PREQUEL Study In PRE-manifest HD of CoQ10/UbiquinonE Leading to Preventive Trials

辅酶 Q10/泛醌 E 预清单 HD 的前传研究导致预防性试验

• 批准号: 7942954
• 负责人: Christopher A Ross
• 金额: $ 122.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942954
• 关键词: 8-hydroxy-2' -deoxyguanosine; 8-hydroxyguanosine; Adverse event; Affect; Basal Ganglia; Biological; Biological Markers; CAG repeat; Caring; Clinical; Clinical Trials; Coenzyme Q10; DNA Repair; Data; Disease; Dose; Double-Blind Method; Future; Goals; Huntington Disease; Individual; Magnetic Resonance Imaging; Measures; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; OGG1 gene; Observational Study; Outcome Measure; Oxidative Stress; Participant; Phase; Population; Preventive; Process; Randomized; Risk; Safety; Serum; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapy Clinical Trials; Ubiquinone; cognitive change; dosage; efficacy trial; mouse model; neuroprotection; neuropsychological; prevent; randomized placebo controlled trial; research study; trend; 8-hydroxy-2' -deoxyguanosine; 8-hydroxyguanosine; Adverse event; Affect; Basal Ganglia; Biological; Biological Markers; CAG repeat; Caring; Clinical; Clinical Trials; Coenzyme Q10; DNA Repair; Data; Disease; Dose; Double-Blind Method; Future; Goals; Huntington Disease; Individual; Magnetic Resonance Imaging; Measures; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; OGG1 gene; Observational Study; Outcome Measure; Oxidative Stress; Participant; Phase; Population; Preventive; Process; Randomized; Risk; Safety; Serum; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapy Clinical Trials; Ubiquinone; cognitive change; dosage; efficacy trial; mouse model; neuroprotection; neuropsychological; prevent; randomized placebo controlled trial; research study; trend

DESCRIPTION (provided by applicant): The search for neuroprotective therapeutic interventions for HD is accelerating. Volumetric MRI studies indicate that neurodegeneration in the basal ganglia begins ten years or more prior to manifest HD. Therapeutic neuroprotective trials in the pre- manifest population aimed at delaying the onset of manifest HD could potentially have a significant impact on this devastating disorder. CoEnzyme Q10 (CoQ) has emerged as one of the leading therapeutic candidates for neuroprotection in manifest HD, with strong near-significant trends for efficacy in several outcome measures in a 30 month study (CARE-HD) of 600 mg per day. While there are substantial data on the tolerability of CoQ at 600 mg/day in symptomatic HD, dose ranging studies suggest the possibility of decreased tolerability in otherwise healthy individuals at higher dosages. We propose to study CoQ at dosages of 600 mg/day, 1200 mg/day and 2400 mg/day to determine, in a population of expansion positive pre-manifest participants, the highest dosage that is tolerable; with the long term objective of developing future preventive therapeutic trials of CoQ at that dosage. In Specific Aim 1, we will establish the safety and tolerability of CoQ at dosages of 600 mg/day, 1200 mg/day and 2400 mg/day in a mutation positive pre-manifest population with the HD CAG repeat expansion, in the context of a randomized double-blind 20 week parallel-group trial. In Specific Aim 2, we will establish that Coenzyme Q10 is biologically active by assessing changes in serum CoQ levels, and 8-Hydroxydeoxyguanosine (8OHdG) and 8-Hydroxyguanosine (8OHrG) levels in the same trial. We will assess the relationships between serum levels of CoQ, biomarkers of oxidative stress, biomarkers of DNA repair mechanisms (OGG1) and dosage levels of CoQ. The proposed trial is significant in that it will be the first study to evaluate a potential therapeutic agent in a population of individuals at 100% risk for developing a neurodegenerative illness, but who are not yet ill. It will allow us to select a dosage of CoQ for future definitive randomized placebo controlled trials in pre-manifest HD to delay or prevent onset of manifest HD, and will give us valuable information about the process and feasibility of such trials in pre-manifest participants.

描述（由申请人提供）：搜索HD的神经保护性治疗干预措施正在加速。体积MRI研究表明，在明显的HD之前，基底神经节的神经变性开始了十年或更长时间。旨在延迟明显HD发作的较明显人群的治疗性神经保护试验可能会对这种毁灭性疾病产生重大影响。 Coenzyme Q10（COQ）已成为明显HD中神经保护的领先治疗候选者之一，在每天30个月的研究（CARE-HD）中，在几项结果中，有效的效率很近，每天为600 mg。尽管有症状的HD有600 mg/天的COQ的耐受性有实质性数据，但剂量范围的研究表明，在较高剂量下健康个体的耐受性可能会降低。我们建议以600毫克/天，1200 mg/天和2400 mg/天的剂量研究COQ，以确定在阳性阳性前药参与者中，最高剂量是可容忍的最高剂量；长期目标是在该剂量下开发COQ的未来预防性治疗试验。在特定目标1中，我们将在突变阳性的阳性阳性前种群中以600 mg/天，1200 mg/天和2400 mg/天的剂量建立COQ的安全性和耐受性，并在HD CAG重复膨胀的情况下，在一项随机的双重双轴20周平行组试验的背景下。在特定的目标2中，我们将通过评估血清COQ水平的变化以及8-羟基氧鸟苷（8OHDG）和8-羟基鸟苷（8OHRG）水平来确定辅酶Q10具有生物学上的活性。我们将评估COQ的血清水平，氧化应激的生物标志物，DNA修复机制的生物标志物（OGG1）和COQ剂量水平之间的关系。拟议的试验很重要，因为它将是第一个评估患有神经退行性疾病风险100％风险但尚未病情的人群中潜在治疗剂的研究。它将允许我们选择COQ剂量，以在Manifest HD前的未来确定的随机安慰剂对照试验中，以延迟或防止明显HD的发作，并为我们提供有关此类试验前参与者的过程和可行性的宝贵信息。