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NiaMIT Continuation With Early-stage Mitochondrial Myopathy Patients

Sponsor
University of Helsinki (Other)
Overall Status
Completed
CT.gov ID
NCT04538521
Collaborator
Helsinki University Central Hospital (Other), Institute for Molecular Medicine (Other)
3
Enrollment
1
Location
1
Arm
19.2
Actual Duration (Months)
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Dietary Supplement: Niacin
 N/A

Study Design

Study Type:
Interventional
Actual Enrollment :
3 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
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
Actual Study Start Date :
Feb 11, 2019
Actual Primary Completion Date :
Sep 18, 2020
Actual Study Completion Date :
Sep 18, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Niacin in early-stage mitochondrial myopathy patients

The arm includes mitochondrial myopathy patients supplemented with niacin.

Dietary Supplement: Niacin
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.
Other Names:
  • Nicotinic acid

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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

    2. Mitochondrial biogenesis [Baseline and 10 months]

      Change in mitochondria immunohistochemical staining intensity

    3. Muscle mitochondrial oxidative capacity [Baseline and 10 months]

      Change in muscle histochemical activity of mitochondrial cytochrome c oxidase

    4. Muscle and blood metabolomic profiles [Baseline and 10 months]

      Change in muscle or serum/plasma metabolite concentrations measured with mass spectrometry

    5. 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)

    6. 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

    7. Muscle mitochondrial DNA deletions [Baseline and 10 months]

      Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification

    8. Muscle transcriptomic profile [Baseline and 10 months]

      Change in muscle gene expression determined using RNA sequencing approach

    Other Outcome Measures

    1. Body weight [Baseline and 10 months]

      Change in body weight

    2. Body composition [Baseline and 10 months]

      Change in fat mass and fat free mass measured with bioimpedance

    3. Ectopic lipid accumulation, i.e. liver and muscle lipid content [Baseline and 10 months]

      Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy

    4. Circulating lipid profiles [Baseline, 4 months and 10 months]

      Change in circulating HDL, LDL and triglyceride concentrations measured using standard photometric enzymatic assay

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    17 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Helsinki Helsinki Finland

    Sponsors and Collaborators

    • University of Helsinki
    • Helsinki University Central Hospital
    • Institute for Molecular Medicine

    Investigators

    • Principal Investigator: Anu Suomalainen Wartiovaara, MD, PhD, Research Program Unit, University of Helsinki, Helsinki, Finland

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Anu Wartiovaara, Academy Professor, Professor of Clinical Molecular Medicine; Chief Physician, University of Helsinki
    ClinicalTrials.gov Identifier:
    NCT04538521
    Other Study ID Numbers:
    • NiaMIT_002
    First Posted:
    Sep 4, 2020
    Last Update Posted:
    Jan 25, 2021
    Last Verified:
    Jan 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Anu Wartiovaara, Academy Professor, Professor of Clinical Molecular Medicine; Chief Physician, University of Helsinki
    Vitamin B3
    Niacin
    Nicotinic acid
    Mitochondrial myopathy
    Mitochondria
    Muscle
    Muscle strength
    Nicotinamide adenine dinucleotide
    NAD+
    NAD+ precursor
    NAD-booster
    Additional relevant MeSH terms:
    Muscular Diseases
    Mitochondrial Myopathies
    Niacin
    Nicotinic Acids

    Study Results

    No Results Posted as of Jan 25, 2021