CancerPhase 1/2NCT03789175
Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
A Phase 1/2 study testing Nicotinamide Riboside (NR) in people with Cancer and Skin Fibroblasts, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Cancer, Skin Fibroblasts, Muscle Weakness
- What is being tested?
- Nicotinamide Riboside (NR)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Mar 2019to 1 Nov 2019
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: Exploratory Study of Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
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.
Read more
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.
Read the 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 patients 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 patients 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.
- Conditions
- Cancer, Skin Fibroblasts, Muscle Weakness
- Being tested
- Nicotinamide Riboside (NR)
- Keywords
- Oxidative Phosphorylation Capacity, Increased Oxidative Metabolism, Regeneration of Phosphocreatine (PCr), Inherited Mutation of TP53 Tumor Suppressor Gene
- Medical subject headings
- Neoplasms, Muscle Weakness
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nicotinamide Riboside (NR)Dietary supplement
Also called Niagen; Nicotinamide Riboside (NR)
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 group | Role | What they receive |
|---|---|---|
| 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. Receives: Dietary Supplement: Nicotinamide Riboside (NR) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measure change in time of cardiopulmonary exercise test (CPET) to determine exercise tolerance from baseline to 12 weeks of NR supplementation.
Measured: Baseline to 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2018
- Study start25 Mar 2019
- Primary completion1 Nov 2019
- Study completion1 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for CancerStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Paul M Hwang, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03789175
- Sponsor's protocol ID
- 190034
- Other IDs
- 19-H-0034
- Status last verified
- 26 Nov 2019
- First submitted
- 27 Dec 2018
- Last updated
- 8 Dec 2020
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exploratory Study of Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
- ClinicalTrials.gov ID
- NCT03789175
- Acronym / sponsor ID
- 190034
- Conditions
- Cancer, Skin Fibroblasts, Muscle Weakness
- Keywords
- Oxidative Phosphorylation Capacity, Increased Oxidative Metabolism, Regeneration of Phosphocreatine (PCr), Inherited Mutation of TP53 Tumor Suppressor Gene
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 25 Mar 2019 (actual)
- Primary completion
- 1 Nov 2019 (actual)
- Study completion
- 1 Nov 2019 (actual)
- First posted
- 28 Dec 2018 (actual)
- Results
- Posted 8 Dec 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 patients 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 patients 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 design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nicotinamide riboside (NR) in Li-Fraumeni syndrome | Other | Dietary Supplement: Nicotinamide Riboside (NR)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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nicotinamide Riboside (NR)Also: Niagen; Nicotinamide Riboside (NR)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. | Dietary supplement | Nicotinamide riboside (NR) in Li-Fraumeni syndrome |
Primary outcome
Change in PCr Recovery Tc Measurement From Baseline to 12 Week NR Supplementation Using the 31P-MRS Skeletal Muscle Submaximal Exercise.
Time frame: Baseline to 12 weeks
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.
1 secondary outcome
Change in Time of CPET Time as a Measure of Exercise Tolerance From Baseline to 12 Weeks of NR Supplementation.
Time frame: Baseline to 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Dec 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul M Hwang, M.D. principal investigator
National Heart, Lung, and Blood Institute (NHLBI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nicotinamide Riboside (NR) in people with Cancer and Skin Fibroblasts, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in PCr Recovery Tc Measurement From Baseline to 12 Week NR Supplementation Using the 31P-MRS Skeletal Muscle Submaximal Exercise. (time frame: Baseline to 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Dec 2020.