Clinical trial NCT02710240
Conditions: Suspected Central Nervous System Tumors
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2015-06-10; Completion date: 2020-04-02
Enrollment: 336 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is a single center, open-label, two-part study to assess image guided surgery of intramolecular imaging in nervous system tumors. Subjects with a diagnosis of a resectable nervous system tumor who are at risk of recurrence are included. The primary goal is to observe what tissues fluoresce in the OR, and then to identify if that tissue is cancerous/tumor or normal when the histopathology is performed.

Detailed description:

Arms: arm 1: Subjects undergo indocyanine green injection within 72 hours prior to surgery. Permitting infusion time within 72 hours of operation is believed to be adequate for tissue glow/surgical visualization. Alternately, patients may receive 25 mg of indocyanine green during induction. Dose and time of administration will be determined by the neurosurgeon during surgical planning. This 25 mg dose of indocyanine green is similar to dosing for other intraoperative vascular visualization.
Interventions: intervention 1: Indocyanine Green (ICG) intervention 2: Intraoperative near-infrared (NIR)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
TumorGlow™ for All Nervous System Tumors 
 
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This material is the property of the University of Pennsylvania. 
Title: Two-Part Study to Evaluate the Safety and Efficacy of Image Guided 
Surgery using Near-Infrared dyes for Intramolecular Imaging of Nervous 
System Tumors Compared to Standard of Care, (TumorGlow™) 
 
 
Principal Investigator:  
John Y-K. Lee, M.D. 
 
 
 
 
Department of Neurosurgery 
 
 
 
 
Pennsylvania Hospital 
 
 
 
 
801 Spruce Street 
 
 
 
 
8th floor 
 
 
 
 
Philadelphia PA, 19106 
 
 
Clinical and Scientific Expert:  
 
 
 
 
Sunil Singhal, M.D. 
 
 
 
 
Department of Surgery – School of Medicine 
 
 
 
 
3400 Spruce Street, 4 Silverstein 
 
 
 
 
Philadelphia, PA 19104 
 
 
Business Administrator:  
Dan Howard 
 
 
 
 
Department of Neurosurgery 
3400 Spruce Street, 3 Silverstein 
Philadelphia, PA 19104 
 
 
Funding Sponsor: 
Department of Neurosurgery Penn Medicine 
Neuroscience Center Grant 
 
 
Investigational Imaging Agent: 
Indocyanine Green 
 
 
Protocol IRB Number:  
822231/UPCC #09315 
 
 
Protocol Version:  
 
15Nov2019 
 
 
IND Number:  
 
Exempt 7/7/2015 
 
 
 
 


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Table of Contents 
Contents 
List of Abbreviations ................................................................................................................... 4 
Study Summary............................................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Background .................................................................................................................. 7 
1.2 
Name and Description of the Investigational Product .................................................. 7 
1.3 
Name and Description of the Investigational Devices .................................................. 8 
1.4 
Preclinical Data............................................................................................................. 9 
1.5 
Clinical Data to Date ..................................................................................................... 9 
1.6 
Dose Rationale ........................................................................................................... 11 
1.7 
Risk/Benefit Assessment ............................................................................................ 12 
1.7.1 
Known Potential Risks ............................................................................................. 12 
1.7.2 
Known Potential Benefits ........................................................................................ 14 
1.7.3 
Assessment of Potential Risks and Benefits ........................................................ 15 
2 
Study Objectives ............................................................................................................... 15 
3 
Study Design ..................................................................................................................... 15 
3.1 
General Design........................................................................................................... 15 
3.2 
Primary Study Endpoints ............................................................................................ 16 
3.3 
Secondary Study Endpoints ....................................................................................... 16 
4 
Study Population and Duration of Participation ............................................................ 16 
4.1 
Inclusion Criteria ......................................................................................................... 16 
4.2 
Exclusion Criteria........................................................................................................ 16 
4.3 
Subject Recruitment and Screening ........................................................................... 17 
4.4 
Duration of Study Participation ................................................................................... 17 
4.5 
Total Number of Subjects and Sites ........................................................................... 17 
4.6 
Vulnerable Populations .............................................................................................. 17 
4.7 
Evaluable Subjects ..................................................................................................... 17 
4.7.1 
Non-Evaluable Subjects .......................................................................................... 17 
4.7.2 
Data Collection  ........................................................................................................ 18 
5 
Investigational Product .................................................................................................... 18 
5.1 
Description .................................................................................................................. 18 
5.2 
Treatment Regimen .................................................................................................... 18 
5.3 
Method for Assigning Subjects to Treatment Groups ................................................ 18 
5.4 
Preparation and Administration of Study Drug ........................................................... 18 
5.5 
Prior and Concomitant Therapy ................................................................................. 19 
5.6 
Packaging ................................................................................................................... 19 
5.7 
Blinding of Study Drug ................................................................................................ 19 
5.8 
Receiving, Storage, Dispensing and Return .............................................................. 19 
6 
Study Procedures ............................................................................................................. 19 
6.1 
Visit 1: Initial Consult (approximately 2 weeks prior to operation) ............................. 20 
6.2 
Visit 2 (CTRC, Infusion visit within 72 hours before operation) .................................. 21 
6.3 
Visit 3: Operative Visit ................................................................................................ 21 
6.4 
Annual Assessments and Subject Follow-Up ............................................................ 23 
6.5 
Rescue Therapy ......................................................................................................... 23 
7 
Statistical Plan ................................................................................................................... 23 
7.1 
Primary Endpoint ........................................................................................................ 23 
7.2 
Secondary Endpoints ................................................................................................. 23 
7.3 
Sample Size Determination ........................................................................................ 23 
7.4 
Statistical Methods ..................................................................................................... 24 


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8 
Safety and Adverse Events .............................................................................................. 24 
8.1 
Definitions ................................................................................................................... 24 
8.2 
Expected Adverse Events and Treatment .................................................................. 26 
8.3 
Recording of Adverse Events ..................................................................................... 27 
8.4 
Reporting of Serious Adverse Events (SAEs) and Unanticipated Problems ............. 28 
8.5 
Reporting Serious Adverse Events (SAEs) to the Data Safety Monitoring Committee 
(DSMC) at the Local PI site ........................................................................................ 28 
8.6 
Pregnancy .................................................................................................................. 28 
8.7 
Unblinding Procedures ............................................................................................... 29 
8.8 
Medical Monitoring ..................................................................................................... 29 
9 
Data Handling, and Record Keeping ............................................................................... 29 
9.1 
Confidentiality ............................................................................................................. 29 
9.2 
Data Collection and Management .............................................................................. 29 
9.3 
Records Retention ...................................................................................................... 30 
10 
Study Monitoring, Auditing, and Inspecting .................................................................. 30 
10.1 
Study Monitoring Plan ................................................................................................ 30 
10.2 
Auditing and Inspecting .............................................................................................. 31 
10.3 
Reporting of Exceptions and Deviations .................................................................... 31 
11 
Ethical Considerations ..................................................................................................... 32 
11.1 
Informed Consent Process / HIPAA Authorization ..................................................... 32 
12 
Study Finances .................................................................................................................. 32 
12.1 
Funding Sources ........................................................................................................ 32 
12.2 
Conflict of Interest ...................................................................................................... 32 
13 
Publication Plan ................................................................................................................ 32 
14 
References ......................................................................................................................... 32 
15 
Attachments ...................................................................................................................... 36 
 
 
 


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List of Abbreviations 
 
ACC – Abramson Cancer Center 
AE – Adverse Event 
APP – Advanced Practice Provider 
BP – Blood Pressure 
CRF – Case Report Form 
CT – Computed Tomography 
CTCAE – Common Terminology Criteria for Adverse Events 
CTRC – Clinical Translational Research Center 
CTSRMC - Clinical Trials Scientific Review and Monitoring 
DOB – Date of Birth 
DSMC – Data Safety Monitoring Committee 
ER – Emergency Room 
FDA – Food and Drug Administration 
GCP – Good Clinical Practice 
hCG – Human Chorionic Gonadotropin 
H&E – Hematoxylin and Eosin 
HIPAA – Health Insurance Portability and Accountability Act 
HR – Heart Rate 
HUP – Hospital of the University of Pennsylvania 
HTN – Hypertension 
ICH – International Conference on Harmonization 
ID – Identification 
IP – Investigational Product 
IRB – Institutional Review Board 
IV – Intravenous 
LD50 – Median lethal dose 
MRI – Magnetic Resonance Imaging 
NIR – Near-Infrared 
OR – Operating Room 
PAH – Pennsylvania Hospital 
PET – Positron Emission Tomography 
PHI – Protected Health Information 
PI – Principal Investigator 
PPMC – Penn Presbyterian Medical Center 
RR – Respiratory Rate 
SAE – Serious Adverse Event 
UADE – Unanticipated Adverse Device Effect 
US – United States 
USP – United States Pharmacopeia 
VATS – Video Assisted Thoracoscopic Surgeries 
 
 


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Study Summary 
 
Title 
Two-Part Study to Evaluate the Safety and Efficacy of Image Guided 
Surgery using Near-Infrared Dyes for Intramolecular Imaging of 
Nervous System Tumors Compared to Standard of Care, 
(TumorGlow™) 
Short Title 
Indocyanine Green for All Nervous System Tumors 
Protocol/IRB Number 
822231/UPCC #09315 
Phase 
Phase I/II 
Methodology 
Open Label; Part 1 observational and Part 2 permitting deviation from 
surgical plan based on indocyanine green intraoperative imaging.  
Study Duration 
5 years 
Clinical Sites 
Penn Medicine: 
Hospital of the University of Pennsylvania 
Penn Medicine Pennsylvania Hospital 
Penn Medicine Presbyterian Hospital 
Objectives 
Part I: To determine safety/efficacy of high dose, delayed indocyanine 
green (second window ICG) during surgery of nervous system tumors. 
 
Part II: To determine diagnostic test characteristics 
(sensitivity/specificity) of delayed, high dose indocyanine green 
(second window ICG) as a diagnostic aid during surgery of nervous 
system tumors. 
 
Part IIb: To optimize timing and dose of second window IcG during 
surgery of nervous system tumors, based on sensitivity/specificity. 
 
Part IIc: Compare SOC dyes with indocyanine green to determine 
efficacy for tumor visualization, answering the question is one dye 
superior to another, more accurate and precise. 
Number of Subjects 
We intend on enrolling 500 subjects in this study. 
Diagnosis and Main 
Inclusion Criteria 
Patients presenting with suspected resectable nervous system 
tumors who are considered to be good surgical candidates and are at 
risk of local recurrence. 
Investigational 
Product, Dose, 
Route, Regimen 
The study drug is indocyanine green, single dose of up to 5 mg/kg 
administered up to 72 hours prior to resection or a single dose of 25 
mg administered during induction, diluted into sterile water for 
intravenous (IV) injection  prior to tumor resection. Dye and dose plan is  
determined by PI based on tumor type, surgical timing, and signal to 
background ratio. 
Investigational Devices 
 
VS3 Iridium – Visionsense Stereoscopic High Definition (3DHD) 
including IR Fluorescence Vision System 
 
Stryker 1588 AIM (Advanced Imaging Modality) Video Camera 
with Infrared Compatibility with Stryker AIM HD Autoclavable 
Laparoscope 
 
Zeiss INFRARED™ 800 for OPMI® PENTERO® 800 
 
Leica FL800 ICG Fluorescence Module with the Leica M530 


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OH6 
 
Surgical Dual Imager 
Statistical 
Methodology 
Statistical methodology includes analyses of sensitivity, specificity, and 
predictive value as they relate to indocyanine green-mediated tumor 
identification as compared to histopathology. 
 
 


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1 
Introduction 
This study is conducted according to United States (US) and international 
standards of Good Clinical Practice (GCP) (Food and Drug Administration [FDA] 
Title 21 part 312 and International Conference on Harmonization [ICH] guidelines), 
applicable government regulations and institutional research policies and 
procedures. 
1.1 Background 
Primary malignant and non-malignant brain tumors account for an estimated 21.42 
cases per 100,000 for a total count of 343,175 incident tumors based on worldwide 
population estimates [1]. These entities result in variable but disappointing rates of 
survival, particularly for primary brain tumors (5-year survival rates: anaplastic 
astrocytoma 27%; glioblastoma multiforme 5%) [2, 3]. Metastatic brain tumors 
outnumber primary brain tumors (estimates as high as 10:1) as they affect 
approximately 25% of patients diagnosed with cancer [4-6]. In terms of brain tumor 
surgery, the extent of surgical resection—a factor that is greatly impacted by a 
Neurosurgeon’s ability to visualize these tumors—is directly associated with 
patient outcomes and survival [7-9]. Although spinal cord tumors are lower in terms 
of their incidence [10], data correlating extent-of-resection to outcomes and 
survival have been demonstrated in patients with intramedullary tumors [11]. 
 
Using systemically delivered compounds with a high sensitivity of detection by 
near-infrared (NIR) fluorescence, it would be possible for us to improve surgical 
resection thus minimizing chances of recurrence and improving survival. Simply, if 
the tumor cells will “glow” during surgery, the surgeons are more likely to identify 
tumor margins and residual disease, and are, therefore more likely to perform a 
superior cancer operation. By ensuring a negative margin through NIR imagery, it 
would make it possible to decrease the rates of recurrence and thus improve 
overall survival. 
 
This concept of intraoperative molecular imaging requires two innovations: 
(i) a fluorescent contrast agent that can be injected systemically into the 
subject and that selectively accumulates in the tumor tissues, and  
(ii) an imaging system that can detect and quantify the contrast agent in the 
tumor tissues.[12, 13] 
 
Subjects undergo intraoperative imaging, receiving an injection of indocyanine 
green and then undergoing intraoperative imaging of the surgery site with a NIR 
imaging system. The imaging devices allow the operating field to be observed in 
real-time. 
1.2 Name and Description of the Investigational Product  
Indocyanine green is a water-soluble tricarbocyanine dye routinely used in clinical 
settings for measuring cardiac output, hepatic function, liver blood flow and 
ophthalmic angiography and has been in use for over 60 years [14]. This protocol 
utilizes Patheon’s indocyanine green, NDC 17238-424. The chemical formula is 


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C45H47N2O6S2Na and the compound has a molecular weight of 774.96Da (CAS 
number 3599-32-4). It has a peak absorption in the NIR spectrum at 800nm and 
maximal emission at 835nm. Indocyanine green is rapidly and completely bound 
to plasma proteins (especially albumin) after intravenous (IV) injection in the blood 
[15]. 
 
 
 
Indocyanine Green for Injection USP is a sterile, lyophilized green powder 
containing 25 mg of indocyanine green with no more than 5% sodium iodide. It is 
packaged with Sterile Water for Injection, USP, which is used to dissolve the 
indocyanine green, and is to be administered intravenously. 
1.3 Name and Description of the Investigational Devices 
Imaging Systems Intended for Use in the Neurosurgical Operating Room (OR): 
 
Investigational Device 
Manufacturer 
FDA Product 
Classification / 510(k) 
Use of Device 
(Visit 3: 
Operative 
Visit) 
Hospital 
Used 
VS3 Iridium – Visionsense 
Stereoscopic High 
Definition (3DHD) 
including IR Fluorescence 
Vision System 
VisionSense 
(Medtronic) 
Confocal Optical Imaging; 
Endoscope and 
accessories; Class II; 
VS3-IR 510(k):  K152204 
1) Dura View; 
2) Cortex View; 
3) Tumor View; 
4) Margin View 
5) Ex-vivo View 
PAH; 
HUP 
Stryker 1588 AIM 
(Advanced Imaging 
Modality) Video Camera 
with Infrared Compatibility 
with Stryker AIM HD 
Autoclavable Laparoscope 
Stryker 
Confocal Optical Imaging; 
Endoscope and 
accessories; Class II; 
VS3-IR 510(k):  K173866 
1) Dura View; 
2) Cortex View; 
3) Tumor View; 
4) Margin View 
5) Ex-vivo View 
PPMC 
INFRARED™ 800 for 
OPMI® PENTERO® 800 
Carl Zeiss 
Surgical 
GMBH 
System, X-Ray, 
Angiographic; 
Angiographic x-ray 
system; Class II; 510(k):  
K100468 
Tumor View 
PAH; 
HUP; 
PPMC 
Leica FL800 ICG 
Fluorescence Module with 
the Leica M530 OH6 
Leica 
Microsystems 
System, X-Ray, 
Angiographic; 
Angiographic x-ray 
Tumor View 
PAH; 
HUP 


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Investigational Device 
Manufacturer 
FDA Product 
Classification / 510(k) 
Use of Device 
(Visit 3: 
Operative 
Visit) 
Hospital 
Used 
system; Class II; 510(k):  
K141136 
Surgical Dual Imager 
Dr. Yodh Lab 
Confocal Optical Imaging; 
Endoscope and 
accessories; Class II; 
510(k): Not Yet Approved 
1) Tumor 
View 
2) Margin 
View 
3) Ex-vivo 
View 
PAH 
HUP = Hospital of the University of Pennsylvania; NIR = near-infrared; PAH = Pennsylvania Hospital; PPMC = Penn 
Presbyterian Medical Center 
1.4 Preclinical Data 
The use of indocyanine green for imaging has been well-documented over the last 
20 years. It is believed that indocyanine green, which is normally cleared quickly 
in vivo, gets “stuck” in tumors. The University of Pennsylvania laboratories have 
shown that indocyanine green can be used to safely and accurately image lung, 
breast, renal and ovarian cancers in mice and dogs. Work done at the Hospital of 
the University of Pennsylvania (HUP) in the lab of Dr. Sunil Singhal has shown 5 
mg/kg (given to mice in his lab) is an optimal dose for tumor imaging [25, 28]. In 
addition, performing optical imaging within 72 hours following dosing of 
indocyanine green is optimal based on Penn’s experience [25]. The LD50 after IV 
administration ranges between 60 and 80 mg/kg in mice, 50 and 70 mg/kg in rats 
and 50 and 80 mg/kg in rabbits [16, 22]. 
 
Studies in a rat glioma model demonstrated that indocyanine green remained 
within tumors with relatively few glioma cells seen beyond the indocyanine green-
laden tumor margin. The doses utilized ranged from 60 to 120 mg/kg with imaging 
taking place at least 1 hour following the dose [22]. In Dr. Singhal’s lab, 
indocyanine green-injection utilizing canine tumor models demonstrated reliable 
uptake into flank tumor xenografts with visualization of the tumor/normal tissue 
interface [23-25]. 
1.5 Clinical Data to Date 
Indocyanine green has been used in the clinical settings since 1957. There is a 
wealth of data available attesting to the safety of this drug injected at its current 
clinically indicated dosing level. Indocyanine green has been shown to 
preferentially uptake in esophageal tumors as opposed to surrounding epithelial 
lumen after 1 minute of IV exposure [26]. Additionally, the same group reported 
being able to better characterize the vascularization of the tumor to further clarify 
the invasiveness of the cancer. Indocyanine green usage has been shown to be 
safe in a similar clinical setting by the Gotoh group, who used indocyanine green 


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to detect and characterize bullous and emphysematous lesion of the lung in video 
assisted thoracoscopic surgeries (VATS) with Infrared Thoracoscopy that were not 
previously detectable by white light [18]. Finally, indocyanine green has been 
utilized in applications relating to brain tumors. In a rat glioma model, areas imaged 
using indocyanine green correlated to the tumor margin within 1 mm [27]. Although 
dosing and the timing of administration of indocyanine green were variable, tumor 
demarcation was made possible with the use of intraoperative NIR imaging of 
indocyanine green [22]. Since then, Dr. Singhal’s group has demonstrated uptake 
into human lung tumors [23].  In addition, Dr. Lee’s group has demonstrated uptake 
in human gliomas, meningiomas and brain metastasis [20, 21, 25]. 
 
Previous studies conducted in full-term pregnant women demonstrated no 
maternal or fetal reactions to the dye. It appeared that indocyanine green clearance 
is a safe and sensitive test for evaluation of liver function during pregnancy [19]. 
 
Prior and ongoing studies with solid tumors at the University of Pennsylvania using 
indocyanine green  and imaging devices have enrolled over 500 subjects to date 
(17, 20, 23, 25, 28-46). The data collected from these subjects have provided us 
with knowledge that this method of imaging can be helpful to surgeons in the 
operating room, including identifying inflammatory processes in lymph nodes and 
metastatic disease in the thoracic cavity that was not visible on CT or PET scans 
(17, 20, 23, 25, 28-46). 
 
The standard of care dye, Gleolan™, is the first and only FDA approved optical 
imaging agent for use in Fluorescence-Guided Surgery. Gleolan [aminolevulinic 
acid hydrochloride (ALA HCl)] is an optical imaging agent indicated in patients with 
glioma (suspected World Health Organization Grades III or IV on preoperative 
imaging) as an adjunct for the visualization of malignant tissue during surgery. It is 
orally administered 2-4 hours prior to anesthesia. A standard surgical operating 
microscope adapted with a blue light emitting light source and ancillary excitation 
and emission filters to visualize fluorescence excitation in the wavelength of 375 
to 440 nm and for observation from 620 to 710 nm will be used to view Gleolan 
(50, 51, 52). 
 
In this current study, we intend to compare SOC dyes with indocyanine green to 
find out which dye is more accurate and precise. This may lead to patients 
receiving more than one (1) drug prior to surgery and visualizing the tumor with 
different cameras during surgery. 
 
There are no additional risks of administering both dyes. However, due to imaging 
with multiple cameras, the surgical procedure may be prolonged 15 minutes. In 
this study, there is no anticipated risk by extending the surgical procedure. 
 
As of January 2019, this protocol completed Part 1, observational, and began Part 
2, permitting deviation from the surgical plan based on indocyanine green 
intraoperative imaging, of the study. A total of 327 subjects consented with 296 


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subjects receiving infusion of indocyanine green and 26 non-evaluable subjects (4 
subjects have been consented but not infused as of yet). The reasons for non-
evaluable subjects are the following:  iodine/shellfish allergy (4 subjects), surgical 
procedures cancelled (4 subjects), decline participation (9 subjects), scheduling 
conflicts (5 subjects), and clinical issues (4 subjects; i.e., pre-infusion hypertension 
[HTN]; no medical clearance for surgery). 
 
Of the 296 subjects infused, 110 subjects were administered 2.5 mg/kg and 186 
subjects were administered 5 mg/kg of indocyanine green. Of 296 infusions, there 
were 55 total adverse events (AEs) observed in 35 patients, which are presented 
in more detail in Section 1.7 below. 
1.6 Dose Rationale 
In this study, the indocyanine green dose began at 5 mg/kg, aligned with previous 
nonclinical and clinical experience at the University of Pennsylvania. Given the 
incidence of HTN in our CNS cohort and seeking optimal signal to background 
ratio, we decreased to 2.5 mg/kg to assess efficacy and safety. Thus, we intend to 
evaluate dose ranges but will not exceed 5mg/kg. Alternately, based on 
neurosurgeon plan,  patients may receive a 25 mg bolus of ICG at the time of 
induction administered intravenously by the anesthesiologist. This 25 mg dose of 
indocyanine green is similar to dosing for other intraoperative vascular 
visualization. This can cause less usage of the drug, lower risk of adverse event 
occurrences. 
 
We make no changes to the route of administration.. The most important difference 
between what is labeled on the package and this protocol is the dose regimen (up 
to 5 mg/kg) and the amount of time elapsing before intraoperative imaging begins 
(up to 72 hours). This protocol began with 24-hour infusions the day before surgery 
based on previous nonclinical and clinical experience at the University of 
Pennsylvania. Interested in strength of signal to background ratio over extended 
or shortened timeframes, we allow for a range of up to 72 hours. The rationale for 
dosing timing prior to surgical intervention is based on the minimal risks with 
indocyanine exposure, to accommodate logistical scheduling of surgeries, and to 
collect data on optimal signal to background ratio in various tumor types. 
 
Indocyanine green has been used in a dose-escalation trial up to a maximum dose 
of 10 mg/kg [22] and in other trials 3-5 mg/kg [13, 17-21]. Indocyanine green has 
a LD50 after IV administration of 50 to 75 mg/kg [22]. 
 
As Dr. Singhal and other researchers have used an IV injection of indocyanine 
green to obtain imaging sufficient to describe discrepancies in the structure of 
abnormal hyper-vascularized tissue [47], it therefore stands to reason that we 
would be able to accomplish our objective of imaging tumors with indocyanine 
green using a similar dose. 
 


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Interim data analysis (see Section 7.2), specifically the fluorescence signal to 
background ratio, will determine the optimal timing of indocyanine green infusion, 
which will guide future infusion in this protocol and future protocols. 
1.7 Risk/Benefit Assessment 
1.7.1 Known Potential Risks 
 
Risks of Indocyanine Green: 
 
The risks of using indocyanine green are well described and exceedingly rare [15, 
28]. Indocyanine green is known to have a rare but serious side effect known as 
anaphylaxis and because of this, patients with a history of iodide allergies will not 
be considered candidates in this study. There is no connection with any other 
particular contrast agent or drug or food allergy. Anaphylaxis is an allergic reaction 
to a substance that can cause swelling of the skin, shortness of breath, dizziness, 
increased heart rate (HR), rash, and/or death. The indocyanine green dye will be 
administered in a procedure room with trained nurses who will closely monitor the 
subject’s vital signs (HR, blood pressure [BP], oxygen level [pulse oximetry], and 
skin color) to check for any signs of anaphylaxis. In the event of an anaphylactic 
reaction, the indocyanine green injection will be stopped and medication will be 
used to control the reaction. One study placed the rate of adverse reactions for 
indocyanine green injections at fewer than 4 in 240,000 [29]. 
 
Adverse Events (as of January 2019): 
 
The AEs table below outlines the number of events that occurred by Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0 event category in this 
protocol as of January 2019. Subjects could have had more than one AE. Of 296 
infusions, there were 55 total AEs observed in 35 patients:  36 events in the 5 
mg/kg dose cohort and 19 events in the 2.5 mg/kg dose cohort. Out of the 55 AEs, 
one was a serious adverse event (SAE) (HTN). One patient experienced two 
unique AEs during infusion (HTN-General Disorder). 
 
Overall, in 296 patients, HTN accounted for 5.7% of AEs; mild arm pain/discomfort 
accounted for 7.4% of AEs, general disorders accounted for 2.7%, administration 
site conditions accounted for 2% of AEs and 0.6% patients reported a 
gastrointestinal issue. 
 
Of the patients in the 5 mg/kg dose cohort, 5.4% reported vascular disorders, 
9.1% reported mild arm discomfort or pain, 3.2% had general disorders and 1.6% 
had administration site conditions. 
 
Of the patients in the 2.5 mg/kg dose cohort, 6.4% reported vascular AEs, 4.6% 
of them had mild arm discomfort or pain, 1.8% had general disorders, 2.7% had 
administration site conditions and 1.8% had gastrointestinal AEs. 


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Table 1 
Adverse Events (Protocol #822231, as of February 14, 2019) 
  
Total Total % Total 
% 
Total Total % 
Dose (mg/kg) 
 
 
5 
  
2.5 
  
# of infusion 
296 
 
186 
  
110 
  
Vascular disorder: HTN 
17 
5.7 
10 
5.38 
7 
6.36 
Mild arm discomfort/pain 
22 
7.4 
17 
9.14 
5 
4.55 
General disorders 
8 
2.7 
6 
3.23 
2 
1.82 
Admin site conditions 
6 
2 
3 
1.61 
3 
2.73 
GI 
2 
0.6 
0 
0.00 
2 
1.82 
 
Out of the 55 AEs, one subject in the 5.0 mg/kg dosage cohort experienced a 
serious adverse event (SAE). This patient, with a past medical history of HTN, 
began the infusion with high BP. At the direction of the Principal Investigator (PI), 
infusion was started and directed discontinuation if the patient’s systolic BP 
exceeded 200. The patient’s baseline pre-infusion BP was 177/89. The patient 
received 5.0 mg/kg for a total dose of 276 mg out of the prescribed 533 mg dose 
ordered (mg/kg). Mid-infusion, the patient’s systolic BP was 220 and the infusion 
was discontinued. During post-infusion observation, BP remained high without 
return to baseline of 177/89, and although the patient was asymptomatic, was 
evaluated and treated in the ER then discharged home. Patient arrived for planned 
craniotomy procedure following day as scheduled. This event was Grade 3. 
 
Of the 296 patients who received indocyanine green under this protocol, we 
observed an average of 4% decrease in pulse oximetry from baseline compared 
to end of infusion. At discharge, this group demonstrated an average of 0.20% 
decrease from pre-infusion in pulse oximetry. Between the two dose cohorts, we 
observed that the 2.5 mg/kg cohort has less deceleration in pulse oximetry than 
the 5 mg/kg cohort. To date, 186 patients were infused with 5 mg/kg indocyanine 
green. These patients experienced a 5% deceleration from pre-infusion to during 
infusion. From pre-infusion to discharge, we observed an average of 0.38% 
decrease in pulse oximetry. To date, 110 patients were infused with 2.5 mg/kg 
indocyanine green. Of those, a 2.4% deceleration from pre-infusion to during 
infusion was observed. These patients experienced an average of 0.08% increase 
in pulse oximetry from pre-infusion to discharge. 
 
Risks of Gleolan (aminolevulinic acid hydrochloride (ALA HCI) (5-ALA) [53]: 
• 
Adverse reactions occurring in >1% of patients in the week following 
surgery were pyrexia, hypotension, nausea, and vomiting.    
• 
Adverse reactions occurring in < 1% of patients in the first 6 weeks after 
surgery were: chills, photosensitivity reaction, solar dermatitis, hypotension, 
abnormal liver function test, and diarrhea.    


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• 
Neurologic events related to the surgical procedure occurred in 29% of 
patients and included:  aphasia, hemiparesis, hemianopia, headache, 
seizure, hemiplegia, monoparesis, hypoesthesia, and brain edema.   
• 
Elevated liver enzymes occurred in clinical studies. 
There are no anticipated risks of dosing of simultaneous dosing of Indocyanine 
green and 5-ALA. 
 
Risks of the Use of NIR Imaging Systems: 
 
The video images that we will take intraoperatively may result in the surgeon 
changing the operation. He/she will not change the scale of the operation to do 
anything that was not described to the subject during the surgical consent process 
beforehand. The possible risks associated with taking these images are as follows: 
 
 There is a chance that an area without any cancer in it will glow in the video 
images. If that happens, the surgeon may remove healthy tissue that did 
not need to be removed and that would not have been removed in a 
standard surgery. 
 There is a chance that while removing additional tissue that glows in the 
video images, the subject could be put at an increased risk of having a 
surgical complication. A surgical complication includes, but is not limited to 
bleeding, infection, pain, injury to a major organ, nerve damage, blood clot 
in the arms/legs/other region of the body, and/or death. 
 There is a chance that being under anesthesia for the extra 15-20 minutes 
that it takes to obtain the images for this study could put the subject at an 
increased risk of having of a common side effect associated with 
anesthesia. These common side effects include, but are not limited to 
nausea and vomiting after surgery, sore throat and hoarseness, 
shivering/chills, confusion, increased BP, and/or muscle aches. 
 Finally, there is a chance that the imaging technique could falsely reassure 
the surgeon that all of the cancer has been taken out, so not as much tissue 
will be removed. In other words, not all of the cancer could be taken out. 
 
Oncologic surgery in the brain is always balanced by the potential 
neurologic/functional risks of additional resection, and for this reason 
neurosurgeons are always weighing the risks and benefits of additional tumor 
resection. The addition of the fluorescent dye does not change the calculus for the 
treating physician/neurosurgeon. The surgeon will continue to weigh the risks and 
minimize these risks. If he/she thinks that removing the extra tissue is too risky, 
they will not remove the extra tissue. If removal of additional tissue has minimal 
risk, the surgeon may choose to remove the additional tissue for diagnostic test 
considerations. 


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1.7.2 Known Potential Benefits 
The purpose of this study is not to investigate a possible benefit for each subject. 
We do not know whether these video images truly identify cancerous tissue, so we 
cannot guarantee any benefits from being part of this study. However, there is a 
chance that because of the video images, the surgeon will remove additional 
cancerous tissue that they would not have removed during a standard operation. 
1.7.3 Assessment of Potential Risks and Benefits 
The PI weighs the risks of participating in the study with the potential benefits of 
participating in the study for each subject enrolled. We feel that the very low risk 
of adverse reactions expected from the study compared to the practical potential 
benefit of improving nervous system tumor resection and related outcomes using 
a non-toxic imaging agent are acceptable. 
2 
Study Objectives 
The primary study objective is to determine safety/efficacy of high dose, 
delayed indocyanine green (second window ICG) during surgery of nervous 
system tumors. 
 
The 
first 
objective 
is 
to 
determine 
diagnostic 
test 
characteristics 
(sensitivity/specificity) of delayed, high dose indocyanine green (second window 
ICG) as a diagnostic aid during surgery of nervous system tumors. Additionally, to 
optimize timing and dose of second window IcG during surgery of nervous system 
tumors, based on sensitivity/specificity. Lastly, to compare SOC dyes with 
indocyanine green to determine efficacy for tumor visualization, answering the 
question is one dye superior to another, more accurate and precise.  
 
3 
Study Design 
3.1 General Design 
This study is a single center, open-label, two-part study to assess image guided 
surgery of intramolecular imaging in nervous system tumors. Subjects with a 
diagnosis of a resectable nervous system tumor who are at risk of recurrence are 
included. The primary goal is to observe what tissues fluoresce in the OR, and 
then to identify if that tissue is cancerous/tumor or normal when the histopathology 
is performed. 
 
This study is split into two parts. The purpose of Part 1 is to confirm dose, assess 
timing of the operation and assess the feasibility of using indocyanine green as a 
fluorescent for neurosurgical tumor resection without extending surgery beyond 
what is seen on the standard of care MRI. The purpose of Part 2 is expansion of 
the margin view phase of the operation, where residual fluorescence can be 
resected at the discretion of the surgeon; in addition, further evaluation of optimal 
dosing and timing. 


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Candidates are those with a presumed tumor in the nervous system that requires 
surgery. There is no randomization or control group. 
 
Subjects undergo indocyanine green injection within 72 hours prior to surgery. 
Permitting infusion time within 72 hours of operation is believed to be adequate for 
tissue glow/surgical visualization. Alternately, patients may receive 25 mg of 
indocyanine green during induction. Dose and time of administration will be 
determined by the neurosurgeon during surgical planning. This 25 mg dose of 
indocyanine green is similar to dosing for other intraoperative vascular 
visualization. 
 
3.2 Primary Study Endpoints 
The primary end-point of the study is to determine the test characteristics (i.e., 
sensitivity, specificity, positive predictive value, negative predictive value) of 
second window indocyanine green in detection of tumors using intraoperative NIR 
imaging as compared to the standard of care histopathology report. 
3.3 Secondary Study Endpoints 
The secondary end-point of the study is to identify based on signal to background 
noise the optimal timing for surgery following infusion of indocyanine green and 
dose for optimal safety without toxicity for visualization of indocyanine green during 
intraoperative imaging in nervous system tumors. 
 
3.4 
Additional Study Endpoints 
Additional study end-points is to compare standard of care dyes with indocyanine 
green to determine which dye is more accurate and precise.  
 
4 
Study Population and Duration of Participation 
4.1 Inclusion Criteria 
1. Adult patients 18 years of age and older. 
2. Patients presenting with a nervous system tumor presumed to be resectable 
and at risk for local recurrence on pre-operative assessment. 
3. Good operative candidate as determined by the treating physician and 
multidisciplinary team. 
4. Subject capable of giving informed consent. 
4.2 Exclusion Criteria 
1. Pregnant women as determined by urinary or serum beta hCG within 48 
hours of surgery. 
2. Subjects with a history of iodide allergies. 


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3. Vulnerable patient populations. 
a. Patients unable to participate in the consent process. 
4. History of uncontrolled hypertension (requiring ER admission or ≥ 3 blood 
pressure medications) 
4.3 Subject Recruitment and Screening 
Subject recruitment is performed by the patient’s treating physician in clinical 
practice during consultation at a Penn Medicine location. All eligible candidates 
are invited to participate in the research in the following manner: 
 
1. During the patient's initial surgical consultation, the treating physician or a 
member of the study team describes the study and its risks and benefits. 
2. The potential subject is given a copy of the consent form to review and have 
all questions answered by the PI or Sub-I. If the patient decides to 
participate, the consent form is signed. 
3. The subject is screened for history of iodine/shellfish allergy by clinical staff. 
4. The subject is scheduled for injection at a Penn Medicine location and 
advised to call with any questions. 
4.4 Duration of Study Participation 
Each subject participates in the treatment phase of the trial for approximately 2-4 
weeks until surgical resection then is followed for 5 years for survival and 
recurrence. 
4.5 Total Number of Subjects and Sites 
It is expected that up to 500 subjects will be enrolled in this study, see Section 7.3 
for the sample size determination. 
4.6 Vulnerable Populations 
Pregnant women, prisoners, children, or other vulnerable populations will not be 
included. Although not directly targeted, mentally disabled persons, economically or 
educationally disadvantaged persons, and/or employees or students of the 
University of Pennsylvania will not be denied enrollment and any special protections 
and/or additional safeguards will be undertaken in order to protect the rights and 
welfare of these subjects from coercion or undue influence as appropriate. Students 
or employees of Penn are informed that their decision to participate does not affect 
their standing with the University in any way. 
4.7 Evaluable Subjects 
4.7.1 Non-Evaluable: When and How to Withdraw Subjects 
Subjects will be not evaluable if study visits 2 and 3 are not complete. Reasons may 
include: 
1. The subject decides that he/she does not wish to have their surgery. 


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2. The subject experiences a SAE or an AE during the injection, which would 
require an intervention of steroids or epinephrine. 
3. The subject fails to meet eligibility criteria. 
4. The PI or sub-I determine it is in the subject’s best interest to not continue in 
the study. 
5. Other reasons such as logistical or scheduling conflicts. 
4.7.2 Data Collection 
Subject study data is entered into Penn CTMS and a RedCap database as part of 
the Center of Precision Surgery in order to capture demographic and study data as 
well as surgeon impression from surgery, which are both encrypted and password 
protected databases maintained on secure servers. 
 
Data collection and access to medical records will continue for all evaluable subjects 
on survival and recurrence data for up to five years after their surgery. 
5 
Study Intervention 
5.1 Investigational Product 
5.1.1 Description 
Indocyanine green is a NIR contrast agent. It is a water-soluble tricarbocyanine dye 
supplied as a lyophilized powder in 25 mg vials. The powder will be reconstituted in 
sterile diluent. 
5.1.2 Treatment Regimen 
The dose is a single infusion of up to 5 mg/kg reconstituted indocyanine green 
injected intravenously in the dark, within 72 hours of the operation. Alternately, 
subjects may receive a 25 mg dose of indocyanine green administered by the 
anesthesiology team during induction. If subjects experience any AEs, please 
reference Section 8.2 for protocol intervention. There is no second dose. 
5.2 Approved Product 
5.2.1 Description 
Gleolan (aminolevulinic acid hydrochloride) is an optical imaging agent for oral 
solution. The 50-mL, clear vial contains 1,500 mg of lyophilized ALA HCl powder 
(equivalent to 1,170 mg ALA). After reconstitution, the product has a concentration 
of 30 mg ALA HCl per mL (equivalent to 23.4 mg ALA per mL). 
5.2.2 Treatment Regimen 
The recommended reconstituted oral dose of Gleolan is 20 mg/k administered 3 
hours (range 2 to 4 hours) before anesthesia. If subjects experience any AEs, 
please reference Section 8.2 for protocol intervention. There is no second dose. 


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5.3 Method for Assigning Subjects to Treatment Groups 
As this is an open-label study, there will be no randomization of treatment. 
5.4 Preparation and Administration of Study Drug 
Penn Investigational Drug Service (HUP and Penn Presbyterian Medical Center 
[PPMC]) or Pennsylvania Hospital (PAH) Pharmacy prepares the study intervention 
upon notification. The study intervention is administered after preparation once a 
member of the study team picks up the drug(s) and delivers to the HUP CTRC or 
the in-house INCU RN, Farm Journal Building at PAH or the in-house ICU RN, or 
the Abramson Cancer Center (ACC) at PPMC in a light sensitive bag(s), where the 
staff nurse administers the drug. 
5.5 Prior and Concomitant Therapy 
Any therapies that are normally not exclusionary criteria for surgical resection are 
permitted in this study. 
5.6 Packaging 
Indocyanine green is supplied in a kit (NDC 17238-424) containing six 25mg 
indocyanine green vials and six 10mL sterile water plastic vials. The label is 
provided in Section 15. 
 
Gleolan is supplied as 1,500 mg of lyophilized ALA HCl powder (equivalent to 1,170 
mg ALA), for oral solution in a 50-mL clear, colorless, glass vial with a rubber stopper 
and an aluminum crimp seal. 
5.7 Blinding of Study Drug 
As this is strictly an open-label imaging study, no blinding of the drug is necessary. 
5.8 Receiving, Storage, Dispensing and Return 
Penn Investigational Drug Service (HUP and PPMC) or PAH Pharmacy is 
responsible for all aspects of receiving, storage, dispensing and return of the study 
intervention. 
6 
Study Procedures 
When the infusion is done pre-operatively (Table 2a), study participation consists of 
1) a screening visit, followed by 2) an infusion visit 72 hours prior to surgery, and 3) 
the operative visit. 
 
Table 2a  Pre-Op Infusion Schedule of Evaluations 
Study Procedure 
Visit 1: 
Screening 
Visit 2: 
Infusion Visit 
Visit 3 
Operative Visit 
Annual 
Assessment 
(Until Year 5) 
Informed Consent 
X 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 


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Study Procedure 
Visit 1: 
Screening 
Visit 2: 
Infusion Visit 
Visit 3 
Operative Visit 
Annual 
Assessment 
(Until Year 5) 
Demographics/Medical History 
X 
 
 
 
Physical Examination 
X 
 
 
 
Vital Signs: BP, HR, RR 
X 
X 
X 
 
Height and Weight 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
Prior/Concomitant Medications 
X 
 
 
 
Iodine/Shellfish Allergy Test 
X 
 
 
 
Dispense IP 
 
X 
 
 
AE/Unanticipated Problems 
 
X 
X 
 
Annual Medical Record Review: 
Survival, Recurrence 
 
 
 
X 
AE = adverse event; BP = blood pressure; HR = heart rate; IP = investigational product; RR = respiratory rate 
When the infusion is done intraoperatively (Table 2b), study participation consists 
of 1) a screening visit, followed by 2) the operative visit in which the anesthesiology 
team may infuse the NIR drug intra-operatively. This will be a 25mg infusion. 
 
Table 2b Intra-op Infusion Schedule of Evaluations 
 
Study Procedure 
Visit 1: 
Screening 
Visit 2: 
Operative 
Visit 
Annual 
Assessment 
(Until Year 5) 
Informed Consent 
X 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
Demographics/Medical History 
X 
 
 
Physical Examination 
X 
 
 
Vital Signs: BP, HR, RR 
X 
X 
 
Height and Weight 
X 
 
 
Pregnancy Test 
X 
 
 
Prior/Concomitant Medications 
X 
 
 
Iodine/Shellfish Allergy Test 
X 
 
 
Dispense IP to Anesthesia for 
injection intra-op 
 
X 
 
AE/Unanticipated Problems 
 
X 
 
Annual Medical Record Review: 
Survival, Recurrence 
 
 
X 
AE = adverse event; BP = blood pressure; HR = heart rate; IP = investigational product; RR = respiratory rate 


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6.1 Visit 1: Initial Consult (approximately 2 weeks prior to operation) 
Patients are given the consent form to examine at their leisure and are encouraged 
to ask questions and have time to have all questions answered. The PI or member 
of the study team obtains consent from the patient. He/she will be screened for 
history of iodine/shellfish allergy by clinical staff. 
6.2 Visit 2 (CTRC, Infusion visit within 72 hours before operation) 
For subjects receiving ICG with 72 hours of surgery, they will arrive at the Perelman 
Center for Advanced Medicine Clinical & Translational Research Center, 3400 
Civic Center Blvd., Philadelphia, PA 19104 or the ACC, Farm Journal Building at 
PAH, 230 W. Washington Square, Philadelphia PA, 19106, or the ACC at PPMC, 
1st floor CUPP Building, 51 N 39th St, Philadelphia, PA 19104 for their infusions 
at their respective infusion locations within 72 hours prior to the scheduled surgery 
to receive their injection of indocyanine green by trained nursing staff. The nursing 
staff places a peripheral IV and calls the pharmacy for the scheduled infusion of 
up to 5 mg/kg of indocyanine green diluted in sterile water administered 
intravenously in the dark, over 40 minutes. The nurse monitors subjects pre 
infusion, during the 40-minute infusion and for 30 minutes post infusion for any 
signs of anaphylaxis. For all AEs and prescribed treatment, please see Section 
6.5 and 8.2 Expected Adverse Events and Treatment). 
 
During the study visit, subjects’ vital signs are monitored as follows: pre infusion; 
then at 5 minutes after infusion starts, then at every 15 minutes over the 40-60 
minute infusion time frame. During the post infusion 30 minute observation period, 
vital signs are completed at 10-minute intervals and the subject is monitored for 
any signs of anaphylaxis. The following vital signs are monitored and recorded 
during each time point: HR, BP, skin color, and oxygen levels (pulse oximetry) and 
the subject is observed for any adverse sign or symptoms that could include but is 
not limited to HTN, mild pain or discomfort at infusion site and signs of anaphylaxis. 
Symptoms are treated according to prescribed interventions outlined in the ICG 
Treatment Plan. 
 
The Neurosurgeon may want to compare both indocyanine green with other 
Standard of Care NIR dyes (ex: 5-ALA) intra-operatively to see which dye localizes 
more accurately and precisely at the region of interest. This may result in using 
more than one dye for your surgery. 
6.3 Visit 3: Operative Visit 
Patients  will come to one of the University of Pennsylvania Heath System 
hospitals to undergo removal of their tumor as clinically indicated. Surgical 
approach and exposure are performed according to standard of care. The entire 
procedure is photo-documented and recorded as per standard of care. There are 
five phases of NIR imaging; however, one or more of the phases may be omitted. 
Patients receiving intra-op ICG by anesthesia will report day of surgery and not 
have an infusion suite visit. 
 


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Dura View:  upon opening the skull at the level of the dura but prior to opening the 
dura, a brief view of the dura is obtained with the NIR imaging system – Dura View. 
 
Cortex View:  upon opening the dura but prior to violating the cortex of the brain, 
another brief view of the cortex is with the NIR imaging system – Cortex View. 
 
Tumor View:  Prior to initial resection but upon identification of the tumor, the NIR 
imaging system (i.e. VS3 Iridium, Stryker 1588 AIM) is used to visualize the tumor 
in its native and untouched form. The lights in the OR are turned off and the infrared 
imaging system is turned on. The video screen displays the images of the tumor 
area, and the surgeon measures the spectral reading from the tumor. The imaging 
system captures the infrared signal that is emitted from the indocyanine green that 
has been taken up by the tumors. Initial tumor fluorescence will be recorded and 
visualized. After initial visualization, surgical resection will proceed as per standard 
of care. A NIR microscope (i.e. Leica FL800, Zeiss INFRARED™ 800) will be used 
to assist with the surgical resection. 
 
Margin View:  After completion of the surgery based on standard techniques, the 
NIR imaging system (i.e. VS3 Iridium, Stryker 1588 AIM) will be used to determine 
if there is any residual fluorescence in the resection bed. In Part 1 of this study, the 
surgeon will proceed to biopsy suspected areas of residual or abnormal tissue or 
abnormal fluorescence without extending surgery beyond what is seen on the 
standard of care MRI. In Part 2 of this study, the surgeon will proceed to resect 
suspected areas of residual or abnormal tissue or abnormal fluorescence. These 
biopsy and/or resected sites will be correlated with the final pathology, which will 
be considered the gold standard. Fluorescence of the biopsy and/or resected 
specimen with the NIR imaging system will be studied both in vivo and ex vivo. In 
addition, surgeon’s judgment as to whether the biopsy and/or additional resection 
specimen represents tumor will be recorded in a binary outcome questionnaire 
(yes/no). 
 
Final View:  Last, prior to closing a final view of the cavity will be obtained with the 
NIR imaging system – Final View. 
 
Ex Vivo View:  Specimens will be placed in a specimen cup. These specimens 
will be imaged on a back table with the NIR imaging system. 
 
Once the tumor is resected, a small section of the path specimen will be divided 
and appropriately labelled: 1) histopathology, 2) research lab specimen. Each 
tissue sample will be placed in its own unique specimen cup. The tissue will be 
sent to pathology for standard processing, following OSHA and Institutional policy 
and procedures for tissue handling and transport. 
 
Of note, it is not always possible to be sure of diagnosis prior to surgical sampling 
and pathologic analysis. Nevertheless, all subjects and specimens will contribute 
to the final analysis. For example, if the subject is thought to harbor a malignant 


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glioma, but at the time of surgery, an intraoperative diagnosis of lymphoma is 
made, this subject’s pathology and indocyanine green fluorescence status will still 
contribute to the final analysis plan. 
6.4 Annual Assessments and Subject Follow-Up 
For a period of up to 5 years after enrollment, the PI and research team will review 
the subjects’ medical records annually to obtain information about their medical 
condition. Re-occurrence will be tracked with the subject’s oncologist. We utilize 
the standard protocol used by the oncologist for tracking re-occurrence, which 
includes, but is not limited to MRI, CT, or PET scans. 
6.5 Rescue Therapy 
There is a possibility of anaphylaxis in patients with iodide allergies and these 
patients are not considered candidates in this study. Anaphylaxis is a reversible 
condition when treated quickly, and our subject population is monitored at the time 
of injection (see Section 8.2). 
7 
Statistical Plan 
7.1 Primary Endpoint 
The primary endpoint is the sensitivity, specificity, positive predictive value, 
negative predictive value of indocyanine green fluorescence as compared to the 
gold standard – H&E histopathology. 
 
We compute estimates of the sensitivity (fraction of path-positive margins that are 
called correctly) and specificity (fraction of path-negative margins that are called 
correctly), and calculate Bayesian 90% probability intervals around them. We 
estimate the sensitivity of our method by evaluating the fraction of marginal biopsy 
and/or resected specimens that we call correctly, and similarly estimate the 
specificity by the fraction of path-negative biopsy and/or resected specimens that 
we call correctly. 
7.2 Secondary Endpoints 
For the secondary endpoint, we will use descriptive data on signal to background 
noise and safety data by tumor type to identify optimal dosing and timing of 
indocyanine green for intraoperative imaging in nervous system tumors. We will 
conduct an interim analysis after approximately 185 subjects are treated at the 
2.5mg dose and 185 at the 5mg/kg dose. 
 
Other important endpoints include safety and toxicity that includes review of vital 
signs and any reported or observed AE. 
7.3 Sample Size Determination 
There is no sample size calculation for this study as the purpose here is to assess 
safety and feasibility of using indocyanine green as an imaging agent for viewing 


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with NIR imaging systems during nervous system tumor surgery. To accomplish 
this goal, we propose a 500 patient non-randomized prospective design with 
annual follow-up for 5 years. This is intended to inform the design and planning of 
a future randomized study. 
7.4 Statistical Methods 
All data are summarized, with means and standard deviations for continuous 
variables and proportions for categorical variables. Graphical techniques will be 
used for data exploration. Analyses will be primarily descriptive. The remainder of 
the statistical approaches is described above. 
8 
Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
 
Unexpected in nature, severity, or frequency (i.e. not described in study-
related documents such as the Institutional Review Board (IRB)-approved 
protocol or consent form, the investigators brochure, etc.) 
 
Related or possibly related to participation in the research (i.e. possibly 
related means there is a reasonable possibility that the incident 
experience, or outcome may have been caused by the procedures 
involved in the research) 
 
Suggests that the research places subjects or others at greater risk of 
harm (including physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study. Intercurrent illnesses or 
injuries should be regarded as AEs. Abnormal results of diagnostic procedures are 
considered to be AEs if the abnormality: 
 
results in study withdrawal 
 
is associated with an SAE 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
A pre-existing condition should be recorded as an AE if the frequency, intensity or 
the character of the condition changes.  
 
Serious Adverse Event (SAE) 
Adverse events (AEs) are classified as serious or non-serious. An SAE is any AE 
that, in the view of either the investigator or the sponsor, is: 
 
fatal 
 
life-threatening 
 
requires or prolongs hospital stay 


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 
results in persistent or significant disability or incapacity 
 
a congenital anomaly or birth defect 
 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance. They may jeopardize the subject, and 
may require intervention to prevent one of the other serious outcomes noted 
above. For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious. 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-
serious adverse events. 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in 
the investigational plan or application, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an AE if the frequency, intensity, or the character 
of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition. At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an AE must also be recorded and 
documented as an AE. 
 
Post-study Adverse Event 
All unresolved AEs are followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the AE is otherwise explained. At the last 
scheduled visit, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization is documented 
and reported as an SAE unless specifically instructed otherwise in this protocol. 
Any condition responsible for surgery should be documented as an AE if the 
condition meets the criteria for an AE. 
 


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Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an AE in the following circumstances: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition. Surgery should not be 
reported as an outcome of an AE if the purpose of the surgery was elective 
or diagnostic and the outcome was uneventful. 
 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
 
Hospitalization or prolonged hospitalization for therapy of the target 
disease of the study, unless it is a worsening or increase in frequency of 
hospital admissions as judged by the clinical investigator. 
8.2 Expected Adverse Events and Treatment 
For all expected AEs, the treatment decisions would be to watchful wait, slow the 
rate of infusion or discontinue infusion, as appropriate. 
 
Anaphylactic or Urticarial Reactions 
Anaphylactic or urticarial reactions have been reported in patients with or without 
history of allergy to iodides. If such reactions occur, treatment with the appropriate 
agents (e.g., epinephrine, antihistamines, and corticosteroids) should be 
administered. 
 
Hypertension 
Infusion of indocyanine green may need to be stopped if patient becomes 
symptomatic at any level or, in the asymptomatic elevation of diastolic BP to >100 
or systolic BP >200. The PI/APP are notified when the BP elevations are reaching 
levels of concern. 
 
Mild Arm Discomfort/Pain 
If patients experience any arm/shoulder pain or discomfort at the IV site, the 
nursing staff are instructed to apply a hot pack or compress at the area of pain. 
Infusion of indocyanine green may need to be stopped if patient cannot handle 
pain or pain has not subsided. 
 
General Disorders 
If subjects become symptomatic (fatigue, headache, fever-like symptoms, itching, 
etc), the PI/APP would be consulted for treatment and infusion decisions. 
 
Administration Site Conditions 
If subjects experience tenderness or muscle spasms during the infusion, the 
nursing staff evaluates as necessary and provides hot pack/compress to the IV 
site. If subjects experience extravasation of the drug, the infusion may be changed 
to the other arm or discontinued. 
 
Gastrointestinal Disorders 
If subjects become nauseous during the infusion, the infusion is discontinued. 


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Impact of Indocyanine Green on Pulse Oximetry Readings 
A slight decrease of pulse oximetry readings is expected. To date, no treatment 
has been necessary, as pulse oximetry readings return to normal following 
completion of infusion. 
8.3 Recording of Adverse Events 
Safety is assessed by monitoring and recording potential adverse effects using the 
CTCAE Version 4.0 at each study visit. Participants are monitored by medical 
histories, physical examinations, and other studies. If CTCAE grading does not 
exist for an AE, the severity of mild, moderate, severe, life-threatening, and death, 
corresponding to Grades 1-5, is used whenever possible. 
 
At each contact with the subject, the investigator must seek information on AEs by 
non-directive questioning and, as appropriate, by examination. Adverse events 
may also be detected when they are volunteered by the subject during the 
screening process or between visits, or through physical examination, laboratory 
test, or other assessments. Information on all AEs should be recorded immediately 
in the source document, and also in the appropriate AE module of the case report 
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic 
procedures results are recorded in the source document, grouped under one 
diagnosis. 
 
As much as possible, each AE or follow-up information will be evaluated to 
determine: 
 
1. Severity grade (CTCAE Grade 1-5) 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – [Reasonable possibility that 
AE is related: No (unrelated/ not suspected) or Yes (a suspected adverse 
reaction)].  If yes (suspected) - is the event possibly, probably or definitely 
related to the investigational treatment?  
4. Expectedness to study treatment or process – [Unexpected – if the event 
severity and/or frequency is not described in the investigator brochure (if 
applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process 
(none, dose adjusted, temporarily interrupted, permanently discontinued, 
unknown, not applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug 
therapy, concomitant medication/non-drug therapy) 
7. Whether the event is serious 
 
All AEs occurring during the study period are recorded. The clinical course of each 
event is followed until resolution, stabilization, or until the cause is determined. 
Serious adverse events (SAEs) ongoing at the end of the study period are followed 
up to determine the final outcome. 


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8.4 Reporting of Serious Adverse Events (SAEs) and Unanticipated 
Problems 
Reporting period 
 
Adverse events are reported from the time of informed consent until study 
completion. For this study, study completion is defined as the conclusion of 
surgery. 
 
Investigator reporting: 
 
Every SAE, regardless of suspected causality (e.g., relationship to study drug(s) 
or study procedure or disease progression) is reported to the Pharmacovigilance 
Officer within 24 hours of learning of its occurrence. 
 
Recurrent episodes, complications, or progression of the initial SAE is reported as 
the follow-up to the original episode within 24 hours of the investigator receiving 
the follow-up information. An SAE considered completely unrelated to a previously 
reported one is reported separately as a new event. 
 
Send the notification (MedWatch or CIOMS form) to the Pharmacovigilance 
Officer. 
 
New information regarding the SAE is reported as it becomes available and in the 
same manner that the initial SAE (i.e. MedWatch or CIOMS). The investigator 
follows the event to resolution or until the event is deemed and documented 
irreversible, whichever is longer.  
 
Investigator Reporting: Local Reporting Requirements 
 
The investigator reports AEs and SAEs to his/her IRB of record and other local 
regulatory groups per the local requirements. 
8.5 Reporting Serious Adverse Events (SAEs) to the Data Safety Monitoring 
Committee (DSMC) at the Local PI site 
The following are reported to the DSMC:  
 All SAEs defined as reportable in the protocol. 
 All AEs grade 3 or higher within 10 days of knowledge. 
 All unexpected deaths within 24 hours of knowledge. 
 All other deaths within 30 days of knowledge. 
8.6 Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that 
study drug or device or process may have interfered with the effectiveness of a 
contraceptive medication or method. When a pregnancy is confirmed in a subject 
during maternal or paternal exposure to study drug and/or process, data on fetal 


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outcome should be collected for regulatory reporting and drug safety evaluation. 
Follow-up should be conducted for each pregnancy to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
8.7 Unblinding Procedures 
As this is an open-label study, there is no need to specify unblinding procedures. 
8.8 Medical Monitoring 
It is the responsibility of the PI to oversee the safety of the study at his site. This 
includes careful assessment and appropriate reporting of AEs. 
9 Data Handling, and Record Keeping 
9.1 Confidentiality 
Information about study subjects is kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). Those regulations require a signed subject authorization informing the 
subject of the following: 
 
 What protected health information (PHI) will be collected from subjects in 
this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their 
PHI. 
 
The potential subjects are reassured that their personal information is protected by 
de-identifying study documents by replacing the subject’s identifiable information 
with a unique subject ID number. In an effort to protect each subject’s privacy, the 
study coordinator maintains an enrollment log on an encrypted hard-drive that links 
the subject ID number with the subject’s name, date of birth (DOB), and gender. 
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization. For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
9.2 Data Collection and Management 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of 
the trial. Source data are contained in source documents. Examples of these 


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original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies 
or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical trial. 
 
The study CRF in RedCap and Penn CTMS, for all safety information, is the 
primary data collection instrument for the study. All data requested on the CRF 
must be recorded. All missing data must be explained. If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, 
write “N/D”. If the item is not applicable to the individual case, write “N/A”. All entries 
should be printed legibly in black ink. If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it. All such changes must be initialed and dated. DO NOT 
ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
 
Subject study data is entered into an excel database as well as a RedCap 
database. Data will be stored on-site for 5 years after the last follow-up visit. After 
5 years, it may be archived. Data will be de-identified and each subject will be 
given a subject identification (ID) number immediately after consent is signed and 
they are enrolled in the study. Only the study staff will have access to the identifying 
information that would link the subject to their unique study ID number; this 
information will be kept in a secure location. 
9.3 Records Retention 
It is the investigator’s responsibility to retain study essential documents per Penn 
policy. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study is monitored according to the monitoring plan in Section 15. The 
investigator allocates adequate time for such monitoring activities. This study will 
be audited by the Department of Compliance and Monitoring on behalf of the ACC 
Data and Safety Monitoring Committee every 6 months from the first subject 
enrolled and every 6 months thereafter for the life of the study. The Investigator 
ensures monitors or other compliance or quality assurance reviewers are given 
access to all noted study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 


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10.2 Auditing and Inspecting 
The investigator permits monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.). The investigator ensures 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of inspection by 
government regulatory authorities and applicable University compliance and 
quality assurance offices. 
10.3 Reporting of Exceptions and Deviations 
Exception 
 
A one time, intentional action or process that departs from the IRB and Clinical 
Trials Scientific Review and Monitoring (CTSRMC) approved study protocol, 
intended for one occurrence. If the action disrupts the study progress, such that 
the study design or outcome may be compromised, or the action compromises the 
safety and/or welfare of study subjects, advance documented approval per 
institutional guidelines, is required. 
 
Deviation 
 
A one time, unintentional action or process that departs from the IRB and 
CTSRMC approved study protocol, involving one incident and identified 
retrospectively. If the deviation disrupts the study progress, such that the study 
design or outcomes may be compromised, or the deviation compromises the 
safety and/or welfare of study subjects, the deviation must be reported to the 
CTSRMC within 5 business days of PI knowledge and to local regulatory review 
committees per institutional guidelines. 
 
Report the following information on the exception/deviation form: 
 
 Protocol number 
 Subject number 
 Description of the exception or deviation 
 Impact on subject safety 
 Impact on data integrity  
 
Deviations that are assessed by the PI to not disrupt the study progress, such as 
not affecting the study design or outcome, or compromising the safety and/or 
welfare of study subjects, should be documented in site records and contain 
documentation of the PI’s assessment. 


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11 Ethical Considerations 
This study is to be conducted according to US and international standards of GCP 
(FDA Title 21 part 312 and ICH guidelines), applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent IRB, in agreement with local legal prescriptions, for formal approval 
of the study conduct. The decision of the IRB concerning the conduct of the study 
will be made in writing to the investigator before commencement of this study. 
11.1 Informed Consent Process / HIPAA Authorization 
After a patient is determined to be a good candidate for the study, the informed 
consent / HIPAA authorization process is conducted by the PI or treating physician 
in their clinic. The potential subject is given the consent form to go over in detail 
during the initial consultation visit. He/she is encouraged to ask questions 
throughout the consent process and is given adequate time afterwards to ask any 
additional questions about the study. If the patient agrees to participate, the PI or 
treating physician obtains consent from patient and prints, signs, and dates the top 
line of the informed consent form. The consent form is given to the patient to print, 
sign, and date on the second line of the consent form. Documentation of this 
process occurs in each subject’s electronic medical record in the office note of the 
day that consent was obtained. 
12 Study Finances 
12.1 Funding Sources 
This clinical trial is being funded through a Penn Medicine Neuroscience Center 
Grant. 
12.2 Conflict of Interest 
All University of Pennsylvania Investigators follow the University of Pennsylvania 
Policy on Conflicts of Interest Related to Research. The Investigator states conflict, 
if any. 
13 Publication Plan 
No part of this study will be published without conformation with the Department of 
Neurosurgery of the University of Pennsylvania standards for publishing. 
14 References 
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2. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: 
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53. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208630s000l
bl.pdf  
15 Attachments 
 Study Flowchart 
 CRFs 
 DSMP 
 Informed Consent Form (ICF) 
 Equipment 
 

ICF_001.pdf: 
17-December-2019 
  
1 of 10 
UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT & HIPAA AUTHORIZATION FORM 
 
 
Protocol Title:   
Two-Part Study to Evaluate the Safety and Efficacy of Image 
Guided Surgery using Near-Infrared dyes for Intramolecular 
Imaging of Nervous System Tumors Compared to Standard of 
Care, (TumorGlow™) 
Principal Investigator:
John Lee, MD
Department of Neurosurgery
235 S 8th Street
Philadelphia, PA 19106 
#215-829-6700 
Emergency Contact: 
Neurosurgery Resident On-call 
215-829-3000  
Why am I being asked to volunteer? 
You are being invited to participate in a research study because you are having brain, spine, or 
peripheral nerve (nervous system) tumor surgery. Your participation is voluntary which means 
you can choose whether or not you want to participate. If you choose not to participate, there 
will be no loss of benefits to which you are otherwise entitled. Before you can make your 
decision, you will need to know what the study is about, the possible risks and benefits of being 
in this study, and what you will have to do in this study. The research team is going to talk to 
you about the research study, and they will give you this consent form to read. You may also 
decide to discuss it with your family, friends, or family doctor. You may find some of the medical 
language difficult to understand. Please ask the study doctor and/or the research team about 
this form. If you decide to participate, you will be asked to sign this form. 
What is the purpose of this research study? 
 
The purpose of this study is to determine if an intravenous injection of indocyanine green 
detected by using an imaging system can be a useful tool to identify tumor from normal tissues. 
In addition, this study will assess whether a dose of indocyanine green larger than is currently 
approved is safe to use. Indocyanine green has been used in a clinical setting for over sixty (60) 
years for mapping the blood vessels of the eye, liver blood flow tests, and heart function tests. 
Because the drug has not been approved for use in the manner in which we are proposing, this 
research is considered experimental. 
 
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How long will I be in the study?  
 
Your participation in the study will last from your screening visit until the end of your surgery 
(approximately 2-4 weeks). However, at the conclusion of your active participation, we will 
collect your health information for a period of up to five (5) years. You will not have to return to 
the hospital for this portion of the study. The Principal Investigator and research team will 
review your medical records for the period of up to five (5) years to obtain information about 
your medical condition. The study as a whole is expected to last about five years. We expect to 
enroll a total of 500 patients from The University of Pennsylvania Heath System. 
 
What am I being asked to do? 
 
Administration of NIR drug: 
Permitting infusion time within 72 hours of operation is believed by the Investigator to be 
adequate for tissue glow/surgical visualization. Data analysis will determine optimal timing of 
indocyanine green infusion. For your operation you will go to either the Hospital of University of 
Pennsylvania (HUP); Perelman Center for Advanced Medicine Clinical & Translational Research 
Center, 3400 Civic Center Blvd., Philadelphia PA, 19104 or the Abramson Cancer Center at 
Pennsylvania Hospital (PAH), 230 W. Washington Square, Philadelphia PA, 19106 or the 
Abramson Cancer Center at Penn Presbyterian Medical Center (PPMC), 1st floor CUPP Building, 
51 N 39th St, Philadelphia, PA 19104 to receive a single dose of indocyanine green. This 
indocyanine green dose is within range of other research studies (including studies with the 
liver). The nurse will place a peripheral IV (intravenous catheter) for the indocyanine green 
infusion. The injection of the indocyanine green is expected to take about 40 to 60 minutes. 
You will be monitored before, during and after the injection for signs of anaphylaxis (see below).
Alternately, based on neurosurgeon plan, patients may receive a 25 mg bolus of ICG at the time 
of induction administered intravenously by the anesthesiologist. 
Standard of care dyes such as Gleolan, is the first and only FDA approved optical imaging agent 
for use in Fluorescence-Guided Surgery. Gleolan™ [aminolevulinic acid hydrochloride (ALA HCl)] is 
an optical imaging agent indicated in patients with glioma (suspected World Health Organization 
Grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue 
during surgery. It is orally administered 2-4hours prior to anesthesia.  
 
In this current study, we may intend to compare SOC dyes with indocyanine green to find out 
which dye is more accurate and precise. This may lead to patients receiving more than one (1) 
drug prior surgery and visualizing the tumor with different cameras during surgery. This may result 
in added time to your surgical procedure. 
 
There are no additional risks of administering both dyes together. In this study, there is no 
anticipated risk by extending the surgical procedure and imaging both dyes together. 
When you return for your operation, during your surgery for a period of five (5) to ten (10) 
minutes, before resection, during resection, and after resection, the surgeon will take video 
images of your tumor with a specialized imaging system. 
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Once the tumor is removed, if the surgeon sees any remaining glowing tissue, he/she will resect 
the area if it is safe to do so. There may be instances that the area cannot be removed or 
biopsied without significantly changing the operation, specifically for safety concerns. In that 
event, the nodule will be left in place. Once the tumor is removed, a small section of the tissue 
will be sent to pathology for standard processing. The imaging procedure is expected to add 
another five (5) to ten (10) minutes to the time your operation would normally last. Indocyanine 
green is typically eliminated by the liver. Weight, height, age, overall health, etc. all factor into 
how fast your body eliminates the indocyanine green. 
 
The injection and recording of the indocyanine green activity with the imaging machines, along 
with removal of tissue that will be glowing, are the only experimental procedures to be 
performed in this study. 
 
For a period of up to five (5) years after your enrollment in this clinical study, the Principal 
Investigator and research team will review your medical records to obtain information about 
your medical condition. 
 
What are the possible risks or discomforts?  
 
Indocyanine Green Risks/Discomfort: 
Indocyanine green is known to have a rare but serious side effect known as anaphylaxis, a form 
of allergic reaction, especially in patients with iodide allergies. For example, iodides are found in 
shellfish. If you have an allergy to iodides, you will not be allowed to participate in this study. 
Anaphylaxis 
Anaphylaxis is an allergic reaction to a substance, which can cause inflammation (swelling) of 
the skin, shortness of breath, dizziness, increased heart rate, rash, and possibly death. As you 
will be given indocyanine green in a procedure room with trained nurses, you will be closely 
monitored for anaphylaxis via steady collection of your heart rate, blood pressure, oxygen levels 
and skin color. In the event of an anaphylactic reaction, injection will be stopped and drugs will 
be used to control the reaction. 
Hypertension 
Infusion of indocyanine green may need to be stopped if you have symptoms of hypertension 
(high blood pressure) at any level or, do not have symptoms but your diastolic blood pressure is 
elevated >100 or systolic >200. The doctor is notified when the BP elevations reach levels of 
concern. 
 
Mild Arm Discomfort/Pain 
Subjects may experience arm/shoulder pain or discomfort at the site of infusion. If this occurs, 
the nursing staff will apply a hot pack or compress at the area of pain. Infusion of indocyanine 
green may be stopped if the pain is too great or the pain has not stopped. 
 
General Disorders 
Other symptoms, such as fatigue (getting tired), headache, fever-like symptoms, itching, etc., 
may occur. The doctor will be consulted for treatment and infusion decisions. 
 
 
 
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Administration Site Conditions 
Subjects may experience tenderness or muscle spasms during the infusion.  If this occurs, the 
nursing staff will evaluate as necessary and provide a hot pack/compress to the IV site. If you 
experience extravasion of the drug, the infusion may be changed to the other arm or 
discontinued. 
 
Gastrointestinal Disorders 
Subjects may become nauseous during the infusion. If this occurs, the infusion is discontinued. 
 
Impact of Indocyanine Green on Pulse Oximetry Readings 
Subjects may experience a slight decrease of pulse oximetry readings (blood oxygen level). To 
date, no treatment has been necessary, as pulse oximetry readings return to normal following 
completion of infusion. 
 
Video Imaging 
The video images that we will take may result in your surgeon changing your operation. Your 
surgeon will not change the magnitude of the operation to do anything that was not described 
to you when you agreed to undergo the surgery. If the surgeon images your tumor with multiple 
cameras and/or NIR dyes, your surgical procedure may be extended. However, your surgeon will 
keep the imaging to 15 minutes. 
 
However, because the video images are being taken as part of a research study, they do come 
with some risks: 
 
 
There is a chance that an area that does not have any tumor will glow in the video 
images. If that happens, your surgeon may remove healthy tissue that did not need to 
be removed and that would not have been removed in a standard surgery. 
 
There is a chance that while removing additional tissue that glows in the video images 
you could be put at an increased risk of having a surgical complication. 
 
Finally, there is a chance that the imaging technique may falsely reassure the surgeon that all of 
the tumor has been taken out, so not as much tissue will be removed. In other words, not all of 
the tumor could be taken out. 
 
Your surgeon will do everything possible to minimize these risks. If your surgeon thinks that 
removing the additional tissue is too risky, they will not remove the additional tissue. 
 
Risks of Gleolan (aminolevulinic acid hydrochloride (ALA HCI) (5-ALA): 
• 
Adverse reactions occurring in >1% of patients in the week following surgery were 
pyrexia, hypotension, nausea, and vomiting.   
• 
Adverse reactions occurring in < 1% of patients in the first 6 weeks after surgery were: 
chills, photosensitivity reaction, solar dermatitis, hypotension, abnormal liver function 
test, and diarrhea.    
• 
Neurologic events related to the surgical procedure occurred in 29% of patients and 
included:  aphasia, hemiparesis, hemianopia, headache, seizure, hemiplegia, 
monoparesis, hypoesthesia, and brain edema.   
• 
Elevated liver enzymes occurred in clinical studies. 
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Surgical Complication 
A surgical complication includes, but is not limited to: 
 
 
Impaired brain function, bleeding, infection, pain, injury to a major organ, nerve 
damage, blood clot in the arms/legs/other region of the body, and death. 
 
 
Risk of Anesthesia 
There is a chance that being under anesthesia for the additional fifteen (15) to twenty (20) 
minutes, you could be put at an increased risk of having of a common side effect associated with 
anesthesia. These common side effects include, but are not limited to: 
 
 
Nausea and vomiting after surgery, sore throat and hoarseness, shivering/chills, 
confusion, increased blood pressure and muscle aches. 
 
Reproductive Risks
Indocyanine green has no known side effects to a pregnant or nursing mother. Indocyanine 
green does not have any known fetal toxicity. Nevertheless, we are NOT enrolling pregnant or 
nursing mothers in the study. If you are currently pregnant, it is important that you inform the 
investigator because you will not be able participate in the study. If you are able to become 
pregnant, you will be given a blood or urine pregnancy test before entry into the study. If the 
test is positive, you will not be able to participate in this study. 
It is possible that there are additional risks involved with the use of indocyanine green and/or 
gleolan that are unknown at this time. 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to you. 
This includes information that, once learned, might cause you to change your mind about being 
in the study. We will notify you as soon as possible if such information becomes available. 
 
What are the possible benefits of the study? 
Most likely, no direct medical benefit will come to the subjects of this research project. The 
proposed study may generate important data regarding your tumor and prognoses. We do not 
know whether these video images truly identify tumor however, there is a chance that because 
of the video images your surgeon will remove additional tumor that they would not have 
removed during a standard operation. Pathology will occur on any “glowing” tissue that is 
removed and an official report will be generated. 
In addition, your participation may make it possible for future patients diagnosed with tumors to 
benefit from the information that we collect during your participation. 
What other choices do I have if I do not participate?  
Your other option is to not participate in this study. Your decision to participate will in no way 
affect your care. Alternative treatment/surgery to being in this study can be discussed with your 
personal physician. 
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Will I be paid for being in this study? 
You will not be paid for your participation in this study.
Will I have to pay for anything? 
You will not have to pay for the study medications or costs directly relating to the experimental 
procedure. 
You and/or your health insurance may be billed for the costs of medical care during this study if 
these expenses would have happened even if you were not in the study.
What happens if I am injured from being in the study? 
 
We will offer you the care needed to treat injuries directly resulting from taking part in this 
research. We may bill your insurance company or other third parties, if appropriate, for the 
costs of the care you get for the injury, but you may also be responsible for some of them. 
 
There are no plans for the University of Pennsylvania to pay you or give you other compensation 
for the injury. You do not give up your legal rights by signing this form. 
 
If you think you have been injured as a result of taking part in this research study, tell the person 
in charge of the research study as soon as possible. The researcher’s name and phone number 
are listed in the consent form. 
 
When is the Study over? Can I leave the Study before it ends? 
 
This study is expected to end after all participants have completed all visits, and all information 
has been collected. This study may also be stopped at any time by your physician, the study 
Sponsor, or the Food and Drug Administration (FDA) without your consent because: 
 
 
The Primary Investigator feels it is necessary for your health or safety. Such an action 
would not require your consent, but you will be informed if such a decision is made and 
the reason for this decision. 
 
You have not followed study instructions. 
 
The Sponsor, the study Principal Investigator, or the Food and Drug Administration 
(FDA) has decided to stop the study. 
 
If you decide to participate, you are free to leave the study at any time. Withdrawal will not 
interfere with your future care. 
 
Who can see or use my information? How will my personal information be protected? 
 
We will do our best to make sure that the personal information obtained during the course of this 
research study will be kept private. However, we cannot guarantee total privacy. Your personal 
information may be given out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. If 
this study is being overseen by the Food and Drug Administration (FDA), they may review your 
research records. Your privacy and the protection of your health information are important to us. 
This section of the consent will cover: 
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What personal health information about you will be collected in this study? 
 
Who will use your information within the institution and why? 
 
Who may disclose your information and to whom? 
 
Your rights to access research information about you. 
 
Your right to withdraw your authorization (approval) for any future use of your personal 
health information. 
 
What Information about me may be collected, used or shared with others?
 
The following personal health information will be collected, used for research and may be 
disclosed or released during your involvement with this research study. 
 
 
Name 
 
Address 
 
Telephone Number 
 
Elements of dates 
 
Medical Record Number 
 
Results of information used in the management or diagnosis of your tumor, 
including history, physical and neurologic examination, laboratory studies, 
and/or imaging studies 
Personal Medical History, current and past medications or therapies
 
Previous advanced imaging that may have been collected outside of the 
University of Pennsylvania Hospital 
 
Why is my information being used? 
 
Your information is used by the research team to contact you during the study. Your information 
and results of tests and procedures are used to: 
 
 
do the research 
 
oversee the research 
 
to see if the research was done right 
 
to evaluate and manage research functions. 
 
Who may use and share information about me? 
 
The following individuals may use or share your information for this research study: 
 
 
The Principal Investigator and the Investigator’s Study team (other PA Heath System 
staff associated with the study). 
 
The Center for Precision Surgery at the University of Pennsylvania. 
 
The University of Pennsylvania’s Institutional Review Boards (the committees charged 
with overseeing research on human subjects) and the University of Pennsylvania Office 
of Regulatory Affairs. 
 
The University of Pennsylvania Office of Human Research (the office that monitors 
research studies). 
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Authorized members of the University of Pennsylvania and the University of 
Pennsylvania Health system and School of Medicine workforce who may need to access 
your information in the performance of their duties (for example, to provide treatment). 
 
Who, outside of the School of Medicine, might receive my information? 
 
Oversight organizations
 
The Food and Drug Administration 
 
The Office of Human Research Protections 
 
Once your personal health information is disclosed to others outside the School of Medicine, it 
may no longer be covered by federal privacy protection regulations. 
 
The Principal Investigator or study staff will inform you if there are any additions to the list above 
during your active participation in the trial. Any additions will be subject to University of 
Pennsylvania procedures developed to protect your privacy. 
 
How long may the School of Medicine use or disclose my personal health information? 
 
Your authorization for use of your personal health information for this specific study does not 
expire. 
 
Your information may be held in a research database. However, the School of Medicine may not 
re-use or re-disclose information collected in this study for a purpose other than this study unless: 
 
 
You have given written authorization 
 
The University of Pennsylvania’s Institutional Review Board grants permission 
 
As permitted by law 
 
Can I change my mind about giving permission for use of my information? 
 
Yes. You may withdraw or take away your permission to use and disclose your health information 
at any time. You do this by sending written notice to the investigator for the study. If you withdraw 
your permission, you will not be able to stay in this study. 
 
What if I decide not to give permission to use and give out my health information? 
 
Then you will not be able to be in this research study. 
 
You will be given a copy of this Research Subject HIPAA Authorization describing your 
confidentiality and privacy rights for this study. 
 
By signing this document, you are permitting the School of Medicine to use and disclose personal 
health information collected about you for research purposes as described above. 
 
In order to protect patient privacy, once you sign informed consent you will be given a study ID 
number. You will be identified by your study ID number and initials listed, not your name, date of 
birth or medical record number. If any publications arise from this study, you will not be identified 
by name or any other personal identifier. The link to this data set will be maintained by the 
Neurosurgery Clinical Research Division in a password-protected database. 
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Electronic Medical Records and Research Results 
 
What is an Electronic Medical Record? 
 
An Electronic Medical Record (EMR) is an electronic version of the record of your care within a 
health system. An EMR is simply a computerized version of a paper medical record. 
 
A clinical trial management system (CTMS) is used to register your information as a participant 
in a study and to allow for your research data to be entered/stored for the purposes of data 
analysis and any other required activity for the purpose of the conduct of the research. 
 
If you are receiving care or have received care within the University of Pennsylvania Health 
System (UPHS) (outpatient or inpatient) and are participating in a University of Pennsylvania 
research study, results of research-related procedures (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in your existing EMR maintained by UPHS. Information 
related to your participation in clinical research will also be contained in the CTMS. 
 
If you have never received care within UPHS and are participating in a University of Pennsylvania 
research study that uses UPHS services, an EMR will be created for you for the purpose of 
maintaining any results of procedures performed as part of this research study. The creation of 
this EMR is required for your participation in this study. In order to create your EMR, the study 
team will need to obtain basic information about you that would be similar to the information 
you would provide the first time you visit a hospital or medical facility (i.e. your name, the name 
of your primary doctor, the type of insurance you have). Results of research procedures 
performed as part of your participation in the study (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in this EMR. 
 
Once placed in your EMR, these results are accessible to appropriate UPHS workforce members 
that are not part of the research team. Information within your EMR may also be shared with 
others who are determined by UPHS to be appropriate to have access to your EMR (e.g. health 
insurance company, disability provider, etc.). 
 
Who can I call with questions, complaints or if I’m concerned about my rights as a research 
subject? 
 
If you have questions, concerns or complaints regarding your participation in this research study 
or if you have any questions about your rights as a research subject, you should speak with the 
Principal Investigator listed on page one of this form. If a member of the research team cannot 
be reached or you want to talk to someone other than those working on the study, you may 
contact the Office of Regulatory Affairs with any question, concerns or complaints at the 
University of Pennsylvania by calling (215) 898-2614. 
 
 
 
 
 
When you sign this form, you are agreeing to take part in this research study. This means that 
you have read the consent form, your questions have been answered, and you have decided 
to volunteer. Your signature also means that you are permitting the University of 
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Pennsylvania to use your personal health information collected about you for research 
purposes within our institution. You are also allowing the University of Pennsylvania to 
disclose that personal health information to outside organizations or people involved with 
the operations of this study.
A copy of this consent form will be given to you. 
 
___________________________             ______________________________________ 
Name of Subject (Please Print)               Signature of Subject  
 
Date/Time 
 
 
________________________ 
             _______________________________________ 
Name of Person Obtaining 
              Signature                                  
       Date/Time 
Consent (Please Print) 
 
 
________________________                   _______________________________________ 
PI Name  
 
 
 
PI Signature                                          Date/Time 
(Please Print) 
 
 
________________________ 
 
 
_______________________________________ 
Name of Legal Authorized Representative 
Signature                                         Date/Time 
(Please Print) 
 
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