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

The VITDALIZE Study: Effect of High-dose Vitamin D3 on 28-day Mortality in Adult Critically Ill Patients With Severe Vitamin D Deficiency: a Multicenter, Placebo-controlled Double-blind Phase III Randomized Controlled Trial (RCT)

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.

Study Overview

• Status: Recruiting
• Conditions: Critical Illness; Covid19; Vitamin D Deficiency
• Intervention / Treatment: Drug: Placebo; Drug: Cholecalciferol

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 Type: Interventional
• Enrollment (Estimated): 2400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Astrid Friedel; Phone Number: 72061 +43 316 385; Email: astrid.friedel@medunigraz.at
• Study Contact Backup: Name: Karin Amrein, MD, MSc; Phone Number: 81188589 +43 681; Email: karin.amrein@medunigraz.at

Study Locations

• Austria
  • Enzenbach, Austria
    • Recruiting
    • LKH Enzenbach
    • Contact: Otmar Schindler
  • Feldbach, Austria
    • Recruiting
    • LKH Feldbach
    • Contact: Norbert Watzinger
  • Graz, Austria
    • Recruiting
    • Medical University of Graz
    • Contact: Karin Amrein, MD, MSc
  • Klagenfurt, Austria
    • Recruiting
    • Klinikum am Wörthersee
    • Contact: Rudolf Likar, MD
  • Leoben, Austria
    • Recruiting
    • LKH Hochsteiermark Standort Leoben
    • Contact: Viktor Wutzl
  • Linz, Austria
    • Recruiting
    • Barmherzige Schwestern
    • Contact: Johann Reisinger, MD
  • Linz, Austria
    • Recruiting
    • Kepler Universitätsklinikum Linz
    • Contact: Jens Meier
  • Schwarzach Im Pongau, Austria
    • Recruiting
    • Krankenhaus Schwarzach
    • Contact: Franz Wimmer, MD
  • Vienna, Austria
    • Recruiting
    • Medical University of Vienna
    • Contact: Peter Schellongowski, MD
  • Vienna, Austria
    • Recruiting
    • Barmherzige Brüder
    • Contact: Rene Schmutz, MD
  • Villach, Austria
    • Not yet recruiting
    • LKH Villach
    • Contact: Ernst Trampitsch
  • Wien, Austria
    • Recruiting
    • Kaiser Franz Josef Spital Wien
    • Contact: Sabine Schmaldienst
• Belgium
  • Brussel, Belgium
    • Recruiting
    • Erasme hospital
    • Contact: Jean-Charles Preiser
  • Charleroi, Belgium
    • Recruiting
    • CHU de Charleroi
    • Contact: Maxime van Cutsem
  • Liège, Belgium
    • Recruiting
    • CHR Citadelle
    • Contact: Vincent Fraipont
  • Mons, Belgium
    • Recruiting
    • CHU Ambroise Pare
    • Contact: Alain D´hondt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; oral/enteral loading dose of 37.5 ml MCT followed by 10 drops daily for 90 days	Drug: Placebo; oral/enteral loading dose of 37.5 ml MCT followed by 10 drops daily for 90 days
Experimental: High Dose Vitamin D3; 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)	Drug: Cholecalciferol; oral/enteral loading dose of 37.5 ml MCT including 540,000 IU vitamin D3 followed by 10 drops daily (4000 IU) for 90 days; Other Names: Vitamin D3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day mortality	all-cause mortality	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital Length of stay	Length of stay in days	90 days
Hypercalcemia at day 5		Day 5 - 48 hours tolerance
Hospital readmissions	Number of readmissions	90 days

Collaborators and Investigators

• Sponsor: Medical University of Graz
• Collaborators: Medical University of Vienna; Goethe University; Guy's and St Thomas' NHS Foundation Trust; University Hospital, Bonn; University of Plymouth; Johannes Gutenberg University Mainz; Johannes Kepler University of Linz; Wuerzburg University Hospital; East Lancashire Hospitals NHS Trust; The Queen Elizabeth Hospital; Erasme University Hospital; Krankenhaus Barmherzige Schwestern Linz; Centre Hospitalier Régional de la Citadelle; Klinikum Klagenfurt am Wörthersee; Barmherzige Brüder Vienna; Centre Hospitalier Universitaire de Charleroi; Hospital Barmherzige Brüder St. Veit; Kages; KABEG Management; Centre Hospitalier Universitaire Mons; Royal Bolton Hospital NHS Foundation Trust; Heartlands Hospital; Royal Oldham Hospital; The Royal Victoria Hospital, Belfast; Great Western Hospital; Musgrove Park Hospital; Scunthorpe General Hospital; Nottingham University Hospitals; Hospital Barmherzige Brüder Graz; Mid Yorkshire Teaching NHS Trust; University Hospital Kiel
• Investigators: Principal Investigator: Karin Amrein, MD, MSc, Medical University of Graz

Publications and helpful links

General Publications

• Amrein K, Schnedl C, Holl A, Riedl R, Christopher KB, Pachler C, Urbanic Purkart T, Waltensdorfer A, Munch A, Warnkross H, Stojakovic T, Bisping E, Toller W, Smolle KH, Berghold A, Pieber TR, Dobnig H. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014 Oct 15;312(15):1520-30. doi: 10.1001/jama.2014.13204. Erratum In: JAMA. 2014 Nov 12;312(18):1932.
• Amrein K, Christopher KB, McNally JD. Understanding vitamin D deficiency in intensive care patients. Intensive Care Med. 2015 Nov;41(11):1961-4. doi: 10.1007/s00134-015-3937-4. Epub 2015 Jul 4. No abstract available.
• Amrein K. Vitamin D status in critical care: Contributor or marker of poor health? Lung India. 2014 Jul;31(3):299-300. No abstract available.
• Amrein K, Papinutti A, Mathew E, Vila G, Parekh D. Vitamin D and critical illness: what endocrinology can learn from intensive care and vice versa. Endocr Connect. 2018 Dec 1;7(12):R304-R315. doi: 10.1530/EC-18-0184.
• Shakoor H, Feehan J, Al Dhaheri AS, Cheikh Ismail L, Ali HI, Alhebshi SH, Apostolopoulos V, Stojanovska L. Role of vitamin D supplementation in aging patients with COVID-19. Maturitas. 2021 Oct;152:63-65. doi: 10.1016/j.maturitas.2021.03.006. Epub 2021 Mar 16. No abstract available.
• Amrein K, Parekh D, Westphal S, Preiser JC, Berghold A, Riedl R, Eller P, Schellongowski P, Thickett D, Meybohm P; VITDALIZE Collaboration Group. Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: a study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study). BMJ Open. 2019 Nov 12;9(11):e031083. doi: 10.1136/bmjopen-2019-031083.
• National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Ginde AA, Brower RG, Caterino JM, Finck L, Banner-Goodspeed VM, Grissom CK, Hayden D, Hough CL, Hyzy RC, Khan A, Levitt JE, Park PK, Ringwood N, Rivers EP, Self WH, Shapiro NI, Thompson BT, Yealy DM, Talmor D. Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients. N Engl J Med. 2019 Dec 26;381(26):2529-2540. doi: 10.1056/NEJMoa1911124. Epub 2019 Dec 11.

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2017
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: June 13, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (Actual): June 15, 2017

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: critical care; COVID-19; vitamin D
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; COVID-19; Vitamin D Deficiency; Critical Illness; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: VITDALIZE 1.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No