An interventional study of Nicotinamide Riboside in Mitochondrial Diseases, Mitochondrial Myopathies and Progressive External Ophthalmoplegia, sponsored by Cambridge University Hospitals NHS Foundation Trust. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2023-07-20.
Sponsored by Cambridge University Hospitals NHS Foundation Trust · Not applicable, Interventional, and Treatment
Mitochondria are important parts of the cell that are responsible for producing energy. The amount of energy they produce depends on how much energy the body needs to function and this energy production can be severely impaired in people with mitochondrial disease. Symptoms of mitochondrial disease vary widely but usually involve the brain, nerves and muscles, as these are tissues that need a lot of energy. Mitochondrial disorders affect 1 in 5000 of the UK population and there is currently no cure.
Some scientists think that increasing the number of mitochondria in the body (mitochondrial biogenesis) might be an effective treatment for the symptoms of mitochondrial disease. Studies carried out in mice have shown that a type of B-vitamin called Nicotinamide Riboside (NR) is able to increase the number of mitochondria, leading to increased energy and a reduction in the symptoms of mitochondrial disease.
The aim of this study is to investigate if the same B vitamin, Nicotinamide Riboside, can increase energy production and reduce symptoms in humans with mitochondrial disease.
The study will consist of two parts:
Part 1: Participants will be given a single oral dose of Nicotinamide Riboside and the levels of NR in their bloodstream will be measured at regular intervals. This will involve a single overnight stay and simple blood tests.
Part 2: This requires 6 separate visits from each participant. Each participant will undergo a series of standard tests including a muscle biopsy and an MRI scan, then they will take a course of Nicotinamide Riboside (twice daily for 4 weeks). After 4 weeks of treatment, the participants will undergo the same tests again to see if there have been any changes in response to the treatment.
Mitochondria are the primary source of energy within the cell, in the form of adenosine triphosphate (ATP). Mitochondrial ATP production is tightly regulated according to the energy requirements of the cell, but little is known about the underlying control mechanisms. This is important for the understanding of the biology of cell energetics and also relevant for patients with rare mitochondrial diseases where it has been proposed that inducing mitochondrial proliferation (biogenesis) might be an effective treatment. However, before embarking on therapeutic studies, it is essential to develop our understanding of the homeostatic mechanisms. Patients with mitochondrial diseases show an enhanced capacity for mitochondrial proliferation, and therefore provide an ideal platform to study mitochondrial homeostasis in vivo in man. The aim of this study, therefore, is to investigate the homeostatic mechanisms in this group of individuals because we are most likely to see an effect in this context.
Nicotinamide riboside (NR), a NAD+ natural precursor, boosts the PGC1α-dependent mitochondrial biogenesis pathway, leading to increased transcription of genes of the oxidative phosphorylation and improved motor performance of myopathic mice. This study is an open-label experimental medicine study using NR with the primary aim of determining whether there is mechanistic link between mitochondrial biogenesis and physiological function in humans with a similar mitochondrial disease.
This project consists of two studies, carried out in series. Both will investigate patients with a clinical and genetic diagnosis of:
i. Progressive external ophthalmoplegia (PEO) plus exercise intolerance/fatigue, caused by a single deletion of mitochondrial DNA
or
ii. Mitochondrial disease caused by the m.3243A>G mutation in mitochondrial DNA
Study 1: a 24 hour study before the experimental intervention, to confirm bioavailability of NR at a dosage within the range of a published study.
Patients (n=5) will be invited to the CRF for an overnight stay. If applicable, a urinary pregnancy test will be carried out before any study procedures commence. A baseline blood sample will be taken before administration of the supplement. Oral NR will be administered at a dosage of 10mg/kg -, and blood samples will be drawn at 30 mins,1, 2, 6, 12 and 24 hours post administration. These samples will be used for measurement of NR/NAD+ levels in blood at the relevant time points and ensure these are at expected levels before proceeding to experimental intervention.
Study 2: a 4-week study to determine whether NR induces mitochondrial biogenesis and affects mitochondrial function in patients with mitochondrial disease.
Patients (n=10) will undergo measurements of mitochondrial biogenesis and physiological activities. Oral NR will be administered at a dosage of 10mg/kg b.i.d, (taken twice daily, after food) and patients will be asked to return weekly for standard observations and to provide a blood sample. After 4 weeks of NR administration, patients will return for a repeat measure of the mitochondrial biogenesis parameters and physiological activities
37 studies on the registry are indexed under MELAS Syndrome; 8 are open to participants now.
This study's enrollment of 13 is below the median of 24 across 29 interventional studies indexed under MELAS Syndrome.
Browse MELAS Syndrome studies →Cambridge University Hospitals NHS Foundation Trust is the lead sponsor of 171 studies on the registry; 37 are open to participants now.
Compared within MELAS Syndrome, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Mitochondrial Diseases. The counts are of registry records indexed under each term, refreshed daily. How we classify →
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Clinical and genetic diagnosis of:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
This is an open-label experimental medicine study. All subjects will receive the same dosage of the supplement Nicotinamide Riboside.
Dietary Supplement: Nicotinamide Riboside
Nicotinamide Riboside is a member of the Vitamin B family which acts as a precursor to NAD+, an enzyme involved in energy production.
Also known as: Niagen, Nicotinamide Riboside Chloride
Bioavailability
Change in baseline levels of Nicotinamide Riboside detectable in the bloodstream of participants after a standard oral dose of the supplement (at 0, 0.5, 1, 2, 6, 12 and 24 hours)
Time frame: Pharmacokinetic measure - 0, 0.5, 1, 2, 6, 12 and 24 hours post-dose
Safety - Incidence of treatment related adverse events
Observation over 24 hours after Nicotinamide Riboside administration. Recording of any adverse events or reactions
Time frame: 24 hours
Safety - change in blood analytes
Change from baseline in safety blood analyte levels - CK, Creatinine, Alanine Transaminase, Aspartate Transaminase (Units U/L)
Time frame: 24 hours
Safety - temperature
Change from baseline in patient temperature (degrees celsius, measurement at 0, 0.5, 1, 2, 6, 12 and 24 hours)
Time frame: Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose
Safety - blood pressure
Change from baseline in patient blood pressure (mmHg, measurement at 0, 0.5, 1, 2, 6, 12 and 24 hours)
Time frame: Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose
Safety - pulse
Change from baseline in patient pulse (bpm, measurement at 0, 0.5, 1, 2, 6, 12 and 24 hours)
Time frame: Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose
Mitochondrial biogenesis - Magnetic Resonance Imaging
Change in in vivo measurement of mitochondrial function at the start and end of the 4 weeks of NR treatment (31P-MRS measurement of mitochondrial function - Phosphocreatine replenishment after exercise)
Time frame: 4 weeks
Mitochondrial biogenesis - Respiratory Chain Enzyme Analysis
Change from baseline in mitochondrial function at the start and end of the 4 weeks of NR treatment (Respiratory chain enzyme analysis)
Time frame: 4 weeks
Mitochondrial biogenesis - mitochondrial DNA quantification
Change from baseline in the amount of mitochondrial DNA at the start and end of the 4 weeks of NR treatment (mtDNA quantification)
Time frame: 4 weeks
Impact on mitochondrial disease symptoms - Dynamometric measure of muscle strength
Participants will be asked to complete the dynamometric measure of muscle strength test, using a hand held dynamometer, before and after treatment. Force measured in kg.
Time frame: 4 weeks
Impact on mitochondrial disease symptoms - 6-minute walk
Participants will be asked to complete the 6 minute walk test before and after treatment. The distance they can walk in 6 minutes will be measured in metres.
Time frame: 4 weeks
Impact on mitochondrial disease symptoms - Quality of life (SF36 - qualitative)
Participants will be asked to complete the SF36 (Short Form 36) Quality of life questionnaire before and after treatment. This is a standard health survey used routinely in clinical practice.
Time frame: 4 weeks
Impact on mitochondrial disease symptoms - Timed get-up-and-go.
Participants will be asked to complete the Timed up and go test before and after treatment. The time taken to get up from sitting to standing will be measured in seconds.
Time frame: 4 weeks
Plan to share: No
No publications or documents are linked to this record.
Ran from Dec 2017 to primary completion in Dec 2022, 60 months.
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This study is completed, as verified in Jul 2023. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Nicotinamide-beta-riboside
Cambridge University Hospitals NHS Foundation Trust →