Phase 2: Impact of Lipoic Acid on Cystine Nephrolithiasis; IND129545 (01/29/2016)

项目摘要 胱氨酸尿症是一种罕见的(1：15,000)常染色体隐性遗传病，其特征是尿液水平显著升高 胱氨酸，以及反复发作的疼痛，组织损害肾结石的形成。没有成功的 这种疾病的医疗管理，即使患者可以通过外科手术获得暂时的缓解 干预措施，缓解期通常很短，而且他们患终末期肾病的风险更高。 时间到了。我们提出了一种治疗胱氨酸尿症的新方法，将在第二阶段随机双盲安慰剂试验中进行。 评估α-硫辛酸(硫辛酸)对胱氨酸结石生长和结石影响的临床对照试验 复发，需要手术干预。使用半胱氨酸尿症的小鼠模型，我们发现这一点广泛存在 使用、耐受性良好的天然膳食补充剂，均可预防胱氨酸结石的发生。 形成并减缓现有石块的生长。这些结果极大地掩盖了 现有的药物在相同的小鼠模型中进行了测试，并用于人类治疗胱氨酸尿症。在这只鼠标里 添加硫辛酸的半胱氨酸尿症模型饮食不影响小鼠的体重、耗水量或活动水平。 这些充满希望的小鼠数据启发了这次人体试验。 我们提出了一项随机、双盲、安慰剂对照试验，纳入50名半胱氨酸尿症患者。 来自我们建立的临床结石中心(&gt；30年)，这将促进快速注册。该设计将 评估连续三年每天补充1200毫克硫辛酸对临床结果的影响。 结果指标将包括：1)疾病的临床进展，以结石复发为标志 常规成像、生活质量测量、结石通过和/或手术干预的需要；2) 在传统的24小时尿液采集中定量测定尿胱氨酸水平和胱氨酸溶解度； 结石和尿样的代谢组学和金属组学分析。按照正常的、常规的临床护理、研究 参与者将每4个月接受一次全面的临床评估，包括血清实验室、成像、 以及24小时尿检。除了临床数据，结石、尿液和血液样本将在 测定代谢组和金属组学和尿胱氨酸溶解度的研究，以鉴定 有助于预测治疗效果的生物标志物，并形成患者个性化用药的基础 这种罕见的疾病。这些后一种措施代表了一种努力，以确定现成的预测标记物 石块的形成和形成(目前还不存在)，并提供了对可能的 硫辛酸的作用机理。如果成功，硫辛酸的使用将从根本上改变人们的健康和生活- 胱氨酸尿症是一种罕见的孤儿和使人衰弱的疾病。此外，还研究了适当的 胱氨酸尿症的代谢组学和金属组学生物标志物也可能对其他类型的 尿路结石。

PROJECT ABSTRACT Cystinuria is a rare (1:15,000) autosomal recessive disease characterized by markedly elevated levels of urinary cystine, and recurrent episodes of painful, tissue damaging kidney stone formation. There is no successful medical management of this disorder and even though patients may receive temporary relief through surgical intervention, the period of remission is typically brief and they have a higher risk of end-stage renal disease over time. We propose a novel treatment for cystinuria, to be tested in a Phase 2 randomized double-blind, placebo- controlled clinical trial to assess the impact of alpha-lipoic acid (lipoic acid) on cystine stone growth and recurrence, and need for surgical intervention. Using a mouse model of cystinuria, we have found that this widely used, well tolerated and naturally occurring dietary supplement, both prevents the onset of cystine stone formation and slows the growth of existing stones. These results dramatically overshadow the minimal action of existing pharmaceuticals tested in the same murine model and used in humans to treat cystinuria. In this mouse cystinuria model lipoic acid-supplemented diets did not impact mice weight, water consumption or activity levels. These promising murine data inspired this human trial. We propose a randomized double-blind placebo-controlled trial enrolling 50 cystinuric patients from our established clinical stone center (>30 years) that will facilitate rapid enrollment. The design will assess how daily 1200 mg of lipoic acid supplementation for three years will impact clinical outcomes. Outcome measures will include: 1) clinical progression of disease, marked by stone recurrence based on routine imaging, quality of life measurement, stone passage, and/or the need for surgical intervention; 2) quantitative urinary cystine levels and cystine solubility on traditional 24-hour urine collection; and 3) metabolomic and metallomic analyses of stone and urine samples. As per normal, routine clinical care, study participants will be seen every 4 months for comprehensive clinical evaluation including serum labs, imaging, and 24-hour urine studies. In addition to clinical data, stone, urine, and blood samples will be collected over the study to determine metabolomic and metallomic profiles and urinary cystine solubility, to identify biomarkers to help predict treatment effect and to form the basis of personalized medicine for patients with this rare disease. These latter measures represent an effort to identify readily available predictive makers of stone initiation and formation (none of which exist at the present time), and provide insight into the possible mechanism of action of lipoic acid. If successful, the use of lipoic acid will radically change the health and life- styles of patients with cystinuria, a rare, orphan and debilitating disease. Furthermore, the study of appropriate metabolomics and metallomic biomarkers for cystinuria may also yield important insights into other types of urinary stones.