Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

NCT ID: NCT04802707

Last Updated: 2025-05-31

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-18
• Study Completion Date: 2029-12-30

Brief Summary

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.

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.

Conditions

Mitochondrial Diseases; Mitochondrial Encephalomyopathy; Mitochondrial Encephalopathy; Mitochondrial DNA Depletion; Mitochondrial Metabolism Disorders

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

dC/dT100-400 Arm

Children \& Adult (0-60 Y), who takes the investigational product deoxynucleosides pyrimidine (mix of deoxycytidine and deoxythymidine), following the protocol.

Group Type: EXPERIMENTAL

deoxycytidine and deoxythymidine

Intervention Type: COMBINATION_PRODUCT

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.

Interventions

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.

Intervention Type: COMBINATION_PRODUCT

Eligibility Criteria

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

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kenneth Myers, MD

OTHER

Sponsor Role: lead

Responsible Party

Kenneth Myers, MD

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Kenneth Alexis MD Myers, MD PhD FRCPC

Role: PRINCIPAL_INVESTIGATOR

RI-MUHC, Children Hospital of Montreal (MUHC), McGill University

Locations

Research InstituMcGill University Health Centre - Children Hospital of Montreal

Montreal, Quebec, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Kenneth Alexis MD Myers, MD PhD FRCPC

Role: CONTACT

kenneth.myers@mcgill.ca

514-934-1934 ext. 23316

Saoussen Dr Berrahmoune, PhD

Role: CONTACT

saoussen.berrahmoune@rimuhc.ca

514-934-1934 ext. 76204

Facility Contacts

Dr. Kenneth Myers, MD

Role: primary

kenneth.myers@mcgill.ca

514-934-1934 ext. 76204

Saoussen Berrahmoune, PhD

Role: backup

saoussen.berrahmoune@rimuhc.ca

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Other Identifiers

2021-7654 dC-dT-MDS

Identifier Type: -

Identifier Source: org_study_id