Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients (NiaMIT)
Primary Purpose
Mitochondrial Myopathies
Status
Completed
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Niacin
Sponsored by
About this trial
This is an interventional basic science trial for Mitochondrial Myopathies focused on measuring vitamin B3, niacin, mitochondrial myopathy, mitochondria, muscle, muscle strength, NAD+ precursor, NAD+, NAD-booster
Eligibility Criteria
Inclusion Criteria:
- Manifestation of pure mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA
- Age and gender matched healthy controls for every patient
- 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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Niacin in controls
Niacin in mitochondrial myopathy patients
Arm Description
The arm includes healthy controls supplemented with niacin.
The arm includes mitochondrial myopathy patients supplemented with niacin.
Outcomes
Primary Outcome Measures
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 high performance liquid chromatography-mass spectrometry
Secondary Outcome Measures
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
Mitochondrial biogenesis
Change in mitochondria immunohistochemical staining intensity
Muscle mitochondrial oxidative capacity
Change in muscle histochemical activity of mitochondrial cytochrome c oxidase
Muscle metabolomic profile
Change in muscle metabolite concentrations measured with mass spectrometry
Core muscle strength
Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)
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
Muscle mitochondrial DNA deletions
Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification
Muscle transcriptomic profile
Change in muscle gene expression determined using RNA sequencing approach
Full Information
NCT ID
NCT03973203
First Posted
May 24, 2019
Last Updated
May 10, 2023
Sponsor
University of Helsinki
Collaborators
Helsinki University Central Hospital, Institute for Molecular Medicine, University of Iowa
1. Study Identification
Unique Protocol Identification Number
NCT03973203
Brief Title
Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients
Acronym
NiaMIT
Official Title
The Effect of Niacin Supplementation on Systemic Nicotinamide Adenine Dinucleotide (NAD+) Metabolism, Physiology and Muscle Performance in Healthy Controls and Mitochondrial Myopathy Patients
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
June 1, 2014 (Actual)
Primary Completion Date
December 31, 2017 (Actual)
Study Completion Date
December 31, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Helsinki
Collaborators
Helsinki University Central Hospital, Institute for Molecular Medicine, University of Iowa
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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. The investigators have previously observed that supplementation with an NAD+ precursor vitamin B3, nicotinamide riboside, prevented and delayed disease symptoms by increasing mitochondrial biogenesis in a mouse model for mitochondrial myopathy. Vitamin B3 exists in several forms: nicotinic acid (niacin), nicotinamide, and nicotinamide riboside, and it 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.
In this study, the form of vitamin B3, niacin, was used to activate dysfunctional mitochondria and to rescue signs of mitochondrial myopathy. 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 either with sporadic single mtDNA deletions or a mutation in a Twinkle gene causing multiple mtDNA deletions were recruited. In addition, for every patient, two gender- and age-matched healthy controls are recruited. Clinical examinations and collection of muscle biopsies are performed at the time points 0, 4 and 10 months (patients) or at 0 and 4 months (controls). Fasting blood samples are collected every second 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 in humans.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mitochondrial Myopathies
Keywords
vitamin B3, niacin, mitochondrial myopathy, mitochondria, muscle, muscle strength, NAD+ precursor, NAD+, NAD-booster
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
All participants (healthy controls and mitochondrial myopathy patients) receive orally administered a slow-released form of niacin.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Niacin in controls
Arm Type
Experimental
Arm Description
The arm includes healthy controls supplemented with niacin.
Arm Title
Niacin in mitochondrial myopathy patients
Arm Type
Experimental
Arm Description
The arm includes mitochondrial myopathy patients supplemented with niacin.
Intervention Type
Dietary Supplement
Intervention Name(s)
Niacin
Other Intervention Name(s)
Nicotinic acid
Intervention Description
The dose for a slow-released form of niacin will be 750-1000 mg/day. The daily niacin dose, 250 mg/day, is gradually escalated by 250 mg/month so that the full dose is reached after 3 months. The intervention time with the full niacin dose is 1 and 7 months for controls and patients, respectively, and subsequently total intervention time 4 and 10 months, respectively. At the end of the study, the daily dose will be decreased by 250 mg/month rate.
Primary Outcome Measure Information:
Title
NAD+ and related metabolite levels in blood and muscle
Description
Change in concentrations of NAD+ and related metabolites such as: nicotinamide adenine dinucleotide phosphate, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide measured using high performance liquid chromatography-mass spectrometry
Time Frame
Baseline, 4 months and 10 months
Secondary Outcome Measure Information:
Title
Number of diseased muscle fibers
Description
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
Time Frame
Baseline, 4 months and 10 months
Title
Mitochondrial biogenesis
Description
Change in mitochondria immunohistochemical staining intensity
Time Frame
Baseline, 4 months and 10 months
Title
Muscle mitochondrial oxidative capacity
Description
Change in muscle histochemical activity of mitochondrial cytochrome c oxidase
Time Frame
Baseline, 4 months and 10 months
Title
Muscle metabolomic profile
Description
Change in muscle metabolite concentrations measured with mass spectrometry
Time Frame
Baseline, 4 months and 10 months
Title
Core muscle strength
Description
Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)
Time Frame
Baseline, 4 months and 10 months
Title
Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15)
Description
Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits
Time Frame
Baseline, 4 months and 10 months
Title
Muscle mitochondrial DNA deletions
Description
Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification
Time Frame
Baseline, 4 months and 10 months
Title
Muscle transcriptomic profile
Description
Change in muscle gene expression determined using RNA sequencing approach
Time Frame
Baseline, 4 months and 10 months
Other Pre-specified Outcome Measures:
Title
Body weight and body composition
Description
Change in body weight as well as fat mass and fat free mass measured with bioimpedance
Time Frame
Baseline, 4 months and 10 months
Title
Ectopic lipid accumulation, i.e. liver and muscle lipid content
Description
Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy
Time Frame
Baseline, 4 months and 10 months
Title
Circulating lipid profiles
Description
Change in circulating HDL, LDL and triglyceride concentrations measured using standard photometric enzymatic assay
Time Frame
Baseline, 4 months and 10 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
17 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Manifestation of pure mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA
Age and gender matched healthy controls for every patient
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anu Suomalainen Wartiovaara, MD,PhD
Organizational Affiliation
Research Programs Unit, University of Helsinki, Helsinki, Finland
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
28792006
Citation
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Citation
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Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients
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