PragmaTic, ProspEctive, Randomized, Controlled, Double-Blind, MulTi-Centre, Multinational Study on the Safety and Efficacy of a 6% HydroxYethyl Starch (HES) Solution Versus an Electrolyte Solution in Trauma Patients: Study Protocol for the TETHYS Study

Research Square

Abstract

Abstract BackgroundTrauma may be associated with significant to life-threatening blood loss, which in turn may increase the risk of complications and death, particularly in the absence of adequate treatment. Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss to maintain or re-establish hemodynamic stability with the ultimate goal to avoid organ hypoperfusion and cardiovascular collapse. The current study compares a 6% HES 130 solution (Volulyte 6%) versus an electrolyte solution (Ionolyte) for volume replacement therapy in adult patients with traumatic injuries, as requested by the European Medicines Agency to gain more insights into the safety and efficacy of HES in the setting of trauma care. MethodsTETHYS is a pragmatic, prospective, randomized, controlled, double-blind, multicenter, multinational trial performed in two parallel groups. Eligible consenting adults >18 years, with an estimated blood loss of ≥ 500 ml, and in whom initial surgery is deemed necessary within 24 hours after blunt or penetrating trauma, will be randomized to receive intravenous treatment at an individualized dose with either a 6% HES 130, or an electrolyte solution, for a maximum of 24 hours or until reaching the maximum daily dose of 30 ml/kg body weight, whatever occurs first. Sample size is estimated as 175 patients per group, 350 patients total (α=0.025 one-tailed, power 1–β=0.8). Composite primary endpoint evaluated in an exploratory manner will be 90-day mortality and 90-day renal failure, defined as AKIN stage ≥ 2, RIFLE injury/failure stage, or use of renal replacement therapy (RRT) during the first 3 months. Secondary efficacy and safety endpoints are fluid administration and balance, changes in vital signs and hemodynamic status, changes in laboratory parameters including renal function, coagulation, and inflammation biomarker, incidence of adverse events during treatment period, hospital, and intensive care unit (ICU) length of stay, fitness for ICU or hospital discharge, and duration of mechanical ventilation and/or RRT. DiscussionThis pragmatic study will increase the evidence on safety and efficacy of 6% HES 130 for treatment of hypovolemia secondary to acute blood loss in trauma patients. Trial registration Registered in EudraCT, No.: 2016-002176-27 (21/04/2017) and ClinicalTrials.gov, ID: NCT03338218 (09/11/2017)Abstract word count: 349 (max 350)Trial status Recruitment phase, as of 02/12/2021. End of recruitment is expected by 30/04/2022

Authors 17

1. Clementina Duran Palma
   Affiliation as printed

   Trident Clinical Northern Cape Clinical Research Site

2. Musawenkosi Mamba
   Affiliation as printed

   Gama Research Center

3. Johan Geldenhuys
   Affiliation as printed

   FCRN Clinical Trials Centre

4. Oluwafolajimi Fadahun
   Affiliation as printed

   Gama Research Centre, Leratong Hospital

5. Rolf Rossaint Aachen

   Universitätsklinikum Aachen

   Affiliation as printed

   Uniklinik RWTH Aachen

6. Kai D. Zacharowski

   Goethe University Frankfurt

   Affiliation as printed

   University of Frankfurt

7. Martin Brand

   Steve Biko Hospital

   Affiliation as printed

   Steve Biko Academic Hospital

8. Óscar Díaz‐Cambronero

   Hospital Universitari i Politècnic La Fe

   Affiliation as printed

   Hospital La Fe

9. Francisco Javier Belda

   Hospital Universitari i Politècnic La Fe

   Affiliation as printed

   Hospital La Fe

10. Martin Westphal

    Fresenius (Germany)

    Affiliation as printed

    Fresenius Kabi Deutschland GmbH

11. Ute Brauer

    B. Braun (Germany) · B. Braun (Netherlands)

    Affiliation as printed

    B Braun Melsungen AG

12. Tamara Dehnhardt

    B. Braun (Germany) · B. Braun (Netherlands)

    Affiliation as printed

    B Braun Melsungen AG

13. Martin Hernandez-Gonzalez

    Fresenius (Germany)

    Affiliation as printed

    Fresenius Kabi Deutschland GmbH

14. Sonja Schmier

    Chris Hani Baragwanath Hospital · Maastricht University Medical Centre · Maastricht University · B. Braun (Germany) · B. Braun (Netherlands)

    Affiliation as printed

    B Braun Melsungen AG

    Chris Hani Baragwanath Hospital

    Dianne de Korte-de Boer Maastricht University Hospital

    Fresenius Kabi Deutschland

    Maastricht University Hospital

15. Dianne de Korte‐de Boer

    Maastricht University Medical Centre · Maastricht University

    Affiliation as printed

    Maastricht University Hospital

16. Frank Plani

    Chris Hani Baragwanath Hospital · Maastricht University Medical Centre · Maastricht University

    Affiliation as printed

    Chris Hani Baragwanath Hospital

    Dianne de Korte-de Boer Maastricht University Hospital

    Fresenius Kabi Deutschland

    Maastricht University Hospital

17. Wolfgang Bühre corresponding

    Chris Hani Baragwanath Hospital · Maastricht University Medical Centre · Maastricht University

    Affiliation as printed

    Maastricht University Hospital

    Chris Hani Baragwanath Hospital

    Dianne de Korte-de Boer Maastricht University Hospital

    Fresenius Kabi Deutschland