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.

BACKGROUND: Trauma 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. METHODS: TETHYS 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 h 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 h 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-ß = 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 biomarkers, 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. DISCUSSION: This 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 April 2017) and ClinicalTrials.gov, ID: NCT03338218 (09 November 2017).

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.

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.

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.

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.