The Effect of Nicotinamide Riboside on Skeletal Muscle Function in Heart Failure Subjects

NCT ID: NCT03565328

Last Updated: 2020-10-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-27
• Study Completion Date: 2019-11-18

Brief Summary

Background:

People are living longer and are more likely to survive a heart attack if they have one. Longer life expectancy is good but it also means more people get chronic heart failure over time. This is a condition in which the heart doesn't pump blood as well as it should. Treatment of chronic heart failure has not improved much in a few decades. Researchers want to see if giving a dietary supplement to people with heart failure can help their heart function. The supplement is nicotinamide riboside (NR).

Objective:

To study how NR affects skeletal muscle function in people with heart failure.

Eligibility:

Adults ages 18-70 with clinically stable systolic heart failure

Design:

Participants will be screened with a medical history and physical exam. They will answer demographic questions and review their current medical treatments. They will have blood and urine tests. They will have an echocardiogram. This uses sound waves to test heart function.

Participants will have 8 study visits over 16 weeks. At these visits, they will have some of the following:

Repeat of screening tests

Skin sample taken

Skeletal muscle exercise Nuclear magnetic resonance (NMR) spectroscopy. Muscles will be measured while participants do foot exercises.

Cardiopulmonary exercise testing. Participants may ride a stationary bike or walk on a treadmill. A facemask will analyze their breath. Heart and blood pressure measurements will be taken.

Participants will take the supplement in pill form each day for 12 weeks. Pill bottles will be checked at study visits.

Participants should not significantly change their activity levels during the study.

Detailed Description

As life expectancy increases and acute cardiac mortality decreases, the incidence of chronic heart failure (HF) continues to rise, and despite this, conceptual advances in the treatment of chronic heart failure have not increased substantially over last few decades. One intracellular component of heart failure progression is mitochondrial bioenergetic dysfunction. Although the mechanism underpinning this is not completely understood, recent metabolomics data demonstrated an incomplete flux of metabolites through oxidative phosphorylation (OX PHOS) in HF. In parallel, data has shown that hyperacetylation of mitochondrial bioenergetic enzymes, with the concomitant blunting of enzymatic activity is evident in HF. Putting these together, an emerging hypothesis implicates excessive acetylation of mitochondrial proteins with the subsequent blunting of bioenergetic enzyme function, as a mechanism underpinning incomplete flux through OX PHOS resulting in HF progression.

In parallel with cardiac bioenergetic deficiency chronic HF subjects display disrupted skeletal muscle OX PHOS, which is thought to contribute towards overall fatigue and reduced exercise tolerance. Interestingly exercise training in HF subjects improves skeletal muscle mitochondrial OX PHOS capacity and subject activity levels. Exercise training additionally increases activity of the mitochondrial regulatory deacetylase sirtuin enzymes SIRT1 and SIRT3, in parallel with improved skeletal muscle OX PHOS capacity. At the same time HF-associated disruption in skeletal muscle metabolic function activates skeletal muscle cytokine production. These inflammatory programs, in turn, are proposed to contribute towards impaired functional capacity in HF. Interestingly, and mirroring improved OX PHOS following exercise programs in HF studies, exercise training similarly reduces skeletal muscle inflammatory effects.

Biochemical and bioenergetic consequences of impaired mitochondrial OX PHOS leads to decreased NAD+ levels, which exacerbate mitochondrial dysfunction by inactivating the NAD+ dependent sirtuin enzymes. Experimental studies using NAD+ precursors to increase NAD+ production have been shown to normalize NADH/NAD+ ratios and activate Sirtuin enzymes, resulting in enhanced OX PHOS with beneficial effects in numerous systems including skeletal muscle and in the blunting of inflammation.

In this pilot study we will directly assess the effect of the NAD+ precursor, nicotinamide riboside (NR) on skeletal muscle mitochondrial OX PHOS in HF subjects using: skeletal muscle Nuclear magnetic resonance (NMR) spectroscopy assessment of the rate of high energy phosphate recovery in response to submaximal exercise; assessment of the effect of NR on functional capacity using cardiopulmonary exercise testing (CPET) to determine VO(2max) and anaerobic threshold; evaluation of the NR effect on serum metabolomics at rest and in response to CPET; and by measuring circulating cytokine levels pre- and post- NR administration. These studies would enable a more comprehensive assessment of the role for NR supplementation on skeletal muscle mitochondrial function in subjects with systolic HF

Conditions

Heart Failure

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Nicotinamide Riboside in patients with stable heart failure

Nicotinamide Riboside (NR) will be started at 500 mg daily (250 mg BID) then increased at two weekly intervals by 250 mg/dose (BID) (500 mg/day) to a final dose of 1000 mg PO BID (2000 mg/day) in patients with stable, systolic heart failure.

Group Type: EXPERIMENTAL

Nicotinamide Riboside

Intervention Type: DIETARY_SUPPLEMENT

Nicotinamide Riboside (NR) will be started at 500 mg daily (250 mg BID) be increased at two weekly intervals by 250 mg/dose (BID) (500 mg/day) to a final dose of 1000mg PO BID (2000 mg/day).

Interventions

Nicotinamide Riboside

Nicotinamide Riboside (NR) will be started at 500 mg daily (250 mg BID) be increased at two weekly intervals by 250 mg/dose (BID) (500 mg/day) to a final dose of 1000mg PO BID (2000 mg/day).

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

Niagen; Nicotinamide Riboside (NR)

Eligibility Criteria

Inclusion Criteria

Men and women between the ages of 18 and 75 years with New York Heart Association (NYHA) Functional Classification Class II-III systolic heart failure ( Left Ventricular Ejection Fraction (LVEF) by standard echocardiography or radionuclide ventriculography of less than or equal to 45%) deemed 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, skeletal muscle exercise NMR spectroscopy and CPET testing

Willingness/ability to provide informed consent

Must be DEERS eligible to be enrolled in a research protocol at Walter Reed National Military Medical Center (WRNMMC).

Exclusion Criteria

Heart failure with preserved ejection fraction (LVEF greater than 45%)

Change in heart failure medications due to deterioration of function with the exception of up- or down-titration of diuretic dose up to 100% of baseline dose.

Heart failure due 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/TIA or arrhythmias within the previous 3 months

Inability to perform Study visits or procedures (e.g., physical inability to perform exercise testing)

Unwillingness/inability to provide informed consent

ALT greater than x3 upper limit of normal, hepatic insufficiency or active liver disease

Recent history of acute gout

Chronic renal insufficiency with creatinine greater than 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 drug study

History of intolerance to NR precursor compounds, including niacin or nicotinamide

MRI incompatible hardware including pacemakers or ICD s

Study adherence concerns

Individuals with diabetes type 1 and 2 who use insulin

Women of child-bearing potential unwilling to use contraception or unwilling to practice abstinence

Breastfeeding women unwilling to stop breastfeeding

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael N Sack, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Heart, Lung, and Blood Institute (NHLBI)

Locations

Walter Reed National Military Medical Center

Bethesda, Maryland, United States

National Institutes of Health Clinical Center

Bethesda, Maryland, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

18-H-0107

Identifier Type: -

Identifier Source: secondary_id

180107

Identifier Type: -

Identifier Source: org_study_id