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 (n ≈ 20,000) of high-dose vitamin D in people aged 65-84 years through general practitioner (GP) practices, and to cluster randomise participating practices between open-label and double-blind randomisation to compare effects on recruitment, compliance and contamination. 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 D3 or placebo as 5 ml oily solution) were posted after randomisation and at 1 year (100,000 IU per month corresponds to 3300 IU per day). Reminders were sent monthly by e-mail, text message or post. 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 (p = 0.7). The proportion still taking study medication at 2 years was 91.2% in open practices and 89.2% in double-blind practices (p = 0.4). The proportion of control participants taking > 400 IU vitamin D per day at 2 years was 5.0% in open practices and 4.8% in double-blind practices. Mean serum 25(OH)D concentration was 51.5 nmol/l [95% confidence interval (CI) 50.2 to 52.8 nmol/l] with 82.6% of participants < 75 nmol/l at baseline. At 2 years, this increased to 109.6 nmol/l (95% CI 107.1 to 112.1 nmol/l) with 12.0% < 75 nmol/l in those allocated to vitamin D and was unaltered at 51.8 nmol/l (95% CI 49.8 to 53.8 nmol/l) in those allocated to no vitamin D (no treatment or placebo). 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 Health Technology Assessment; Vol. 24, No. 10. See the NIHR Journals Library website for further project information.

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 65­84 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.

Controlled trials of vitamin D, causality and type 2 statistical error.

Two recent studies published in The Lancet (Autier et al. (2013) Lancet Diabetes Endocrinol 2, 76-89 and Bolland et al. (2014) Lancet Diabetes Endocrinol 2, 307-320) have concluded that low levels of vitamin D are not a cause but a consequence of ill health brought about by reduced exposure to the sun, an association known as 'reverse causality'. The scientific evidence and reasoning for these conclusions are examined here and found to be faulty. A null result in a clinical trial of vitamin D in adults need not lead to a conclusion of reverse causation when low vitamin D is found in observational studies of the same disease earlier in life. To assume an explanation of reverse causality has close similarities with type 2 statistical error. For example, a null result in providing vitamin D for treatment of adult bones that are deformed in the pattern of the rachitic rosary would not alter the observation that lack of vitamin D can cause rickets in childhood and may have lasting consequences if not cured with vitamin D. Other examples of diseases considered on a lifetime basis from conception to adulthood are used to further illustrate the issue, which is evidently not obvious and is far from trivial. It is concluded that deficiency of vitamin D in cohort studies, especially at critical times such as pregnancy and early life, can be the cause of a number of important diseases. Denial of the possible benefits of vitamin D, as suggested by insistent interpretation of studies with reverse causation, may lead to serious harms, some of which are listed.

The Scots' Paradox: can sun exposure, or lack of it, explain major paradoxes in epidemiology?

Five epidemiological paradoxes that have puzzled epidemiologists for a decade or more can be explained by the UVB-vitamin D hypothesis. The Scots' Paradox is examined in detail as an example. Many subsidiary factors varying over time and place influence the amount of UVB which reaches the skin of individuals and so the amount of vitamin D synthesised, while other factors influence the amount ingested. These factors are plotted leading to a common pathway that ends in vitamin D insufficiency and consequent disease. Examples suggest that the factors interact to increase mortality in Scotland in a way consistent with causation according to the criteria of Bradford Hill. It is suggested that different degrees of vitamin D insufficiency in populations can explain important differences in the health of nations and resolve health paradoxes. The analysis also shows that vitamin D insufficiency is a consequence of industrialisation and, like other consequences of industrial growth, such as water and air pollution, needs to be corrected by public health measures. Direct intervention with use of supplements and fortification of foods with vitamin D can be expected to provide considerable health gains, but progress will be slow until there is greater recognition of the vitamin D health crisis by the public, professionals and politicians. Health professionals need to be trained and motivated to encourage use of supplements, particularly by pregnant and nursing mothers, and infants. The importance of open sunny spaces and clean air that allows full penetration of UVB needs to be recognised by city planners and politicians. New advice and new fashions are needed to encourage maximum exposure of skin to summer sun without burning. Use of sunlamps to boost vitamin D synthesis could be useful.

Sunlight robbery: a critique of public health policy on vitamin D in the UK.

The British Isles have a very cloudy climate and as a result receive fewer hours of clear sunlight than most other industrial regions. The majority of people in these islands have low blood levels of vitamin D [25(OH)D] all year round. Few food products are fortified with vitamin D in the UK and the government does not recommend any vitamin D supplement for most adults in the UK. Diseases associated with vitamin D insufficiency such as cancer, heart disease, diabetes (types 1 and 2) and multiple sclerosis are more frequent in the UK, and particularly in Scotland, than in many other European countries and some, such as multiple sclerosis and diabetes (types 1 and 2), are increasing in incidence. Present knowledge suggests that the risk of some chronic diseases could be reduced if vitamin D intake or sun exposure of the population were increased. Yet policy and public health recommendations of the UK government and its agencies (e.g. the Health Protection Agency, the Food Standards Agency) and of Cancer Research UK have failed to take full account of established and putative benefits of vitamin D and/or sunshine. The epidemic of chronic disease in the UK, which is associated with and caused at least in part by vitamin D insufficiency, has not been adequately recognized by these agencies, and too often measures taken by them have been misguided, inappropriate or ineffective.