Back to resultsStudy of Fibrinogen Concentrate (Human) (FCH) to Control Bleeding During Complex Cardiovascular Surgery (REPLACE)
Primary Purpose
Surgical Blood Loss, Postoperative Blood Loss
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Fibrinogen Concentrate (Human) (FCH)
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Surgical Blood Loss
Eligibility Criteria
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.
Sites / Locations
- Allgemeines Krankenhaus der Stadt Wien - Universitätskliniken
- Fundacao Universitaria de Cardiologia - Instituto de Cardiol
- InCor
- Providence Health-St Paul's Hospital
- Hamilton Health Science
- Ottawa General Hospital
- University of Toronto - St. Michael's Hospital
- Toronto General Hospital
- Universite Laval - Cardiologie et de Pneumologie de Quebec
- University Hospital St. Anna Brno
- Fakultni nemocnice Ostrava
- Kobenhavns Universitet-Det Sundhedsvidenskabelige Fakultet
- HUCH Anaestesia and Surgery
- Klinikum der Universität München
- Klinikum der J.-W.-Goethe-Universität
- Study Site
- Policlinico S. Orsola Malpighi
- Fondazione Centro San Raffaele
- Azienda Ospedaliera di Udine
- Nagoya University Hospital
- Kurume University Hospital
- Hamamatsu University Hospital
- Kobe University Hospital
- Kyoto University Hospital
- Tohoku University Hospital
- Tenri Hospital
- National Cerebral and Cardiovascular Center
- Keio University Hospital
- Inst. Kardiologii im. Prymasa Tysiaclecia Kard. S. Wyszynskiego
- Krakowski Szpital Specjalistyczny im. Jana Pawla II
- Samodzielny Publiczny Szpital Kliniczny nr 2
- Papworth Hospital
- University Hospital of Leicester
- Liverpool Heart and Chest Hospital
- Southampton General Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Fibrinogen Concentrate (Human)
Placebo
Arm Description
Outcomes
Primary Outcome Measures
Total units of allogeneic blood products
Number of units administered of all allogeneic blood products combined (fresh frozen plasma, platelets, and red blood cells)
Secondary Outcome Measures
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
Quantity of blood loss (6 hours)
Blood drainage volume from the chest
Quantity of blood loss (12 hours)
Blood drainage volume from the chest
Quantity of blood loss (24 hours)
Blood drainage volume from the chest
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.
Mortality (Day 10)
Mortality with adjudicated cause of death up to 10 days after surgery
Mortality (Day 30)
Mortality with adjudicated cause of death up to 30 days after surgery
FFP consumption (24 hours)
FFP consumption (10 days)
Platelet consumption (24 hours)
Platelet consumption (10 days)
Red blood cells (RBC) consumption (24 hours)
RBC consumption (10 days)
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
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
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
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
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
Time from administration of study drug to completion of skin closure
Mortality (24 hours)
Mortality with adjudicated cause of death during the first 24 hours after administration of IMP
Peak plasma concentration of fibrinogen (Cmax)
Maximum clot firmness
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01475669
Brief Title
Study of Fibrinogen Concentrate (Human) (FCH) to Control Bleeding During Complex Cardiovascular Surgery
Acronym
REPLACE
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
September 2014
Overall Recruitment Status
Completed
Study Start Date
January 2012 (undefined)
Primary Completion Date
July 2014 (Actual)
Study Completion Date
September 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CSL Behring
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Surgical Blood Loss, Postoperative Blood Loss
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
152 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Fibrinogen Concentrate (Human)
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Biological
Intervention Name(s)
Fibrinogen Concentrate (Human) (FCH)
Intervention Description
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
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
Single dose of sodium chloride solution infused intravenously within 5 minutes at a volume equivalent to that needed for FCH
Primary Outcome Measure Information:
Title
Total units of allogeneic blood products
Description
Number of units administered of all allogeneic blood products combined (fresh frozen plasma, platelets, and red blood cells)
Time Frame
Up to 24 hours after investigational medicinal product (IMP) administration
Secondary Outcome Measure Information:
Title
Total avoidance of allogeneic blood transfusions
Description
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
Time Frame
24 hours after IMP administration
Title
Quantity of blood loss (6 hours)
Description
Blood drainage volume from the chest
Time Frame
6 hours after skin closure
Title
Quantity of blood loss (12 hours)
Description
Blood drainage volume from the chest
Time Frame
12 hours after skin closure
Title
Quantity of blood loss (24 hours)
Description
Blood drainage volume from the chest
Time Frame
24 hours after skin closure
Title
Change in bleeding mass
Description
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.
Time Frame
Immediately before and 5 minutes after completion of IMP administration
Title
Mortality (Day 10)
Description
Mortality with adjudicated cause of death up to 10 days after surgery
Time Frame
Up to 10 days after surgery
Title
Mortality (Day 30)
Description
Mortality with adjudicated cause of death up to 30 days after surgery
Time Frame
Up to 30 days after surgery
Title
FFP consumption (24 hours)
Time Frame
24 hours after IMP administration
Title
FFP consumption (10 days)
Time Frame
10 days after IMP administration
Title
Platelet consumption (24 hours)
Time Frame
24 hours after IMP administration
Title
Platelet consumption (10 days)
Time Frame
10 days after IMP administration
Title
Red blood cells (RBC) consumption (24 hours)
Time Frame
24 hours after IMP administration
Title
RBC consumption (10 days)
Time Frame
10 days after IMP administration
Title
Total units of all allogeneic blood products (6 hours)
Description
Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP
Time Frame
6 hours after IMP administration
Title
Total units of all allogeneic blood products (12 hours)
Description
Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP
Time Frame
12 hours after IMP administration
Title
Volume of all allogeneic blood products (6 hours)
Description
Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP
Time Frame
6 hours after IMP administration
Title
Volume of all allogeneic blood products (12 hours)
Description
Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP
Time Frame
12 hours after IMP administration
Title
Volume of all allogeneic blood products (24 hours)
Description
Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 24 hours after administration of IMP
Time Frame
24 hours after IMP administration
Title
Time from administration of study drug to completion of skin closure
Time Frame
Average 2 hours
Title
Mortality (24 hours)
Description
Mortality with adjudicated cause of death during the first 24 hours after administration of IMP
Time Frame
WIthin 24 hours after IMP administration
Title
Peak plasma concentration of fibrinogen (Cmax)
Time Frame
At up to 10 time points from baseline and up to Day 11 after surgery.
Title
Maximum clot firmness
Time Frame
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).
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Niels Rahe-Meyer, MD, PhD
Organizational Affiliation
Hannover Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
Allgemeines Krankenhaus der Stadt Wien - Universitätskliniken
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
Fundacao Universitaria de Cardiologia - Instituto de Cardiol
City
Porto Alegre
State/Province
Rio Grande do Sul
ZIP/Postal Code
90620001
Country
Brazil
Facility Name
InCor
City
Sao Paulo
ZIP/Postal Code
05403-000
Country
Brazil
Facility Name
Providence Health-St Paul's Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6Z 1Y6
Country
Canada
Facility Name
Hamilton Health Science
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8L 2X2
Country
Canada
Facility Name
Ottawa General Hospital
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
University of Toronto - St. Michael's Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5B 1W8
Country
Canada
Facility Name
Toronto General Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2C4
Country
Canada
Facility Name
Universite Laval - Cardiologie et de Pneumologie de Quebec
City
Sainte Foy
State/Province
Quebec
ZIP/Postal Code
G1V 4G5
Country
Canada
Facility Name
University Hospital St. Anna Brno
City
Brno
ZIP/Postal Code
65691
Country
Czech Republic
Facility Name
Fakultni nemocnice Ostrava
City
Ostrava - Poruba
ZIP/Postal Code
708 52
Country
Czech Republic
Facility Name
Kobenhavns Universitet-Det Sundhedsvidenskabelige Fakultet
City
Copenhagen
ZIP/Postal Code
2200
Country
Denmark
Facility Name
HUCH Anaestesia and Surgery
City
Helsinki
ZIP/Postal Code
FI-00290
Country
Finland
Facility Name
Klinikum der Universität München
City
Munich
State/Province
Bayern
ZIP/Postal Code
81377
Country
Germany
Facility Name
Klinikum der J.-W.-Goethe-Universität
City
Frankfurt am Main
State/Province
Hessen
ZIP/Postal Code
60590
Country
Germany
Facility Name
Study Site
City
Bielefeld/Hannover
Country
Germany
Facility Name
Policlinico S. Orsola Malpighi
City
Bologna
Country
Italy
Facility Name
Fondazione Centro San Raffaele
City
Milano
ZIP/Postal Code
20132
Country
Italy
Facility Name
Azienda Ospedaliera di Udine
City
Udine
ZIP/Postal Code
33100
Country
Italy
Facility Name
Nagoya University Hospital
City
Nagoya
State/Province
Aichi
ZIP/Postal Code
466-8560
Country
Japan
Facility Name
Kurume University Hospital
City
Kurume
State/Province
Fukuoka-ken
ZIP/Postal Code
830-0011
Country
Japan
Facility Name
Hamamatsu University Hospital
City
Hamamatsu
State/Province
Higashi-ku
ZIP/Postal Code
431-3192
Country
Japan
Facility Name
Kobe University Hospital
City
Kobe
State/Province
Hyogo
ZIP/Postal Code
650-0017
Country
Japan
Facility Name
Kyoto University Hospital
City
Kyoto
State/Province
Kamigyo-ku
ZIP/Postal Code
602-8566
Country
Japan
Facility Name
Tohoku University Hospital
City
Sendai
State/Province
Miyagi
ZIP/Postal Code
980-8574
Country
Japan
Facility Name
Tenri Hospital
City
Tenri
State/Province
Nara
ZIP/Postal Code
632-8552
Country
Japan
Facility Name
National Cerebral and Cardiovascular Center
City
Suita, Osaka
State/Province
Osaka
ZIP/Postal Code
565-8565
Country
Japan
Facility Name
Keio University Hospital
City
Shinjuku
ZIP/Postal Code
160-8582
Country
Japan
Facility Name
Inst. Kardiologii im. Prymasa Tysiaclecia Kard. S. Wyszynskiego
City
Warszawa - Anin
State/Province
Mazowieckie
ZIP/Postal Code
04-628
Country
Poland
Facility Name
Krakowski Szpital Specjalistyczny im. Jana Pawla II
City
Krakow
ZIP/Postal Code
31-202
Country
Poland
Facility Name
Samodzielny Publiczny Szpital Kliniczny nr 2
City
Szczecin
ZIP/Postal Code
70-111
Country
Poland
Facility Name
Papworth Hospital
City
Cambridge
ZIP/Postal Code
CB23 3RE
Country
United Kingdom
Facility Name
University Hospital of Leicester
City
Leicester
ZIP/Postal Code
LE3 9QT
Country
United Kingdom
Facility Name
Liverpool Heart and Chest Hospital
City
Liverpool
ZIP/Postal Code
L14 3PE
Country
United Kingdom
Facility Name
Southampton General Hospital
City
Southampton
ZIP/Postal Code
SO16 6YD
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
30462259
Citation
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.
Results Reference
derived
PubMed Identifier
27317703
Citation
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.
Results Reference
derived
Learn more about this trial
Study of Fibrinogen Concentrate (Human) (FCH) to Control Bleeding During Complex Cardiovascular Surgery
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