Nicotinamide Riboside in Systolic Heart Failure

Heart Failure, Systolic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03423342
• Other study ID #: STUDY00001830
• Secondary ID: 1R21HL126209-01
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 19, 2016
• Est. completion date: June 30, 2019

Study information

• Verified date: October 2022
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: June 30, 2019
• Est. primary completion date: April 11, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Systolic
• Systolic Murmurs

Intervention

Dietary Supplement:
• nicotinamide riboside
nicotinamide riboside capsule

Drug:
• Placebo
matching placebo capsule

Locations

Country	Name	City	State
United States	University of Washington	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
University of Washington	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Endpoint: Effect of NR on Functional Capacity	Change in Six Minute Walk Distance	Week 12 - Week 0
Other	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
Other	Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function	Tissue Doppler Imaging, e'	Week 12 - Week 0
Primary	Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	Adverse Events	up to 12 weeks
Secondary	On-Trial Change in Whole Blood NAD+ Levels	Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels	Week 12-Week 0
Secondary	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
Secondary	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