Nicotinamide Riboside in LVAD Recipients

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

EARLY_PHASE1

Total Enrollment

5 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-09-26

Study Completion Date

2018-11-26

Brief Summary

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While preliminary data show that oral nicotinamide riboside (NR) supplementation increases myocardial levels of oxidized nicotine-adenine dinucleotide (NAD+) levels in mice, there has been no direct evidence that suggests oral NR increases NAD+ levels or improves mitochondrial function in human hearts. This Pilot Study is designed to obtain feasibility data for a planned, larger study testing the hypothesis that oral NR supplementation will increase myocardial NAD+ levels and improve cardiomyocyte mitochondrial function in participants with advanced heart failure planned for elective left ventricular assist device (LVAD) implantation. To demonstrate safety and feasibility of NR in this patient population, the investigators propose to enroll 5 participants planned for LVAD implantation in a Pilot Study of NR in which participants will receive NR, up-titrated over 3 days to a final NR dose of 1000mg twice daily. Blood and myocardial tissue analyses collected previously from age- and gender-matched LVAD recipients will serve as controls.

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Detailed Description

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This Pilot Study will examine the following Aims:

Aim 1: Enroll 5 participants scheduled for elective left ventricular assist device (LVAD) placement into an open-label study of nicotinamide riboside (NR).

a. Participants will have labs (including safety panels) drawn at baseline (Day 1), then receive escalating doses of NR to a maximum dose of 1000mg twice daily by Day 3. Participants will be continued on NR at 1000mg twice daily until LVAD implantation surgery.

On the morning of LVAD implantation Surgery (Day 5 or later), participants will have final labs drawn. Samples of fresh cardiac tissue removed from the left ventricular apex during LVAD implantation surgery will be collected in the operating room. The primary analyses will be performed on NR-treated participants who were on the maximum NR dose of 1000mg twice daily for at least 2 days prior to LVAD implantation surgery. The maximum duration of NR administration will be capped at 14 days. If the surgery doesn't happen by then, the participant will be withdrawn from the study.

Aim 2: Determine the effect of NR (as compared to historical controls) on levels of the oxidized and reduced forms of nicotine-adenine dinucleotide (NAD+ and NADH, respectively), mitochondrial function and its regulation through modifications of the epigenome 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, respectively, electron microscopy (EM) and isolated mitochondria.
3. Determine protein acetylation in the mitochondrial and non-mitochondrial compartments and changes in nuclear gene regulation.

Aim 3: Test the hypothesis that NR improves mitochondrial function and reduces inflammatory response in heart failure (HF) patients receiving NR (as compared to historical controls).

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

Conditions

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Heart Failure，Congestive Heart Failure New York Heart Association Class IV Mitochondrial Alteration

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SINGLE_GROUP

This single-center, open-label study will compare blood and myocardial NAD+ levels and other mitochondrial endpoints in participants with end-stage heart failure receiving open-label nicotinamide riboside prior to LVAD implantation to similar endpoints from patients previously undergoing LVAD implantation.

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study biostatistician will be blinded to group (NR vs. untreated controls)

Study Groups

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Open-label nicotinamide riboside

Participants scheduled to receive an LVAD will be prescribed nicotinamide riboside (NR) 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

Group Type EXPERIMENTAL

Nicotinamide riboside

Intervention Type DIETARY_SUPPLEMENT

nicotinamide riboside supplied as 250mg capsules

Baseline controls

Patients previously receiving LVADs, in whom blood and myocardial tissue assays for NAD+ levels and mitochondrial function were performed.

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Nicotinamide riboside

nicotinamide riboside supplied as 250mg capsules

Intervention Type DIETARY_SUPPLEMENT

Eligibility Criteria

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Inclusion Criteria

* Diagnosis of advanced heart failure.
* Planned elective LVAD implantation surgery with patient agreements for candidacy in place as required by UWMC.
* Hospital inpatient at time of enrollment.
* Ability to undergo Study procedures.
* Willingness/ability to provide informed consent.

Exclusion Criteria

* Current smoking
* Receiving certain concurrent supplements (to be determined at discretion of the PI). Note that UWMC Nutrition Care standards call for a general multivitamin (1 tab PO daily) as part of the advanced heart failure therapy (AHFT) work-up.
* Known allergies to niacin or nicotinamide.
* Hepatic, renal, endocrine, or neurological disease that disqualify them from consideration for LVAD implantation.
* Inability to perform Study visits or procedures.
* Unwillingness/inability to provide informed consent.
* Women who are currently pregnant or who wish to become pregnant over the course of the study follow-up are not allowed to join this study. This exclusion is built into the LVAD candidate selection process.

Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No