14 days
Analyses of correlations of myocardial NAD(H) levels and their changes with secondary outcome measures in the NR-treated group
Up to 14 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Washington

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Kevin D O'Brien, MD, University of Washington

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 26, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 30, 2024

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 31, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 18, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 21, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 27, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 23, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • STUDY00007432
  • 1R01HL144937-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The Investigators plan to deposit study results in BioLINCC. The Study will generate data that is primarily applicable to the basic research questions that are proposed. 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/). Data sets will be submitted 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.

IPD Sharing 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.

IPD Sharing 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/).

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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