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

描述（由申请人提供）：慢性肾脏疾病（CKD）患者患有矿物质平衡紊乱，骨病和心血管钙化，统称为CKD-矿物质骨疾病（CKD- mbd）。目前抑制甲状旁腺激素治疗CKD-MBD的方法是肾活化形式的维生素D-骨化三醇和类似物如多骨化醇的药理学制剂。然而，现在我们知道维生素D在肾脏外也有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，而与维生素D对骨骼和矿物质代谢的影响无关。然而，没有随机对照试验将骨化三醇或其类似物（如多钙钙化醇）与更便宜的胆骨化醇进行比较。因此，我们将验证多骨化醇比胆骨化醇更有效的假设，并且两者在治疗ckd -矿物质骨疾病（CKD-MBD）方面都比安慰剂更有效。为了验证这一假设，我们将计划一项为期两年的多中心随机对照试验，对300名慢性肾病3期和4期患者进行随机对照试验，这些患者维生素D缺乏SHPT，以2:2:1的比例随机分为三种治疗方法：1)多羟基钙化醇1.0微克，每日口服1次；2)胆钙化醇4000微克，每日口服1次；或3)安慰剂，以确定多羟基钙化醇、胆钙化醇和安慰剂对骨骼和矿物质代谢、体力和功能、蛋白尿和肾功能的疗效和安全性。本U34提案的目的是组建指导委员会并实现以下具体目标：1)确定研究设计和标准操作程序，以确保临床试验的快速启动；a)确定方案、研究者手册、数据和安全监测计划、病例报告表格；b)制定现场标准操作程序（sop）；c)制定数据共享、发布和招聘政策，d)确定所有站点，e)在每个站点获得IRB和其他批准，f)确定研究的成本和所需合同。2)理顺开展多中心临床试验的中心基础设施，并制定研究地点的培训手册和实施计划：a)数据协调中心将开发基于网络的数据输入系统，随机化协议，SOP和质量控制（QC）程序；b) DXA协调中心制定SOP和QC程序、数据传递方法，确定DXA幻影的需求；c)试验药房将最终确定研究药物获取或配制、包装和分销的计划和合同，并制定药房标准操作规程；d)物理性能和功能协调核心将制作培训录像带、培训手册和现场培训认证程序；e)放射学核心将以去识别的方式优化x光片的传输，以便中央读取；f)指导委员会将确定中央实验室和标本储存库，以供未来研究之用。

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.