Polycystic Kidney Disease Clinical Trials Network

多囊肾临床试验网络

• 批准号: 6547204
• 负责人: RONALD D PERRONE
• 金额: $ 25万
• 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/6547204
• 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)： 常染色体显性遗传性多囊肾病(ADPKD)是最常见的致死性单基因疾病，影响美国人口的1/500至1/1000。受ADPKD影响的人中，有50%将在60岁时发展为终末期肾脏疾病。目前还没有有效的治疗方法来减缓进展性疾病患者不可避免的肾功能丧失。阻断肾素-血管紧张素-醛固酮系统(RAAS)已被证明可以减轻糖尿病和非糖尿病肾脏疾病的肾功能进行性下降，但这些结果是否延伸到ADPKD尚不清楚。大量证据表明血管紧张素II与高血压的发病机制有关，但有限时间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。本申请是对RFA DK-01-029的响应，目的是建立PKD临床试验中心网络，每个中心将招募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。 我们已经提出了一项随机、双盲试验，比较有肾功能不全(GFR 30-65ml/min/1.73m2)的高血压ADPKD患者ACE-I和主动对照在达到血肌酐翻倍、ESRD或死亡的综合结果方面的时间。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。首席和联合首席调查员对ADPKD有着长期的兴趣，并亲自照顾大量ADPKD患者。我们已经在我们的临床站点内确定了107名潜在的合格患者。将使用其他战略来瞄准当地和毗邻的新英格兰各州的患者。在最高级别，包括NEMC和BIDMC的综合临床研究中心，都有强有力的机构支持。作为这项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，环氧合酶-2抑制与ADPKD动物模型的血管生成和囊变有关。30名GFR&GT；为70ml/min/1.73m2的ADPKD患者将被随机分为塞来昔布和安慰剂两组，并进行为期16周的随访。GFR的变化是主要的预后指标，并将评估高钾血症、液体滞留和血压升高的发生率。