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.
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.
