Nicotinamide Riboside in Systolic Heart Failure

Safety and Tolerability of the Nutritional Supplement, Nicotinamide Riboside, in Systolic Heart Failure

Mitochondrial dysfunction has been implicated in heart failure (HF), and is associated with an imbalance in intracellular ratio of reduced nicotinamide-adenine dinucleotide (NADH) to oxidized nicotinamide-adenine dinucleotide (NAD), or the NADH/NAD ratio. In mouse models of HF, we have found that normalization of the NADH/NAD, through supplementation with NAD+ precursors, is associated with improvement in cardiac function. This Study will randomize participants with systolic HF (ejection fraction ≤40%) to treatment with the NAD precursor, nicotinamide riboside (NR) or matching placebo, uptitrated to a final oral dose of 1000mg twice daily, to determine the safety and tolerability of NR in participants with systolic HF.

Study Overview

• Status: Completed
• Conditions: Heart Failure, Systolic
• Intervention / Treatment: Drug: Placebo; Dietary supplement: nicotinamide riboside

Detailed Description

Aim 1: Determine the safety and tolerability of NR in patients with clinically stable, systolic heart failure (LVEF <40%). To accomplish this Aim:

A) a total of 30 participants with clinically stable, systolic heart failure (LVEF <40%) will undergo 2:1 randomization to NR 250mg PO twice daily or matching placebo B) NR (or matching placebo), will be increased weekly by 250mg/dose (500mg/day) to a final dose of 1000mg PO twice daily. Clinic visits with labs bi-weekly during dose escalation will assess HF symptoms and monitor labs [B-type natriuretic peptide (BNP), complete blood count (CBC), glycosylated hemoglobin, alanine aminotransferase (ALT), creatine kinase (CK), insulin/glucose, uric acid, electrolytes, blood urea nitrogen (BUN) and creatinine (Cr).

C) to ensure intermediate-term safety and tolerability, participants will continue on their maximum tolerated dose (of NR or placebo) through Study Week 12

Aim 2: Determine whether, at the doses employed, NR and NAD are detectable in whole blood.

Aim 3 (Exploratory): Assess the range of potential effect sizes of NR on HF surrogate endpoints using:

A) Six-minute walk tests (6MWTs) at each visit (including Screening) to assess functional capacity B) Echocardiography at Baseline and Week 12 to assess LV systolic function (by real-time, 3D echocardiography) and diastolic function (by integrated Doppler and tissue Doppler imaging)

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women aged 18 and older with systolic heart failure [left ventricular ejection fraction (LVEF) by standard 2D echocardiography or radionuclide ventriculography of ≤40%] deemed, in the clinical opinion of their treating cardiologist to be non-ischemic or ischemic in origin.
• Clinically stable (no cardiac procedures or hospitalizations for hospitalizations for cardiac causes, including HF, ischemia or arrhythmia) within the previous 3 months
• Ability to undergo study procedures, including scheduled visits, blood draws and six-minute walk test (6MWT)
• Willingness/ability to provide informed consent

Exclusion Criteria:

• Heart failure with preserved ejection fraction (LVEF greater than 40%)
• Heart failure due, in the opinion of their treating cardiologist, to etiologies other than non-ischemic or ischemic. Examples of exclusionary heart failure etiologies include primary valvular disease, or infiltrative or inflammatory cardiomyopathies.
• Cardiac surgery, percutaneous coronary intervention (PCI) or cardiac device implantation within the previous 3 months
• Hospitalizations for cardiovascular causes, including heart failure, chest pain, stroke, transient ischemic attack or arrhythmias within the previous 3 months
• Inability to perform Study visits or procedures (e.g., physical inability to perform 6MWT)
• Unwillingness/inability to provide informed consent
• ALT greater than 3 times the upper limit of normal, hepatic insufficiency or active liver disease
• Recent history of acute gout
• Chronic renal insufficiency with creatinine ≥2.5mg/dL
• Pregnant (or likely to become pregnant) women
• Significant co-morbidity likely to cause death in the 6 month follow-up period
• Significant active history of substance abuse within the previous 5 years
• Current participation in another long-term clinical trial
• History of intolerance to NR precursor compounds, including niacin or nicotinamide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nicotinamide Riboside; Nicotinamide riboside will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12.	Dietary supplement: nicotinamide riboside; nicotinamide riboside capsule; Other Names: Niagen
Placebo Comparator: Placebo; Matching placebo will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12.	Drug: Placebo; matching placebo capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	Adverse Events	up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
On-Trial Change in Whole Blood NAD+ Levels	Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels	Week 12-Week 0
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment	Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment	16 weeks
Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate)	Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay	Week 12 - Week 0

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Endpoint: Effect of NR on Functional Capacity	Change in Six Minute Walk Distance	Week 12 - Week 0
Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function	Change in Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography	Week 12 - Week 0
Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function	Tissue Doppler Imaging, e'	Week 12 - Week 0

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Kevin D O'Brien, MD, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2016
• Primary Completion (Actual): April 11, 2019
• Study Completion (Actual): June 30, 2019

Study Registration Dates

• First Submitted: April 11, 2017
• First Submitted That Met QC Criteria: January 30, 2018
• First Posted (Actual): February 6, 2018

Study Record Updates

• Last Update Posted (Actual): November 16, 2022
• Last Update Submitted That Met QC Criteria: October 26, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: nicotinamide riboside; Nicotinamide-Adenine Dinucleotide
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Murmurs; Heart Failure; Systolic Murmurs; Heart Failure, Systolic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: STUDY00001830; 1R21HL126209-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: A de-identified, public access database will be made available two years after publication of the primary study results. Data files will be delivered in electronic format, providing meta-data that completely describes the tables, variables and coding. Both the raw data and the primary analysis files will be included. Primary analysis files are a compilation of key variables used to generate the statistical results, to help assure that investigators reach consistent conclusions when analyzing the data to published results. Data, documentation and all other materials will be delivered to NHLBI, as well as a document that fully describes the data, steps taken to de-identify the data, and quality control procedures. A document summarizing data tables and other files that are being delivered and describing the data manipulations applied to the data to assure data anonymity, including an annotated clinical study report providing the database variable names.
• IPD Sharing Time Frame: 2 years following Study completion
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

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