Nicotinamide Riboside in Systolic Heart Failure

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)

• nicotinamide riboside (Dietary supplement), also known as Niagen: nicotinamide riboside capsule
• Placebo (Drug): matching placebo capsule

Primary outcomes

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

Secondary outcomes

• On-Trial Change in Whole Blood NAD+ Levels [Week 12-Week 0]: Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels
• Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment [16 weeks]: Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment
• Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate) [Week 12 - Week 0]: Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay

Other outcomes

• Exploratory Endpoint: Effect of NR on Functional Capacity [Week 12 - Week 0]: Change in Six Minute Walk Distance
• Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function [Week 12 - Week 0]: Change in Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography
• Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function [Week 12 - Week 0]: Tissue Doppler Imaging, e'

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) (Primary), Mean, events/participant: Nicotinamide Riboside 3.1 (0.0 to 9.0); Placebo 3.2 (1.0 to 7.0)
• On-Trial Change in Whole Blood NAD+ Levels (Secondary), Mean, uM: Nicotinamide Riboside 29.0 +/- 3.2; Placebo -0.3 +/- 0.6 (p <0.0001)
• Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment (Secondary), Number, participants: Nicotinamide Riboside 0; Placebo 0 (p <0.05)
• Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate) (Secondary), Mean, pmol/min/1,000,000 cells: Nicotinamide Riboside 21 +/- 42; Placebo 2 +/- 23 (p <0.05)
• Exploratory Endpoint: Effect of NR on Functional Capacity (Other pre specified), Mean, meters: Nicotinamide Riboside 6 +/- 8; Placebo 1 +/- 15 (p <0.05)
• Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function (Other pre specified), Mean, percentage of ejection fraction: Nicotinamide Riboside 0.0 +/- 2.2; Placebo 0.3 +/- 2.2 (p <0.05)
• Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function (Other pre specified), Mean, cm/sec: Nicotinamide Riboside 0.37 +/- 0.54; Placebo -0.44 +/- 0.39 (p <0.05)

Adverse events

Time frame: 16 weeks

Serious adverse events by term

Other adverse events by term

• Results publication: 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. PMID 36644285

• Study Protocol (PDF, 2018-01-29)
• Statistical Analysis Plan (PDF, 2022-09-27)

• Kevin D O'Brien, MD, Principal investigator, University of Washington

NIH grants: R21HL126209