Clinical trial NCT03639701: Treatment of TK2 Deficiency With Thymidine and Deoxycytidine
Official title: Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Mitochondrial DNA Depletion Syndrome 2 Myopathic Type
Thymidine Kinase 2 Deficiency
Keywords: Thymidine
Deoxycytidine
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Muscular Dystrophy Association
name: Hospital Universitario 12 de Octubre
name: Instituto de Salud Carlos III
name: University of Seville
name: Medical Research Council Mitochondrial Biology Unit
name: Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Spain
name: Hospitales Universitarios Virgen del Rocío
name: Universitat Autonoma de Barcelona
First posted: 2018-08-21
Enrollment: 23
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label treatment with thymidine and deoxycytidine
Primary purpose: TREATMENT

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.

Detailed description: Mitochondrial are responsible for the production of cellular energy. Mitochondria contain DNA which is the encoding system ( "recipe") for making the proteins that allow the mitochondria to function. Reduced amount of mitochondrial DNA, caused by genetic mutations in certain genes, Mitochondrial DNA Depletion Syndrome. This can result in symptoms; such as fatigue, weakness, and deficiencies in various body systems. TK2 deficiency is considered a mitochondrial depletion syndrome. Patients with TK2 deficiency have weakness and walking difficulty. They also have depleted levels of chemicals (phosphorylated deoxythymidine and deoxycytidine) used to make mitochondrial DNA. Based on previous studies with a similar compound, patients reported more energy and better motor skills.

Eligible patients include those with genetic mutations in the TK2 gene who are willing to attend several outpatient visits, and have motor skills testing, neurological exam by doctor, and blood samples.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Alanine aminotransferase
timeFrame: Up to 60 months
measure: Aspartate aminotransferase
timeFrame: Up to 60 months
measure: Gamma-glutamyltransferase
timeFrame: Up to 60 months
measure: Blood lymphocyte count
timeFrame: Up to 60 months
measure: Creatinine
timeFrame: Up to 60 months
measure: Electrocardiogram
timeFrame: Up to 60 months
measure: Diarrhea
timeFrame: Up to 60 months
Secondary outcomes:
measure: Event-free survival
timeFrame: Up to 60 months
measure: 6-minute walk test
timeFrame: Up to 60 months
measure: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)
timeFrame: Up to 60 months
measure: Hammersmith Functional Motor Scale Expanded (HFMSE)
timeFrame: Up to 60 months
measure: Vital Capacity
timeFrame: Up to 60 months
measure: Time on Mechanical Ventilation
timeFrame: Up to 60 months
measure: euro Quality of Life (Neuro-QoL) in adults
timeFrame: Up to 60 months
measure: Neuro Quality of Life (Neuro-QoL) in pediatric subjects
timeFrame: Up to 60 months
measure: Suicidal Ideation
timeFrame: Up to 60 months
Other outcomes:
Locations:
city: New York City
country: United States
facility: Columbia University Irving Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Michio Hirano, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.