Mitochondrial DiseasesPhase 2dC-dT-MDSNCT04802707
Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
A Phase 2 study testing deoxycytidine and deoxythymidine in people with Mitochondrial Diseases and Mitochondrial Encephalomyopathy, run by Kenneth Myers, MD at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 month to 60 years
- Conditions the study is for
- Mitochondrial Diseases, Mitochondrial Encephalomyopathy, Mitochondrial Encephalopathy
- What is being tested?
- deoxycytidine and deoxythymidine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 1 siteCanada
- Study dates
- 18 Oct 2021to 30 Dec 2029
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 60 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- Inability of a parent or legal guardian to give informed consent for any reason
- Chronic severe diarrhea
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
Research InstituMcGill University Health Centre - Children Hospital of Montreal
Montreal, Quebec, H4A 3J1
Dr. Kenneth Myers, MD, 514-934-1934 ext. 76204, kenneth.myers@mcgill.ca
Saoussen Berrahmoune, PhD, saoussen.berrahmoune@rimuhc.ca
About this study
Official title: 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.
Read more
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.
Read the 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:
- 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.
- Evaluation of growth differentiation factor 15 (GDF15; a marker of severity of mitochondria dysfunction).
Secondary Outcomes:
- 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.
- Neurological improvement by electroencephalography (EEG), seizure diary, development and quality of life questionnaires (PED and adults), clinical status observed during the neurological follow-up.
- 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).
- mtDNA quantification.
- 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
- Being tested
- deoxycytidine and deoxythymidine
- Keywords
- Deoxycytidine, Deoxythymidine, Deoxynucleoside, Pyrimidine, Mitochondria, mtDNA, Depletion
- Medical subject headings
- Mitochondrial Diseases, Mitochondrial Encephalomyopathies, Mitochondrial encephalopathy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
deoxycytidine and deoxythymidineCombination 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.
| Study group | Role | What they receive |
|---|---|---|
| dC/dT100-400 Arm | Experimental | Children \& Adult (0-60 Y), who takes the investigational product deoxynucleosides pyrimidine (mix of deoxycytidine and deoxythymidine), following the protocol. Receives: Combination Product: deoxycytidine and deoxythymidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of Responder versus Non-Responder Status with investigational product
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.
Measured: 260 weeks
Secondary outcomes (1)
Number of participants experiencing dose-limiting toxicities, adverse events (AEs), serious adverse events (SAEs)
"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.
Measured: 260 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2021
- Study start18 Oct 2021
- Primary completion30 Jun 2029 (estimated)
- Study completion30 Dec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (68)Papers the sponsor has linked to this study.
- Other trials for Mitochondrial DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Phase II, One Site, Open label study in the pediatric and adult population
- Masking
- None (open label)
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Kenneth Myers, MD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Kenneth Myers, MD, McGill University Health Centre/Research Institute of the McGill University Health Centre
- Investigators
- Kenneth Alexis MD Myers, MD PhD FRCPC, Principal investigator, RI-MUHC, Children Hospital of Montreal (MUHC), McGill University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04802707
- Sponsor's protocol ID
- 2021-7654 dC-dT-MDS
- Acronym
- dC-dT-MDS
- Status last verified
- Oct 2026
- First submitted
- 10 Mar 2021
- Last updated
- 19 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Publications
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.
PubMed 23168274Miller 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.
PubMed 12771225DiMauro 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.
PubMed 12826641Huang CC, Hsu CH. [Mitochondrial disease and mitochondrial DNA depletion syndromes]. Acta Neurol Taiwan. 2009 Dec;18(4):287-95. Chinese.
PubMed 20329599Rusecka 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.
PubMed 29344903Viscomi 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.
PubMed 28324239Blazquez-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.
PubMed 30848931El-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.
PubMed 23385875Nogueira C, Almeida LS, Nesti C, Pezzini I, Videira A, Vilarinho L, Santorelli FM. Syndromes associated with mitochondrial DNA depletion. Ital J Pediatr. 2014 Apr 3;40:34. doi: 10.1186/1824-7288-40-34.
PubMed 24708634Basel D. Mitochondrial DNA Depletion Syndromes. Clin Perinatol. 2020 Mar;47(1):123-141. doi: 10.1016/j.clp.2019.10.008. Epub 2019 Oct 31.
PubMed 32000920Rahman S, Poulton J. Diagnosis of mitochondrial DNA depletion syndromes. Arch Dis Child. 2009 Jan;94(1):3-5. doi: 10.1136/adc.2008.147983. No abstract available.
PubMed 19103785Spinazzola A, Invernizzi F, Carrara F, Lamantea E, Donati A, Dirocco M, Giordano I, Meznaric-Petrusa M, Baruffini E, Ferrero I, Zeviani M. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis. 2009 Apr;32(2):143-58. doi: 10.1007/s10545-008-1038-z. Epub 2008 Dec 27.
PubMed 19125351Suomalainen A, Isohanni P. Mitochondrial DNA depletion syndromes--many genes, common mechanisms. Neuromuscul Disord. 2010 Jul;20(7):429-37. doi: 10.1016/j.nmd.2010.03.017. Epub 2010 May 4.
PubMed 20444604Copeland WC. Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol. 2012 Jan-Feb;47(1):64-74. doi: 10.3109/10409238.2011.632763.
PubMed 22176657Khan NA, Govindaraj P, Meena AK, Thangaraj K. Mitochondrial disorders: challenges in diagnosis & treatment. Indian J Med Res. 2015 Jan;141(1):13-26. doi: 10.4103/0971-5916.154489.
PubMed 25857492