FALCON: a Multicenter Randomized Controlled Trial

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Brief Title

FALCON: a Multicenter Randomized Controlled Trial

Official Title

Near-infrared Fluorescence Cholangiography Assisted Laparoscopic Cholecystectomy Versus Conventional Laparoscopic Cholecystectomy (FALCON): a Multicenter Randomized Controlled Trial

Brief Summary

      Rationale: Several clinical feasibility studies have shown the potential benefit of
      near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) for enhanced and
      earlier biliary anatomy visualization during laparoscopic cholecystectomy with the aim to
      reduce the number of vascular and biliary injuries. Although the incidence of injuries is low
      (0.7%), the impact on patients in terms of morbidity, quality of life and costs are dramatic.
      The Critical View of Safety (CVS) technique is regarded as the safety valve in conventional
      laparoscopic cholecystectomy (CLC). It is hypothesized that standard application of
      near-infrared fluorescence imaging during laparoscopic cholecystectomy can be useful to
      obtain establishment of CVS (at least 5 minutes) earlier and with more certainty regarding
      visualization when compared to conventional laparoscopic imaging alone.

      Study design: A multicenter randomized controlled trial with two study arms. Patients
      scheduled for an elective laparoscopic cholecystectomy will be recruited and randomized at
      the outpatient clinic (n = 308 total). One group will undergo near-infrared fluorescence
      cholangiography assisted laparoscopic cholecystectomy (NIRF-LC) and the other group will
      undergo conventional laparoscopic cholecystectomy (CLC).

      Compared with standard care, patients in the NIRF-LC group have to receive one preoperative
      intravenous injection of ICG. This is the only additional minimally invasive action for the
      patient. Initially, patients participating in this study will not benefit from the
      application of NIRFC during the surgical procedure. The administration of ICG and the
      modified laparoscope itself are not related with any kind of additional risk for the patient.

      Despite the encouraging results from several (pre)clinical feasibility studies, wide clinical
      acceptance of the routine use of ICG fluorescence laparoscopy is still lacking due to the
      absence of reliable and validated clinical data. A randomized clinical study is desirable to
      assess the potential added value of the NIRF imaging technique during laparoscopic
      cholecystectomy. Strong evidence in favor of routine implementation of this new imaging
      technique during laparoscopic cholecystectomy, will probably lead to worldwide routine
      application of the NIRF technique. Therewith long term sustainability of this research
      project is guaranteed.
    

Detailed Description

      Laparoscopic cholecystectomy (LC) is one of the most commonly performed laparoscopic
      procedures in gastrointestinal surgery. Bile duct injury during this procedure is rare but
      constitutes a serious complication (0.3-0.7%) (Flum 2003, Fletcher 1999, Nuzzo 2005 and Waage
      2005). Misidentification of the extra-hepatic bile duct anatomy during laparoscopic
      cholecystectomy is the main cause of bile duct injury (Way 2006).

      The Critical View of Safety (CVS) technique, which was first described by Strasberg in 1995
      (Strasberg 2003) and recommended by the Dutch Guidelines and Best Practice for laparoscopic
      cholecystectomy (Lange 2006), was introduced to reduce the risk of bile duct injury. To
      establish CVS, two windows need to be created: one window between the cystic artery, cystic
      duct and gallbladder, another window between the cystic artery, gallbladder and liver. The
      CVS technique is especially aimed at mobilizing the gallbladder neck from the liver, in order
      to obtain a circumferential identification of the transition of the cystic duct into the
      gallbladder.

      Intraoperative cholangiography has been advised to reduce the risk of bile duct injury (Flum
      2003, Buddinhg 2011). However, this radiological imaging of the biliary tree is only used
      selectively, as the process takes time, radiation exposure is involved and additional
      equipment and manpower for the procedure are required. Therefore, worldwide consensus about
      implementation of intraoperative cholangiography is still lacking (Ford 2012).

      Near-infrared fluorescence (NIRF) imaging after intravenous injection of indocyanine green
      (ICG) is a promising new technique for easier intraoperative recognition of the biliary
      anatomy. It may help improve the outcome of laparoscopic cholecystectomy (Buddingh 2011,
      Agarwal 2009). ICG is cleared quickly and exclusively by the liver after intravenous
      administration. Neither radiological support nor additional intervention, such as opening the
      biliary tree, is required. The NIRF laparoscopy technique using ICG has been evaluated in
      various animal models (Figueiredo 2010, Figueiredo 2011, Tagaya 2010, Matsui 2010) and in
      open, laparoscopic, and single-incision laparoscopic cholecystectomy (Tagaya 2010, Ishazawa
      2010, Ishazawa 2011 Aoki 2010). Promising results were presented for successful
      intraoperative identification of the common bile duct and the cystic duct, compared to
      conventional laparoscopic imaging. Another clinical study showed that the NIRFC technique
      provides significantly earlier identification of the extra-hepatic bile ducts during the CVS
      dissection phase: up to 10 minutes earlier identification of cystic duct and common bile duct
      could be obtained (Schols 2012). Real-time simultaneous imaging of the hepatic and cystic
      arteries can also be obtained (Ashitate 2011, Mitsuhashi 2008, Schols 2013).

      Despite the encouraging results from these (pre)clinical feasibility studies, wide clinical
      acceptance of the routine use of ICG fluorescence laparoscopy is still lacking due to the
      absence of reliable clinical data. Therefore, a multicenter randomized clinical study is
      desirable to assess the potential added value of the fluorescence imaging technique during
      laparoscopic cholecystectomy in order to perform a more safe procedure leading to a reduction
      in the vascular and bile duct injuries. This study will compare NIRF assisted laparoscopic
      cholecystectomy to conventional laparoscopic cholecystectomy.

      The main objective of this study is to evaluate whether earlier establishment of Critical
      View of Safety can be obtained using the NIRF laparoscopy technique during laparoscopic
      cholecystectomy. This will shorten the operation time, and thereby reduce the cost of the
      procedure.

      Study design: Multicenter randomized controlled trial. 308 patients will be included for
      randomization. All patients (age >18 years) scheduled for an elective laparoscopic
      cholecystectomy and meeting the inclusion criteria will be suitable for inclusion. Patients
      will be included in at least 3 hospitals in The Netherlands: Maastricht University Medical
      Center+; Leiden University Medical Center; Catharina Hospital.

      Treatment of subjects: All operations will be performed by a surgical resident, assisted by a
      surgeon or surgical resident with a track record of at least 50 laparoscopic
      cholecystectomies, or will be performed by a surgeon or surgical resident with that track
      record him/herself. In the CLC group conventional laparoscopic cholecystectomy will be
      performed using conventional laparoscopic imaging systems. In the NIRF-LC group, using
      laparoscopic fluorescence imaging systems near-infrared fluorescence cholangiography
      technique will be conducted to assist during laparoscopic cholecystectomy. To obtain
      fluorescence imaging of the biliary tract a contrast agent has to be administered. Directly
      after induction of anesthesia the fluorescent dye, indocyanine green (ICG), will be
      administered for intraoperative visualization of the extra-hepatic bile ducts with the NIR
      fluorescence laparoscope. Since many years ICG has been approved for commercial and clinical
      diagnostic use by the FDA.

      Randomization: After inclusion in the study (i.e., after written informed consent is
      obtained) patients will be randomized to NIRF-LC or CLC group. Randomization will be
      performed centrally. Computerized treatment allocation will be conducted on the day of
      surgery. There will be no blinding of patients or surgeons.Stratification factor will be
      performed for participating center.The experience level of the surgical team will be
      recorded, but no stratification will take place for this factor, as due to the large volume
      of patients an even distribution of skill level over both randomization arms in expected.
      Experience is defined in performing laparoscopic cholecystectomy as first surgeon.

      Study procedures: The laparoscopic cholecystectomy procedure itself will not be performed
      differently than usual. Next, there will not be any radiation involved for the patient.
      Neither are any psychological or psychiatric investigations involved. Patients are not asked
      to undergo additional testing after the surgical procedure, they are also not requested to
      fulfill any questionnaire.

      The following procedures will be conducted during this study:

        -  Preoperative (NIRF-LC group): Directly after induction of anesthesia 1ml (2,5mg/ml)
           indocyanine green will be administrated via intravenous injection, by the surgeon or
           surgical trainee (under supervision of the surgeon and the anesthesiologist).

        -  Intraoperative (CLC and NIRF-LC group): Intraoperatively the PhD researcher / local
           researcher (to be appointed in each participating center) systematically whether the
           localization of the common bile duct, cystic duct and cystic artery can be identified at
           set time points, by both the conventional camera mode (CLC group) and fluorescence
           camera mode (NIRF-LC group). Also establishment of CVS is registered. For agreement on
           the identification of the aforementioned structures the attending surgeon is consulted.
           A structure is scored as 'identified' if its localization is confirmed with great
           certainty by the experienced surgeon. In case of the common bile duct this does
           explicitly not mean that it was surgically exposed, as this is contradictory to the
           CVS-technique. In accordance with regular care, all laparoscopic surgical procedures
           will be digitally recorded.

        -  Postoperative qualitative video analysis (CLC and NIRF-LC group)

      Performed by expert panel of 3 surgeons:

        -  Is CVS actually established? (and: at what time is CVS established?)

        -  Time until identification of the cystic duct, and time until identification of the
           transition of the cystic duct in the gallbladder during dissection of CVS;

        -  Time until identification of the cystic artery, and time until identification of the
           transition of the cystic artery in the gallbladder during dissection of CVS;
           Postoperative quantitative fluorescence image analysis (NIRF-LC group): For objective
           assessment of the degree of fluorescence illumination in the extra-hepatic bile ducts
           and artery, OsiriX 5.5.1 Imaging Software will be used. The fluorescence images will be
           analyzed by determining target-to-background ratio (TBR). TBR is defined as the mean
           fluorescence intensity (FI) of two point regions of interest (ROIs) in the target (i.e.
           CBD, CD or CA) minus the mean fluorescence intensity of two background (BG) ROIs in the
           liver hilum, divided by the mean fluorescence intensity of the two background ROIs in
           the liver hilum; in formula: TBR = (FI of target - FI of BG) / FI of BG.

      Postoperative registration of secondary endpoints (CLC and NIRF-LC group). The researcher
      will document the following remaining secondary endpoints: Intraoperative bile leakage from
      the gallbladder or cystic duct; Bile duct injury; Postoperative length of hospital stay;
      Complications due to the intravenously injected contrast agent; Conversion to open
      cholecystectomy; Postoperative complications (until 90 days after surgery) After 90 days the
      patient will contacted by telephone to register any complications that occurred after the
      routine visits.

      Cost-effectiveness minimisation of the procedure will be calculated, limited to the
      per-operative period. The observed reduction in time until CVS, calculated in cost per minute
      use of the operating suite, will be weighed against the extra cost of the use of the
      equipment and the fluorescent dye.

      Postoperative analysis of time measurements (CLC and NIRF-LC group) Regarding the primary and
      secondary endpoints, a linear regression analysis will be applied for determination of
      possible significant differences between the time measurements from "first look at liver
      hilum" until "establishment of CVS" / "identification of transition CD in gallbladder" /
      "identification of transition CA in gallbladder"; therewith comparing fluorescence
      laparoscopic imaging with conventional laparoscopic imaging. In case of missing values (which
      can occur with the expert panel analysis, when the panel concludes that actually no CVS was
      obtained or the transition of the mentioned structures in the gallbladder had not been
      properly identified) a Cox regression analysis will be used.
    


Study Type

Interventional


Primary Outcome

time to identification of CVS

Secondary Outcome

 time until identification of the transition of the cystic duct in the gallbladder during dissection of CVS

Condition

Cholecystolithiasis

Intervention

Laparoscopic Fluorescence Imaging System (Karl Storz)

Study Arms / Comparison Groups

 NIRF-LC
Description:  This group of patients will undergo near-infrared fluorescence cholangiography assisted laparoscopic cholecystectomy by use of a Laparoscopic Fluorescence Imaging System (Karl Storz), in combination with one intravenous injection of contrast agent ICG. The ICG is given directly after induction of anesthesia in a dose of 1 ml of 2,5 mg/ml solution.
Intraoperatively every 2-5 minutes (more often if desired by surgeon) camera is switched to ICG mode for fluorescence cholangiography, until CVS is established.
Registration of time until establishment of CVS, visualization of the individual structures as described as secondary endpoints, and total operation time will be done.
The complete procedure will be recorded on video.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

308

Start Date

January 2016

Completion Date

July 2020

Primary Completion Date

December 2019

Eligibility Criteria

        Inclusion Criteria:

          -  Scheduled for elective laparoscopic cholecystectomy

          -  Normal liver and renal function

          -  No hypersensitivity for iodine or ICG

          -  Able to understand nature of the study procedures

          -  Willing to participate and with written informed consent

          -  Physical Status Classification: ASA I / ASA II

        Exclusion Criteria:

          -  Age < 18 years

          -  Liver or renal insufficiency

          -  Known iodine or ICG hypersensitivity

          -  Pregnancy or breastfeeding

          -  Not able to understand nature of the study procedure

          -  Physical Status Classification: ASA III and above

          -  iv Heparin injection in the last 24 h; (LMWH not contraindicated)
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Laurents PS Stassen, MD, PhD, 0031613206302, [email protected]

Location Countries

Netherlands

Location Countries

Netherlands

Administrative Informations


NCT ID

NCT02558556

Organization ID

NL47718.068.14


Responsible Party

Sponsor

Study Sponsor

Maastricht University Medical Center


Study Sponsor

Laurents PS Stassen, MD, PhD, Principal Investigator, Maastricht UMC


Verification Date

March 2019