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

Primary Purpose

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

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Nicotinamide riboside

Placebo

About this trial

This is an interventional basic science trial for Heart Failure, Systolic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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:
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)
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

Sites / Locations

University of WashingtonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Nicotinamide riboside

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Between-group comparisons of myocardial NAD(H) levels

Comparisons of myocardial NAD(H) levels in participants randomized to NR vs. placebo

Between-group comparisons of myocardial mitochondrial respiratory function.

Comparisons of myocardial mitochondrial respiration in participants randomized to NR vs. placebo

Between-group comparisons of myocardial mitochondrial morphology.

Comparisons of myocardial mitochondrial morphology, by electron microscopy, in participants randomized to NR vs. placebo

Between-group comparisons of myocardial protein acetylation

Comparisons of myocardial protein acetylation in participants randomized to NR vs. placebo

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

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)

Between-group comparisons of inflammatory markers in blood

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

Between-group comparisons of inflammatory markers in myocardium

Comparisons by quantitative morphometry of immunohistochemical staining of macrophages (including M1 and M2 phenotypes) in myocardium in participants randomized to NR vs. placebo

Full Information

NCT ID

NCT04528004

First Posted

August 18, 2020

Last Updated

July 17, 2023

Sponsor

University of Washington

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT04528004

Brief Title

Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure

Acronym

NRII

Official Title

Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 26, 2020 (Actual)

Primary Completion Date

March 31, 2025 (Anticipated)

Study Completion Date

July 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Washington

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

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. 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. 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. Measure NAD+ and NADH levels in the blood and myocardium of the participants. Assess mitochondrial morphology and function in cardiac tissue using electron microscopy (EM) and isolated mitochondria. 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. Measure mitochondrial function in peripheral blood mononucleated cells (PBMC). Determine the inflammatory response in PBMC from NR-treated vs. placebo participants. Compare effects on the circulating inflammasome vs. myocardial inflammation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Model Description

Randomized, interventional trial

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

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.

Allocation

Randomized

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Nicotinamide riboside

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Nicotinamide riboside

Intervention Description

Nicotinamide riboside 250mg capsules

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Matching placebo 250mg capsules

Primary Outcome Measure Information:

Title

Between-group comparisons of whole blood NAD+ levels

Description

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

Time Frame

Up to 14 days

Secondary Outcome Measure Information:

Title

Between-group comparisons of myocardial NAD(H) levels

Description

Comparisons of myocardial NAD(H) levels in participants randomized to NR vs. placebo

Time Frame

Up to 14 days

Title

Between-group comparisons of myocardial mitochondrial respiratory function.

Description

Comparisons of myocardial mitochondrial respiration in participants randomized to NR vs. placebo

Time Frame

Up to 14 days

Title

Between-group comparisons of myocardial mitochondrial morphology.

Description

Comparisons of myocardial mitochondrial morphology, by electron microscopy, in participants randomized to NR vs. placebo

Time Frame

Up to 14 days

Title

Between-group comparisons of myocardial protein acetylation

Description

Comparisons of myocardial protein acetylation in participants randomized to NR vs. placebo

Time Frame

Up to 14 days

Title

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

Description

Time Frame

Up to 14 days

Title

Between-group comparisons of inflammatory markers in blood

Description

Time Frame

Up to 14 days

Title

Between-group comparisons of inflammatory markers in myocardium

Description

Comparisons by quantitative morphometry of immunohistochemical staining of macrophages (including M1 and M2 phenotypes) in myocardium in participants randomized to NR vs. placebo

Time Frame

Up to 14 days

Other Pre-specified Outcome Measures:

Title

Correlations of whole blood NAD+ levels with secondary outcome measures

Description

Analyses of correlations of whole blood NAD+ levels and their changes with each of the secondary outcome measures in the NR-treated group

Time Frame

Up to 14 days

Title

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

Description

Analyses of correlations of myocardial NAD(H) levels and their changes with secondary outcome measures in the NR-treated group

Time Frame

Up to 14 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Laura Curtin

Phone

206-616-6432

LCurtin@Cardiology.washington.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Shannon L Yedinak

Phone

206-221-2142

syedinak@uw.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kevin D O'Brien, MD

Organizational Affiliation

University of Washington

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Washington

City

Seattle

State/Province

Washington

ZIP/Postal Code

98195

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kevin D O'Brien, MD

Phone

206-529-7802

cardiac@uw.edu

First Name & Middle Initial & Last Name & Degree

Rong Tian, MD

Phone

206 616-5672

rongtian@u.washington.edu

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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/).

Learn more about this trial

Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure

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