Efficacy and safety of early target-controlled plasma volume replacement with a balanced gelatine solution versus a balanced electrolyte solution in patients with severe sepsis/septic shock: study protocol, design, and rationale of a prospective, randomized, controlled, double-blind, multicentric, international clinical trial : GENIUS-Gelatine use in ICU and sepsis

Gernot Marx, Kai Zacharowski, Carole Ichai, Karim Asehnoune, Vladimír Černý, Rolf Dembinski, Ricard Ferrer Roca, Dietmar Fries, Zsolt Molnar, Peter Rosenberger, Manuel Sanchez-Sanchez, Tobias Schürholz, Tamara Dehnhardt, Sonja Schmier, Elke von Kleist, Ute Brauer, Tim-Philipp Simon, Gernot Marx, Kai Zacharowski, Carole Ichai, Karim Asehnoune, Vladimír Černý, Rolf Dembinski, Ricard Ferrer Roca, Dietmar Fries, Zsolt Molnar, Peter Rosenberger, Manuel Sanchez-Sanchez, Tobias Schürholz, Tamara Dehnhardt, Sonja Schmier, Elke von Kleist, Ute Brauer, Tim-Philipp Simon

Abstract

Background: Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime.

Methods: This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90.

Discussion: This study aims to generate evidence regarding which regimen-a gelatine-crystalloid regimen or a pure crystalloid regimen-is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload.

Trial registration: The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466 . Registered on 17 March 2016.

Keywords: Capillary leakage; Colloids; Critically ill; Fluid management; Gelatine; Resuscitation; Sepsis.

Conflict of interest statement

Authors:

GM received grants/research support and honouraria/consultation fees from B. Braun Melsungen AG and Adrenomed and participated in company-sponsored speakers bureaus from B. Braun Melsungen AG, Edwards Life Sciences, Philips and Adrenomed. GM acted as coordinator of the S3 guideline on volume therapy for the Association of the Scientific Medical Societies in Germany (AWMF, see [11]).

KZ received research grants, advisory and lecture honouraria, and financial support (education) for his department from Aesculap Akademie GmbH, Affinites Sante, Ashai Kasai Pharma, B. Braun Melsungen AG, B. Braun Avitum AG, Bayer AG, Biotest AG, Christian Doppler Stiftung, CSL Behring GmbH, Cyto Sorbents GmbH, Edward Lifescience Corporation, Executive Insight AG, Fresenius Kabi GmbH, Fresenius Medical Care, Haemonetics Corporation, Hartmannbund Landesverband, Health Advances GmbH, Heinen+Löwenstein GmbH, Hexal AG, INC Research, Johnson & Johnson, Josef Gassner, Maquet GmbH, Markus Lücke Kongress Organisation, Masimo International, med update GmbH, Medizin & Markt Gesundheitsnetzwerk, MSD Sharp & Dohme GmbH, Nordic Group, Nordic Pharma, Novo Nordisk Pharma GmbH, Pfizer Pharma GmbH, Pharmacosmos, Ratiopharm GmbH, Salvia Medical GmbH, Schering Stiftung, Schöchl Medical Österreich, Serumwerke, Verlag für Printmedien und PR, Forum Sanitas, Vifor Pharma GmbH, Wellington, Werfen.

CI received reimbursement of registration fees and travel expenses for congress participation by B. Braun Melsungen AG and Baxter, as well as honouraria for participation in expert meetings by Fresenius.

KA received lecture honouraria from Fresenius, Baxter, LFB and Boehringer.

VC received lecture honouraria from Fresenius, B. Braun Melsungen AG, CSL Behring, AOP Orphan, Bard, AbbVie.

RD received advisory fees from B. Braun Melsungen AG.

RF received speaker fees and advisory fees from B. Braun Melsungen AG and Grifols.

DF received honouraria for consulting, lecture fees, and sponsoring for academic studies from Baxter, B. Braun Melsungen AG, CSL Behring, Instrumental Laboratories, LFB, Mitsubishi Pharma, Octapharm, Takeda and Tem-Innovation.

ZM was a member of the Pulsion medical advisory board and received lecture honouraria from Pulsion-Maquet (member of the Getinge Group), Biotest, CytoSorbents, and ThermoFisher. Currently, he is a member of the medical directors of CytoSorbents Europe

PR declares that he has no competing interests.

MS declares that he has no competing interests.

TS received restricted grants from B. Braun Melsungen AG, Fresenius Kabi Deutschland GmbH and Fresenius Medical GmbH, Germany.

TD (Director Clinical Development Plasma Volume Replacement), SSch (Senior Scientific Manager Clinical Development), EvK (Vice President Preclinical and Clinical Development), and UB (Chief Medical Officer) are employed by B. Braun Melsungen AG.

TPS received research grants and lecture honouraria from B. Braun Melsungen AG.

DSMB Members:

The DRS academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland; the Swiss Society of Anaesthesiology and Reanimation (SGAR), Berne, Switzerland; the Swiss Foundation for Anaesthesia Research, Zurich, Switzerland; Vifor SA, Villars-sur-Glâne, Switzerland; and Vifor (International) AG, St. Gallen, Switzerland. DRS 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. DRS received honouraria/travel support for consulting or lecturing from: Danube University of Krems, Austria; US Department of Defense, Washington, USA; European Society of Anaesthesiology, 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, New Jersey, 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.

PFL received honouraria consultation with B. Braun Melsungen AG, Melsungen, Germany.

HS is employed by Pharmalog –Institut für klinische Forschung and contracted by B. Braun Melsungen AG, Melsungen, Germany, for statistical consulting services.

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