Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03565328 |
| Other study ID # |
180107 |
| Secondary ID |
18-H-0107 |
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
September 27, 2018 |
| Est. completion date |
November 18, 2019 |
Study information
| Verified date |
November 2019 |
| Source |
National Institutes of Health Clinical Center (CC) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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
