Control of Major Bleeding After Trauma Study (COMBAT)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Trauma; Hemorrhagic Shock	Biological: Type AB plasma; Drug: Crystalloid fluid (standard of care for resuscitation)	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	144 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Prospective, Randomized Comparison of Fresh Frozen Plasma Versus Standard Crystalloid Intravenous Fluid as Initial Resuscitation Fluid
Actual Study Start Date :	April 7, 2014
Actual Primary Completion Date :	April 3, 2017
Actual Study Completion Date :	April 3, 2017

Arms and Interventions

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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 Name: 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 Name: Normal saline

Outcome Measures

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Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Composite Outcome of 28-day In-hospital Mortality and Postinjury Multiple Organ Failure (MOF) Incidence [ Time Frame: 28 days ]
   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).
2. Admission Coagulopathy [ Time Frame: within 30 minutes of Emergency Department (ED) arrival ]
   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.
3. Number of Participants With Admission Severe Coagulopathy [ Time Frame: within 30 minutes of Emergency Department (ED) arrival ]
   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.
4. Admission Clot Strength [ Time Frame: within 30 minutes of ED arrival ]
   Admission clot strength will be measured by thrombelastography G-value upon ED arrival. Clot strength measured in kilodynes per square centimetre (kdyn/cm^2).
5. Admission Acidosis [ Time Frame: within 30 minutes of ED arrival ]
   Admission acidosis measured by lactate upon ED arrival.
6. Number of Participants With Admission Severe Acidosis [ Time Frame: within 30 minutes of ED arrival ]
   Admission severe acidosis measured by lactate>5 upon ED arrival.
7. Admission Acidosis [ Time Frame: within 30 minutes of ED arrival ]
   Admission acidosis will be defined by base deficit (BD) upon ED arrival.
8. Number of Participants With Admission Severe Acidosis [ Time Frame: within 30 minutes of ED arrival ]
   Admission severe acidosis will be defined by base deficit (BD>10) upon ED arrival.

Other Outcome Measures:

1. Baseline (Field) Coagulation Factor Levels [ Time Frame: after injury and prior to hospital arrival, at about 15 minutes after injury ]

   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
2. Number of Participants With Abnormal Baseline (Field) Coagulation Factor XIII Level [ Time Frame: after injury prior to hospital arrival ]
   defined as abnormal coagulation factor XIII level obtained in the field prior to intervention
3. Admission (First Arrival) Coagulation Factor Levels [ Time Frame: after injury prior to hospital arrival ]

   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
4. Number of Participants With Abnormal Admission Coagulation Factor XIII (Fibrin-stabilizing Factor) Level [ Time Frame: within 30 minutes of Emergency Department (ED) arrival ]
   defined as the first abnormal factor XIII (fibrin-stabilizing factor) level obtained upon ED arrival
5. Exploratory Analyses [ Time Frame: Hospital stay up to 28 days. ]
   Number of participants with 24-hour mortality, adverse outcome free days and transfusions
6. Exploratory Analyses. [ Time Frame: Hospital stay up to 28 days. ]
   Adverse outcome free days
7. Number of Participants With Mortality, Adverse Outcome-free Days and Transfusions in the Sub-group With Less Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
   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
8. Adverse Outcome-free Days in a Sub-group With Less Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
   Adverse outcome-free days in the patients with initial systolic blood pressure (SBP) 71-90 mmHg and heart rate (HR) of 108 or greater
9. Level of Haemoglobin (Hb) in a Sub-group With Less Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
   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
10. Blood Product Transfusion in a Sub-group With Less Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
    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
11. Time to Admission and First Blood Transfusion in a Sub-group With Less Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
    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
12. Number of Participants With Mortality, Adverse Outcome-free Days and Transfusions in a Sub-group With Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
    Mortality, adverse outcome-free days and transfusions in the patients with initial systolic blood pressure (SBP) <=70 mmHg
13. Number of Adverse Outcome Free Days in a Sub-group With Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
    Adverse outcome-free days in the patients with initial systolic blood pressure (SBP) <=70 mmHg
14. Number of Participants in a Sub-group With no Severe Traumatic Brain Injury (TBI) [ Time Frame: Hospital stay up to 28 days. ]
    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.
15. Exploratory Analyses in a Sub-group With Severe Traumatic Brain Injury (TBI) [ Time Frame: Hospital stay up to 28 days. ]
    Number of participants with 28-day mortality. Traumatic brain injury (TBI) is defined as Abbreviated Injury Score (AIS) for Head/Neck >=3.
16. Severe Adverse Events (SAE) [ Time Frame: Hospital stay up to day 28 ]
    Number of participants with severe adverse events (SAE)
17. Haemoglobin (Hb) Level in a Sub-group With Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
    Haemoglobin (Hb) level in the patients with initial systolic blood pressure (SBP) <=70 mmHg
18. Blood Product Transfusion in a Sub-group With Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
    Number of blood products transfused in units in the patients with initial systolic blood pressure (SBP) <=70 mmHg
19. Time to Admission and First Blood Transfusion in a Sub-group With Severe Hemorrhagic Shock [ Time Frame: Hospital stay up to 28 days. ]
    Time to Admission and First Blood Transfusion in the patients with initial systolic blood pressure (SBP) <=70 mmHg
20. Haemoglobin (Hb) Level [ Time Frame: Hospital stay up to 28 days. ]
    Haemoglobin (Hb) level in g/dL units.
21. Number of Blood Products Transfused. [ Time Frame: Hospital stay up to 28 days. ]
    Number of blood products transfused in units.
22. Time to Admission and First Blood Transfusion [ Time Frame: Hospital stay up to 28 days. ]
    Time to admission and first blood product transfusion in minutes.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Denver Health and Hospital Authority

U.S. Army Medical Research and Materiel Command

University of Colorado, Denver

Investigators

Principal Investigator:	Ernest E Moore, MD	Denver Health Medical Center

  Study Documents (Full-Text)

Documents provided by Ernest E. Moore, MD, Denver Health and Hospital Authority:

Study Protocol and Statistical Analysis Plan  [PDF] December 27, 2016

Informed Consent Form  [PDF] February 7, 2017

More Information

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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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 1:63-70. doi: 10.1097/SHK.0000000000000376.

Responsible Party:	Ernest E. Moore, MD, Professor and Vice Chair, Department of Surgery, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier:	NCT01838863 History of Changes
Other Study ID Numbers:	COMIRB# 12-1349; W81XWH1220028 ( Other Grant/Funding Number: Department of Defense TATRC )
First Posted:	April 24, 2013
Results First Posted:	July 18, 2018
Last Update Posted:	July 18, 2018
Last Verified:	July 2018

Keywords provided by Ernest E. Moore, MD, Denver Health and Hospital Authority:

coagulopathy; hemorrhagic shock; plasma; blood product transfusion

Additional relevant MeSH terms:

Shock, Hemorrhagic; Hemorrhage; Pathologic Processes; Shock