NiaMIT Continuation With Early-stage Mitochondrial Myopathy Patients

January 21, 2021 updated by: Anu Wartiovaara, University of Helsinki

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Finland
      • Helsinki, Finland
        • University of Helsinki

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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 a quantitative colorimetric assay.
Baseline, 4 months and 10 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of diseased muscle fibers
Time Frame: 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
Baseline and 10 months
Mitochondrial biogenesis
Time Frame: Baseline and 10 months
Change in mitochondria immunohistochemical staining intensity
Baseline and 10 months
Muscle mitochondrial oxidative capacity
Time Frame: Baseline and 10 months
Change in muscle histochemical activity of mitochondrial cytochrome c oxidase
Baseline and 10 months
Muscle and blood metabolomic profiles
Time Frame: Baseline and 10 months
Change in muscle or serum/plasma metabolite concentrations measured with mass spectrometry
Baseline and 10 months
Core muscle strength
Time Frame: Baseline and 10 months
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)
Time Frame: Baseline and 10 months
Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits
Baseline and 10 months
Muscle mitochondrial DNA deletions
Time Frame: Baseline and 10 months
Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification
Baseline and 10 months
Muscle transcriptomic profile
Time Frame: Baseline and 10 months
Change in muscle gene expression determined using RNA sequencing approach
Baseline and 10 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline, 4 months and 10 months
Body weight
Time Frame: Baseline and 10 months
Change in body weight
Baseline and 10 months
Body composition
Time Frame: Baseline and 10 months
Change in fat mass and fat free mass measured with bioimpedance
Baseline and 10 months
Ectopic lipid accumulation, i.e. liver and muscle lipid content
Time Frame: Baseline and 10 months
Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy
Baseline and 10 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Helsinki

Collaborators

Helsinki University Central Hospital
Institute for Molecular Medicine

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 11, 2019

Primary Completion (Actual)

September 18, 2020

Study Completion (Actual)

September 18, 2020

Study Registration Dates

First Submitted

August 29, 2020

First Submitted That Met QC Criteria

August 29, 2020

First Posted (Actual)

September 4, 2020

Study Record Updates

Last Update Posted (Actual)

January 25, 2021

Last Update Submitted That Met QC Criteria

January 21, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NiaMIT_002

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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