Thymidine Kinase 2 Deficiency Clinical Trial
Official title:
Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
Verified date | January 2024 |
Source | Columbia University |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
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 |
Country | Name | City | State |
---|---|---|---|
United States | Columbia University Irving Medical Center | New York | New York |
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 |
United States,
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
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 |
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