Randomized trial of active vitamin D, cholecalciferol and placebo for CKD-MBD

活性维生素 D、胆钙化醇和安慰剂治疗 CKD-MBD 的随机试验

• 批准号: 8127455
• 负责人: Sharon M Moe
• 金额: $ 43.76万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127455
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; 7-dehydrocholesterol; Agreement; Albuminuria; Biochemical; Blood; Blood Pressure; Bone Diseases; Bone Tissue; Calcitriol; Calibration; Cardiovascular Diseases; Cardiovascular system; Case Report Form; Cells; Certification; Cholecalciferol; Chronic Kidney Failure; Clinical Trials; Contracts; Data; Data Coordinating Center; Diabetes Mellitus; Disease; Dose; Doxercalciferol; Dual-Energy X-Ray Absorptiometry; Ensure; Epidemiologic Studies; Epidemiology; Ergocalciferols; Fracture; Funding; General Population; Glomerular Filtration Rate; Grant; Guidelines; High Prevalence; Homeostasis; Hormones; Hydroxylation; Hypertension; Institutional Review Boards; Insulin Resistance; Kidney; Kidney Diseases; Knowledge; Laboratories; Light; Liver; Malignant Neoplasms; Manuals; Measurement; Measures; Metabolism; Methodology; Methods; Minerals; Mixed Function Oxygenases; Monitor; Multi-Institutional Clinical Trial; Multiple Sclerosis; National Institute of Diabetes and Digestive and Kidney Diseases; Online Systems; Pamphlets; Parathyroid gland; Patients; Performance; Pharmaceutical Preparations; Pharmacy facility; Physical Function; Placebos; Play; Policies; Preparation; Procedures; Protocols documentation; Publications; Quality Control; Radiology Specialty; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Reading; Renal function; Research; Research Design; Research Infrastructure; Research Personnel; Risk; Role; Safety; Secondary Hyperparathyroidism; Site; Skin; Source; Specimen; Staging; Supplementation; System; Testing; The Sun; Time; Training; United States National Institutes of Health; Vascular calcification; Vision; Vitamin D; Vitamin D Deficiency; Vitamin D2; Vitamin D3 Receptor; Vitamins; Work; analog; base; bone; bone health; calcification; cost; data sharing; frailty; interest; mortality; muscle strength; news; paricalcitol; prevent; protocol development; randomized trial; response; trial comparing

DESCRIPTION (provided by applicant): Patients with chronic kidney disease (CKD) suffer from disordered mineral homeostasis, bone disease, and cardiovascular calcification, collectively known as CKD-Mineral Bone Disorder (CKD-MBD). The current approach to suppress parathyroid hormone for the treatment of CKD-MBD is pharmacologic preparations of the kidney activated form of vitamin D- calcitriol and analogs such as doxercalciferol. However, it is now known that there is vitamin D conversion outside the kidneys and that cholecalciferol may have direct effects on the target tissues bone and parathyroid gland. In addition, there is increasing data that vitamin D deficiency may be associated with increased risk of multiple diseases and mortality, unrelated to its effects on bone and mineral metabolism. However, there are no randomized controlled trials that compare calcitriol or its analogs (such as doxercalciferol) to the cheaper cholecalciferol. Therefore, we will test the hypothesis that doxercalciferol is more effective than cholecalciferol, and both are more effective than placebo for the treatment of CKD-Mineral Bone Disorder (CKD-MBD). To test this hypothesis we will plan a two-year multi center-randomized controlled trial of 300 patients with CKD stage 3 and 4 who are vitamin D insufficient with SHPT, randomized 2:2:1 to one of three treatments: 1) doxercalciferol at 1.0 mcg orally once daily 2) cholecalciferol at 4000 U orally once daily or 3) placebo to determine the efficacy and safety of doxercalciferol, cholecalciferol, and placebo on bone and mineral metabolism, physical strength and function, albuminuria, and kidney function. The purpose of the present U34 proposal is to form a Steering Committee and accomplish the following Specific Aims: 1) To finalize the study design and standard operating procedures to ensure rapid initiation of the clinical trial: a) finalize the protocol, investigator brochure, data and safety monitoring plan, case report forms; b) develop site standard operating procedures (SOPs); c) develop data sharing, publication and recruitment policies, d) identify all sites, e) obtain IRB and other approvals at each site, and f) finalize costs and needed contracts for the study. 2) rationalize the central infrastructure for conducting the multi-center clinical trial and develop training manuals and implementation plans for study sites: a) the Data Coordinating Center will develop a web based data entry system, randomization protocol, and SOP and quality control (QC) procedures; b) the DXA coordinating center will develop SOP and QC procedures, data transfer methods, and determine needs of DXA phantoms; c) the Investigational Pharmacy will finalize the plan and contract for study drug acquisition or compounding, packaging, and distribution and prepare pharmacy SOPs; d) The Physical Performance and Function Coordinating Core will develop a training video tape, training manual and site training certification procedures; e) The Radiology core will optimize transfer of radiographs in de-identified manner for central reading; f) The Steering Committee will identify the Central Laboratory and Specimen storage for future research. PUBLIC HEALTH RELEVANCE: Patients with kidney disease have increased bone fractures and are deficient in vitamin D. The kidney plays an important role in the activation of the form of vitamin D contained in vitamins. This study will compare the standard vitamin D type contained in vitamins to that which is the equivalent form of vitamin D metabolized by the kidney (activated vitamin D). During this U34 grant, we will fully implement study policies and procedures and finalize the study protocol in anticipation of funding through a U01 mechanism for a clinical trial. The trial will compare vitamin D with active vitamin D or placebo in a multi center two year study to determine the differences in the effect on bone health, muscle strength, and kidney disease.

描述（由申请人提供）：慢性肾病（CKD）患者患有矿物质稳态紊乱、骨疾病和心血管钙化，统称为CKD-矿物质骨紊乱（CKD-MBD）。目前用于治疗CKD-MBD的抑制甲状旁腺激素的方法是维生素D-骨化三醇和类似物如度骨化醇的肾活化形式的药理学制剂。然而，现在已知维生素D在肾脏外转化，胆钙化醇可能对靶组织骨和甲状旁腺有直接影响。此外，越来越多的数据表明，维生素D缺乏可能与多种疾病和死亡率的风险增加有关，与其对骨骼和矿物质代谢的影响无关。然而，没有随机对照试验比较骨化三醇或其类似物（如doxercalciferol）与更便宜的胆钙化醇。因此，我们将检验以下假设：度骨化醇比胆钙化醇更有效，并且两者在治疗CKD-矿物质骨病（CKD-MBD）方面均比安慰剂更有效。为了验证这一假设，我们将计划在300例维生素D不足的CKD 3期和4期患者中开展一项为期两年的多中心随机对照试验，这些患者接受SHPT治疗，以2：2：1的比例随机接受以下三种治疗之一：1）度钙化醇1.0 mcg，每日一次口服; 2）胆钙化醇4000 U，每日一次口服;或3）安慰剂，以确定度钙化醇、胆钙化醇、和安慰剂对骨和矿物质代谢、体力和功能、蛋白尿和肾功能的影响。本U34提案的目的是成立一个指导委员会，并实现以下具体目标：1）最终确定研究设计和标准操作规程，以确保快速启动临床试验：a）最终确定方案、研究者手册、数据和安全性监测计划、病例报告表; B）制定研究中心标准操作规程（SOP）; c）制定数据共享、出版和招募政策，d）确定所有研究中心，e）在每个研究中心获得IRB和其他批准，f）最终确定研究费用和所需合同。2)合理化开展多中心临床试验的中心基础设施，并为研究中心制定培训手册和实施计划：a）数据协调中心将制定基于网络的数据输入系统、随机化方案、SOP和质量控制（QC）程序; B）DXA协调中心将制定SOP和QC程序、数据传输方法，并确定DXA体模的需求; c）研究药房将最终确定研究药物采购或配制、包装和分发的计划和合同，并准备药房SOP; d）体能和功能协调核心将制定培训录像带、培训手册和研究中心培训认证程序; e）放射科核心将以去识别方式优化X光片的传输，以供中心阅读; f）指导委员会将确定中心实验室和样本储存库，以供未来研究。 公共卫生相关性：肾脏疾病患者骨折增加，缺乏维生素D。肾脏在激活维生素D中所含维生素D的形式中起着重要作用。本研究将比较维生素中所含的标准维生素D类型与肾脏代谢的维生素D等效形式（活化维生素D）。在U34资助期间，我们将全面实施研究政策和程序，并最终确定研究方案，以通过U01机制进行临床试验。该试验将在一项为期两年的多中心研究中比较维生素D与活性维生素D或安慰剂，以确定对骨骼健康，肌肉力量和肾脏疾病影响的差异。