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

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, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4. Subjects with MDS expressing neurological phenotypes dysfunction.

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. First Outcome Efficacy of dC/dT100-400 : Neurological improvement by electroencephalography (EEG), seizure diary, development and quality of life, clinical status observed during the neurological follow-up. Improved clinical status observed during the genetic follow-up and the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS), which are forms used by geneticist to allow evaluation of the progression of mitochondrial disease in patients less than 18 years of age. Bloodwork for different assessments: 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). Evaluation of mitochondrial function with capillary/venous blood gas, serum lactate, plasma amino acids, acylcarnitine profile, urine amino acids, urine purines and pyrimidines acids, and growth differentiation factor 15 (GDF15; a marker of severity of mitochondria dysfunction). Secondary Outcome - 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.

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

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

The Investigational Product (IP) dC/dT100-400 will be administered orally every day (QD) and the dose is divided over 3 taking/day 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 730. Doses was chosen according to the safety and efficacy doses used in the literature.

"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) Normal Organics and Metabolism functions Description of the primary variable(s) The primary efficacy endpoint is the composite cluster of the first occurrence, over the duration of study, of Mitochondria Depletion Syndrome.

Number of participants experiencing dose-limiting toxicities, adverse events (AEs), serious adverse events (SAEs)

Safety profile will be assessed through number of participants experiencing adverse events (AEs), serious adverse events (SAEs), laboratory evaluations, vital signs, and physical examinations.

Inclusion Criteria: Children & Adults (0 -60 Y) Written informed consent obtained, Clinical Diagnosis of a Mitochondrial Depletion Disorder. Pathogenic variant(s) in one of the following genes: POLG, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4 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

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

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)

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