VINDICATE 2 will be a randomised, placebo-controlled, parallel group, double-blind study of vitamin D versus placebo in otherwise optimally-managed patients with CHF due to LVSD and vitamin D deficiency (<50nmol/L). The intervention will be a daily dose of 4000IU (100µg) per day or matching placebo for a minimum of 2 years and a maximum of 4 years.

DESIGN: Multi-centre, phase III, double-blind, parallel-group, placebo-controlled trial.

SETTING: Secondary care heart failure clinics across the UK. TARGET POPULATION: Higher-risk patients with CHF due to LVSD recruited from CHF clinics.

HEALTH TECHNOLOGY: 4000IU (100mcg) vitamin D3 or placebo daily for minimum 2yrs and maximum 4yrs.

MEASUREMENT OF OUTCOMES:

Primary end-point is a composite of HF hospitalisation or death Secondary outcomes include all-cause mortality, hospitalisations and cost-effectiveness. Patient outcomes will be obtained from NHS Digital (KKW is an approved researcher) with a transfer of linked data to be held at the Leeds Institute for Data Analysis.

Patient reported outcomes will be Minnesota Living with HF questionnaire and EQ-5D which will be assessed at twelve-monthly research visits.

SAMPLE SIZE: Based on VINDICATE, 2-yr CV mortality or hospitalisation in stable high-risk HF is 28% in those receiving placebo and 21% in those receiving vitamin D3 (hazard ratio 0.717). In the largest observational study (n=1800) of the effect of vitamin D deficiency on outcomes in patients with CHF on optimal medical therapy, balanced for all important variables except vitamin D, there was a significant adverse effect of vitamin D deficiency on all-cause mortality, demonstrating a 14% reduction in death for each 2.72-fold increase in vitamin D.

To demonstrate this effect 379 events in 1278 patients are required. Calculations assume time to CV event follows an exponential distribution, 2-sided 5% level of significance, 90% power, 20% dropout, 2.5-yrs recruitment and min. 2-yr follow-up.

ANALYSIS: Primary analysis will be on an intention-to-treat basis. Cox proportional hazards regression will be fitted to the time to first CV event adjusted for stratification factors.

Health Economics: A model will estimate lifetime incremental costs from an NHS/PSS perspective and QALYs gained based data from VINDICATE-2 and the literature. ICERs will be estimated and compared to standard cost-effectiveness thresholds to determine if vitamin D3 supplementation is cost-effective. Further analyses will explore the value of investing in activities to support uptake of vitamin D3 in clinical practice.

CURRENT AND PLANNED CARE PATHWAYS: The pathway within the study will be 4000IU vitamin D3 daily or placebo followed by safety and adherence visits at 3m and 12 monthly post-randomisation up to final visit at 24-48m. Patients will be screened, recruited and followed up during standard clinic visits. A small parcel containing three months of the intervention will be posted to participants by Leeds Teaching Hospitals Pharmacy every three months for the duration of their involvement in the study.

If adopted into standard care pathways, vitamin D could be prescribed and monitored cheaply and easily in primary care with annual blood tests.

PROJECT TIMETABLES: Set-up 6m, recruitment 30m, follow-up 24m, data cleaning, analysis and reporting 6m - total 66m.

RECRUITMENT RATE: 5 main centres (+2 PIC sites), 3.55 pts/mth/centre.

Inclusion Criteria:

• LVSD (LVEF <50%);
• stable medical and device therapy for >3mths;
• 25[OH]vitamin D3 <50nmol/L
• At least one of: recent (<1 year) hospitalisation for HF, high dose loop diuretic requirement (>80mg daily furosemide equiv), diabetes mellitus, ischaemic aetiology

Exclusion Criteria:

• Unwilling/unable to sign consent,
• Severe cognitive impairment,
• Severe COPD,
• Anaemia,
• Other life-threatening co-morbidity (in the opinion of the local co-investigator),
• Known and active sarcoidosis or tuberculosis

Anonymised data to be made available from the Leeds Institute of Data Analytics