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，人们对血尿家族性形式的分子遗传学和自然史有了很大的了解。然而，对这些疾病的深入了解尚未产生有效的治疗Alport综合征的方法，这是一种与终末期肾病相关的家族性血尿。患有Alport综合征的男性不可避免地发展为终末期肾衰竭，到25岁时有50%的可能性需要透析或肾移植。目前还没有有效的治疗Alport综合征的方法，尽管动物研究已经提出了几种有希望的潜在疗法。可能延迟或预防肾衰竭发展的药物或生物治疗是存在的，但需要通过临床试验进行评估。有兴趣在Alport综合征中实施临床试验的研究人员将面临几个挑战，其中最重要的是该疾病相对罕见，需要积极努力识别和招募潜在的受试者进行多中心合作临床试验。这项可行性研究的资金将使美国、加拿大、中国、法国和德国的五个区域招募中心能够查询现有的Alport综合征登记和数据库，并监测18个月内新Alport病例的累积，以量化感兴趣疾病类别中的受试者。资金还将使我们能够检查尿调节素排泄作为Alport综合征临床试验中肾损伤和潜在试验终点标志物的效用。Alport综合征研究合作组织（ARC）成立于2009年，是Alport综合征治疗和结局登记处（阿斯特），欧洲Alport登记处以及加拿大，中国和法国的Alport综合征研究中心的合作伙伴，旨在测试延迟或预防Alport综合征患者终末期肾衰竭的潜在治疗方法。该提案寻求资金，以（1）证明参与中心可以获得足够数量的Alport综合征男性和女性患者，以填充足够的临床试验，重点是两个临床目标，微量白蛋白尿和明显的蛋白尿，以及（2）为了检验这一假设，即在Alport综合征的男性中，尿尿调节素排泄随着白蛋白尿和蛋白尿的增加而减少，尿调节素提供了一个独立的，对肾纤维化和对治疗反应有深刻见解的测量。 公共卫生相关性：Alport综合征是终末期肾病的重要遗传原因，目前尚无有效的治疗方法。Alport综合征研究合作组织（ARC）是一个由美国，加拿大，中国，法国和德国中心组成的联盟，其目标是通过进行临床研究来改善Alport综合征患者的生活，这些研究将导致延迟或预防患者肾衰竭的治疗。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有关。

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.