Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Комбинированный продукт 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.

Первичные конечные точки

• Rate of Responder versus Non-Responder Status with investigational product [Срок оценки: 260 weeks]

Вторичные конечные точки (1)

• Number of participants experiencing dose-limiting toxicities, adverse events (AEs), serious adverse events (SAEs) [Срок оценки: 260 weeks]

Критерии участия

Критерии включения

• 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

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Канада · 1 центр

• Research InstituMcGill University Health Centre - Children Hospital of Montreal — Montreal

Публикации

• Osellame LD, Blacker TS, Duchen MR. Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab. 2012 Dec;26(6):711-23. doi: 10.1016/j.beem.2012.05.003. Epub 2012 Jun 23. PMID 23168274
• Miller FJ, Rosenfeldt FL, Zhang C, Linnane AW, Nagley P. Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age. Nucleic Acids Res. 2003 Jun 1;31(11):e61. doi: 10.1093/nar/gng060. PMID 12771225
• DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003 Jun 26;348(26):2656-68. doi: 10.1056/NEJMra022567. No abstract available. PMID 12826641
• Huang CC, Hsu CH. [Mitochondrial disease and mitochondrial DNA depletion syndromes]. Acta Neurol Taiwan. 2009 Dec;18(4):287-95. Chinese. PMID 20329599
• Rusecka J, Kaliszewska M, Bartnik E, Tonska K. Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA. J Appl Genet. 2018 Feb;59(1):43-57. doi: 10.1007/s13353-017-0424-3. Epub 2018 Jan 17. PMID 29344903
• Viscomi C, Zeviani M. MtDNA-maintenance defects: syndromes and genes. J Inherit Metab Dis. 2017 Jul;40(4):587-599. doi: 10.1007/s10545-017-0027-5. Epub 2017 Mar 21. PMID 28324239
• Blazquez-Bermejo C, Carreno-Gago L, Molina-Granada D, Aguirre J, Ramon J, Torres-Torronteras J, Cabrera-Perez R, Martin MA, Dominguez-Gonzalez C, de la Cruz X, Lombes A, Garcia-Arumi E, Marti R, Camara Y. Increased dNTP pools rescue mtDNA depletion in human POLG-deficient fibroblasts. FASEB J. 2019 Jun;33(6):7168-7179. doi: 10.1096/fj.201801591R. Epub 2019 Mar 8. PMID 30848931
• El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics. 2013 Apr;10(2):186-98. doi: 10.1007/s13311-013-0177-6. PMID 23385875

Идентификаторы

NCT: NCT04802707 · 2021-7654 dC-dT-MDS

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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