Nicotinamide Riboside in Systolic Heart Failure
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 8/3/2018 |
| Start Date: | May 19, 2016 |
| End Date: | June 30, 2019 |
| Contact: | Kevin D O'Brien, MD |
| Email: | cardiac@uw.edu |
| Phone: | 206 685-3930 |
Safety and Tolerability of the Nutritional Supplement, Nicotinamide Riboside, in Systolic Heart Failure
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.
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.
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)
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)
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
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