Pilot Randomized Trial of Fibrinogen in Trauma Haemorrhage

Effect of Immediate, Pre-emptive Fibrinogen Concentrate in Patients With Trauma Haemorrhage Needing Haemostatic Resuscitation - a Randomized, Controlled, Double-blinded Investigator-initiated Pilot Trial

Effect of immediate, pre-emptive fibrinogen concentrate in patients with trauma haemorrhage needing haemostatic resuscitation - a randomized, controlled, double-blinded investigator-initiated pilot trial

Study Overview

• Status: Completed
• Conditions: Trauma; Haemorrhage
• Intervention / Treatment: Drug: Fibrinogen; Drug: Placebo

Detailed Description

Objective To assess the efficacy and safety of an immediate pre-emptive first-line treatment with fibrinogen concentrate in patients with trauma haemorrhage in need of haemostatic resuscitation.

Hypothesis Immediate, pre-emptive first-line treatment of fibrinogen concentrate in trauma patients with ongoing critical haemorrhage will increase the clot strength.

Background Trauma haemorrhage remains a leading cause of morbidity and mortality. Fibrinogen is an essential endogenous component of haemostasis and the plasma level is associated to bleeding, transfusion and outcome.

Trial rationale Fibrinogen concentrate is widely used to correct acquired hypofibrinogenaemia, recommended by several international guidelines including in trauma, but evidence is lacking regarding the treatment safety and efficacy.

Trial population The trial population are patients' ≥ 18 years admitted to the Trauma Centre at Rigshospitalet with immediate need for blood transfusion at arrival and an expected need for haemostatic resuscitation with multiple transfusions during the initial resuscitation. Estimated 30-day mortality is 20 % in the population. Patients included in the trial will be temporarily incompetent because of acute, severe illness related to the ongoing critical bleeding needing multiple transfusion and immediate intervention to control bleeding.

Trial design This is a single centre, randomized (1:1, active:placebo), placebo controlled, double-blind investigator-initiated phase II trial in patients with traumatic, critical bleeding, investigating the safety and efficacy of immediate and pre-emptive administration of fibrinogen concentrate (Riastap®) or placebo as i.v infusion in 40 patients. All patients will receive standard of care including damage control surgery, radiological interventions and haemostatic resuscitation as part of their treatment at Rigshospitalet.

Patients considered to be included in the trial will be temporarily incompetent because of the acute, critical bleeding related to trauma, so scientific guardians will co-sign the informed consent form. Next-of-kin and the patients' general practitioner or the patients will co-sign as soon as possible.

During the study blood samples will be taken at different time points. Patients will be observed and assessed continuously throughout the first 72 hours. During the extended follow up period at day 30, contact will be made with the patients to follow up on safety events and establish potential mortality.

Investigational product Immediate intravenous administration as a single dose of fibrinogen concentrate (Riastap®, CSL Behring), when haemostatic resuscitation is deemed necessary by the clinician. The aim is to give the intervention < 1 hour of arrival, and the intervention should, when possible, be given prior to blood products.

Placebo and blinding Saline 0.9% will be used as placebo. The volume of placebo to be administered is equal to the volume active drug administered. The content (Riastap® or placebo) will be provided in opaque syringes and infusion sets (yellow-coloured) to disguise the content of the allocation to the treatment team.

Outcome measures

Primary outcome measure:

• Thrombelastograph (TEG®) Functional Fibrinogen (FF) maximum amplitude (MA) in mm at 15 min post intervention

Secondary outcome measures:

• TEG® FF MA in mm at 2, 6, 24 and 72 hours post intervention
• TEG® MA in mm at 15 min., 2, 6, 24 and 72 hours post intervention
• Transfusion requirements (Red blood cells (RBC) or fresh frozen plasma (FFP) or platelets (PLT)) at 2, 6, 24, 72 hours and in total at day 30
• Total use of haemostatic therapy (i.e. use of coagulation factor concentrates and tranexamic acid) in the first 24 and 72 hours, omitted from this is active treatment (intervention)
• Time to intervention or placebo
• Time to FFP and PLT transfusion
• Percentage of patients receiving intervention or placebo < 1 hour of arrival
• Time to surgical control of bleeding as noted by the surgeon
• Severe adverse reactions at day 30, defined as symptomatic thromboembolism at day 30 and anaphylaxis at day 30
• 24-hour and 30-day mortality

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet, Copenhagen University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Trauma patient received directly from the scene of the accident AND
• Age ≥ 18 years AND
• Initiated order of transfusion of at least one blood component within the 1st hour of arrival AND
• Predicted to need transfusion package therapy during the initial resuscitation (first 2 hours) AND
• Consent obtainable from patient or scientific guardians (independent physicians and/or next of kin

Exclusion Criteria:

• Duration of > 2 hours from time of accident to arrival at trauma centre OR
• Known anticoagulant treatment (vitamin K antagonist, dabigatran, rivaroxiban, apixaban) OR
• Severe isolated traumatic brain injury OR
• Moribund patient with devastating injuries and expected to die within one hour of admission OR
• Withdrawal from active therapy OR
• Previously, within 30 days, included in a randomized trial, if known at the time of enrolment OR
• Known body weight < 55 kg OR
• Any blood product prior to inclusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Saline 0.9%	Drug: Placebo; Saline 0.9% as a injection; Other Names: Saline 0.9%
Active Comparator: Fibrinogen; Immediate intravenous administration as a single dose of fibrinogen concentrate (Riastap®, CSL Behring), when haemostatic resuscitation is deemed necessary by the clinician.	Drug: Fibrinogen; Human fibrinogen concentrate as a injection; Other Names: Riastap®, CSL Behring

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TEG® Functional Fibrinogen maximum amplitude 15 min	Thrombelastograph (TEG®) Functional Fibrinogen (FF) maximum amplitude (MA) in mm	15 min after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TEG® Functional Fibrinogen maximum amplitude 2 hours	Thrombelastograph (TEG®) Functional Fibrinogen (FF) maximum amplitude (MA) in mm	2 hours after intervention
TEG® Functional Fibrinogen maximum amplitude 6 hours	Thrombelastograph (TEG®) Functional Fibrinogen (FF) maximum amplitude (MA) in mm	6 hours after intervention
TEG® Functional Fibrinogen maximum amplitude 24 hours	Thrombelastograph (TEG®) Functional Fibrinogen (FF) maximum amplitude (MA) in mm	24 hours after intervention
TEG® Functional Fibrinogen maximum amplitude 72 hours	Thrombelastograph (TEG®) Functional Fibrinogen (FF) maximum amplitude (MA) in mm	72 hours after intervention
TEG® maximum amplitude 15 min	Thrombelastograph (TEG®) maximum amplitude (MA) in mm	15 min after intervention
TEG® maximum amplitude 2 hours	Thrombelastograph (TEG®) maximum amplitude (MA) in mm	2 hours after intervention
TEG® maximum amplitude 6 hours	Thrombelastograph (TEG®) maximum amplitude (MA) in mm	6 hours after intervention
TEG® maximum amplitude 24 hours	Thrombelastograph (TEG®) maximum amplitude (MA) in mm	24 hours after intervention
TEG® maximum amplitude 72 hours	Thrombelastograph (TEG®) maximum amplitude (MA) in mm	72 hours after intervention
Transfusions requirements	Transfusion requirements (Red blood cells (RBC) or fresh frozen plasma (FFP) or platelets (PLT)) at 2, 6, 24, 72 hours and in total at day 30	2, 6, 24, 72 hours and in total at day 30
Total use of haemostatic therapy	Total use of haemostatic therapy (i.e. use of coagulation factor concentrates and tranexamic acid) in the first 24 and 72 hours, omitted from this is active treatment (intervention)	24 hours and 27 hours
Time to intervention or placebo	Time from arrival to active intervention or placebo in minutes	No of minutes from arrival, an expected average of 45 minutes
Time to FFP and PLT transfusion	Time to FFP and PLT transfusion in minutes	No of minutes from arrival, an expected average of 50 minutes
Percentage of patients receiving intervention or placebo < 1 hour of arrival	Percentage of patients receiving intervention or placebo < 1 hour of arrival	60 min from arrival
Time to surgical control of bleeding	Time to surgical control of bleeding as noted by the surgeon	No of minutes from arrival, an expected average of 120 minutes
Thromboembolism day 30	Symptomatic thromboembolism at day 30 (Severe adverse reaction)	30 days
Anaphylaxis day 30	Anaphylaxis day 30 (Severe adverse reaction)	30 days
24-hour mortality	Mortality in the first 24 hours	24 hours from arrival
30-day mortality	Mortality in the first 30 days	30 days from arrival

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: CSL Behring
• Investigators: Principal Investigator: Jakob Stensballe, MD, PhD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Steinmetz J, Sorensen AM, Henriksen HH, Lange T, Larsen CF, Johansson PI, Stensballe J. Pilot Randomized trial of Fibrinogen in Trauma Haemorrhage (PRooF-iTH): study protocol for a randomized controlled trial. Trials. 2016 Jul 19;17(1):327. doi: 10.1186/s13063-016-1439-5.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: January 14, 2015
• First Submitted That Met QC Criteria: January 16, 2015
• First Posted (Estimate): January 22, 2015

Study Record Updates

• Last Update Posted (Actual): April 11, 2017
• Last Update Submitted That Met QC Criteria: April 10, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Fibrinogen
• Additional Relevant MeSH Terms: Pathologic Processes; Wounds and Injuries; Hemorrhage
• Other Study ID Numbers: PRooF-iTH; 2014-003978-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO