Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR)

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.

Study Overview

• Status: Completed
• Conditions: Trauma
• Intervention / Treatment: Biological: 1:1:1 Blood Transfusion Ratio; Biological: 1:1:2 Blood Transfusion Ratio

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.

• Study Type: Interventional
• Enrollment (Actual): 680
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Science Center
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama
  • Arizona
    • Tucson, Arizona, United States, 85721
      • University of Arizona
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California, Los Angeles
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45221
      • University of Cincinnati
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • University of Tennessee Health Science Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center- Memorial Hermann Hospital
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington- Harborview Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1:1:1 Blood Transfusion Ratio	Biological: 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.
ACTIVE_COMPARATOR: 1:1:2 Blood Transfusion Ratio	Biological: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Blood samples were collected at time of ED admission and over time to determine the incidence of reported venous thrombolic events (VTE).	From time of ED admission, for up to 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital Free Days		first 30 days after ED admission
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.	ED admission to hospital discharge or 30 days, whichever comes first
Amount of Randomized Blood Products Given to Hemostasis		24 hours from randomization
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.	Hospital discharge or 30 days, whichever comes first
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
Initial Hospital Discharge Status		Hospital discharge or 30 days, whichever comes first
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

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); United States Department of Defense; Defence Research and Development Canada; Resuscitation Outcomes Consortium
• Investigators: Study Director: John Holcomb, MD, The University of Texas Health Science Center, Houston

Publications and helpful links

General Publications

• McCully BH, Wade CE, Fox EE, Inaba K, Cohen MJ, Holcomb JB, Schreiber MA; PROPPR study group. Temporal profile of the pro- and anti-inflammatory responses to severe hemorrhage in patients with venous thromboembolism: Findings from the PROPPR trial. J Trauma Acute Care Surg. 2021 May 1;90(5):845-852. doi: 10.1097/TA.0000000000003088.
• DeSantis SM, Brown DW, Jones AR, Yamal JM, Pittet JF, Patel RP, Wade CE, Holcomb JB, Wang H; PROPPR Study Group. Characterizing red blood cell age exposure in massive transfusion therapy: the scalar age of blood index (SBI). Transfusion. 2019 Aug;59(8):2699-2708. doi: 10.1111/trf.15334. Epub 2019 May 3.
• Jones AR, Patel RP, Marques MB, Donnelly JP, Griffin RL, Pittet JF, Kerby JD, Stephens SW, DeSantis SM, Hess JR, Wang HE; PROPPR Study Group. Older Blood Is Associated With Increased Mortality and Adverse Events in Massively Transfused Trauma Patients: Secondary Analysis of the PROPPR Trial. Ann Emerg Med. 2019 Jun;73(6):650-661. doi: 10.1016/j.annemergmed.2018.09.033. Epub 2018 Nov 15.
• Cardenas JC, Zhang X, Fox EE, Cotton BA, Hess JR, Schreiber MA, Wade CE, Holcomb JB; PROPPR Study Group. Platelet transfusions improve hemostasis and survival in a substudy of the prospective, randomized PROPPR trial. Blood Adv. 2018 Jul 24;2(14):1696-1704. doi: 10.1182/bloodadvances.2018017699.
• Henry B, Perez A, Trpcic S, Rizoli S, Nascimento B. Protecting study participants in emergency research: is community consultation before trial commencement enough? Trauma Surg Acute Care Open. 2017 Jul 12;2(1):e000084. doi: 10.1136/tsaco-2017-000084. eCollection 2017.
• Galvagno SM Jr, Fox EE, Appana SN, Baraniuk S, Bosarge PL, Bulger EM, Callcut RA, Cotton BA, Goodman M, Inaba K, O'Keeffe T, Schreiber MA, Wade CE, Scalea TM, Holcomb JB, Stein DM; PROPPR Study Group. Outcomes after concomitant traumatic brain injury and hemorrhagic shock: A secondary analysis from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial. J Trauma Acute Care Surg. 2017 Oct;83(4):668-674. doi: 10.1097/TA.0000000000001584. Epub 2017 Jun 6.
• Naumann DN, Vincent LE, Pearson N, Beaven A, Smith IM, Smith K, Toman E, Dorrance HR, Porter K, Wade CE, Cotton BA, Holcomb JB, Midwinter MJ. An adapted Clavien-Dindo scoring system in trauma as a clinically meaningful nonmortality endpoint. J Trauma Acute Care Surg. 2017 Aug;83(2):241-248. doi: 10.1097/TA.0000000000001517.
• Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, Cohen MJ, Cotton BA, Fabian TC, Inaba K, Kerby JD, Muskat P, O'Keeffe T, Rizoli S, Robinson BR, Scalea TM, Schreiber MA, Stein DM, Weinberg JA, Callum JL, Hess JR, Matijevic N, Miller CN, Pittet JF, Hoyt DB, Pearson GD, Leroux B, van Belle G; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015 Feb 3;313(5):471-82. doi: 10.1001/jama.2015.12.
• Baraniuk S, Tilley BC, del Junco DJ, Fox EE, van Belle G, Wade CE, Podbielski JM, Beeler AM, Hess JR, Bulger EM, Schreiber MA, Inaba K, Fabian TC, Kerby JD, Cohen MJ, Miller CN, Rizoli S, Scalea TM, O'Keeffe T, Brasel KJ, Cotton BA, Muskat P, Holcomb JB; PROPPR Study Group. Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial: design, rationale and implementation. Injury. 2014 Sep;45(9):1287-95. doi: 10.1016/j.injury.2014.06.001. Epub 2014 Jun 10.
• Lissauer ME, Galvagno SM Jr, Rock P, Narayan M, Shah P, Spencer H, Hong C, Diaz JJ. Increased ICU resource needs for an academic emergency general surgery service*. Crit Care Med. 2014 Apr;42(4):910-7. doi: 10.1097/CCM.0000000000000099.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (ACTUAL): December 1, 2013
• Study Completion (ACTUAL): December 1, 2013

Study Registration Dates

• First Submitted: February 29, 2012
• First Submitted That Met QC Criteria: March 5, 2012
• First Posted (ESTIMATE): March 6, 2012

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2019
• Last Update Submitted That Met QC Criteria: February 6, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Inflammation; Pathologic Processes; Shock; Mortality; Massive Transfusion; Trauma; Hemorrhage; Plasma; Platelets; Red Blood Cells; Wounds and Injuries; Coagulation; Coagulopathy; Hemostatics; Shock, Hemorrhagic; Trauma Induced Coagulopathy; Transfusion-related acute lung injury (TRALI)
• Additional Relevant MeSH Terms: Wounds and Injuries
• Other Study ID Numbers: HSC-GEN-11-0174; U01HL077863 (U.S. NIH Grant/Contract)