Clinical trial NCT04538521: NiaMIT Continuation With Early-stage Mitochondrial Myopathy Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Mitochondrial Myopathies
Keywords: Vitamin B3
Niacin
Nicotinic acid
Mitochondrial myopathy
Mitochondria
Muscle
Muscle strength
Nicotinamide adenine dinucleotide
NAD+
NAD+ precursor
NAD-booster
Lead sponsor: University of Helsinki
Sponsor class: OTHER
Collaborators: name: Helsinki University Central Hospital
name: Institute for Molecular Medicine
First posted: 2020-09-04
Enrollment: 3
Sex: ALL
Minimum age (years): 17
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

1. Early-stage, genetically diagnosed mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA
2. Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study
3. Written, informed consent to participate in the study

Exclusion Criteria:

1. Inability to follow study protocol
2. Pregnancy or breast-feeding at any time of the trial
3. Malignancy that requires continuous treatment
4. Unstable heart disease
5. Severe kidney disease requiring treatment
6. Severe encephalopathy
7. Regular usage of intoxicants

Primary outcomes:
measure: NAD+ and related metabolite levels in blood and muscle
timeFrame: Baseline, 4 months and 10 months
Secondary outcomes:
measure: Number of diseased muscle fibers
timeFrame: Baseline and 10 months
measure: Mitochondrial biogenesis
timeFrame: Baseline and 10 months
measure: Muscle mitochondrial oxidative capacity
timeFrame: Baseline and 10 months
measure: Muscle and blood metabolomic profiles
timeFrame: Baseline and 10 months
measure: Core muscle strength
timeFrame: Baseline and 10 months
measure: Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15)
timeFrame: Baseline and 10 months
measure: Muscle mitochondrial DNA deletions
timeFrame: Baseline and 10 months
measure: Muscle transcriptomic profile
timeFrame: Baseline and 10 months
Other outcomes:
measure: Body weight
timeFrame: Baseline and 10 months
measure: Body composition
timeFrame: Baseline and 10 months
measure: Ectopic lipid accumulation, i.e. liver and muscle lipid content
timeFrame: Baseline and 10 months
measure: Circulating lipid profiles
timeFrame: Baseline, 4 months and 10 months
Locations:
city: Helsinki
country: Finland
facility: University of Helsinki
Study officials:
affiliation: Research Program Unit, University of Helsinki, Helsinki, Finland
name: Anu Suomalainen Wartiovaara, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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