Title: Survival Improvement with Cholecalciferol in Patients on Dialysis – the SIMPLIFIED registry trial
Funder: Department of Health and Social Care

Abstract: Vitamin D deficiency is highly prevalent in patients with kidney failure and is associated with increased mortality. Kidney failure patients are treated with “active” vitamin D compounds (VDRAs) based on the now disproven belief that activation can only occur in the kidneys. VDRAs induce hypercalcaemia, result in tissue deficiency of calcitriol, and may promote vascular calcification. Contemporary treatment guidelines now recommend administration of “native” vitamin D (Cholecalciferol). This guidance is not currently implemented given the lack of evidence from randomised trials. Cholecalciferol has been used to treat vitamin D deficiency for more than 80 years. It is cheap and safe, even at high doses. In contrast, VDRAs are expensive and despite their wide use, their efficacy and safety have never been tested in interventional trials. There is an urgent unmet need for a trial to determine which approach is preferable. In this trial, we will test the hypothesis that population-wide supplementation with high-dose cholecalciferol (inactive vitamin D) patients receiving dialysis will reduce mortality and improve quality of life. DESIGN Randomised open-label registry-facilitated trial of high dose cholecalciferol versus standard care in patients receiving dialysis SETTING All UK dialysis units TARGET POPULATION Dialysis patients aged 18 years or older TECHNOLOGIES BEING ASSESSED High dose vitamin D supplementation (cholecalciferol) versus standard care. OUTCOME MEASURES All outcome measures will be captured using routinely collected data from the UK Renal Registry (UKRR) and the Health and Social Care Information Centre (HSCIC). The primary efficacy endpoint will be all-cause mortality, given that the three leading causes of death for patients on dialysis (cardiovascular, infectious and malignant disease) are all strongly associated with vitamin D deficiency and likely to be impacted by its supplementation. Secondary endpoints: 1) Hospitalisation for composite cardiovascular endpoint of CV death, acute coronary syndrome, heart failure or arrhythmia admissions, or stroke 2) Hospitalisation for infection 3) Incidence of malignancy 4) Health-related Quality of life (EQ5D, KDQoL) 5) Cost effectiveness of cholecalciferol from the perspective of the NHS. SAMPLE SIZE The study will recruit 4200 patients over 3 years. We estimate that the control arm has a 3-year survival of 68%. Using Cox proportional hazards regression (two-sided 5% significance) will enable a hazard ratio of 0.87 to be detected with 90% power assuming that 2200 events occur during the trial (estimated to require a duration of 7 years). TIMETABLE Recruitment will require 3 years. The trial will conclude once 2200 events have occurred.

Lay abstract: Vitamin D deficiency is common in kidney failure patients, and is a strong predictor of death from cardiovascular disease, infections and cancer. Dialysis patients almost all receive pre-activated vitamin D, since it used to be thought that only the kidneys activate vitamin D. However, this approach increases blood calcium concentrations which may be harmful, and paradoxically makes vitamin D deficiency worse. International treatment guidelines therefore now recommend that kidney patients receive inactive vitamin D (known as cholecalciferol), since we now know that every organ activates its own vitamin D as required, even in patients with kidney failure. However, this is not currently used in the NHS as it has not yet been tested in a trial. We will test whether supplementation with cholecalciferol increases survival in UK dialysis patients. THE STUDY We will randomly assign adult UK dialysis patients to high dose cholecalciferol or standard care. Instead of seeing patients for extra study visits, we will use existing data sources (the UK Renal Registry (UKRR), Hospital Episode Statistics (HES)), and death records to find out what happens to patients in the study. HOW WILL WE KNOW IF CHOLECALCIFEROL WORKS? We will determine the number of deaths over time in the two groups, to establish whether cholecalciferol improves survival. Whether patients are alive or dead at the end of the study will be determined from the national deaths register, and the date of death identified. We will also measure any differences in survival free from cardiovascular events, infections and cancers, the three leading causes of death in those on dialysis. Then, we will use questionnaires to compare the quality of life of those in the two groups. Finally, we will measure whether cholecalciferol use is cost-effective from the point of view of the NHS. HOW MANY PATIENTS DO WE NEED? Currently only 68% of patients survive 3 years or more on dialysis. Assuming that this will be the case in the control group, we would need to witness 2200 deaths during the study to determine with a sufficient degree of certainty whether cholecalciferol improves survival. We estimate that this would require the inclusion of 4200 patients, followed for a total study duration of 7 years. Put differently, this trial is designed to detect whether cholecalciferol has a clinically relevant effect by saving 4 or more lives for every 100 patients treated. HOW WILL WE MAKE THE STUDY AFFORDABLE? After including patients in the study, we will have no dedicated study visits. In stead, we will obtain the data we need from the UKRR, HES and the deaths register. We will measure the patients’ quality of life by sending questionnaires by mail or by phone interview. This approach will have the important benefit of keeping to a minimum the burden of trial participation on patients and their clinical teams.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL