A Phase II, Monocenter, Single Arm Study To Assess The Safety and Efficacy Of Combination Deoxycytidine and Deoxythymidine For Mitochondrial Depletion Disorders
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 200
- 试验地点
- 2
- 主要终点
- Rate of Responder versus Non-Responder Status with investigational product
研究概览
简要总结
Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis. MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal.
No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. No treatment for MDS.
Clinical trials studies and in vitro/in vivo research studies showed that the enhancement of the salvage pathway by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion.
Early recognition and immediate therapy to restore mitochondrial function could potentially improve clinical course.
Confirming the benefit of deoxynucleosides as a safe and potentially efficacious therapy, will lead to the availability of the first specific and effective treatment for Mitochondria Depletion Disorders.
In this phase II Trial a mix of Deoxynucleosides Pyrimidine (Deoxycytidine dC and Deoxythymidine dT) will be used as early treatment of MDS.
The dose used has been already used in other clinical trials, and appears to effective and well-tolerated. The subjects included are children (0-18Y), with positive MDS diagnosis and express mutations in one of the following genes: POLG, POLG2, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK. Subjects with MDS expressing neurological phenotypes dysfunction.
详细描述
This Trial is designed as Phase II, Monocenter, Open label study in the pediatric population.
The aim is to evaluate the safety, tolerability and efficacy of Deoxycytidine and Deoxythymidine in treatment of children with Mitochondrial Depletion Disorders.
Primary Objectives The primary objective of this study is to evaluate the efficacy of dC/dT100-400 in subjects with mitochondria depletion disorders.
Secondary Objectives The secondary objectives of this study are to evaluate tolerability and safety of dC/dT100-400 in subjects with mitochondria depletion disorders.
Efficacy of dC/dT100-400 :
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
- 年龄范围
- 1 Month 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children & Adults (0 -60 Y)
- •Written informed consent obtained,
- •Clinical Diagnosis of a Mitochondrial Depletion Disorder.
- •Pathogenic variant(s) Homozygote and Heterozygote in one of the following genes: POLG, POLG2, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK
- •Females of childbearing age:
- •Negative urinary pregnancy test at screening Agree to use effective contraception for the duration of the study
排除标准
- •Inability of a parent or legal guardian to give informed consent for any reason
- •Chronic severe diarrhea
研究组 & 干预措施
dC/dT100-400 Arm
Children & Adult (0-60 Y), who takes the investigational product deoxynucleosides pyrimidine (mix of deoxycytidine and deoxythymidine), following the protocol.
干预措施: deoxycytidine and deoxythymidine (Combination Product)
结局指标
主要结局
Rate of Responder versus Non-Responder Status with investigational product
时间窗: 260 weeks
There is no estimation of sample size, the number will depend on subjects enrolled. We assume we can include about 50 to 100 subjects with mitochondrial depletion disorder. This study is designed as Phase II trial case series, the data will be presented graphically The IP of study will be considered positive if more than 2 responders are observed in 5 subjects. This design yields a marginal one-sided type I error rate (α) of 5% and power of 80%. For more than one participant engages in a study, the spaghetti plot showing all of their data in the same figure will be used as tool for visualization. Visual analysis of graphed data has been the traditional method for evaluating treatment effects in series cases research.
次要结局
- Number of participants experiencing dose-limiting toxicities, adverse events (AEs), serious adverse events (SAEs)(260 weeks)
研究者
Kenneth Myers, MD
Principal Investigator
McGill University Health Centre/Research Institute of the McGill University Health Centre