Clinical trial NCT03188796: The VITDALIZE Study: Effect of High-dose Vitamin D3 on 28-day Mortality in Adult Critically Ill Patients
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Critical Illness
Vitamin D Deficiency
Covid19
Keywords: vitamin D
critical care
COVID-19
Lead sponsor: Medical University of Graz
Sponsor class: OTHER
Collaborators: name: Medical University of Vienna
name: Hospital Barmherzige Brüder St. Veit
name: Klinikum Klagenfurt am Wörthersee
name: Johannes Kepler University of Linz
name: Krankenhaus Barmherzige Schwestern Linz
name: Barmherzige Brüder Vienna
name: Erasme University Hospital
name: The Queen Elizabeth Hospital
name: Goethe University
name: Kages
name: KABEG Management
name: Centre Hospitalier Régional de la Citadelle
name: Centre Hospitalier Universitaire de Charleroi
name: Centre Hospitalier Universitaire Mons
name: Wuerzburg University Hospital
name: Royal Bolton Hospital NHS Foundation Trust
name: Heartlands Hospital
name: Royal Oldham Hospital
name: East Lancashire Hospitals NHS Trust
name: University of Plymouth
name: Royal Victoria Hospital, Belfast
name: Great Western Hospital
name: Mid Yorkshire Teaching NHS Trust
name: Musgrove Park Hospital
name: Scunthorpe General Hospital
name: Guy's and St Thomas' NHS Foundation Trust
name: Nottingham University Hospitals
name: Hospital Barmherzige Brüder Graz
name: University Hospital Kiel
name: University Hospital, Bonn
name: Johannes Gutenberg University Mainz
name: University Hospital, Essen
name: Klinikum rechts der Isar der TUM
name: Landeskrankenhaus Villach
First posted: 2017-06-15
Enrollment: 2400
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 28-day mortality
timeFrame: 28 days
Secondary outcomes:
measure: Hospital Length of stay
timeFrame: 90 days
measure: Hypercalcemia at day 5
timeFrame: Day 5 - 48 hours tolerance
measure: Hospital readmissions
timeFrame: 90 days
Other outcomes:
Locations:
city: Enzenbach
country: Austria
facility: LKH Enzenbach
city: Feldbach
country: Austria
facility: LKH Feldbach
city: Graz
country: Austria
facility: Medical University of Graz
city: Klagenfurt
country: Austria
facility: Klinikum am Wörthersee
city: Leoben
country: Austria
facility: LKH Hochsteiermark Standort Leoben
city: Linz
country: Austria
facility: Barmherzige Schwestern
city: Linz
country: Austria
facility: Kepler Universitätsklinikum Linz
city: Schwarzach Im Pongau
country: Austria
facility: Krankenhaus Schwarzach
city: Vienna
country: Austria
facility: Barmherzige Brüder
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Villach
country: Austria
facility: LKH Villach
city: Wien
country: Austria
facility: Kaiser Franz Josef Spital Wien
city: Brussel
country: Belgium
facility: Erasme Hospital
city: Charleroi
country: Belgium
facility: CHU de Charleroi
city: Liège
country: Belgium
facility: CHR Citadelle
city: Mons
country: Belgium
facility: CHU Ambroise Pare
city: Würzburg
country: Germany
facility: University Hospital Wuerzburg
city: Birmingham
country: United Kingdom
facility: University of Birmingham
Study officials:
affiliation: Medical University of Graz
name: Karin Amrein, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
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.
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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.