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Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome

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ClinicalTrials.gov Identifier: NCT03789175
Recruitment Status : Recruiting
First Posted : December 28, 2018
Last Update Posted : June 19, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
First Submitted Date  ICMJE December 27, 2018
First Posted Date  ICMJE December 28, 2018
Last Update Posted Date June 19, 2019
Actual Study Start Date  ICMJE March 25, 2019
Estimated Primary Completion Date June 3, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 27, 2018)
intra-subject comparison of baseline to 12 wk NR supplementation PCr recovery Tc measurements using the 31P-MRS skeletal muscle submaximal exercise. [ Time Frame: 12 weeks ]
The effect of NR supplementation on the PCr recovery Tc of skeletal muscle after exercise as a marker of mitochondrial oxidative phosphorylation capacity.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03789175 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 27, 2018)
Examine whether NR supplementation affects the respiratory capacity of blood mononuclear cells, CPET, self-reported symptoms of fatigue. [ Time Frame: 7 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
Official Title  ICMJE Exploratory Study of Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
Brief Summary

Background:

Nicotinamide riboside (NR) is a vitamin B3 dietary supplement. It may help improve muscle function, that may in turn may improve a person s exercise capacity. Researchers want to study how skeletal muscle responds to NR in an individual who has Li-Fraumeni Syndrome and slow muscle energy recovery after exercise.

Objective:

To study how nicotinamide riboside affects skeletal muscle after exercise.

Eligibility:

One person at least 18 years old with Li-Fraumeni syndrome and a certain gene mutation

Design:

The participant will be screened with a medical history, physical exam, and blood and urine tests.

The participant may also have a heart test.

The participant will maintain their regular diet and supplements during the study.

The participant will take the study drug as 1-4 tablets twice a day for 12 weeks. The participant may be contacted with reminders and questions about side effects.

The participant will have 4-5 visits over 18-30 weeks. At visits, the participant will repeat screening tests. At some visits they will also have:

  • Ultrasound of the heart with a wand placed on the chest.
  • Test of oxygen used at rest and exercise, while wearing a face mask.
  • Exercise test on a treadmill or bicycle with electrodes on the skin.
  • Magnetic resonance spectroscopy. The participant will have no caffeine for 12 hours. Then they will lie in a machine for about 2 hours. Sometimes they will lie still. Sometimes they will be asked to move.

Health questionnaire

The participant may have a skin sample taken by needle.

The participant will be withdrawn from the study if they become pregnant.

Detailed Description

We have previously reported that inherited mutations of TP53, which causes the premature cancer disorder Li-Fraumeni syndrome (LFS), can promote mitochondrial function both in patients and mouse models. In the course of our follow up studies, we encountered a LFS patient with a long-standing history of fatigue and muscle weakness of unclear etiology. Notably, we observed in vivo evidence of markedly decreased mitochondrial function in her leg skeletal muscle during exercise using noninvasive phosphorus-31 magnetic resonance spectroscopy (31P-MRS), a technique that has previously been used to study patients with primary mitochondrial disorders. The decrease in mitochondrial function was also confirmed by the patient s skin fibroblasts in vitro using standard biochemical measurements.

There is growing evidence that nicotinamide adenine dinucleotide (NAD+) homeostasis plays a significant role in maintaining the mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. Remarkably, we observed that culturing the LFS patient s fibroblasts in medium containing NR rescued the severe deficit in mitochondrial respiration. While continuing our investigations into the molecular mechanism(s) underlying the mitochondrial dysfunction observed in this patient, the in vitro rescue of the respiratory deficiency by NR presents a unique opportunity to investigate whether it can also be observed in vivo using skeletal muscle 31P-MRS. We propose to explore the effect of NR, currently available as a dietary supplement, on in vivo mitochondrial function in this LFS patient.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Cancer
  • Skin Fibroblasts
  • Muscle Weakness
Intervention  ICMJE Dietary Supplement: Niagen
Niacin is a form of vitamin B3 and has been used to treat hypercholesterolemia for many years. There is growing evidence that nicotinamide adenine dinucleotide (NAD+ can maintain mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. We have observed that culturing the fibroblasts of a LFS patient with mitochondrial deficiency in medium containing NR rescues the defect in mitochondrial respiration.
Study Arms  ICMJE Subjects receiving supplement
Subjects with Li-Fraumeni syndrome with TP53 mutations will receive NR
Intervention: Dietary Supplement: Niagen
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 27, 2018)
1
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 12, 2021
Estimated Primary Completion Date June 3, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • At least 18-years of age and able to give informed consent
  • Have delayed PCr recovery time constant >45 sec by 31P-MRS testing and a history of fatigue symptoms
  • Ability to undergo study procedures, including scheduled visits, blood draws and skeletal muscle exercise NMR spectroscopy
  • Have Li-Fraumeni syndrome and confirmed TP53 mutation by genetic testing
  • Committed to using reliable contraception which may include abstinence during study participation
  • Female participants of child-bearing ability and potential willing to commit to reliable contraception while participating in the study

EXCLUSION CRITERIA:

  • Current systemic treatment for cancer
  • Unable to perform required study visits or procedures
  • MRI incompatible hardware
  • Pregnant or breastfeeding women
  • History of intolerance to NR precursor compounds, including niacin or nicotinamide
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rebecca D Huffstutler, C.R.N.P. (301) 594-1281 rebecca.huffstutler@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03789175
Other Study ID Numbers  ICMJE 190034
19-H-0034
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paul M Hwang, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date January 17, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP