Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 Nanogram(ng)/Kilogram(kg)/Minute(Min)) in Trauma Patients With Haemorrhagic Shock Induced Endotheliopathy.
Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 Nanogram(ng)/Kilogram(kg)/Minute(Min)) in Trauma Patients With Haemorrhagic Shock Induced Endotheliopathy.
A multicenter, randomized (1:1, iloprost: placebo), placebo controlled, blinded, investigator-initiated phase 2b trial in trauma patients with haemorrhagic shock and shock induced endotheliopathy (SHINE), investigating the efficacy and safety of continuous intravenous administrating of iloprost (1 ng/kg/min) versus placebo for 72-hours, in a total of 220 patients.
The study hypothesis is that iloprost may be beneficial as an endothelial rescue treatment as it is anticipated to deactivate the endothelium and restore vascular integrity in trauma patients with haemorrhagic shock (SHINE) suffering from organ failure caused by endothelial breakdown, ultimately improving survival.
The main objective in this trial is to investigate whether continuous infusion of iloprost at a dose of 1 ng/kg/min for 72-hours is safe and significantly increase the number of intensive care unit (ICU) free days, within 28 days from admission compared to infusion of placebo in trauma patients with haemorrhagic shock and SHINE.
Patients are presented at the investigator site in an acute critical condition and therefore informed consent will be obtained from a scientific guardian. Next-of-kin and subsequently the patient will co-sign as soon as possible. During the trial additional blood samples will be obtained daily for the first 72 hours. Patients will be observed and assessed continuously. During the extended follow up period at day 28 and 90, no contact will be made to the patient, but the data will be collected from department/hospital databases to establish length of stay and potential mortality.
The trial is conducted in accordance with the Helsinki 2 declaration and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline for Good Clinical Practice (ICH-GCP) and in compliance with the protocol. As part of the quality assurance site monitoring will be performed by an independent GCP-Unit including source data verification. Standard Operation Procedure to address protocol specific procedures such as data collection and adverse event reporting are developed.
The power calculation is based on not yet published data from the following trial 'Implementing Treatment Algorithms for the Correction of Trauma Induced Coagulopathy (iTACTIC)' [NTC 02593877] having the same in- and exclusion criteria as the present trial. The number of ICU free days within 30-days from admission is chosen as the primary endpoint and a clinically relevant increase in ICU free days within 28-days of 30% with α 0.05, power 0.85 will require 107 patients in each 1:1 randomization group. We plan on including 110 patients in each group and 220 in total. The final statistical analysis plan will be published before the last patient is included in the trial and analysis of the data from the randomized trial will be performed by Theis Lange, Associate Professor, Section of Biostatistics, Department of Public Health, University of Copenhagen.
The primary end point will be analyzed using linear regression adjusted for site. Effect size will be summarized using adjusted mean differences with confidence intervals based on robust standard errors as residuals are not expected to be normally distributed. The same analysis will be employed to continuous secondary outcomes. All-cause mortality will be further illustrated using Kaplan-Meier curves. All analysis will be conducted following the intention to treat principle (this will be the primary analysis) and per-protocol. In addition, the following patient subgroup will also be analyzed separately:
• Patients with traumatic brain injury
Inclusion Criteria:
Exclusion Criteria: