Nicotinamide Riboside in LVAD Recipients

Early Phase 1

Completed

• Conditions: Heart Failure New York Heart Association Class IV; Mitochondrial Alteration; Heart Failure，Congestive
• Interventions: Dietary Supplement: Nicotinamide riboside

• Registration Number: NCT03727646
• Lead Sponsor: University of Washington

Brief Summary

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.

Detailed Description

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 If the surgery doesn't happen by then, the participant will be withdrawn from the study.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.

Study Timeline

• Study Start: 2018-09-26
• Study First Submitted: 2018-10-16
• Study First Submitted QC: 2018-10-31
• Study First Posted: 2018-11-01
• Primary Completion: 2018-11-26
• Study Completion: 2018-11-26
• Status Verified: 2020-08
• Last Update Submitted: 2020-08-28
• Last Update Posted: 2020-09-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 5

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Open-label nicotinamide riboside	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

Primary Outcome Measures

Name	Time	Method
Number of Participates Experiencing Treatment-Emergent Adverse Events (Safety and Tolerability)	from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14)	Participants experiencing adverse events during the time they are on the study drug.; Regarding time frame: Day 1 is the first day that the study subjects start taking the study drug (NR). The participants stop taking the study drug on the day before his/her LVAD surgery (between Days 6 and 14).
Pre/Post NR Comparison of Maximal Mitochondrial Respiration in PBMCs	from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14)	Comparison of maximal mitochondrial respiration in PBMCs on the Day of LVAD Surgery Pre- vs Post-NR Administration

Secondary Outcome Measures

Name	Time	Method
Effect of NR on Whole Blood NAD+ Levels	from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14)	Change in whole blood NAD+ levels from Baseline to Day of Surgery in NR-treated participants
Between-group Comparison of Mitochondrial Respiration (Seahorse Assay) in Isolated Peripheral Blood Mononuclear Cells (PBMCs)	Data collected 6-14 days after study intervention (oral NR) has been initiated.	Comparison of mitochondrial respiration (Seahorse assay) in isolated peripheral blood mononuclear cells (PBMCs) on the Day of LVAD Surgery in NR-treated vs. historical control patients
Between-group Comparison of Whole Blood NAD+ Levels	Data collected 6-14 days after study intervention (oral NR) has been initiated.	Comparison of whole blood NAD+ levels on the Day of LVAD Surgery in NR-treated vs. historical control patients

Trial Locations

Locations (1)

University of Washington; 🇺🇸 Seattle, Washington, United States