Clinical trial NCT03903939: Infusion of Prostacyclin vs Placebo for 72-hours in Trauma Patients With Haemorrhagic Shock Suffering From Organ Failure
Official title: Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 Nanogram(ng)/Kilogram(kg)/Minute(Min)) in Trauma Patients With Haemorrhagic Shock Induced Endotheliopathy.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multi Organ Failure
Keywords: Trauma patients
Shock-induced endotheliopathy
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Aarhus University Hospital
name: Aalborg University Hospital
name: Oslo University Hospital
First posted: 2019-04-04
Enrollment: 228
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Present with clinical signs of hemorrhagic shock (defined by systolic blood pressure \<90 millimetre of mercury (mmHg) or use of pre-hospital blood transfusion).
* Activation of local massive transfusion protocol and initiation of the first transfusion after admission.
* Randomised within 5 hours of injury and 3 hours of admission to the emergency department of the participating trial site.
* Consent is provided on behalf of incapacitated patients by Scientific Guardian

Exclusion Criteria:

* Withdrawal from active therapy
* Known hypersensitivity to Iloprost.
* Pregnancy (non-pregnancy confirmed by patient having a negative urine or plasma choriogonadotropin (hCG) or being postmenopausal defined as females at 60 years old and beyond)
* Known severe heart failure (New York Heart Association (NYHA) class IV)
* Suspected acute coronary syndrome
* Estimated weight \< 40 kg

Primary outcomes:
measure: ICU free days
timeFrame: 28 days after admission
Secondary outcomes:
measure: All-cause mortality
timeFrame: 90 days after admission
measure: Hospital length of stay
timeFrame: 90 days after admission
measure: Vasopressor free days
timeFrame: 28 days after admission
measure: Ventilator free days
timeFrame: 28 days after admission
measure: Renal replacement free days
timeFrame: 28 days after admission
measure: Serious adverse reactions
timeFrame: 4 days after randomization
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet (University of Copenhagen)
city: Odense
country: Denmark
facility: Odense University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
Study officials:
affiliation: University of Copenhagen (Rigshospitalet)
name: Pär I Johansson, MD, MPA
role: STUDY_DIRECTOR
References:
citation: Johansson PI, Eriksen CF, Schmal H, Gaarder C, Pall M, Henriksen HH, Bovbjerg P, Lange T, Naess PA, Nielsen C, Kirkegaard H, Stensballe J. Efficacy and safety of iloprost in trauma patients with haemorrhagic shock-induced endotheliopathy-Protocol for the multicentre randomized, placebo-controlled, blinded, investigator-initiated shine-trauma trial. Acta Anaesthesiol Scand. 2021 Apr;65(4):551-557. doi: 10.1111/aas.13776. Epub 2021 Jan 11.