Trauma
Conditions
Keywords
Massive Transfusion, Trauma, Coagulopathy, Trauma Induced Coagulopathy, Plasma, Platelets, Red Blood Cells, Mortality, Wounds and Injuries, Shock, Hemorrhagic, Shock, Pathologic Processes, Hemorrhage, Hemostatics, Coagulation, Transfusion-related acute lung injury (TRALI), Inflammation
Brief summary
Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR)is a Phase III trial designed to evaluate the difference in 24-hour and 30-day mortality among subjects predicted to receive massive transfusion (\[MT\] (defined as receiving 10 units or more red blood cells (RBCs) within the first 24 hours). The goal of PROPPR is to improve the basis on which clinicians make decisions about transfusion protocols for massively bleeding patients. PROPPR is a Resuscitation Outcomes Consortium (ROC) Protocol. ROC is funded by the National Heart, Lung, and Blood Institute (NHLBI), the United States' Department of Defense (DoD) and the Defence Research and Development Canada. PROPPR will be conducted as a Phase III trial at Level I Adult Trauma Centers in North America.
Detailed description
Background: Multiple observational studies have reported that blood product component ratios (i.e., plasma:platelets:RBCs) that approach the 1:1:1 ratio, found in fresh whole blood, are associated with significant decreases in truncal hemorrhagic death and in overall 24-hour and 30-day mortality among injured patients. The rationale for the 1:1:1 ratio is that the closer a transfusion regimen approximates whole blood, the faster hemostasis will be achieved with minimum risk of coagulopathy. The current DoD guideline specifies the use of 1:1:1, and this practice is followed on almost all combat casualties. In other observational studies, leading centers have reported good outcomes across a range of different blood product ratios. For example, a 1:2 plasma:RBC ratio is used with little guidance regarding platelets. The proposed randomized trial is intended to resolve debate and uncertainty regarding optimum blood product ratios. Study Design: Randomized, two-group, controlled Phase III trial with a Vanguard stage. Equal random allocation to treatment using stratified, permuted blocks with randomly chosen block sizes and stratification by site. Objective: To conduct a Phase III multi-site, randomized trial in subjects predicted to have a massive transfusion, comparing the efficacy and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells (the closest approximation to reconstituted whole blood) with the 1:1:2 ratio. The co-primary outcomes will be 24-hour and 30-day mortality. The PROPPR Trial will be conducted with exception from informed consent (EFIC). Additionally, laboratory data from the trial will add to the understanding of trauma induced coagulopathy (TIC) and inflammation.
Interventions
BIOLOGICAL1:1:1 Blood Transfusion Ratio
Group 1 will be randomized to receive the 1:1:1 ratio of plasma:platelets:RBC. Blood bank will prepare the initial container containing 6 units plasma, 1 unit platelets (a pool of 6 units on average) and 6 units RBC; the blood bank will send the initial and all subsequent containers until notified of the discontinuation of the PROPPR transfusion protocol.
BIOLOGICAL1:1:2 Blood Transfusion Ratio
Group 2 will be randomized to receive the 1:1:2 ratio of plasma:platelets:RBC. The blood bank will prepare the initial container containing 3 units plasma, 0 units platelets and 6 units RBC, a second container containing 3 units plasma, 1 unit platelets (a pool of 6 units on average) and 6 units RBC, and the blood bank will send this sequence of 2 containers repeatedly, until notified of the discontinuation of the PROPPR transfusion protocol.
Sponsors
United States Department of Defense
National Heart, Lung, and Blood Institute (NHLBI)
Resuscitation Outcomes Consortium
Defence Research and Development Canada
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects who require the highest trauma team activation at each participating center, * Estimated age of 15 years or older or greater than/equal to weight of 50 kg if age unknown, * Received directly from the injury scene, * Initiated transfusion of at least one unit of blood component within the first hour of arrival or during prehospital transport, and * Predicted to receive a MT by exceeding the threshold score of either the Assessment of Blood Consumption (ABC) score or the attending trauma physician's judgment criteria
Exclusion criteria
* Received care (as defined as receiving a life saving intervention) from an outside hospital or healthcare facility (Procedures and care given at an outside health facility cannot be documented or controlled resulting in a high variability of standards of care and clinical outcomes.) * Moribund patient with devastating injuries and expected to die within one hour of Emergency Department (ED) admission * Prisoners, defined as those who have been directly admitted from a correctional facility * Patients requiring an emergency thoracotomy * Children under the age of 15 years or under 50 kg body weight if age unknown * Known pregnancy in the ED * Greater than 20% total body surface area (TBSA) burns * Suspected inhalation injury * Received greater than five consecutive minutes of cardiopulmonary resuscitation (CPR with chest compressions) in the pre-arrival or ED setting * Known Do Not Resuscitate (DNR) prior to randomization * Enrolled in a concurrent, ongoing interventional, randomized clinical trial * Patients who have activated the opt-out process or patients/legally authorized representatives that refuse blood products on arrival to ED.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 24-hour Mortality | First 24 hours after ED admission | — |
| 30-day Mortality | First 30 days after ED admission | — |
| Coagulation as Indicated by Number of Participants With Reported Venous Thrombolic Events (VTE) | From time of ED admission, for up to 72 hours | Blood samples were collected at time of ED admission and over time to determine the incidence of reported venous thrombolic events (VTE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional Status at Time of Hospital Discharge | Hospital discharge or 30 days, whichever comes first | The Glasgow Outcome Extended Score (GOSE) is a tool used to measure recovery following brain injury and assists with prediction of long-term rehabilitation. The 8 scoring categories are death, vegetative state, lower severe disability, upper severe disability, lower moderate disability, upper moderate disability, lower good recovery and upper good recovery. A higher GOSE score correlates with better outcome. |
| Incidence of Primary Surgical Procedure | ED admission to hospital discharge or 30 days, whichever comes first | — |
| Incidence of Transfusion Related Serious Adverse Events | ED admission to hospital discharge or 30 days, whichever comes first | — |
| Hospital Free Days | first 30 days after ED admission | — |
| Ventilator Free Days | first 30 days after ED admission | — |
| ICU Free Days | first 30 days after ED admission | — |
| Amount of Blood Products Given From Hemostasis to 24 Hours After ED Admission | 24 hours after ED admission | — |
| Initial Hospital Discharge Status | Hospital discharge or 30 days, whichever comes first | — |
| Time to Hemostasis | ED admission to hospital discharge or 30 days, whichever comes first | Time to hemostasis refers to the time that the subject achieved hemorrhage control (anatomic hemostasis and resuscitation complete)following emergency department (ED) arrival. |
| Amount of Randomized Blood Products Given to Hemostasis | 24 hours from randomization | — |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1:1:1 Blood Transfusion Ratio 1:1:1 Blood Transfusion Ratio: Group 1 will be randomized to receive the 1:1:1 ratio of plasma:platelets:RBC. Blood bank will prepare the initial container containing 6 units plasma, 1 unit platelets (a pool of 6 units on average) and 6 units RBC; the blood bank will send the initial and all subsequent containers until notified of the discontinuation of the PROPPR transfusion protocol. | 338 |
| 1:1:2 Blood Transfusion Ratio 1:1:2 Blood Transfusion Ratio: Group 2 will be randomized to receive the 1:1:2 ratio of plasma:platelets:RBC. The blood bank will prepare the initial container containing 3 units plasma, 0 units platelets and 6 units RBC, a second container containing 3 units plasma, 1 unit platelets (a pool of 6 units on average) and 6 units RBC, and the blood bank will send this sequence of 2 containers repeatedly, until notified of the discontinuation of the PROPPR transfusion protocol. | 342 |
| Total | 680 |
Baseline characteristics
| Characteristic | 1:1:2 Blood Transfusion Ratio | Total | 1:1:1 Blood Transfusion Ratio |
|---|---|---|---|
| Age, Customized | 342 participants | 680 participants | 338 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 59 Participants | 120 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 283 Participants | 560 Participants | 277 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 8 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 29 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 93 Participants | 186 Participants | 93 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 17 Participants | 3 Participants |
| Race (NIH/OMB) White | 224 Participants | 434 Participants | 210 Participants |
| Sex: Female, Male Female | 59 Participants | 134 Participants | 75 Participants |
| Sex: Female, Male Male | 283 Participants | 546 Participants | 263 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 297 / 338 | 310 / 342 |
| serious Total, serious adverse events | 2 / 338 | 4 / 342 |
Outcome results
Primary
24-hour Mortality
Time frame: First 24 hours after ED admission
Population: Number of subjects who were randomized to each group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | 24-hour Mortality | 43 participants |
| 1:1:2 Blood Transfusion Ratio | 24-hour Mortality | 58 participants |
Comparison: Initial sample size (580) planned to detect a clinically meaningful 10% difference in 24-hour mortality (11% vs. 21%) supported by prior data. Data Safety Monitoring Board (DSMB) increased sample size to 680 according to trial's adaptive design. With 680 pts. \& given the final observed mortality proportions in 1:1:1 group, PROPPR had 95% power to detect the pre-specified 10% difference at 24 hours if such differences existed.p-value: 0.1295% CI: [0.52, 1.08]Mantel Haenszel
Primary
30-day Mortality
Time frame: First 30 days after ED admission
Population: Number of subjects enrolled into each group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | 30-day Mortality | 75 participants |
| 1:1:2 Blood Transfusion Ratio | 30-day Mortality | 89 participants |
Comparison: Initial sample size of 580 planned to detect clinically meaningful a 12% difference in 30-day mortality (23% vs. 35%),supported by prior data. DSMB increased sample size to 680 according to trial's adaptive design. With 680 patients \& given final observed mortality proportions in the 1:1:1 group, PROPPR had 92% power to detect the pre-specified 12% difference at 30 days, if such differences existed.p-value: 0.2695% CI: [0.65, 1.12]Mantel Haenszel
Primary
Coagulation as Indicated by Number of Participants With Reported Venous Thrombolic Events (VTE)
Blood samples were collected at time of ED admission and over time to determine the incidence of reported venous thrombolic events (VTE).
Time frame: From time of ED admission, for up to 72 hours
Population: Number of subjects who were randomized to each group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Coagulation as Indicated by Number of Participants With Reported Venous Thrombolic Events (VTE) | 45 participants |
| 1:1:2 Blood Transfusion Ratio | Coagulation as Indicated by Number of Participants With Reported Venous Thrombolic Events (VTE) | 42 participants |
Secondary
Amount of Blood Products Given From Hemostasis to 24 Hours After ED Admission
Time frame: 24 hours after ED admission
Population: Unit of measure for outcome measures below is median number of blood product units that given in each group (1:1:1 or 1:1:2) from time initial hemostasis was complete (PROPPR randomized study products stopped) up to 24 hours following ED admission. Number of participants is based on those who survived up to 24 hours, not participants randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Amount of Blood Products Given From Hemostasis to 24 Hours After ED Admission | 1 units of blood products |
| 1:1:2 Blood Transfusion Ratio | Amount of Blood Products Given From Hemostasis to 24 Hours After ED Admission | 2 units of blood products |
Secondary
Amount of Randomized Blood Products Given to Hemostasis
Time frame: 24 hours from randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Amount of Randomized Blood Products Given to Hemostasis | 16 units of blood products |
| 1:1:2 Blood Transfusion Ratio | Amount of Randomized Blood Products Given to Hemostasis | 15 units of blood products |
Secondary
Functional Status at Time of Hospital Discharge
The Glasgow Outcome Extended Score (GOSE) is a tool used to measure recovery following brain injury and assists with prediction of long-term rehabilitation. The 8 scoring categories are death, vegetative state, lower severe disability, upper severe disability, lower moderate disability, upper moderate disability, lower good recovery and upper good recovery. A higher GOSE score correlates with better outcome.
Time frame: Hospital discharge or 30 days, whichever comes first
Population: Glasgow Outcome Extended Score (GOSE) Score on discharged patients who had a head injury (Abbreviated Injury Score (AIS) \> 1) ranging from 1 to 8. The AIS is a coding scale to classify the injury severity. A score is created for each body region, type of anatomic structure (i.e. whole area, vessels,organs), and severity(minor to maximum).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Functional Status at Time of Hospital Discharge | 4 units on the GOSE scale |
| 1:1:2 Blood Transfusion Ratio | Functional Status at Time of Hospital Discharge | 4.5 units on the GOSE scale |
p-value: 0.11van Elteren's test for medians
Secondary
Hospital Free Days
Time frame: first 30 days after ED admission
Population: Number of hospital free days for each group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Hospital Free Days | 1 days |
| 1:1:2 Blood Transfusion Ratio | Hospital Free Days | 0 days |
p-value: 0.83van Elteren's test for medians
Secondary
ICU Free Days
Time frame: first 30 days after ED admission
Population: Number of ICU free days for each group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | ICU Free Days | 5 days |
| 1:1:2 Blood Transfusion Ratio | ICU Free Days | 4 days |
p-value: 0.1van Elteren's test for medians
Secondary
Incidence of Primary Surgical Procedure
Time frame: ED admission to hospital discharge or 30 days, whichever comes first
Population: Incidence of primary surgical procedure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Incidence of Primary Surgical Procedure | 290 participants |
| 1:1:2 Blood Transfusion Ratio | Incidence of Primary Surgical Procedure | 284 participants |
95% CI: [-2.8, 8.3]
Secondary
Incidence of Transfusion Related Serious Adverse Events
Time frame: ED admission to hospital discharge or 30 days, whichever comes first
Population: Incidence of transfusion related serious adverse events-Reportable to FDA
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Incidence of Transfusion Related Serious Adverse Events | 1 participants |
| 1:1:2 Blood Transfusion Ratio | Incidence of Transfusion Related Serious Adverse Events | 0 participants |
95% CI: [-0.8, 1.7]
Secondary
Initial Hospital Discharge Status
Time frame: Hospital discharge or 30 days, whichever comes first
Population: Disposition of subject at time of hospital discharge
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Initial Hospital Discharge Status | Other | 59 participants |
| 1:1:1 Blood Transfusion Ratio | Initial Hospital Discharge Status | Remained hospitalized at 30 days | 82 participants |
| 1:1:1 Blood Transfusion Ratio | Initial Hospital Discharge Status | Morgue | 75 participants |
| 1:1:1 Blood Transfusion Ratio | Initial Hospital Discharge Status | Unknown | 4 participants |
| 1:1:1 Blood Transfusion Ratio | Initial Hospital Discharge Status | Home | 118 participants |
| 1:1:2 Blood Transfusion Ratio | Initial Hospital Discharge Status | Unknown | 0 participants |
| 1:1:2 Blood Transfusion Ratio | Initial Hospital Discharge Status | Home | 105 participants |
| 1:1:2 Blood Transfusion Ratio | Initial Hospital Discharge Status | Remained hospitalized at 30 days | 77 participants |
| 1:1:2 Blood Transfusion Ratio | Initial Hospital Discharge Status | Other | 71 participants |
| 1:1:2 Blood Transfusion Ratio | Initial Hospital Discharge Status | Morgue | 89 participants |
p-value: 0.37generalized logit model regression
Secondary
Time to Hemostasis
Time to hemostasis refers to the time that the subject achieved hemorrhage control (anatomic hemostasis and resuscitation complete)following emergency department (ED) arrival.
Time frame: ED admission to hospital discharge or 30 days, whichever comes first
Population: Time to anatomic hemostasis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Time to Hemostasis | 105 minutes |
| 1:1:2 Blood Transfusion Ratio | Time to Hemostasis | 100 minutes |
p-value: 0.44van Elteren's test for medians
Secondary
Ventilator Free Days
Time frame: first 30 days after ED admission
Population: Number of ventilator free days for each group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1:1:1 Blood Transfusion Ratio | Ventilator Free Days | 8 days |
| 1:1:2 Blood Transfusion Ratio | Ventilator Free Days | 7 days |
p-value: 0.14van Elteren's test for medians