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

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ClinicalTrials.gov Identifier: NCT03565328
Recruitment Status : Recruiting
First Posted : June 21, 2018
Last Update Posted : May 20, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

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 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.


Condition or disease Intervention/treatment Phase
Heart Failure Dietary Supplement: Niagen Phase 2

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 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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Pilot Study to Evaluate the Effect of Nicotinamide Riboside on Skeletal Muscle Function in Heart Failure Subjects
Actual Study Start Date : September 27, 2018
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : June 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1 Dietary Supplement: Niagen
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).




Primary Outcome Measures :
  1. NR enhancement of mitochondrial function in skeletal muscle [ Time Frame: baseline-12 week-16 week ]
    To measure whether NR enhances mitochondrial function in skeletal muscle NMR spectroscopy will be performed at baseline, at the end of the 12-week (plus and or minus 5-days) NR supplementation period and repeated 4 weeks (plus and or minus 5-days) post-NR washout, using a protocol developed at the NIH.


Secondary Outcome Measures :
  1. effects of NR on oxidative phosphorylation and inflammation in respective subject primary skin fibroblasts [ Time Frame: Baseline, 12 week ]
  2. quantitative serum cytokine immunoassay profiling to assess whether NR blunts HF linked inflammation [ Time Frame: Baseline, 12 week ]
  3. serum quantitative metabolomic profiling, pre and post-CPET to evaluate whether NR increases the rate of oxidative phorphorylation [ Time Frame: Baseline, 12 week ]
  4. VO2 max and anaerobic tresholds [ Time Frame: Baseline, 12 week ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Men and women between the ages of 18 and 75 years with NYHA Class II-III systolic heart failure (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 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03565328


Contacts
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Contact: Autumn Mains, R.N. (410) 627-3494 autumn.mains.ctr@usuhs.edu

Locations
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United States, Maryland
Walter Reed National Military Medical Center Recruiting
Bethesda, Maryland, United States, 20889
Contact: Autumn Mains, B.A.    410-627-3494    autumn.mains.ctr@usuhs.edu   
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Michael N Sack, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT03565328     History of Changes
Other Study ID Numbers: 180107
18-H-0107
First Posted: June 21, 2018    Key Record Dates
Last Update Posted: May 20, 2019
Last Verified: May 14, 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Mitochondrial bioenergetic dysfunction
Mitochondrial oxidative phosphorylation in sceletal muscles
Hyperacetylation of mitochondrial bioenergetic enzymes
NAD+ dependent sirtuin enzymes
NAD+/NADH ratio
Additional relevant MeSH terms:
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Niacinamide
Niacin
Nicotinic Acids
Heart Failure
Heart Diseases
Cardiovascular Diseases
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Vasodilator Agents