Prospective, randomized, controlled, double-blind, multi-center, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) sOlution versus an Electrolyte solutioN In patients undergoing eleCtive abdominal Surgery: study protocol for the PHOENICS study

Abstract

Background: Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss and to maintain hemodynamic stability. This study was requested by the European Medicines Agency (EMA) to provide more evidence on the long-term safety and efficacy of HES solutions in the perioperative setting.

Methods: PHOENICS is a randomized, controlled, double-blind, multi-center, multinational phase IV (IIIb) study with two parallel groups to investigate non-inferiority regarding the safety of a 6% HES 130 solution (Volulyte 6%, Fresenius Kabi, Germany) compared with a crystalloid solution (Ionolyte, Fresenius Kabi, Germany) for infusion in patients with acute blood loss during elective abdominal surgery. A total of 2280 eligible patients (male and female patients willing to participate, with expected blood loss ≥ 500 ml, aged > 40 and ≤ 85 years, and ASA Physical status II-III) are randomly assigned to receive either HES or crystalloid solution for the treatment of hypovolemia due to surgery-induced acute blood loss in hospitals in up to 11 European countries. The dosing of investigational products (IP) is individualized to patients' volume needs and guided by a volume algorithm. Patients are treated with IP for maximally 24 h or until the maximum daily dose of 30 ml/kg body weight is reached. The primary endpoint is the treatment group mean difference in the change from the pre-operative baseline value in cystatin-C-based estimated glomerular filtration rate (eGFR), to the eGFR value calculated from the highest cystatin-C level measured during post-operative days 1-3. Further safety and efficacy parameters include, e.g., combined mortality/major post-operative complications until day 90, renal function, coagulation, inflammation, hemodynamic variables, hospital length of stay, major post-operative complications, and 28-day, 90-day, and 1-year mortality.

Discussion: The study will provide important information on the long-term safety and efficacy of HES 130/0.4 when administered according to the approved European product information. The results will be relevant for volume therapy of surgical patients.

Trial registration: EudraCT 2016-002162-30 . ClinicalTrials.gov NCT03278548.

Keywords: Blood loss; Colloids; Double-blinded; HES; Hydroxyethyl starch; Multi-center; Multinational; Non-inferiority trial; Randomized controlled trial; Safety; Surgery; Volume therapy.

Conflict of interest statement

Wolfgang Buhre is a member of the Steering Committee of the Prodigy Study (sponsored by Medtronic), POSE Study (supported by ESAIC), Designation Study (supported with a grant from ZonMw), and PI of the AMAZONE study (supported with grants from the Dutch Cancer Society and ESAIC). Ute Brauer, Tamara Dehnhardt, and Sonja Schmier are employees of B. Braun Melsungen AG. Martin Westphal is and Jean-Francois Baron was an employee of Fresenius Kabi. Thomas Scheeren received research grants and honoraria from Edwards Lifesciences (Irvine, CA, USA) and Masimo Inc. (Irvine, CA, USA) for consulting and lecturing and from Pulsion Medical Systems SE (Feldkirchen, Germany) for lecturing (all payments made to the institution). Matthias Grunewald has received honoraria from CSL Behring, GE Healthcare, Gruenenthal, and Vifor Pharma (all unrelated to the PHOENICS study). Donald Spahn’s department is receiving grant support from Swiss National Science Foundation, the Swiss Society of Anesthesiology and Reanimation (SGAR), the Swiss Foundation for Anesthesia Research, Vifor SA, and Vifor (International) AG, Switzerland. Dr. Spahn is co-chair of the ABC-Trauma Faculty, sponsored by unrestricted educational grants from Novo Nordisk Health Care AG, Zurich, Switzerland; CSL Behring GmbH, Marburg, Germany; LFB Biomédicaments, Courtaboeuf Cedex, France; and Octapharma AG, Lachen, Switzerland. Dr. Spahn received honoraria/travel support for consulting or lecturing from Danube University of Krems, Austria; US Department of Defense, Washington, USA; European Society of Anesthesiology, Brussels, BE; Korean Society for Patient Blood Management, Seoul, Korea; Korean Society of Anesthesiologists, Seoul, Korea; Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis, Paris, France; Baxalta Switzerland AG, Volketswil, Switzerland; Bayer AG, Zürich, Switzerland; B. Braun Melsungen AG, Melsungen, Germany; Boehringer Ingelheim GmbH, Basel, Switzerland; Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France and Baar, Switzerland; CSL Behring GmbH, Hattersheim am Main, Germany, and Berne, Switzerland; Celgene International II Sàrl, Couvet, Switzerland; Daiichi Sankyo AG, Thalwil, Switzerland; Haemonetics, Braintree, MA, USA; Instrumentation Laboratory (Werfen), Bedford, MA, USA; LFB Biomédicaments, Courtaboeuf Cedex, France; Merck Sharp & Dohme, Kenilworth, NJ, USA; PAION Deutschland GmbH, Aachen, Germany; Pharmacosmos A/S, Holbaek, Denmark; Pfizer AG, Zürich, Switzerland; Pierre Fabre Pharma, Alschwil, Switzerland, Portola Schweiz GmbH, Aarau, Switzerland; Roche Diagnostics International Ltd., Reinach, Switzerland; Sarstedt AG & Co., Sevelen, Switzerland and Nümbrecht, Germany; Shire Switzerland GmbH, Zug, Switzerland; Tem International GmbH, Munich, Germany; Vifor Pharma, Munich, Germany; Neuilly sur Seine, France and Villars-sur-Glâne, Switzerland; Vifor (International) AG, St. Gallen, Switzerland; and Zuellig Pharma Holdings, Singapore, Singapore. All other authors declare that they have no competing interests.

© 2022. The Author(s).