PDE5i with Tadalafil Changes the Extent of Renal Damage (PITCH_ER)

PDE5i 与他达拉非一起改变肾损伤的程度 (PITCH_ER)

• 批准号: 8606587
• 负责人: RAVI THADHANI
• 金额: $ 41.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606587
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Albumins; Albuminuria; Ancillary Study; Area; Attenuated; Basic Science; Biological; Biological Markers; Biological Testing; Biology; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Research; Collection; Consensus; Creatinine; Cyclic GMP; Data; Development; Diabetes Mellitus; Double-Blind Method; Enrollment; Ensure; Environment; Equation; Event; FDA approved; Frequencies; Functional disorder; Funding; Gelatinase A; Glomerular Filtration Rate; Heart Diseases; Heart failure; Hospitalization; Incidence; Inflammation; Injury; Intervention; Investigation; Kidney; Kidney Diseases; Left; Link; Measures; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Natriuresis; Outcome; Oxidative Stress; Parents; Participant; Patients; Phosphodiesterase Inhibitors; Physiological; Placebos; Play; Population; Population Study; Protocols documentation; Pulmonary Hypertension; Randomized; Renal Blood Flow; Renal function; Renin-Angiotensin System; Request for Applications; Research; Research Infrastructure; Risk; Safety; Sampling; Serum; Severities; Spottings; Testing; Text; Time; Translational Research; Urine; Venous blood sampling; Ventricular; Vulnerable Populations; adjudicate; adjudication; base; clinical care; cost effective; experience; follow-up; improved; inhibitor/antagonist; injury prevention; innovation; kidney vascular structure; mortality; outcome forecast; patient oriented; phosphodiesterase V; phosphoric diester hydrolase; post gamma-globulins; pre-clinical; public health relevance; tadalafil; treatment effect; urinary; vasoconstriction

The NHLBI-sponsored PITCH-HF trial (#U01HL105562) will begin enrollment in Q1 2013. PITCH-HF is the first well-controlled, randomized, large-scale (n=2,012) trial studying the effect of tadalafil, an FDA-approved selective phosphodiesterase type 5 inhibitor (PDE5i), on cardiovascular (CV) deaths and heart failure (HF) hospitalizations in patients with left ventricular systolic dysfunction and secondary pulmonary hypertension. The biology of PDE5i strongly suggests a potential renoprotective effect, but PITCH-HF currently lacks renal endpoints. Both chronic kidney disease (CKD) (reflected by albuminuria and reduced glomerular filtration rate [GFR]) and acute kidney injury (AKI) significantly contribute to morbidity and mortality in patients with CV disease and HF. We expect e30% of participants in PITCH-HF will develop one or more of these endpoints over the study period. Therapies that alter the course of renal disease in patients with HF are sorely lacking. This application requests modest funding for PITCH-ER, an ancillary study to address two major patient- oriented questions: (1) Does chronic tadalafil treatment slow the rate of GFR decline and/or modify the development/progression of albuminuria vs placebo? We will examine longitudinal measures of eGFR (utilizing state-of-the-art equations that incorporate serum creatinine and cystatin C) and spot urine albumin-to- creatinine ratios; (2) Does PDE5i treatment reduce AKI frequency and/or the magnitude of urinary biomarker changes reflecting subclinical renal injury vs placebo? Using an AKI adjudication committee, we will monitor the incidence of AKI events and their severity using the latest KDIGO consensus criteria for AKI. We will also detect subclinical renal injury using the validated urinary biomarkers: neutrophil gelatinase-associated lipocalin and kidney injury marker 1. We expect that 30% of the overall PITCH-HF population will have diabetes, which amplifies the risk for renal injury in HF patients, thus, we include in this proposal a plan to repeat our analyses stratified by baseline diabetes status as Sub-Aims 1 and 2 should treatment effects differ between those with and without diabetes. The parent study lacks urine collection and modern measures of GFR such as serum cystatin C, and will not examine decline in GFR or frequency of AKI episodes during the study period. Thus, this proposal is particularly time-sensitive. By taking advantage of the PITCH-HF infrastructure and randomization, this ancillary study provides an efficient, economical, and well-powered approach to identify potential renoprotective effects of PDE5 inhibition. Our collaborative team has experience in performing high quality ancillary studies with renal endpoints, and collection and testing of biological samples from such studies utilizing state-of-the-art measures of renal function and biology. Our aims are well-powered and focus on well- defined endpoints, allowing us to answer important clinical and scientific questions with minimal burden to subjects and the parent study. The PITCH-HF Executive Committee and the NHLBI reviewers agree this proposal may radically shift the clinical care paradigm for patients with CKD, AKI, and CHF.

NHLBI赞助的Pitch-HF试验（＃U01HL105562）将开始入学2013年第1季度。Pitch-HF是第一个 良好控制，随机，大规模（n = 2,012）试验，研究了Tadalafil的效果，FDA批准 选择性磷酸二酯酶5型抑制剂（PDE5I），心血管（CV）死亡和心力衰竭（HF） 左心室收缩功能障碍和继发性肺动脉高压患者的住院治疗。 PDE5I的生物学强烈表明潜在的肾脏保护作用，但Pitch-HF目前缺乏肾脏 端点。慢性肾脏疾病（CKD）（由蛋白尿反射和肾小球滤过率降低 [GFR]）和急性肾脏损伤（AKI）显着导致CV患者的发病率和死亡率 疾病和HF。我们预计E30％的参与者将在HF中发展一个或多个这些终点 在研究期间。缺乏改变HF患者肾脏疾病进程的疗法。 该申请要求为Pitch-ER提供适度的资金，这是一项辅助研究，以解决两名主要患者 - 定向问题：（1）慢性达拉非治疗是否会降低GFR下降速度和/或修改 蛋白尿与安慰剂的发展/进展？我们将检查EGFR的纵向测量（利用 结合血清肌酐和半胱氨酸蛋白酶c）的最先进方程 肌酐比； （2）PDE5I治疗会降低AKI频率和/或尿生物标志物的大小 反映了亚临床肾脏损伤与安慰剂的变化？使用AKI裁决委员会，我们将监视 使用最新的AKI共识标准，AKI事件的发生率及其严重性。我们也会 使用经过验证的尿生物标志物检测亚临床肾脏损伤：中性粒细胞明胶酶相关的脂肪素 和肾脏损伤标记1。我们预计总体脉搏HF的30％将患有糖尿病，这是 放大HF患者肾脏损伤的风险，因此，我们在此提案中包括一个重复分析的计划 由基线糖尿病状态分层为子1和2，应治疗效应在患有 并且没有糖尿病。家长研究缺乏尿液收集和现代GFR的测量，例如血清 抑制蛋白C，并且不会检查研究期间的GFR或AKI发作频率的下降。因此， 该建议特别敏感。通过利用Pitch-HF基础架构和 随机化，这项辅助研究提供了一种有效，经济且能力良好的方法来识别 PDE5抑制的潜在肾脏保护作用。我们的协作团队具有高表现的经验 具有肾脏终点的质量辅助研究，并从此类研究中收集和测试生物样品 利用肾功能和生物学的最先进措施。我们的目标是有力的，专注于 定义的终点，使我们能够以最小的负担回答重要的临床和科学问题 受试者和父母研究。 Pitch-HF执行委员会和NHLBI审稿人同意这一点 提案可能会从根本上改变CKD，AKI和CHF患者的临床护理范例。