NiaMIT Continuation With Early-stage Mitochondrial Myopathy Patients
- Conditions
- Mitochondrial Myopathies
- Interventions
- Dietary Supplement: Niacin
- Registration Number
- NCT04538521
- Lead Sponsor
- University of Helsinki
- Brief Summary
The most frequent form of adult-onset mitochondrial disorders is mitochondrial myopathy, often manifesting with progressive external ophthalmoplegia (PEO), progressive muscle weakness and exercise intolerance. Mitochondrial myopathy is often caused by single heteroplasmic mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions, the former being sporadic and latter caused by mutations in nuclear-encoded proteins of mtDNA maintenance. Currently, no curative treatment exists for this disease. However, an NAD+ precursor vitamin B3 has been demonstrated to give power to diseased mitochondria in animal studies by increasing intracellular levels of NAD+, the important cofactor required for the cellular energy metabolism. Vitamin B3 exists in several forms: nicotinic acid (niacin), nicotinamide, and nicotinamide riboside. Nicotinamide riboside has been shown to prevent and improve disease symptoms in several mouse models of mitochondrial myopathy. In addition, the investigators have previously observed that treatment with another form of vitamin B3, niacin, improved NAD+ deficiency and muscle performance in mitochondrial myopathy patients.
In this study, the form of vitamin B3, niacin, is used to activate dysfunctional mitochondria and to rescue signs of mitochondrial myopathy in early-stage patients. Of the vitamin B3 forms, niacin, is employed, because it has been used in large doses to treat hypercholesterolemia patients, and has a proven safety record in humans. Phenotypically similar mitochondrial myopathy patients are studied, as the investigator's previous expertise indicates that similar presenting phenotypes predict uniform physiological and clinical responses to interventions, despite varying genetic backgrounds. Patients with mitochondrial myopathy, typically harboring a sporadic single mtDNA deletion or a mutation in nuclear mtDNA maintenance gene causing multiple mtDNA deletions, are recruited. In addition, data from healthy controls from the primary NiaMIT study (ClinicalTrials.gov Identifier: NCT03973203) are utilized to analyse the collected data. Clinical examinations and collection of muscle biopsies are performed at the time points 0 and 10 months. Fasting blood samples are collected every second week until 1.5 months, every fourth week until 4 months and thereafter every six weeks until the end of the study. The effects of niacin on disease markers, muscle mitochondrial biogenesis, muscle strength and the metabolism of the whole body are studied in patients and healthy controls.
The hypothesis is that an NAD+ precursor, niacin, will increase intracellular NAD+ levels, improve mitochondrial biogenesis and alleviate the symptoms of mitochondrial myopathy already in early stages of the disease.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 3
- Early-stage, genetically diagnosed mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA
- Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study
- Written, informed consent to participate in the study
- Inability to follow study protocol
- Pregnancy or breast-feeding at any time of the trial
- Malignancy that requires continuous treatment
- Unstable heart disease
- Severe kidney disease requiring treatment
- Severe encephalopathy
- Regular usage of intoxicants
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Niacin in early-stage mitochondrial myopathy patients Niacin The arm includes mitochondrial myopathy patients supplemented with niacin.
- Primary Outcome Measures
Name Time Method NAD+ and related metabolite levels in blood and muscle Baseline, 4 months and 10 months Change in concentrations of NAD+ and related metabolites such as: nicotinamide adenine dinucleotide phosphate, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide measured using a quantitative colorimetric assay.
- Secondary Outcome Measures
Name Time Method Muscle mitochondrial oxidative capacity Baseline and 10 months Change in muscle histochemical activity of mitochondrial cytochrome c oxidase
Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15) Baseline and 10 months Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits
Mitochondrial biogenesis Baseline and 10 months Change in mitochondria immunohistochemical staining intensity
Muscle and blood metabolomic profiles Baseline and 10 months Change in muscle or serum/plasma metabolite concentrations measured with mass spectrometry
Muscle transcriptomic profile Baseline and 10 months Change in muscle gene expression determined using RNA sequencing approach
Core muscle strength Baseline and 10 months Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)
Number of diseased muscle fibers Baseline and 10 months Change in number of abnormal muscle fibers (frozen sections, in situ histochemical activity analysis of cytochrome c oxidase negative / succinate-dehydrogenase positive muscle fibers; and immunohistochemistry of complex I negative muscle fibers
Muscle mitochondrial DNA deletions Baseline and 10 months Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification
Trial Locations
- Locations (1)
University of Helsinki
🇫🇮Helsinki, Finland