Nicotinamide Riboside in Systolic Heart Failure

NCT ID: NCT03423342

Last Updated: 2022-11-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-19
• Study Completion Date: 2019-06-30

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)

Conditions

Heart Failure, Systolic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

nicotinamide riboside

Intervention Type: DIETARY_SUPPLEMENT

nicotinamide riboside capsule

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

matching placebo capsule

Interventions

nicotinamide riboside

nicotinamide riboside capsule

Intervention Type: DIETARY_SUPPLEMENT

Placebo

matching placebo capsule

Intervention Type: DRUG

Other Intervention Names

Niagen

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

Kevin O'Brien

Professor, Medicine/Cardiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kevin D O'Brien, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

University of Washington

Seattle, Washington, United States

Countries

United States

References

Wang DD, Airhart SE, Zhou B, Shireman LM, Jiang S, Melendez Rodriguez C, Kirkpatrick JN, Shen DD, Tian R, O'Brien KD. Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction. JACC Basic Transl Sci. 2022 Sep 14;7(12):1183-1196. doi: 10.1016/j.jacbts.2022.06.012. eCollection 2022 Dec.

Reference Type: DERIVED

PMID: 36644285 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

1R21HL126209-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00001830

Identifier Type: -

Identifier Source: org_study_id