Clinical trial NCT02736812: Pre-hospital Administration of Lyophilized Plasma for Post-traumatic Coagulopathy Treatment (PREHO-PLYO)
Official title: Interest of Pre-hospital Administration of Lyophilized Plasma to Prevent or Treat Coagulopathy Associated With Post-traumatic Hemorrhagic Shock (PREHO-PLYO Study )
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Shock Hemorrhagic
Keywords: Randomized controlled trial
Lyophilized Plasma
Advanced Trauma Life Support Care
Lead sponsor: French Defence Health Service
Sponsor class: OTHER_GOV
Collaborators: name: Bataillon des marins pompiers de Marseille, France
name: Military Hospital Laveran,Marseille, France
name: Samu of Marseille, France
name: Samu of Lyon, France
name: Lyon-South Hospital, France
name: Hôpital Edouard Herriot
name: Fire Brigade Of Paris Emergency Medicine Dept
name: CH Annecy Genevois
name: Institut de Recherche Biomedicale des Armees
name: Marseille North Hospital, France
name: Samu of Necker, Paris, France
name: Samu of Annecy, France
name: Military Hospital Percy , Clamart, France
name: Military Hospital Begin, Saint-Mandé, France
name: Centre de transfusion sanguine des Armées, Clamart, France
name: Henri Mondor University Hospital
name: Samu of Beaujon, Clichy-La-Garenne, France
name: Samu of Lariboisière, Paris, France
name: Samu of Henri Mondor, Créteil, France
name: Samu of Brest, Brest , France
name: Samu of Pau , Pau , France
First posted: 2016-04-13
Enrollment: 140
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: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: the International Normalized Ratio level (international unit IU) at hospital admission
timeFrame: 1 day
Secondary outcomes:
measure: number of plasma units administered at 24 and 48 hours
timeFrame: 48 hours
measure: Number of RBC Concentrates units administered at 24 and 48 hours
timeFrame: 48 hours
measure: Number of platelet concentrates units administered at 24 and 48 hours
timeFrame: 48 hours
measure: Total Intensive care unit of stay (days)
timeFrame: 30 days
measure: Survival
timeFrame: 30 days
measure: FLYP prehospital usability in civilian population (questionnaire)
timeFrame: 30 days
measure: Fibrinogen level (grams)
timeFrame: 1 day
measure: Prothrombin level change (percentage)
timeFrame: 48 hours
measure: the level of coagulation factors (international unit IU) at hospital admission
timeFrame: 1 day
measure: Quantity of fibrinogen administered in grams at 24 and 48 hours
timeFrame: 48 hours
measure: quantity of coagulation factors administered (international units IU)
timeFrame: 48 hours
measure: Thromboelastometry median clotting time (CT) (minutes).
timeFrame: 1 hour
measure: Thromboelastometry median Clot Formation Time (CFT) in minutes and seconds
timeFrame: 1 hour
measure: Thromboelastometry median maximal lysis (ML) time in minutes ans seconds
timeFrame: 1 hour
measure: Thromboelastometry alpha angle (degrees)
timeFrame: 1 hour
measure: Thromboelastometry median Maximal Clot Firmness (MCF) time in minutes and seconds
timeFrame: 1 hour
Other outcomes:
Locations:
city: Annecy
country: France
facility: Centre Hospitalier Annecy Genevois
city: Annecy
country: France
facility: Samu 74 Annecy Genevois
city: Brest
country: France
facility: Samu de BREST
city: Clamart
country: France
facility: Hopital d'instruction des Armées PERCY
city: Clamart
country: France
facility: Centre de Transfusion Sanguine des Armées
city: Clichy
country: France
facility: Hopital Beaujon
city: Créteil
country: France
facility: Henri Mondor University Hospital
city: Le Kremlin Bicetre
country: France
facility: Hopital Kremlin Bicetre
city: Lyon
country: France
facility: Centre Hospitalier EDOUARD HERRIOT
city: Lyon
country: France
facility: Samu de LYON
city: Lyon
country: France
facility: Centre Hospitalier LYON SUD
city: Marseille
country: France
facility: Hopital d'Instruction des Armées LAVERAN
city: Marseille
country: France
facility: Bataillon des marins-pompiers de Marseille
city: Marseille
country: France
facility: Hopital Nord de Marseille
city: Marseille
country: France
facility: Samu de Marseille
city: Paris
country: France
facility: Hopital Pitié Salpétrière
city: Paris
country: France
facility: Hopital Europen Georges Pompidou
city: Paris
country: France
facility: Samu de Paris
city: Paris
country: France
facility: Fire Brigade Of Paris Emergency Medicine Dept
city: Paris
country: France
facility: Smur Lariboisiere
city: PAU
country: France
facility: Samu de PAU
city: Saint-Mandé
country: France
facility: Hopital des Instructions des Armées BEGIN
Study officials:
affiliation: Fire Brigade Of Paris Emergency Medicine Dept
name: Jean-Pierre TOURTIER, Professor
role: STUDY_CHAIR
affiliation: Fire Brigade Of Paris Emergency Medicine Dept
name: Daniel JOST, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre de Transfusion Sanguine des Armées
name: Anne SAILLIOL, Professor
role: STUDY_CHAIR
affiliation: Institut de recherche biomedicale des armées
name: Catherine VERRET, MD
role: STUDY_CHAIR
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