Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Creatinine
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Open label thymidine and deoxycytidine
All patients will receive open label thymidine and deoxycytidine
干预措施: Thymidine (Drug)
结局指标
主要结局
Creatinine
时间窗: Up to 60 months
Serum creatinine level increased relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Alanine aminotransferase
时间窗: Up to 60 months
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.
Electrocardiogram
时间窗: Up to 60 months
Number of patients with treatment related electrocardiogram (ECG) QT corrected interval (QTc) grade 3 or higher as defined by CTCAE version 4.03.
Aspartate aminotransferase
时间窗: Up to 60 months
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.
Gamma-glutamyltransferase
时间窗: Up to 60 months
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.
Blood lymphocyte count
时间窗: Up to 60 months
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.
Diarrhea
时间窗: Up to 60 months
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)
次要结局
- 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)
- Time on Mechanical Ventilation(Up to 60 months)
- euro Quality of Life (Neuro-QoL) in adults(Up to 60 months)
- Neuro Quality of Life (Neuro-QoL) in pediatric subjects(Up to 60 months)
- Suicidal Ideation(Up to 60 months)
研究者
Michio Hirano, MD
Professor of Neurology
Columbia University