Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome (dC-dT-MDS)

May 27, 2025 updated by: Kenneth Myers, MD

A Phase II, Monocenter, Single Arm Study To Assess The Safety and Efficacy Of Combination Deoxycytidine and Deoxythymidine For Mitochondrial Depletion Disorders

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis. MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal.

No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. No treatment for MDS.

Clinical trials studies and in vitro/in vivo research studies showed that the enhancement of the salvage pathway by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion.

Early recognition and immediate therapy to restore mitochondrial function could potentially improve clinical course.

Confirming the benefit of deoxynucleosides as a safe and potentially efficacious therapy, will lead to the availability of the first specific and effective treatment for Mitochondria Depletion Disorders.

In this phase II Trial a mix of Deoxynucleosides Pyrimidine (Deoxycytidine dC and Deoxythymidine dT) will be used as early treatment of MDS.

The dose used has been already used in other clinical trials, and appears to effective and well-tolerated. The subjects included are children (0-18Y), with positive MDS diagnosis and express mutations in one of the following genes: POLG, POLG2, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK. Subjects with MDS expressing neurological phenotypes dysfunction.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This Trial is designed as Phase II, Monocenter, Open label study in the pediatric population.

The aim is to evaluate the safety, tolerability and efficacy of Deoxycytidine and Deoxythymidine in treatment of children with Mitochondrial Depletion Disorders.

Primary Objectives The primary objective of this study is to evaluate the efficacy of dC/dT100-400 in subjects with mitochondria depletion disorders.

Secondary Objectives The secondary objectives of this study are to evaluate tolerability and safety of dC/dT100-400 in subjects with mitochondria depletion disorders.

Efficacy of dC/dT100-400 :

First Outcomes:

  1. Improved clinical status observed during the genetic follow-up and the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) or Adult Newcastle Mitochondrial Disease Scale (ANMDS), which are validated measures used by geneticists to allow evaluation of the progression of mitochondrial disease in patients 0-60 y.
  2. Evaluation of growth differentiation factor 15 (GDF15; a marker of severity of mitochondria dysfunction).

Secondary Outcomes:

  1. Safety and tolerability will be tested by recording adverse effects (AE): AE will be monitored and collected throughout the study.

    • Diarrhea: Reported diarrhea frequency during the treatment, will permit to define the tolerability of dC/dT100-400.
    • AE leading to study drug discontinuation, treatment-emergent adverse events (TEAEs), SAEs (Severe Adverse Effect) will be reported from the first day the subjects start taking medication until the last dose taken.
  2. Neurological improvement by electroencephalography (EEG), seizure diary, development and quality of life questionnaires (PED and adults), clinical status observed during the neurological follow-up.

  3. Bloodwork for different assessments:

    Complete blood and platelet counts (CBC) will be performed to monitor any potential toxicity, liver function (aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), bilirubin and albumin.), kidney function (creatinine, urea, electrolytes). Assess for myopathy with serum creatine kinase (CK).

  4. mtDNA quantification.
  5. Evaluation of mitochondrial function with capillary/venous blood gas, serum lactate, plasma amino acids, acylcarnitine profile, urine amino acids, urine purines and pyrimidines acids.

Study Type

Interventional

Enrollment (Estimated)

200

Phase

  • Phase 2

Contacts and Locations

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

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Quebec
      • Montréal, Quebec, Canada, H4A 3J1
        • Recruiting
        • Research InstituMcGill University Health Centre - Children Hospital of Montreal
        • Contact:
        • Sub-Investigator:
          • Daniela Buhas, MD
        • Principal Investigator:
          • Kenneth Myers, MD
        • Contact:

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

1 month to 60 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Children & Adults (0 -60 Y)
  • Written informed consent obtained,
  • Clinical Diagnosis of a Mitochondrial Depletion Disorder.
  • Pathogenic variant(s) Homozygote and Heterozygote in one of the following genes: POLG, POLG2, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK
  • Females of childbearing age:

Negative urinary pregnancy test at screening Agree to use effective contraception for the duration of the study

Exclusion Criteria:

  • Inability of a parent or legal guardian to give informed consent for any reason
  • Chronic severe diarrhea

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: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: dC/dT100-400 Arm
Children & Adult (0-60 Y), who takes the investigational product deoxynucleosides pyrimidine (mix of deoxycytidine and deoxythymidine), following the protocol.
Combination product: deoxycytidine and deoxythymidine
The Investigational Product (IP) dC/dT100-400 will be administered orally every day (QD) and the dose is divided over trid or bid for the daily dose of 100 mg/kg from Day 1-7, 200 mg/kg from Day 8-14, 300 mg/kg from Day 15- 21 and 400 mg/kg from Day 22 to 1825. Doses was chosen according to the safety and efficacy doses used in the literature.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of Responder versus Non-Responder Status with investigational product
Time Frame: 260 weeks
There is no estimation of sample size, the number will depend on subjects enrolled. We assume we can include about 50 to 100 subjects with mitochondrial depletion disorder. This study is designed as Phase II trial case series, the data will be presented graphically The IP of study will be considered positive if more than 2 responders are observed in 5 subjects. This design yields a marginal one-sided type I error rate (α) of 5% and power of 80%. For more than one participant engages in a study, the spaghetti plot showing all of their data in the same figure will be used as tool for visualization. Visual analysis of graphed data has been the traditional method for evaluating treatment effects in series cases research.
260 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants experiencing dose-limiting toxicities, adverse events (AEs), serious adverse events (SAEs)
Time Frame: 260 weeks
"Responder" defined as having ≥ 2 of (1) electroencephalography EEG improvement, (2) decreased seizure frequency, (3) cognitive improvement, (4) caregiver impression of improvement, (5) clinical improvement, (6) Safety profile will be assessed through number of participants experiencing adverse events (AEs), serious adverse events (SAEs), laboratory evaluations, vital signs, and physical examinations.
260 weeks

Collaborators and Investigators

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

Sponsor

Kenneth Myers, MD

Investigators

  • Principal Investigator: Kenneth Alexis MD Myers, MD PhD FRCPC, RI-MUHC, Children Hospital of Montreal (MUHC), McGill University

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)

October 18, 2021

Primary Completion (Estimated)

June 30, 2029

Study Completion (Estimated)

December 30, 2029

Study Registration Dates

First Submitted

March 10, 2021

First Submitted That Met QC Criteria

March 15, 2021

First Posted (Actual)

March 17, 2021

Study Record Updates

Last Update Posted (Actual)

May 31, 2025

Last Update Submitted That Met QC Criteria

May 27, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2021-7654 dC-dT-MDS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

REDCap software will be used as IPD. The data's will be shared anonymous, subject will bes identified by an Identifiant (ID).

REDCap is managed by quality data's teams of research institute of McGill University Health Center (RI-MUHC).

For clinical study reports since the study is planned at the Children Hospital of Montreal, Clinical Study Report (CSR) access will be done through open architecture clinical information system (Oacis) tool of hospital Study Protocol And Informed Consent Form (ICF) will be shared by Email or on core network of RIMUHC

IPD Sharing Time Frame

104 weeks

IPD Sharing Access Criteria

Research Staff, Principal Investigator (PI), Co-Investigator, regulation authority and clinical research associate (CRA) for monitoring are authorized to access to the data's for CRA (anonymous data's)

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

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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