High-dose oral vitamin D supplementation and mortality in people aged 65-84 years: the VIDAL cluster feasibility RCT of open versus double-blind individual randomisation.

BACKGROUND

Randomised controlled trials demonstrating improved longevity are needed to justify high-dose vitamin D supplementation for older populations.

OBJECTIVES

To demonstrate the feasibility of a large trial (

DESIGN

Twenty GP practices were randomised in matched pairs between open-label and double-blind allocation. Within each practice, patients were individually randomised to vitamin D or control (i.e. no treatment or placebo). Participants were invited to attend their GP practice to provide a blood sample and complete a lifestyle questionnaire at recruitment and again at 2 years. Randomisation by telephone followed receipt of a serum corrected calcium assay confirming eligibility (< 2.65 nmol/l). Treatment compliance was reported by quarterly follow-up forms sent and returned by e-mail or post (participant choice). GP visits and infections were abstracted from GP records. Hospital attendances, cancer diagnoses and deaths were ascertained by linkage to Hospital Episode Statistics and national registration through NHS Digital.

SETTING

GP practices in England.

PARTICIPANTS

Recruitment opened in October 2013 and closed in January 2015. A total of 1615 registered patients aged 65-84 years were randomised: 407 to vitamin D and 421 to no treatment in open practices; 395 to vitamin D and 392 to placebo in blind practices.

INTERVENTIONS

There was a 24-month treatment period: 12 monthly doses (100,000 IU of vitamin D

MAIN OUTCOME MEASURES

Recruitment, compliance, contamination and change in circulating 25-hydroxyvitamin D [25(OH)D] from baseline to 2 years.

RESULTS

Participation rates (randomised/invited) were 15.0% in open practices and 13.4% in double-blind practices (

CONCLUSIONS

A trial could recruit 20,000 participants aged 65-84 years through 200 GP practices over 2 years. Approximately 80% would be expected to adhere to allocated treatment (vitamin D or placebo) for 5 years. The trial could be conducted entirely by e-mail in participants aged < 80 years, but some participants aged 80-84 years would require postal follow-up. Recruitment and treatment compliance would be similar and contamination (self-administration of vitamin D) would be minimal, whether control participants are randomised openly to no treatment with no contact during the trial or randomised double-blind to placebo with monthly reminders.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN46328341 and EudraCT database 2011-003699-34.

FUNDING

This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in

High-dose vitamin D may reduce the risk of many diseases, but without large randomised controlled trials the evidence will remain inconclusive. We therefore proposed the Vitamin D and Longevity (VIDAL) trial, with 20,000 older people randomised to either no vitamin D medication or vitamin D medication for 5 years. The VIDAL feasibility study was conducted to establish the procedures required for the main trial, including assessment of recruitment, compliance (taking study treatment as directed) and contamination (how many control participants started taking vitamin D). This was done in two sets of general practitioner (GP) practices: (1) ‘open’ practices, in which participants knew their treatment allocation (2 years of 100,000 IU vitamin D monthly or no treatment), and (2) ‘double-blind’ practices, in which participants and their GPs did not know whether they were taking vitamin D or placebo oil. We invited 11,376 men and women aged 65–84 years from 20 GP practices in England and 1615 (14%) took part. Ninety per cent of participants allocated to monthly oil took it for 2 years and few participants used vitamin supplements outside the trial, with no marked differences between open-label and double-blind arms. The best way to conduct the main trial will therefore depend on other considerations. A double-blind trial provides reliable evidence on effects where reporting could be influenced by you or your doctor knowing your treatment, which is important for many illnesses and any side effects of treatment. However, any long-term effects are likely to be considerably greater if treatment continues instead of stopping after 5 years when the main trial ends. An open trial is easier to conduct and, when it ends, those taking vitamin D can be offered a continuing supply so that the effect of lifelong treatment can be studied for major diseases and life expectancy, which are unlikely to be affected by individuals knowing whether or not they are taking vitamin D.

Déclaration de conflit d'intérêts

Irwin Nazareth was on the Health Technology Assessment (HTA) Commissioning Board from 2012 to July 2017. For the duration of the Vitamin D and Longevity (VIDAL) trial, Irwin Nazareth’s PRIMENT Clinical Trials Unit was funded by the National Institute for Health Research (NIHR). He was a member of the HTA Disease Prevention Panel, a member of the HTA Commissioning Sub-board (Expression of Interest) and a member of the HTA Primary Care Themed Call. Benoit Aigret reported that Queen Mary University of London received a grant from the London School of Hygiene & Tropical Medicine to develop the VIDAL online application during the conduct of the study.