Study of Fibrinogen Concentrate (Human) (FCH) to Control Bleeding During Complex Cardiovascular Surgery (REPLACE)

REPLACE (Randomized Evaluation of Fibrinogen Versus Placebo in Complex Cardiovascular Surgery): a Prospective, Multinational, Multicenter, Randomized, Double-blind, Placebo-controlled, Phase III Study for the Use of Fibrinogen Concentrate (Human) (FCH) in Complex Cardiovascular Surgery

The purpose of this study is to demonstrate that Fibrinogen Concentrate (Human)(FCH) can reduce the amount of donor blood products needed during complex cardiovascular surgery, and that it is safe and well tolerated. Subjects in this study will get either a FCH or placebo infusion during surgery. This will be in addition to the standard treatment, which is donor blood or blood products. Placebo does not contain any effective medicine.

The study is randomised. This means that the likelihood that subjects will get FCH or placebo is 50%. To make the comparison between FCH and placebo as fair as possible, the study is "double blind". This means that neither the subjects nor the study doctor will know if FCH or placebo is administered. If necessary, the study doctor can find out which treatment the subjects are receiving.

Study Overview

• Status: Completed
• Conditions: Surgical Blood Loss; Postoperative Blood Loss
• Intervention / Treatment: Biological: Fibrinogen Concentrate (Human) (FCH); Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Allgemeines Krankenhaus der Stadt Wien - Universitätskliniken
• Brazil
  • Sao Paulo, Brazil, 05403-000
    • InCor
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90620001
      • Fundacao Universitaria de Cardiologia - Instituto de Cardiol
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Providence Health-St Paul's Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton Health Science
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa General Hospital
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5B 1W8
      • University of Toronto - St. Michael's Hospital
  • Quebec
    • Sainte Foy, Quebec, Canada, G1V 4G5
      • Universite Laval - Cardiologie et de Pneumologie de Quebec
• Czech Republic
  • Brno, Czech Republic, 65691
    • University Hospital St. Anna Brno
  • Ostrava - Poruba, Czech Republic, 708 52
    • Fakultni Nemocnice Ostrava
• Denmark
  • Copenhagen, Denmark, 2200
    • Kobenhavns Universitet-Det Sundhedsvidenskabelige Fakultet
• Finland
  • Helsinki, Finland, FI-00290
    • HUCH Anaestesia and Surgery
• Germany
  • Bielefeld/Hannover, Germany
    • Study Site
  • Bayern
    • Munich, Bayern, Germany, 81377
      • Klinikum der Universität München
  • Hessen
    • Frankfurt am Main, Hessen, Germany, 60590
      • Klinikum der J.-W.-Goethe-Universität
• Italy
  • Bologna, Italy
    • Policlinico S. Orsola Malpighi
  • Milano, Italy, 20132
    • Fondazione Centro San Raffaele
  • Udine, Italy, 33100
    • Azienda Ospedaliera di Udine
• Japan
  • Shinjuku, Japan, 160-8582
    • Keio University Hospital
  • Aichi
    • Nagoya, Aichi, Japan, 466-8560
      • Nagoya University Hospital
  • Fukuoka-ken
    • Kurume, Fukuoka-ken, Japan, 830-0011
      • Kurume University Hospital
  • Higashi-ku
    • Hamamatsu, Higashi-ku, Japan, 431-3192
      • Hamamatsu University Hospital
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0017
      • Kobe University Hospital
  • Kamigyo-ku
    • Kyoto, Kamigyo-ku, Japan, 602-8566
      • Kyoto University Hospital
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University Hospital
  • Nara
    • Tenri, Nara, Japan, 632-8552
      • Tenri Hospital
  • Osaka
    • Suita, Osaka, Osaka, Japan, 565-8565
      • National Cerebral and Cardiovascular Center
• Poland
  • Krakow, Poland, 31-202
    • Krakowski Szpital Specjalistyczny im. Jana Pawla II
  • Szczecin, Poland, 70-111
    • Samodzielny Publiczny Szpital Kliniczny Nr 2
  • Mazowieckie
    • Warszawa - Anin, Mazowieckie, Poland, 04-628
      • Inst. Kardiologii im. Prymasa Tysiaclecia Kard. S. Wyszynskiego
• United Kingdom
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital
  • Leicester, United Kingdom, LE3 9QT
    • University Hospital of Leicester
  • Liverpool, United Kingdom, L14 3PE
    • Liverpool Heart and Chest Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital

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:

At Screening:

• Undergoing elective open surgical procedures on any part of the aorta requiring cardiopulmonary bypass (CPB), with or without other cardiac surgical procedures (e.g. valve replacement or repair, coronary artery bypass grafting, etc.).
• 18 years of age or older.
• Written informed consent for study participation obtained before undergoing any study specific procedures.

Intraoperative (at the 1st 5-minute bleeding mass):

• A 5-minute bleeding mass of 60 to 250 g following discontinuation of CPB, administration of protamine, and establishment of surgical hemostasis.
• Minimum core body temperature 35°C, measured according to local practice.
• Activated clotting time ± 25% of baseline levels.
• Blood pH > 7.3.

Exclusion Criteria:

At Screening and/or baseline:

• Undergoing emergency aortic repair surgery.
• Reoperative aortic surgery at the same anatomic site as the original procedure such as replacement of a previously placed aortic graft. Resternotomy and rethoracotomy are permitted.
• Any operation for infection.
• Proof or suspicion of a congenital or acquired coagulation disorder (e.g. Von Willebrand's disease, hemophilia or severe liver disease) or a prothrombotic disorder (e.g. protein C or S deficiency).
• Myocardial infarction (MI), acute coronary syndrome or stroke in the 2 months preceding study surgery.
• Low molecular weight or unfractionated heparin in the 24 hours preceding study surgery.
• Clopidogrel administration within 5 days preceding study surgery or prasugrel administration within 7 days preceding study surgery or ticagrelor administration in the 48 hours preceding study surgery.
• Factor Xa inhibitors within 2 days preceding study surgery.
• IIb/IIIa antagonist administration in the 24 hours preceding study surgery.
• Use of direct thrombin inhibitors: within 3 days preceding study surgery for dabigatran and within 24 hours preceding study surgery for all others.
• An international normalized ratio > 1.3 immediately preceding the start of surgery.

Intraoperative (at the 1st 5-minute bleeding mass):

• Use of any systemic hemostatic therapy (such as FFP, platelets, prothrombin complex concentrates) from the beginning of surgery until IMP administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Biological: Placebo; Single dose of sodium chloride solution infused intravenously within 5 minutes at a volume equivalent to that needed for FCH
Experimental: Fibrinogen Concentrate (Human)	Biological: Fibrinogen Concentrate (Human) (FCH); Single dose infused intravenously within 5 minutes of the completion of the measurement of the 5-minute bleeding mass; the dose is determined individually based on the measured maximum clot firmness (MCF) and subject body weight

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total units of allogeneic blood products	Number of units administered of all allogeneic blood products combined (fresh frozen plasma, platelets, and red blood cells)	Up to 24 hours after investigational medicinal product (IMP) administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total avoidance of allogeneic blood transfusions	Number of subjects who are alive and do not have any administration of platelets, fresh frozen plasma (FFP), and red blood cells (RBCs) during the first 24 hours after administration of IMP	24 hours after IMP administration
Quantity of blood loss (6 hours)	Blood drainage volume from the chest	6 hours after skin closure
Quantity of blood loss (12 hours)	Blood drainage volume from the chest	12 hours after skin closure
Quantity of blood loss (24 hours)	Blood drainage volume from the chest	24 hours after skin closure
Change in bleeding mass	The 5-minute bleeding mass is measured as the difference in weight of surgical swabs after 5 minutes of surgical packing of the aortic surgical site.	Immediately before and 5 minutes after completion of IMP administration
Mortality (Day 10)	Mortality with adjudicated cause of death up to 10 days after surgery	Up to 10 days after surgery
Mortality (Day 30)	Mortality with adjudicated cause of death up to 30 days after surgery	Up to 30 days after surgery
FFP consumption (24 hours)		24 hours after IMP administration
FFP consumption (10 days)		10 days after IMP administration
Platelet consumption (24 hours)		24 hours after IMP administration
Platelet consumption (10 days)		10 days after IMP administration
Red blood cells (RBC) consumption (24 hours)		24 hours after IMP administration
RBC consumption (10 days)		10 days after IMP administration
Total units of all allogeneic blood products (6 hours)	Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP	6 hours after IMP administration
Total units of all allogeneic blood products (12 hours)	Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP	12 hours after IMP administration
Volume of all allogeneic blood products (6 hours)	Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP	6 hours after IMP administration
Volume of all allogeneic blood products (12 hours)	Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP	12 hours after IMP administration
Volume of all allogeneic blood products (24 hours)	Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 24 hours after administration of IMP	24 hours after IMP administration
Time from administration of study drug to completion of skin closure		Average 2 hours
Mortality (24 hours)	Mortality with adjudicated cause of death during the first 24 hours after administration of IMP	WIthin 24 hours after IMP administration
Peak plasma concentration of fibrinogen (Cmax)		At up to 10 time points from baseline and up to Day 11 after surgery.
Maximum clot firmness		At baseline; on the day of surgery at: 30 min before CPB, the 1st 5 min bleeding mass, the end of IMP infusion, the 2nd 5-min bleeding mass, and closure; and on Day 2, 3, 4 and at the end of the study (discharge/Day 11 or at discontinuation if earlier).

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Principal Investigator: Niels Rahe-Meyer, MD, PhD, Hannover Medical School

Publications and helpful links

General Publications

• Rahe-Meyer N, Levy JH, Mazer CD, Schramko A, Klein AA, Brat R, Okita Y, Ueda Y, Schmidt DS, Gill R. Randomized evaluation of fibrinogen versus placebo in complex cardiovascular surgery: post hoc analysis and interpretation of phase III results. Interact Cardiovasc Thorac Surg. 2019 Apr 1;28(4):566-574. doi: 10.1093/icvts/ivy302.
• Rahe-Meyer N, Levy JH, Mazer CD, Schramko A, Klein AA, Brat R, Okita Y, Ueda Y, Schmidt DS, Ranganath R, Gill R. Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy. Br J Anaesth. 2016 Jul;117(1):41-51. doi: 10.1093/bja/aew169.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: November 17, 2011
• First Submitted That Met QC Criteria: November 17, 2011
• First Posted (Estimate): November 21, 2011

Study Record Updates

• Last Update Posted (Estimate): September 18, 2014
• Last Update Submitted That Met QC Criteria: September 17, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Intraoperative Complications; Hemorrhage; Blood Loss, Surgical; Postoperative Hemorrhage
• Other Study ID Numbers: BI3023_3002; 2011-002685-20 (EudraCT Number)