Clinical trial NCT03058705
Conditions: Bladder Cancer
Sponsor: Edward Messing
Start date: 2017-11-28; Completion date: 2018-07-25
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary outcome of this study is to determine the minimal dwell time needed for adequate detection of hexaminolevinulate HCL avid tumors using protoporphyrin IX (PpIX) near infrared fluorescence (NIRF).

Detailed description:

Arms: arm 1: During the transurethral resection of the bladder procedure, the bladder will initially be examined in a systematic meridian fashion. Suspicious tumors identified by white light only, NIRF only, and both will be identified. If intense fluorescence is observed in the initial patient(s) at 10 min, dwell duration will be reduced to 5 min for the next patient(s); if abundant fluorescence is detected there as well, dwell duration will be shortened again to 2.5 min. At least three patients will be studied at each duration to document intense fluorescence before proceeding to shorter instillation durations in subsequent patients.
Interventions: intervention 1: Hexaminolevulinate HCL intervention 2: Near Infrared Fluorescence (NIRF)
Intervention descriptions: intervention 1: Intravesical instillation of 100 mg hexaminolevulinate HCL will be performed via foley catheter at the initiation of the procedure. Although NIRF is more sensitive than bluelight cystoscopy, the current FDA approved dose will be used. Hexaminolevulinate has a favorable safety profile at this dose. intervention 2: NIRF is a highly sensitive multi-spectral imaging modality that speeds the detection of bladder cancer fluorescence after infusion of hexaminolevinulate.

Protocol documents:
Prot_SAP_000.pdf: 
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Department of Urology 
 
NCT03058705 
Pilot Study: Assessing Near Infrared Fluorescence Imaging Medical Technology 
for the Detection of Bladder Cancer 
 
Principal Investigator: Edward Messing, MD, FACS 
 
(Department of Urology) 
 
 


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1. PURPOSE OF THE STUDY AND BACKGROUND 
 
1.1. Purpose of the study 
 
Primary Aim 
The primary outcome of this study is to determine the minimal dwell time needed for 
adequate detection of Cysview avid tumors using protoporphyrin IX (PpIX) near 
infrared fluorescence (NIRF). 
 
Secondary Aim 
To determine in vivo the ratio of intensity of near infrared fluorescence (NIRF) signal 
arising from the tumor compared to that arising from normal tissue as a function of 
dwell time.  
 
1.2. Background 
 
Bladder cancer is the fifth most commonly diagnosed solid malignancy in the United 
States, with patients experiencing multifocal occurrences/recurrences even after 
seemingly successful treatment of non-muscle invading urothelial cancer.  There is 
level 1 evidence that more complete tumor eradication results in patients experiencing 
fewer recurrences [1, 2].  Bladder cancer is the most costly malignancy to treat over 
the lifetime of patients in large part because of the need for multiple re-treatments and 
surgeries as well as lifelong endoscopic surveillance [3].  Thus, a practical way to 
improve tumor detection and removal will not only benefit individual patients but also 
should reduce the overall cost of managing this malignancy. 
 
One method that improves the completeness of transurethral resection of bladder 
tumors (TURBTs) utilizes intravesical administration of the hematoporphyrin derivative 
Cysview™ (brand name Hexvix™ elsewhere) to detect tumors not readily visualized 
with standard white light cystoscopy.  Tumor lesions are visualized intra-operatively by 
shining a blue light throughout the bladder that excites the resultant intracellular PpIX 
to emit red fluorescence; tumor cells exhibit a lower clearing rate of PpIX because of 
altered catabolism and transport [4-6], thus it accumulates and permits differential 
visualization. 
 
Standard of care at UR for diagnosis of bladder tumors consists of white light 
cystoscopy only in office and then in OR where tumor is biopsied or resected.  
Fluorescence (blue light cystoscopy) is rarely done in large part because it requires 
preoperative catheter passage and drug (Cysview) instillation for 60 minutes before 
surgery (causes patient discomfort) and the actual operation is lengthened.  While this 
technique is efficacious, it requires expensive special equipment, a need to examine 
the bladder under both white to blue light repeatedly during the case, and the solution 
(Cysview™) must be instilled 60 minutes before the procedure via a catheter. This 
inconvenient requirement leads to delay and greater expense for the facility as well as 
prolonging patient discomfort and apprehension.  For these reasons, blue light 
cystoscopy has not been as widely adopted as one might expect given its clear 
benefits [1, 2]. 
 


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We hope to eliminate the obstacles to better care by employing new and more 
sensitive imaging technologies that should enable more rapid tumor identification and 
a reduction in bladder dwell time.  Agent administration could be done in the operating 
room just minutes before cystoscopy is performed.  We will achieve this by using 
highly sensitive imaging technologies similar to those used in astronomy to detect near 
infrared fluorescence (NIRF); this imaging system will detect NIRF emitted by PpIX. 
Note that conventional blue light cystoscopy detects the red fluorescence emitted by 
PpIX.  This enables two significant advances.  First, NIRF can be elicited by white light 
excitation alone, so there is no need to use separate blue light excitation.  Second, the 
white light image can be simultaneously acquired (viewed and/or recorded) with the 
NIRF image, so there is no need for switching between the blue light and the white 
light imaging modes as in conventional blue light cystoscopy.  
 
Thus, this new technology will obviate the need for pre-anesthetic urethral 
catheterization, the hour wait in the pre-anesthetic area.  This reduction in dwell time is 
made possible by the increased sensitivity of NIRF imaging to PpIX florescence.  We 
have found ex-vivo the NIRF imaging is well over 10 times more sensitive to Cysview 
florescence than standard blue light cystoscopy.  Ex-vivo preliminary studies have 
shown that blue light cystoscopy can detect PpIX concentrations 1 microgram per 
milliliter.  In contrast, NIRF imaging was able to detect PpIX concentrations down to 
0.01 microgram per milliliter, a 100 fold difference (Appendix 4).  In addition, as this 
imaging technology utilizes existing conventional white light cystoscopes, it also averts 
the requirement for current costly and single purpose blue light generating equipment 
that cannot be used for other endoscopic procedures. 
 
Many large tumors are readily seen with white light, and we expect to visualize large 
tumor fluorescence in a few minutes with the new system. 
 
 
2. STUDY DESIGN 
 
2.1. Overview 
 
The study will be a single center prospective nonrandomized trial of an investigational 
imaging technology.  All patients will undergo investigational imaging and concomitant 
standard of care transurethral resection of bladder tumor (TURBT).  Patients with 
suspected bladder cancer on cystoscopy will be enrolled to have subsequent 
intraoperative intravesical administration of Cysview and NIRF cystoscopy immediately 
prior to TURBT. 
 
2.2. Rationale for Study Design 
 
Although studies have evaluated optimal dwell time for Cysview fluorescence when 
cystoscopy is performed under blue light, the optimal dwell time for NIRF visualization 
has not been determined.  Prior to conducting randomized studies comparing efficacy 
of NIRF and blue light we must first establish that a useful and short dwell time can in 
fact be used successfully.  This pilot study will allow us to identify a dwell time for 
subsequent NIRF cystoscopy studies. 
 


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Because from a practical point of view, that is the longest time period we want to 
prolong surgery with a product that should equal or improve on current blue light 
cystoscopy.  We use blue light very selectively now for these reasons:  The Dwell 
study and the subsequent research that comes from it – should permit avoidance of 
the pre-op catheterization and significantly shorten the procedure.  We have found ex-
vivo the NIRF imaging is well over 10 times more sensitive to Cysview florescence and 
should have no problem with visualization at 10 minutes. 
 
 
2.3. Rationale for Dosage 
 
Intravesical instillation of 100 mg Cysview (hexaminolevulinate hydrochloride) will be 
performed via foley catheter at the initiation of the procedure.  Although NIRF is more 
sensitive than blue light cystoscopy, we will use the current FDA approved dose.  
Cysview has a favorable safety profile at this dose. 
 
 


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2.4. Equipment 
This protocol relies on intravesical administration of an FDA-approved agent for 
bladder cancer detection (Cysview™) that fluoresces upon illumination with an FDA-
approved cystoscopic white light source.  Standard light sources emit near-infrared 
wavelengths that would interfere with detecting NIRF, so the cystoscopy light source is 
filtered to block these wavelengths and thus improve the signal to noise ratio.  A 
standard (FDA-approved) cystoscope is introduced into the bladder and used to guide 
resection of any detected tumors, i.e. Trans Urethral Resection of Bladder Tumors 
(TURBT). Color and near-infrared image streams will be recorded.  The surgeon will 
be able to display white light images, white light images with pseudocolor highlighting 
the near-infrared fluorescent tumor, a NIRF image, or a combination of images. 
 
 
 
 
 
 
 
 
 
 
 
FDA-approved 
white light cystoscopy light 
source provides 
illumination 
Imaging system 
(optics and cameras) 
FDA-approved cystoscope 
Near-infrared light blocked  
Bladder  


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3. CHARACTERISTICS OF THE RESEARCH POPULATION 
 
3.1. Subject Characteristics 
 
a) Number of Subjects: 
 
We will enroll 20 subjects to get 10 evaluable subjects in the study.  It is expected 
there may be a high withdrawal rate due to the availability of the study team to all 
be present on the subject’s surgery date. 
 
b) Gender and Age of Subjects: 
 
Male and female patients who are 18 years or older will be included.  Cysview is 
equally efficacious and safe across both sexes.  There is no scientific or medical 
justification to restrict inclusion of the adult population further by age. 
 
c) Racial and Ethnic Origin: 
 
There is no restriction of or subject population based on racial or ethnic grounds. 
 
d) Vulnerable Subjects:  
 
No vulnerable subjects will participate in this study. 
 
 
3.2. Inclusion and Exclusion Criteria 
 
a) Inclusion Criteria:   
• 
Diagnosis of bladder mass on office cystoscopy suspicious for malignancy, 
either newly diagnosed or a recurrent tumor 
• 
Planned transurethral resection of bladder tumor in the operating room 
• 
Men or women (age 18 or older) 
• 
Any racial or ethnic origin 
• 
Ability to give informed consent 
 
b) Exclusion Criteria:  
• 
Pregnancy 
• 
Nursing mother 
• 
Diagnosis of porphyria 
• 
Gross hematuria 
• 
BCG immunotherapy or intravesical chemotherapy within the past 90 days 
• 
Known hypersensitivity to hexaminolevulinate or any derivative of 
aminolevulinic acid 
 
 


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3.3. Discussion of Subject Population 
 
The inclusion/exclusion criteria will be representative of the population that would 
benefit from reduced Cysview dwell time provided by NIRF cystoscopy.  Patients will 
be excluded based upon the known contraindications for Cysview. 
 
 
4. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
 
4.1. Method of Subject Identification and Recruitment 
 
Subjects will be identified through eRecord or clinic schedules by the study team and 
will be recruited from the clinical offices in the Urology Department at the University of 
Rochester. 
 
 
4.2. Process of Consent 
 
A member of the study team with routine access to all UR Urology patients will identify 
potential subjects via eRecord or clinic schedules.  Once a potential subject is 
identified and the urologist notified, the study team will introduce the study at a 
scheduled clinic visit and check for interest in participation.  If interested, eligible 
subjects may be enrolled at this visit.  If potential subjects wish to take the consent 
form home to read and review with family or friends, a member of the study team will 
call the patient to check their interest in participation and answer any questions they 
may have about the study.  Informed consent will then be obtained by a member of the 
study team at their pre-operative visit (see Schedule of Activities – Appendix I).   
 
Subjects will be reminded that they can elect not to participate without risking loss of 
any present they would normally receive.  Any questions the subject may have will be 
answered.  A copy of the signed consent form will be given to the subject and the 
original consent form will be placed in the research record.  All research records will be 
accessed by the study team and stored in a locked office of the study team.  Consent 
will be obtained in a private setting with a closed door to ensure privacy. 
 
 
5. METHODS AND STUDY PROCEDURES 
 
The study will be a single center prospective nonrandomized trial of an investigational 
imaging technology.  All patients will undergo investigational imaging and the 
concomitant standard of care, i.e. transurethral resection of bladder tumor (TURBT).  
Patients with suspected bladder cancer on cystoscopy will be enrolled to have 
subsequent intraoperative intravesical administration of Cysview and NIRF cystoscopy 
prior to TURBT. 
 
Ten patients will be recruited to demonstrate the feasibility of using this NIRF imaging 
system at shorter intravesical instillation durations (Cysview™ dwell time).  The 
instillation duration will be 10, 5, or 2. 5 minutes in this patient series.  The subject will 
be anesthetized, positioned, prepped, and draped for the white light TURBT.  A 
catheter will be passed, Cysview instilled, and the catheter clamped for the assigned 
dwell time.  It will then be unclamped after the dwell time designated, Cysview will be 


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allowed to drain out, the catheter removed, and cystoscopy performed.  The 
cystoscope is inserted and imaging of the entire bladder commences while recording 
both color and near-infrared image streams (movies and periodic stills).  This initial 
survey that includes catheterization of the bladder under anesthesia, instillation of 
Cysview, dwell time as indicated and subsequent evaluation with the color and near-
infrared imaging for research purposes.  Cysview with blue light cystoscopy has been 
indicated to be desirable at the time of TURBT but it is not standard of care; it is an 
optional procedure to increase detection and decrease recurrence.  A useful dwell time 
for Cysview before NIRF imaging will be identified in this study; an effort will be made 
to minimize the interval between administration and imaging. 
 
The procedure and all study portions will be performed by the subject’s surgeon.  
During the procedure, the bladder will initially be examined in a systematic meridian 
fashion.  Suspicious tumors identified by white light only, NIRF only, and both will be 
identified.  If fluorescence is detected in 3/3 subjects at a given dwell time, the study 
will continue to shorter dwell times. The initial 3 subjects will have 10 min dwell 
duration, followed by 5 min and 2.5 min.  If fluorescence is not detected in 3/3 subjects 
at any time period, the study will not progress to shorter dwell times.  If no 
fluorescence is visualized after 10 minutes, we will not proceed to a longer dwell time. 
 
When tumor NIRF is detected, the localized intensity of the fluorescence image will be 
quantified by comparing the emission arising from the tumor location to the 
background emission from surrounding normal tissue.  The ratio of intensity between 
the tumor location and the surrounding normal tissue will be used to quantify the signal 
strength and provide evidence of comparative sensitivity for dwell times. 
 
When the tumor survey is completed, resection of the identified lesions commences 
according to normal standards of care, i.e. TURBT.  Random bladder biopsies are 
considered standard of care at the time of TURBT.  We will take directed biopsies of 
areas identified by NIRF imaging and treat these as random bladder biopsies. 
 
All specimens will be handled according to standard of care practice and pathologic 
diagnosis conducted by a genitourinary pathologist. 
 
Study medication will be ordered from the UR Pharmacy and distributed by the 
Department of Urology at no cost to the subject.  Study medication will be stored in a 
locked cabinet and only accessed by the study team. 
 
Imagin Medical will pay for the cost of the study medication (Cysview) and consigned 
the NIRF imaging equipment for the study. 
 
 


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5.1. Treatment Dosage and Administration 
 
 
REGIMEN DESCRIPTION 
 
Agent 
Pre-medications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length 
Cysview 
None 
100 mg 
 
Bladder 
instillation 
by catheter 
Intraoperative 
10 
minutes 
maximum 
 
 
 
5.2. Efficacy Assessments 
 
This initial series is designed solely to demonstrate that tumors identifiable under white 
light will be seen to fluoresce in the near-infrared spectrum after relatively short dwell 
times.  We will document detectability of individual tumors under white light and NIRF 
at short intervals after Cysview instillation.   
 
 
5.3. Safety Assessments 
 
Standard patient preoperative assessment will be performed including medical history, 
physical exam, vital signs, pertinent clinical labs and pre-anesthesia evaluation if 
deemed necessary.  No additional procedures specific to this study will be performed 
for safety assessment. 
 
5.4. Assessment of Subject Compliance 
 
There are no subject compliance issues to be monitored. 
 
5.5. Costs to the Subject 
 
There will be no cost to the subject.  The subject will have no additional research visits.   
Study medication and the use of the NIRF Imaging equipment will be provided by 
Imagin Medical. 
 
5.6. Payment for Participation 
 
There will be no payment for participation. 
 
5.7. Return of Individual Research Results 
 
No research results will be provided to the subject.  They will have a discussion of 
resection pathology with their surgeon post procedure as is standard of care. 
 
 


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6. CONCOMITANT AND DISALLOWED MEDICATIONS 
 
No medications will preclude participation.  No medications will need to be stopped for 
participation, except as needed for anesthesia and to undergo TURBT (eg. anticoagulants). 
 
 
 
7. SUBJECT WITHDRAWALS 
 
N/A 
 
 
8. STUDY DRUG/DEVICE/BIOLOGIC ADMINISTRATION/ASSIGNMENT 
 
8.1. Study Drug 
 
Cysview™ (hexaminolevulinate HCL) 
 
Study Device 
 
This protocol relies on intravesical administration of an FDA-approved agent for 
bladder cancer detection (Cysview™) that will fluoresce upon illumination with an FDA-
approved cystoscopic light source.  This study will use lowered intensities from the 
light source; near-infrared wavelengths in the spectral region of interest (spectrally 
overlapping with NIRF signal) that are emitted by a white light source will be removed 
with a filter to enable detection of the same wavelengths emitted by tumor 
fluorescence.  The imaging system is new.  
 
A standard (FDA-approved) cystoscope that is currently in use in the SMH OR is 
introduced into the bladder and is used to guide resection of any detected tumors, i.e. 
Trans Urethral Resection of Bladder Tumors (TURBT).  Color and near-infrared image 
streams will be recorded.  The surgeon will be able to display white light images, white 
light images with pseudocolor highlighting the near-infrared fluorescent tumor, near-
infrared image, or any pair of images.  Since the NIRF is in a spectrum that is not 
visible to the human eye, the computer will display this florescence in a color that is in 
the visible spectrum or psuedocolor. 
 
Our imaging system does not fit the definition of significant risk device study and 
therefore qualifies as a non-significant risk device study as follows: 
• 
NIRF imaging is not an implant and does not present a potential for serious risk 
to health, safety or welfare of a subject. 
• 
NIRF imaging is not for use supporting or sustaining human life. 
• 
Although NIRF imaging will be used during cystoscopy, resection and 
pathologic diagnosis of cancer will occur independently to NIRF imaging. 
• 
There is no potential for serious risk to health, safety or welfare of the subject 


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8.2. Dosage of Study Drug/Biologic 
 
REGIMEN DESCRIPTION 
 
Agent 
Pre-medications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length 
Cysview 
None 
100 
mg 
 
Bladder 
instillation 
by catheter 
Intraoperative 
10 minute  
maximum 
 
 
 
8.3. Subject Enrollment/Randomization 
 
Subjects will be assigned a drug dwell duration based upon the order of study entry. 
No randomization will occur.  The first three study subjects will have a 10 minute dwell 
time.  If the dwell time fluorescence is adequate, dwell time will be reduced to 5 
minutes for the next three subjects and then 2.5 minutes accordingly.  
 
 
8.4. Accountability of Investigational Supplies 
 
Study medication will be stored in a locked cabinet and only accessed by the study 
team.  Study medication will be distributed intra-operatively directly by the study team. 
Any returned medication will be documented within the study subject’s research record 
and disposed of according to the research pharmacy recommendations.  The 
investigational imaging system will be maintained according to operating room 
standards.  The system will be stored in a locked room and only accessed by the study 
team.  
 
 
 
FDA-approved 
blue light cystoscopy light 
source provides white or 
blue light 
Imaging system 
(optics and cameras) 
FDA-approved cystoscope 
Nearinfrared light blocked  
Bladder  


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8.5. Subject Withdrawal of Study Drug 
 
Subjects who withdraw from the study will not be eligible to re-enroll in the study. 
  
8.6. Emergency Drug Disclosure 
 
As this is not a blinded study, emergency drug disclosure does not apply. 
 
 
9. SAFETY AND REPORTABLE EVENTS 
 
9.1. Adverse Event Definition 
 
An adverse event is any symptom, sign, illness, or experience which develops or 
worsens during the course of the study, whether or not the event is considered related 
to the study intervention. 
 
9.2. Serious Adverse Event Definition 
 
A serious adverse event is defined as any adverse medical experience that results in 
any of the following outcomes: 
• 
death 
• 
is life-threatening; 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in persistent or significant disability/incapacity; 
• 
is a congenital anomaly/birth defect; or 
• 
requires medical or surgical intervention to prevent permanent impairment or 
damage 
 
 
9.3. Recording Adverse Events 
 
The study staff will assess adverse events by recording all voluntary complaints of the 
subject post-TURBT (i.e., after Cysview administration in the OR). 
 
All adverse events, whether observed by the Investigator, elicited from or volunteered 
by the subject, will be documented on the Adverse Event Summary Log.  Each 
adverse event will include a brief description of the experience, the date of onset, the 
date of resolution, duration, attribution, severity grade, relationship to investigational 
product (i.e., drug or device), contributing factors, any action taken in response to the 
study drug/device, and whether the adverse event was expected vs unexpected.  The 
CTCAE (version 4) will be used to assign severity grade of the adverse event. 
 
Adverse events will be documented from the time of Cysview administration until their 
post-op visit. 
 
 
 


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9.4. Responsibilities for Reporting Serious Adverse Events 
 
All serious adverse events will be documented on the Adverse Event Summary Log 
and subject’s research chart.  The principal investigator will be notified immediately of 
any serious adverse events, and subsequently, the RSRB while complying with 
regulations and RSRB policy regarding the reporting of adverse events.  Since 
Cysview has a favorable safety profile, we do not anticipate any SAE’s in this study. 
 
All serious adverse events will be reported to the Wilmot Cancer Institute’s Data Safety 
Monitoring Committee (DSMC) using the DSMC SAE Review Form.  All unexpected 
and related adverse events will be reported to both the RSRB and to the DSMC within 
10 calendar days. 
 
 
10. 
RISK/BENEFIT ASSESSMENT 
 
10.1. Potential Risks 
 
Known adverse effects of hexaminolevulinate administration include: headache or 
procedural pain (1%-10%), bladder spasms (2%), bladder pain, dysuria, hematuria 
(<10%).  Abnormal urinalysis, cystitis have been reported (<1%). Anaphylaxis and 
hypersensitivity reaction has occurred (<1%). [7] 
 
There is no increased risk of adverse effects from the use of the NIRF imaging 
system.  All medications and equipment components in contact with the subject are 
FDA approved for use in this patient group.  Clinical engineering electrical safety 
certification will be performed.  Cystoscopic light sources approved for human use will 
be used, but at reduced near infrared intensity for imaging purposes; thus less energy 
is introduced into the patient than would normally occur.  
 
10.2. Protection Against Risks 
 
To protect subjects from risk, all individuals with hypersensitivity to hexaminolevulinate 
or any derivative of aminolevulinic acid will be excluded from participation in this study. 
The installation time utilized in this study will be 10 minutes as compared with the 60 
minute instillation time approved by the FDA, further reducing risk of potential adverse 
events.  Subjects will be hemodynamically monitored by anesthesiologists throughout 
the instillation which will provide early warning of adverse events if any.  
 
10.3. Potential Benefits to Subjects 
 
Blue light cystoscopy with the use of Cysview augments identification of hard to 
visualize tumors and aids in identifying additional areas requiring tumor resection.  The 
use of Cysview with blue light cystoscopy requires dwell times of 60 minutes that is a 
logistical challenge.  The development of highly sensitive detection equipment may 
allow a reduction of the Cysview dwell time.  The reduction in dwell time may also 
reduce unintended side effects by reducing the duration of mucosal contact with 
Cysview. 
 
 


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10.4 Alternatives to Participation 
 
There are no alternatives to participation.  This study is voluntary and subjects do not 
have to participate. 
 
 
11. 
CONFIDENTIALITY OF DATA AND INFORMATION STORAGE  
 
All subjects will be assigned a unique code number and the key will be kept on a 
password-protected database in a locked office of the study team.  Signed consent 
forms, case report forms, and data collection sheets will be kept in binders in the locked 
office of the Clinical Trials Office. 
 
Imaging data will be kept on a secure Information Systems Division private network 
server within the University of Rochester Medical Center.  This data will be password-
protected, accessible only by study team members listed on this study.  The data will be 
kept indefinitely.  Only the study team will have access to the data. 
 
 
12. 
RESEARCH INFORMATION IN MEDICAL RECORDS 
 
Administration of study medication will be documented in the medical record. 
 
 
 
13. 
DATA ANALYSIS AND MONITORING 
 
13.1. Sample Size Determination 
 
Conventional blue light cystoscopy has a sensitivity of better than 0.9 (90%) for Ta-T4 
tumors.  Therefore, the probability that we will fail to detect the tumors in three subjects 
due to the sensitivity of the blue light method is less than 0.001 (0.1%).  We thus 
believe that 3 subjects represent a sufficient sample size to determine the efficacy of 
this method.  
 
13.2. Planned Statistical Analysis 
 
The procedure will be digitally recorded during simultaneous acquisition of the visible 
(white light) image and the fluorescence image from separate cameras with precisely 
aligned fields of view.  At any time point, both cameras record the image from the 
same tissue location as relayed by the cystoscope.  Therefore, the images are 
completely spatially coordinated and the location of any feature (tumor) observed on 
the white light image will be known in the corresponding image recorded by the 
fluorescence detection camera.  Accordingly, tumors visualized by the white light 
image should be visible in the fluorescence image as features with enhanced 
emission.  This association thus enables us to determine if PPIX emission arising from 
tumors is detectable within the specified dwell time.  The localized intensity of the 
fluorescence image will be quantified by comparing the emission arising from the 
tumor location to the background emission from surrounding normal tissue.  The ratio 


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of intensity between the tumor location and the surrounding normal tissue will be used 
to quantify the signal strength.  We will use this value for further analysis to quantify 
the signal strength as a function of dwell time. 
 
13.3. Data and Safety Monitoring 
 
Study Investigators will conduct continuous review of data and subject safety.  The 
Investigator will submit semi-annual progress reports of these data to the Data Safety 
Monitoring Committee at the Wilmot Cancer Institute for review.  The review will 
include for each treatment arm/dose level:  the number of subjects enrolled, 
withdrawals, significant toxicities as described in the protocol, serious adverse events 
both expected and unexpected, dose adjustments, and responses observed. 
 
The PI maintains a database of all adverse events with toxicity grade and information 
regarding treatment required, complications, or sequelae.  The Investigator will submit 
a copy of the AE spreadsheet along with the Progress Report to the Data Safety 
Monitoring Committee at the Wilmot Cancer Institute for review.  Actual review dates 
will be assigned when the first subject is accrued. 
 
• 
Any serious adverse event that is serious, related AND unexpected must be 
reported within 10 calendar days to both the Safety Coordinator at the Wilmot 
Cancer Institute and the RSRB (see RSRB guidelines).  The DSMC Chair will 
determine whether further action is required, and when subject safety is of 
concern, an interim meeting may be called. 
 
• 
Serious adverse events that are related AND expected or unrelated AND 
unexpected will be reported to the DSMC for review at the next quarterly 
meeting.  SAE reports are expected to include sufficient detail so that the DSMC 
can determine the severity, toxicity grade, expectedness, treatment required, and a 
follow up report documenting resolution or if there are sequelae.  Unless otherwise 
specified in the protocol, serious adverse events that require detailed reports (but 
not necessarily expedited) are expected, related, non-hematologic toxicities of 
grades 3, 4 or 5. 
 
The Data Safety Monitoring Committee provides oversight of study progress and 
safety by review of accrual and events at regularly scheduled meetings.  The 
frequency of review is determined by the size, risk and complexity of the trial, and is 
assigned by the Protocol Review Committee at the time of their initial review and 
approval.  The Data and Safety Monitoring Committee will monitor all adverse event 
rates utilizing a cumulative spreadsheet listing of all events submitted along with 
progress reports by the PI.  All serious adverse events that have occurred in the prior 3 
months will be reviewed at the regular quarterly meeting of the DSMC in order to 
confirm toxicity grade, expectedness, relatedness, sequelae, follow up required, and 
risk to current or future subjects.  
 
 
 


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14. 
REFERENCES 
 
1. Grossman, H.B., et al., Long-term decrease in bladder cancer recurrence with 
hexaminolevulinate enabled fluorescence cystoscopy. J Urol, 2012. 188(1): p. 58-
62.PMC3372634  http://www.ncbi.nlm.nih.gov/pubmed/22583635 
http://ac.els-cdn.com/S0022534712030108/1-s2.0-S0022534712030108-
main.pdf?_tid=ed4c6b4c-4865-11e6-97be-
00000aab0f6c&acdnat=1468351509_fdecabf3754c0ff233fe229ec69b0b9c 
 
2. Grossman, H.B., et al., A phase III, multicenter comparison of hexaminolevulinate 
fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary 
lesions in patients with bladder cancer. J Urol, 2007. 178(1): p. 62-7. 
http://www.ncbi.nlm.nih.gov/pubmed/17499283 
http://ac.els-cdn.com/S0022534707005435/1-s2.0-S0022534707005435-
main.pdf?_tid=eaa56498-4865-11e6-adb2-
00000aab0f27&acdnat=1468351504_ac62489e673091ac976d93ca2d09e5c4 
 
3. Botteman, M.F., et al., The health economics of bladder cancer: a comprehensive review 
of the published literature. Pharmacoeconomics, 2003. 21(18): p. 1315-30.  
 
4. Nakai, Y., et al., Expression of ferrochelatase has a strong correlation in protoporphyrin 
IX accumulation with photodynamic detection of bladder cancer. Photodiagnosis Photodyn 
Ther, 2016. 13: p. 225-32. https://www.ncbi.nlm.nih.gov/pubmed/26226642 
 
5. Nakanishi, T., et al., Kinetic Evaluation of Determinant Factors for Cellular Accumulation 
of Protoporphyrin IX Induced by External 5-Aminolevulinic Acid for Photodynamic Cancer 
Therapy. J Pharm Sci, 2015. 104(9): p. 3092-100. 
https://www.ncbi.nlm.nih.gov/pubmed/25959076 
 
6. Krieg, R.C., et al., Cell-type specific protoporphyrin IX metabolism in human bladder 
cancer in vitro. (0031-8655 (Print)). 
7.    Lexicomp. (2016, 12 14). Lexicomp. Retrieved from 
http://online.lexi.com.ezpminer.urmc.rochester.edu/lco/action/doc/retrieve/docid/patch_f/
2850879 
 
 
 
 


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Appendix 1 
 
Schedule of Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*If not obtained at the Research visit, may be obtained at the Pre-op visit 
 
^If not obtained at the Research visit, may be obtained Day of Surgery 
 
 
 
 
 
 
 
PROCEDURES 
Research 
Visit 
Pre-Op 
Visit 
Day of 
Surgery 
Confirm Eligibility 
X 
X* 
 
Obtain Informed Consent 
X 
X* 
 
Medical History and Demographics 
X 
 
X^ 
Concomitant Medication Review 
X 
 
X^ 
Dispense Study Drug 
 
 
X 
Near-Infrared Imaging 
 
 
X 
Adverse Event Review 
 
 
X 


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Appendix 2 
 
Cysview Packet Insert 
 
 
 


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Appendix 3 
 
Data Collection Form 
 
 
 
 
Subject 
Number 
Male 
or 
Female 
Age 
History 
of 
Bladder 
Cancer 
Video 
File 
Dwell 
Time 
Adequate 
Assessment 
of 
Florescence 
Pathology 
of 
Directed 
Biopsies 
Pathology 
of Primary 
Specimen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4 
 
Preliminary ex-vivo results: Comparison of sensitivity between imaging modalities 
 
 
 
 

ICF_001.pdf: 
RSRB # 66682 – Dwell study 
Page 1 of 8 
Rev. 03/01/18 
 
 
 
 
 
 
 
                      Department of Urology 
 
NCT03058705 
CONSENT FORM 
 
 
Near Infrared Fluorescence Imaging for Bladder Cancer Detection 
 
 
 
Principal Investigator: Edward Messing, MD, FACS 
 
 
This consent form describes a research study, what you may expect if you decide to 
take part and important information to help you make your decision.  Please read 
this form carefully. 
 
The study staff will explain this study to you.  Please ask questions about anything that is 
not clear before you agree to participate.  You may take this consent form home to think 
about and discuss with family or friends. 
 
 Being in this study is voluntary – it is your choice. 
 If you join this study, you can change your mind and stop at any time. 
 If you choose not to take part, your routine medical care will not be changed in any 
way. 
 There are risks from participating and you should understand what these mean to you. 
 
 
INTRODUCTION 
You are being asked to take part in this study because you have been diagnosed with 
bladder cancer or are suspected of having bladder cancer tumors and you are scheduled to 
undergo a transurethral resection of the bladder tumor (TURBT) surgery. 
 
This study is being conducted by Dr. Edward M. Messing (Principal Investigator) of the 
University of Rochester, Department of Urology. 


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PURPOSE AND BACKGROUND OF STUDY 
The purpose of this study is to (1) determine if an investigational light source can aid in 
taking a biopsy and diagnosing bladder cancer and (2) whether using an investigational 
light source can potentially reduce the time Cysview has to sit in the bladder. 
 
Cysview is an FDA-approved drug that is instilled into the bladder to better identify 
bladder tumors while undergoing TURBT surgery.  Currently, the Cysview is instilled 
into the bladder through a Foley catheter for approximately one hour before surgery. 
 
During your surgery, the investigational light source will be used with a cystoscope and 
Cysview.  The cystoscope is an FDA-approved instrument that allows visualization of 
your bladder and bladder tumors. 
 
DESCRIPTION OF STUDY PROCEDURES 
While in the operating room when you are under general anesthesia, Cysview will be 
instilled into your bladder using a Foley catheter.  The Cysview will sit in your bladder 
for up to 10 minutes.  Then the Cysview will be drained out of your bladder via the Foley 
catheter which will then be removed. 
 
We will then insert the cystoscope into your bladder and use the investigational light 
source, which will be attached to the cystoscope, to view the interaction of Cysview and 
the bladder tumors.  Use of the investigational light source might identify additional areas 
that the surgeon may want to biopsy. 
 
Once we have obtained images of your bladder and any tumors, you will undergo your 
routine transurethral resection of bladder tumor (TURBT) surgery. 
 
In addition, we will collect information about you from your medical record for the 
purposes of this research study. 
 
NUMBER OF SUBJECTS 
Locally, approximately 20 subjects will take part in this study. 
 
DURATION OF THE STUDY 
The study will begin and end on the day of your TURBT surgery. 
 
 
 


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RISKS OF PARTICIPATION 
There are some risks to participating in this study.   
Known adverse effects of the Cysview include headache or procedural pain (1%-10%), 
bladder spasms (2%), bladder pain, painful urination, blood in your urine (<10%).  
Abnormal urine tests (urinalysis) and inflammation of the bladder (cystitis) have been 
reported (<1%).  A generalized allergy (anaphylaxis) causing fainting, low blood 
pressure, difficulty breathing, shortness of breath, hives, rashes, nausea or vomiting has 
occurred (<1%). 
 
There are risks associated with foley catheter placement.  The main risk of using a 
urinary catheter is that it can sometimes allow bacteria to enter the body.  This risk is 
minimal because the catheter is only left for a short period of time, and placed in the 
sterile operating room.  It is also possible to cause injury to the urethra (the tube that 
carries urine out of the body) when the catheter is inserted.  This can cause future 
narrowing of the urethra because of scar tissue caused by catheter use. 
 
There is no increased risk from the use of the investigational light source.  All 
medications and equipment components in contact with you are FDA-approved for use in 
this patient group.  Clinical engineering electrical safety certification will be performed.  
Cystoscopic light sources approved for human use will be used, but at reduced near 
infrared intensity for imaging purposes; so less energy is introduced into your bladder 
than would normally occur. 
 
Privacy and Confidentiality: 
There is a minimal risk of invasion of privacy and loss of confidentiality since study 
personnel will have access to the data that we collect about you.  However, we will 
protect the privacy and confidentiality of your information by assigning you a code 
number.  The database generated in this study will be kept secured in a password 
protected computer program at the University of Rochester Medical Center. 
 
 
BENEFITS OF PARTICIPATION 
You might not benefit from being in this research study, however, the reduction in dwell 
time may reduce unintended side effects by reducing the duration of mucosal contact 
with Cysview. 
 
 
ALTERNATIVES TO PARTICIPATION 
You do not have to participate in this study if you don’t want to.  Your TURBT surgery 
will be performed as part of standard care. 
 


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SPONSOR SUPPORT 
The University of Rochester is receiving payment from Imagin Medical for the study 
drug (Cysview) and the use of the imaging equipment. 
 
CONFLICT OF FINANCIAL INTEREST 
Dr. Stavros Demos, a sub-investigator on this study, is a co-inventor of the technology 
being studied, and therefore has a financial interest in the development of this 
technology.  Please feel free to ask any further questions you might have about this 
matter. 
 
COSTS 
There is no cost to you for your participation in this study.   
 
You and/or your insurance company will be responsible for paying for costs associated 
with your TURBT surgery (standard of care). 
 
PAYMENTS 
You will not be paid for participating in this study. 
 
COMPENSATION FOR INJURY 
If you are directly injured by the drug and device being studied, or by medical procedures 
needed because of this study, and you receive medical care for the injury, you may need 
to pay for that care.  You will be reimbursed for reasonable and necessary medical costs 
for such care, but you might not be reimbursed for care covered and paid for by a third 
party like your health insurance provider, or costs such as required co-payments or 
deductibles related to that coverage.  No other funds have been set aside to pay for such 
things as lost wages or expenses due to a current underlying illness or condition. 
 
If your research injury is paid for by the University, we will collect your name, date of 
birth, gender, and Medicare Health Insurance Claim Number or Social Security Number 
to determine your Medicare status.  This information will be used only in accordance 
with the law.  If you are a Medicare beneficiary, information about the study you are in, 
and any payments made related to your injury, will be reported to the Centers for 
Medicare & Medicaid Services (CMS), in accordance with CMS requirements.  This 
information will not be used for any other purpose. 
 
 


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CONFIDENTIALITY OF RECORDS 
The University of Rochester makes every effort to keep the information collected from 
you private.  In order to do so, we will keep all collected data in a secured password-
protected computer database program at the University of Rochester Medical Center.  
Sometimes, however, researchers need to share information that may identify you with 
people that work for the University, regulators or study sponsors.  If this does happen we 
will take precautions to protect the information you have provided.  Results of the 
research may be presented at meetings or in publications, but your name will not be used. 
 
If you have never received a copy of the University of Rochester Medical Center (URMC) 
and Affiliates Notice of Privacy Practices, please ask the investigator for one.  
 
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
• Research records 
• Records about phone calls made as part of this research 
• Past and present medical records related to the study 
• Results of medical tests related to the study (imaging) 
 
Who may use and give out information about you? 
• The study doctor and the study staff 
• URMC and Affiliates 
 
Your information may be given to:  
• The Department of Health and Human Services 
• The University of Rochester  
• Imagin Medical 
• The U.S. Food and Drug Administration (FDA) may also need to inspect study 
records at some point during the study or even after it has been completed.  In the 
event that this should occur, every effort will be made to keep identifying 
information about you private.  
 
Why will this information be used and/or given to others? 
• To do the research  
• To study the results  
• To see if the research was done right   
 
If the results of this study are made public, information that identifies you will not be used. 
 
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. 


RSRB # 66682 – Dwell study 
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May I review or copy my information? 
Yes, but only after the research is over. 
 
How long will this permission be valid? 
This permission will last indefinitely.  
 
May I cancel my permission to use and disclose information? 
Yes. You may cancel your permission to use and disclose your health information at any 
time.  You do this by sending written notice to the study doctor.  Upon receiving the 
written notice, the study team will no longer use or disclose your health information and 
you will not be able to stay in this study.  Information that has already been gathered may 
need to be used and given to others for the validity of the study.   
 
May I withdraw from the study? 
Yes. If you withdraw your permission to be in the study, no new health information 
identifying you will be gathered after that date.  Information that has already been 
gathered may still be used and given to others.   
 
Is my health information protected after it has been given to others? 
No. There is a risk that your information will be given to others without your permission. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this website 
at any time.  
 
CONTACT PERSONS 
For more information concerning this research, please contact the study coordinator at 
(585) 275-0126.  If you experience any of the potential side effects described in the 
“risks” section above or if you feel that your participation has resulted in any research-
related injury, emotional or physical discomfort, please contact the study doctor, 
Dr. Edward M. Messing at (585) 275-0126 between 8am-5pm.  After 5pm, call (585) 
275-0998 and ask for the urologist on-call. 
 
You may also contact the University of Rochester Research Subjects Review Board at 
265 Crittenden Blvd., CU 420628, Rochester, NY 14642, Telephone (585) 276-0005 or 
(877) 449-4441 for the following reasons: 
 
• You wish to talk to someone other than the research staff about your rights as a 
research subject; 
• To voice concerns about the research; 
• To provide input concerning the research process 
• In the event the study staff could not be reached. 
 


RSRB # 66682 – Dwell study 
Page 7 of 8 
Rev. 03/01/18 
VOLUNTARY PARTICIPATION 
Taking part in this study is voluntary.  You are free not to take part or to withdraw at any 
time, for whatever reason.  No matter what decision you make, there will be no penalty or 
loss of benefit to which you are entitled.  In the event that you do withdraw from this 
study, the information you have already provided will be kept in a confidential manner. 


RSRB # 66682 – Dwell study 
Page 8 of 8 
Rev. 03/01/18 
************************************************************************ 
 
SIGNATURE/DATES 
After reading and discussing the information in this consent form you should understand: 
• 
Why this study is being done; 
• 
What will happen during the study; 
• 
Any possible risks and benefits to you; 
• 
Other options you may have instead of being in the study;  
• 
How your personal information will be protected; 
• 
What to do if you have problems or questions about this study. 
 
 
SUBJECT CONSENT 
I have read (or have had read to me) the contents of this consent form and have been 
encouraged to ask questions.  I have received answers to my questions.  I agree to 
participate in this study.  I have received (or will receive) a signed copy of this form for 
my records and future reference. 
 
 
 
 
 
 
 
 
 
 
Subject Name (Printed by Subject) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Subject  
 
 
 
 
Date 
 
 
 
PERSON OBTAINING CONSENT 
I have read this form to the subject and/or the subject has read this form.  I will provide 
the subject with a signed copy of this consent form.  An explanation of the research was 
given and questions from the subject were solicited and answered to the subject’s 
satisfaction.  In my judgment, the subject has demonstrated comprehension of the 
information.  I have given the subject adequate opportunity to read the consent before 
signing. 
 
 
 
 
 
 
 
 
 
 
Name and Title (Print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
 
Date