Nicotinamide Riboside in Systolic Heart Failure

Sponsor

University of Washington (Other)

Overall Status

Completed

CT.gov ID

NCT03423342

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Enrollment

Location

Arms

37.4

Actual Duration (Months)

0.8

Patients Per Site Per Month

Study Details

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.

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 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).
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:

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

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Intervention Model Description:

2:1 randomization to nicotinamide riboside vs. matching placebo2:1 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

Actual Primary Completion Date :

Apr 11, 2019

Actual Study Completion Date :

Jun 30, 2019

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [up to 12 weeks]
Adverse Events

Secondary Outcome Measures

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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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