Polycystic Kidney Disease Clinical Trials Network

多囊肾临床试验网络

• 批准号: 6643546
• 负责人: RONALD D PERRONE
• 金额: $ 64.11万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643546
• 关键词: ACE inhibitors; angiogenesis; angiotensin /renin /aldosterone hypertension; angiotensin II; autosomal dominant trait; blood pressure; cell proliferation; chronic renal failure; clinical research; clinical trial phase I; cooperative study; diltiazem; drug screening /evaluation; endocrine disorder chemotherapy; endocrine pharmacology; human subject; human therapy evaluation; lisinopril; longitudinal human study; patient oriented research; pharmacokinetics; polycystic kidney; prostaglandin endoperoxide synthase; renin angiotensin system

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.

描述（由申请人提供）： 常染色体显性多囊肾病 (ADPKD) 是最常见的致命性单基因疾病，影响 1/500 至 1/1000 的美国人口。 50% 的 ADPKD 患者将在 6 岁时患上终末期肾病。对于患有进行性疾病的患者，目前还没有经过证实的疗法可以减缓肾功能不可避免的丧失。肾素-血管紧张素-醛固酮系统 (RAAS) 的中断已被证明可以减少糖尿病和非糖尿病肾脏疾病中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血管紧张素转换酶抑制剂 (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 的要求而提交的，目的是建立一个由临床中心组成的 PKD 临床试验网络，每个临床中心将招募 500 名 ADPKD 患者并进行临床试验，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，以比较肾功能不全的高血压 ADPKD 患者（GFR 30-65 ml/min/1.73 m2）的 ACE-I 与主动对照在达到血清肌酐加倍、ESRD 或死亡的复合结果的时间。该临床中心将设在新英格兰医疗中心和贝斯以色列女执事医疗中心。首席和联合首席研究员对 ADPKD 有着长期的兴趣，并亲自护理了大量的 ADPKD 患者。我们已在我们的临床中心内确定了 107 名可能符合资格的患者。将使用其他策略来针对当地和邻近的新英格兰州内的患者。最高层提供强大的机构支持，包括 NEMC 和 BIDMC 的综合临床研究中心。作为本次 RFA 的一部分，我们提出了一项初步研究来评估 cyclooxygenase-2 抑制的安全性，该酶与 ADPKD 动物模型中的血管生成和囊肿发育有关。 30 名 GFR >70 ml/min/1.73 m2 的 ADPKD 患者将被随机分配接受塞来昔布治疗与安慰剂治疗，并随访 16 周。 GFR 的变化是主要结果指标，将评估高钾血症、液体潴留和血压升高的发生率。