Controlled Trial of Renin Angiotensin Blockade in ADPKD

描述（由申请人提供）：梅奥诊所目前的提议是继续支持作为NIDDK支持的HALT-PKD临床试验的参与临床中心（PCC）。梅奥诊所是参与HALTPKD的四个PCCs之一，并与堪萨斯大学医学中心和克利夫兰诊所建立了一个联盟。尽管有大量数据表明肾素-血管紧张素系统参与ADPKD的发病机制，但尚未进行大型随机试验来确定其阻断的有效性。HALT-PKD包括两项5年双盲随机试验。研究A和B验证了一种假设，即在ADPKD高血压（bbb130 /80 mm Hg）患者中，使用血管紧张素转换酶抑制剂（ACE-I）联合血管紧张素受体阻滞剂（ARB）进行强化联合阻断比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还探讨了低血压是否会延缓病程早期的进展。GFR为60 mL/min/1.73 m2的受试者将在研究a中随机分为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毫米汞柱）或标准血压（收缩压120-130/舒张压70-80毫米汞柱）。主要结果是MRI测量的总肾体积变化百分比。次要测量包括左室质量指数和肾血流（MR）、白蛋白排泄和GFR。在研究B中，GFR为25-60 ml_/min/1.73 m2的受试者将被随机分为ACE-I/ARB治疗组和ACE-I单药治疗组（均为标准血压）。主要转归是血清肌酐翻倍、ESRD或死亡的综合时间。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名参与者，研究B有470名参与者，将提供90%的能力来检测每个研究治疗组中25%的差异。逐步增加赖诺普利和替米沙坦/安慰剂的剂量，然后逐步添加其他药物，以达到血压目标。在2006年3月至2008年1月期间，600名患者被随机分组（210名在该PCC）， 205名完成了1年（89名在该PCC）， 73名（34名）完成了18个月的随访。研究a的平均血压基本达到了目标，在标准血压组和低血压组之间的收缩压、舒张压和平均血压以及用药步骤都有很好的分离。预计将于2008年底完成入组。该PCC计划招收334名参与者（梅奥诊所188名，KUMC 86名，克利夫兰诊所60名）。这代表了79名患者的超额招募，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.