NiaMIT Continuation With Early-stage Mitochondrial Myopathy Patients

Study Overview
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Brief Summary
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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.

Official Title
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NiaMIT (NiaMIT_0001) Continuation for Early-stage Mitochondrial Myopathy Patients to Investigate the Effect of Niacin Supplementation on Systemic Nicotinamide Adenine Dinucleotide (NAD+) Metabolism, Physiology and Muscle Performance

Conditions
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Mitochondrial Myopathies

Intervention / Treatment
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* Dietary Supplement: Niacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Niacin in early-stage mitochondrial myopathy patients<br>The arm includes mitochondrial myopathy patients supplemented with niacin. | Dietary Supplement: Niacin<br>* The dose for a slow-released form of niacin will be 500-1000 mg/day. The daily niacin dose, 250 mg/day, is gradually escalated by 250 mg/month so that the full dose is reached after 2 months. The intervention time with the full niacin dose is 8 months and subsequently total intervention time 10 months.<br>* Other names: Nicotinic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAD+ and related metabolite levels in blood and muscle | 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. | Baseline, 4 months and 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of diseased muscle fibers | 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 | Baseline and 10 months | 
| Mitochondrial biogenesis | Change in mitochondria immunohistochemical staining intensity | Baseline and 10 months | 
| Muscle mitochondrial oxidative capacity | Change in muscle histochemical activity of mitochondrial cytochrome c oxidase | Baseline and 10 months | 
| Muscle and blood metabolomic profiles | Change in muscle or serum/plasma metabolite concentrations measured with mass spectrometry | Baseline and 10 months | 
| Core muscle strength | Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats) | Baseline and 10 months | 
| Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15) | Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits | Baseline and 10 months | 
| Muscle mitochondrial DNA deletions | Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification | Baseline and 10 months | 
| Muscle transcriptomic profile | Change in muscle gene expression determined using RNA sequencing approach | Baseline and 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin B3, Niacin, Nicotinic acid, Mitochondrial myopathy, Mitochondria, Muscle, Muscle strength, Nicotinamide adenine dinucleotide, NAD+, NAD+ precursor, NAD-booster