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

Surgical Blood Loss Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01475669
• Other study ID #: BI3023_3002
• Secondary ID: 2011-002685-20
• Status: Completed
• Phase: Phase 3
• First received: November 17, 2011
• Last updated: September 17, 2014
• Start date: January 2012
• Est. completion date: September 2014

Study information

• Verified date: September 2014
• Source: CSL Behring
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Paul-Ehrlich-InstitutFinland: Finnish Medicines AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyItaly: Ethics CommitteeAustria: Austrian Medicines and Medical Devices AgencyCanada: Health CanadaIndia: Central Drugs Standard Control OrganizationPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsJapan: Pharmaceuticals and Medical Devices Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 152
• Est. completion date: September 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Blood Loss, Surgical
• Hemorrhage
• Postoperative Blood Loss
• Postoperative Hemorrhage
• Surgical Blood Loss

Intervention

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
Single dose of sodium chloride solution infused intravenously within 5 minutes at a volume equivalent to that needed for FCH

Locations

Country	Name	City	State
Austria	Allgemeines Krankenhaus der Stadt Wien - Universitätskliniken	Vienna
Brazil	Fundacao Universitaria de Cardiologia - Instituto de Cardiol	Porto Alegre	Rio Grande do Sul
Brazil	InCor	Sao Paulo
Canada	Hamilton Health Science	Hamilton	Ontario
Canada	Ottawa General Hospital	Ottawa	Ontario
Canada	Universite Laval - Cardiologie et de Pneumologie de Quebec	Sainte Foy	Quebec
Canada	Toronto General Hospital	Toronto	Ontario
Canada	University of Toronto - St. Michael's Hospital	Toronto	Ontario
Canada	Providence Health-St Paul's Hospital	Vancouver	British Columbia
Czech Republic	University Hospital St. Anna Brno	Brno
Czech Republic	Fakultni nemocnice Ostrava	Ostrava - Poruba
Denmark	Kobenhavns Universitet-Det Sundhedsvidenskabelige Fakultet	Copenhagen
Finland	HUCH Anaestesia and Surgery	Helsinki
Germany	Study Site	Bielefeld/Hannover
Germany	Klinikum der J.-W.-Goethe-Universität	Frankfurt am Main	Hessen
Germany	Klinikum der Universität München	Munich	Bayern
Italy	Policlinico S. Orsola Malpighi	Bologna
Italy	Fondazione Centro San Raffaele	Milano
Italy	Azienda Ospedaliera di Udine	Udine
Japan	Hamamatsu University Hospital	Hamamatsu	Higashi-ku
Japan	Kobe University Hospital	Kobe	Hyogo
Japan	Kurume University Hospital	Kurume	Fukuoka-ken
Japan	Kyoto University Hospital	Kyoto	Kamigyo-ku
Japan	Nagoya University Hospital	Nagoya	Aichi
Japan	Tohoku University Hospital	Sendai	Miyagi
Japan	Keio University Hospital	Shinjuku
Japan	National Cerebral and Cardiovascular Center	Suita, Osaka	Osaka
Japan	Tenri Hospital	Tenri	Nara
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla II	Krakow
Poland	Samodzielny Publiczny Szpital Kliniczny nr 2	Szczecin
Poland	Inst. Kardiologii im. Prymasa Tysiaclecia Kard. S. Wyszynskiego	Warszawa - Anin	Mazowieckie
United Kingdom	Papworth Hospital	Cambridge
United Kingdom	University Hospital of Leicester	Leicester
United Kingdom	Liverpool Heart and Chest Hospital	Liverpool
United Kingdom	Southampton General Hospital	Southampton

Sponsors (1)

Lead Sponsor	Collaborator
CSL Behring

Countries where clinical trial is conducted

Austria,  Brazil,  Canada,  Czech Republic,  Denmark,  Finland,  Germany,  Italy,  Japan,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	Quantity of blood loss (6 hours)	Blood drainage volume from the chest	6 hours after skin closure	No
Secondary	Quantity of blood loss (12 hours)	Blood drainage volume from the chest	12 hours after skin closure	No
Secondary	Quantity of blood loss (24 hours)	Blood drainage volume from the chest	24 hours after skin closure	No
Secondary	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	No
Secondary	Mortality (Day 10)	Mortality with adjudicated cause of death up to 10 days after surgery	Up to 10 days after surgery	No
Secondary	Mortality (Day 30)	Mortality with adjudicated cause of death up to 30 days after surgery	Up to 30 days after surgery	No
Secondary	FFP consumption (24 hours)		24 hours after IMP administration	No
Secondary	FFP consumption (10 days)		10 days after IMP administration	No
Secondary	Platelet consumption (24 hours)		24 hours after IMP administration	No
Secondary	Platelet consumption (10 days)		10 days after IMP administration	No
Secondary	Red blood cells (RBC) consumption (24 hours)		24 hours after IMP administration	No
Secondary	RBC consumption (10 days)		10 days after IMP administration	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Time from administration of study drug to completion of skin closure		Average 2 hours	No
Secondary	Mortality (24 hours)	Mortality with adjudicated cause of death during the first 24 hours after administration of IMP	WIthin 24 hours after IMP administration	No
Secondary	Peak plasma concentration of fibrinogen (Cmax)		At up to 10 time points from baseline and up to Day 11 after surgery.	No
Secondary	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).	No