Controlled Trial of Renin Angiotensin Blockade in ADPKD

描述(申请人提供)：梅奥诊所目前的提案是作为NIDDK支持的HALT-PKD临床试验的参与临床中心(PCC)继续提供支持。梅奥诊所是参与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一个财团。尽管大量数据表明肾素-血管紧张素系统与ADPKD的发病机制有关，但还没有进行大型随机试验来确定其阻断的有效性。HALT-PKD包括两个为期5年的双盲随机试验。研究A和B测试了这样一种假设，即在患有ADPKD的高血压(&gt；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(ARB)的强化联合阻断比ACE-I单一疗法更有效地延缓疾病进展，与BP控制水平无关。研究A还检查了较低的血压是否会延缓病程早期的进展。GFR&GT；为60毫升/分钟/1.73平方米的受试者将在研究A中被随机分成ACE-I/ARB疗法或ACE-I单一疗法，以及低血压(收缩压95-110/舒张压60-75毫米汞)或标准血压(收缩压120-130/舒张压70-80毫米汞)。主要结果是MRI测量的总肾脏体积的百分比变化。次要指标包括左心室重量指数、肾血流量(MR)、白蛋白排泄量和肾小球滤过率。GFR为25-60毫升/分钟/1.73平方米的受试者将在研究B中随机分为ACE-I/ARB治疗和ACE-I单一治疗(均为标准BP)。主要结果是血肌酐增加一倍、终末期肾病或死亡的综合时间。在这两项研究中，BP都是通过家庭血压进行评估的。研究A的总共548名参与者和研究B的470名参与者将提供90%的能力来检测每个研究的治疗武器中25%的差异。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方案来实现血压目标。在2006年3月至2008年1月期间，600名患者被随机分组(本委员会为210名)，205名患者完成了一年的随访(本委员会的)，73名患者(本委员会的34名)完成了18个月的随访。平均血压大多已达到目标，收缩压、舒张压和平均血压的良好分离以及研究A的标准血压和低血压分支之间的用药步骤已经实现。预计研究A的登记工作将于2008年底完成。该委员会计划招募334名参与者(梅奥诊所188名，KUMC 86名，克利夫兰诊所60名)。这意味着超额招募了79名患者，将有助于实现整体招募目标。

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.