Nicotinamide Riboside in Systolic Heart Failure

Study Overview
=================
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)

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

Conditions
-----------------
Heart Failure, Systolic

Intervention / Treatment
-----------------
* Dietary Supplement: nicotinamide riboside
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: 2:1 randomization to nicotinamide riboside vs. matching placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotinamide Riboside<br>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<br>* nicotinamide riboside capsule<br>* Other names: Niagen;|
| Placebo Comparator: Placebo<br>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<br>* matching placebo capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Adverse Events | up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| On-Trial Change in Whole Blood NAD+ Levels | Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels | Week 12-Week 0 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
nicotinamide riboside, Nicotinamide-Adenine Dinucleotide