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

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ClinicalTrials.gov Identifier: NCT01475669
Recruitment Status : Completed
First Posted : November 21, 2011
Last Update Posted : September 18, 2014
Sponsor:
Information provided by (Responsible Party):
CSL Behring

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.


Condition or disease Intervention/treatment Phase
Surgical Blood Loss Postoperative Blood Loss Biological: Fibrinogen Concentrate (Human) (FCH) Biological: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 152 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : January 2012
Actual Primary Completion Date : July 2014
Actual Study Completion Date : September 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding
Drug Information available for: Fibrinogen

Arm Intervention/treatment
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

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




Primary Outcome Measures :
  1. Total units of allogeneic blood products [ Time Frame: Up to 24 hours after investigational medicinal product (IMP) administration ]
    Number of units administered of all allogeneic blood products combined (fresh frozen plasma, platelets, and red blood cells)


Secondary Outcome Measures :
  1. Total avoidance of allogeneic blood transfusions [ Time Frame: 24 hours after IMP administration ]
    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

  2. Quantity of blood loss (6 hours) [ Time Frame: 6 hours after skin closure ]
    Blood drainage volume from the chest

  3. Quantity of blood loss (12 hours) [ Time Frame: 12 hours after skin closure ]
    Blood drainage volume from the chest

  4. Quantity of blood loss (24 hours) [ Time Frame: 24 hours after skin closure ]
    Blood drainage volume from the chest

  5. Change in bleeding mass [ Time Frame: Immediately before and 5 minutes after completion of IMP administration ]
    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.

  6. Mortality (Day 10) [ Time Frame: Up to 10 days after surgery ]
    Mortality with adjudicated cause of death up to 10 days after surgery

  7. Mortality (Day 30) [ Time Frame: Up to 30 days after surgery ]
    Mortality with adjudicated cause of death up to 30 days after surgery

  8. FFP consumption (24 hours) [ Time Frame: 24 hours after IMP administration ]
  9. FFP consumption (10 days) [ Time Frame: 10 days after IMP administration ]
  10. Platelet consumption (24 hours) [ Time Frame: 24 hours after IMP administration ]
  11. Platelet consumption (10 days) [ Time Frame: 10 days after IMP administration ]
  12. Red blood cells (RBC) consumption (24 hours) [ Time Frame: 24 hours after IMP administration ]
  13. RBC consumption (10 days) [ Time Frame: 10 days after IMP administration ]
  14. Total units of all allogeneic blood products (6 hours) [ Time Frame: 6 hours after IMP administration ]
    Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP

  15. Total units of all allogeneic blood products (12 hours) [ Time Frame: 12 hours after IMP administration ]
    Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP

  16. Volume of all allogeneic blood products (6 hours) [ Time Frame: 6 hours after IMP administration ]
    Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP

  17. Volume of all allogeneic blood products (12 hours) [ Time Frame: 12 hours after IMP administration ]
    Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP

  18. Volume of all allogeneic blood products (24 hours) [ Time Frame: 24 hours after IMP administration ]
    Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 24 hours after administration of IMP

  19. Time from administration of study drug to completion of skin closure [ Time Frame: Average 2 hours ]
  20. Mortality (24 hours) [ Time Frame: WIthin 24 hours after IMP administration ]
    Mortality with adjudicated cause of death during the first 24 hours after administration of IMP

  21. Peak plasma concentration of fibrinogen (Cmax) [ Time Frame: At up to 10 time points from baseline and up to Day 11 after surgery. ]
  22. 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). ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01475669


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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: CSL Behring
ClinicalTrials.gov Identifier: NCT01475669     History of Changes
Other Study ID Numbers: BI3023_3002
2011-002685-20 ( EudraCT Number )
First Posted: November 21, 2011    Key Record Dates
Last Update Posted: September 18, 2014
Last Verified: September 2014
Additional relevant MeSH terms:
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Hemorrhage
Blood Loss, Surgical
Postoperative Hemorrhage
Pathologic Processes
Intraoperative Complications
Postoperative Complications