Condition category
Surgery
Date applied
18/02/2010
Date assigned
28/05/2010
Last edited
19/09/2012
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

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 CRF’s 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 measures

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

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

http://www.jnj.com/connect/

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

Results - basic reporting

Publication summary

1. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22791099

Publication citations

  1. 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.

Additional files

Editorial Notes