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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)
  1. Karin Amrein1,
  2. Dhruv Parekh2,
  3. Sabine Westphal3,
  4. Jean-Charles Preiser4,
  5. Andrea Berghold5,
  6. Regina Riedl5,
  7. Philipp Eller6,
  8. Peter Schellongowski7,
  9. David Thickett2,8,
  10. Patrick Meybohm3,9
  11. the VITDALIZE Collaboration Group
    1. 1Department of Internal Medicine, Medical University of Graz, Graz, Austria
    2. 2Birmingham Acute Care Research Group, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
    3. 3Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
    4. 4Intensive Care Medicine, Erasme University Hospital, Brussels, Belgium
    5. 5Institute for Medical Informatics, Statstics, and Documentation, Medical University of Graz, Graz, Austria
    6. 6Intensive Care Unit, Department of Internal Medicine, University Hospital of Graz, Graz, Austria
    7. 7University Hospital of Internal Medicine I, Medical University Wien, Wien, Austria
    8. 8University of Birmingham School of Clinical and Experimental Medicine, Birmingham, UK
    9. 9Department of Anesthesiology, University Hospital Wuerzburg, Wuerzburg, Germany
    1. Correspondence to Dr Patrick Meybohm; patrick.meybohm{at}kgu.de

    Abstract

    Introduction Observational studies have demonstrated an association between vitamin D deficiency and increased risk of morbidity and mortality in critically ill patients. Cohort studies and pilot trials have suggested promising beneficial effects of vitamin D replacement in the critical ill, at least in patients with severe vitamin D deficiency. As vitamin D is a simple, low-cost and safe intervention, it has potential to improve survival in critically ill patients.

    Methods and analysis In this randomised, placebo-controlled, double-blind, multicentre, international trial, 2400 adult patients with severe vitamin D deficiency (25-hydroxyvitamin D≤12 ng/mL) will be randomised in a 1:1 ratio by www.randomizer.at to receive a loading dose of 540 000 IU cholecalciferol within 72 hours after intensive care unit (ICU) admission, followed by 4000 IU daily for 90 days or placebo. Hypercalcaemia may occur as a side effect, but is monitored by regular checks of the calcium level. The primary outcome is all-cause mortality at 28 days after randomisation. Secondary outcomes are: ICU, hospital, 90-day and 1-year mortality; hospital and ICU length of stay, change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment (SOFA) score, number of organ failures; hospital and ICU readmission until day 90; discharge destination, self-reported infections requiring antibiotics until day 90 and health-related quality of life. Recruitment status is ongoing.

    Ethics and dissemination National ethical approval was obtained by the Ethics Committee of the University of Graz for Austria, Erasme University Brussels (Belgium) and University Hospital Frankfurt (Germany), and will further be gained according to individual national processes. On completion, results will be published in a peer-reviewed scientific journal. The study findings will be presented at national and international meetings with abstracts online.

    Trial registration NCT03188796, EudraCT-No: 2016-002460-13.

    • vitamin D
    • critically ill patients
    • intensive care unit
    • vitamin D supplementation
    • severe vitamin D deficiency

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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    Footnotes

    • KA and DP are joint first authors.

    • DT and PM are joint senior authors.

    • Twitter @drdhruvparekh

    • Collaborators The VITDALIZE collaboration group will be listed as an author, and the names of the individual members of the group will be searchable through their individual PubMed records: AUSTRIA: Barmherzige Brueder, Vienna, Austria: Corinna Marschalek (corinna.marschalek@bbwiwn.at), Rene Schmutz (rene.schmutz@bbwien.at); Barmherzige Brueder, Linz, Austria: Martin Clodi (martin.clodi@bblinz.at), Michael Resl (michael.resl@bblinz.at); Ordensklinikum Linz, Austria: Mario Krasser (mario.krasser@ordensklinikum.at), Matthias Michlmayr (matthias.michlmayr@ordensklinikum.at), Johann Reisinger (johann.reisinger@ordensklinikum.at), Alexandra Schiller (alexandra.schiller@ordensklinikum.at); Medical University Graz, Austria: Nicolas Dominik Verheyen (nicolas.verheyen@medunigraz.at), Dirk von Lewinski (dirk.von-lewinski@medunigraz.at), Marlene Sandra Deininger (marlene.deininger@medunigraz.at), Andreas Muench (andreas.muench@medunigraz.at), Holger Simonis (holger.simonis@medunigraz.at), Paul Zajic (paul.zajic@medunigraz.at), Ines Lindenau (ines.lindenau@medunigraz.at), Philipp Eller (Philipp.eller@medunigraz.at), Alexander Holl (alexander.holl@klinikum-graz.at), Alexander Pichler (alexander.pichler@medunigraz.at), Tadeja Urbanic Purkart (tadeja.urbanic-purkart@medunigraz.at), Magdalena Hoffmann (Magdalena.hoffmann@medunigraz.at), Katharina Ritsch (katharina.ritsch@medunigraz.at), Simon Schmidt (simon.schmidt@medunigraz.at); Medical University Innsbruck, Austria: Romuald Bellmann (romuald.bellmann@tirol-kliniken.at), Anna Brandtner (anna.brandtner@tirol-kliniken.at), Adelheid Ditlbacher (adelheid.ditlbacher@tirol-kliniken.at), Julia Hasslacher (julia.hasslachen@tirol-kliniken.at), Michael Joannidis (michael.joannidis@i-med.ac.at), Andreas Peer (a.peer@tirol-kliniken.at), Klemens Zotter (klemens.zotter@tirol-kliniken.at); Kardinal Schwarzenberg Klinikum, Schwarzach, Austria: Christoph Martin Biedermann (christoph.biedermann@ks-klinikum.at), Andreas Valentin (andreas.valentin@ks-klinikum.at), Franz Wimmer (franz.wimmer@ks-klinikum.at); Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria: Susanne Demschar (susanne.demschar@kabeg.at), Markus Koestenberger (markus.koestenberger@kabeg.at), Rudolf Likar (rudolf.likar@kabeg.at), Stefan Neuwersch (stefan.neuwersch@kabeg.at), Michael Pogatschnigg (michael.pogatschnigg@kabeg.at), Brigitte Trummer (brigitte.trummer@kabeg.at); Kepler University Hospital, Linz, Austria: Martin Duenser (martin.duenser@keplerklinikum.at), Jens Meier (jens.meier@kepleruniklinikum.at); LKH Leoben, Standort Bruck/ Mur, Austria: Johann Kainz (johann.kainz@kages.at), Romana Sommer (romana.sommer@kages.at); LKH Graz II, Standort Enzenbach, Austria: Otmar Schindler (otmar.schindler@kages.at); LKH Feldbach, Austria: Alexander Lehr (alexander.lehr@kages.at), Guenter Mesaric (guenter.mesaric@kages.at), Yasmin Tinawi (yasmin.tinawi2@kages.at), Norbert Watzinger (norbert.watzinger@kages.at); LKH Fuerstenfeld, Austria: Randolf Hammerl (randolf.hammerl@kages.at), Peter Krippl (peter.krippl@kages.at), Stefan Langner (Stefan.langner@kages.at), Martin Lux (martin.lux@kages.at), Matthias Unteregger (matthias.unteregger@kages.at); LKH Hochsteiermark, Standort Leoben, Austria: Gerwig Fruehauf (gerwig.fruehauf@kages.at), Barbara Gruber (barbara.gruber@kages.at), Bertram Harzl (bertram.harzl@lkh-leoben.at), Viktor Wutzl (viktor.wutzl@kages.at); Barmherzige Brueder St.Veit/ Glan, Austria: Juergen Berghofer (juergen.berghofer@bbstveit.at), Nadine Fuch (nadine.fuchs@bbstveit.at), Gilbert Hainzl (gilbert.hainzl@bbstveit.at), Isolde Pessentheiner (Isolde.pessentheiner@bbst.veit.at), Michael Zink (michael.zink@bbstveit.at); LKH Villach, Austria: Petra Hoernler (petra.hoernler@kabeg.at), Ernst Trampitsch (ernst.trampitsch@kabeg.at); Medical University Vienna, Austria: Jakob Muehlbacher (jakob.muehlbacher@meduniwien.ac.at), Philipp Riss (philipp.riss@meduniwien.ac.at), Roman Ullrich (roman.ullrich@meduniwien.ac.at), Martin Bernardi (martin.bernardi@meduniwien.ac.at), Michael Hiesmayr (michael.hiesmayr@meduniwien.ac.at), Katharina Kovac (katharina.kovac@meduniwien.ac.at), Cecilia Veraar (cecilia.veraar@meduniwien.ac.at), Bernhard Zapletal (bernhard.zapletal@meduniwien.ac.at), Elisabeth Lobmeyr (elisabeth.lohmeyr@meduniwien.ac.at), Esther Tiller (estehr.tiller@meduniwien.ac.at); Wiener Krankenanstaltverband, Vienna, Austria: Georg Hinterholzer (georg.hinterholzer@wienkav.at), Daniel Mydza (daniel.mydza@wienkav.at), Sabine Schmaldienst (sabine.schmaldienst@wienkav.at).

      BELGIUM: CHU de Charleroi, Belgium: Maxime van Cutsem (maxime.vancutsem@chu-charleroi.be), CHU Ambroise Paré, Mons, Belgium: Marianne Blockmans (marianne.blockmans@hap.be), Alain D’hondt (alain.dhondt@hap.be); CHR Citadelle, Liège, Belgium: Vincent Fraipont (vincent.fraipont@chrcitadelle.be), Sophie Jacquet (sophie.jacquet@chrcitadelle.be); Erasme University Hospital, Brussels, Belgium: Caroline Abbenhuijs (caroline.abbenhuijs@erasme.ulb.ac.be); Katarina Halenarova (katarina.halenarova@erasme.ulb.ac.be), Romain Courcelle (romain.courcelle@erasme.ulb.ac.be), Dominique Durand (dominique.durand@erasme.ulb.ac.be), Amedee Ego (amedee.ego@erasme.ulb.ac.be), Amina Khaldi (amina.khaldi@erasme.ulb.ac.be), Itesa Nancy Matumikina (itesa.nancy.matumikina@erasme.ulb.ac.be).

      GERMANY: University Hospital Frankfurt, Germany: Kai Zacharowski (kai.zacharowski@kgu.de), Simone Lindau (simone.lindau@kgu.de), Philipp Helmer (philipp.helmer@kgu.de); University Hospital Schleswig-Holstein, Campus Kiel, Germany: Gunnar Elke (gunnar.elke@uksh.de), Norbert Weiler (norbert.weiler@uksh.de), Lars Hummitzsch (lars.hummitzsch@uksh.de), Guenther Zick (guenther.zick@uksh.de), Tobias Becher (tobias.becher@uksh.de), Dirk Schaedler (dirk.schaedler@uksh.de), Matthias Kott (matthias.kott@uksh.de), Barbara Vogt (barbara.vogt@uksh.de), Ingmar Lautenschlaeger (Ingmar.lautenschlaeger@uksh.de); University Hospital Schleswig-Holstein, Campus Luebeck, Germany: Georg Fuernau (georg.fuernau@uksh.de); University Hospital Bonn: Christian Putensen (Christian.putensen@ukb.uni-bonn.de), Stefan Ehrentraut (stefan.ehrentraut@ukb.uni-bonn.de), Maria Wittmann (maria.wittmann@ukbonn.de); Klinikum rechts der Isar, TUM, Munich, Germany: Barbara Kapfer (b.kapfer@tum.de); Muenchen Klinikum Neuperlach, Munich, Germany: Thomas Felbinger (thomas.felbinger@muenchen-klinik.de), Ines Kaufmann (ines.kaufmann@muenchen-klinik.de); HGZ Bad Bevensen, Germany: Bjoern Andrew Rempiss (ba.rempiss@hgz-bb.de); Charité-Universitaetsmedizin: Claudia Spiess (Claudia.spiess@charite.de), Stefan Schaller (stefan.schaller@charite.de); University Hospital Wuerzburg, Wuerzburg, Germany: Patrick Meybohm (meybohm_p@ukw.de), Peter Kranke (kranke_p@ukw.de), Tobias Schlesinger (schlesinge_t@ukw.de), Markus Kredel (kredel_m@ukw.de), Magdalena Sitter (sitter_m@ukw.de), Jan Stumpner (stumpner_j@ukw.de), Nico Schlegel (schlegel_n@ukw.de), Christoph Schimmer (schimmer_c@ukw.de), Ekkehard Kunze (kunze_e@ukw.de); Universitätsmedizin Mainz, Mainz, Germany: Thomas Kerz (thomas.kerz@unimedizin-mainz.de), Dominik Wesp (dominik.wesp@unimedizin-mainz.de), Axel Neulen (axel.neulen@unimedizin-mainz.de), Florian Ringel (florian.ringel@unimedizin-mainz.de); RWTH Aachen University Hospital, Aachen, Germany: Christian Stoppe (christian.stoppe@gmail.com);

      SWITZERLAND: University Hospital Zurich, Switzerland: Mario Maggiorini (mario.maggiorini@usz.ch); Bern University Hospital, Switzerland: Stephan Jakob (stephan.jakob@insel.ch), Joerg Schefold (joerg.schefold@insel.ch).

      UK: BCTU, Birmingham, UK: Rebekah Wale, (r.wale@bham.ac.uk); Gemma Slinn, (g.slinn@bham.ac.uk); Peter Brocklehurst, (p.brocklehurst@bham.ac.uk); Louise Jackson, (l.jackson.1@bham.ac.uk); Queen’s University Belfast, UK: Danny McAuley (d.f.mcauley@ qub.ac.uk); UHB, Birmingham, UK: Teresa Melody (teresa.melody@heartofengland.nhs.uk); Jaimin Patel (jaimin.patel@uhb.nhs.uk); Warwick University, UK: Gavin Perkins (g.d.perkins@warwick.ac.uk); GSTT, London, UK: Marlies Ostermann (marlies.ostermann@gstt.nhs.uk); Cardiff University, UK: Matthew Morgan (morganmjw@ cardiff.ac.uk); UCLH, London, UK: Mervyn Singer (msinger@ ucl.ac.uk); University of Oxford, UK: Matthew Rowland (matthew.rowland@ ndcn.ox.ac.uk)

    • Contributors All authors have substantially contributed to the interpretation of current specific knowledge, which resulted in the conception and design of the present trial. KA, DP, SW, JCP, PE, PS, DT and PM are investigators of the present trial and participated in the acquisition of funding and contribute to the collection of data. AB and RR wrote the statistical methods. All authors have been involved in drafting the manuscript or revising it critically for important intellectual content, and approved the final manuscript.

    • Funding This work is supported by the Federal Ministry of Education and Research (BMBF 01KG1815), the European Society of Intensive Care Medicine (ESICM), Fresenius Kabi and the National Institute for Health Research (NIHR).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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