Control of Major Bleeding After Trauma Study (COMBAT)

A Prospective, Randomized Comparison of Fresh Frozen Plasma Versus Standard Crystalloid Intravenous Fluid as Initial Resuscitation Fluid

Bleeding is the most avoidable cause of death in trauma patients. Up to one-third of severely injured trauma patients are found to be coagulopathic and forty percent of the mortality following severe injury is due to uncontrollable hemorrhage in the setting of coagulopathy. It has been established that early administration of fresh frozen plasma decreases mortality following severe injury, replacing lost coagulation factors, improving the coagulopathy and restoring blood volume. This study will determine if giving plasma to severely injured trauma patients during ambulance transport versus after arrival to the hospital will help reduce hemorrhage, thus decreasing both total blood product administration and mortality.

Study Overview

• Status: Terminated
• Conditions: Trauma; Hemorrhagic Shock
• Intervention / Treatment: Biological: Type AB plasma; Drug: Crystalloid fluid (standard of care for resuscitation)

Detailed Description

Study Design: Severely injured trauma patients with a systolic blood pressure (SBP) ≤ 70 or SBP ≤ 90 with a heart rate ≥ 108 bpm at the scene will be enrolled and randomized to receive either 2 units of frozen plasma thawed in the field or normal saline (the current standard of care), as the initial resuscitation fluid. After this initial resuscitation fluid, both groups will receive the same standard of care, including packed red blood cells, additional normal saline, or plasma as needed based on laboratory and clinical evidence of coagulopathy. Blood samples and clinical information will be collected throughout the hospital stay up to 28 days after injury.

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center

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:

• Age>=18 years
• Acutely injured
• SBP<70 mmHg or SBP 71-90 mmHg with heart rate (HR)>108 beats per minute.

Exclusion Criteria:

• Visibly or verbally reported pregnant women
• known prisoners
• unsalvageable injuries (defined as asystolic or cardiopulmonary resuscitation prior to randomization)
• known objection to blood products
• the patient has an opt-out bracelet or, necklace or wallet card
• a family member present at the scene objects to the patient's enrollment in research.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Plasma; If the patient is randomized to experimental arm, 2 units of frozen type AB plasma (FP24) will be thawed in the Plasmatherm Dry Thawing and Warming Device according to the operator manual as approved by the FDA in the ambulance and infusion will commence as soon as the type AB plasma is ready, and will continue during transport to the emergency department (ED). After infusion of 2 units of type AB plasma is completed, subsequent care will proceed per institutional, Advanced Trauma Life Support (ATLS) guided resuscitation with acute packed red blood cells (pRBC) administration determined by the hemodynamic response and additional blood component administration guided by rapid thrombelastography (rTEG) and coagulation panel assessment in conjunction with clinical scenario.	Biological: Type AB plasma; The plasma is thawed and administered to subjects in the experimental (plasma) arm.; Other Names: Plasma frozen within 24 hours (FP24, PF24)
Active Comparator: Standard; If the patient is randomized to the standard arm, the patient will be given intravenous crystalloid fluid (normal saline) as the initial resuscitation fluid with 2 large bore IVs based on the current ATLS guidelines, the standard of care. Subsequent care will proceed per institutional, ATLS guided resuscitation with acute packed red blood cells pRBC administration determined by the hemodynamic response and additional blood component administration guided by rTEG and coagulation panel assessment in conjunction with clinical scenario.	Drug: Crystalloid fluid (standard of care for resuscitation); Normal saline will be give to subjects in the standard arm as the current standard of care for an initial resuscitation fluid; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants That Died Within 28 Days Post Injury	death within 28 days post injury (death of any cause except for death due to a second, clearly unrelated traumatic injury suffered after discharge)	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Outcome of 28-day In-hospital Mortality and Postinjury Multiple Organ Failure (MOF) Incidence	The occurrence of in-hospital death or MOF within the first 28 days postinjury. MOF is defined using the validated Denver MOF score (Denver MOF score>3 of simultaneously obtained scores after 48 hours postinjury).	28 days
Admission Coagulopathy	Defined as the first international normalized ratio (INR) obtained upon ED arrival. The international normalized ratio (INR) is an international standard for the prothrombin time (PT). This measures the time it takes for blood to clot. The normal range for a healthy person is 0.83-1.19. Usually, a high INR indicates a higher risk of bleeding, while a low INR suggests a higher risk of developing a clot.	within 30 minutes of Emergency Department (ED) arrival
Number of Participants With Admission Severe Coagulopathy	Defined as international normalized ratio (INR) >1.3 obtained upon ED arrival. The international normalized ratio (INR) is an international standard for the prothrombin time (PT). This measures the time it takes for blood to clot. The normal range for a healthy person is 0.83-1.19. Usually, a high INR indicates a higher risk of bleeding, while a low INR suggests a higher risk of developing a clot.	within 30 minutes of Emergency Department (ED) arrival
Admission Clot Strength	Admission clot strength will be measured by thrombelastography G-value upon ED arrival. Clot strength measured in kilodynes per square centimetre (kdyn/cm^2).	within 30 minutes of ED arrival
Admission Acidosis	Admission acidosis measured by lactate upon ED arrival.	within 30 minutes of ED arrival
Number of Participants With Admission Severe Acidosis	Admission severe acidosis measured by lactate>5 upon ED arrival.	within 30 minutes of ED arrival
Admission Acidosis	Admission acidosis will be defined by base deficit (BD) upon ED arrival.	within 30 minutes of ED arrival
Number of Participants With Admission Severe Acidosis	Admission severe acidosis will be defined by base deficit (BD>10) upon ED arrival.	within 30 minutes of ED arrival

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline (Field) Coagulation Factor Levels	defined as the first coagulation factor level obtained in the field prior to intervention Coagulation Factor Reference Ranges F2 F5 F7 F8 F9 F11; % % % % % % 67.0 - 107.0 63.0 - 116.0 52.0 - 120.0 58.0 - 132.0 47.0 - 122.0 52.0 - 120.0	after injury and prior to hospital arrival, at about 15 minutes after injury
Number of Participants With Abnormal Baseline (Field) Coagulation Factor XIII Level	defined as abnormal coagulation factor XIII level obtained in the field prior to intervention	after injury prior to hospital arrival
Admission (First Arrival) Coagulation Factor Levels	defined as the first coagulation factor level obtained upon ED arrival Coagulation Factor Reference Ranges F2 F5 F7 F8 F9 F11; % % % % % % 67.0 - 107.0 63.0 - 116.0 52.0 - 120.0 58.0 - 132.0 47.0 - 122.0 52.0 - 120.0	after injury prior to hospital arrival
Number of Participants With Abnormal Admission Coagulation Factor XIII (Fibrin-stabilizing Factor) Level	defined as the first abnormal factor XIII (fibrin-stabilizing factor) level obtained upon ED arrival	within 30 minutes of Emergency Department (ED) arrival
Exploratory Analyses	Number of participants with 24-hour mortality, adverse outcome free days and transfusions	Hospital stay up to 28 days.
Exploratory Analyses.	Adverse outcome free days	Hospital stay up to 28 days.
Number of Participants With Mortality, Adverse Outcome-free Days and Transfusions in the Sub-group With Less Severe Hemorrhagic Shock	Mortality, adverse outcome-free days and transfusions in the patients with initial systolic blood pressure (SBP) 71-90 mmHg and heart rate (HR) of 108 or greater	Hospital stay up to 28 days.
Adverse Outcome-free Days in a Sub-group With Less Severe Hemorrhagic Shock	Adverse outcome-free days in the patients with initial systolic blood pressure (SBP) 71-90 mmHg and heart rate (HR) of 108 or greater	Hospital stay up to 28 days.
Level of Haemoglobin (Hb) in a Sub-group With Less Severe Hemorrhagic Shock	Level of Haemoglobin (Hb) in g/dL in the patients with initial systolic blood pressure (SBP) 71-90 mmHg and heart rate (HR) of 108 or greater	Hospital stay up to 28 days.
Blood Product Transfusion in a Sub-group With Less Severe Hemorrhagic Shock	Transfusions of blood products in units in the patients with initial systolic blood pressure (SBP) 71-90 mmHg and heart rate (HR) of 108 or greater	Hospital stay up to 28 days.
Time to Admission and First Blood Transfusion in a Sub-group With Less Severe Hemorrhagic Shock	Time to Admission and First Blood Transfusion in minutes in the patients with initial systolic blood pressure (SBP) 71-90 mmHg and heart rate (HR) of 108 or greater	Hospital stay up to 28 days.
Number of Participants With Mortality, Adverse Outcome-free Days and Transfusions in a Sub-group With Severe Hemorrhagic Shock	Mortality, adverse outcome-free days and transfusions in the patients with initial systolic blood pressure (SBP) <=70 mmHg	Hospital stay up to 28 days.
Number of Adverse Outcome Free Days in a Sub-group With Severe Hemorrhagic Shock	Adverse outcome-free days in the patients with initial systolic blood pressure (SBP) <=70 mmHg	Hospital stay up to 28 days.
Number of Participants in a Sub-group With no Severe Traumatic Brain Injury (TBI)	Number of participants with mortality, adverse outcome-free days and transfusions in the patients with no severe traumatic brain injury (TBI) is defined as Abbreviated Injury Score (AIS) for Head/Neck >=3.	Hospital stay up to 28 days.
Exploratory Analyses in a Sub-group With Severe Traumatic Brain Injury (TBI)	Number of participants with 28-day mortality. Traumatic brain injury (TBI) is defined as Abbreviated Injury Score (AIS) for Head/Neck >=3.	Hospital stay up to 28 days.
Severe Adverse Events (SAE)	Number of participants with severe adverse events (SAE)	Hospital stay up to day 28
Haemoglobin (Hb) Level in a Sub-group With Severe Hemorrhagic Shock	Haemoglobin (Hb) level in the patients with initial systolic blood pressure (SBP) <=70 mmHg	Hospital stay up to 28 days.
Blood Product Transfusion in a Sub-group With Severe Hemorrhagic Shock	Number of blood products transfused in units in the patients with initial systolic blood pressure (SBP) <=70 mmHg	Hospital stay up to 28 days.
Time to Admission and First Blood Transfusion in a Sub-group With Severe Hemorrhagic Shock	Time to Admission and First Blood Transfusion in the patients with initial systolic blood pressure (SBP) <=70 mmHg	Hospital stay up to 28 days.
Haemoglobin (Hb) Level	Haemoglobin (Hb) level in g/dL units.	Hospital stay up to 28 days.
Number of Blood Products Transfused.	Number of blood products transfused in units.	Hospital stay up to 28 days.
Time to Admission and First Blood Transfusion	Time to admission and first blood product transfusion in minutes.	Hospital stay up to 28 days.

Collaborators and Investigators

• Sponsor: Denver Health and Hospital Authority
• Collaborators: University of Colorado, Denver; U.S. Army Medical Research and Development Command
• Investigators: Principal Investigator: Ernest E Moore, MD, Denver Health Medical Center

Publications and helpful links

General Publications

• Pusateri AE, Moore EE, Moore HB, Le TD, Guyette FX, Chapman MP, Sauaia A, Ghasabyan A, Chandler J, McVaney K, Brown JB, Daley BJ, Miller RS, Harbrecht BG, Claridge JA, Phelan HA, Witham WR, Putnam AT, Sperry JL. Association of Prehospital Plasma Transfusion With Survival in Trauma Patients With Hemorrhagic Shock When Transport Times Are Longer Than 20 Minutes: A Post Hoc Analysis of the PAMPer and COMBAT Clinical Trials. JAMA Surg. 2020 Feb 1;155(2):e195085. doi: 10.1001/jamasurg.2019.5085. Epub 2020 Feb 19.
• Reynolds PS, Michael MJ, Cochran ED, Wegelin JA, Spiess BD. Prehospital use of plasma in traumatic hemorrhage (The PUPTH Trial): study protocol for a randomised controlled trial. Trials. 2015 Jul 30;16:321. doi: 10.1186/s13063-015-0844-5.
• Moore HB, Moore EE, Chapman MP, McVaney K, Bryskiewicz G, Blechar R, Chin T, Burlew CC, Pieracci F, West FB, Fleming CD, Ghasabyan A, Chandler J, Silliman CC, Banerjee A, Sauaia A. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet. 2018 Jul 28;392(10144):283-291. doi: 10.1016/S0140-6736(18)31553-8. Epub 2018 Jul 20.
• Chapman MP, Moore EE, Chin TL, Ghasabyan A, Chandler J, Stringham J, Gonzalez E, Moore HB, Banerjee A, Silliman CC, Sauaia A. Combat: Initial Experience with a Randomized Clinical Trial of Plasma-Based Resuscitation in the Field for Traumatic Hemorrhagic Shock. Shock. 2015 Aug;44 Suppl 1(0 1):63-70. doi: 10.1097/SHK.0000000000000376.

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2014
• Primary Completion (Actual): April 3, 2017
• Study Completion (Actual): April 3, 2017

Study Registration Dates

• First Submitted: April 22, 2013
• First Submitted That Met QC Criteria: April 22, 2013
• First Posted (Estimate): April 24, 2013

Study Record Updates

• Last Update Posted (Actual): January 8, 2019
• Last Update Submitted That Met QC Criteria: December 15, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: coagulopathy; plasma; hemorrhagic shock; blood product transfusion
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Shock; Shock, Hemorrhagic
• Other Study ID Numbers: COMIRB# 12-1349; W81XWH1220028 (Other Grant/Funding Number: Department of Defense TATRC)