A pragmatic, randomised, open-label, multi-centre UK registry-facilitated trial evaluating the effect of high-dose cholecalciferol on mortality in patients on dialysis: the SIMPLIFIED trial

TL;DR

This trial investigates whether high-dose vitamin D3 improves survival in dialysis patients, using existing data to reduce research burden.

Contribution

The study introduces a pragmatic trial design using real-world data to evaluate cholecalciferol's impact on mortality in dialysis patients.

Findings

The trial will assess whether high-dose cholecalciferol improves survival in dialysis patients.

It uses existing data sources to streamline trial conduct and reduce patient and staff burden.

The study aims to enroll 4200 patients to observe 2200 deaths over seven years.

Abstract

Vitamin D deficiency is common in patients with end stage kidney disease (ESKD) and is a strong predictor of death from cardiovascular disease, infections and cancer. Currently only 68% of patients in the UK survive 3 years or more on dialysis. Vitamin D replacement typically utilises activated (1α-hydroxylated) vitamin D compounds allowing for impaired renal activation. However, this approach increases blood calcium concentrations and may paradoxically accelerate vitamin D catabolism. Contemporary treatment guidelines recommend replacement with inactive (unhydroxylated) vitamin D3 (cholecalciferol), instead relying on autocrine and paracrine vitamin D activation in target tissues. However, the impact of this approach on clinical outcomes has not yet been tested in adequately powered trials.

The SIMPLIFIED (Survival Improvement with Cholecalciferol in Patients on Dialysis) trial will test whether supplementation with high-dose cholecalciferol improves survival. Adult dialysis patients will be recruited from one of 72 UK renal centres, by local clinicians and research nurses, and randomly assigned in a 1:1 ratio to high-dose open-label cholecalciferol or standard care, stratified by site. Trial outcomes will be captured using existing data sources including Office of National Statistics (ONS) for deaths and Hospital Episode Statistics (HES) for secondary endpoints. The primary endpoint of the trial is all-cause mortality. Key secondary endpoints include survival free from cardiovascular events, infections and cancers, and quality of life and cost-effectiveness measures utilising the Eq5D tool. Severe adverse event line listings will be generated from HES data for safety reporting. In this superiority trial, it is anticipated that approximately 4200 patients in total will need to be enrolled to observe 2200 deaths over a period of about 7 years, which will yield 90% power to demonstrate a hazard ratio of 0.87.

Outcomes for patients on dialysis remain very poor. The pragmatic design of this study leveraging routinely collected data streamlines trial conduct, reducing burden on patients and local site study staff. Furthermore, since cholecalciferol is a low-cost and easy to administer intervention, evidence of benefit could be readily incorporated into dialysis care across healthcare systems globally.

EudraCT Number: 2015-005003-88; ISRCTN Number: 15087616 (registration date 30th December 2015) (https://doi.org/10.1186/ISRCTN15087616). Recruitment commenced in March 2017.

Figures