Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients (NiaMIT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03973203
Recruitment Status : Completed
First Posted : June 4, 2019
Last Update Posted : June 4, 2019
Sponsor:
Collaborators:
Helsinki University Central Hospital
Institute for Molecular Medicine
University of Iowa
Information provided by (Responsible Party):
Anu Wartiovaara, 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. 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.


Condition or disease Intervention/treatment Phase
Mitochondrial Myopathies Dietary Supplement: Niacin Not Applicable

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: All participants (healthy controls and mitochondrial myopathy patients) receive orally administered a slow-released form of niacin.
Masking: None (Open Label)
Primary Purpose: Basic Science
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
Actual Study Start Date : June 1, 2014
Actual Primary Completion Date : December 31, 2017
Actual Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Niacin in controls
The arm includes healthy controls supplemented with niacin.
Dietary Supplement: Niacin
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.
Other Name: Nicotinic acid

Experimental: Niacin in 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 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.
Other Name: Nicotinic acid




Primary Outcome Measures :
  1. NAD+ and related metabolite levels in blood and muscle [ Time Frame: 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 high performance liquid chromatography-mass spectrometry


Secondary Outcome Measures :
  1. Number of diseased muscle fibers [ Time Frame: Baseline, 4 months 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 [ Time Frame: Baseline, 4 months and 10 months ]
    Change in mitochondria immunohistochemical staining intensity

  3. Muscle mitochondrial oxidative capacity [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle histochemical activity of mitochondrial cytochrome c oxidase

  4. Muscle metabolomic profile [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle metabolite concentrations measured with mass spectrometry

  5. Core muscle strength [ Time Frame: Baseline, 4 months 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) [ Time Frame: Baseline, 4 months and 10 months ]
    Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits

  7. Muscle mitochondrial DNA deletions [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification

  8. Muscle transcriptomic profile [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle gene expression determined using RNA sequencing approach


Other Outcome Measures:
  1. Body weight and body composition [ Time Frame: Baseline, 4 months and 10 months ]
    Change in body weight as well as fat mass and fat free mass measured with bioimpedance

  2. Ectopic lipid accumulation, i.e. liver and muscle lipid content [ Time Frame: Baseline, 4 months and 10 months ]
    Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy

  3. Circulating lipid profiles [ Time Frame: Baseline, 4 months and 10 months ]
    Change in circulating HDL, LDL and triglyceride concentrations measured using standard photometric enzymatic assay



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   17 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Manifestation of pure mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA
  2. Age and gender matched healthy controls for every patient
  3. Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study
  4. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03973203


Sponsors and Collaborators
University of Helsinki
Helsinki University Central Hospital
Institute for Molecular Medicine
University of Iowa
Investigators
Layout table for investigator information
Principal Investigator: Anu Suomalainen Wartiovaara, MD,PhD Research Programs Unit, University of Helsinki, Helsinki, Finland

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Anu Wartiovaara, Academy Professor, Professor of Clinical Molecular Medicine, University of Helsinki
ClinicalTrials.gov Identifier: NCT03973203    
Other Study ID Numbers: NiaMIT_0001
First Posted: June 4, 2019    Key Record Dates
Last Update Posted: June 4, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Anu Wartiovaara, University of Helsinki:
vitamin B3
niacin
mitochondrial myopathy
mitochondria
muscle
muscle strength
NAD+ precursor
NAD+
NAD-booster
Additional relevant MeSH terms:
Layout table for MeSH terms
Muscular Diseases
Mitochondrial Myopathies
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Mitochondrial Diseases
Metabolic Diseases
Niacin
Nicotinic Acids
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Vasodilator Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs