Vitamin B12 and Folinic Acid Supplementation in Mitochondrial DNA Deletion Syndromes

December 15, 2023 updated by: Andre Mattman, University of British Columbia

The purpose of this single center study is to evaluate whether there is a concordant improvement in macrocytosis in patient with mtDNA deletions with established macrocytosis following a trial of Vitamin B12 and Folinic acid supplementation.

This study aims to assess if macrocytosis in patients with mtDNA deletion syndromes improve following empiric supplementation with vitamin B12 and folic acid. Complete blood counts (CBC) will be followed during this study (at initiation, 3 months, and 6 months) to assess for response in MCV to supplementation. The potential involvement of the region affected by the mtDNA deletion in mitochondrial folate-mediated transport and metabolism [5,6] may serve as the possible link between the deletion and observed macrocytosis.

Neurologic/cognitive outcomes will also be followed at the above time intervals to assess if 3-6 months of Vitamin B12/folinic supplementation is an adequate vs insufficient time to observe a change in the Newcastle Mitochondrion Disease Adult Scale (NMDAS). The value of this study is that it may produce pilot data to support empiric supplementation of B12 and folate for patients with macrocytosis and mtDNA deletion syndromes.

Disease Large single mtDNA (mitochondrial DNA) deletion syndrome is a rare inborn error of metabolism, and chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial deletino syndrome. Upon recent review of cases from our Adult Metabolic Diseases Clinic (AMDC), several patients with mtDNA deletion syndromes (as opposed to mtDNA missense mutations identified over the same 2016-2022-year period) were found to have unexplained macrocytosis and this is the relevant study population for this assessment.

Intervention Participants will be followed as a single group for this pilot study. The study will include two phases; 6 months without micronutrient supplementation, followed by 6 months of folinic acid and B12 supplementation. Subjects will have bloodwork to establish baseline complete blood count (macrocytosis with/without anemia) as well as at 3 and 6 months without supplementation to establish a trend in the hematologic parameters above. Participants will also complete a baseline Newcastle Mitochondrion Disease Adult Scale (NMDAS) prior to supplementation, as well as at 3 and 6 months of starting supplementation. This next phase of folinic acid and B12 supplementation will continue for 6 months with biomarker monitoring again at 9 and 12 months, and the same biochemical investigations will take place to assess if there was a true association between peripheral serum macrocytosis and nutrient supplementation during the time periods.

Phase

1

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Study Design:

  • Study type: Pilot single group study
  • Actual Enrollment: 25 participants
  • Allocation: N/A
  • Intervention Model: Single Group Assignment

  • Intervention Model Description:

    • Vitamin B12 (also known as Cyanocobalamin) daily sublingual supplementation of 1000 mcg/day and folinic acid orally 1mg/day
    • Laboratory: Complete blood count, electrolytes, reticulocytes, creatinine, urea, alkaline phosphatase (ALP), alanine transaminase, ferritin, total homocysteine, lactate and hemoglobin A1c. Routine blood will be collected as regular standard of care with each visit. MMA will also be assessed. Peripheral serum values (CBC, B12) will serve as a representation of central micronutrient availability
    • Clinical Evaluation: the Newcastle mitochondrial disease adult scale (NMDAS)
  • Masking: None (Open Label)

  • Primary Purpose:

    • Assess for the proportion of subjects whose macrocytosis corrects (MCV, measured in fL, returns to the normal range of the testing laboratory) with Vitamin B12 and folinic acid supplementation in patient population with mtDNA deletion syndrome
    • Follow the Newcastle mitochondrial disease adult scale (NMDAS) with Vitamin B12 and folinic acid supplementation in patient population with mtDNA deletion syndromes for any clinical evidence of change.

The NMDAS has a maximum score of 140 (sections I, II (excluding question 8), and III). A higher score indicates more severe disease.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
25

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Ages eligible for study: 19 years and older (Adult, Older Adult)
  • All subjects reviewed previously at the Adult Metabolic Diseases Clinic with clinical features characteristic of major mtDNA deletion cases with biochemical macrocytosis
  • Continue prior administration of other therapies pertaining to their necessary medical care
  • Subjects must be clinically stable for more than one month after any stroke-like episodes
  • Written, informed consent to participate in the study

Exclusion Criteria:

  • Subjects with mitochondrial disease with a genetic etiology other than a major mtDNA deletion
  • Palliative care patients
  • Patients with a progressive neurologic disorder clinically attributable to a cause other than mitochondrial disease (e.g., ischemic stroke due to embolism from atrial fibrillation, atherosclerosis, malignant hypertension,)
  • Subjects who decline blood test and/or the follow-up schedule
  • Inability or refusal to give informed consent
  • Coexisting participation with other investigational drug study

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: Diagnostic
  • Allocation: N/A
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Macrocytosis
Time Frame: 1 year
• Proportion of patients who normalize their MCV (measured in fL) such that the MCV Is within the normal range of the testing laboratory after 6 months of vitamin therapy
1 year

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Newcastle mitochondrial disease adult scale (NMDAS)
Time Frame: 1 year
NMDAS scores (sections I-III with the exception of question 8 in section II) at scheduled intervals to assess for any clinically-evident change following supplementation introduction. Total score 140. Higher score indicates more severe disease
1 year

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of British Columbia

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 (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 1, 2023

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 15, 2023

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 29, 2023

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 29, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 15, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • H23-02541

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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