Nicotinamide Riboside in Systolic Heart Failure

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Heart Failure, Systolic	Dietary Supplement: nicotinamide riboside; Drug: Placebo	Phase 1; Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	30 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Intervention Model Description:	2:1 randomization to nicotinamide riboside vs. matching placebo
Masking:	Triple (Participant, Care Provider, Investigator)
Masking Description:	Randomization and dispensing of matching placebo will be performed by Investigational Drug Services at the University of Washington
Primary Purpose:	Other
Official Title:	Safety and Tolerability of the Nutritional Supplement, Nicotinamide Riboside, in Systolic Heart Failure
Actual Study Start Date :	May 19, 2016
Estimated Primary Completion Date :	May 1, 2018
Estimated Study Completion Date :	June 30, 2018

Arms and Interventions

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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
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

Outcome Measures

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Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: up to 12 weeks ]
   Adverse Events

Secondary Outcome Measures :

1. Effect of NR on Whole Blood NAD+ Levels [ Time Frame: Week 12 ]
   Between-group comparison of Whole Blood NAD+ Levels at Week 12
2. Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment [ Time Frame: up to 12 weeks ]
   Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment
3. Effect of NR on Mitochondrial Function [ Time Frame: Week 12 ]
   Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay

Other Outcome Measures:

1. Exploratory Endpoint: Effect of NR on Functional Capacity [ Time Frame: Clinic Visits at Weeks -2 (Screening), 0 (Baseline), 2, 4, 8 and 12 (Final) ]
   Six Minute Walk Test
2. Exploratory Endpoint: Effect of NR on Left Ventricular Systolic Function [ Time Frame: Clinic Visits at Weeks 0 (Baseline) and 12 (Final) ]
   Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography
3. Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function [ Time Frame: Clinic Visits at Weeks 0 (Baseline) and 12 (Final) ]
   Tissue Doppler Imaging

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Contacts

Contact: Kevin D O'Brien, MD	206 685-3930	cardiac@uw.edu
Contact: Rong Tian, MD	206 616-5672	rongtian@u.washington.edu

Locations

United States, Washington
University of Washington	Recruiting
Seattle, Washington, United States, 98195
Contact: Kevin D O'Brien, MD 206-529-7802 cardiac@uw.edu
Contact: Rong Tian, MD 206 616-5672 rongtian@u.washington.edu

Sponsors and Collaborators

University of Washington

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:	Kevin D O'Brien, MD	University of Washington

  Study Documents (Full-Text)

Documents provided by Kevin O'Brien, University of Washington:

Study Protocol  [PDF] February 17, 2016

Statistical Analysis Plan  [PDF] February 17, 2016

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Kevin O'Brien, Professor, Medicine/Cardiology, University of Washington
ClinicalTrials.gov Identifier:	NCT03423342 History of Changes
Other Study ID Numbers:	STUDY00001830; 1R21HL126209-01 ( U.S. NIH Grant/Contract )
First Posted:	February 6, 2018
Last Update Posted:	February 6, 2018
Last Verified:	January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
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.
Supporting Materials:	Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
Time Frame:	2 years following Study completion

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

Keywords provided by Kevin O'Brien, University of Washington:

nicotinamide riboside; Nicotinamide-Adenine Dinucleotide

Additional relevant MeSH terms:

Niacinamide; Niacin; Nicotinic Acids; Heart Failure; Heart Failure, Systolic; Heart Diseases; Cardiovascular Diseases; Vitamin B Complex; Vitamins	Micronutrients; Growth Substances; Physiological Effects of Drugs; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Vasodilator Agents