Condition category
Nutritional, Metabolic, Endocrine
Date applied
05/07/2011
Date assigned
02/08/2011
Last edited
27/06/2012
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Lay summary under review 3

Trial website

Contact information

Type

Scientific

Primary contact

Prof Julian Peto

ORCID ID

Contact details

Department of Non-Communicable disease Epidemiology
London School of Hygiene & Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom
+44 (0)20 7927 2632
julian.peto@lshtm.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

HTA 08/116/48

Study information

Scientific title

Feasibility study for a large randomised controlled trial measuring the effect of oral vitamin D on morbidity and mortality in men and women aged 65-84

Acronym

VIDAL

Study hypothesis

This is the feasibility study is that monthly oral vitamin D will reduce overall mortality in men and women aged 65-84.

Background
A consensus is emerging that circulating 25-hydroxyvitamin D (25(OH)D) concentration - the measure of vitamin D status - should be at least 75 nmol/l (30 ng/ml) for optimal health and increased life expectancy. Over eighty percent of the UK population aged over 65 years have levels of 25(OH)D below 75 nmol/l.

Several epidemiological studies report a correlation between low circulating 25(OH)D and the risk of developing various cancers, particularly colorectal cancer. Positive associations have however been reported between vitamin D status and risk of prostate cancer and pancreatic cancer, highlighting the need for large randomised trials. The epidemiological evidence that various other vitamins prevent cancer has been disproved in randomized trials. Associations between inadequate vitamin D status and increased risk of cancer reported in observational studies could thus be at least partly due to confounding, and no adequately powered trial has tested vitamin D in doses that are high enough to achieve serum 25(OH)D concentration > 75 nmol/l.

Evidence on vitamin D and heart disease from nested case-control studies includes elevated risk of myocardial infarction in men with low 25(OH)D levels in stored blood samples. A systematic review suggested that optimal serum 25(OH)D for all endpoints should exceed 75 nmol/l and that this can be achieved with the proposed dose without increasing health risks. Other effects of low circulating 25(OH)D may include compromised immunity. These pleotropic effects are supported by experimental studies. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D, suppresses proliferation and induces differentiation of cancer cells in vitro, and its receptor and the enzyme that synthesises it are both expressed in many cell types. However, although the majority of observational studies report associations between vitamin D deficiency and susceptibility to a range of pathologies, some studies are null, and a few report opposite associations. The existing evidence is thus not sufficient as a basis for a universal policy of high-dose vitamin D supplementation.

A meta-analysis of published randomized trials on the effect of vitamin D on overall mortality (Autier and Gandini 2007, Arch Intern Med 167: 1730-7) showed a marginally significant reduction in overall mortality of 7% (95% CI 1%-14%: p<0.05). The meta-analysis included a British study of people aged 65-85 years randomised to 100,000 IU oral vitamin D3 or placebo every four months over five years. The authors¡¯ main recommendation was for large population-based randomised trials of prolonged vitamin D3 treatment at adequate dose, with total mortality as the primary endpoint.

The International Agency for Research on Cancer (IARC) Working Group on vitamin D and cancer reviewed the epidemiological evidence on vitamin D and cancer and concluded that the evidence was strong for colorectal cancer but inconclusive for other individual cancers (IARC Working Group on Vitamin D, 2008) Their report concluded: ¡°The only way to further address the cause-effect issue is to organise new randomized trials to evaluate the impact of vitamin D on all-cause mortality and on the incidence and mortality from common conditions including cancer. These trials should make sure that key parameters of vitamin D status (e.g., serum 25-hydroxyvitamin D levels before and in trial) can be assessed.¡±

Rationale For Current Study:
The proposed regimen (100,000 IU vitamin D monthly, equivalent to 3200 IU per day) is less than the current tolerable upper intake limit of 4000 IU/day for vitamin D in North America, defined as ¡°the highest daily level of chronic nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population¡± (Institute of Medicine of the National Academies, 2011). Indeed a risk assessment based on a review of clinical trial data concluded that a daily dose of at least 10,000 IU/day is safe, and the Institute of Medicine report accepts that this intake represents the NOAEL (no observable adverse effect level), which was adjusted for uncertainty to establish an upper limit of 4000 IU per day.

The main trial for which this is the feasibility study will be a randomized trial with 20,000 subjects followed for 10 years. A trial of that size will be needed to detect the 7% reduction that vitamin D supplementation might plausibly achieve in total mortality in healthy adults aged over 65 (Autier and Gandini 2007, Arch Intern Med 167: 1730-7). If self-administered vitamin D supplementation were shown to confer substantial health benefits it would be routinely recommended and widely adopted. This would also provide a rationale for a national policy of vitamin D supplementation for the general population, a review of the relative risks and benefits of sun exposure, and a revision of existing policy on vitamin D fortification of foods. If we show no benefit or unforeseen disadvantages this will also be a valuable contribution to knowledge.

An important public health priority is therefore to demonstrate the feasibility of a large randomized trial of prolonged vitamin D supplementation in older people, and to show that this will increase serum 25(OH)D to >=75 nmol/l in the majority of subjects. As well as demonstrating an expected increase in circulating 25-hydroxyvitamin D levels, the feasibility study will provide estimates of cost and establish the study design and procedures required for the main trial. An important feature of the feasibility study will be the comparison of a placebo control group with an open control group with no treatment. Randomized double-blind placebo-controlled trials are considered the gold standard, particularly where the endpoint is subjective, but an open control design may be acceptable where the main endpoint is overall mortality. The primary purpose of this feasibility study is to ascertain recruitment levels, but the study will also include a cluster randomized comparison of the effects of placebo versus open control trial design on the reliability of self-reported minor infections and adverse effects as well as on recruitment, participant acceptability and treatment compliance. The study will thus provide much needed evidence on an important methodological (and economic) issue in the design of pragmatic trials in preventive medicine.

Ethics approval

South East MREC, 10 August 2011

Study design

Randomised controlled trial, open or double-blind placebo control, and individual randomisation to vitamin D or control within each practice.

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

GP practices

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Vitamin D supplement on morbidity and mortality

Intervention

Participants will receive either:
1. 100,000 IU monthly (average 3300 IU/day) of oral vitamin D3 or double-blind placebo control (800 participants)
2. 100,000 IU monthly (average 3300 IU/day) of oral vitamin D3 or open control (800 participants)

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

1. The successful establishment of the procedures required to identify, invite and recruit eligible patients. Our target is to randomise 1,600 participants aged 65-84 through 20 GP practices.
2. Overall recruitment rate and comparison of recruitment rate in placebo versus open control studies
3. Overall level of compliance with study medication and comparison of placebo versus open control medication compliance (to evaluate whether participants taking open label vitamin D are more or less compliant than those who are unaware of IMP status)
4. Contamination: whether open controls are more likely to take vitamin D supplements than placebo controls
5. Overall level of attrition over 2 years and comparison of attrition rates in open label and placebo-controlled practices
6. Costs of placebo versus open control study designs to determine whether the extra costs of placebo would be justified in the main trial (participants randomised to an open untreated control arm may take supplements containing vitamin D more frequently than those on placebo)
7. Comparison of incidence of serious adverse events between vitamin D and control in placebo-controlled practices
8. Comparison between vitamin D and control of infections, GP prescriptions and frequency of GP visits:
8.1. In placebo-controlled practices, and
8.2. In open-label practices
This will provide an estimate of the bias in these measures in participants allocated to vitamin D in an open control design
9. Serum 25(OH)D concentration at recruitment and at 2-year follow-up in relation to potential determinants of vitamin D status including self-reported compliance with study medication
10. Cause-specific mortality and cancer incidence will be ascertained by flagging in the National Health Service Information Centre (NHS IC)
11. Hospital records will be collected by NHS number linkage with Hospital Episode Statistics (HES)

Secondary outcome measures

Before randomisation:
1. An online lifestyle questionnaire on foreign holidays, sunbathing, sunbed use and use of vitamin supplements will be completed at the GP practice by all participants (treated and control) before randomisation
2. A blood sample will also be taken, and corrected serum calcium will be assayed before randomisation to establish eligibility. Serum 25(OH)D will also be assayed. Aliquots (plasma and buffy coat) will be stored in liquid nitrogen for further analysis (subject to additional funding) including genetic studies.

At two years:
1. All 1600 participants will attend the GP practice 2 years after randomization. A further blood sample for 25(OH)D assay and a second copy of the same online questionnaire will be obtained to quantify differences in vitamin D status between the intervention and control groups in blinded versus open label studies.
2. Summaries of GP records for all participants will also be extracted for GP visits, prescriptions and infections for one year pre-randomisation and 2 years post-randomisation.

Overall trial start date

01/01/2012

Overall trial end date

31/12/2013

Reason abandoned

Eligibility

Participant inclusion criteria

1. Aged between 65 and 84 years at enrolment
2. Contactable by telephone, able to attend enrolment at the GP surgery, and able to give informed consent
3. Baseline corrected serum calcium 2.65 mmol/L
4. Rregistered with one of the 20 participating GP practices

Participant type

Patient

Age group

Senior

Gender

Both

Target number of participants

1600 members of the general population registered with one of the 20 participating GP practices

Participant exclusion criteria

1. Aged <65 or >84 years
2. No telephone
3. Terminal illness
4. Known active tuberculosis
5. Referral for suspected hepatic or renal dysfunction
6. Known sarcoidosis, hyperparathyroidism or nephrolithiasis
7. <3 years since remission from cancer (except non-melanoma skin cancer)
8. Taking >400mg daily vitamin D
9. Any other Investigational Medicinal Product (IMP) therapy within 4 months
10. Concomitant carbamazepine, phenobarbital, phenytoin, primidone, oral 1-alpha-hydroxylated vitamin D preparations (e.g. alfalcalcidol, calcitriol) or the combination of a thiazide diuretic (e.g. bendrofluazide, metolazone) with a calcium supplement

Recruitment start date

01/01/2012

Recruitment end date

31/12/2013

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Department of Non-Communicable disease Epidemiology
London
WC1E 7HT
United Kingdom

Sponsor information

Organisation

London School of Hygiene & Tropical Medicine (UK)

Sponsor details

c/o Ms Patricia Henley
QA Manager
London School of Hygiene & Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom

Sponsor type

University/education

Website

http://www.lshtm.ac.uk/

Funders

Funder type

Government

Funder name

The NIHR Health Technology Assessment Programme - HTA (UK) ref: 08/116/48

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes