Efficacy Of Near Infrared Incisionless Fluorescent Cholangiography (NIFC) During Laparoscopic Cholecystectomy
Phase: NA
Conditions: Cholecystitis, Cholelithiasis
Sponsor: The Cleveland Clinic

Multi-center Study Protocol: Efficacy of Near Infrared Incisionless Fluorescent 
Cholangiography (NIFC) during Laparoscopic Cholecystectomy 
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CONFIDENTIAL 
January 2017 
Fluorescent Cholangiography vs White Light for Bile Ducts Identification     
NCT02702843 
 
 
 
 
 
Multi-Center Study Protocol 
 
 
Efficacy of Near Infrared Incisionless Fluorescent 
Cholangiography (NIFC) during Laparoscopic 
Cholecystectomy. 

Multi-center Study Protocol: Efficacy of Near Infrared Incisionless Fluorescent 
Cholangiography (NIFC) during Laparoscopic Cholecystectomy 
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CONFIDENTIAL 
 
 
 
CONFIDENTIALITY STATEMENT 
 
 
This protocol contains proprietary and confidential information. 
 
Acceptance of this document constitutes agreement by the Lead Site 
Investigator (LSI) that no unpublished information contained herein will be 
published or disclosed without the prior written approval of the Principal 
Investigator (PI), except that this document may be disclosed to 1) study 
personnel under supervision of the LSI who need to know the contents of this 
document to properly conduct the study and 2) appropriate Institutional Review 
Boards under the condition that they keep it confidential. The foregoing shall 
not apply to disclosure required by governmental regulations or laws; however, 
the PI must be promptly notified of any such disclosure. 

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Cholangiography (NIFC) during Laparoscopic Cholecystectomy 
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Lead Site Investigator Agreement 
 
I, the undersigned, will provide copies of this protocol, any subsequent protocol 
amendments and access to all information furnished by KARL STORZ to study 
personnel under my supervision. 
 
I will discuss this material with them to ensure that they are fully informed 
about the study protocol and the medical device and drug to which it pertains. 
 
I agree to conduct this clinical study according to the protocol described herein, 
except when mutually agreed upon in writing by the Principal Investigator. I also 
agree to conduct this study in compliance with all applicable regulations, as well 
as with the requirements of the appropriate Institutional Review Board and any 
other institutional requirements. 
 
 
Lead Site Investigator Signature:  _____________________________________ 
 
Signature Date:  __________________________________________________ 
 
Name:  __________________________________________________________ 
 
Title:  ___________________________________________________________ 
 
Institution:  ______________________________________________________ 
 
Address:  ________________________________________________________ 
 
Phone:  _________________________________________________________ 
 
Email:  _________________________________________________________ 

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Table of Contents 
 
Efficacy of Near Infrared Incisionless Fluorescent Cholangiography (NIFC) 
during Laparoscopic Cholecystectomy. .............................................................. 1 
CONFIDENTIALITY STATEMENT .......................................................................... 2 
Lead Site Investigator Agreement ...................................................................... 3 
Table of Contents ............................................................................................... 4 
1. 
Summary..................................................................................................... 7 
2. 
Introduction ................................................................................................ 9 
a. Background ........................................................................................................ 9 
b. Significance / Rationale ................................................................................... 10 
c. 
Strengths and Limitations ................................................................................ 11 
3. 
Study Overview ......................................................................................... 11 
4. 
Study Objectives ....................................................................................... 11 
a. Primary Objective: ........................................................................................... 11 
b. Secondary Objectives: ...................................................................................... 12 
5. 
Study Endpoints ........................................................................................ 12 
a. Primary Endpoint: ............................................................................................ 12 
b. Secondary Endpoints: ...................................................................................... 12 
6. 
Covariates ................................................................................................. 13 
7. 
Additional Observations (NIFC group only)............................................... 13 
a. “Reflux Maneuver” .......................................................................................... 13 
8. 
Design ....................................................................................................... 13 
a. Study Population.............................................................................................. 13 
b. Setting(s) .......................................................................................................... 13 
c. 
Enrollment Process .......................................................................................... 14 
d. Randomization Process .................................................................................... 14 
e. Flow chart ........................................................................................................ 14 
9. 
Data collection and procedures ................................................................ 15 
a. Pre-Op data collection ..................................................................................... 15 
i. 
Patient data ......................................................................................................................... 15 
ii. 
Patient clinical characteristics .............................................................................................. 16 
b. Intra-Op data collection ................................................................................... 16 
i. 
For NIFC arm only ................................................................................................................ 16 

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ii. 
For both arms: PRIOR to dissection ...................................................................................... 16 
iii. 
For both arms: AFTER dissection .......................................................................................... 16 
iv. 
For NIFC arm only ................................................................................................................ 16 
c. 
One-week Post-Op data collection (usual control after surgery) ..................... 16 
10. 
Subject Selection ................................................................................... 17 
a. Inclusion Criteria .............................................................................................. 17 
b. Exclusion Criteria ............................................................................................. 17 
11. 
Study Device .......................................................................................... 17 
a. Indocyanine Green (ICG) Fluorescent Dye........................................................ 17 
b. Equipment........................................................................................................ 17 
c. 
Regulatory Status of Device ............................................................................. 18 
d. Rationale for Safe Use of the Device ................................................................ 18 
12. 
Study procedures ................................................................................... 19 
a. Informed Consent ............................................................................................ 19 
b. Pre-Operative Case Report Form ..................................................................... 19 
c. 
Patient Randomization .................................................................................... 19 
i. 
Control arm (WLI only) procedures ...................................................................................... 19 
ii. 
Experimental arm (NIFC) procedures .................................................................................... 20 
d. Post-Operative Case Report Form .................................................................... 20 
e. Bile Duct Injury Form (if needed) ..................................................................... 20 
13. 
Statistical Plan ...................................................................................... 21 
a. Sample size ...................................................................................................... 21 
b. Data Analysis.................................................................................................... 21 
14. 
Anticipated Problems and Solutions ..................................................... 22 
a. Lower than expected Enrollment ..................................................................... 22 
b. Approaches to Missing Data ............................................................................ 22 
15. 
Safety and Adverse Effects .................................................................... 22 
a. Risks and Benefits ............................................................................................ 22 
b. Potential Risks.................................................................................................. 22 
c. 
Procedure to Minimize Risk ............................................................................. 23 
d. Potential Benefits ............................................................................................ 23 
16. 
Data Handling and Record keeping (REDCap) ....................................... 23 
a. Overview .......................................................................................................... 23 
b. The data will be safely uploaded in REDCap .................................................... 23 
17. 
Responsibilities ..................................................................................... 24 

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a. Principal Investigator (PI) ................................................................................. 24 
b. Lead Site Investigator (LSI) ............................................................................... 24 
c. 
Clinical Data Manager (CDM) ........................................................................... 25 
d. Study Monitoring, Auditing and Inspecting ..................................................... 25 
18. 
Publication Plan .................................................................................... 26 
19. 
References ............................................................................................. 26 
20. 
Appendices ............................................................................................ 29 
a. 510(k) Acknowledgement Letter from FDA ...................................................... 30 
b. Patient Informed Consent Form ....................................................................... 32 
c. 
Pre-Op Case Report Form................................................................................. 35 
d. Intra-Op Case Report Form – Surgeon ............................................................. 36 
e. Intra-Op Case Report Form – Observer ............................................................ 38 
f. 
Post-op Case Report Form ............................................................................... 40 
g. 
Bile Duct Injury (BDI) Form .............................................................................. 42 
h. Schedule of events ........................................................................................... 45 
i. 
WMA Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects....................................................................................... 46 
i. 
Preamble ............................................................................................................................. 46 
ii. 
General Principals ................................................................................................................ 46 
iii. 
Risks, Burdens and Benefits.................................................................................................. 47 
iv. 
Vulnerable Groups and Individuals ....................................................................................... 48 
v. 
Scientific Requirements and Research Protocols .................................................................. 48 
vi. 
Research Ethics Committees ................................................................................................ 49 
vii. 
Privacy and Confidentiality .............................................................................................. 49 
viii. 
Informed Consent ............................................................................................................ 49 
ix. 
Use of Placebo ..................................................................................................................... 50 
x. 
Post-Trial Provisions ............................................................................................................. 51 
xi. 
Research Registration and Publication and Dissemination of Results .................................... 51 
xii. 
Unproven Interventions in Clinical Practice ...................................................................... 51 
 

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1. Summary 
Title: 
Efficacy 
of 
Near 
Infrared 
Incisionless 
Fluorescent 
Cholangiography 
(NIFC) 
during 
Laparoscopic 
Cholecystectomy (LC) 
Primary Objective: 
Demonstrate that NIFC performs better than standard white 
light (WLI) alone in visualizing and identifying extra-
hepatobiliary structures (Cystic Duct, Right Hepatic Duct, 
Common Hepatic Duct, Common Bile Duct, Cystic-CBD 
junction, Cystic-Gallbladder junction, and any Accessory 
Ducts) before and after dissection during Laparoscopic 
Cholecystectomy (LC). 
Secondary Objectives: 
1. Demonstrate that NIFC is an effective teaching tool to assist 
students and residents present in the O.R. during the 
procedure 
to 
identify 
extra-hepatobiliary 
structures 
(before/after dissection). 
2. Demonstrate that the Time to Clip, which is defined as the 
time from the moment Calot’s Triangle is first visualized to 
when the clip is applied, is reduced when using NIFC vs WLI 
alone. 
3. Compare the mean number of procedures that required 
Conversion to Open using NIFC vs WLI alone. 
4. Compare the mean Volume of Bleeding using NIFC vs WLI 
alone. 
5. Compare the Incidence rate of Bile Leakage from the liver 
bed using NIFC vs WLI alone. 
6. Compare the Incidence rate of Bile Duct Injury (BDI) using 
NIFC vs WLI alone. 
7. Compare the mean Surgeon Confidence Level using NIFC vs 
WLI alone. 
Indication: 
Laparoscopic Cholecystectomy (LC) 
Investigational  Design: 
Two arms multi-center randomized controlled clinical trial 
with patients randomized by center. 
Inclusion/exclusion 
criteria: 
Inclusion Criteria 
1. Patients  of both genders  
2. Minimum age: 18 years old 
3. Spoken and written command of the language spoken in the 
country's center  

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4. Ability to understand and follow the study procedures and 
sign the informed consent 
Exclusion Criteria 
1. Known allergies to iodides 
2. Known 
history 
of 
cholangitis, 
pancreatitis, 
CBDS’s, 
coagulopathy 
3. Known liver disease 
4. Women who are pregnant or breastfeeding, or for whom 
possibility of pregnancy was not ruled out 
Number of Subjects: 
1,000 patients enrolled across all centers  
Target Population: 
Male 
or 
female 
subjects 
undergoing 
laparoscopic 
cholecystectomy that fulfil all of the inclusion and none of 
the exclusion criteria. 
Length of 
Investigation: 
Approximately 1 year 
Primary Endpoints: 
 
Detection Rate (DR) of each particular extra-hepatobiliary 
structure during Laparoscopic Cholecystectomy (LC)  defined 
as the total number of patients in which the particular 
structure is detected before and after dissection in that arm 
of the Study (WLI or NIFC),  divided by the total number of 
patients in that arm.  Extra-hepatobiliary structures to be 
included in this assessment: Cystic Duct, Right Hepatic Duct, 
Common Hepatic Duct, Common Bile Duct, Cystic-CBD 
junction, Cystic-Gallbladder junction, and any Accessory 
Ducts. 
Secondary Endpoints: 
1. The DR for students/residents only (apart from experienced 
surgeons), both before and after dissection. 
2. Time to Clip  
3. Incidence of Conversion to Open Surgery 
4. Volume of Bleeding  
5. Incidence of Bile Leakage from the liver bed  
6. Incidence of Bile Duct Injury (BDI)  
7. Surgeon Confidence Level 
Test Device/  
Procedure: 
Image1 SPIES (Storz Professional Image Enhancement 
System) Endoscopic ICG Imaging System 
Comparator Device/  
Procedure: 
Standard Image1 SPIES Endoscopic System using white light 
imaging  (WLI) only 
Statistical Analysis: 
The DR (before and after dissection) between arms will be 
compared using the chi-square test while the number of 

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structures detected will be analyzed  using non-parametric 
tests.  Regression models (logistic or generalized mixed 
models) will be fitted to evaluate if the effect of NIFC on the 
primary outcomes is modified by the patient's or surgeon's 
characteristics or the site.  
 
  
2. Introduction  
a. Background 
Around 750,000 laparoscopic cholecystectomies are performed in the U.S. every 
year.  This minimally invasive approach has demonstrated to have several 
advantages like shorter hospital stay, less operative pain and prompt recovery 
when compared to the open approach (1,2,3,4,5). 
Since its first description, the main concern on laparoscopic cholecystectomy 
has been bile duct injuries, with an estimated incidence rate of between 0.4 and 
1 % (6,7,8,9,10). Most common situations involved in a bile duct injury are lack 
of visualization and tactile feedback, misidentification of structures and 
anatomic variations (11,12).   
Anatomic anomalies have been identified in 19% of patients (13, 14) and 
hepatic accessory ducts in 8.4% (15,16,17). Different approaches have been 
proposed to avoid a bile duct injury. Strassberg described the critical view 
approach of safety dissecting the Calot´s triangle and identifying the cystic 
artery and extra-hepatic biliary ducts (18,19,20,21,22). Even though the critical 
view approach of safety proved to be very useful, it could not diminish the rate 
of bile duct injury (23). Pablo Mirizzi (1931) developed the intraoperative 
cholangiography (IOC), an invasive method to map the intrahepatic and extra-
hepatic bile ducts (24,25,26,27,28,29,30).  Although the goal was to diminish 
the severity of the injuries, there are still disadvantages of this technique 
including: 
 radiation exposure for patient and OR staff, 
 risk of bile duct injury – during insertion of the trans-cystic catheter, 
 the need of bulky material, and 
 increased misidentification of the cystic duct. 
Recently, a novel technique to visualize structures using fluorescent light and 
intravenous dye has been developed. 
Near Infrared Incisionless Fluorescent Cholangiography (NIFC) is a medical 
imaging technique that uses fluorescence to detect properly labeled structures 
during surgery.  
NIFC is performed using imaging devices with the purpose of providing real-time 
simultaneous information from color reflectance images (white light) and 
fluorescence emission (near infrared light).  One or more light sources are used 

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to excite and illuminate the sample.  Light is collected using optical filters that 
match the emission spectrum of the fluorophore. Imaging lenses and digital 
cameras are used to produce the final image.  
Fluorescence excitation is accomplished using various kinds of light sources.  
Halogen lamps have the advantage of delivering high power for a relatively low 
cost.  Using different band-pass filters, the same source can be used to produce 
several excitation channels from the UV to the near infrared.  
NIFC seems to be a promising method for identification of the extra-hepatic 
biliary anatomy during laparoscopic cholecystectomy. Real utility of the method 
should be evaluated in different clinical scenarios through a randomized clinical 
trial. 
b. Significance / Rationale  
During laparoscopic cholecystectomies, the visualization of the extra-hepatic 
bile ducts with fluorescence is called Near Infrared Incisionless Fluorescent 
Cholangiography (NIFC).  Fluorescence equipment and a dye are necessary in 
order to perform a NIFC, but the technique requires no radiation or incision. A 
fluorescence dye is administrated intravenously at least 45 minutes before the 
surgery, which is excreted by the liver and the bile duct (31,32,33). 
Different publications have described the utility of this technique in order to 
visualize the extra-hepatic bile ducts (31,32,33,34,35,36,37).  There is no doubt 
that the method is feasible and accurate (38,39,40).  But to establish the 
method as a standard of care or at least as a recommendation, it is important to 
determine 
the 
real 
impact 
of 
this 
technique 
during 
laparoscopic 
cholecystectomy in different pathologies and patients.  
Ishizawa et al (41) demonstrated that NIFC 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. 
Shols et al published an initial experience with 15 patients. The group found 
that 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. (42) 
Cost effectiveness of the technique was validated by Dip et al (35) with a total 
of 43 patients (21 males and 22 females). Mean age was 49.53 ± 14.35 years old 
and mean body mass index was 28.35 ± 8 kg/m2 (2). Overall mean operative 
time was 64.95 ± 17.43 min. NIFC was faster than IOC (0.71 ± 0.26 vs. 7.15 ± 
3.76 min; p < 0.0001). NIFC was successfully performed in 43 of 43 cases (100%) 
and intraoperative cholangiography (IOC) in 40 of 43 cases (93.02%) while in 3 
patients IOC was not possible. NIFC was less expensive than IOC (US$14.10 ± 
4.31 vs. US$778.43 ± 0.40; p < 0.0001). All surgeons found routine use of NIFC 
useful. Identification rates of extra-hepatic bile duct using NIFC ranges between 
71 and 100 % depending on the study (32,33,34,35).  
Osayi et al (36) studied eighty-two patients that underwent elective 
laparoscopic cholecystectomy and compared the use and utility of near infrared 

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incisionless 
fluorescent 
cholangiography 
(NIFC) 
vs 
intraoperative 
cholangiography (IOC). Mean age and body mass index (BMI) of the patients 
were 42.6 ± 13.7 years and 31.5 ± 8.2 kg/m2, respectively. Indocyanine green 
was administered 73.8 ± 26.4 min prior to incision. NIFC was significantly faster 
to complete than IOC (1.9 ± 1.7 vs. 11.8 ± 5.3 min, p < 0.001). IOC was 
unobtainable in 20 (24.4 %) patients while NIFC did not visualize biliary 
structures in four (4.9 %) patients. After complete dissection, the rates of 
visualization of the cystic duct, common bile duct, and common hepatic duct 
using NIF 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, NIFC 
successfully identified biliary structures in 80 % of the cases. (39) 
Spinoglio et al (40) reported 45 cases between July 2011 and January 2012 with 
NIFC. The rates of visualization were 93 % for the cystic duct, 88 % for the 
common hepatic duct, and 91 % for the common bile duct prior to Calot's 
dissection; after Calot's dissection, the rates were 97 % for all three ducts. Mean 
hospital stay was 1.1 days and there were no bile duct injuries or any other 
major complications. (40) 
The studies described above are observational and so far no randomized clinical 
trial has been published evaluating the efficacy of NIFC to improve the 
identification of the extra-hepatic biliary structures. Additionally it would be 
relevant to investigate the ability of the NIFC to reduce intraoperative bleeding, 
duration of laparoscopic cholecystectomy. Further, it is central to assess 
whether NIFC can improve the outcomes in some subpopulation of patients for 
whom the evaluation and dissection of the Calot's triangle is difficult, e.g. obese 
patients or patients undergoing inflammatory processes. Finally, the potential 
use of NIFC as a training tool in laparoscopic surgery is still to be studied.  
c. Strengths and Limitations 
The strength of the study is the ability to investigate whether the extra-hepatic 
biliary tract is more visible using NIFC when compared with white light (WLI) 
alone. It is a multicenter study with diverse patient populations and surgeons 
from different countries/continents that will validate this method globally. 
Limitations may include impossibility to randomize by surgeon. 
3. Study Overview 
The Study is designed to compare the effectiveness of Near Infrared 
Fluorescence Cholangiography (NIFC) to standard white light imaging (WLI) in 
visualizing and identifying the main biliary and hepatic structures (Cystic Duct, 
Right Hepatic Duct, Common Hepatic Duct, Common Bile Duct, Cystic-CBD 
junction, Cystic-Gallbladder junction and any Accessory Ducts) during 
laparoscopic cholecystectomy.   
4. Study Objectives  
a. Primary Objective: 

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Demonstrate that NIFC performs better than standard white light (WLI) alone 
in visualizing and identifying extra-hepatobiliary structures (Cystic Duct, Right 
Hepatic Duct, Common Hepatic Duct, Common Bile Duct, Cystic-CBD junction, 
Cystic-Gallbladder junction, and any Accessory Ducts) before and after 
dissection during Laparoscopic Cholecystectomy (LC). 
 
b. Secondary Objectives: 
1. Demonstrate that NIFC is an effective teaching tool to assist students and 
residents present in the O.R. during the procedure to identify extra-
hepatobiliary structures (before/after dissection). 
2. Demonstrate that the Time to Clip, which is defined as the time from the 
moment Calot’s Triangle is first visualized to when the clip is applied, is 
reduced when using NIFC vs WLI alone. 
3. Compare the mean number of procedures that required Conversion to 
Open using NIFC vs WLI alone. 
4. Compare the mean Volume of Bleeding using NIFC vs WLI alone. 
5. Compare the Incidence rate of Bile Leakage from the liver bed using NIFC vs 
WLI alone. 
6. Compare the Incidence rate of Bile Duct Injury (BDI) using NIFC vs WLI alone. 
7. Compare the mean Surgeon Confidence Level using NIFC vs WLI alone. 
5. Study Endpoints  
a. Primary Endpoint: 
Detection Rate (DR) of each particular extra-hepatobiliary structure during 
Laparoscopic Cholecystectomy (LC)  defined as the total number of patients in 
which the particular structure is detected before and after dissection in that 
arm of the Study (WLI or NIFC),  divided by the total number of patients in that 
arm.  Extra-hepatobiliary structures to be included in this assessment: Cystic 
Duct, Right Hepatic Duct, Common Hepatic Duct, Common Bile Duct, Cystic-CBD 
junction, Cystic-Gallbladder junction, and any Accessory Ducts. 
b. Secondary Endpoints: 
1. The DR for students/residents only (apart from experienced surgeons), both 
before and after dissection. 
2. Time to Clip 
3. Incidence of Conversion to Open Surgery 
4. Volume of Bleeding 
5. Incidence of Bile Leakage from the liver bed 
6. The mean Incidence of Bile Duct Injury (BDI) 
7. Surgeon Confidence Level 

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6. Covariates 
Besides the comparison of the outcomes in both study arms, we will conduct an 
exploratory analysis to identify potential effect modifiers. The following 
baseline variables will be considered:  
1) Patient data:  
a) Age 
b) Gender 
c) BMI 
2) Patient history/condition: 
a) obesity 
b) liver disease 
c) lithiasis 
d) surgery status (elective/urgent/emergent) 
3) Intra-operative factors: 
a) amount of fat covering cystic artery 
b) amount of inflammation 
c) presences of adhesions / scar tissue 
4) Surgeon expertise (resident/attendant) 
7. Additional Observations (NIFC group only) 
a. “Reflux Maneuver” 
According to previous publications, in some cases the Cystic Duct may not be 
seen with NIFC because the Cystic Duct may not contain ICG at the time of 
viewing.  In those cases, a “reflux maneuver” [defined as using an atraumatic 
laparoscopic instrument to push on the Common Bile Duct in order to move 
more of the ICG from the Common Bile Duct through the Cystic Duct into the 
Gallbladder – thereby increasing visualization of the Cystic-Gallbladder junction] 
can be performed. 
We will evaluate the usefulness of the Reflux Maneuver to visualize the Cystic 
Duct. 
8. Design  
a. Study Population  
Participants will include patients aged 18-years old and above selected for 
Laparoscopic Cholecystectomy (LC).  
b. Setting(s) 
Participants will be recruited by the Department of Surgery at the following 
study sites, all of which are recognized hepato-bilio-pancreatic surgery centers:  
 Cleveland Clinic (Weston, FL, USA) 

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 Cleveland Clinic (Cleveland, OH, USA) 
 Cedars-Sinai Medical Center (Los Angeles, CA, USA) 
 Hospital de Clínicas José de San Martín (Buenos Aires, Argentina) 
 Tokyo Medical University Hospital (Tokyo, Japan) 
 Asklepios Westklinikum (Hamburg, Germany) 
 University of Insurbia (Varese, Italy) 
 Klinikum Südstadt Rostock (Rostock, Germany) 
 Kliniken Essen-Mitte (Essen, Germany) 
Surgeons trained in laparoscopic and hepato-bilio-pancreatic (HBP) surgery will 
participate in the study. Principal and Lead Site Investigators of this Protocol are 
seniors and recognized HBP surgeons. Additionally, junior surgeons will be 
involved in the study.  When a resident is present in the OR, he/she will perform 
the procedure under the supervision of the senior surgeon. 
c. Enrollment Process 
Eligible patients will be identified through clinical and test evaluation.  Eligibility 
will be verified by the patient's primary surgeon. The surgeon will determine the 
indication and date of the surgery. Once a patient is confirmed as eligible, the 
surgeon will introduce the study in detail. If after being introduced to the study 
and having had the opportunity to ask questions, the patient is willing to 
participate, he/she will be asked to review and sign the informed consent 
document (Appendix XXX).  
Upon entry in the clinical trial patients will be randomly allocated to the 
intervention arm. Data will be collected at enrolment time, during surgery, at 
the end of surgery and one week after surgery.  
d. Randomization Process 
Upon entry in the clinical trial, the master study database (REDCap, described 
later in Section 16) will randomly allocated patients to one of the study arms 
(1:1) within site (1:1) using a computer generated random sequence. This will 
provide an allocation sequence for each site. Once a patient is enrolled and a 
database file in REDCap is initiated for that patient, he/she will be assigned 
electronically to one of the study arms.   
Patient will be blind to the intervention but surgeon blinding will not be feasible 
due to the nature of the intervention. The study will involve a considerable 
number of surgeons in each site, which should compensate any potential bias of 
some of them in favor or against either approach.   
e. Flow chart 

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Figure 1 shows the flow chart for the study, a multi-centered randomized controlled 
trial (RCT) 1:1 with two arms:  
1. Control: WLI  
A laparoscopic cholecystectomy will be performed using Xenon white light imaging 
(WLI) only.  
2. Experimental: NIFC 
A laparoscopic cholecystectomy will be performed using both white light imaging 
and near infrared light imaging with indocyanine green (ICG) intravenous dye. 
 
9. Data collection and procedures 
Data will be collected before, during and at the end of surgery; and one week 
after surgery. 
a. Pre-Op data collection 
i. Patient data 
 Age  
 Gender 
 Weight  
 Height 
 BMI 

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ii. Patient clinical characteristics 
 Liver disease 
 Lithiasis 
 Surgical status:  elective/urgent/emergent 
b. Intra-Op data collection  
i. For NIFC arm only 
 Time of ICC administration 
 Was there any Adverse Reaction?  If so, what happened and how 
was the patient treated? 
ii. For both arms: PRIOR to dissection 
 Categorize initial visualization 
 Amount of fat 
 Amount of inflammation 
 Presence of adhesions / scar tissue 
 Remove the fat from the Calot’s triangle area, retract the 
gallbladder and Hartmann’s pouch 
 Surgeon/Observer documents which extra-hepatic biliary structures 
are identified without doubt 
 Start Dissection.  Document the time hilar dissection was begun 
(baseline time) 
iii. For both arms: AFTER dissection 
 Surgeon/Observer documents which extra-hepatic biliary structures 
are identified without doubt 
 Time to Clip:  Document the time the Cystic Duct was clipped 
 Volume of Bleeding 
 Incidence of Bile Leakage 
 Incidence of Anatomic Anomalies of the extra-hepatic biliary system, 
including any Accessory Ducts 
 Incidence of performing IOC 
 Incidence of CBD stones 
 Incidence of Conversion to open surgery 
 Incidence of Bile Duct Injury (BDI)? 
iv. For NIFC arm only 
 PRIOR to and AFTER DISSECTION: Surgeon/Observer documents 
which extra-hepatic biliary structures are identified without doubt 
using the “Reflux Maneuver” during NIFC 
 Was the “reflux maneuver” useful? 
 Surgeon preference:  Was NIFC helpful? 
c. One-week Post-Op data collection (usual control after surgery) 
 Length of hospital stay 

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 Readmission? 
 Complications? 
 Adverse drug reactions 
 Hemorrhage 
 Bile leak 
 Bile duct injury 
 Death? 
10. Subject Selection 
a. Inclusion Criteria  
1. Patients  of both genders  
2. Minimum age: 18 years old 
3. Spoken and written command of the language spoken in the country's 
center  
4. Ability to understand and follow the study procedures and sign the 
informed consent 
b. Exclusion Criteria 
1. Known allergies to iodides 
2. Known history of cholangitis, pancreatitis, CBDS’s, coagulopathy 
3. Known liver disease 
4. Women who are pregnant or breastfeeding, or for whom possibility of 
pregnancy was not ruled out 
11. Study Device 
a. Indocyanine Green (ICG) Fluorescent Dye  
The drug used in these studies to evaluate the extra-hepatic bile duct is 
indocyanine green (ICG) and the equipment uses a wavelength around 800 nm 
(32,33,34,35,36,37). ICG, a cyanine dye, has been used in various medical 
diagnostic procedures since its FDA approval in 1956 (38). 
ICG is a fluorophore responding to near-infrared irradiation that absorbs light 
between 790 and 805 nm, and re-emits it with an excitation wavelength of 835 
nm. When given intravenously, ICG binds to plasma proteins and becomes 
confined to the intravascular space [15] . It is then exclusively metabolized by 
the liver and excreted by the biliary system 15 to 20 minutes after 
administration. These properties, in conjunction with the absence of any native 
biological fluorescence within these wavelengths, make ICG an ideal agent for 
the acquisition of high-quality images of the biliary tract. 
b. Equipment  
KARL STORZ (Tuttlingen, Germany) has developed a laparoscopic fluorescence 
imaging system that is suitable for both near-infrared fluorescence and xenon 

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(white) light imaging. During laparoscopic cholecystectomies, alternate 
exposure from xenon white light (STD mode) to near infrared light (ICG mode) is 
used to identify the biliary structures before, during and after dissection.   
The fluorescent imaging system by KARL STORZ consists of a xenon light source 
(D-Light P) that can emit both near infrared (>780 nm) and white light, NIR-
transmitting telescopes and a full HD 3-chip fluorescence imaging (FI) camera 
head capable of capturing both white light and NIR images.  A foot pedal allows 
for a quick change between fluorescence and white light.   
The KARL STORZ Endoscopic ICG Imaging System is comprised of the following 
components: 
Model Number 
Description 
20133720-1 
D-Light P light source 
20010130 
Foot switch 
495 NCSC 
Fiber optic light cable 
26003 ACA/BCA 
ICG endoscopes (0° and 30°) 
TH102 
Image1 SPIES H3-Z FI camera head 
TC200 + TC300 
Image1 SPIES camera control unit 
n/a 
Any medical-grade HD monitor with DVI-D or 
3G-SDI input 
c. Regulatory Status of Device 
KARL STORZ has submitted a 510(k) to the FDA for this fluorescent imaging 
system [Appendix A, #K152583, submitted 9/10/15], but clearance has not yet 
been granted.  As such, any clinical use requires IRB approval.   
d. Rationale for Safe Use of the Device 
The KARL STORZ Endoscopic ICG Imaging System is based on the same 
fluorescent imaging Principals using ICG as the FDA-approved da Vinci® Firefly 
Surgical System [510(k) #K124031, approval date September 13, 2013] 
produced by Intuitive Surgical, Inc.  The man difference is the KARL STORZ 
system uses a filtered Xenon light source to produce the required NIR light, 
whereas the Intuitive device uses a laser diode.  
It is the Principal Investigator’s belief that the KARL STORZ imaging equipment 
does not pose significant risk to patients and therefore no Investigational Device 
Exemption (IDE) filing is required.   
Each center will have available at least one KARL STORZ fluorescent imaging 
system.  

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12. Study procedures 
a. Informed Consent 
Prior to admission, the observer/resident/fellow/surgeon, from now on called 
"Researcher," will review the Informed Consent Form (Appendix B) with the patient 
and, if they desire to participate, both the patient and the Researcher will execute and 
dated the form. 
 
 
b. Pre-Operative Case Report Form 
At admission, the Researcher will complete a Pre-Operative Case Report Form 
(Appendix C) with baseline information abstracted from the patient chart. 
c. Patient Randomization 
Each surgeon will follow the standard laparoscopic surgical protocol of his/her 
center, and will comply with the following additional steps according to which 
arm of the study the patient is assigned:  
i. Control arm (WLI only) procedures 
1. After inserting the scope in the abdominal cavity, once other 
standard operatory procedures (e.g., taking down adhesions if 
necessary, or releasing scar tissue) are completed using white light 
imaging (WLI) only, the Researcher will record the time when Calot’s 
triangle is first visualized. From this moment on, the surgery will be 
recorded. 
2. After removing the fat from the gallbladder area, lifting the 
gallbladder over the liver, and grabbing the Hartman's pouch to 
visualize the Calot's triangle, but PRIOR TO DISSECTION, the 
Researcher will determine what extra-hepatic biliary structures can 
be specifically identified.  Of note: because one of the goals of the 
Study is to evaluate NIFC as a teaching tool, residents and juniors 
should record what structures they were able to identify by 
themselves before any intervention of the attendant surgeon. 
3. Then, AFTER DISSECTION, a similar assessment of what extra-
hepatic biliary structures can be specifically identified using WLI only 
will be performed. 
4. Anatomic anomalies of the biliary system will be documented on the 
case form and if an anatomic variation is found, a snap shot photo 
will be taken in addition to the video.   
5. Immediately before clipping or proceeding with open surgery, the 
total time from Step 1 will be recorded, known herein as the “Time 
to Clip”; 

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6. Before leaving the operation room, all participant surgeons and 
observers will complete the Intra-Operative Case Report Form 
(Appendices D and E, respectively).     
ii. Experimental arm (NIFC) procedures 
1. Patient randomized to the experimental arm, at least 45 mins before 
surgery, will receive a weight-scaled dose of indocyanine green (0.05 
mg/kg) by IV and the time of administration and any adverse 
reactions will be recorded.  
2. After inserting the scope in the abdominal cavity, once other 
standard operatory procedures (e.g., taking down adhesions if 
necessary, or releasing scar tissue) are completed using white light 
imaging (WLI) only, the Researcher will record the time when the 
Calot’s triangle is first visualized. From this moment on, the surgery 
will be recorded. 
3. After removing the fat from the gallbladder area, lifting the 
gallbladder over the liver, and grabbing the Hartman's pouch to 
visualize the Calot's triangle, but PRIOR TO DISSECTION, the 
Researcher will use NIFC to determine what extra-hepatic biliary 
structures can be specifically identified.  This involves toggling the 
light source back and forth between STD mode (WLI) and ICG mode 
(NIFC).  Of note: because one of the goals of the Study is to evaluate 
NIFC as a teaching tool, residents and juniors should record what 
structures they were able to identify by themselves before any 
intervention of the attendant surgeon. 
4. Then, AFTER DISSECTION, a similar assessment of what extra-
hepatic biliary structures can be specifically identified using NIFC will 
be performed. 
5. Anatomic anomalies of the biliary system will be documented on the 
case form and if an anatomic variation is found, a snap shot photo 
will be taken in addition to the video.   
6. Immediately before clipping or proceeding with open surgery, the 
total time from Step 1 will be recorded, known herein as the “Time 
to Clip”; 
7. Before leaving the operation room, all participant surgeons and 
observers will complete the Intra-Operative Case Report Form 
(Appendices D and E, respectively).     
d. Post-Operative Case Report Form 
During the standard follow-up exam, typically 7-10 day post-op, the Researcher 
will complete the Post-Operative Case Report Form (Appendix F). 
e. Bile Duct Injury Form (if needed) 
If the procedure results in a bile duct injury, the operating surgeon will complete the 
ancillary Bile Duct Injury Form (Appendix G). 

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13. Statistical Plan  
a. Sample size  
We estimate that the six participant centers will be able to enroll a minimum of 
1000 patients in a 12 months period. Table XX shows the minimum effect size 
(increase in the rate of detection) that we will be able to detect with a 90% 
power or more, 5% level of significance, one-side test, when the detection rate 
in the control group are the ones indicated in the first column.  
 
 
 
 
Before dissection 
After dissection 
Structure 
DR control 
group 
DR increase 
(effect size) 
DR control 
group 
DR increase 
(effect size) 
Cystic 
50% 
10% 
100% 
-- 
Right Hepatic Duct 
40% 
10% 
80% 
7% 
Common Hepatic Duct 
46% 
10% 
70% 
8% 
Common Bile Duct 
46% 
10% 
96% 
3% 
Cystic-CBD junction 
29% 
9% 
60% 
9% 
Cystic-Gallbladder 
junction 
60% 
9% 
70% 
8% 
Accessory Ducts 
1% 
3% 
2% 
4% 
 
Regarding the main secondary outcome, incidence of injuries, the power to 
detect a drop from 8/1000 in the control arm to 2/1000 in the intervention arm, 
with a sample size of 500 patients per arm is 15%. Regretfully, with an 
achievable sample size as the one proposed above, the study will not have 
enough power to detect a drop in the incidence as important as the one 
considered.  
b. Data Analysis  
In general, descriptive statistics including frequencies and means will be used to 
characterize patient's baseline characteristics in both study arms. Analyses are 
designed to test the following hypotheses based on the primary objectives: 
Compared to those in the control arm, surgeons using NIFC will be able to 
identify a) more frequently the gallbladder cystic union (both before dissection 
and before clipping); b) a larger number of hepato-biliary structures and; c) 
more frequently some of the five hepato-biliary structures. We will test the first 
hypothesis using the chi-square test, the second one using non-parametric test 
(e.g. Kruskal-Wallis) and the third one using generalized mixed or hierarchical 
models to account for the clustering induced by the patient.  

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Regression models (logistic or generalized mixed models) will be fitted including 
covariates to evaluate if the effect of NIFC on the primary outcomes is modified 
by the patient's or surgeon's characteristics and site.  
Regarding secondary outcomes we will use the Fisher's exact test or Chi square 
test (as needed) to compare proportion of patients with bile duct injury, open 
surgery or bleeding. Time to clipping and time to end of surgery will be 
compared between arms using the Kruskal-Wallis' test.  Regression models will 
be used when possible -we expect very low incidence of injuries and open 
surgeries- to evaluate patient's and surgeon's effect modification.  
Finally, for those outcomes specific for the NIFC group we will use logistic or 
generalized linear models to assess whether the reported helpfulness of the NIR 
light or the reflux maneuver is associated to patient's characteristics or 
surgeon's experience. 
All statistical analysis will be conducted in R software.  
14.   Anticipated Problems and Solutions 
a.  
Lower than expected Enrollment 
If necessary, and if agreed upon by KARL STORZ, the enrollment period will be 
extended to reach the proposed 1,000 patients.  
b.  
Approaches to Missing Data 
We do not expect missing data for the main outcome as this information will be 
collected immediately after or during the surgery. Some of the secondary 
outcomes will be collected in a very short follow up period (7-10 days); we have 
however considered the alternative of phone calls to recover information in 
those patients not attending to clinic after surgery. Missing data on covariates 
are not expected either, as they are routine laboratory tests and studies.  
15. Safety and Adverse Effects 
a. Risks and Benefits 
The dye may cause a feeling of warmth for several minutes following the 
injection.  It may cause a change in the color of the stool (green).  Uncommon 
allergic reactions include itchy skin and hives. Rare more severe allergic 
reactions such as wheezing, difficulty breathing, and low blood pressure may 
occur.    
There is no personal benefit by participating in this research study. The 
increased visualization of the extra-hepatobiliary anatomy may aid the surgeon. 
The knowledge to be gained from this research may be beneficial for other 
patients, society or science.  
b. Potential Risks 

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Potential risks are similar to routine laparoscopic cholecystectomy, including 
possible bile duct injury, bleeding, and/or conversion to open surgery.  
Drug related adverse complications may be due to allergic reactions.  
c. Procedure to Minimize Risk 
Administration and dose of ICG will be confirmed and performed only by 
trained medical personnel. During the surgical procedure, the patient will be 
closely monitored by the operating room staff.   
d. Potential Benefits 
The increased visualization of the extra-hepatic biliary anatomy may aid the 
surgeon. 
The knowledge to be gained from this research may be beneficial for other 
patients, society or science.  
16. Data Handling and Record keeping (REDCap) 
a. Overview 
The medical and research information recorded about the patient for this 
research will be used within the Institution and/or disclosed outside the 
Institution as part of this multi-center study. The procedure done solely for this 
research study may be placed in the medical record to indicate the patient’s 
participation in this study. 
The information recorded about the patient as part of this research will be 
maintained in a confidential manner. 
Federal regulations require that the patient authorize the release of any health 
information that may reveal patient identity. The results of this research may be 
presented at meetings or in publications; however, Patient identity will not be 
disclosed in any presentation. 
The Institution will not use or disclose the information collected in this study for 
another research purpose without patient written permission, unless the 
Institution’s Institutional Review Board (IRB) gives permission after ensuring 
that appropriate privacy safeguards are in place. 
b. The data will be safely uploaded in REDCap  
REDCap (Research Electronic Data Capture) is a mature, secure web application 
for building and managing online surveys and databases. While REDCap can be 
used to collect virtually any type of data, it is specifically geared to support data 
capture for research studies. The REDCap Consortium is composed of 1,589 
active institutional partners in 92 countries who utilize and support REDCap in 
various ways 

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Using REDCap's stream-lined process for rapidly developing projects, we will be 
able to  create and design this  project using 1) the online method from our web 
browser using the Online Designer; and/or 2) the offline method by 
constructing a 'data dictionary' template file in Microsoft Excel, which can be 
later uploaded into REDCap. Both surveys and databases (or a mixture of the 
two) are going to be  be built using these methods. REDCap provides audit trails 
for tracking data manipulation and user activity, as well as automated export 
procedures for seamless data downloads to Excel, PDF, and common statistical 
packages (SPSS, SAS, Stata, R). 
17. Responsibilities 
a. Principal Investigator (PI) 
The Principal Investigator (PI) leads the team that conducts the clinical trial and is 
ultimately accountable for its conduct.  The PI’s responsibilities include: 
 
Designing, conducting and monitoring the Protocol 
 
Recruiting Lead Site Investigators at the various clinical sites to participate in 
the Multi-Center Study according to the Protocol 
 
Overseeing the integrity and analysis of research data collected during the 
Study 
 
Ensuring that the Protocol is followed by the various sites and that data are 
collected promptly and accurately 
 
Ensuring that subject’s rights, safety, and welfare are protected 
 
Informing and educating Lead Site Investigators of their role in the multi-center 
Study 
 
Assisting, as needed, to help train personnel at the various Sites about their 
role in the Study 
 
Gathering aggregate data from the Sites 
 
Summarizing the results of the Study, with the assistance of a biostatistician 
 
Publishing the results of the Study as lead author, with reference to the other 
Lead Site Investigators 
b. Lead Site Investigator (LSI) 
The Lead Site Investigator (LSI) is responsible for the day-to-day activities at his/her 
particular site to conduct the Study according to the Protocol.  The LSI’s responsibilities 
include: 
 
Overseeing the informed consent process 
 
Educating research participants and other staff of their role in the Study 
according to the Protocol 
 
Ensuring necessary approvals are obtained 
 
Recruiting, screening and scheduling patient procedures 

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 
Implementing Study requirements 
 
Maintaining the integrity of the Protocol, including the research data collected 
 
Documenting patient information, protocol deviations/violations, and 
regulatory compliance based on their own IRB requirements 
 
Providing records for inspection 
 
Complying with record-keeping and record-retention requirements 
c. Clinical Data Manager (CDM) 
The Clinical Data Manager at each site is responsible for organizing and collecting the 
data per the requirements outlined in the Protocol including: 
 
Collecting source documents before, during, and after each Study procedure, 
including  
o Informed Consent Forms 
o Case Report Forms (Pre-op, Intra-op, and Post-op) 
o Video and Still recordings from the procedure 
 
Inputting the data into the general Study REDCap database (as described in 
Section 17.b above. 
d. Study Monitoring, Auditing and Inspecting  
The conduct of the study will be monitored by representatives of Karl Storz 
( William Schnorr)and the Global Coordinator (Raul Rosenthal and 
Fernando Dip ) to ensure compliance with the protocol, GCP, ICH and 
applicable regulations. The coordinator will have regular contacts with the 
study centers, including remote access to provide information and support 
to the investigator(s) and confirm that the investigational team is adhering 
to the protocol, that data are being accurately and timely recorded in the 
RedCap. 
 
The coordinator will perform source data verification (SDV) (a comparison 
of the data in the RedCap with the patient’s medical records and other 
records relevant to the study including verification of informed consent of 
participating patients. This will require direct access to all original records 
for each patient (eg, clinic charts). 
 
The Investigator must ensure that clinical study records are retained 
according to national regulations, as documented in the clinical trial 
agreement entered into with the Sponsor in connection with this study. 
Subject files and other source data must be kept for the maximum period of 
time permitted by the hospital, institution, or private practice. The 
Investigator must inform The Main Center ( Cleveland clinic Florida) 
immediately if any documents are to be destroyed, to be transferred to a 
different facility, or to be transferred to a different owner. 
 
The co- investigators will permit study-related monitoring, audits, and 
inspections by the IRB, the sponsor, government regulatory bodies, and 

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Institutional compliance and quality assurance groups of all study related 
documents (for example, source documents, regulatory documents, data 
collection instruments, study data etc.). Participation as an investigator in 
this study implies acceptance of potential inspection by government 
regulatory authorities and applicable Institutional compliance and quality 
assurance offices.” 
18. Publication Plan                                 
The parties, recognizing the importance of communicating clinical trial results to 
the public and to the medical and scientific communities in an accurate and 
complete manner, intend for the first Publication of the Study to include the 
results from all of the study centers and to appear in a peer-reviewed scientific 
journal, in accordance with the Protocol.   
Without the prior written agreement of the Principal Investigator and KARL 
STORZ, Institution shall not Publish or submit for Publication, directly or 
indirectly, any Manuscript prior to the publication of an article in a peer-
reviewed scientific journal summarizing the data generated by all of the study 
centers, unless no such article is so published before the first anniversary of the 
finalization of the multi-center database, in which case Institution may Publish 
or submit for Publication a Manuscript without further delay. 
19. References  
1. Phatak UR, Chan WM, Lew DF, Escamilla RJ, Ko TC, Wray CJ, Kao LS. Is Nighttime 
the Right Time? Risk of Complications after Laparoscopic Cholecystectomy at 
Night. J Am Coll Surg. 2014 May 29 
2. Berci G, Hunter J, Morgenstern L, Arregui M, Brunt M, Carroll B, Edye 
M, Fermelia 
D, Ferzli 
G, Greene 
F, Petelin 
J, Phillips 
E, Ponsky 
J, Sax 
H, Schwaitzberg 
S,Soper 
N, Swanstrom 
L, Traverso 
W. 
Laparoscopic 
cholecystectomy: first, do no harm; second, take care of bile duct stones. Surg 
Endosc. 2013 Apr;27(4):1051-4 
3. Zhou MW, Gu XD, Xiang JB, Chen ZY. Comparison of Clinical Safety and 
Outcomes of Early versus Delayed Laparoscopic Cholecystectomy for Acute 
Cholecystitis: A Meta-Analysis. Scientific World Journal. 2014;2014:274516 
4. Strasberg SM, Brunt LM. Rationale and use of the critical view of safety in 
laparoscopic cholecystectomy. J Am Coll Surg. 2010 Jul;211(1):132-8. 
5. Yamashita Y, Kimura T, Matsumoto S. A safe laparoscopic cholecystectomy 
depends upon the establishment of a critical view of safety. Surg Today. 2010 
Jun;40(6):507-13 
6. Williamson JM Bile duct injury following laparoscopic cholecystectomy. Br J 
Hosp Med (Lond). 2014 Jun;75(6):325-30 
7. Richardson MC, Bell G, Fullarton GM. Incidence and nature of bile duct injuries 
following laparoscopic cholecystectomy: an audit of 5913 cases. West of 
Scotland Laparoscopic Cholecystectomy Audit Group. Br J Surg. 1996 
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8. Archer SB, Brown DW, Smith CD, Branum GD, Hunter JG. Bile duct injury during 
laparoscopic cholecystectomy: results of a national survey. Ann Surg. 2001 
Oct;234(4):549-58; 
9. Gigot J, Etienne J, Aerts R, Wibin E, Dallemagne B, Deweer F, Fortunati 
D, Legrand M, Vereecken L, Doumont J, Van Reepinghen P, Beguin C. The 
dramatic reality of biliary tract injury during laparoscopic cholecystectomy. An 
anonymous multicenter Belgian survey of 65 patients. Surg Endosc. 1997 
Dec;11(12):1171-8. 
10. Bauer TW, Morris JB, Lowenstein A, Wolferth C, Rosato FE, Rosato EF. The 
consequences of a major bile duct injury during laparoscopic cholecystectomy. J 
Gastrointest Surg. 1998 Jan-Feb;2(1):61-6 
11. Dekker SW, Hugh TB. Laparoscopic bile duct injury: understanding the 
psychology and heuristics of the error.ANZ J Surg. 2008 Dec;78(12):1109-14 
12. Way LW, Stewart L, Gantert W, Liu K, Lee CM, Whang K, Hunter JG. Causes and 
prevention of laparoscopic bile duct injuries: analysis of 252 cases from a 
human factors and cognitive psychology perspective. Ann Surg. 2003 
Apr;237(4):460-9. Review. 
13. Suzuki 
M, Akaishi 
S, Rikiyama 
T, Naitoh 
T, Rahman 
MM, Matsuno 
S. 
Laparoscopic cholecystectomy, Calot's triangle, and variations in cystic arterial 
supply. Surg Endosc. 2000 Feb;14(2):141-4. 
14. Ding YM, Wang B, Wang WX, Wang P, Yan JS. New classification of the anatomic 
variations of cystic artery during laparoscopic cholecystectomy. World J 
Gastroenterol. 2007 Nov 14;13(42):5629-34. 
15. Bicaj B, Qamirani S, Blakaj F, Bicaj T, Zejnullahu V, Hamza A, Hoxha F,Muçaj S. 
Variations of cystic duct (CD)--common hepatic duct (CHD) junction determined 
by ERCP. Med Arch. 2013;67(5):346-7. 
16. Schnelldorfer T, Sarr MG, Adams DB. What is the duct of Luschka?--A systematic 
review. J Gastrointest Surg. 2012 Mar;16(3):656-62 
17. Spanos CP, Syrakos T. Bile leaks from the duct of Luschka (subvesical duct): a 
review. Langenbecks Arch Surg. 2006 Sep;391(5):441-7 
18. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury 
during laparoscopic cholecystectomy.J Am Coll Surg. 1995 Jan;180(1):101-25. 
Review 
19. Yamashita Y, Kimura T, Matsumoto S. A safe laparoscopic cholecystectomy 
depends upon the establishment of a critical view of safety. Surg Today. 2010 
Jun;40(6):507-13 
20. Lam T, Usatoff V, Chan ST. Are we getting the critical view? A prospective study 
of photographic documentation duringlaparoscopic cholecystectomy. HPB 
(Oxford). 2014 Sep;16(9):859-63 
21. Vettoretto N, Saronni C, Harbi A, Balestra L, Taglietti L, Giovanetti M. Critical 
view of safety during laparoscopic cholecystectomy. JSLS. 2011 Jul-
Sep;15(3):322-5 
22. Avgerinos C, Kelgiorgi D, Touloumis Z, Baltatzi L, Dervenis C. One 
thousand laparoscopic cholecystectomies in a single surgical unit using the 
"critical view of safety" technique. J Gastrointest Surg. 2009 Mar;13(3):498-503 
23. Strasberg SM, Brunt LM. Rationale and use of the critical view of safety in 
laparoscopic cholecystectomy. J Am Coll Surg. 2010 Jul;211(1):132-8 

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24. Nieuwenhuijs VB. Impact of routine intraoperative cholangiography during 
laparoscopic cholecystectomy on bile duct injury (Br J Surg 2014; 101: 677-684). 
25. Alvarez FA, de Santibañes M, Palavecino M, Sánchez Clariá R, Mazza O, Arbues 
G, de Santibañes E, Pekolj J. Impact of routine intraoperative cholangiography 
during laparoscopic cholecystectomy on bile duct injury. Br J Surg. 2014 
May;101(6):677-84 
26. Huesch MD, Romley J. Intraoperative cholangiography during cholecystectomy. 
JAMA. 2013 Dec 25;310(24):2673-4 
27. Flum DR. Intraoperative cholangiography during cholecystectomy. JAMA. 2013 
Dec 25;310(24):2672-3. 
28. Sheffield KM, Riall TS, Han Y, Kuo YF, Townsend CM Jr, Goodwin JS. Association 
between cholecystectomy with vs without intraoperative cholangiography and 
risk of common duct injury. JAMA. 2013 Aug 28;310(8):812-20 
29. Iorga C, Cirimbei S, Strambu V, Popa. Intraoperative cholangiography still a 
current investigation. J Med Life. 2013 Dec 15;6(4):399-40 
30. Bilimoria KY, Chung J, Soper NJ. Laparoscopic cholecystectomy, intraoperative 
cholangiograms, and common duct injuries. JAMA. 2013 Aug 28;310(8):801- 
31. Ishizawa T, Bandai Y, Hasegawa K, Kokudo N. Fluorescent cholangiography 
during laparoscopic cholecystectomy: indocyanine green or new fluorescent 
agents? World J Surg. 2010 Oct;34(10):2505-6 
32. Aoki T, Murakami M, Yasuda D, Shimizu Y, Kusano T, Matsuda K, Niiya T, Kato H, 
Murai N, Otsuka K, Kusano M, Kato T Intraoperative fluorescent imaging using 
indocyanine green for liver mapping and cholangiography. J Hepatobiliary 
Pancreat Sci. 2010 Sep;17(5):590-4 
33. Ishizawa T, Bandai Y, Kokudo N. Fluorescent cholangiography using indocyanine 
green for laparoscopic cholecystectomy: an initial experience. Arch Surg. 2009 
Apr;144(4):381-2. Doi 
34. Ishizawa T, Tamura S, Masuda K, Aoki T, Hasegawa K, Imamura H, Beck Y, 
Kokudo N Intraoperative fluorescent cholangiography using indocyanine green: 
a biliary road map for safe surgery. J Am Coll Surg. 2009 Jan;208(1) 
35. Dip FD, Asbun D, Rosales-Velderrain A, Lo Menzo E, Simpfendorfer CH, 
Szomstein S, Rosenthal RJ. Cost analysis and effectiveness comparing the 
routine use of intraoperative fluorescent cholangiography with fluoroscopic 
cholangiogram in patients undergoing laparoscopic cholecystectomy. Surg 
Endosc. 2014 Jun;28(6):1838-43 
36. Osayi SN, Wendling MR, Drosdeck JM, Chaudhry UI, Perry KA, Noria SF, Mikami 
DJ, Needleman BJ, Muscarella P 2nd, Abdel-Rasoul M, Renton DB, Melvin WS, 
Hazey JW, Narula VK. Near-infrared fluorescent cholangiography facilitates 
identification of biliary anatomy during laparoscopic cholecystectomy. Surg 
Endosc. 2014 Jul 2 
37. 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. 2014 Apr;28(4):1076-82 
38. Strasberg SM, Callery MP, Soper NJ. Laparoscopic surgery of the bile ducts. 
Gastrointest Endosc Clin N Am. 1996 Jan;6(1):81-105 

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39. Sylvester N. Osayi, Mark R. Wendling, Joseph M. Drosdeck, Umer I. Chaudhry, 
Kyle A. Perry, Sabrena F. Noria, Dean J. Mikami, Bradley J. Needleman, Peter 
Muscarella II, Mahmoud Abdel-Rasoul, David B. Renton, W. Scott Melvin, Jeffrey 
W. Hazey, Vimal K. Narula Near-infrared fluorescent cholangiography facilitates 
identification of biliary anatomy during laparoscopic cholecystectomy Surg 
Endosc. 2014 Jul 2. 
40. Spinoglio G1, Priora F, Bianchi PP, Lucido FS, Licciardello A, Maglione V, Grosso F, 
Quarati R, Ravazzoni F, Lenti LM. Real-time near-infrared (NIR) fluorescent 
cholangiography in single-site robotic cholecystectomy (SSRC): a single-
institutional prospective study. Surg Endosc. 2013 Jun;27(6):2156-62 
41. Ishizawa T1, Bandai Y, Ijichi M, Kaneko J, Hasegawa K, Kokudo N. Fluorescent  
cholangiography 
illuminating 
the 
biliary 
tree 
during 
laparoscopic 
cholecystectomy. Br J Surg. 2010 Sep;97(9):1369-77 
42. Schols RM1, 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. 
 
20. Appendices  

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a. 510(k) Acknowledgement Letter from FDA 
 
 

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b. Patient Informed Consent Form 
 

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c. Pre-Op Case Report Form 

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d. Intra-Op Case Report Form – Surgeon 
 
 

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e. Intra-Op Case Report Form – Observer 
 

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f. Post-op Case Report Form 
 

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g. Bile Duct Injury (BDI) Form 
 

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h. Schedule of events  
(from Section 8.f.  Trial Flow) 
 

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i. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
 29th WMA General Assembly, Tokyo, Japan, October 1975 
 35th WMA General Assembly, Venice, Italy, October 1983 
 41st WMA General Assembly, Hong Kong, September 1989 
 48th WMA General Assembly, Somerset West, Republic of South Africa, 
October 1996 
 52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
 53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added) 
 55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of 
Clarification added) 
 59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
 64th WMA General Assembly, Fortaleza, Brazil, October 2013 
i. Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical Principals for medical research involving 
human subjects, including research on identifiable human material and data. 
            The Declaration is intended to be read as a whole and each of its 
constituent paragraphs should be applied with consideration of all other 
relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed 
primarily to physicians. The WMA encourages others who are involved in 
medical research involving human subjects to adopt these Principals.  
ii. General Principals 
3.         The Declaration of Geneva of the WMA binds the physician with the 
words, “The health of my patient will be my first consideration,” and the 
International Code of Medical Ethics declares that, “A physician shall act in the 
patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-
being and rights of patients, including those who are involved in medical 
research. The physician's knowledge and conscience are dedicated to the 
fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include 
studies involving human subjects. 
6.         The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 

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preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
7.         Medical research is subject to ethical standards that promote and ensure 
respect for all human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new 
knowledge, this goal can never take precedence over the rights and interests of 
individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to 
protect the life, health, dignity, integrity, right to self-determination, privacy, 
and confidentiality of personal information of research subjects. The 
responsibility for the protection of research subjects must always rest with the 
physician or other health care professionals and never with the research 
subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and 
standards for research involving human subjects in their own countries as well 
as applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises 
possible harm to the environment. 
12.       Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other 
health care professional. 
13.       Groups that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
14.       Physicians who combine medical research with medical care should 
involve their patients in research only to the extent that this is justified by its 
potential preventive, diagnostic or therapeutic value and if the physician has 
good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed 
as a result of participating in research must be ensured. 
iii. Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve 
risks and burdens. 
           Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects. 

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17.       All medical research involving human subjects must be preceded by 
careful assessment of predictable risks and burdens to the individuals and 
groups involved in the research in comparison with foreseeable benefits to 
them and to other individuals or groups affected by the condition under 
investigation. 
           Measures to minimize the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human 
subjects unless they are confident that the risks have been adequately assessed 
and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when 
there is conclusive proof of definitive outcomes, physicians must assess 
whether to continue, modify or immediately stop the study.            
iv. Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically 
considered protection. 
20.       Medical research with a vulnerable group is only justified if the research 
is responsive to the health needs or priorities of this group and the research 
cannot be carried out in a non-vulnerable group. In addition, this group should 
stand to benefit from the knowledge, practices or interventions that result from 
the research. 
v. Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally 
accepted scientific Principals, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of animals 
used for research must be respected. 
22.       The design and performance of each research study involving human 
subjects must be clearly described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations 
involved and should indicate how the Principals in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects 
and information regarding provisions for treating and/or compensating subjects 
who are harmed as a consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate 
arrangements for post-trial provisions. 

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vi. Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, 
guidance and approval to the concerned research ethics committee before the 
study begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
           The committee must have the right to monitor ongoing studies. The 
researcher must provide monitoring information to the committee, especially 
information about any serious adverse events. No amendment to the protocol 
may be made without consideration and approval by the committee. After the 
end of the study, the researchers must submit a final report to the committee 
containing a summary of the study’s findings and conclusions.  
vii. Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research 
subjects and the confidentiality of their personal information. 
viii. Informed Consent  
25.       Participation by individuals capable of giving informed consent as 
subjects in medical research must be voluntary. Although it may be appropriate 
to consult family members or community leaders, no individual capable of 
giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26.       In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods 
used to deliver the information. 
           After ensuring that the potential subject has understood the information, 
the physician or another appropriately qualified individual must then seek the 
potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
           All medical research subjects should be given the option of being 
informed about the general outcome and results of the study. 

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27.       When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a dependent 
relationship with the physician or may consent under duress. In such situations 
the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed 
consent, the physician must seek informed consent from the legally authorised 
representative. These individuals must not be included in a research study that 
has no likelihood of benefit for them unless it is intended to promote the health 
of the group represented by the potential subject, the research cannot instead 
be performed with persons capable of providing informed consent, and the 
research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving 
informed consent is able to give assent to decisions about participation in 
research, the physician must seek that assent in addition to the consent of the 
legally authorised representative. The potential subject’s dissent should be 
respected. 
30.       Research involving subjects who are physically or mentally incapable of 
giving consent, for example, unconscious patients, may be done only if the 
physical or mental condition that prevents giving informed consent is a 
necessary characteristic of the research  group. In such circumstances the 
physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them 
unable to give informed consent have been stated in the research protocol and 
the study has been approved by a research ethics committee. Consent to 
remain in the research must be obtained as soon as possible from the subject or 
a legally authorised representative. 
31.       The physician must fully inform the patient which aspects of their care 
are related to the research. The refusal of a patient to participate in a study or 
the patient’s decision to withdraw from the study must never adversely affect 
the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as 
research on material or data contained in biobanks or similar repositories, 
physicians must seek informed consent for its collection, storage and/or reuse. 
There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may 
be done only after consideration and approval of a research ethics committee. 
ix. Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must 
be tested against those of the best proven intervention(s), except in the 
following circumstances: 

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           Where no proven intervention exists, the use of placebo, or no 
intervention, is acceptable; or 
           Where for compelling and scientifically sound methodological reasons the 
use of any intervention less effective than the best proven one, the use of 
placebo, or no intervention is necessary to determine the efficacy or safety of 
an intervention  
           and the patients who receive any intervention less effective than the best 
proven one, placebo, or no intervention will not be subject to additional risks of 
serious or irreversible harm as a result of not receiving the best proven 
intervention.  
           Extreme care must be taken to avoid abuse of this option. 
x. Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all participants 
who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent 
process. 
xi. Research Registration and Publication and Dissemination of 
Results 
35.       Every research study involving human subjects must be registered in a 
publicly accessible database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results of 
research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the Principals of this Declaration should not 
be accepted for publication. 
xii. Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do 
not exist or other known interventions have been ineffective, the physician, 
after seeking expert advice, with informed consent from the patient or a legally 
authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object 
of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.