c1 onderzoeksprotocol rct falcon trial versie 5.3 21 juli · pdf file ·...

NL47718.068.14 / METC 142049 FALCON trial

RESEARCH PROTOCOL

Near-infrared Fluorescence Cholangiography assisted Laparoscopic

Cholecystectomy versus Conventional Laparoscopic Cholecystectomy

FALCON trial

A multicenter randomized controlled trial

Fluorescentiebeeldvorming versus normale beeldvorming van de

galwegen tijdens kijkoperaties van de galblaas: een vergelijkend

onderzoek


PROTOCOL TITLE: Near-infrared Fluorescence Cholangiography assisted Laparoscopic

Cholecystectomy versus Conventional Laparoscopic Cholecystectomy (FALCON): a

multicenter randomized controlled trial

Protocol ID FALCON

Short title FALCON: a multicenter randomized controlled trial

Version 5.3

Date 21.07.2016

Coordinating

investigator/project leader

Prof. Dr. L.P.S. Stassen, surgeon

Maastricht University Medical Center

[email protected] / 043-3875492

Principal investigator(s)

• Prof. Dr. L.P.S. Stassen, surgeon



• Drs J van den Bos, PhD student general surgery


[email protected] / 0613206302

• Prof. Dr. N.D. Bouvy, surgeon



• Dr. R.M. van Dam, surgeon



Participating medical centers • Dr. A.L. Vahrmeijer, surgeon

Leiden University Medical Center

[email protected]

• Prof. Dr. G.M. van Dam, surgeon

University Medical Center Groningen

[email protected]

• Dr. P.D. Gobardhan, surgeon

Amphia Hospital Breda

[email protected]

• Dr. M.D.P. Luyer, surgeon

Catharina Hospital Eindhoven

[email protected]


Potential Dutch participating center

• Dr. W.J.H.J. Meijerink, surgeon

VU Medical Center Amsterdam

[email protected]

Interantional participating Center:

• Luigi Boni, MD, FACS

Associate Professor of Surgery

Minimally Invasive Surgery Research Center

Department of Surgical and Morphological Sciences

University of Insubria, Varese, Italy

Potential international participating centers:

• Prof Dr med Thomas Carus

Clinic for general, visceral and vascular surgery,

Asklepios Westklinikum Hamburg, Germany

• Prof Dr Filip Mysoms

Algemeen Ziekenhuis Maria Middelares Gent, Gent,

België

• Dr. Florian Ulmer

Universitätsklinikum Aachen, Germany

Advisor Cost Effectiveness Professor Carmen Dirksen, professor of Health

Technology Assessment of Clinical Interventions,


Sponsor Department of Surgery

Academisch Ziekenhuis Maastricht (azM)

Subsidising party Karl Storz (Germany) provides the laparoscopic

fluorescence imaging systems free of charge to the

participating medical centers

Independent expert (s) Dr. M. Poeze, trauma surgeon



PROTOCOL SIGNATURE SHEET

Name Signature Date

Sponsor or legal representative:

Department of Surgery


Head of Department:

Prof. Dr. M.J.H.M. Jacobs

Coordinating Investigator/Project

leader/Principal Investigator:

Prof. Dr. L.P.S. Stassen


TABLE OF CONTENTS

1. INTRODUCTION AND RATIONALE ............................................................................... 112. OBJECTIVES .................................................................................................................. 143. STUDY DESIGN ............................................................................................................. 154. STUDY POPULATION .................................................................................................... 16

4.1 Population (base) ..................................................................................................... 164.2 Inclusion criteria ....................................................................................................... 164.3 Exclusion criteria ...................................................................................................... 174.4 Sample size calculation ........................................................................................... 17

5. TREATMENT OF SUBJECTS ......................................................................................... 185.1 Investigational product/treatment ............................................................................. 185.2 Use of co-intervention (if applicable) ........................................................................ 195.3 Escape medication (if applicable) ............................................................................ 19

6. INVESTIGATIONAL PRODUCT ..................................................................................... 206.1 Name and description of investigational product(s) ................................................ 206.2 Summary of findings from non-clinical studies ......................................................... 206.3 Summary of findings from clinical studies ................................................................ 206.4 Summary of known and potential risks and benefits ................................................ 266.5 Description and justification of route of administration and dosage ......................... 266.6 Dosages, dosage modifications and method of administration ................................ 266.7 Preparation and labelling of Investigational Medicinal Product ................................ 266.8 Drug accountability .................................................................................................. 26

7. NON-INVESTIGATIONAL PRODUCT ............................................................................ 277.1 Name and description of non-investigational product(s) .......................................... 277.2 Summary of findings from non-clinical studies ......................................................... 287.3 Summary of findings from clinical studies ................................................................ 297.4 Summary of known and potential risks and benefits ................................................ 307.5 Description and justification of route of administration and dosage ......................... 337.6 Dosages, dosage modifications and method of administration ................................ 337.7 Preparation and labelling of Non Investigational Medicinal Product ........................ 347.8 Drug accountability .................................................................................................. 34

8. METHODS ...................................................................................................................... 358.1 Study parameters/endpoints .................................................................................... 35

8.1.1 Main study parameter/endpoint ........................................................................ 358.1.2 Secondary study parameters/endpoints (if applicable) ..................................... 358.1.3 Other study parameters (if applicable) .............................................................. 35

8.2 Randomisation, blinding and treatment allocation ................................................... 368.3 Study procedures ..................................................................................................... 378.4 Withdrawal of individual subjects ............................................................................. 42

8.4.1 Specific criteria for withdrawal (if applicable) .................................................... 428.5 Replacement of individual subjects after withdrawal ............................................... 428.6 Follow-up of subjects withdrawn from treatment ...................................................... 42


8.7 Premature termination of the study .......................................................................... 429. SAFETY REPORTING .................................................................................................... 43

9.1 Section 10 WMO event ..................................... Fout! Bladwijzer niet gedefinieerd.9.2 AEs, SAEs and SUSARs ......................................................................................... 43

9.2.1 Adverse events (AEs) ....................................................................................... 439.2.2 Serious adverse events (SAEs) ........................................................................ 43

9.3 Follow-up of adverse events .................................................................................... 459.4 Data Safety Monitoring Board (DSMB) / Safety Committee .................................... 45

10. STATISTICAL ANALYSIS ........................................................................................... 4610.1 Primary study parameter(s) ...................................................................................... 4610.2 Secondary study parameter(s) ................................................................................. 4610.3 Other study parameters ........................................................................................... 4610.4 Interim analysis (if applicable) .................................................................................. 47

11. ETHICAL CONSIDERATIONS .................................................................................... 4711.1 Regulation statement ............................................................................................... 4711.2 Recruitment and consent ......................................................................................... 4711.3 Objection by minors or incapacitated subjects (if applicable) .................................. 4711.4 Benefits and risks assessment, group relatedness .................................................. 4811.5 Compensation for injury ........................................................................................... 4811.6 Incentives (if applicable) .......................................................................................... 48

12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................... 4912.1 Handling and storage of data and documents ......................................................... 4912.2 Monitoring and Quality Assurance ........................................................................... 4912.3 Amendments ............................................................................................................ 4912.4 Annual progress report ............................................................................................ 4912.5 End of study report ................................................................................................... 4912.6 Public disclosure and publication policy ................................................................... 50

13. STRUCTURED RISK ANALYSIS ................................................................................ 5013.1 Potential issues of concern ...................................................................................... 5013.2 Synthesis ................................................................................................................. 50

14. REFERENCES ............................................................................................................ 52


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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS

ABR ABR form, General Assessment and Registration form, is the application

form that is required for submission to the accredited Ethics Committee

(In Dutch, ABR = Algemene Beoordeling en Registratie)

AE Adverse Event

AR Adverse Reaction

BDI Bile Duct Injury

CA Competent Authority

CCMO Central Committee on Research Involving Human Subjects; in Dutch:

Centrale Commissie Mensgebonden Onderzoek

CBD

CD

CE

CLC

Common Bile Duct

Cystic Duct

Conformité Européene

Conventional Laparoscopic Cholecystectomy

CV Curriculum Vitae

CVS Critical View of Safety

DSMB Data Safety Monitoring Board

EU European Union

EudraCT European drug regulatory affairs Clinical Trials

FDA United States Food and Drug Administration

GCP Good Clinical Practice

IB Investigator’s Brochure

IC Informed Consent

ICG Indocyanine Green

IMP Investigational Medicinal Product

IMPD Investigational Medicinal Product Dossier

IOC

LC

Intraoperative Cholangiography

Laparoscopic cholecystectomy

METC Medical research ethics committee (MREC); in Dutch: medisch ethische

toetsing commissie (METC)

MUMC Maastricht University Medical Center

NIR Near-Infrared

NIRFC Near-Infrared Fluorescence Cholangiography

NIRF-LC Near-Infrared Fluorescence Cholangiography assisted Laparoscopic

Cholecystectomy



RCT Randomized Controlled Trial

(S)AE (Serious) Adverse Event

SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie

IB1-tekst)

Sponsor The sponsor is the party that commissions the organisation or

performance of the research, for example a pharmaceutical company,

academic hospital, scientific organisation or investigator. A party that

provides funding for a study but does not commission it is not regarded

as the sponsor, but referred to as a subsidising party.

SUSAR Suspected Unexpected Serious Adverse Reaction

Wbp Personal Data Protection Act (in Dutch: Wet Bescherming

Persoonsgevens)

WL

WMO

White Light

Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-

wetenschappelijk Onderzoek met Mensen



SUMMARY

Rationale: Several clinical feasibility studies have shown the potential benefit of near-infrared

fluorescence (NIRF) imaging using indocyanine green (ICG) for enhanced (and even earlier)

biliary anatomy visualization during laparoscopic cholecystectomy with the aim to reduce the

number of vascular and biliary injuries. Wide clinical acceptance of this new technique is

however still lacking, due to the absence of sufficient evidence-based data. Although the

incidence of injuries is low (0.7%), the impact on patients in terms of morbidity, quality of live

and costs are dramatic. Due to the low incidence, clinical studies which aim to reduce the

number of injuries are impractical to carry out based on the number of patients needed to be

randomized. The Critical View of Safety (CVS) technique is regarded as the safety valve in

conventional laparoscopic cholecystectomy (CLC). In pilot studies NIRF-guided identification

of the CVS showed to be a promising endpoint.

It is hypothesized that standard application of near-infrared fluorescence imaging during

laparoscopic cholecystectomy can be useful to obtain establishment of Critical View of Safety

(at least 5 minutes) earlier and with more certainty regarding visualization when compared to

conventional laparoscopic imaging alone.

Objective: This multicenter randomized controlled trial aims to evaluate whether earlier

establishment as well as improved visualization of CVS can be obtained during laparoscopic

cholecystectomy, by applying NIRF laparoscopic imaging as an adjunct to conventional

laparoscopic imaging versus conventional laparoscopic imaging alone.

Study design: A multicenter randomized controlled trial with two study arms.

Study population: Patients scheduled for an elective laparoscopic cholecystectomy will be

recruited and randomized at the outpatient clinic (n = 308 total). Stratification is performed per

participating center. A sample size of minimum 131 patients in each randomization arm has

been calculated to detect a reduction of at least 5 minutes in time until establishment of CVS

(80% power and α = 0.05 (two-tailed)).

Intervention: One group will undergo near-infrared fluorescence cholangiography assisted

laparoscopic cholecystectomy (NIRF-LC) and the other group will undergo conventional

laparoscopic cholecystectomy (CLC).

Main study parameters/endpoints: Primary endpoint of this trial is “time to identification of

CVS”. Secondary endpoints are: “time until identification of the cystic duct (CD) during

dissection of CVS”; “time until identification of common bile duct (CBD)”; “time until

identification of the transition of CD in the gallbladder during dissection of CVS”; “time until

identification of the transition of the cystic artery in the gallbladder during dissection of CVS”;

“visualization of CVS and visualization of the transition of the cystic duct and cystic artery in

the gallbladder”; “total surgical time”; “intraoperative bile leakage from the gallbladder or cystic


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duct”; “bile duct injury”; “postoperative length of hospital stay”, “complications due to the

injected contrast agent”; “conversion to open cholecystectomy”; “postoperative complications

(until 90 days after surgery)”; cost-minimization.

Nature and extent of the burden and risks associated with participation, benefit and

group relatedness: Compared with standard care, patients in the NIRF-LC group have to

receive one preoperative intravenous injection and one peroperative 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 (FDA approved and already used for several clinical

diagnostic indications, previously used in the NIRFC-LC pilot study: NL38521.068.11) 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. The FALCON trial will provide evidence on the benefit of standard

application of NIRF imaging during laparoscopic cholecystectomy. Strong evidence in favor of

routine implementation of this new imaging technique during laparoscopic cholecystectomy,

the most commonly performed laparoscopic procedure worldwide, will probably lead to

worldwide routine application of the NIRF technique. Therewith long term sustainability of this

research project is guaranteed.


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1. INTRODUCTION AND RATIONALE 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%) (3-6). Misidentification of the extra-hepatic bile

duct anatomy during laparoscopic cholecystectomy is the main cause of bile duct injury (7).

The Critical View of Safety (CVS) technique, which

was first described by Strasberg in 1995 (8) and

recommended by the SAGES Annual Meeting of

2005 (9) and the Dutch Guidelines and Best Practice

for laparoscopic cholecystectomy (10), 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 (see Figure 1). 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.

Laparoscopic cholecystectomy procedure is performed briefly as follows (10):

- the gallbladder is grabbed at the fundus and is cranialised over the liver against the

anterior abdominal wall, second the infundibulum is grabbed;

- the hepatocystic triangle (see Figure 1) is visualized and Critical View of Safety (CVS)

is obtained (see Figure 2);

- the cystic artery and cystic duct are transsected;

- the gallbladder is dissected from the liver bed;

- the liver hilum and gallbladder bed are being checked once more for hemostasis;

- the gallbladder is removed from the abdomen.

Figure 1 – Calot’s triangle (1)


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Intraoperative cholangiography has been advised to reduce the risk of bile duct injury (3,

11). 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 (12).

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 (11, 13). 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 (14-17) and in

open, laparoscopic, and single-incision laparoscopic cholecystectomy (16, 18-20). 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 (21). Real-time simultaneous imaging of the hepatic

and cystic arteries can also be obtained (22-24).

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


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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.


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2. OBJECTIVES

Primary Objective

- Time until establishment of Critical View of Safety (CVS).

Secondary Objectives

- Time until identification of the cystic duct (CD) during dissection of CVS;

- Time until identification of common bile duct (CBD);

- Time until identification of the transition of CD in the gallbladder during dissection of CVS;

- Time until identification of the transition of the cystic artery (CA) in the gallbladder during

dissection of CVS;

- Visualization of CVS and visualization of the transition of the cystic duct and cystic artery

in the gallbladder;

- Total surgical time;

- 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);

- Cost-minimization


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3. STUDY DESIGN

Study design

A multicenter randomized controlled trial, with two randomization arms:

- NIRF-LC group: this group of patients will undergo near-infrared fluorescence

cholangiography assisted laparoscopic cholecystectomy;

- CLC group: this group will undergo conventional laparoscopic cholecystectomy.

Duration of the study

Planned duration of the project: 2 year (i.e., 12-18 months inclusion period and follow-up of

308 patients; 6 months video- and data analysis + reporting).

Starting date: 1 January 2016

Setting

This study will be performed by the Departments of Surgery of three University Medical Centers

and two large peripheral training hospitals in The Netherlands (willingness to participate has

been confirmed and approval of the study protocol given by all participating centers):

- Maastricht University Medical Center+ (MUMC+, Maastricht, The Netherlands)

- Leiden University Medical Center (LUMC, Leiden, The Netherlands);

- University Medical Center Groningen (UMCG, Groningen, The Netherlands);

- Amphia Hospital (Breda, The Netherlands)

- Catharina Hospital (Eindhoven, The Netherlands)

- Minimally Invasive Surgery Research Center, Department of Surgical and Morphological

Sciences, University of Insubria, Varese, Italy (Luigi Boni, MD, FACS

Associate Professor of Surgery)

Potential Dutch Participant

- VU University Medical Center (VUmc Amsterdam, The Netherlands)

Optional international participants (willingness to participate expressed)

- Clinic for general, visceral and vascular surgery, Asklepios Westklinikum Hamburg,

Germany (Prof Dr med Thomas Carus)

- Algemeen Ziekenhuis Maria Middelares Gent, Gent, Belgium (Prof Dr Filip Mysoms)

- Universitätsklinikum Aachen, Germany (Dr. Florian Ulmer)

Trial Register: The study is registered in ClinicalTrials.gov, with the following registration

number: NCT02558556


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4. STUDY POPULATION

4.1 Population (base)

In the FALCON 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.

Each year around 20,000 laparoscopic cholecystectomies are being performed in the

Netherlands (source: Central Bureau of Statistics, http://statline.cbs.nl/). Patients will be

included in at least 6 hospitals, so it is expected that inclusion of patients for this RCT can be

conducted in a relatively short period of time (approximately 12-18 months).

Inclusion number per participating medical center:

- MUMC+ Maastricht 60

- LUMC Leiden 35

- UMCG Groningen 25

- Amphia Hospital Breda 58

- Catharina Hospital Eindhoven 65

- University of Insumbira 65

Note: these numbers serve as a guideline and will be reconsidered according to speed of

inclusion of patients in each center. In centers with more inclusions per month than expected,

the total inclusion number might be higher than expected as well. The inclusion in each center

continues until 308 patients in the total study are included.

4.2 Inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following

criteria:

- Male or female patients, aged 18 years and above

- 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 give written informed consent

- Physical Status Classification: ASA I / ASA II


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4.3 Exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation

in this study:

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

4.4 Sample size calculation

Based on the primary objective of this study, a sample size is calculated with a power of 80%

and α of 0.05 (95%-confidence). This has been done in consultation with a statistician (A.G.H.

Kessels Dept of Methodology and Statistics, Faculty of Health, Medicine and Life Sciences,

Maastricht).

Based on the pilot data (21, 24), in which identification of the cystic duct (CD) and the common

bile duct (CBD) was established respectively 11 and 10 minutes earlier using fluorescence

laparoscopic imaging compared to conventional laparoscopic imaging.

- Subgroup 1 (cholecystolithiasis, n=20): reduction of 13 (CD) and 13 (CBD) minutes

- Subgroup 2 (cholecystitis/after biliary pancreatitis, n=10): reduction of 9 (CD) and 4 minutes

We extrapolated the observed reduction in “time to identification of CD and CBD” to an

estimated reduction in “time to identification of CVS”: a ‘safe’ estimation, feasible in any of the

participating centers, of 5 minutes was chosen. As such:

- Mu1: conventional laparoscopy à mean time until CVS: 41.7 min (based on pilot data)

- Mu2: fluorescence laparoscopy à mean time until CVS: 36.7 min (estimated)

- Sigma (STDEV): 14.4 min (based on pilot data)

Result of sample size calculation: 131 per arm.

A sample size of 131 patients in each randomization arm has been calculated to detect a

reduction in “time to identification of CVS” of at least 5 minutes (80% power and α = 0.05 (two-

tailed)). It is expected that this time reduction can possibly be up to 10 minutes.

Assuming an expected withdrawal rate of ≤ 15% (due to usual reasons for drop-out in

combination with technical difficulties concerning the video recordings) during the trial, a total

of 308 (n = 2 x 131 + 15%) will be required.


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5. 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 (see paragraph 5.1) 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 anaesthesia the fluorescent dye, indocyanine green (ICG), will be

administered for intraoperative visualization of the extra-hepatic bile ducts with the NIR

fluorescence laparoscope. A repeat intravenous injection of 2.5 mg of ICG at establishment of

the CVS will be given for concomitant arterial and biliary fluorescence delineation.

Since many years ICG has been approved for commercial and clinical diagnostic use by the

FDA. See also the Summary of Product Characteristics, in attachment.

5.1 Investigational product

Investigational product: laparoscopic fluorescence imaging system

• Karl Storz GmbH & CO. KG, Tuttlingen, Germany: a CE-approved, laparoscopic

fluorescence imaging system, including plasma light guide and 30-degree 10-mm

laparoscope applicable for white light, autofluorescence and ICG imaging. This system is

applicable for conventional laparoscopy (WL camera mode) and near-infrared

fluorescence laparoscopy (ICG camera mode). The system is equipped with a foot pedal,

allowing the surgeon to easily switch from WL camera mode to ICG camera mode, and

back.

Direct fluorescence image-overlay on the conventional anatomical image is not yet

possible with the current systems. Because of the instantaneous changing of images and

the stable position of the laparoscope, anatomical orientation can be maintained.

Comparator: conventional laparoscopic imaging system

These concern conventional laparoscopic imaging systems as regularly used in hospitals

worldwide for minimally invasive surgical procedures, such as laparoscopic cholecystectomies.


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5.2 Use of co-intervention

To obtain fluorescence imaging of the biliary tract, using the laparoscopic fluorescence imaging

system, a contrast agent has to be administered. Directly after induction of anaesthesia the

fluorescent dye, indocyanine green (ICG), will be administered for intraoperative visualization

of the extra-hepatic bile ducts with the NIR fluorescence laparoscope. When the CVS is

established, a second dose is given to visualize the cystic artery.

5.3 Escape medication

Not applicable


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6. INVESTIGATIONAL PRODUCT

6.1 Name and description of investigational product(s)

Karl Storz Laparoscopic Fluorescence Imaging System (21, 24, 25):

A CE-approved system including plasma light guide and 30-degree 10-mm laparoscope

applicable for white light and ICG imaging. This system is applicable for conventional

laparoscopy (WL camera mode) and near-infrared fluorescence laparoscopy (ICG camera

mode). The system is equipped with a foot pedal, allowing the surgeon to switch from WL

camera mode to ICG camera mode, and back.

For comparison conventional white light imaging mode of the laparoscopic imaging system will

be used.

6.2 Summary of findings from non-clinical studies

See Summary of Product Characteristics (SPC) of Karl Storz. The system concerns a CE-

marked system for clinical purposes, therefore no findings from non-clinical studies are

included.

6.3 Summary of findings from clinical studies

NIRF cholangiography during laparoscopic cholecystectomy, by MUMC

Schols RM, Bouvy ND, Masclee AA, van Dam RM, Dejong CH, Stassen LP. Fluorescence

cholangiography during laparoscopic cholecystectomy: a feasibility study on early biliary tract

delineation. Surg Endosc. 2013 May;27(5):1530-6. doi: 10.1007/s00464-012-2635-3. Epub

2012 Oct 18.(21)

Background and aim: Laparoscopic cholecystectomy (LC) is one of the most commonly

performed laparoscopic procedures. Bile duct injury is a rare but serious complication during

this procedure, mostly caused by misidentification of the extrahepatic bile duct anatomy.

Intraoperative cholangiography may be helpful to reduce the risk of bile duct injury; however,

this is not a common procedure worldwide. Near-infrared fluorescence cholangiography

(NIRFC) using indocyanine green (ICG) is a promising alternative for the identification of the

biliary tree. This prospective observational study was designed to assess the feasibility and

image quality of intermittent NIRFC during LC, using a newly developed laparoscopic

fluorescence system.


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Methods: Consecutive patients undergoing elective LC were included and received a single

intravenous injection of ICG directly after induction of anesthesia. During dissection of the base

of the gallbladder and the cystic duct, the extrahepatic bile ducts were visualized by using a

dedicated laparoscope (KARL STORZ), which offers both conventional state-of-the-art

imaging and fluorescence imaging. Intraoperative recognition of the biliary structures was

registered at set time points, as well as the establishment of the critical view of safety.

Results: Fifteen patients were included between December 2011 and May 2012. ICG was

visible in the liver and bile ducts within 20 min after intravenous administration and remained

for approximately 2 h, using the fluorescence mode of the laparoscope. The common bile duct

and cystic duct could be clearly identified at an early stage of the operation and, more

important, significantly earlier than with the conventional camera mode. No per- or

postoperative complications occurred as a consequence of ICG use.

Conclusions: Intermittent fluorescence imaging using a newly developed laparoscope and

preoperative administration of ICG seems a useful aid in accelerating visualization of the

extrahepatic bile ducts during laparoscopic cholecystectomy.

Schols RM, Bouvy ND, van Dam RM, Masclee AA, Dejong CH, Stassen LP. Combined

vascular and biliary fluorescence imaging in laparoscopic cholecystectomy. Surg

Endosc. 2013 Dec;27(12):4511-7. doi: 10.1007/s00464-013-3100-7. Epub 2013 Jul 23.(24)

Background and aim: Bile duct injury in patients undergoing laparoscopic cholecystectomy

is a rare but serious complication. Concomitant vascular injury worsens the outcome of bile

duct injury repair. Near-infrared fluorescence imaging using indocyanine green (ICG) is a

promising, innovative, and noninvasive method for the intraoperative identification of biliary

and vascular anatomy during cholecystectomy. This study assessed the practical application

of combined vascular and biliary fluorescence imaging in laparoscopic gallbladder surgery for

early biliary tract delineation and arterial anatomy confirmation.

Methods: Patients undergoing elective laparoscopic cholecystectomy were enrolled in this

prospective, single-institutional study. To delineate the major bile ducts and arteries, a

dedicated laparoscope, offering both conventional and fluorescence imaging, was used. ICG

(2.5 mg) was administered intravenously immediately after induction of anesthesia and in half

of the patients repeated at establishment of critical view of safety for concomitant arterial

imaging. During dissection of the base of the gallbladder and the cystic duct, the extrahepatic

bile ducts were visualized. Intraoperative recognition of the biliary structures was registered at

set time points, as well as visualization of the cystic artery after repeat ICG administration.

Results: Thirty patients were included. ICG was visible in the liver and bile ducts within 20

minutes after injection and remained up to approximately 2 h, using the ICG-filter of the

laparoscope. In most cases, the common bile duct (83%) and cystic duct (97%) could be


Version date: 21.07.2016 22 of 54

identified significantly earlier than with conventional camera mode. In 13 of 15 patients (87%),

confirmation of the cystic artery was obtained successfully after repeat ICG injection. No per-

or postoperative complications occurred as a consequence of ICG use.

Conclusions: Biliary and vascular fluorescence imaging in laparoscopic cholecystectomy is

easily applicable in clinical practice, can be helpful for earlier visualization of the biliary tree,

and is useful for the confirmation of the arterial anatomy.

NIRF cholangiography during open and laparoscopic cholecystectomy, by LUMC

Verbeek FP, Schaafsma BE, Tummers QR, van der Vorst JR, van der Made WJ, Baeten

CI, Bonsing BA, Frangioni JV, van de Velde CJ, Vahrmeijer AL,Swijnenburg RJ. Optimization

of near-infrared fluorescence cholangiography for open and laparoscopic surgery. Surg

Endosc. 2013 Nov 14. (25)

Background and aim: During laparoscopic cholecystectomy, common bile duct (CBD) injury

is a rare but severe complication. To reduce the risk of injury, near-infrared (NIR) fluorescent

cholangiography using indocyanine green (ICG) has recently been introduced as a novel

method of visualizing the biliary system during surgery. To date, several studies have shown

feasibility of this technique; however, liver background fluorescence remains a major problem

during fluorescent cholangiography. The aim of the current study was to optimize ICG dose

and timing for NIR cholangiography using a quantitative intraoperative camera system during

open hepatopancreatobiliary (HPB) surgery. Subsequently, these results were validated during

laparoscopic cholecystectomy using a laparoscopic fluorescence imaging system.

Methods: Twenty-seven patients who underwent NIR imaging using the Mini-FLARE image-

guided surgery system during open HPB surgery were analyzed to assess optimal dosage and

timing of ICG administration. ICG was intravenously injected preoperatively at doses of 5, 10,

and 20 mg, and imaged at either 30 min (early) or 24 h (delayed) post-injection. Next, the

optimal doses found for early and delayed imaging were applied to two groups of seven

patients (n = 14) undergoing laparoscopic NIR fluorescent cholangiography during

laparoscopic cholecystectomy.

Results: Median liver-to-background contrast was 23.5 (range 22.1-35.0), 16.8 (range 11.3-

25.1), 1.3 (range 0.7-7.8), and 2.5 (range 1.3-3.6) for 5 mg/30 min, 10 mg/30 min, 10 mg/24 h,

and 20 mg/24 h, respectively. Fluorescence intensity of the liver was significantly lower in the

10 mg delayed-imaging dose group compared with the early imaging 5 and 10 mg dose groups

(p = 0.001), which resulted in a significant increase in CBD-to-liver contrast ratio compared

with the early administration groups (p < 0.002). These findings were qualitatively confirmed

during laparoscopic cholecystectomy.


Version date: 21.07.2016 23 of 54

Conclusions: This study shows that a prolonged interval between ICG administration and

surgery permits optimal NIR cholangiography with minimal liver background fluorescence.

NIRF cholangiography during laparoscopic cholecystectomy, by VUMC

Van Dam DA, Ankersmit M, Van Der Pas MH, Meijerink WJ. Visualisation of the Common Bile

Duct and Cystic Duct With a Novel Near-infrared Camera and Indocyanine Green During

Laparoscopic Cholecystectomy. Presented at SAGES Annual Meeting 2012.(26)

Background and aim: We present a novel technology to visualize the common bile duct

(CBD) and cystic duct (CD) in patients. Injuries to the CBD are rare but serious complications

with need for re-intervention, risk of permanent disability and prolonged hospital stay, and

occur most often in presence of unclear or anatomic variations. An intra-operative

cholangiogram requires additional operating time, a X-ray machine with trained personnel, and

the bile ducts need to be perforated or cannulated to administer the contrast fluid to the biliary

structures. Indocyanine Green (ICG) is a well used green contrast fluid, and with the recent

introduction of a near-infrared (NIR) camera (Olympus, Hamburg Germany) ICG can also be

used for its fluorescent qualities. After intravenous administration ICG is exclusively cleared by

the liver and secreted into the bile, where it can be visualised with the near-infrared

camera. Aim: a new method of early visualization of the CBD and CD during laparoscopic

cholecystectomy and prevention of injuries to biliary structures.

Methods: Patients eligible for elective laparoscopic cholecystectomy diagnosed with

uncomplicated cholecystolithasis are included in the study after oral and written consent. A

single intravenous injection of ICG is administered after induction of general anaesthesia,

before the start of surgery. During standard laparoscopic cholecystectomy, the specially build

NIR camera to is used to visualise the biliary structures. Time of administration of the ICG and

assessment of visible structures with both NIR and conventional camera is noted, and

procedures are recorded . Post-operatively patients are admitted to the day-care centre and

are discharged at the day of surgery conform standard surgical procedures. In total 30 patients

are required to obtain 90% power for significant results in regard of early visualisation of the

CBD and CD with the NIR camera compared to conventional camera imaging. The power

calculation was based on the pilot series of 7 patients.

Preliminary results: In the first 19 patients, no per- or postoperative complications due to the

administration of ICG or the laparoscopic cholecystectomy occurred. ICG in the liver, CBD and

CD could be detected as early as 20-30 minutes after intravenous administration. In 18/19

patients, the CBD could be visualised with the NIR before identification of the CBD on

conventional camera was possible. Early identification with ICG-NIR of the CD was successful


Version date: 21.07.2016 24 of 54

in 6/19 patients. 4 anatomic variations were detected during laparoscopic cholecystectomy,

and in 2 patients the use of ICG-NIR could prevent conversion to open surgery when Critical

View of Safety could not be confirmed.

Van Dam DA, Ankersmit M, Van de Ven P, Gisbertz SS, Meijerink WJHJ. Visualisatie van de

galwegen met Indocyanine Groen en een near-infrared camera tijdens laparoscopische

cholecystectomie. Presented at Chirurgendagen, 10 May 2012(27)

Background and aim: Tijdens laparoscopische cholecystectomieën wordt gebruik gemaakt

van de Critical View of Safety (CVS) voor een veilige dissectie van de hilaire structuren. De

literatuur vermeldt echter een constante incidentie van galwegletsels. Doel van deze studie is

het vroeg identificeren van de d. cysticus en d. choledochus tijdens laparoscopische

cholecystectomieën.

Methods: Patiënten met ongecompliceerd galsteenlijden, die een electieve cholecystectomie

ondergaan, krijgen na inductie van anesthesie éénmalig een intraveneuze injectie Indocyanine

Groen (ICG) toegediend. Door middel van near-infrared licht krijgt deze groene

contrastvloeistof fluorescerende eigenschappen. Na intraveneuze injectie wordt ICG actief

door de lever uitgescheiden in de gal. Tijdens de dissectie van de leverhilus worden met

conventioneel en near-infrared licht de galwegen gevisualiseerd. Zichtbaarheid van deze

structuren in de tijd worden op een scoringsformulier bijgehouden.

Results: Op basis van een powerberekening werden 28 patiënten geïncludeerd. Er zijn geen

per- of postoperatieve complicaties opgetreden door ICG gebruik. Postoperatief ontstond 1

gallekkage uit een cysticus stomp, waarvoor reïnterventie nodig was. ICG in de lever en

galwegen was binnen 20-30 minuten na injectie zichtbaar. Met ICG kon de d. choledochus bij

de eerste beoordeling in 19/28 patiënten geïdentificeerd worden versus 2/28 met

conventioneel beeld (p= 0.000). De d. choledochus werd tevens significant eerder

gevisualiseerd in vergelijking met conventioneel camera beeld (gem. 26.7 vs 35.9 minuten, p

= 0.015). De d. cysticus kon bij de eerste beoordeling in 9/28 patiënten met ICG geïdentificeerd

worden versus 1/28 met conventioneel beeld (p = 0.008). Ook de d. cysticus werd met ICG

eerder geïdentificeerd dan met conventioneel beeld (gem. 37.2 vs 46.6 minuten, p = 0.000).

Bij het bereiken van CVS werd de d. choledochus bij 24/28 patiënten met ICG geïdentificeerd

en bij 8/28 met conventioneel beeld (p= 0.000). Er was geen verschil in visualisatie van de d.

cysticus bij het bereiken van CVS tussen ICG en conventioneel beeld. Met ICG werden 4

anatomische variaties geïdentificeerd. Bij onduidelijke CVS in 2 patiënten werd met ICG

voorkomen dat geconverteerd moest worden naar open cholecystectomie.

Conclusions: Uit deze studie kan geconcludeerd worden dat de combinatie van ICG en een

near-infrared camera zorgt voor een significant eerdere visualisatie van de d. cysticus en d.

choledochus tijdens electieve laparoscopische cholecystectomie. Daarnaast heeft deze


Version date: 21.07.2016 25 of 54

techniek mogelijk meerwaarde bij de identificatie van anatomische variaties in de leverhilus.

In tegenstelling tot het per-operatief cholangiogram, is visualisatie met ICG en near-infrared

camera een eenvoudige techniek.

NIRF cholangiography by The Ohio State University Wexner Medical Center:

Osayi SN, Wendling MR, Drosdeck JM, Chaudhry UI, Perry KA, Noria SF, et al. Near-infrared

fluorescent cholangiography facilitates identification of biliary anatomy during laparoscopic

cholecystectomy. Surg Endosc. 2015 Feb;29(2):368-75.(28)

Background and aim: Intraoperative cholangiography (IOC) is the current gold standard for

biliary imaging during laparoscopic cholecystectomy (LC). However, utilization of IOC remains

low. Near-infrared fluorescence cholangiography (NIRF-C) is a novel, noninvasive method for

real-time, intraoperative biliary mapping. Our aims were to assess the safety and efficacy of

NIRF-C for identification of biliary anatomy during LC.

Methods: Patients were administered indocyanine green (ICG) prior to surgery. NIRF-C was

used to identify extrahepatic biliary structures before and after partial and complete dissection

of Calot's triangle. Routine IOC was performed in each case. Identification of biliary structures

using NIRF-C and IOC, and time required to complete each procedure were collected.

Results: Eighty-two patients underwent elective LC with NIRF-C and IOC. Mean age and body

mass index (BMI) were 42.6 ± 13.7 years and 31.5 ± 8.2 kg/m(2), respectively. ICG was

administered 73.8 ± 26.4 min prior to incision. NIRF-C was significantly faster than IOC (1.9 ±

1.7 vs. 11.8 ± 5.3 min, p < 0.001). IOC was unobtainable in 20 (24.4 %) patients while NIRF-

C did not visualize biliary structures in 4 (4.9 %) patients. After complete dissection, the rates

of visualization of the cystic duct, common bile duct, and common hepatic duct using NIRF-C

were 95.1, 76.8, and 69.5 %, respectively, compared to 72.0, 75.6, and 74.3 % for IOC. In 20

patients where IOC could not be obtained, NIRF-C successfully identified biliary structures in

80 % of the cases. Higher BMI was not a deterrent to visualization of anatomy with NIRF-C.

No adverse events were observed with NIRF-C.

Conclusion: NIRF-C is a safe and effective alternative to IOC for imaging extrahepatic biliary

structures during LC. This technique should be evaluated further under a variety of acute and

chronic gallbladder inflammatory conditions to determine its usefulness in biliary ductal

identification.


Version date: 21.07.2016 26 of 54

6.4 Summary of known and potential risks and benefits

There are no additional risks accompanied by the laparoscopic fluorescence imaging systems,

compared to conventional laparoscopic imaging.

6.5 Description and justification of route of administration and dosage

Not applicable.

6.6 Dosages, dosage modifications and method of administration

Not applicable.

6.7 Preparation and labelling of Investigational Medicinal Product

Not applicable.

6.8 Drug accountability

Not applicable.


Version date: 21.07.2016 27 of 54

7. NON-INVESTIGATIONAL PRODUCT

The information given hereunder is derived from the SPC (Summary of Product

Characteristics of ICG-Pulsion.

7.1 Name and description of non-investigational product(s)

INDOCYANINE GREEN:

ICG-PULSION 5 mg/ml Injection

25 mg / 50 mg, Powder for Solution for Injection

PULSION Medical Systems AG

PO Box 820564

D-81805 Munich

Germany

Each vial contains 25 mg indocyanine green (to be reconstituted with 5 ml of water for

injections) or 50 mg indocyanine green (to be reconstituted with 10 ml of water for

injections).

1 ml of the reconstituted solution for injection contains 5 mg indocyanine green.

This medicinal product is for diagnostic use only.

Diagnostic indications

Cardiac, circulatory and micro-circulatory diagnostics:

- measurement of cardiac output and stroke volume

- measurement of circulating blood volumes

- measurement of cerebral perfusion

Liver function diagnostics:

- measurement of liver blood flow

- measurement of excretory function of the liver

Ophthalmic angiography diagnostics:

- measurement of perfusion of the choroid


Version date: 21.07.2016 28 of 54

Packaging

Container: amber glass vial (type I)

Closure: rubber stopper (bromobutyl, grey) fixed by an aluminium cap covered by a blue

polypropylene cap

5 vials, each with a content of 25 mg powder for solution for injection

5 vials, each with a content of 50 mg powder for solution for injection

7.2 Summary of findings from non-clinical studies

Acute toxicity: the LD50 after single IV dose was 87 mg/kg in rats, 60 mg/kg in mice, and

between 50 mg/kg and 80 mg/kg in rabbits. After dissolution in water for injections and

administration by intraperitoneal injection in mice the LD50

was found to be 650 mg/kg body

weight. No macroscopic or histopathological changes were ob-served.

Genetic toxicity: indocyanine green was not found to be mutagenic in the tests per-formed

(Ames test, gene mutation assay - thymidin kinase locus/TK+/-

- in mouse lymphoma L5178Y

cells, chromosome aberration test in Chinese hamster V79 cells).

No studies for reproduction, teratogenicity, or carcinogenic properties in animals are

available but decades of experience in humans have not revealed any incidence of these

properties.

Characteristics: it concerns a fluorescent dye, which is intended for intravenous injection. Once

injected into the blood stream ICG will circulate through the whole body and will accumulate in

different amounts, depending on the blood-circulation to the respective organs or tissue. The

absorption and emission spectrum of ICG are both in the near infrared range. For this reason

it can be detected and quantified by optical procedures.

Pharmacodynamic properties

Pharmacotherapeutic group: Other diagnostic agents

ATC code: V04CX

The active substance in ICG-PULSION is 2-{7-[1,1-dimethyl-3-(4-sulfobutyl)-benz[e]indolin-2-

ylidene]-1,3,5-heptatrienyl}-1,1-dimethyl-3-(sulfobutyl)-1H-benz[e]-indolium hydroxide, inner

salt, sodium salt).

The molecular formula is C43

H47

N2NaO

6S

2. The molecular weight is 774.96 daltons.


Version date: 21.07.2016 29 of 54

Indocyanine green has a sharply defined spectral peak absorption of near-infrared light at

800 nm in blood plasma or blood. This is the same wavelength at which the optical density of

oxygenated haemoglobin in blood approximately equals that of reduced haemoglobin.

Therefore, this coincidental light absorption makes it possible to measure indocyanine green

concentrations in blood, plasma and serum in terms of its optical density at 800 nm,

independent of variations in oxygen saturation level.

Indocyanine green permits recording of the indicator-dilution curves for both diagnostic and

research purposes.

Indocyanine green exhibits no pharmacological effects when administered intravenously.

Pharmacokinetic properties

Distribution: After intravenous injection indocyanine green undergoes no significant

extrahepatic or enterohepatic circulation; simultaneous arterial and venous blood estimations

have shown negligible renal, peripheral, or lung uptake of the dye. In healthy volunteers

indocyanine green cannot be detected in either urine or cerebrospinal fluid. Indocyanine green

does not cross the placental barrier. The volume of distribution corresponds to the blood

volume. After oral or rectal administration indocyanine green is not absorbed from the gut.

Protein-binding: Following intravenous injection, indocyanine green is rapidly bound to plasma

proteins, of which beta-apolipoprotein B is the principle carrier (95 %).

Metabolism: Indocyanine green is not metabolized.

Elimination: Plasma disappearance is biphasic, showing an initial elimination half-life t1/2 of 3-

4 min and a secondary phase with a dose-dependent t1/2 of approximately 60-80 min.

Indocyanine green is taken up from the plasma almost exclusively by the hepatic parenchymal

cells with a maximum rate of uptake (transport maximum: Tm of about 0,1 mg/minute/kg) and

is secreted un-metabolized and unconjugated entirely into the bile. The concentration

maximum in bile is reached after about 1/2–2 hours depending on the amount injected.

After biliary obstruction, the dye appears in the hepatic lymph, independently of the bile,

suggesting that the biliary mucosa is sufficiently intact to prevent diffusion of the dye, though

allowing diffusion of bilirubin.

As indocyanine green is not reabsorbed in the intestine there is no enterohepatic circulation.

7.3 Summary of findings from clinical studies

The near-infrared fluorescence cholangiography (NIRFC) technique after local or intravenous

administration of indocyanin green (ICG) has been evaluated in various animal models (14-


Version date: 21.07.2016 30 of 54

17) and in open, laparoscopic, and single-incision laparoscopic cholecystectomy in humans

(16, 18-20). 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 dissection of Calot’s triangle (21). Real-time

simultaneous imaging of the hepatic and cystic arteries can also be obtained (22, 23).

Ishizawa et al (18), investigated the novel fluorescent cholangiography technique using the

intravenous injection of indocyanine green (ICG).

In 52 patients undergoing laparoscopic cholecystectomy, 2.5 mg ICG was injected

intravenously 30 min before the patient entered the operating room or following intubation. A

fluorescent imaging system, which consisted of a xenon light source and a laparoscope with a

charge-coupled device camera that could filter out light wavelengths below 810 nm, was used.

Fluorescent cholangiography was performed during dissection of Calot's triangle, and its ability

to delineate biliary anatomy was compared with that of preoperative cholangiography.

Fluorescent cholangiography delineated the cystic duct in all 52 patients, and the cystic duct-

common hepatic duct junction was visible before dissection of Calot's triangle in 50 patients.

Fluorescent imaging also identified all accessory bile ducts that had been diagnosed before

surgery in eight patients.

They conclude that fluorescent cholangiography enables real-time identification of biliary

anatomy during dissection of Calot's triangle. This simple technique may become standard

practice for avoiding bile duct injury during laparoscopic cholecystectomy, replacing

radiographic cholangiography.

Besides for fluorescence cholangiography (21, 24, 25), indocyanine green, as a contrast agent,

has been applied for intraoperative NIR fluorescence imaging in a wide variety of other clinical

indications: such as lymphatic road-mapping in colorectal cancer surgery (29), gastric cancer

surgery (30) and cervical cancer surgery (31).

7.4 Summary of known and potential risks and benefits

It is expected that clearer identification of the biliary anatomy is possible by using ICG for NIR

fluorescence cholangiography during laparoscopic cholecystectomy.

Contra indications

ICG-PULSION is contraindicated for safety reasons in:

• patients with hypersensitivity to indocyanine green or to sodium iodide unless special

precautions are taken,


Version date: 21.07.2016 31 of 54

• patients with hypersensitivity to iodine,

• patients with hyper-thyroidism, patients with autonomic thyroid adenomas

• as in-vitro experiments have shown that indocyanine green displaces bilirubin from its

protein binding, ICG-PULSION should not be used in premature infants or neonates in whom

an exchange transfusion is indicated due to of hyperbilirubinemia,

• if injection of ICG-PULSION was poorly tolerated in the past it must not be used again,

since severe anaphylactic reactions might occur.

Special warnings and precautions for use

- Since severe anaphylactic reactions might occur after application of ICG, it must only

be applied under supervision of a physician.

- Due to an increased incidence of adverse reactions in patients with severe renal

insufficiency, ICG-Pulsion must only be applied after a careful benefit/risk assessment.

- Heparin preparations containing sodium bisulphite reduce the absorption peak of

indocyanine green in plasma and blood and, therefore, should not be used as an

anticoagulant for the collection of samples for analysis.

- Indocyanine green is stable in plasma and whole blood so that samples obtained in

discontinuous sampling techniques may be read hours later. Sterile techniques have

to be used in handling the dye solution.

- The iodine content of ICG can interfere with thyroid tests performed before or after

administration of the dye. Therefore, radio-active iodine uptake studies should not be

performed for at least a week following the use of ICG.

Interaction with other medicinal products and other forms of interaction

The clearance of indocyanine green may be altered by medicinal products that interfere with

liver function.

Probenecid and some of its metabolites may be secreted into the bile, and may depress the

biliary secretion of indocyanine green. This may influence its secretion which is of importance

when ICG secretion is used as a liver function test.

Concomitant use of certain medicinal products and injectables can alter the absorption. The

absorption is reduced by injectables containing sodium bisulphite (particularly in combination

with heparin).

Medicinal products and substances that can reduce absorption:


Version date: 21.07.2016 32 of 54

Anticonvulsants, bisulphite compounds, haloperidol, heroin, pethidine, meperidine,

metamizole, methadone, morphine, nitrofurantoin, opium alkaloids, phenobarbital,

phenylbutazone.

Medicinal products and substances that can increase absorption:

Cyclopropane, probenicid, rifamycin.

Pregnancy and lactation

Data on a limited number (242) of exposed pregnancies indicate no adverse effects of

indocyanine green on pregnancy or on the health of the foetus/new-born child. To date, no

other relevant epidemiological data are available. No studies for reproduction, teratogenicity,

or carcinogenic properties in animals are available. The potential risk for humans is unknown.

Caution should be exercised when prescribing to pregnant women. Repeated applications on

one day have to be avoided.

It is not known whether this medicinal product is excreted in human milk. Because many

medicinal products are excreted in human milk, caution should be exercised when indocyanine

green is administered to a nursing woman.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

Undesirable effects

Anaphylactic or urticarial reactions have been reported in patients with or without history of

allergy to iodides. Also in very rare cases coronary artery spasm has been described.

It is known that injection of indocyanine green preparations can in very rare cases cause

nausea and anaphylactoid or anaphylactic reactions (<1/10000). In patients with terminal renal

insufficiency the possibility that an anaphylactic reaction occurs seems to be increased.

Symptoms which should be mentioned are: unrest, feeling of warmth, pruritus, urticaria,

acceleration of heart rate, fall in blood pressure and shortness of breath, bronchospasm, flush,

cardiac arrest, laryngospasm, facial oedema, nausea. Together with the anaphylactoid

reaction, hypereosinophilia may occur.

If, contrary to expectations, symptoms of anaphylaxis do occur, the following immediate

measures should be taken:

• stop further administration of ICG-Pulsion

• leave injection catheter or cannula in the vein

• keep airways free


Version date: 21.07.2016 33 of 54

• inject 100-300 mg hydrocortisone or a similar preparation by rapid intravenous injection

• substitute volume with isotonic electrolyte solution

• give oxygen, monitor circulation

• slowly administer antihistamines intravenously

The following additional measures are indicated in cases of anaphylactic shock:

• place patient in recumbent position with legs raised

• rapidly substitute volume with e.g. isotonic electrolyte solution (pressure infusion), plasma

expanders

• immediately administer 0.1–0.5 mg adrenaline (epinephrine) diluted to 10 ml with 0.9 %

saline intravenously (repeat after 10 minutes if necessary).

Urticarial reactions of the skin occurred very rarely (<1/10000).

Two anaphylactic deaths have been reported following indocyanine green administration

during cardiac catheterization. One of these was in a patient with a history of penicillin and

sulfa allergy. Deaths due to anaphylaxis occurred in less than 1/330000 (estimate) including

single reports.

Overdose

Up to now no case of medicinal product overdose or laboratory findings accompanying

overdose of ICG has been reported.

7.5 Description and justification of route of administration and dosage

The administration and site of ICG are of critical importance for the quality of the

measurements. In principle, for obtaining optimal quality first pass indicator dilution curves, the

injection should be as close as possible to the vascular bed, organ or tissue of interest.

On peripheral injection the injection should be given immediately after application of tourniquet

and the arm should be raised after release of tourniquet. This ensures rapid transport of the

dye from the site of injection and peripheral injection is then practically equivalent to central

venous injection.

7.6 Dosages, dosage modifications and method of administration

Before administration the powder must be reconstituted with water-for-injection for injections.

The reconstituted solution is clear and free from visible particles.

Diagnostic procedures with ICG should be performed under the supervision of a physician.


Version date: 21.07.2016 34 of 54

ICG is intended for intravenous injection via an injection needle, a central or peripheral catheter

or cardiac catheter.

Single dose per measurement in adults, elderly, children:

Cardiac, circulatory, micro-circulatory and tissue perfusion diagnostics as well as cerebral blood flow: 0.1 to 0.3 mg/kg body weight as bolus injection

Liver function diagnostics: 0.25 – 0.5 mg/kg body weight as bolus injection

Ophthalmic angiography: 0.1 to 0.3 mg/kg body weight as bolus injection

Total daily dose: adults, elderly, adolescents 11-18 years:

The total daily dose of ICG-Pulsion should be kept below 5 mg/kg body weight.

7.7 Preparation and labelling of Non Investigational Medicinal Product

Preparation and labelling will be controlled by the hospital pharmacy of Maastricht UMC+.

7.8 Drug accountability

ICG must not be diluted with solutions containing salts (saline, Ringer's solution etc.) as this

can lead to precipitation of the dye. This medicinal product must not be mixed with other

medicinal products than mentioned below under “Disposal precautions”

Shelf Life: 3 years.

After reconstitution, the solution should be used immediately, protected from light.

Special precautions for storage: do not store above 25 °C. Keep vials in the outer carton in

order to protect from light.

Container: amber glass vial (type I).

Closure: rubber stopper (bromobutyl, grey) fixed by an aluminium cap.

Disposal precautions:

ICG should be reconstituted immediately prior to use. This medicinal product is reconstituted

by addition of 10 ml of solvent for injections to the vial containing 25 mg of active substance

giving a dark-green solution for injection with a concentration of 2.5 mg/ml.

If an incompatibility is noted in the form of unclear solution then the reconstituted solution

should be discarded!

Visually inspection of the reconstituted solution should be followed out. Only clear solutions

free from visible particles should be used. ICG is for single use only.


Version date: 21.07.2016 35 of 54

8. METHODS

8.1 Study parameters/endpoints

8.1.1 Main study parameter/endpoint

- Time until establishment of Critical View of Safety (CVS).

CVS is established if the following three criteria are met:

1) Mobilization of the gallbladder infundibulum for 1/3rd of the length of the gallbladder in

liver bed

2) Circumferential exposure of the cystic duct and confirmation of its transition in the

gallbladder

3) Circumferential exposure of the cystic artery and confirmation of its transition in the

gallbladder

8.1.2 Secondary study parameters/endpoints (if applicable)

- Time until identification of the cystic duct (CD) during dissection of CVS;

- Time until identification of common bile duct (CBD);

- Time until identification of the transition of CD in the gallbladder during dissection of CVS;

- Time until identification of the transition of the cystic artery in the gallbladder during

dissection of CVS;

- Visualization of CVS and visualization of the transition of the cystic duct and cystic artery

in the gallbladder;

- Total surgical time;


- Bile duct injury;

- Postoperative length of hospital stay


- Conversion to open cholecystectomy

- Postoperative complications (until 90 days after surgery)

- Using: Accordion Severity Grading System of Surgical Complications.

- Cost- minimization of the procedure

8.1.3 Other study parameters

Not applicable.


Version date: 21.07.2016 36 of 54

8.2 Randomisation, blinding and treatment allocation

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

Unexpected findings of (chronic) cholecystitis will be documented.

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. See also Chapter 5, page 18, treatment of subjects. At

least one member of the team must be a surgeon or surgical resident who has performed

more than 50 procedures as first surgeon. This is not a prerequisite for the second member

of team. An operation is always performed by a “first surgeon” who performs the whole

procedure or most of the procedure; assisted by an “assisting surgeon/assistant”. The

assistant may be a surgeon, a resident or a scrub nurse.

0-20 20-50 50-100 >100

1st surgeon 1 2 3 4

Assisting

surgeon/assistant

1 2 3 4

• Both the “first surgeon” and “assisting surgeon/assistant” as defined above can

have experience level 1-4, but as at least one member of the team must have

level 3, the sum of the score of “1st surgeon” and “assisting surgeon/assistant” will

result in a score between 4 and 8.

• The following categories representing the skill level of the surgical team will be

possible:

è I = 4

è II = 5

è III= 6

è IV= 7

è V = 8


Version date: 21.07.2016 37 of 54

8.3 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 (see Figure 8a and 8b):

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 registers on a paper form 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. CVS is established if the following three criteria are met:


liver bed


gallbladder


gallbladder

After all three criteria are met in the NIRF-LC group, a second dose of 1 ml ICG is injected

intravenously to ascertain the visualization of CVS. 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

(note: these video recordings will be kept for a fifteen years after the end of the study, along

with the other study data). After completion of surgery, length of time between “first look at liver

hilum” (this is T0) until the first recognition of the following components will be calculated, based


Version date: 21.07.2016 38 of 54

on the intraoperative registration: cystic duct (CD), cystic artery (CA), Critical View of Safety

(CVS), common bile duct (CBD).

Using conventional imaging the CBD is regularly not displayed; this is partly a result of the

CVS technique. The video recordings of the surgical procedure will be used for postoperative

video analysis by three other observers (also for double check of the intraoperative time

registration: cystic duct (CD), cystic artery (CA), Critical View of Safety (CVS), common bile

duct (CBD). The mean ‘total fluorescence imaging time’ during the laparoscopic procedures

will be calculated based on the video recordings, in order to measure the duration of the

procedure due to application of the fluorescence technique.

All 5 observers (the surgeon or surgical trainee, PhD researcher or local researcher during the

operation and the three postoperative observers) will individually assess the endpoints. The

mean values of the five assessments will be used for each of the endpoints.

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.

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?)

Using the video recordings of the surgical procedures, objective visualization of CVS will

be scored using a 3-item score:


liver bed


gallbladder


gallbladder

If not all three items are achieved, CVS is not established.

Besides “CVS: YES/NO”, also registration of the individual items is saved.


Version date: 21.07.2016 39 of 54

- 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;

Prior to video analysis by the panel, the PhD researcher(s) will prepare a cut of the relevant

fragments of the video recordings (e.g. starting at first look at liver hilum until clipping of CD

and CA, with only including the relevant dissection phases). Full video recordings will, however,

be available for the panel if the prepared video fragment is not sufficient for assessment.

Dr J.Meijerink (VU Medical Center) has agreed to be one of the members of the expert panel

in case the VU Medical Center will not participate in inclusion of patients in the trial.

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), as previously described (21, 24).

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:


- Bile duct injury;

- Postoperative length of hospital stay;


- Conversion to open cholecystectomy

- Postoperative complications (until 90 days after surgery)

- Using: Accordion Severity Grading System of Surgical Complications. The

complications during hospital stay will be monitored closely in every patient. After

discharge from the hospital stay the complications will be monitored during routine

visits in the outpatient clinic. After 90 days the patient will contacted by telephone

to register any complications that occurred after the routine visits.

- Cost minimization 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.


Version date: 21.07.2016 40 of 54

Figure8a–Flowchartofstudyprocedures:NIRFlaparoscopiccholecystectomy(NIRF-LC)group

IntraoperativePreoperative Postoperative

Dataanalysisofregistered

timemeasurements

Registrationoftimeuntil:

-establishmentofCVS

Also:

-visualizationofstructures

asdescribedinsecondary

endpoints(e.g.,CD,CA,

CBD)

Patienteligiblefor

inclusion?

Startprocedureusing

conventionalcameramode

Patientundergoingelective

laparoscopiccholecystectomy

Videoevaluation:

-CVSestablished?

(3-pointscore)

-transitionCDinto

gallbladdervisualized?

-transitionCAinto


-Cost-minimisationwillbe

calculated

Writteninformed

consent?

Videorecordingof

completelaparoscopic

procedure

IntravenousICGinjection

directlyafterinductionof

anesthesia

Every2-5minutes(and

moreoftenifdesiredby

thesurgeon)switchcamera

toICG-modefor

fluorescence

cholangiography,untilCVS

isestablished:then,a

seconddoseofICGwillbe

administeredtoconfirm

thepositionofthecystic

artery


Version date: 21.07.2016 41 of 54

Figure8b–Flowchartofstudyprocedures:conventionallaparoscopiccholecystectomy(CLC)group

IntraoperativePreoperative Postoperative

Dataanalysisofregistered

timemeasurements

Registrationoftimeuntil:

-establishmentofCVS

Also:

-visualizationofstructures

asdescribedinsecondary

endpoints(e.g.,CD,CA,

CBD)

Patienteligiblefor

inclusion?

Fullprocedureusing

conventionallaparoscopy

Patientundergoingelective

laparoscopiccholecystectomy

Videoevaluation:

-CVSestablished?

(3-pointscore)

-transitionCDinto


-transitionCAinto


-Cost-minimisationwillbe

calculated

Writteninformed

consent?

Videorecordingof

completelaparoscopic

procedure


Version date: 21.07.2016 42 of 54

8.4 Withdrawal of individual subjects

Subjects can leave the study at any time for any reason if they wish to do so without any

consequences. The investigator can decide to withdraw a subject from the study for urgent

medical reasons.

8.4.1 Specific criteria for withdrawal

Conversion to open cholecystectomy, before CVS is established, is a reason for study

withdrawal. Furthermore, if the video recordings of the laparoscopic procedure did not

succeed, the procedure will be unsuitable for analysis of all predefined endpoints. There are

no other specific criteria for withdrawal after the surgical procedure has been completed.

8.5 Replacement of individual subjects after withdrawal

In case of withdrawal, individual subjects will be replaced to achieve the calculated sample

size.

8.6 Follow-up of subjects withdrawn from treatment

Not applicable.

8.7 Premature termination of the study

Not applicable.


Version date: 21.07.2016 43 of 54

9. SAFETY REPORTING

9.1 Temporary halt for reasons of subject safety

In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if

there is sufficient ground that continuation of the study will jeopardise subject health or safety.

The sponsor will notify the accredited METC without undue delay of a temporary halt including

the reason for such an action. The study will be suspended pending a further positive decision

by the accredited METC. The investigator will take care that all subjects are kept informed.

9.2 AEs, SAEs, SADEs and reporting thereof

9.2.1 Adverse events (AEs)

Adverse events are defined as any undesirable experience occurring to a subject during the

study, whether or not considered related to [the investigational product / the experimental

intervention]. All adverse events reported spontaneously by the subject or observed by the

investigator or his staff will be recorded, except for the following adverse events:

- Nausea

- Decreased appetite

- Dizziness

- Abdominal pain

- Pain around skin incisionWhen these AE’s cause a prolonged hospital stay, they will be noted.

9.2.2 Serious adverse events (SAEs)

A serious adverse event is any untoward medical occurrence or effect that at any dose:

- results in death;

- is life threatening (at the time of the event);

- requires hospitalisation or prolongation of existing inpatients’ hospitalisation;

- results in persistent or significant disability or incapacity;

- is a congenital anomaly or birth defect; or

- Any other important medical event that did not result in any of the outcomes listed above

due to medical or surgical intervention but could have been based upon appropriate

judgement by the investigator.

An elective hospital admission will not be considered as a serious adverse event.

The investigator will report all SAEs to the sponsor without undue delay after obtaining

knowledge of the events, except for the following SAEs:


Version date: 21.07.2016 44 of 54

- Hospital stay prolonged with 1 day due to nausea, dizziness, or abdominal pain

without clear underlying pathology.

The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited

METC that approved the protocol, within 7 days of first knowledge for SAEs that result in

death or are life threatening followed by a period of maximum of 8 days to complete the initial

preliminary report. All other SAEs will be reported within a period of maximum 15 days after

the sponsor has first knowledge of the serious adverse events.

9.2.3: Serious adverse device events (SADEs):

Definitions:

Adverse Device Event (or –Effect), ADE:

Adverse event related to the use of an investigational medical device.

Note 1. This includes any adverse event resulting from insufficiencies or inadequacies

in the instructions for use, the deployment, the implantation, the installation, the

operation, or any malfunction of the investigational medical device.

Note 2. This includes any event that is a result of a use error or intentional misuse.

Serious Adverse Device Event (or –Effect), SADE:

Adverse device event that has resulted in any of the consequences characteristic of a serious

adverse event (see paragraph 9.2.2):

9.2.4: Policy regarding reporting of Serious adverse events (SAEs) or Serious

adverse device events (SADEs):

The principal investigator of the participating centre where a SAE/SADE occurs is responsible

to report the SAE/SADE by email to the coordinating centre (MUMC+) within 24 hours.

The the coordinating investigator (J. van den Bos, MUMC+) is responsible for SAE/SADE

assessment and expedited reporting through the web portal ToetsingOnline to the accredited

METC that approved the protocol, within 15 days after the sponsor has first knowledge of the

SAEs/SADEs. SAEs/SADEs that result in 1 extra day postoperative hospital stay will be

reported every half a year through line listing. SAEs/SADEs that result in death or are life threatening should be reported expedited. The

expedited reporting will occur not later than 7 days after the responsible investigator has first

knowledge of the adverse reaction. This is for a preliminary report with another 8 days for

completion of the report.


Version date: 21.07.2016 45 of 54

The above is in accordance with the guidelines of the European Commission Directorate

General for Health and Consumers (http://ec.europa.eu/health/medical-

devices/files/meddev/2_7_3_en.pdf)

9.3 Follow-up of adverse events

All AEs will be followed until they have abated, or until a stable situation has been reached.

Depending on the event, follow up may require additional tests or medical procedures as

indicated, and/or referral to the general physician or a medical specialist.

SAEs and SADEs need to be reported till end of study within the Netherlands, as defined in

the protocol.

9.4 Data Safety Monitoring Board (DSMB)

Given the nature of this study and the described extent of the burden and risks associated with

participation we believe assignment of a Data Safety Monitoring Board is not necessary.


Version date: 21.07.2016 46 of 54

10. STATISTICAL ANALYSIS

Patient clinical history (including: previous surgery, history of cholecystitis / pancreatitis, etc.)

baseline characteristics (including: age, length, body weight, BMI, etc.) indications and results

of the procedure, intraoperative findings (including primary and secondary endpoints), as well

as hospital course and postoperative follow-up evaluation will be prospectively recorded and

computerized in an database. Categoric variables will be compared by the Chi-Square test.

Numerical variables will be compared by the independent sample T- test or the Mann-Whitney

U test, depending on distribution. All p-values will be 2-sided. A P-value of less than 0.05 will

indicate a statistically significant difference. All data will be analyzed on an intention-to-treat

principle.

10.1 Primary study parameter(s)

Primary outcome parameter of “time until establishment of CVS” will be given in minutes, with

a mean and standard deviation.

A linear regression analysis will be applied for determination of possible significant differences

between the time measurements, therewith comparing the NIRF-LC group to the CLC group.

This concerns the time measurements as recorded during the operation, indicated by the

surgical team.

This will be conducted to determine whether a reduction in time can in fact be achieved using

NIRF technique compared to CLC.

10.2 Secondary study parameter(s)

All numeric secondary outcomes such as time until visualization of cystic duct and cystic

artery will be analyzed with a linear regression analysis. In case of missing values a Cox

regression analysis will be performed. Missing values can occur especially in the

postoperative analysis by the expert panel, when the panel concludes that, contrary to the

opinion of the operating team, actually no CVS was obtained or that the transition of the

cystic duct or cystic artery in the gallbladder had actually not been properly identified.

All categorical secondary outcomes such as bile duct injury and conversion to open surgery

will be analyzed with a logistic regression analysis.

10.3 Other study parameters

Not applicable.


Version date: 21.07.2016 47 of 54

10.4 Interim analysis

Not applicable.

11. ETHICAL CONSIDERATIONS

11.1 Regulation statement

This study will be conducted according to the principles of the Declaration of Helsinki

(Fortaleza, Brazil, October 2013) and in accordance with the Medical Research Involving

Human Subjects Act (WMO).

11.2 Recruitment and consent

The study concerns patients that are operated on in the MUMC+ and the other participating

centers. If a patient meets the inclusion criteria, he/she will initially be informed by the surgeon

at a regular visit in the outpatient clinic about the existing study. If the patient is interested

he/she will receive oral and written information about the study and have the occasion to ask

questions freely. The patient will be handed the approach letter, the information sheet for study

subjects and the informed consent form. If available, the (local) researcher will be called to

give this oral information directly after the regular visit at the outpatient clinic and to hand the

mentioned documents. This approach letter is signed by their consulting surgeon, the informed

consent form by the researcher.

The consulting physician or the researcher will ask permission for further contact by the

researcher. The researcher will be the first point of call from then on. Patients will have at least

one week to decide whether or not they want to participate in the study. In every participating

centre, patients will be contacted to ask for their decision by the researcher. This will be done

by phone. In case of participation, the informed consent form will be signed on the day of

operation, in the presence of both the patient and the (local) researcher.

The following procedure will be conducted:

- The patient will be informed of the research project, stating that the option to participate in

the study is without obligation, and that either inclusion or exclusion does not affect the

patient’s place on the waiting list. Furthermore, the patient will be informed about the

independent doctor (dr Poeze) who he or she can consult to ask questions.

Patient information letter and informed consent form are attached as a separate document.

11.3 Objection by minors or incapacitated subjects

Not applicable.


Version date: 21.07.2016 48 of 54

11.4 Benefits and risks assessment, group relatedness

Compared with standard care, patients in the NIRF-LC group have to receive one preoperative

intravenous injection and one peroperative intravenous injection of indocyanine green. This is

the only additional (minimally) invasive action for the patient.

It is known that injection of ICG preparations, in very rare cases, can cause nausea and

anaphylactoid or anaphylactic reactions (< 1:10,000). Patients with terminal renal insufficiency

seem to be more prone for such an anaphylactic reaction. Estimated death due to anaphylaxis

is reported as less than 1/330,000 (see Paragraph 7.4).

Symptoms that should be mentioned to the patient are: anxiety, feeling of warmth, pruritus,

urticaria, acceleration of heart rate, decrease in blood pressure, shortness of breath,

bronchospasm, flushing, cardiac arrest, laryngospasm, facial edema, nausea.

Together with the anaphylactoid reaction hypereosinophilia may occur.

In chapter 7, paragraph 7.4 of this protocol is described in detail, how to react in case of an

anaphylactoid or anaphylactic reaction.

The patients in the NIRF-LC group will possibly benefit from a shorter period to establishment

of CVS and its clearer identification. The administration of ICG and the modified laparoscope

itself are related with very low of risk for the patient. The outcome of this multicentre

randomized study will potentially be of great importance to determine added value and

validation of the studied technique: near-infrared fluorescence cholangiography to improve the

identification of biliary anatomy during laparoscopic cholecystectomy.

11.5 Compensation for injury

The sponsor/investigator has a liability insurance which is in accordance with article 7 of the

WMO.

The sponsor (also) has an insurance which is in accordance with the legal requirements in

the Netherlands (Article 7 WMO). This insurance provides cover for damage to research

subjects through injury or death caused by the study.

The insurance applies to the damage that becomes apparent during the study or within 4

years after the end of the study.

11.6 Incentives

Not applicable.


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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION

12.1 Handling and storage of data and documents

All patient data will be encoded to ensure the patient’s privacy. At random patients will be

assigned a number, ranging from 1 to 308; code à PatientX. In this way it will not be possible

to trace patients back to the date of their operation. Only the investigators and principal

investigator will have access to the data. Data (including video recordings) will be kept for

fifteen years after the end of the study.

Patients will be asked for consent for use of these data in order to further clarify the aim or

primary or secondary endpoints of the study.

12.2 Monitoring and Quality Assurance

Not applicable.

12.3 Amendments

Amendments are changes made to the research after a favourable opinion by the accredited

METC has been given. All amendments will be notified to the METC that gave a favourable

opinion.

12.4 Annual progress report

The sponsor/investigator will submit a summary of the progress of the trial to the accredited

METC once a year. Information will be provided on the date of inclusion of the first subject,

numbers of subjects included and numbers of subjects that have completed the trial, serious

adverse events/ serious adverse reactions, other problems, and amendments.

12.5 End of study report

The investigator will notify the accredited METC of the end of the study within a period of 8

weeks. The end of the study is defined as the last patient’s last visit.

The sponsor will notify the METC immediately of a temporary halt of the study, including the

reason of such an action.

In case the study is ended prematurely, the investigator will notify the accredited METC

within 15 days, including the reasons for the premature termination.

Within one year after the end of the study, the investigator/sponsor will submit a final study


Version date: 21.07.2016 50 of 54

report with the results of the study, including any publications/abstracts of the study, to the

accredited METC.

12.6 Public disclosure and publication policy

All data, positive and negative will be published without reservation, preferably in a peer-

reviewed journal. All participating centres and the supplier of the equipment agree with this

policy.

The investigators of the participating centres, as mentioned in the protocol, will participate as

co-author in publications regarding this trial. Manuscripts will be reviewed by all participating

investigators prior to submission.

Publication policy is in accordance with the Dutch CCMO guidelines

(www.CCMO.nl/standaardonderzoekdossier -1; see: M2 wetenschappelijke publicaties,

CCMO-statement-publicatiebeleid-3-02.docx).

The supplier of the equipment will not end this supply before the intake of the patients has

been completed.

STRUCTURED RISK ANALYSIS

12.7 Potential issues of concern

Not applicable.

12.8 Synthesis

Initially, it has already been stated that patients participating in this study will not benefit from

the application of NIRF technique during the surgical procedure.

Chapter 13.1 has been skipped because the laparoscopic fluorescence imaging systems are

CE-marked for the indication ICG fluorescence laparoscopy, the same indication as the

systems are applied for in the present study. The use of the fluorescence laparoscope is not

related with any additional risk (the near-infrared light is not related with any radiation

exposure) compared to conventional laparoscopes.

As described in Chapter 7 and 11 the administration of ICG is related with a very low of risk

for the patient. To further minimize this already low risk of an allergic reaction to the ICG,

specific in- and exclusion criteria are implemented: in case of known iodine or ICG

hypersensitivity patients are not eligible of inclusion in this study. Furthermore, kidney and liver


Version date: 21.07.2016 51 of 54

insufficiency, pregnancy and breastfeeding are also exclusion criteria to prevent any

complications following ICG administration.

The outcome of this multicenter randomized study will potentially be of great importance to

determine added value and validation of the studied technique: near-infrared fluorescence

cholangiography to improve the identification of biliary anatomy during laparoscopic

cholecystectomy.

Regarding the present study, patients will be followed up from the surgical procedure until the

regular postoperative visit to the outpatient clinic (i.e., for registration of secondary endpoints:

bile duct injury; postoperative length of hospital stay; any postoperative complications

diagnosed until 90 days after surgery).

No additional visit to the outpatient clinic specifically for this study will be scheduled.


Version date: 21.07.2016 52 of 54

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19. Ishizawa T, Kaneko J, Inoue Y, Takemura N, Seyama Y, Aoki T, et al. Application of fluorescent

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