Treatment of TK2 Deficiency With Thymidine and Deoxycytidine

NCT03639701 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: AAAQ7552
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with confirmed mitochondrial DNA depletion syndrome 2 (thymidine kinase 2 \[TK2\] deficiency) have reduced levels of nucleotides (deoxythymidine monophosphate and deoxycytidine monophosphate) for mitochondrial DNA synthesis. This results in mitochondrial DNA depletion syndrome (i.e less number of functional mitochondrial DNA). Patients with confirmed TK2 deficiency will be treated with open label deoxythymidine (dThd) and deoxycytidine (dCyt), which are nucleotide precursors, with the expectation that the cells could make additional mitochondrial DNA. This in turn may help reduce the clinical symptoms.

Conditions

Thymidine Kinase 2 Deficiency; Mitochondrial DNA Depletion Syndrome 2 Myopathic Type

Keywords

Thymidine; Deoxycytidine

Outcome Measures

Primary Outcomes (7)

• Alanine aminotransferase

  Number of participants with treatment-related elevated alanine aminotransferase (ALT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.

  Up to 60 months

• Aspartate aminotransferase

  Number of participants with treatment-related elevated aspartate aminotransferase (AST) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.

  Up to 60 months

• Gamma-glutamyltransferase

  Number of participants with treatment-related elevated gamma-glutamyltransferase (GGT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.

  Up to 60 months

• Blood lymphocyte count

  Blood lymphocyte count increased relative to upper limit or normal or decreased relative to lower limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.

  Up to 60 months

• Creatinine

  Serum creatinine level increased relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.

  Up to 60 months

• Electrocardiogram

  Number of patients with treatment related electrocardiogram (ECG) QT corrected interval (QTc) grade 3 or higher as defined by CTCAE version 4.03.

  Up to 60 months

• Diarrhea

  Patient-Reported Outcome Measurement Information System (PROMIS) Scale v1.0 - Gastrointestinal Diarrhea 6a score (score range 0-30 with higher scores indicating more severe diarrhea)

  Up to 60 months

Secondary Outcomes (9)

• Event-free survival

  Up to 60 months

• 6-minute walk test

  Up to 60 months

• Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)

  Up to 60 months

• Hammersmith Functional Motor Scale Expanded (HFMSE)

  Up to 60 months

• Vital Capacity

  Up to 60 months

Study Arms (1)

Open label thymidine and deoxycytidine

EXPERIMENTAL

All patients will receive open label thymidine and deoxycytidine

Drug: Thymidine

Interventions

Thymidine DRUG

Mitochondrial DNA nucleotide precursors. Dose escalation: 130mg/kg/day x 14 days, 260 mg/kg/day x 14 days, and 400mg/kg/day as tolerated. Compounds are taken orally and divided into 3 doses daily.

Also known as: Deoxycytidine

Open label thymidine and deoxycytidine

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Genetically confirmed diagnosis of TK2 deficiency
• Deemed by principle investigator to be symptomatic with TK2 deficiency
• Single gene disease; absence of polygenic disease
• Hematocrit within normal range for age group
• Patient or patient's guardian able to consent and comply with protocol requirements
• Presence of caregiver to ensure study compliance (if needed)
• Abstention from use of all pill-form dietary supplements and non-prescribed medications (except as allowed by the investigator)
• Abstention from use of other investigational medications or other medications according to the study investigator

You may not qualify if:

• Clinical history of bleeding or abnormal prothrombin time (PT)/partial thromboplastin time (PTT)
• Hepatic insufficiency with liver function tests (LFTs) greater than two times normal
• Renal insufficiency requiring dialysis
• Any other concurrent inborn errors of metabolism
• Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis

Sponsors & Collaborators

• Muscular Dystrophy Association: collaborator
• Hospital Universitario 12 de Octubre: collaborator
• Instituto de Salud Carlos III: collaborator
• University of Seville: collaborator
• Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Spain: collaborator
• Hospitales Universitarios Virgen del Rocío: collaborator
• Universitat Autonoma de Barcelona: collaborator
• Columbia University: lead
• Medical Research Council Mitochondrial Biology Unit: collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Related Publications (4)

• Garone C, Taylor RW, Nascimento A, Poulton J, Fratter C, Dominguez-Gonzalez C, Evans JC, Loos M, Isohanni P, Suomalainen A, Ram D, Hughes MI, McFarland R, Barca E, Lopez Gomez C, Jayawant S, Thomas ND, Manzur AY, Kleinsteuber K, Martin MA, Kerr T, Gorman GS, Sommerville EW, Chinnery PF, Hofer M, Karch C, Ralph J, Camara Y, Madruga-Garrido M, Dominguez-Carral J, Ortez C, Emperador S, Montoya J, Chakrapani A, Kriger JF, Schoenaker R, Levin B, Thompson JLP, Long Y, Rahman S, Donati MA, DiMauro S, Hirano M. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018 Aug;55(8):515-521. doi: 10.1136/jmedgenet-2017-105012. Epub 2018 Mar 30.

  PMID: 29602790 RESULT

• Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652. doi: 10.1002/ana.24922. Epub 2017 May 4.

  PMID: 28318037 RESULT

• Garone C, Garcia-Diaz B, Emmanuele V, Lopez LC, Tadesse S, Akman HO, Tanji K, Quinzii CM, Hirano M. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med. 2014 Aug;6(8):1016-27. doi: 10.15252/emmm.201404092.

  PMID: 24968719 RESULT

• Chanprasert S, Wang J, Weng SW, Enns GM, Boue DR, Wong BL, Mendell JR, Perry DA, Sahenk Z, Craigen WJ, Alcala FJ, Pascual JM, Melancon S, Zhang VW, Scaglia F, Wong LJ. Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Mol Genet Metab. 2013 Sep-Oct;110(1-2):153-61. doi: 10.1016/j.ymgme.2013.07.009. Epub 2013 Jul 17.

  PMID: 23932787 RESULT

MeSH Terms

Interventions

Thymidine; Deoxycytidine

Intervention Hierarchy (Ancestors)

Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine

Study Officials

• Michio Hirano, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Model Details: Open label treatment with thymidine and deoxycytidine

Study Record Dates

• First Submitted: August 7, 2018
• First Posted: August 21, 2018
• Study Start: May 16, 2017
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: January 28, 2026

Record last verified: 2026-01

Locations

US (1)