Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 入组人数
- 34
- 主要终点
- Change in interferon activation as measured by interferon response genes
研究概览
简要总结
The overall objectives are to explore the safety and efficacy of Reverse Transcriptase Inhibitors Tenofovir (TDF)/ Emtricitabine (FTC) administered in AGS affected children 2 to 18 years of age.
详细描述
The investigators propose that a trial to assess the proof of principle that antiretroviral therapy through a drug combination of Tenofovir (TDF) and Emtricitabine (FTC) can decrease endogenous retroelement accumulation, and alter interferon signaling in Aicardi Goutières Syndrome (AGS) patients is reasonable and warranted at this time, based on existing in vitro and animal data. Additionally, this trial will further the investigators understanding of this disorder, measuring for the first time retroelements in human participants, exploring the retroviral burden in cerebrospinal fluid (CSF), the Interferon (IFN) signaling response, as well as evaluating antigen targets of autoimmunity and cytokines. If successful, this approach will clearly demonstrate the need for a larger trial of antiretrovirals in AGS with more clinically relevant outcomes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Molecular, neuroimaging, and clinical findings consistent with a diagnosis of AGS, with the exception of Double-stranded RNA-specific adenosine deaminase (ADAR1) and IFIH1, which are not postulated to result in nucleic acid accumulation
- •Evidence of interferon activation such as elevation of CSF neopterin/tetrahydrobiopterin measured on the first evaluation.
- •Ages 2-18 years (the age of 2 years is used because the drugs are FDA approved in children greater than 2 years)
- •Weight of at least 10 kg
- •Willingness to undergo serial lumbar punctures and blow draws for evaluation of laboratory based outcome measures
- •Willingness to abstain from initiating the use of immune modulating therapies including corticosteroids
- •Able to receive medications orally, by nasogastric (NG) tube or by Gastric (G)-tube
- •No concomitant illness which would preclude safe participation as judged by the investigator
- •Signed informed consent by the subject's legally acceptable representative
- •Negative testing for HIV
- •Negative testing for Hepatitis B
- •Concurrent enrollment in the Myelin Disorders Biorepository Project (MDBP, ClinicalTrials.gov NCT03047369) and willingness to undergo associated procedures
排除标准
- •Age < 2 years or >18 years
- •Hepatic insufficiency with liver function tests greater than 3-times the upper limit of normal
- •Renal insufficiency with creatinine clearance <60
- •Significant malabsorption
- •Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at an additional risk by participating in this study
- •HIV infection
- •Hepatitis B infection
- •Mutations in ADAR1 or IFIH1
研究组 & 干预措施
TDF/FTC then Placebo
This is a double-blind, placebo-controlled, 2 arm, cross-over trial involving 34 children with clinical findings and molecular confirmation of Aicardi Goutieres Syndrome, who also have an abnormal interferon signature. For arm 1, half of the patients will receive TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for the first 6 months of the study. There will be a one month washout period before starting on placebo for 6 months.
干预措施: Tenofovir (TDF) and Emtricitabine (FTC) (Drug)
TDF/FTC then Placebo
This is a double-blind, placebo-controlled, 2 arm, cross-over trial involving 34 children with clinical findings and molecular confirmation of Aicardi Goutieres Syndrome, who also have an abnormal interferon signature. For arm 1, half of the patients will receive TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for the first 6 months of the study. There will be a one month washout period before starting on placebo for 6 months.
干预措施: Placebo (Other)
Placebo then TDF/FTC
For arm 2, half of the patients will receive placebo for the first 6 months of the study. There will be a one month washout period before starting on TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for 6 months.
干预措施: Tenofovir (TDF) and Emtricitabine (FTC) (Drug)
Placebo then TDF/FTC
For arm 2, half of the patients will receive placebo for the first 6 months of the study. There will be a one month washout period before starting on TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for 6 months.
干预措施: Placebo (Other)
结局指标
主要结局
Change in interferon activation as measured by interferon response genes
时间窗: From Baseline to 13 months
The investigators propose to measure genes in the IFN stimulatory pathway in AGS patients, as a measure of disease activity and as a possible biomarker of therapeutic activity. Current data suggests that IFN related genes remain elevated in the late teens in AGS affected subjects, making it a more reliable measure of disease activity than IFN alpha. Validation of this preliminary data includes serial measurements in blood across several time points, to assess for variability.
次要结局
- Changes in Adverse Events - Safety monitoring laboratory tests(From Baseline to 13 months and as clinically warranted)
- Determination of immune cell composition in CSF(From Baseline to 13 months)
- Change in presence of non-specific and specific autoantibodies in blood(From Baseline to 13 months)
- Changes in total days hospitalized for disease-related illnesses.(Baseline - 13 months)
- Accumulation of endogenous retroelements as measured in circulating CSF(From Baseline to 13 months)
- Determination of immune cell composition in blood(From Baseline to 13 months)
- Accumulation of endogenous retroelements as measured in circulating immune cells(From Baseline to 13 months)