Polycystic Kidney Disease Clinical Trials Network

描述（由申请人提供）： 常染色体显性遗传性多囊肾病（ADPKD）是最常见的致死性单基因疾病，影响1/500至1/1000的美国人口。50%的ADPKD患者将在生命的第6个十年发展为终末期肾病。目前还没有经过证实的疗法来减缓进行性疾病患者肾功能的不可阻挡的丧失。已证明阻断肾素-血管紧张素-醛固酮系统（RAAS）可减少糖尿病和非糖尿病肾病患者肾功能的进行性下降，但尚不清楚这些结果是否适用于ADPKD。大量证据表明血管紧张素II与高血压的发病机制有关，但持续时间有限的小型单中心研究报告了ACE抑制剂（ACE-I）治疗对疾病进展的不一致结果。本申请是为了响应RFA DK-01-029而提交的，旨在建立一个PKD临床试验网络，每个临床中心将招募500名ADPKD患者，并进行一项临床试验，以评估RAAS治疗中断对肾脏进展的疗效。 我们提出了一项随机、双盲试验，比较ACE-I与活性对照在肾功能不全（GFR 30-65 ml/min/1.73 m2）的高血压ADPKD患者中达到血清肌酐加倍、ESRD或死亡复合结局的时间。临床中心将设在新英格兰医疗中心和贝丝以色列女执事医疗中心。主要和共同主要研究者对ADPKD有着长期的职业兴趣，并亲自护理了大量ADPKD患者。我们在临床研究中心确定了107例潜在合格患者。其他策略将用于针对当地和邻近的新英格兰州内的患者。在最高级别提供强有力的机构支持，包括NEMC和BIDMC的一般临床研究中心。作为RFA的一部分，我们提出了一项初步研究，以评估环氧合酶-2抑制的安全性，这与ADPKD动物模型中的血管生成和囊肿发育有关。30例GFR >70 ml/min/1.73 m2的ADPKD患者将随机接受塞来昔布与安慰剂治疗，并随访16周。GFR的变化是主要结局指标，将评估高钾血症、液体潴留和血压升高的发生率。

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal monogenetic disease, affecting 1/500 to 1/1000 of the US population. 50% of those affected with ADPKD will develop end-stage renal disease by the 6th decade of life. There are no proven therapies to slow the inexorable loss of kidney function in those with progressive disease. Interruption of the renin-angiotensin-aldosterone system (RAAS) has been shown to reduce the progressive decline in renal function in both diabetic and non-diabetic kidney diseases, but it is unknown whether these results extend to ADPKD. Abundant evidence implicates angiotensin II in the pathogenesis of hypertension, but small single-center studies of limited duration have reported inconsistent results of ACE inhibitor (ACE-I) therapy on disease progression. This application is submitted in response to RFA DK-01-029 to establish a PKD Clinical Trials Network of clinical centers that will each enroll 500 ADPKD patients and conduct a clinical trial to assess the efficacy of therapeutic interruption of the RAAS on renal progression. We have proposed a randomized, double-blinded trial to compare ACE-I vs. active control in hypertensive ADPKD patients with renal insufficiency (GFR 30-65 ml/min/1.73 m2) on the time to reach a composite outcome of doubling of serum creatinine, ESRD, or death. The Clinical Center will be based at the New England Medical Center and Beth Israel Deaconess Medical Center. The Principal and Co-Principal Investigators have had career-long interests in ADPKD and personally care for large numbers of ADPKD patients. We have identified 107 potentially eligible patients within our clinical sites. Additional strategies will be used to target patients locally and within contiguous New England States. Strong institutional support is available at the highest levels, including the General Clinical Research Centers at NEMC and BIDMC. As part of this RFA, we have proposed a pilot study to assess the safety of cyclooxygenase-2 inhibition, which has been implicated in angiogenesis and cyst development in animal models of ADPKD. Thirty ADPKD patients with GFR >70 ml/min/1.73 m2 will be randomized to treatment with celecoxib vs. placebo and followed for 16 weeks. Change in GFR is the primary outcome measure and incidence of hyperkalemia, fluid retention, and elevated blood pressure will be assessed.