Controlled Trial of Renin Angiotensin Blockade in ADPKD

描述（由申请方提供）：马约诊所的当前提案是作为NIDDK支持的HALT-PKD临床试验的参与临床中心（PCC）继续提供支持。马约诊所是参与HALTPKD的四个PCC之一，并与堪萨斯大学医学中心和克利夫兰诊所建立了联盟。尽管有大量的数据表明，肾素-血管紧张素系统在ADPKD的发病机制，没有大的随机试验，以确定其封锁的有效性已经完成。HALT-PKD包括两项为期5年的双盲随机试验。研究A和B检验了以下假设：在患有ADPKD的高血压（>130/80 mm Hg）患者中，使用血管紧张素转换酶抑制剂（ACE-I）和血管紧张素受体阻滞剂（AR B）的强化联合阻滞比ACE-I单药治疗更有效地延缓疾病进展，与血压控制水平无关。研究A还检查了较低的血压是否会延迟疾病早期的进展。GFR>60 mL/min/1.73 m2的受试者将在研究A中随机接受ACE-I/ARB治疗或ACE-I单药治疗，以及低血压（收缩压95-110/舒张压60-75 mm Hg）或标准血压（收缩压120-130/舒张压70-80 mm Hg）。主要结果是通过MRI测量的总肾脏体积的百分比变化。次要指标包括LV质量指数和肾血流量（通过MR）、白蛋白排泄和GFR。GFR为25-60 mL/min/1.73 m2的受试者将在研究B中随机分配至ACE-I/AR B治疗相对于ACE-I单一治疗（所有标准BP）。主要结局是至血清肌酐加倍、ESRD或死亡复合终点的时间。在这两项研究中，血压都是通过家庭血压来评估的。研究A共有548例受试者，研究B共有470例受试者，将提供90%的把握度来检测每项研究治疗组的25%差异。采用逐步增加赖诺普利和替米沙坦/安慰剂剂量，然后逐步添加其他药物的逐步方案来实现BP目标。2006年3月至2008年1月，600例患者接受了随机化（本PCC中210例），205例完成了1年随访（本PCC中89例），73例完成了18个月随访（本PCC中34例）。平均BP大部分在目标范围内，研究A的标准和低BP组之间的收缩压、舒张压和平均BP以及用药步骤实现了极好的分离。预计到2008年底将完成招生工作。该PCC计划入组334例受试者（188例来自马约诊所，86例来自KUMC，60例来自克利夫兰诊所）。这意味着超额招募了79名患者，将有助于实现总体招募目标。

DESCRIPTION (provided by applicant): The current proposal from Mayo Clinic is for continued support as a participating clinical center (PCC) for the NIDDK supported HALT-PKD clinical trials. The Mayo Clinic is one of the four PCCs participating in HALTPKD and has established a consortium with the University of Kansas Medical Center and with the Cleveland Clinic. Despite substantial data that implicate the renin-angiotensin system in the pathogenesis of ADPKD, no large randomized trial to determine the effectiveness of its blockade of has been done. HALT-PKD comprises two 5-year double-blind randomized trials. Studies A and B test the hypothesis that intensive combined blockade using an angiotensin-converting enzyme inhibitor (ACE-I) together with an angiotensin receptor blocker (ARB) in hypertensive (>130/80 mm Hg) people with ADPKD delays disease progression more effectively than ACE-I monotherapy, independent of the level of BP control. Study A also examines whether lower BP delays progression early in the course of disease. Subjects with a GFR>60 mL/min/1.73 m2 will be randomized in Study A to either ACE-I/ARB therapy or ACE-I monotherapy, and either low (systolic 95-110/diastolic 60-75 mm Hg) or standard (systolic 120-130/diastolic 70-80 mm Hg) BP. The primary outcome is the percent change in total kidney volume measured by MRI. Secondary measures include LV mass index and renal blood flow (by MR), albumin excretion, and GFR. Subjects with GFR 25-60 ml_/min/1.73 m2 will be randomized in Study B to ACE-I/ARB therapy versus ACE-I monotherapy (all standard BP). The primary outcome is the time to a composite of doubling of serum creatinine, ESRD or death. In both studies BP is assessed by home blood pressures. A total of 548 participants for Study A and 470 for Study B will provide 90% power to detect 25% differences in treatment arms of each study. A stepwise protocol of increasing doses of lisinopril and telmisartan/placebo followed by stepwise addition of other agents is used to achieve BP targets. Between March 2006 and January 2008, 600 patients have been randomized (210 at this PCC), 205 have completed one year (89 at this PCC), and 73 (34 at this PCC) have completed 18 months of follow-up. Mean BPs have been mostly on target and excellent separations in systolic, diastolic and mean BPs and medication steps have been achieved between the standard and the low BP arms of Study A. It is expected that enrollment will be completed by the end of 2008. This PCC plans to enroll 334 participants (188 at the Mayo Clinic, 86 at KUMC and 60 at the Cleveland Clinic). This represents an over-recruitment of 79 patients and will help to achieve the overall recruitment target.