Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome

NCT03789175 | Completed Phase 1 Results

• 2 other identifiers: 19003419-H-0034
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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 The participant will be withdrawn from the study if they become pregnant.

Conditions

Cancer; Skin Fibroblasts; Muscle Weakness

Keywords

Oxidative Phosphorylation Capacity; Increased Oxidative Metabolism; Regeneration of Phosphocreatine (PCr); Inherited Mutation of TP53 Tumor Suppressor Gene

Outcome Measures

Primary Outcomes (1)

• Change in PCr Recovery Tc Measurement From Baseline to 12 Week NR Supplementation Using the 31P-MRS Skeletal Muscle Submaximal Exercise.

  The effect of nicotinamide riboside (NR) supplementation on the phosphocreatine (PCr) recovery time constant (Tc) of skeletal muscle after exercise as a marker of mitochondrial oxidative phosphorylation capacity. The phosphocreatine level will be measured using 31P-magnetic resonance spectroscopy (MRS) during the following sequence of 3-minute rest, 2-minute exercise, and 6-minute recovery periods. The 31P spectra will be obtained during these periods and analyzed with the use of SAGE 7 (GE Healthcare) and IDL, version 6.4 (Exelis Visual Information Solutions), software. The single exponential recovery time constant (Tc) is calculated from the post-exercise recovery period data.

  Baseline to 12 weeks

Secondary Outcomes (1)

• Change in Time of CPET Time as a Measure of Exercise Tolerance From Baseline to 12 Weeks of NR Supplementation.

  Baseline to 12 weeks

Study Arms (1)

Nicotinamide riboside (NR) in Li-Fraumeni syndrome

OTHER

Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.

Dietary Supplement: Nicotinamide Riboside (NR)

Interventions

Nicotinamide Riboside (NR) DIETARY_SUPPLEMENT

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.

Also known as: Niagen; Nicotinamide Riboside (NR)

Nicotinamide riboside (NR) in Li-Fraumeni syndrome

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• At least 18-years of age and able to give informed consent
• Have delayed phosphocreatine (PCr) recovery time constant \>45 sec by 31P-magnetic resonance spectroscopy (MRS) testing and a history of fatigue symptoms
• Ability to undergo study procedures, including scheduled visits, blood draws and skeletal muscle exercise Nuclear Magnetic Resonance (NMR)
• 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

You may not qualify if:

• Current systemic treatment for cancer
• Unable to perform required study visits or procedures
• Magnetic resonance imaging (MRI) incompatible hardware
• Pregnant or breastfeeding women
• History of intolerance to NR precursor compounds, including niacin or nicotinamide

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms; Muscle Weakness

Interventions

nicotinamide-beta-riboside

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Results Point of Contact

• Title: Dr. Paul Hwang
• Organization: NHLBI, NIH

hwangp@mail.nih.gov

3014353068

Study Officials

• Paul M Hwang, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2018
• First Posted: December 28, 2018
• Study Start: March 25, 2019
• Primary Completion: November 1, 2019
• Study Completion: November 1, 2019
• Last Updated: December 8, 2020
• Results First Posted: December 8, 2020

Record last verified: 2019-11-26

Locations

US (1)