Pre-hospital Administration of Lyophilized Plasma for Post-traumatic Coagulopathy Treatment (PREHO-PLYO)

Study Overview
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Brief Summary
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In severe bleeding due to trauma, a decrease in coagulation factors maintains and promotes bleeding. The plasma allows, through its contribution of coagulation factors, early prevention or correction of this post-trauma induced coagulopathy. This study aims to measure the effectiveness of pre-hospital FLYP administration in case of traumatic hemorrhagic shock, in the occurrence or the treatment of a post traumatic induced coagulopathy. Study Design This is a randomized controlled multicenter open label study in two parallel groups. Eligibility criteria : adult, victim of a hemorrhagic shock of traumatic origin with [systolic blood pressure <70 mmHg] or Shock Index >1.1 The patients will receive either FLYP either the usual treatment as given in the recommendations for best practice. The primary endpoint is the International Normalized Ratio (INR) at hospital admission. The study must confirm the link between causality of early administration of plasma in improving post-traumatic coagulopathy. The study must show safe usage in out-of-hospital situations and the ability of medical staff to meet the requirements of the health authorities in terms of product use as well as in terms of traceability of the victims and the treatment they received.

Detailed Description
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In severe bleeding due to trauma, a fall in coagulation factors maintains and promotes bleeding. The plasma allows, through its contribution of coagulation factors, early prevention or correction of this post-traumatic coagulopathy. This labile blood product has so far only been used in armed conflicts by military medical and surgical units deployed in External Operations (EXOP) to meet the logistical constraints of the operating environment and the need to have, without delay, therapeutic plasma to treat bleeding casualties. Unlike frozen plasma used in hospitals, FLYP is stored at room temperature and is reconstituted in less than 6 mins. In the civilian world, FLYP could be used by health institutions who have major logistical difficulties which do not allow them to ensure a cold chain of sub-zero temperatures, or in extreme emergency situations with the need for an immediate therapeutic plasma supply. In this second indication, FLYP should be used until the fresh frozen plasma is thawed and available. Its use in pre-hospital situations is also justified due to its immediate availability and storage conditions. FLYP is sterile and is in powder-form with a residual humidity not exceeding 2%. It is packaged in a sterile and pyrogenic glass vial. The main objective is to measure the effectiveness of pre-hospital FLYP administration in case of traumatic hemorrhagic shock, in the occurrence or the treatment of a post traumatic coagulopathy. The secondary objectives consist in assessing the following outcomes : (1) the need for massive transfusion (3) the ICU length of stay (4) the survival rate on day 30 (5) FLYP prehospital usability in civilian population (the compilation of technical and logistical difficulties encountered with administration of FLYP) (6) the Prothrombin time (PT) at hospital admission. Normal values for PT are 70 - 130%. (7) the fibrinogen level at hospital admission (8) the variation in the level of PT, between the pre-hospital setting and the hospital admission . (9) the variation in the level of INR, between the pre-hospital setting and the hospital admission . (10) the variation in the fibrinogen level between the pre-hospital setting and the hospital admission . Method The attribution of the experimental treatment (FLYP or saline), to each patient who will receive a treatment numbered from 1 to 140, was carried out in advance using STATA 14.0 software. Type of randomisation : randomisation in blocks of 2, stratified by center. Treatments are allocated to participants in each pre-hospital center by ascending number. Participants and investigators are therefore not blinded to the allocated treatment.However, the statistical analysis is planned to be carried out as a blind study regarding knowledge of the allocated treatment. The planned experimental design is identical for each pre-hospital investigation centre. Care of a patient in traumatic hemorrhagic shock is identical from one investigating centre to another: it is based on formalized expert recommendations on hemorrhagic shock resuscitation. Determination of the number of subjects required Coagulation factors were measured in a pre-after study in 2010 in the army in severely traumatized patients. The before period consisted of an isotonic infusion of saline saline chlorine, the after period of FLYP transfusion. In total, the inclusion of 124 patients showed a significant difference between the two groups in terms of PT value. In the absence of any other data available at the time of writing the protocol, we have brought the number of subjects required to 140 (= 2X 70) according to a 10% in the follow-up. There is no planned interim analysis. The administration of the treatment in the study is stopped if any adverse event (AE) occurs (abnormal clinical manifestation,...) and the offending experimental treatment is retained. Usual care and corrective actions are continued in the field, during transport and at the receiving hospital. An independent oversight committee meeting is organized to discuss the stopping or the continuation of the study according to the nature of the AE. Comparability of the 2 groups for the primary endpoint: The median INR values are compared between the two groups, after adjustment on other variables if necessary. Comparability of the 2 groups for the secondary endpoints: Transfusion requirement will be judged by the number of units transfused after arrival at the hospital: packed red blood cells (RBC), platelet concentrates, fibrinogen, coagulation factors and plasma. The transfusion requirement will be measured over a period of 24 to 48 hours. The median number of days in the ICU between the two groups will use the medians test Survival analysis up to 30 days will be based on the comparison of Kaplan-Meier curves, by the log-rank test, and a Cox model to estimate the role of administration of FLYP on survival, taking into account potential confounding factors. The usability of administering FLYP will be judged on the grounds of interruption or non-administration of the experimental treatment, depending on the ability to respect the procedure and the use of a Labile Blood Product according to the rules of good practice. The average differential (pre-hospital -hospital) of coagulation parameters between the two groups will be compared by an ANCOVA adjusted on other variables if needed. INTERRUPTION OR STOPPING OF THE STUDY The sponsor has the responsibility to report, to the national health authority , any serious and unexpected adverse events attributable to the labile blood product of cell therapy and/or protocol within 15 days (7 days in case of death and life-threatening situations). In the case of occurrence of an incident, accident, or event, interruption of the study is planned after analysis and decision by the hemovigilance and safety committee of the study. RISKS A full report on the risks, the description of incidents, accidents and adverse events will be the subject of a chapter in the results section and also in the discussion. FINANCING Funding for the study is provided by the Health Department of the Army (promoter, following the acceptance of the study in the context of Clinical research projects in the Health service of armies). DISCUSSION The study must confirm the link between causality of early administration of plasma in improving post-traumatic coagulopathy. The study must show safe usage in out-of-hospital situations and the ability of medical staff to meet the requirements of the health authorities in terms of product use as well as in terms of traceability of the victims and the treatment they received. CONCLUSION This is the first study that aims to assess the usability and efficiency of FLYP in prehospital situation.

Official Title
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Interest of Pre-hospital Administration of Lyophilized Plasma to Prevent or Treat Coagulopathy Associated With Post-traumatic Hemorrhagic Shock (PREHO-PLYO Study )

Conditions
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Shock Hemorrhagic

Intervention / Treatment
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* Biological: French Lyophilized Plasma
* Biological: Normale Saline Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: hemorrhagic shock of traumatic origin [Systolic Blood Pressure <70 mmHg] OR [Shock index > 1.1] Exclusion Criteria: Refusal to participate in the research Unaffiliated to a social welfare system Age under 18 years Privation of person's liberty Person subject to a safeguard measure of justice Pregnancy Allergy known to Amotosalen® and psoralen Contribution factor clotting other than Plyo Patient initialy in cardiac arrest Patient initially in cardiac arrest, followed by resumption of spontaneous circulation People who could not have blood sample (required for the primary endpoint)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: French Lyophilized Plasma<br>receives French Lyophilized Plasma with the usual treatment for post traumatic hemorrhagic shock as given in the recommendations for best practice | Biological: French Lyophilized Plasma<br>* During the pre-hospital phase, the main events related to this arm are Blood samples taken before treatment (TP, fibrinogen, platelets, RBC, grouping) Usual pre-hospital care according to recommendations in best practices Administration of FLYP<br>|
| Active Comparator: Normal Saline Solution<br>receives Normale Saline Solution with the usual treatment of post traumatic hemorrhagic shock as given in the recommendations for best practice | Biological: Normale Saline Solution<br>* During the pre-hospital phase, the main events related to this arm are Blood samples taken before treatment (TP, fibrinogen, platelets, RBC, grouping) Usual pre-hospital care according to recommendations in best practices Administration of Normale Saline Solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the International Normalized Ratio level (international unit IU) at hospital admission |  | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of plasma units administered at 24 and 48 hours |  | 48 hours | 
| Number of RBC Concentrates units administered at 24 and 48 hours |  | 48 hours | 
| Number of platelet concentrates units administered at 24 and 48 hours |  | 48 hours | 
| Total Intensive care unit of stay (days) |  | 30 days | 
| Survival |  | 30 days | 
| FLYP prehospital usability in civilian population (questionnaire) | Compilation of technical and logistical difficulties encountered before, during and after administration of FLYP | 30 days | 
| Fibrinogen level (grams) |  | 1 day | 
| Prothrombin level change (percentage) | The difference in the level of Prothrombin (PT), between prehospital and hospital admission | 48 hours | 
| the level of coagulation factors (international unit IU) at hospital admission |  | 1 day | 
| Quantity of fibrinogen administered in grams at 24 and 48 hours |  | 48 hours | 
| quantity of coagulation factors administered (international units IU) | quantity of coagulation factors administered (international units IU) | 48 hours | 
| Thromboelastometry median clotting time (CT) (minutes). | Time in minutes and secondes for each step coming from rotational elastometry | 1 hour | 
| Thromboelastometry median Clot Formation Time (CFT) in minutes and seconds | Time in minutes and seconds for each step coming from rotational elastometry | 1 hour | 
| Thromboelastometry median maximal lysis (ML) time in minutes ans seconds | Time in minutes and seconds for each step coming from rotational elastometry | 1 hour | 
| Thromboelastometry alpha angle (degrees) | measure unit : degrees | 1 hour | 
| Thromboelastometry median Maximal Clot Firmness (MCF) time in minutes and seconds | Time in minutes and seconds for each step coming from rotational elastometry | 1 hour | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized controlled trial, Lyophilized Plasma, Advanced Trauma Life Support Care