Ameliorating Sickle Nephropathy and Pulmonary Hypertension

改善镰状肾病和肺动脉高压

• 批准号: 8144666
• 负责人: Punam Malik
• 金额: $ 20.41万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144666
• 关键词: Adult; Affect; Age; Age-Years; Albuminuria; Antibodies; Applications Grants; Biological Markers; Blood; Blood Tests; Cardiac Catheterization Procedures; Child; Childhood; Chronic Kidney Failure; Clinic; Clinic Visits; Clinical Protocols; Clinical Trials; Consent; Cross-Sectional Studies; Data; Defect; Development; Dose; End stage renal failure; Ensure; Environment; Focal Segmental Glomerulosclerosis; Funding; Generations; Glomerular Filtration Rate; Grant; Hematuria; Hospitals; Human; Hypoxia; Infant; Injury; Institutional Review Boards; Investigation; Kidney; Kidney Diseases; Kidney Failure; Kidney Glomerulus; Laboratories; Losartan; Lung; Manuals; Measures; Medical center; Microscopic; Molecular; Molecular Analysis; Monitor; Mus; Myocardial; Nephrons; Observational Study; Ohio; Pamphlets; Patients; Pattern; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Physiologic intraventricular pressure; Pilot Projects; Potassium; Pulmonary Hypertension; Randomized Controlled Trials; Receptor, Angiotensin, Type 1; Recruitment Activity; Rectum; Research; Research Infrastructure; Research Personnel; Sample Size; Screening procedure; Secondary to; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Site; Staging; Testing; Therapeutic; Time; Training; Translating; Tubular formation; Universities; University Hospitals; Urine; Ventricular; Walking; animal data; base; clinical research site; data management; design; infancy; interstitial; longitudinal analysis; next generation; novel; older patient; operation; phase 3 study; pressure; prevent; randomized trial; response; sickling; statistics

DESCRIPTION (provided by applicant): The kidney is affected in several different ways in sickle cell anemia (SCA). Children, and even infants with SCA develop a urine concentrating defect (UCD), increased glomerular filtration rate (GFR), supranormal proximal tubular function and impaired ability to excrete potassium. Also seen is hematuria (gross or microscopic) from medullary tubulo-interstitial damage. With increasing age, glomerulopathy develops, manifest initially as micro-albuminuria, then macro- albuminuria, progressing to renal failure and end stage renal disease. Kidneys and glomeruli are enlarged and GFR increased in early stages. With time, focal and segmental glomerulosclerosis, reduced GFR and end stage renal disease develops. Sickle nephropathy (SN) is present in 40-50% of adults. We have strong preliminary data on novel biomarkers on SN and animal data that supports an interventional trial with losartan to ameliorate UCD, albuminuria and pulmonary hypertension in sickle cell disease. We propose to conduct critical pilot studies in patients with SCA to guide the design of a robust phase III randomized controlled trial of losartan; and to assemble the sites, Statistics and Data Management Center (SDMC), regulatory documents, study monitoring and data management plan to ensure effective execution of a phase III multi-center study. In aim 1, we will conduct pilot studies to study the progression of SN and the feasibility of reducing/preventing SN with losartan, in order to gather critical data necessary to design a phase III randomized control trial for SN and PH. The pilot studies will help estimate feasibility of accruing patients, determine a refined duration/dose and the sample size and response rate necessary in the first two years of funding. In aim 2, we will design a multi-center phase III randomized trial of losartan for SN in the third year of funding. In aim 3, we will assemble the infrastructure to carry out a well executed multi-center trial. in the third year of funding, we will identify additional clinical sites based on eligible patients, and engage a SDMC to develop the clinical protocol, consent and assent forms, manual of operations, investigators brochure, extend the IND and prepare documents for IRB submission, establish a DSMB, data management and study monitoring plan and training materials for the study staff. We have assembled four participating sites: two adult and two pediatric sites for the pilot studies: Cincinnati Childrens Hospital Medical Center, University Hospital at the University of Cincinnati in Cincinnati and Nationwide Childrens Hospital and the Ohio State University Hospital in Columbus, Ohio for the pilot studies. These sites will also participate in the phase III study, while additional sites are identified and recruited, as needed based on the pilot data obtained from this planning grant. The above aims are a focused approach in this planning grant to obtain data critical for the design of a robust phase III trial, apply for RO1 funding and amass the infrastructure necessary to execute a well-designed phase III study and effectively translate research discoveries made in our laboratory to the clinic to affect effective therapeutic approaches to sickle nephropathy. PUBLIC HEALTH RELEVANCE: The kidney is affected as early as infancy and is damaged progressively with increasing age in patients with sickle cell anemia, with nearly 40-50% of adults suffering from kidney damage (sickle nephropathy), that eventually results in end stage renal disease. Currently, there are no established therapies for preventing or reducing sickle nephropathy. With this R34 grant proposal, we plan to study the course of sickle nephropathy and perform pilot studies to treat or prevent sickle nephropathy with losartan, a drug that has been identified through our basic investigations in sickle mice. The pilot studies will help design a robust definitive clinical trial to test the therapeutic benefit of losartan in sickle nephropathy.

描述（由申请人提供）：镰状细胞性贫血 (SCA) 会以多种不同方式影响肾脏。患有 SCA 的儿童甚至婴儿会出现尿液浓缩缺陷 (UCD)、肾小球滤过率 (GFR) 增加、近端肾小管功能异常以及排钾能力受损。还可以看到因髓质小管间质损伤引起的血尿（肉眼或镜下）。随着年龄的增长，肾小球病逐渐发展，最初表现为微量白蛋白尿，然后表现为大量白蛋白尿，进展为肾功能衰竭和终末期肾病。早期肾脏和肾小球增大，GFR 升高。随着时间的推移，会出现局灶性和节段性肾小球硬化、肾小球滤过率降低和终末期肾病。 40-50% 的成年人患有镰状肾病 (SN)。我们拥有有关 SN 新型生物标志物的强有力的初步数据和动物数据，支持氯沙坦改善镰状细胞病中 UCD、蛋白尿和肺动脉高压的介入试验。我们建议对 SCA 患者进行关键的试点研究，以指导氯沙坦的稳健 III 期随机对照试验的设计；整合站点、统计和数据管理中心（SDMC）、监管文件、研究监测和数据管理计划，以确保有效执行 III 期多中心研究。在目标 1 中，我们将开展试点研究来研究 SN 的进展以及用氯沙坦减少/预防 SN 的可行性，以便收集设计 SN 和 PH 的 III 期随机对照试验所需的关键数据。试点研究将有助于估计增加患者的可行性，确定精确的持续时间/剂量以及资助头两年所需的样本量和反应率。在目标 2 中，我们将在资助的第三年设计一项氯沙坦治疗 SN 的多中心 III 期随机试验。在目标 3 中，我们将组装基础设施以进行良好的多中心试验。在资助的第三年，我们将根据符合条件的患者确定更多的临床中心，并聘请 SDMC 制定临床方案、知情同意书、操作手册、研究者手册、扩展 IND 并准备提交 IRB 的文件，为研究人员制定 DSMB、数据管理和研究监测计划以及培训材料。我们聚集了四个参与地点：两个成人和两个儿科地点进行试点研究：辛辛那提儿童医院医疗中心、辛辛那提辛辛那提大学医院、全国儿童医院和俄亥俄州哥伦布市的俄亥俄州立大学医院进行试点研究。这些地点也将参与第三阶段研究，同时根据从该规划拨款获得的试点数据，根据需要确定和招募其他地点。上述目标是本次规划拨款的重点方法，旨在获取对于设计稳健的 III 期试验至关重要的数据，申请 RO1 资金并积累执行精心设计的 III 期研究所需的基础设施，并有效转化在我们的实验室到临床影响镰状肾病的有效治疗方法。 公众健康相关性：镰状细胞性贫血患者的肾脏早在婴儿期就受到影响，并随着年龄的增长而逐渐受损，近 40-50% 的成年人患有肾脏损害（镰状肾病），最终导致终末期肾病疾病。目前，尚无预防或减少镰状肾病的既定疗法。通过这项 R34 拨款提案，我们计划研究镰状肾病的病程，并进行试点研究，以用氯沙坦治疗或预防镰状肾病，氯沙坦是我们通过对镰状小鼠的基本研究发现的一种药物。这些试点研究将有助于设计一项强有力的最终临床试验，以测试氯沙坦对镰状肾病的治疗效果。