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

描述（由申请人提供）：对HD的神经保护性治疗干预的研究正在加速。容积MRI研究表明，基底神经节的神经变性在表现HD之前10年或更长时间开始。旨在延迟显性HD发作的预表现人群中的治疗性神经保护试验可能对这种破坏性疾病产生重大影响。辅酶Q10（CoQ）已成为显性HD神经保护的主要治疗候选药物之一，在一项为期30个月的研究（CARE-HD）中，每天600 mg的疗效在几个结果指标中具有接近显著的趋势。虽然有大量的数据CoQ在600毫克/天的耐受性症状HD，剂量范围研究表明，在其他健康的个体在更高的剂量降低耐受性的可能性。我们建议在600 mg/天，1200 mg/天和2400 mg/天的剂量下研究辅酶Q，以确定在扩展阳性预表现参与者群体中可耐受的最高剂量;长期目标是在该剂量下开发未来的辅酶Q预防性治疗试验。在具体目标1中，我们将在随机双盲20周平行组试验的背景下，在HD CAG重复扩增的突变阳性预表现人群中确定600 mg/天、1200 mg/天和2400 mg/天剂量的辅酶Q的安全性和耐受性。在特定目标2中，我们将通过评估同一试验中血清CoQ水平以及8-羟基脱氧鸟苷（8 OHdG）和8-羟基鸟苷（8 OHrG）水平的变化来确定辅酶Q10具有生物活性。我们将评估血清辅酶Q水平、氧化应激生物标志物、DNA修复机制生物标志物（OGG 1）和辅酶Q剂量水平之间的关系。这项拟议的试验意义重大，因为它将是第一项在100%患神经退行性疾病风险但尚未患病的人群中评估潜在治疗药物的研究。它将使我们能够选择一个剂量的辅酶Q为未来明确的随机安慰剂对照试验在前显HD延迟或预防发作的显HD，并将为我们提供有价值的信息的过程和可行性，这样的试验在前显参与者。

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.