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

NCT03188796 | Recruiting Phase 3 DMC

• 1 other identifier: VITDALIZE 1.0
• Study Type: interventional
• Target: 2,400
• Locations: 4 countries
• Sites: 18

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.

Conditions

Critical Illness; Vitamin D Deficiency; Covid19

Keywords

vitamin D; critical care; COVID-19

Outcome Measures

Primary Outcomes (1)

• 28-day mortality

  all-cause mortality

  28 days

Secondary Outcomes (3)

• Hospital Length of stay

  90 days

• Hypercalcemia at day 5

  Day 5 - 48 hours tolerance

• Hospital readmissions

  90 days

Study Arms (2)

Placebo

PLACEBO COMPARATOR

oral/enteral loading dose of 37.5 ml MCT followed by 10 drops daily for 90 days

Drug: Placebo

High Dose Vitamin D3

EXPERIMENTAL

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

Interventions

Cholecalciferol DRUG

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

Also known as: Vitamin D3

High Dose Vitamin D3

Placebo DRUG

oral/enteral loading dose of 37.5 ml MCT followed by 10 drops daily for 90 days

Placebo

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical University of Graz: lead
• Medical University of Vienna: collaborator
• Hospital Barmherzige Brüder St. Veit: collaborator
• Klinikum Klagenfurt am Wörthersee: collaborator
• Johannes Kepler University of Linz: collaborator
• Krankenhaus Barmherzige Schwestern Linz: collaborator
• Barmherzige Brüder Vienna: collaborator
• Erasme University Hospital: collaborator
• The Queen Elizabeth Hospital: collaborator
• Goethe University: collaborator
• Kages: collaborator
• KABEG Management: collaborator
• Centre Hospitalier Régional de la Citadelle: collaborator
• Centre Hospitalier Universitaire de Charleroi: collaborator
• Centre Hospitalier Universitaire Mons: collaborator
• Wuerzburg University Hospital: collaborator
• Royal Bolton Hospital NHS Foundation Trust: collaborator
• Heartlands Hospital: collaborator
• Royal Oldham Hospital: collaborator
• East Lancashire Hospitals NHS Trust: collaborator
• University of Plymouth: collaborator
• Royal Victoria Hospital, Belfast: collaborator
• Great Western Hospital: collaborator
• Mid Yorkshire Teaching NHS Trust: collaborator
• Musgrove Park Hospital: collaborator
• Scunthorpe General Hospital: collaborator
• Guy's and St Thomas' NHS Foundation Trust: collaborator
• Nottingham University Hospitals: collaborator
• Hospital Barmherzige Brüder Graz: collaborator
• University Hospital Kiel: collaborator
• University Hospital, Bonn: collaborator
• Johannes Gutenberg University Mainz: collaborator
• University Hospital, Essen: collaborator
• Klinikum rechts der Isar der TUM: collaborator
• Landeskrankenhaus Villach: collaborator

Study Sites (18)

LKH Enzenbach

Enzenbach, Austria

RECRUITING

LKH Feldbach

Feldbach, Austria

TERMINATED

Medical University of Graz

Graz, Austria

RECRUITING

Klinikum am Wörthersee

Klagenfurt, Austria

RECRUITING

LKH Hochsteiermark Standort Leoben

Leoben, Austria

RECRUITING

Barmherzige Schwestern

Linz, Austria

RECRUITING

Kepler Universitätsklinikum Linz

Linz, Austria

RECRUITING

Krankenhaus Schwarzach

Schwarzach im Pongau, Austria

TERMINATED

Barmherzige Brüder

Vienna, Austria

RECRUITING

Kaiser Franz Josef Spital Wien

Vienna, Austria

SUSPENDED

Medical University of Vienna

Vienna, Austria

RECRUITING

LKH Villach

Villach, Austria

RECRUITING

Erasme Hospital

Brussels, Belgium

TERMINATED

CHU de Charleroi

Charleroi, Belgium

TERMINATED

CHR Citadelle

Liège, Belgium

TERMINATED

CHU Ambroise Pare

Mons, Belgium

TERMINATED

University Hospital Wuerzburg

Würzburg, Germany

RECRUITING

University of Birmingham

Birmingham, United Kingdom

RECRUITING

Related Publications (9)

• 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.

  PMID: 25268295 BACKGROUND

• 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.

  PMID: 26142054 BACKGROUND

• 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.

  PMID: 25125826 BACKGROUND

• 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.

  PMID: 30352414 BACKGROUND

• 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.

  PMID: 31826336 BACKGROUND

• Kobayashi H, Amrein K, Mahmoud SH, Lasky-Su JA, Christopher KB. Metabolic phenotypes and vitamin D response in the critically ill: A metabolomic cohort study. Clin Nutr. 2024 Nov;43(11):10-19. doi: 10.1016/j.clnu.2024.09.030. Epub 2024 Sep 18.

  PMID: 39307095 BACKGROUND

• Geiger C, McNally JD, Christopher KB, Amrein K. Vitamin D in the critically ill - update 2024. Curr Opin Clin Nutr Metab Care. 2024 Nov 1;27(6):515-522. doi: 10.1097/MCO.0000000000001068. Epub 2024 Aug 26.

  PMID: 39302310 BACKGROUND

• 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.

  PMID: 33757717 DERIVED

• 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.

  PMID: 31722941 DERIVED

MeSH Terms

Conditions

Critical Illness; Vitamin D Deficiency; COVID-19

Interventions

Cholecalciferol

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids

Study Officials

• Karin Amrein, MD, MSc

  Medical University of Graz

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Karin Amrein, MD, MSc

CONTACT

+43 681; karin.amrein@medunigraz.at

Astrid Friedel

CONTACT

+43 316 385; astrid.friedel@medunigraz.at

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2017
• First Posted: June 15, 2017
• Study Start: October 10, 2017
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: November 21, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1); BE (4); AU (12); GB (1)