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Nicotinamide Riboside in Systolic Heart Failure

Primary Purpose

Heart Failure, Systolic

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

nicotinamide riboside

Placebo

About this trial

This is an interventional other trial for Heart Failure, Systolic focused on measuring nicotinamide riboside, Nicotinamide-Adenine Dinucleotide

Eligibility Criteria

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

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

Sites / Locations

University of Washington

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Nicotinamide Riboside

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)

Adverse Events

Secondary Outcome Measures

On-Trial Change in Whole Blood NAD+ Levels

Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels

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

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

Full Information

NCT ID

NCT03423342

First Posted

April 11, 2017

Last Updated

October 26, 2022

Sponsor

University of Washington

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT03423342

Brief Title

Nicotinamide Riboside in Systolic Heart Failure

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Completed

Study Start Date

May 19, 2016 (Actual)

Primary Completion Date

April 11, 2019 (Actual)

Study Completion Date

June 30, 2019 (Actual)

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

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.

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)

6. Conditions and Keywords

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

Heart Failure, Systolic

Keywords

nicotinamide riboside, Nicotinamide-Adenine Dinucleotide

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

2:1 randomization to nicotinamide riboside vs. matching placebo

Masking

ParticipantCare ProviderInvestigator

Masking Description

Randomization and dispensing of matching placebo will be performed by Investigational Drug Services at the University of Washington

Allocation

Randomized

Enrollment

30 (Actual)

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

Dietary Supplement

Intervention Name(s)

nicotinamide riboside

Other Intervention Name(s)

Niagen

Intervention Description

nicotinamide riboside capsule

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

matching placebo capsule

Primary Outcome Measure Information:

Title

Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)

Description

Adverse Events

Time Frame

up to 12 weeks

Secondary Outcome Measure Information:

Title

On-Trial Change in Whole Blood NAD+ Levels

Description

Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels

Time Frame

Week 12-Week 0

Title

Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment

Description

Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment

Time Frame

16 weeks

Title

Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate)

Description

Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay

Time Frame

Week 12 - Week 0

Other Pre-specified Outcome Measures:

Title

Exploratory Endpoint: Effect of NR on Functional Capacity

Description

Change in Six Minute Walk Distance

Time Frame

Week 12 - Week 0

Title

Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function

Description

Change in Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography

Time Frame

Week 12 - Week 0

Title

Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function

Description

Tissue Doppler Imaging, e'

Time Frame

Week 12 - Week 0

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

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

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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

Learn more about this trial

Nicotinamide Riboside in Systolic Heart Failure

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