Clinical trial NCT01475669: Study of Fibrinogen Concentrate (Human) (FCH) to Control Bleeding During Complex Cardiovascular Surgery
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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Surgical Blood Loss
Postoperative Blood Loss
Lead sponsor: CSL Behring
Sponsor class: INDUSTRY
First posted: 2011-11-21
Enrollment: 152
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Total units of allogeneic blood products
timeFrame: Up to 24 hours after investigational medicinal product (IMP) administration
Secondary outcomes:
measure: Total avoidance of allogeneic blood transfusions
timeFrame: 24 hours after IMP administration
measure: Quantity of blood loss (6 hours)
timeFrame: 6 hours after skin closure
measure: Quantity of blood loss (12 hours)
timeFrame: 12 hours after skin closure
measure: Quantity of blood loss (24 hours)
timeFrame: 24 hours after skin closure
measure: Change in bleeding mass
timeFrame: Immediately before and 5 minutes after completion of IMP administration
measure: Mortality (Day 10)
timeFrame: Up to 10 days after surgery
measure: Mortality (Day 30)
timeFrame: Up to 30 days after surgery
measure: FFP consumption (24 hours)
timeFrame: 24 hours after IMP administration
measure: FFP consumption (10 days)
timeFrame: 10 days after IMP administration
measure: Platelet consumption (24 hours)
timeFrame: 24 hours after IMP administration
measure: Platelet consumption (10 days)
timeFrame: 10 days after IMP administration
measure: Red blood cells (RBC) consumption (24 hours)
timeFrame: 24 hours after IMP administration
measure: RBC consumption (10 days)
timeFrame: 10 days after IMP administration
measure: Total units of all allogeneic blood products (6 hours)
timeFrame: 6 hours after IMP administration
measure: Total units of all allogeneic blood products (12 hours)
timeFrame: 12 hours after IMP administration
measure: Volume of all allogeneic blood products (6 hours)
timeFrame: 6 hours after IMP administration
measure: Volume of all allogeneic blood products (12 hours)
timeFrame: 12 hours after IMP administration
measure: Volume of all allogeneic blood products (24 hours)
timeFrame: 24 hours after IMP administration
measure: Time from administration of study drug to completion of skin closure
timeFrame: Average 2 hours
measure: Mortality (24 hours)
timeFrame: WIthin 24 hours after IMP administration
measure: Peak plasma concentration of fibrinogen (Cmax)
timeFrame: At up to 10 time points from baseline and up to Day 11 after surgery.
measure: Maximum clot firmness
timeFrame: 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).
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus der Stadt Wien - Universitätskliniken
city: Porto Alegre
country: Brazil
facility: Fundacao Universitaria de Cardiologia - Instituto de Cardiol
state: Rio Grande do Sul
city: Sao Paulo
country: Brazil
facility: InCor
city: Vancouver
country: Canada
facility: Providence Health-St Paul's Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton Health Science
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa General Hospital
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto - St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Sainte Foy
country: Canada
facility: Universite Laval - Cardiologie et de Pneumologie de Quebec
state: Quebec
city: Brno
country: Czech Republic
facility: University Hospital St. Anna Brno
city: Ostrava - Poruba
country: Czech Republic
facility: Fakultni nemocnice Ostrava
city: Copenhagen
country: Denmark
facility: Kobenhavns Universitet-Det Sundhedsvidenskabelige Fakultet
city: Helsinki
country: Finland
facility: HUCH Anaestesia and Surgery
city: Munich
country: Germany
facility: Klinikum der Universität München
state: Bayern
city: Frankfurt am Main
country: Germany
facility: Klinikum der J.-W.-Goethe-Universität
state: Hessen
city: Bielefeld/Hannover
country: Germany
facility: Study Site
city: Bologna
country: Italy
facility: Policlinico S. Orsola Malpighi
city: Milano
country: Italy
facility: Fondazione Centro San Raffaele
city: Udine
country: Italy
facility: Azienda Ospedaliera di Udine
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aichi
city: Kurume
country: Japan
facility: Kurume University Hospital
state: Fukuoka-ken
city: Hamamatsu
country: Japan
facility: Hamamatsu University Hospital
state: Higashi-ku
city: Kobe
country: Japan
facility: Kobe University Hospital
state: Hyogo
city: Kyoto
country: Japan
facility: Kyoto University Hospital
state: Kamigyo-ku
city: Sendai
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Tenri
country: Japan
facility: Tenri Hospital
state: Nara
city: Suita, Osaka
country: Japan
facility: National Cerebral and Cardiovascular Center
state: Osaka
city: Shinjuku
country: Japan
facility: Keio University Hospital
city: Warszawa - Anin
country: Poland
facility: Inst. Kardiologii im. Prymasa Tysiaclecia Kard. S. Wyszynskiego
state: Mazowieckie
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawla II
city: Szczecin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 2
city: Cambridge
country: United Kingdom
facility: Papworth Hospital
city: Leicester
country: United Kingdom
facility: University Hospital of Leicester
city: Liverpool
country: United Kingdom
facility: Liverpool Heart and Chest Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: Hannover Medical School
name: Niels Rahe-Meyer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.