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

Официальное название

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)

Обзор

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.

Подробное описание

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.

Вмешательства

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

Первичные конечные точки

• 28-day mortality [Срок оценки: 28 days]

Вторичные конечные точки (3)

• Hospital Length of stay [Срок оценки: 90 days]
• Hypercalcemia at day 5 [Срок оценки: Day 5 - 48 hours tolerance]
• Hospital readmissions [Срок оценки: 90 days]

Критерии участия

Критерии включения

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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Австрия · 12 центров

• LKH Enzenbach — Enzenbach
• LKH Feldbach — Feldbach
• Medical University of Graz — Graz
• Klinikum am Wörthersee — Klagenfurt
• LKH Hochsteiermark Standort Leoben — Leoben
• Barmherzige Schwestern — Linz
• Kepler Universitätsklinikum Linz — Linz
• Krankenhaus Schwarzach — Schwarzach im Pongau
• … и ещё 4 центра

Бельгия · 4 центра

• Erasme Hospital — Brussels
• CHU de Charleroi — Charleroi
• CHR Citadelle — Liège
• CHU Ambroise Pare — Mons

Германия · 1 центр

• University Hospital Wuerzburg — Würzburg

Великобритания · 1 центр

• University of Birmingham — Birmingham

Публикации

• 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: 10.1 PMID 25268295
• 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
• 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
• 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
• 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):2529-2 PMID 31826336
• 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
• 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
• 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

Идентификаторы

NCT: NCT03188796 · VITDALIZE 1.0

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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