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

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ClinicalTrials.gov Identifier: NCT03188796
Recruitment Status : Recruiting
First Posted : June 15, 2017
Last Update Posted : July 23, 2018
Sponsor:
Collaborators:
Medical University of Vienna
Medical University Innsbruck
Hospital Barmherzige Brüder St. Veit
Klinikum Klagenfurt am Wörthersee
Johannes Kepler University of Linz
Salzburger Landeskliniken
Krankenhaus Barmherzige Schwestern Linz
Barmherzige Brüder Vienna
Erasme University Hospital
University of Birmingham
University Hospital, Frankfurt
Information provided by (Responsible Party):
Medical University of Graz

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.


Condition or disease Intervention/treatment Phase
Critical Illness Vitamin D Deficiency Drug: Cholecalciferol Drug: Placebo Phase 3

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  (Clinical Trial)
Estimated Enrollment : 2400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 10, 2017
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : February 2021

Resource links provided by the National Library of Medicine


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 Name: Vitamin D3




Primary Outcome Measures :
  1. 28-day mortality [ Time Frame: 28 days ]
    all-cause mortality


Secondary Outcome Measures :
  1. Hospital Length of stay [ Time Frame: 90 days ]
    Length of stay in days

  2. Hypercalcemia at day 5 [ Time Frame: Day 5 - 48 hours tolerance ]
  3. Hospital readmissions [ Time Frame: 90 days ]
    Number of readmissions



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03188796


Contacts
Contact: Karin Amrein, MD, MSc +43 316 385 ext 80798 karin.amrein@medunigraz.at
Contact: Astrid Friedel +43 316 385 ext 72061 astrid.friedel@medunigraz.at

Locations
Austria
Medical University of Graz Recruiting
Graz, Austria
Contact: Karin Amrein, MD, MSc         
Medical University Innsbruck Not yet recruiting
Innsbruck, Austria
Contact: Michael Joannidis, MD         
Klinikum am Wörthersee Recruiting
Klagenfurt, Austria
Contact: Rudolf Likar, MD         
Barmherzige Schwestern Recruiting
Linz, Austria
Contact: Johann Reisinger, MD         
Salzburger Landeskliniken Not yet recruiting
Salzburg, Austria
Contact: Daniel Dankl, MD         
Krankenhaus Schwarzach Not yet recruiting
Schwarzach Im Pongau, Austria
Contact: Franz Wimmer, MD         
Barmherzige Brüder Not yet recruiting
Vienna, Austria
Contact: Rene Schmutz, MD         
Medical University of Vienna Recruiting
Vienna, Austria
Contact: Peter Schellongowski, MD         
Sponsors and Collaborators
Medical University of Graz
Medical University of Vienna
Medical University Innsbruck
Hospital Barmherzige Brüder St. Veit
Klinikum Klagenfurt am Wörthersee
Johannes Kepler University of Linz
Salzburger Landeskliniken
Krankenhaus Barmherzige Schwestern Linz
Barmherzige Brüder Vienna
Erasme University Hospital
University of Birmingham
University Hospital, Frankfurt
Investigators
Principal Investigator: Karin Amrein Medical University of Graz

Publications:
Responsible Party: Medical University of Graz
ClinicalTrials.gov Identifier: NCT03188796     History of Changes
Other Study ID Numbers: VITDALIZE 1.0
First Posted: June 15, 2017    Key Record Dates
Last Update Posted: July 23, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Medical University of Graz:
vitamin D
critical care

Additional relevant MeSH terms:
Vitamin D Deficiency
Vitamins
Vitamin D
Critical Illness
Disease Attributes
Pathologic Processes
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders
Ergocalciferols
Cholecalciferol
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents