Multi-center Controlled Clinical Trials in Alport Syndrome-A Feasibility Study

描述(由申请人提供)：在过去的30年里，人们对家族性血尿的分子遗传学和自然病史有了很多了解。然而，对这些情况的进一步了解尚未产生治疗Alport综合征的有效方法，Alport综合征是一种与终末期肾脏疾病相关的家族性血尿形式。患有Alport综合征的男性不可避免地发展为终末期肾功能衰竭，在25岁之前有50%的可能性进行透析或肾移植。尽管在动物身上的研究已经提出了几种有希望的潜在治疗方法，但目前还没有经过证实的治疗阿尔波特综合征的方法。存在可能延缓或防止肾衰竭发展的药物或生物治疗方法，但需要通过临床试验进行评估。对实施Alport综合征临床试验感兴趣的研究人员将面临几个挑战，其中最重要的是这种疾病的相对罕见，需要做出积极努力来确定和招募多中心协作临床试验的潜在受试者。这项可行性研究的资金将使美国、加拿大、中国、法国和德国的五个地区招募中心能够询问现有的阿尔波特综合症登记和数据库，并监测18个月内阿尔波特新病例的累积情况，以便量化感兴趣的疾病类别中的受试者。资金还将使我们能够检验尿调蛋白排泄作为肾脏损伤的标志和Alport综合征临床试验的潜在试验终点的效用。阿尔波特综合征研究合作中心成立于2009年，由阿尔波特综合征治疗和结局登记中心(ASTOR)、欧洲阿尔波特登记中心以及加拿大、中国和法国的阿尔波特综合征研究中心组成，旨在测试延缓或预防阿尔波特综合征患者终末性肾功能衰竭的潜在治疗方法。这项提议寻求资金的目的是(1)证明参与中心能够接触到足够数量的Alport综合征男性和女性患者，以开展以微量蛋白尿和临床蛋白尿这两个临床指标为重点的充足动力的临床试验，以及(2)测试以下假设：在Alport综合征的男性患者中，尿调制素的排泄量随着蛋白尿和蛋白尿的增加而减少，并且尿调制素可提供一种独立的、有洞察力的肾脏纤维化和治疗反应的衡量标准。 公共卫生相关性：Alport综合征是导致终末期肾脏疾病的重要遗传原因，目前还没有得到证实的治疗方法。阿尔波特综合征研究合作中心是由美国、加拿大、中国、法国和德国的中心组成的联盟，其目标是通过进行临床研究来改善阿尔波特综合征患者的生活，这些研究将导致延缓或预防阿尔波特综合征患者肾衰竭的治疗。本提案中要求的资金将支持这一努力，使我们能够证明有能力招募足够数量的Alport综合征患者来进行有意义的临床试验，并帮助我们开发评估治疗反应的新工具。我们希望我们开发的方法将与研究其他不寻常的遗传性肾脏疾病的研究人员相关。

DESCRIPTION (provided by applicant): Over the past 30 years much has been learned about the molecular genetics and natural history of familial forms of hematuria. However, enhanced understanding of these conditions has yet to generate effective therapies for Alport syndrome, the form of familial hematuria associated with end-stage renal disease. Males with Alport syndrome inevitably develop end-stage kidney failure, with a 50% likelihood of dialysis or kidney transplantation by age 25 years. There is no proven treatment for Alport syndrome, although studies in animals have suggested several promising potential therapies. Pharmacological or biological treatments that might delay or prevent the development of kidney failure exist, but need to be evaluated through clinical trials. Researchers interested in implementing clinical trials in Alport syndrome will face several challenges, the foremost of which is the relative rarity of the disease, necessitating aggressive efforts to identify and recruit potential subjects for multi-center collaborative clinical trials. Funding for this feasibility study will enable the five regional recruitment centers in the United States, Canada, China, France and Germany to interrogate existing Alport syndrome registries and databases, and monitor accrual of new Alport cases over an 18-month period, in order to quantify subjects in the disease categories of interest. Funding will also allow us to examine the utility of urinary uromodulin excretion as a marker of kidney injury and potential trial endpoint in Alport syndrome clinical trials. The Alport Syndrome Research Collaborative (ARC) was established in 2009 as a partnership of the Alport Syndrome Treatments and Outcomes Registry (ASTOR), the European Alport Registry and centers of Alport syndrome research in Canada, China and France with the objective of testing potential treatments to delay or prevent terminal renal failure in people with Alport syndrome. This proposal seeks funding to (1) demonstrate that participating centers have access to sufficient numbers of males and females with Alport syndrome to populate adequately-powered clinical trials focused on two clinical targets, microalbuminuria and overt proteinuria, and (2) to test the hypothesis that in males with Alport syndrome urinary uromodulin excretion decreases as albuminuria and proteinuria increase and that uromodulin offers an independent and insightful measure of renal fibrosis and response to therapy. PUBLIC HEALTH RELEVANCE: Alport syndrome is an important genetic cause of end-stage kidney disease for which there is no proven treatment. The goal of the Alport Syndrome Research Collaborative (ARC), a consortium of centers in the United States, Canada, China, France and Germany, is to improve the lives of people with Alport syndrome by performing clinical studies that will lead to treatments that will delay or prevent kidney failure in people with the disease. The funds requested in this proposal will support this effort by enabling us to demonstrate the ability to recruit sufficient numbers of people with Alport syndrome to populate meaningful clinical trials, and by helping us develop new tools for assessing treatment responses. We hope that the approaches we develop will be of relevance to investigators studying other unusual genetic renal disorders.