Treatment of TK2 Deficiency With Thymidine and Deoxycytidine

Thymidine Kinase 2 Deficiency Clinical Trial

Official title:

Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03639701
• Other study ID #: AAAQ7552
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: May 16, 2017
• Est. completion date: April 2025

Study information

• Verified date: January 2024
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 23
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Thymidine
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.

Locations

Country	Name	City	State
United States	Columbia University Irving Medical Center	New York	New York

Sponsors (9)

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

Country where clinical trial is conducted

United States, 

References & Publications (4)

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 depl — View 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. — View 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 — View 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.249 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Event-free survival	Time to mechanical ventilation, death, or both will be assessed.	Up to 60 months
Secondary	6-minute walk test	Distance walked in meters over 6 minutes will be measured in ambulatory patient.	Up to 60 months
Secondary	Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)	Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score (0-64 point range with higher scores indicating better function) will be assessed in infants to assess motor function.	Up to 60 months
Secondary	Hammersmith Functional Motor Scale Expanded (HFMSE)	Hammersmith Functional Motor Scale Expanded (HFMSE) score (0-66 point range with higher scores indicating better function) will be measured in subjects >1 year-old.	Up to 60 months
Secondary	Vital Capacity	Vital capacity (percent of predicted normal based on age and height) will be measure by spirometry	Up to 60 months
Secondary	Time on Mechanical Ventilation	Number of hours per day that subjects use mechanical ventilation will be recorded.	Up to 60 months
Secondary	euro Quality of Life (Neuro-QoL) in adults	Neuro Quality of Life (Neuro-QoL) short forms will be used to assess effects of muscle weakness on motor function and activities of daily living. In adults, Lower and Upper Extremity scales will be assessed (0-80 points with higher scores indicating better function).	Up to 60 months
Secondary	Neuro Quality of Life (Neuro-QoL) in pediatric subjects	Neuro Quality of Life (Neuro-QoL) forms will be used to assess effects of muscle weakness on motor function and activities of daily living. In pediatric subjects (<18 years-old), Lower and Upper Extremity scales will be assessed (0-160 points with higher scores indicating better function).	Up to 60 months
Secondary	Suicidal Ideation	Suicidal ideation will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), which contains 6 "yes" or "no" questions. Answer of "yes" to any question indicates possible suicide risk and answer of "yes: to questions 4, 5, or 6 indicates high-risk.	Up to 60 months