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

Covid19 Clinical Trial

— VITDALIZE  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03188796
• Other study ID #: VITDALIZE 1.0
• Status: Recruiting
• Phase: Phase 3
• Start date: October 10, 2017
• Est. completion date: March 2025

Study information

• Verified date: May 2024
• Source: Medical University of Graz
• Contact: Karin Amrein, MD, MSc
• Phone: +43 681
• Email: karin.amrein[@]medunigraz.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2400
• Est. completion date: March 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• Covid19
• Critical Illness
• Vitamin D Deficiency

Intervention

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

Locations

Country	Name	City	State
Austria	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
Belgium	Erasme Hospital	Brussel
Belgium	CHU de Charleroi	Charleroi
Belgium	CHR Citadelle	Liège
Belgium	CHU Ambroise Pare	Mons

Sponsors (35)

Lead Sponsor

Collaborator

Medical University of Graz

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

Countries where clinical trial is conducted

Austria,  Belgium, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	28-day mortality	all-cause mortality	28 days
Secondary	Hospital Length of stay	Length of stay in days	90 days
Secondary	Hypercalcemia at day 5		Day 5 - 48 hours tolerance
Secondary	Hospital readmissions	Number of readmissions	90 days