Factor Replacement in Surgery (FARES)

Prothrombin Complex Concentrate Versus Frozen Plasma in Bleeding Adult Cardiac Surgical Patients: A Multicentre, Randomized, Active-control, Pragmatic, Phase 2 Pilot Study

This is a multicentre, randomized, active-control, pragmatic, Phase 2 pilot study in adult cardiac surgery patients. Two Canadian hospitals will participate, and it is estimated that the study will take approximately 9 months to complete.

Approximately 120 bleeding adult cardiac surgical patients who require coagulation factor replacement during cardiac surgery will be included. Patients will be randomized to receive either PCC or FP when the blood bank receives the first order for coagulation factor replacement and deems it to be in accordance with accepted clinical standards. Patients will be treated according to their assigned group on the first and second times when coagulation factor replacement is ordered during the treatment period (24 hours after randomization). For any additional doses (i.e., the third dose and thereafter), patients in both groups will receive FP (in 1U increments at the discretion of the ordering physician). No other aspects of care will be modified.

This pilot study aims to select a clinically relevant primary efficacy endpoint for a confirmative Phase 3 study, which will subsequently aim to determine if PCC is non-inferior or superior to FP in terms of effica-cy and safety in bleeding cardiac surgical patients. In the pilot study, safety outcomes will be measured for the first 28 days, which is the duration of participation of each patient in the trial.

Study Overview

• Status: Unknown
• Conditions: Bleeding in Cardiac Surgery
• Intervention / Treatment: Biological: Prothrombin Complex Concentrate; Biological: Frozen Plasma

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Science Centre

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:

Patients undergoing any index cardiac surgery with or without CPB in whom coagulation factor replacement with PCC or FP is ordered in the operating room for:

1. Management of bleeding, or

2. Anticipated bleeding in a patient who has

   1. been on-pump for >2 hours, or
   2. undergone a complex procedure (e.g., ACB + AVR). Coagulation factor deficiency must either be known to exist (as indicated by elevated EXTEM clotting time [CT] or international normalized ratio [INR]), or be suspected based on the clinical situation.

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for the study:

1. Undergoing heart transplantation, insertion or removal of ventricular assist devices (not including intra-aortic balloon pump [IABP]), or repair of thoracoabdominal aneurysm
2. Critical state immediately before emergency surgery with high probability of death within 24 hours of surgery (e.g., acute aortic dissection, cardiac arrest within 24 hours before start of surgery)
3. History of heparin induced thrombocytopenia
4. Last preoperative INR >1.5 and patient on warfarin
5. Taken dabigatran, rivaroxaban, apixaban, or edoxaban within 48 hours of start of surgery
6. Administered PCC or FP within 48 hours before start of surgery
7. History of severe allergic reaction to PCC or FP
8. Refusal of allogeneic blood products due to religious or other reasons
9. Known pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Prothrombin Complex Concentrate	Biological: Prothrombin Complex Concentrate; Octaplex will be administered when the blood bank receives an order for coagulation factor replacement; Other Names: Octaplex
ACTIVE_COMPARATOR: Frozen Plasma	Biological: Frozen Plasma; Frozen Plasma will be administered when the blood bank receives an order for coagulation factor replacement; Other Names: Fresh Frozen Plasma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response	Administration of hemostatic agents including a second dose of IMP, platelet transfusion, or surgical re-exploration	At 4 and 24 hours
Amount of allogeneic blood products		24 hours after the start of surgery
Number of patients who do not receive any RBC transfusions or any allogeneic blood transfusions		first 24 hours after the start of surgery

Collaborators and Investigators

• Sponsor: University Health Network, Toronto

Publications and helpful links

General Publications

• Karkouti K, Bartoszko J, Grewal D, Bingley C, Armali C, Carroll J, Hucke HP, Kron A, McCluskey SA, Rao V, Callum J. Comparison of 4-Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of Hemorrhage During and After Cardiac Surgery: A Randomized Pilot Trial. JAMA Netw Open. 2021 Apr 1;4(4):e213936. doi: 10.1001/jamanetworkopen.2021.3936.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 24, 2019
• Primary Completion (ACTUAL): July 21, 2020
• Study Completion (ANTICIPATED): December 31, 2020

Study Registration Dates

• First Submitted: September 25, 2019
• First Submitted That Met QC Criteria: October 1, 2019
• First Posted (ACTUAL): October 3, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 3, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Transfusion; Phase 2; Pilot; Frozen Plasma (FP); Prothrombin Complex Concentrate (PCC); Octaplex; Coagulation Factor Replacement; Bleeding Cardiac Surgical Patients
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Hemostatics; Coagulants; Thrombin
• Other Study ID Numbers: 19-5393

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No