Clinical trial NCT04942665
Conditions: Cholecystitis Hepatocellular Carcinoma Liver Metastases
Keywords: Biliary Tract Indocyanine Green (ICG) Tumors Near-infrared Fluorescence
Sponsor: University of Florida
Start date: 2021-09-15; Completion date: 2023-04-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Near-infrared fluorescence (NIRF) imaging after an intravenous injection of indocyanine green (ICG) allows for the intraoperative identification of liver anatomy. The investigators have new data that a much lower dose improves this visualization. Confirmation of this hypothesis would mean that ICG can be administered on the same day of surgery in order to augment real-time intraoperative visualization, thereby providing a safe, feasible, and cost-effective strategy for the surgical treatment of liver disease.

Detailed description:
The investigators have a series of surgical cases in which the investigators have been able to achieve excellent intraoperative biliary visualization with a greatly decreased (50-200 fold lower) dose of ICG than the previously published dose. Furthermore, this decreased dose was visible in about 15-20 minutes from the time of injection with low liver background fluorescence, a significant improvement that would make its utilization in the operating room more practical. The investigators hypothesize that a lower dose will: 1) allow adequate visualization of the extrahepatic biliary tree, including the cystic, common hepatic, and common bile ducts. Confirmation of hypotheses would mean that a lower dose of ICG can be administered on the same day of surgery in order to augment real-time intraoperative localization of the extrahepatic biliary tree, thereby providing a safe, feasible, and cost-effective strategy for the surgical treatment of liver disease.

The investigators intend to test our hypothesis with the following specific aims:

Aim 1: To compare the efficacy and utility of a low dose ICG (0.05 mg) protocol with a previously published dose (2.5 mg) in imaging the extrahepatic biliary tract.

Arms: arm 1: Prior to surgery these patients will be given a ICG dose of 0.05 mg IV. arm 2: Prior to surgery these patients will be given the ICG standard dose of 2.5 mg IV.
Interventions: intervention 1: Indocyanine green intervention 2: PINPOINT Endoscopic Fluorescence
Intervention descriptions: intervention 1: Low dose or standard dose ICG will be administered by the anesthesiologist as guided by the study coordinator at the beginning of the case, at two points during the operation (1- prior to the dissection of the biliary tract and 2- upon completion of the dissection and establishment of the critical view of safety). intervention 2: The PINPOINT Endoscopic Fluorescence Imaging System (Stryker Corporation, Kalamazoo, Michigan) will be used. This device enables the surgeon to simultaneously see real-time, high-definition visible-range and NIR fluorescence videos and to superimpose them. It is currently approved by the FDA for intraoperative near-infrared fluorescence imaging.

Protocol documents:
ICF_002.pdf: 
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Low vs Standard Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-
Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial 
 
NCT04942665 
 
4/15/2022 
 
 


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INFORMED CONSENT FORM 
to Participate in Research, and 
AUTHORIZATION  
to Collect, Use, and Disclose Protected Health Information (PHI) 
 
INTRODUCTION 
 
Name of person seeking your consent: 
 
 
Place of employment & position:  
 
 
GENERAL INFORMATION ABOUT THIS STUDY 
 
1. Name of Participant ("Study Subject") 
 
___________________________________________________________________  
 
2. What is the Title of this research study (this “Research Study”)? 
Low dose ICG for near-infrared fluorescence imaging of biliary tract 
 
3. Whom do you call if you have questions about this Research Study (the “Study 
Team”)? 
 
Principal Investigator: Ali Zarrinpar, Office: 352-594-5170 
Co-investigator: Tyler Loftus, Office: 352-265-0535 
Other research staff:  Curtis Warren, Office: 352-594-4111 
 
4.   Who is paying for this Research Study? 
The sponsor of this study is University of Florida, Department of Surgery and The 
Society of University Surgeons. 
5. In general, what do you need to know about this Research Study? 
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
to which you are entitled. If you have questions about your rights as a research 
subject, please call the University of Florida Institutional Review Board (IRB) office at 
(352) 273-9600.     
 
 


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a) In general, what is the purpose of the research, how long will you be involved?  
The purpose of this study is to see how different doses of an imaging dye 
(indocyanine green, ICG) can help us see the anatomy of your liver and bile ducts 
better in the operating room during surgery. You will be involved in this study for no 
longer than two weeks. 
b) What is involved with your participation, and what are the procedures to be 
followed in the research?  
At this time, 2.5 mg of a medical dye called indocyanine green (ICG) is given to 
patients in a vein before surgery so that we can see the bile duct anatomy. We use 
a special camera and light system called PINPOINT in the operating room to see 
the fluorescence. We would like to test whether a dose that is 50 times less (0.05 
mg) is even better and quicker at allowing us to do this with equal (or better) 
effectiveness. This should not add any more time to the operation. 
You will be assigned by chance to receive either the standard dose (2.5 mg) or the 
lower dose (0.05 mg) by blindly drawing an envelope from a box. 
ICG is an FDA approved fluorescent dye, which has been used to measure liver 
function for over 60 years. PINPOINT is an FDA cleared device for laparoscopic 
operations. 
We will keep a coded record of relevant medical data such as labs and other 
testing results including labs, scans, and liver biopsy results, if these tests are 
performed as part of your standard treatment. For the purposes of the study, we 
will record a brief video of the important parts of the operation so that we can make 
some calculations about the quality of the images afterwards. There will be no 
identifiable information in that video; only your insides will be visible.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results. You can 
search this Web site at any time. 
c) What are the likely risks or discomforts to you?  
It is possible that the lower dose of ICG will not be as good as the higher dose. We 
will minimize the risk of this by still using other technology that we usually use in 
the operating room, such as ultrasound or x-ray. 
Injecting ICG through an IV may cause leaking of fluid out of the vein, swelling, 
discomfort, burning, or skin tightness. IVs are routinely used by clinicians and they 
are considered to be low risk. ICG, like any other drug, can also cause an allergic 
reaction. Although ICG is considered to be a safe drug with an estimated allergic 
reaction rate of 5 in every 1000 patients, it has been reported that people with 
history of shellfish and iodine allergy could be sensitive to ICG dye. To avoid this 
this risk, you will not be able to participate in this study if you have history of 
shellfish and/or iodine allergy.   


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d) What are the likely benefits to you or to others from the research? 
There will likely not be any direct benefit to you, but being able to use a lower dose 
may improve the ability to see anatomy better during surgery and lower the risk of 
side effects. 
e) What are the appropriate alternative procedures or courses of treatment, if 
any, that might be helpful to you?  
You may choose not to participate in the research study. Deciding to not 
participate will not affect your care. The standard visualization techniques will be 
used as part of your regular care. 
Additional and more detailed information is provided within the remainder of 
this Informed Consent form, please read before deciding if you wish to 
participate in this study 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results. You can search this Web 
site at any time. 
 
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY? 
 
6. What will be done as part of your normal clinical care (even if you did not 
participate in this Research Study)?  
As part of your normal clinical care, you will receive various assessments and tests 
before your surgery (also known as pre-operative care). After your surgery, similar 
tests and assessments known as post-operative care will be provided. These include 
blood tests, scans, and liver biopsies, as determined by your care team. 
 
7.  What will be done only because you are in this Research Study?  
If you decide to take part in this study, you will be randomly assigned (much like the 
flip of a coin) to receive either the standard 2.5 mg injection of a medical dye called 
indocyanine green (ICG) or low dose (0.05 mg). Your assigned dose will be chosen 
by blindly drawing an envelope from a box. The ICG will be given into a vein (IV) 
before your operation. We will then proceed with your surgery as standard. The 
visualization of your anatomy will be graded and recorded. These measurements will 
be used to understand whether the lower dose is better, just as good, or worse than 
the standard dose. If available, medical information such as the results from your 
surgery, labs, imaging, liver biopsy, and other relevant data from your medical record 
will be collected. 
Once this research study is completed, any information that could identify you might 
be removed from any identifiable private information collected and that, after such 
removal, the information could be used for future research studies or distributed to 
another investigator for future research studies without additional informed consent 


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from you or your legally authorized representative. At the end of the study, the videos 
will also have any identifying information removed and maintained for possible future 
research. To the best of their ability, study team will protect the identity of research 
participants by assigning a unique study code to each patient after the removing 
identifiers and saving study data in a secure UF server designated for research. 
If you have any questions now or at any time during this Research Study, please 
contact one of the Research Team members listed in question 3 of this form. 
 
8. What identifiable health information will be collected about you and how will it be 
used? 
 
The Research Team will collect your name, sex/gender, date of birth, procedure 
dates, medical history, result of blood tests, and liver biopsies, if they are available. 
These will be used to understand how those factors may affect the images during the 
operation and whether knowing more detail about your condition could possibly 
improve the care provided to you. 
The Research Team may collect this information from other healthcare providers, 
such as laboratories, which are a part of this research, as well as healthcare providers 
that are not part of this research (other doctors, hospitals or clinics). Other 
professionals at the University of Florida or Shands Hospital who provide study-
related care, and the University of Florida Institutional Review Board (IRB), may also 
collect your health information.  
The Research Team listed in question 3 above will use or share your health 
information as described below to carry out this research study.  
 
9.  With whom will this health information be shared? 
This health information may be shared with: 
 
• 
the study sponsor (listed in Question 4 of this form); 
• 
United States governmental agencies which are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health 
and Human Services, and the Office of Human Research Protections;  
• 
Government agencies which are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments. 
• 
The IRB that reviewed this Research Study and ensures your rights as a Study 
Subject are protected  
Otherwise, your identifiable health information will not be shared without your 
permission unless required by law or a court order. Once your health information is 
shared with those listed above, it is possible that they could share it without your 
permission because it would no longer be protected by the federal privacy law.  
 


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10. How long will you be in this Research Study? 
You will be involved in this study for no longer than two weeks. 
This Authorization to use and share your health information expires at the end of the 
study, unless you revoke it (take it back) sooner. 
 
11. How many people are expected to take part in this Research Study? 
35 people are expected to participate in this study.  
 
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND  
WHAT ARE YOUR OPTIONS? 
 
12. What are the possible discomforts and risks from taking part in this Research 
Study? 
It is possible that the lower dose of ICG will not be as good as the higher dose. We 
will minimize the risk of this poorer visualization by continuing to incorporate other 
methods of visualization that we routinely use in the operating room, such as 
ultrasound or x-ray. 
Risks associated with indocyanine green (ICG) dye administered through an IV would 
be present even if you were not taking part in this research study.  Most commonly 
reported adverse reactions to indocyanine green (ICG) dye are typically mild allergic 
reactions, sweating, headache, or itching. Less commonly reported events include 
anaphylactic reactions, such as low blood pressure, swelling of mouth, tongue, throat, 
or difficulty breathing. Although ICG is considered to be a safe drug with an estimated 
allergic reaction rate of 5 in every 1000 patients, it’s been reported that people with 
history of shellfish and/or iodine allergy could be sensitive to ICG dye. To avoid this 
this risk, you will not be able to participate in this study if you have history of shellfish 
and/or iodine allergy.   
Administering ICG through an IV may cause collapse of the vein, having the 
medication get into the tissues, swelling, discomfort, burning or tightness in the hand 
or arm. The most commonly reported adverse reactions indocyanine green dye are 
typically mild and included pruritus, shortness of breath, and nausea. Less commonly 
reported events include bronchospasm (a condition wherein muscles lining the 
airways of the lungs constrict or tighten, reducing airflow), laryngospasm (a spasm of 
the vocal cords that temporarily makes it difficult to speak or breath), low blood 
pressure, and cardiac arrest. IVs are routinely used by clinicians and they are 
considered to be low risk.  
This Research Study may also include risks that are unknown at this time. 
Please note, participating in more than one research study or project may further 
increase the risks to you.  If you are already enrolled in a research study, please 
inform one of the Research Team members listed in question 3 of this form or the 


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person reviewing this consent with you before enrolling in this or any other research 
study or project. 
During the study, the Research Team will notify you of new information that may 
become available and might affect your decision to remain in the study.  
The University of Florida is required by law to protect your health information. Your 
health information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices, as required by University 
policy. However, there is a slight risk that information about you could be released 
inappropriately or accidentally. Depending on the type of information, a release could 
upset or embarrass you, or possibly affect your ability to get insurance or a job.  
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the Research Team members listed in 
question 3 in this form. 
 
13a. What are the potential benefits to you for taking part in this Research Study? 
There will likely not be any direct benefit to you, but being able to use a lower dose 
may improve the ability to see anatomy better during surgery and lower the risk of 
side effects. 
 
13b. How could others possibly benefit from this Research Study? 
A lower dose of ICG before surgery may lead to better images during surgery for 
future patients and lower the risk of side effects.  
 
13c. How could the Research Team members benefit from this Research Study? 
In general, presenting research results helps the career of a researcher. Therefore, 
the Research Team listed in question 3 of this form may benefit if the results of this 
Research Study are presented at scientific meetings or in scientific journals. 
 
13d. Will you be allowed to see the research information collected about you for this 
Research Study? 
You may not be allowed to see the research information collected about you for this 
Research Study, including the research information in your medical record, until after 
the study is completed. When this Research Study is over, you will be allowed to see 
any research information collected and placed in your medical record.  
 
14. What other choices do you have if you do not want to be in this study?  
Your participation in this study is voluntary; you may withdraw from the study at any 
time. Leaving the study will not result in any penalty or loss of benefits to which you 
are entitled. For evaluation and reporting purposes, researchers may ask for your 
reasons for withdrawal. 


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You may also refuse to authorize the use of your health information, but if you refuse, 
you may not be allowed to be in this research study or receive any research-related 
treatment that is only available in this research study. However, your decision not to 
sign this Authorization will not affect any other treatment you may be eligible to 
receive. 
 
15a. Can you withdraw from this study? 
You may withdraw your consent and stop participating in this Research Study at any 
time.  If you do withdraw your consent, there will be no penalty to you, and you will not 
lose any benefits to which you are otherwise entitled. 
If you decide to withdraw your consent to participate in this Research Study for any 
reason, please contact the Research Team listed in question 3 of this form. They will 
tell you how to safely stop your participation. 
You can also change your mind and take back this Authorization at any time by 
sending a written notice to the Research Team listed in question 3 of this form to let 
them know your decision. If you take back this Authorization, the Research Team 
may only use and disclose your health information already collected for this research 
study. No additional health information about you will be collected or disclosed to the 
Research Team. However, if you take back this Authorization, you may not be able to 
continue in this study. Please discuss this with a member of the Research Team listed 
in question #3. 
 
15b. Can the Principal Investigator withdraw you from this Research Study?  
 
You may be withdrawn from this Research Study without your consent for the following 
reasons: 
• If the study doctors fear that study procedures could cause you harm. 
 
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE? 
 
16. If you choose to take part in this Research Study, will it cost you anything? 
No. There will be no extra cost to you for participating in this Research Study. 
 
17. Will you be paid for taking part in this Research Study? 
No.  
 
18. What if you are injured while in this Research Study? 
If you are injured as a direct result of your participation in this study, only the 
professional services that you receive from any University of Florida Health Science 
Center healthcare provider will be provided without charge.  These healthcare 
providers include physicians, physician assistants, nurse practitioners, dentists or 
psychologists. Any other expenses, including Shands hospital expenses, will be billed 
to you or your insurance provider.  


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You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
research-related injuries. Please contact your insurance company for additional 
information.  
The Principal Investigator will determine whether your injury is related to your 
participation in this study.  
No additional compensation is routinely offered. The Principal Investigator and others 
involved in this study may be University of Florida employees. As employees of the 
University, they are protected under state law, which limits financial recovery for 
negligence. 
Please contact the Principal Investigator listed in question 3 of this form if you 
experience an injury or have questions about any discomforts that you experience 
while participating in this study. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SIGNATURES 
 
As an investigator or the investigator’s representative, I have explained to the participant 
the purpose, the procedures, the possible benefits, and the risks of this Research Study; 
the alternative to being in the study; and how the participant’s protected health information 
will be collected, used, and shared with others:  
 
 
 
 
 
Signature of Person Obtaining Consent and 
Authorization 
 
Date 
 
You have been informed about this study’s purpose, procedures, possible benefits, and 
risks; the alternatives to being in the study; and how your protected health information will 
be collected, used and shared with others. You have received a copy of this Form. You 
have been given the opportunity to ask questions before you sign, and you have been told 
that you can ask questions at any time. 
 
You voluntarily agree to participate in this study. You hereby authorize the collection, use 
and sharing of your protected health information as described above. By signing this form, 
you are not waiving any of your legal rights. 
 
 
 
 
 
Signature of Person Consenting and Authorizing 
 
Date 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Consent to be Photographed, Video and/or Audio Recorded 
 
With your permission, you will have the following done during this research (check all 
that apply): 
 
 
 photographed 
 video recorded 
 audio recorded 
Your name or personal information will not be identified on the photograph(s), video or 
audio recordings, and confidentiality will be strictly maintained.  However, when these 
photograph(s), video and/ or audio recordings are shown or heard, others may be able 
to identify you. 
 
The Principal Investigator (PI) of this study, _________________, or [his/her] 
successor, will keep the photograph(s), video and/or audio recordings in a locked 
cabinet, in a folder on a password protected computer server drive, or as an encrypted 
electronic file.  These photograph(s), video and/or audio recordings will be shown under 
[his/her] direction to students, researchers, doctors, or other professionals and persons. 
Please indicate under what conditions Dr. ________________ has your permission to 
use the photograph(s), video and/or audio recordings, and sign and date below. 
 
  The following will be destroyed once the study is closed (initial next to all that 
apply):    
 
  ____ photograph(s)      _____ video recording(s)        _____ audio recording(s) 
 
  As described in the Informed Consent Form, and for the purposes of education 
at the University of Florida Health Science Center.  The PI may keep the 
following for an indefinite period of time in a locked file, in a password protected 
computer server drive, or as an encrypted electronic file (initial next to all that 
apply):       
 
  ____ photograph(s)      _____ video recording(s)        _____ audio recording(s) 
 
  As described in the Informed Consent Form; for the purposes of education at 
the University of Florida Health Science Center; and for presentations at 
scientific meetings outside the University.  The PI may keep the following for 
an indefinite period of time in a locked file, in a password protected computer 
server drive, or as an encrypted electronic file (initial next to all that apply): 
 
  ____ photograph(s)      _____ video recording(s)        _____ audio recording(s) 
 
 
 
 
 
Signature 
 
Date 
                                                                                                                           

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low vs Standard Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-
Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial 
 
NCT04942665 
 
12/9/2021 
 
 


 
1. Title: 
• Low dose ICG for near-infrared fluorescence imaging of biliary tract 
2. Investigators: 
 
• Ali Zarrinpar, MD, PhD (PI) 
• Tyler Loftus, MD (co-PI, PI proxy) 
• Alexandra Ladd, MD (co-Investigator) 
• Haley Stone (co-Investigator, medical student) 
• Curtis Warren (Study Coordinator) 
3. Abstract: 
 
We have a series of surgical cases in which we have been able to achieve excellent 
intraoperative biliary visualization with a greatly decreased (50-200X fold lower) dose 
of ICG than the previously published dose. Furthermore, this decreased dose was 
visible in about 15-20 minutes from the time of injection with low liver background 
fluorescence, a significant improvement that would make its utilization in the operating 
room more practical. We hypothesize that a lower dose will allow adequate visualization 
of the extrahepatic biliary tree, including the cystic, common hepatic, and common bile 
ducts. Confirmation of this hypothesis would mean that a lower dose of ICG can be 
administered on the same day of surgery in order to augment real-time intraoperative 
localization of the extrahepatic biliary tree, thereby providing a safe, feasible, and cost-
effective strategy for the surgical treatment of liver disease. 
We intend to test our hypothesis with the following specific aims: 
Aim: To compare the efficacy and utility of a low dose ICG (0.05 mg) protocol with a 
previously published dose (2.5 mg) in imaging the extrahepatic biliary tract. 
 
 


4. Background: 
 
Near-infrared fluorescence (NIRF) imaging after an intravenous injection of indocyanine 
green (ICG) allows for the intraoperative identification of biliary anatomy. ICG binds to 
plasma proteins and emits light with a peak wavelength around 830nm when illuminated 
with near-infrared light. ICG is exclusively excreted by the liver, and biliary excretion 
lasts from several minutes to 24 hours post-injection (1). NIRF imaging has been shown 
to be a safe, easy, fast, cost-effective strategy for delineating biliary anatomy because 
it decreases the risk of bile duct injury and does not require radiation (2)(3)(4). Research 
from our group, among others, has shown that visualization of the extrahepatic biliary 
tract is adequate at a dose on the order of 2.5 mg administered at least 15 minutes prior 
to visualization (5). 
Since the advent of NIRF, imaging technology has improved, with increasing sensitivity 
and improved intraoperative displays. Whether these improvements have resulted in 
increased sensitivity and utility has not yet been demonstrated, nor has the possibility 
of whether improved technology has decreased either the dose required for adequate 
visualization or the time interval prior to optimal visualization. 
5. Specific Aim: 
 
To compare the efficacy and utility of a low dose ICG (0.05 mg) protocol with a 
previously published dose (2.5 mg) in imaging the extrahepatic biliary tract.  
6. Research Plan: 
 
Current standard of care for this service is to administer 2.5 mg of ICG preoperatively 
to patients before surgical bile duct visualization. If there is any further need for 
anatomic information, then a combination of ultrasound and X-ray cholangiography is 
used. For this study, adult patients scheduled to undergo a laparoscopic hepatic or 
biliary operation will be randomized to two groups 1) low dose (0.05 mg) or 2) standard 
dose (2.5 mg) of ICG preoperatively on the day of surgery. Patients with a history of 
adverse reactions or known allergy to ICG, iodine, or iodine dyes will be excluded. 
Pregnant and/or lactating patients will also be excluded. Participants will receive a 
baseline assessment. Demographic information, including age, gender, ethnicity or 
race, body mass index, American Society of Anesthesiologists class, preoperative 
diagnosis, liver function, and complete medical history, will be collected. Case difficulty 
will be graded by the primary surgeon based on standardized 
criteria 
(https://pubmed.ncbi.nlm.nih.gov/29956029/). 
The 
PINPOINT 
Endoscopic 
Fluorescence Imaging System (Stryker Corporation, Kalamazoo, Michigan) will be 
used. This device enables the surgeon to simultaneously see real-time, high-definition 
visible-range and NIR fluorescence videos and to superimpose them. It is currently 
approved by the FDA for intraoperative near-infrared fluorescence imaging. Essentially, 
it is a standard laparoscopic device with an added excitation laser at 805 nm and a filter 
set to allow for visualization of ICG fluorescence. The visualization of the biliary tree will 
be recorded. 


Low 
dose 
or 
standard 
dose 
ICG 
will 
be 
administered by 
the 
anesthesiologist 
as guided by the 
study 
coordinator 
at 
the beginning of 
the case. The 
operating 
surgeon will be 
blinded to the 
dose given. At 
two 
points 
during 
the 
operation 
(1- 
prior 
to 
the 
dissection of the biliary tract and 2- upon completion of the dissection and establishment 
of the critical view of safety), a qualitative assessment will be made by the primary 
surgeon based on the quality of the intraoperative visualization of the extrahepatic 
biliary tree (being able to identify and distinguish the common bile duct, the common 
hepatic duct, and the cystic duct from the surrounding structures and from each other) 
on a scale of 1 to 5 (1 = no improvement/identification not confirmed; 2 = marginally 
improved; 3 = sufficiently improved; 4 = well improved; 5 = greatly improved/exceeds 
expectations). The recorded visualization will also be assessed by a blinded 
independent surgeon who will use the same scale. A quantitative assessment will also 
be performed on the recorded visualization using ImageJ (US National Institutes of 
Health, Bethesda, MD; http://imagej.nih.gov/ij/) by dividing the fluorescence intensity 
signal of the common bile duct by that of the surrounding fat or liver. These quantitative 
measurements will allow an independent measure of duct visualization. Both 
quantitative and qualitative scores will be compared to determine whether there are 
significant differences between the doses. A total of thirty patients (15 in each arm) will 
be required for more than a 90% power to detect a difference in the duct-to-liver ratio 
of 0.2 between the two groups, given an alpha of 0.05 and a standard deviation of 0.15. 
These estimates are based on our previously published results. (5) 
 
 
Patients who are not able to provide informed consent and have a history of sensitivity 
or allergy to shellfish, ICG, or iodine will be excluded from the study. 
 
Randomization: Identical envelopes will be made with a card marked either standard or 
low dose to be chosen in blocks of four. At the time of enrollment, an envelope will be 
selected at random from a box and the subject will be assigned to the corresponding 
arm. This envelope will then be discarded to allow for equal numbers in each group.   
Figure 1. Representative examples of intraoperative images of biliary tract.
GB, gallbladder; L, liver; CHD, common hepatic duct; Cys, cystic duct. 
(Zarrinpar et al, Surgical Innovation 2016)
Example 1
Near-infrared
Superimposed
Conventional
Example 2


 
For the purposes of the study, the recorded videos will be stored on a secure local 
server with access limited only to the study team. This will allow them team to 
perform the image analysis and related calculations. At the end of the study, the 
videos will be deidentified and maintained for possible future research. 
7. Possible Discomforts and Risks: 
 
Using a lower dose of ICG may lead to poorer visualization of the anatomy during 
surgery compared to the standard dose. The surgeons, however, routinely use other 
methods of visualization during surgery (such as ultrasound or x-rays) that would 
decrease the risks of poor visualization during the operation. The most commonly 
reported adverse reactions to ICG are typically mild and included pruritus, shortness 
of breath, and nausea. Less commonly reported events include bronchospasm (a 
condition wherein muscles lining the airways of the lungs constrict or tighten, reducing 
airflow), laryngospasm (a spasm of the vocal cords that temporarily makes it difficult 
to speak or breath), low blood pressure, and cardiac arrest. IVs are routinely used by 
clinicians and they are considered to be low risk. 
8. Possible Benefits: 
Decreasing the dose of ICG may lead to better visualization of the anatomy during 
surgery and also it may decrease the risk of side-effects. 
9. Conflict of Interest: 
 
The investigators have no real or potential conflict of interest with regard to this 
research project. 


10.  Data Safety and Monitoring Plan 
10.1 Data Integrity and Safety Committee 
 
This protocol summary will include a minimum of the following:  
• The UF IRB assigned protocol number, protocol title, PI name, data coordinator 
name or primary study coordinator, regulatory coordinator name, and statistician  
• Date of initial UF IRB approval, date of most recent consent UF IRB 
approval/revision, date of UF IRB expiration, study status, and phase of the study, 
study target accrual and study actual accrual.  
• Protocol objectives with supporting data and list of number of study participants who 
have met each objective.  
• 
Intraoperative measures 
• Summary of toxicities and protocol deviations.  
• Summary of any recent literature which may affect the safety or ethics of the trial.  
 
10.2 Site Monitoring  
 
10.3 Principal Investigator Responsibilities  
As part of the responsibilities assumed by conducting this study, the Principal 
Investigator (PI) agrees to maintain and have available for monitoring adequate case 
records (accurate source documents and CRFs) for the subjects treated under this 
protocol.  
 
The PI will be primarily responsible for monitoring of adverse events, protocol 
violations, and other immediate protocol issues. The study coordinator will collect 
information on subjects enrolled through the use of electronic or paper adverse event 
(AE) forms, CRFs, and Informed Consent forms. 
 
10.4 Interim Analyses & Stopping Rules 
As a phase II feasibility study, our goal is to establish clinical and operative 
expectations around the use of low-dose IV ICG.  Given the standard use of standard 
dose IV ICG, we are not concerned about safety, so a phase I study or safety run-in of 
low dose ICG is not felt to be needed. However, we will monitor and record any AEs 
related to the IV ICG administration in both arms of the study. 
 
Given the published safety data on intraoperative use of ICG, we do not anticipate 
any safety issues between the standard and low dose ICG, but will monitor AEs 
related to ICG administration in real time.  A pre-planned stopping rule for safety is not 
needed. 
 
Given the pilot and feasibility aspects of this study such that a primary efficacy 
difference is not being targeted along with the relatively small numbers of patients and 
short enrollment period, a stopping rule for efficacy is not appropriate. 


11. References 
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Dip F, Roy M, Lo Menzo E, Simpfendorfer C, Szomstein S, Rosenthal RJ. 
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3.  
Matsui A, Tanaka E, Choi HS, Winer JH, Kianzad V, Gioux S, et al. Real-time 
intra-operative near-infrared fluorescence identification of the extrahepatic bile ducts 
using clinically available contrast agents. Surgery. 2010 Jul;148(1):87–95.  
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Ishizawa T, Bandai Y, Ijichi M, Kaneko J, Hasegawa K, Kokudo N. Fluorescent 
cholangiography illuminating the biliary tree during laparoscopic cholecystectomy. Br 
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Zarrinpar A, Dutson EP, Mobley C, Busuttil RW, Lewis CE, Tillou A, et al. 
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Aoki T, Yasuda D, Shimizu Y, Odaira M, Niiya T, Kusano T, et al. Image-
guided liver mapping using fluorescence navigation system with indocyanine green for 
anatomical hepatic resection. World J Surg. 2008 Aug;32(8):1763–1767.  
7.  
Inoue Y, Arita J, Sakamoto T, Ono Y, Takahashi M, Takahashi Y, et al. 
Anatomical Liver Resections Guided by 3-Dimensional Parenchymal Staining Using 
Fusion Indocyanine Green Fluorescence Imaging. Ann Surg. 2015 Jul;262(1):105–
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Ishizawa T, Fukushima N, Shibahara J, Masuda K, Tamura S, Aoki T, et al. 
Real-time identification of liver cancers by using indocyanine green fluorescent 
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9.  
Kudo H, Ishizawa T, Tani K, Harada N, Ichida A, Shimizu A, et al. Visualization 
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Gotoh K, Yamada T, Ishikawa O, Takahashi H, Eguchi H, Yano M, et al. A 
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12.  
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low vs Standard Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-
Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial 
 
NCT04942665 
 
9/1/2022 
 
 


Mann-Whitney tests were conducted for the quantitative and qualitative assessments to identify 
any significant differences between the 2 doses of ICG. A 2-way ANOVA was also conducted to 
compare the individual fluorescence intensities of the liver, bile duct, and background fat 
between the 2 doses. A p value of <0.05 was considered statistically significant. All tests were 
performed using GraphPad Prism software version 9.4.1 (GraphPad Software, San Diego, CA). 
Power analysis based on results from our previous study indicated that a total of 26 patients (13 
in each arm) would be required for 90% power to detect a difference in the primary outcome 
measure of bile duct–to–liver fluorescence intensity ratio of 0.2 between the 2 groups, given an 
alpha of 0.05 and a SD of 0.15. We therefore powered the study to allow for accrual of adequate 
numbers of subjects at each center independently.