Award Title: The VITDALIZE UK Study: Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: UK arm of an international multi-centre, placebo-controlled double-blind trial
Funder: Department of Health and Social Care

Abstract: Background: Sunlight is the major source of vitamin D.  A small proportion comes from the food we eat (e.g. oily fish, fortified cereals). Traditionally, vitamin D has been thought to be primarily important for bone health but the last 20 years of research has revealed important effects of vitamin D on the immune system and health. It has also been found to have potential effects on heart and muscle function. Every type of cell in the human body has the ability to use vitamin D. _x000D_
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Vitamin D deficiency is common (up to 70%) in critical illness and has been found to be associated with poor outcomes, death and increase in infection rates. More than 160,000 patients are admitted to intensive care units every year in the UK with a death rate of 15-20%. They are critically unwell for many reasons including serious infections, after surgery or serious accidents and usually require support of at least one major organ function (heart, lung, kidney or brain). For those that do survive, critical illness can be life changing, with long term mental and physical consequences._x000D_
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Problems with current treatments: Despite the associations, it is unclear if vitamin D deficiency is a cause or effect of critical illness.  Furthermore, there is no clear clinical data from trials, although it is suggested from a previous trial, that the beneficial effects may only be present in those patients with severe deficiency and high doses may therefore be required. Currently there are no guidelines to measure and treat vitamin D deficiency on admission to intensive care. Vitamin D is cheap, safe and readily available in oral form and, if proven, could be quickly introduced into clinical practice._x000D_
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Aims: The trial aims to answer if high dose vitamin D replacement in critical illness can improve outcomes. The main outcome will be if the patient has survived to 28 days. The other important outcomes are 90 day and 1-year survival rate, length of hospital stay, physical function (activities of daily living) and recurrent infections. In the UK, we also plan to collect additional data, including information held on national clinical databases to allow us to investigate the effects on the patients’ health and quality of life up to 1 year and to work out the cost effectiveness of the treatment in the NHS._x000D_
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Methods: This is an international study aiming to recruit 2400 patients from around the world, including the UK, Austria, Germany and Belgium. The UK study will enrol 25% of those patients. Importantly this will allow much quicker and cost-effective completion of the study. Patients will be randomised (allocated to different treatment groups by chance) to either a single high dose of vitamin D liquid or matching placebo (dummy liquid) on recruitment to the study but only to patients with severe deficiency on the intensive care unit, followed by maintenance daily dose for up to 90 days._x000D_
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We have worked closely with our local patient clinical research ambassador group (CRAG) and the charity ICUsteps in developing this UK application. The Chairperson of the CRAG, a former ICU patient and a treated vitamin D deficient patient are co-applicants. Patients and the public will continue to be central in the ongoing design, delivery and reporting of the study._x000D_
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Impact: The results of this study will help clinicians working in the NHS to decide if vitamin D should be measured and treated as a standard of care to improve outcomes in critical illness in intensive care.

Lay Abstract: Vitamin D deficiency (VDD) in critical illness is common and has been found to be associated with poor outcomes. Recently there has been heightened awareness of VDD and its possible treatment amongst ICU physicians. Currently, however there is insufficient evidence of its effectiveness. _x000D_
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Research Questions: _x000D_
In adult critically ill patients with severe VDD_x000D_
1. Does high dose oral vitamin D3 replacement  improve 28-day mortality, longer-term mortality, morbidity and patient specific outcomes?_x000D_
2. Is is cost-effective to test for and treat severe VDD with high dose oral vitamin D3?_x000D_
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Design: UK arm of a large international randomised double blind placebo controlled trial._x000D_
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Setting: 15 general Intensive Care Units (ICUs) within NHS hospitals with a patient case mix typical of UK critical care practice. _x000D_
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Population: Adult critically ill patients admitted to ICU with severe VDD ((25(OH)D=12ng/ml (30nmol/L))_x000D_
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Intervention: Single loading high-dose oral/enteral vitamin D3 (540,000IU cholecalciferol, Oleovit™, Fresenius Kabi, Austria, dissolved in 37.5ml of medium chain triglycerides – MCT) followed by 4000IU daily (10 drops) for 90 days._x000D_
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Control group treatment: Placebo, identical regime of loading dose of 37.5mls MCT (Fresenius Kabi, Austria) followed by 10 drops of MCT daily for 90 days. _x000D_
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Outcomes: _x000D_
Primary outcome is mortality at 28 days after randomisation. _x000D_
Secondary outcomes are: ICU, hospital, 90 day and 1 year mortality; hospital and ICU length of stay (starting at day 0, ending at discharge from the trial site or day 90); change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment score (SOFA), number of organ failures (0-6; defined as >2 SOFA points in each of the 6 categories); Hospital and ICU readmission until day 90; Discharge destination (home, rehabilitation, other hospital); self-reported infections requiring antibiotics until day 90. _x000D_
Safety outcomes: hypercalcaemia at day 5; self-reported falls, fractures until day 90; new episodes of kidney stones._x000D_
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In the UK arm, the following additional secondary outcomes will be evaluated: Health-related Quality of Life (EQ-5D-5L) and Disability assessment (WHODAS 2.0) at 90 days and 1 year; and health care utilisation to 1 year._x000D_
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Health Economic evaluation: In this UK arm we will assess the 1-year and life-time cost-effectiveness of screening for and treating severe VDD in critical illness compared to standard care/placebo._x000D_
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Follow up: This will be for 12 months after randomisation._x000D_
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Sample size: Total sample size of international study n=2400 of whom 25% will be recruited in the UK (sample size in UK n=600)_x000D_
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Projected time frames: 6 months for trial set up to obtain all regulatory approvals. We plan for 15 ICUs and estimate 2 patients will be recruited per ICU per month. Assuming a staggered set up of 6 months, 2 years total recruitment is required with a 1-year follow-up period. Recruitment rates are based on our previous ICU trials, the VITdAL-ICU study and a screen failure rate of 2/3 for severe VDD. Allowing for 12 months for health economics analysis and reporting commencing at 36 months, the total duration is 48 months._x000D_
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Expertise: Our team includes critical care specialists, endocrinologist, nephrologist, health economists, methodologist, trialists and patient representatives. The team has expertise in running complex multi-centre trials in the ICU setting and performing long-term health economic evaluation

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE