The VITDALIZE Study: Effect of High-dose Vitamin D3 on 28-day Mortality in Adult Critically Ill Patients

Phase 3

Recruiting

• Conditions: Covid19; Vitamin D Deficiency; Critical Illness
• Interventions: Drug: Placebo; Drug: Cholecalciferol

• Registration Number: NCT03188796
• Lead Sponsor: Medical University of Graz

Brief Summary

In the VITdAL-ICU trial using a large oral dose of vitamin D3 in 480 adult critically ill patients, there was no benefit regarding the primary endpoint hospital length of stay. However, the predefined subgroup with severe vitamin D deficiency (25(OH)D ≤ 12ng/ml) had significantly lower 28-day mortality (36.3% placebo vs. 20.4% vitamin D group, hazard ratio (HR) 0.52 (0.30-0.89), number needed to treat = 6). Therefore, high-dose vitamin D3 in a population of severely vitamin D deficient critically ill patients is a promising and inexpensive intervention that requires confirmatory multicenter studies.

To date, only 7 interventions (e.g. noninvasive ventilation or prone positioning) have ever demonstrated mortality benefit for Intensive Care Unit (ICU) patients in multicenter trials. In case of benefit, vitamin D treatment in critically ill patients could be immediately implemented worldwide.

Detailed Description

A very limited number of intervention trials, most including less than 30 patients, have been published. The only phase III study, our VITdAL-ICU study recruited from 2010 to 2012 and (n=475) did not find a difference in the primary endpoint "length of hospital stay" between placebo and high-dose vitamin D3. However, there was a non-significant absolute risk reduction in all-cause hospital mortality in the total population. The difference was larger (17.5%) and significant in the predefined subgroup of patients with severe vitamin D deficiency at baseline, see Kaplan Meier curve below (n=200, 28.6 vs 46.1%, p=0.01, 0.56 (0.35-0.90) ), corresponding to a number needed to treat of 6. (51) As this was only a secondary endpoint in the predefined subgroup with severe vitamin D deficiency, this finding is hypothesis generating and requires further study, leading to this application.

In our study, we were unable to identify a mechanism by which this benefit was achieved. Interestingly, looking at the causes of death, the vitamin D group seemed to benefit in every category.

The VITDALIZE study is a pragmatic, multicenter, placebo-controlled double-blind randomized controlled phase III trial in adult critically ill patients which will be conducted in academic and non-academic centers. The sponsor is the Medical University of Graz, Austria.

Subjects will be randomised in a 1:1 ratio to receive either of the two treatments:

Vitamin D: oral/enteral pharmacological dose of cholecalciferol (vitamin D3)

* total dose 900,000

* loading dose of 540,0000 (dissolved in 37.5 ml of medium chain triglycerides - MCT) followed by 4000 IU daily (10 drops) for the entire active study period (90 days)

Placebo: identical regime - loading dose of 37.5 ml MCT followed by 10 drops daily

This study uses a group sequential design, with one interim analysis when 50% of the planned enrolled patients in each arm (N=600 per arm) have completed their day 28 assessment by the independent data safety monitoring board. The enrollment of patients will continue while the interim analyses is performed.

Study Timeline

• Study First Submitted: 2017-06-13
• Study First Submitted QC: 2017-06-13
• Study First Posted: 2017-06-15
• Study Start: 2017-10-10
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-07
• Last Update Posted: 2025-01-09
• Primary Completion: 2026-12
• Study Completion: 2027-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2400

Inclusion Criteria

• ≥18 years
• Anticipated ICU stay ≥ 48 hours
• Admission to ICU ≤ 72 hours before screening
• Severe vitamin D deficiency (≤12 ng/ml or undetectable)

Exclusion Criteria

• Severe gastrointestinal dysfunction (> 400 ml residual volume)/unable to take study medication
• Do not resuscitate (DNR) order/imminent death
• hypercalcemia
• known recent nephrolithiasis, active tuberculosis or sarcoidosis
• pregnancy/lactation
• not deemed appropriate by study team/physician

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	oral/enteral loading dose of 37.5 ml MCT followed by 10 drops daily for 90 days
High Dose Vitamin D3	Cholecalciferol	oral/enteral pharmacological dose of cholecalciferol (vitamin D3) - total dose 900,000 * loading dose of 540,0000 (dissolved in 37.5 ml of medium chain triglycerides - MCT) * followed by 4000 IU daily (10 drops) for the entire active study period (90 days)

Primary Outcome Measures

Name	Time	Method
28-day mortality	28 days	all-cause mortality

Secondary Outcome Measures

Name	Time	Method
Hypercalcemia at day 5	Day 5 - 48 hours tolerance
Hospital readmissions	90 days	Number of readmissions
Hospital Length of stay	90 days	Length of stay in days

Trial Locations

Locations (18)

University Hospital Wuerzburg; 🇩🇪 Würzburg, Germany

University of Birmingham; 🇬🇧 Birmingham, United Kingdom

LKH Enzenbach; 🇦🇹 Enzenbach, Austria

LKH Feldbach; 🇦🇹 Feldbach, Austria

Medical University of Graz; 🇦🇹 Graz, Austria

Klinikum am Wörthersee; 🇦🇹 Klagenfurt, Austria

LKH Hochsteiermark Standort Leoben; 🇦🇹 Leoben, Austria

Barmherzige Schwestern; 🇦🇹 Linz, Austria

Kepler Universitätsklinikum Linz; 🇦🇹 Linz, Austria

Krankenhaus Schwarzach; 🇦🇹 Schwarzach Im Pongau, Austria

Barmherzige Brüder; 🇦🇹 Vienna, Austria

Medical University of Vienna; 🇦🇹 Vienna, Austria

LKH Villach; 🇦🇹 Villach, Austria

Kaiser Franz Josef Spital Wien; 🇦🇹 Wien, Austria

Erasme Hospital; 🇧🇪 Brussel, Belgium

CHU de Charleroi; 🇧🇪 Charleroi, Belgium

CHR Citadelle; 🇧🇪 Liège, Belgium

CHU Ambroise Pare; 🇧🇪 Mons, Belgium