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）常染色体隐性遗传疾病，其特征是尿中胱氨酸水平显著升高。 胱氨酸和反复发作的疼痛、组织损伤性肾结石形成。没有成功的 这种疾病的医疗管理，即使病人可以通过手术得到暂时的缓解， 在这些干预措施中，缓解期通常很短，并且他们患终末期肾病的风险高于 时间我们提出了一种治疗胱氨酸尿症的新方法，将在一项2期随机双盲、安慰剂- 对照临床试验，以评估α-硫辛酸（硫辛酸）对胱氨酸结石生长的影响， 复发和需要手术干预。使用胱氨酸尿症的小鼠模型，我们发现这广泛地 使用，耐受性良好，天然存在的膳食补充剂，都可以预防胱氨酸结石的发生 形成并减缓现有石头的生长。这些结果大大掩盖了最小的行动， 在相同的鼠模型中测试并用于人类以治疗胱氨酸尿症的现有药物。在这只老鼠身上 胱氨酸尿症模型补充硫辛酸的饮食不影响小鼠的体重、水消耗或活动水平。 这些有希望的小鼠数据激发了这项人体试验。 我们提出了一个随机双盲安慰剂对照试验纳入50例胱氨酸尿症患者 从我们已建立的临床结石中心（>30年），这将有助于快速入组。该设计将 评估每天补充1200毫克硫辛酸三年将如何影响临床结果。 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/或需要手术干预; 2） 传统24小时尿液收集的定量尿胱氨酸水平和胱氨酸溶解度;以及3） 结石和尿液样本的代谢组学和金属组学分析。根据正常、常规临床护理，研究 参与者将每4个月进行一次全面的临床评估，包括血清实验室，成像， 和24小时尿液检测除临床数据外，还将收集结石、尿液和血液样本， 本研究旨在确定代谢组学和金属组学特征以及尿胱氨酸溶解度， 生物标志物，以帮助预测治疗效果，并为患者提供个性化药物的基础。 这种罕见的疾病。这些后一种措施代表了一种努力，以确定现成的预测制造商， 石头的启动和形成（目前都不存在），并提供洞察可能的 硫辛酸的作用机制。如果成功，使用硫辛酸将从根本上改变健康和生活- 胱氨酸尿症是一种罕见的孤儿和衰弱性疾病。此外，研究适当的 胱氨酸尿症的代谢组学和金属组学生物标志物也可能产生对其他类型的代谢的重要见解。 泌尿系统结石

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.