Contact information
Type
Scientific
Primary contact
Prof Robert Porte
ORCID ID
Contact details
Chief Department of Hepatobiliary Surgery and Liver Transplantation
University Medical Center Groningen
PO Box 30001
Groningen
9700 RB
Netherlands
r.j.porte@chir.umcg.nl
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
N/A
Study information
Scientific title
Efficacy of fibrin sealant in reducing resection surface crelated complications after partial liver resections (FRESCO trial): A Dutch, multicentre, prospective, randomised, controlled trial
Acronym
FRESCO trial
Study hypothesis
The application of fibrin sealant to the cut surface of the liver remnant and to the diaphragm after elective hepatic resection will decrease the incidence of resection surface-related complications and diaphragm-related complications.
Ethics approval
Medical Ethical Board of University Medical Center Groningen approved on the 12th October 2005 (ref: 2005/183)
Study design
National multicentre prospective randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please contact m.t.de.boer@chir.umcg.nl to request a patient information sheet (Dutch only)
Condition
Partial liver resection complications
Intervention
Randomisation to treatment group will be performed using a sealed envelope and will be performed prior to peritoneal closure after completion of conventional hemostasis and bile stasis. Only the surgeon cannot be blinded to one of two groups. Patients, ward staff and radiologists will be blinded for study medication. Stratification will be done by diagnosis: benign versus malignant.
The fibrin sealant that used in this study is Quixil® Human Surgical Sealant Kit (hereinafter called Quixil®). It consists of a packet containing two components in separate vials of 5 ml. Vial I contains Biological Active Component (BAC): a concentrate of human clottable fibrinogen at a concentration of 40 - 60 mg/ml. A synthetic antifibrinolytic agent, tranexamic acid (85 - 105 mg/ml) is added to the fibrinogen as a stabiliser. Vial II consists of a high concentration of human thrombin (800 - 1200 IU/ml) dissolved in a solution of 5.6 6.2 mg/ml of calcium chloride. Both components undergo double viral-inactivation steps: treatment with solvent detergent followed by pasteurisation (at 60 degrees Celsius for ten hours) for the fibrinogen and nanofiltration for the thrombin. Quixil® is provided by the manufacturer in a 10 ml double-syringe spray-device.
Group 1:
After liver resection and completion of hemostasis the envelope is opened showing treatment arm. Maximum 5 ml of fibrin sealant is sprayed or dripped on the resection surface of the liver. Maximum 5 ml of fibrin sealant is sprayed on the bare diaphragmatic resection surface. Preferably a drain will be placed adjacent to the cut liver surface.
Group 2:
After liver resection and completion of hemostasis the envelope is opened showing control arm. Preferably a drain will be placed adjacent to the cut liver surface.
Duration of treatment: single application during operation when patient is randomised in treatment arm. Total duration of follow-up will be 30 days.
For calculation of the required study-population size, resection surface-related complications such as bleeding, biloma and/or abscess formation are considered the most important target variables. Based on experience and publications of several centres, the overall proportion of these complications is estimated to be 15-20% when no fibrin sealant is applied to the resection surface (control group). A difference of about 50% between the control group and the fibrin sealant group is regarded as clinically significant. This would result in a proportion of 7.5-10% resection surface-related complications in the fibrin sealant group. Based on these assumptions, we calculated that a study size of 220 patients in each group will be needed to achieve 80% power at the 5% significance level. To have some safety margins it was decided to enrol 250 patients in each group.
The primary endpoint of this study, however, will not only be the clinical presentation of a resection surface related complication, but also all CT scan detected complications. Although the exact incidence of CT scan detected complications is not known, this is expected to be higher than that of clinically detected complications. Therefore, an interim analysis will be performed after 180 patients (90 in each group). Main reason to do an interim analysis is to investigate weather the assumed complication rate is indeed 15 to 20%, or much higher. If the complication rate is higher, a smaller number of patients will be required to obtain the same level of statistical power as outlined above.
An interim analysis was performed in November 2009 after we had the completed CRFs of 180 patients enrolled in the FRESCO trial. An independent epidemiologist analysed the complication rate in the control group. This complication rate was higher than expected: 30,4%. Based on the complication percentage of 30.4% and on the assumption that a difference of 50% between the control group and the fibrin sealant group is clinically significant, a study size of 131 patients in each group will be needed to achieve a 80% power at the 5% significance level. To have some safety margins it was decided to enrol 300 patients in total.
Intervention type
Procedure/Surgery
Phase
Not Applicable
Drug names
Primary outcome measure
1. Resection surface related complications detected by computed tomography (CT) scan or clinical symptoms: haematoma, biloma or subphrenic abscess
2. Diaphragm related complications detected by CT scan or clinical symptoms: pleural effusion
3. Need for reintervention for bleeding or bile leakage from the cut surface of the liver, or pleural effusion
CT scan after 7 days, further assessment of complications and reinterventions during hospital stay until first out-patient appointment.
Secondary outcome measures
1. Changes in drain bilirubin (micromol/l), drain hemoglobin concentration (mmol/l) and volume of fluid drainage (ml) from the abdominal drains during the first three days post-operatively
2. Decrease in serum haemoglobin concentration (mmol/l) (lab day 1, 3, 5, 7, thereafter weekly)
3. Transfusion requirement (whole admission until first outpatient appointment)
4. Post-operative morbidity (whole admission until outpatient appointment)
5. Post-operative mortality (whole admission until outpatient appointment)
6. Length of hospital stay (whole admission until outpatient appointment)
Overall trial start date
23/05/2006
Overall trial end date
01/06/2010
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patients aged greater than or equal to 18 years, either sex
2. Undergo liver resections (at least one segment) for benign or malignant tumours or metastatic tumours, or
3. Undergo liver resection in combination with radiofrequency ablation (RFA)
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
600
Participant exclusion criteria
1. Aged less than 18 years
2. Undergo liver resections with extrahepatic biliary resection and reconstruction (Klatskin tumours)
3. Cirrhosis
4. Other disorders of haemostasis
5. Polycystic liver disease
6. Any associated operative gastrointestinal procedures (a needle catheter jejunostomy is not excluded)
7. Wedge resections
8. Pregnancy
9. History of hypersensitivity, allergy or anaphylactic reaction to any plasma derived product, including fibrin sealant
Recruitment start date
23/05/2006
Recruitment end date
01/06/2010
Locations
Countries of recruitment
Netherlands
Trial participating centre
Chief Department of Hepatobiliary Surgery and Liver Transplantation
Groningen
9700 RB
Netherlands
Sponsor information
Organisation
Johnson and Johnson Medical Limited (UK)
Sponsor details
Kirkton Campus
Simpson Parkway
Livingston
EH54 7AT
United Kingdom
Sponsor type
Industry
Website
Funders
Funder type
Hospital/treatment centre
Funder name
University Medical Center Groningen (UMCG) (Netherlands) - local hospital committee performance audit (Doelmatigheidsonderzoek) funding
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Johnson and Johnson Medical Limited (UK) - supplying fibrin sealant and funding of CT scans at one week post-operative
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
1. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22791099
Publication citations
-
Results
de Boer MT, Klaase JM, Verhoef C, van Dam RM, van Gulik TM, Molenaar IQ, Bosscha K, Dejong CH, Van der Jagt EJ, Porte RJ, , Fibrin sealant for prevention of resection surface-related complications after liver resection: a randomized controlled trial., Ann. Surg., 2012, 256, 2, 229-234, doi: 10.1097/SLA.0b013e3182602819.