A Prospective, Open, Comparative, Within Patient Controlled Multicenter Phase 3 Study of Blue Light Cystoscopy With Cysview and White Light Cystoscopy Using KARL STORZ D-Light C PDD Flexible Videoscope System in Detection of Bladder Cancer in Patients With Bladder Cancer
Phase: PHASE3
Conditions: Bladder Cancer
Sponsor: Photocure

 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
Investigational drug: 
Cysview® for Intravesical Solution 
Investigational device: KARL STORZ D-Light C PDD Flexible Videoscope System 
Protocol number: 
PC B308/13 
 
Blue Light Flexible Cystoscopy with Cysview Study 
 
Study title: 
A prospective, open, comparative, within patient controlled 
multicenter phase 3 study of blue light cystoscopy with 
Cysview and white light cystoscopy using KARL STORZ D-
Light C PDD Flexible Videoscope System in detection of 
bladder cancer in patients with bladder cancer 
Study phase: 
3 
Original protocol: 
29.Apr.2015 
Protocol version: 
Protocol including Amendment 1 FINAL 
Date: 
20.Nov.2015 
Amendment history: 
 
Amendment #1: 
20.Nov.2015 
 
 
 
 

 
 
 
 
 
 
Name of sponsor: Photocure ASA 
Name of drug and investigational device: 
Cysview® for Intravesical Solution 
KARL STORZ D-Light C PDD Flexible Videoscope System 
Name of active ingredient: Hexaminolevulinate hydrochloride 
Study title: 
A prospective, open, comparative, within patient controlled multicenter phase 3 study of blue 
light cystoscopy with Cysview and white light cystoscopy using KARL STORZ D-Light C 
PDD Flexible Videoscope System in detection of bladder cancer in patients with bladder 
cancer. 
Protocol number: PC B308/13 Blue Light Flexible Cystoscopy with Cysview Study 
Number of patients/sites planned:  
Approximately 360 patients are planned to be included in the study. Enrolment will continue 
until 100 patients have received repetitive Cysview instillations in the study. 
Approximately 15 sites in the US will participate. 
Phase of development: 3 
Primary objective: 
To compare blue light cystoscopy with Cysview to white light cystoscopy in the detection of 
bladder cancer during surveillance cystoscopy. 
 
Secondary objectives: 
To assess the efficacy and safety of blue light cystoscopy with Cysview after repetitive use. 
 
To compare blue light cystoscopy with Cysview to white light cystoscopy in the detection of 
carcinoma in situ (CIS). 
Study design: 
This is a prospective, open, comparative within-patient controlled phase 3 multicenter study 
in patients with bladder cancer.  
 
There will be a maximum of three study visits: A screening visit, a surveillance cystoscopic 
examination and a cystoscopic examination in the operating room (OR) for patients with 
suspicion of recurrence after the surveillance cystoscopy. In addition there will be a follow-
up telephone call for patients undergoing the OR visit within one week after the patient has 
discussed the pathology report with the study investigator. 
 
The first four patients included at each center will be training patients. The training patients 
will complete the surveillance visit as described below, and then discontinue study 
participation. Further management will be according to the hospital’s clinical routine. 
 
For the design of the clinical trial, the comparator is white light cystoscopy. To reduce 
possible bias in the white light cystoscopic examination, a small number of patients will be 
randomized to discontinue the study following the white light cystoscopy and before the blue 
light examination in the surveillance setting.  
 

 
 
 
 
 
Malignancy is confirmed by consensus pathology panel read of biopsies taken during the 
OR examination. The pathology result is obtained from a consensus pathology panel, and 
the consensus interpretation will be considered the standard of truth for all efficacy 
endpoints. Malignany will be pathology diagnosis of PUNLMP, CIS, Ta, T1 or T2-T4. 
 
Screening visit 
If feasible, the screening visit may be combined with the surveillance visit. Patients may be 
consented for the study before the screeing visit. The patient will be asked questions about 
patient reported outcomes 
 
Surveillance visit: 
Prior to the examination, the patient’s assessment of bladder function will be recorded. All 
patients will receive an instillation of 50 mL Cysview 8 mM solution, which must be retained 
for minimum one and no more than 3 hours before the cystoscopy. After bladder 
evacuation, rinsing and filling of the bladder with cystoscopic irrigation fluid, a standard 
white light cystoscopy using the KARL STORZ D-Light C PDD Flexible Videoscope System 
will be done. Suspected malignant lesions will be counted and evaluated.  
After the white light examination, an envelope with the patient’s randomization allocation will 
be opened. Patients randomized to terminate the study will be treated according to clinical 
practice. The other patients will be examined with the investigational PDD Flexible 
Videoscope System using blue light. Lesions suspected to be malignant seen with blue light 
will be counted and evaluated. To assess possible effects on the bladder endothelium of 
repetitive use of Cysview, non-malignant mucosal abnormalities will be assessed using 
white and blue light. The training patients will not be part of the randomization, but will be 
examined with both white and blue light. Patients undergoing blue light examination will 
again be asked questions about patient reported outcomes. The investigator will be asked if 
the findings under blue light would have caused any change in patient management in the 
investigator’s normal clinical practice. 
 
Operating room visit: 
Upon suspicion of recurrence in the surveillance examination, the patient will be referred to 
further examinations and treatment in the OR. The patient’s assessment of bladder function 
will be recorded for all patients prior to the Cysview instillation. A 50 mL Cysview 8 mM 
solution will be instilled between one and 3 hours before the examination.  
Cystoscopy will then be performed in the OR with anesthesia control, using the approved 
KARL STORZ D-Light C PDD System with rigid cystoscope. The bladder will first be 
examined under white light, and all lesions will be mapped. Cystoscopy will continue under 
blue light, and all lesions detected under blue light will be mapped. Mucosal abnormalities 
will be assessed using white and blue light, and all lesions seen with white and/or blue light 
will be biopsied. A transurethral resection or cold-cup removal of all identified lesions will be 
done according to standard clinical practice, utilizing both white light and blue light. Tissue 
from biopsies will be collected for histological evaluations. The local pathologist will evaluate 
biopsied tissue for clinical pathological evaluations as part of clinical practice before the 
slides are sent for consensus pathology panel read. 
 
Telephone follow-up: 
A final collection of bladder function assessment and patient reported outcomes will be done 
by phone within one week after the  patient has discussed the pathology results with the 
study investigator.   

 
 
 
 
 
Visit flow chart (main efficacy and safety assessments): 
Visit 1: Screening 
May be combined with Visit 2  
Screening procedures 
Patient reported outcomes 
 
 
 
Visit 2: Surveillance 
Within 4 weeks of Visit 1 
Urine cytology 
Patient’s assessment of own bladder function  
Cysview administration procedure 
WL flex. cystoscopy and lesion evaluation 
Randomization 
BL flex. cystoscopy and lesion 
evaluationMucosal abnormality assessment  
Patient management assessment 
Patient reported outcomes 
Record AEs 
 
 If randomized to termination: 
Record AEs and mucosal abnorm. 
Terminate study participation,  
treatment according to normal routine 
 
 
 
 
If suspicion  
of recurrence 
  If training patient or no suspicion of 
recurrence: 
Terminate study participation,  
treatment according to normal routine 
Visit 3: Operating room 
Within 6 weeks of Visit 2 
Patient’s assessment of own bladder function 
Cysview administration procedure 
WL rigid cystoscopy and lesion mapping 
BL rigid cystoscopy and lesion mapping 
Mucosal abnormality assessment 
Biopsy/TURB  
Record AEs 
 
  
 
 
 
 
 
Visit 4: Telephone follow-up 
Within one week after patient has received 
pathology results 
Patient’s assessment of own bladder function 
Patient reported outcomes 
 
WL = white light  
BL = blue light 
flex. cystoscopy = cystoscopy with investigational PDD Flexible Videoscope System 
rigid cystoscopy = cystoscopy with approved rigid PDD System 
 

 
 
 
 
 
Inclusion criteria: 
1.  Patients with bladder cancer in follow-up for tumor recurrence (Note: Patients must be 
included only at the first surveillance cystoscopy after  a histologically confirmed tumor. 
The histologically confirmed tumor could either be from a TURB or from a surveillance 
cystoscopy where a biopsy was taken and a tumor was confirmed by histology) 
2.  History of one or more of the following: 
• 
Multiple tumors 
• 
Recurrent tumors 
• 
High grade tumor(s) 
3. Age 18 or older 
4. Written informed consent signed 
 
Exclusion criteria: 
1. Gross haematuria. (Note: Gross haematuria is defined as a heavy bladder bleed 
resulting in significant amounts of blood in the urine, which may visually limit cystoscopy. 
Where the haematuria is light, the patient should not be excluded, if in the investigator’s 
opinion, rinsing and/or electro-cautery during cystoscopy will alleviate the haematuria 
limitations to cystoscopy) 
2. Patients who cannot undergo in-office or operating room cystoscopy (Note: Training 
patients are eligible even if they cannot undergo operating room cystoscopy) 
3. Patients who have received BCG immunotherapy or intravesical chemotherapy within 
the past 6 weeks prior to the procedure 
4. Porphyria 
5. Known allergy to hexaminolevulinate hydrochloride or a similar compound 
6. Pregnancy or breast-feeding (all women of child-bearing potential must document a 
negative urine pregnancy test before study inclusion and use adequate contraception 
during the study 
7. Participation in other clinical studies with investigational drugs either concurrently or 
within the last 30 days 
8. Patient is the investigator or any sub investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol 
9. Patients that the investigator believes are unlikely to comply with the protocol, e.g. 
mental condition rendering the patient unable to understand the nature, scope, and 
possible consequences of participating in the clinical study, uncooperative attitude or 
unlikelihood of completing the study 
Key dates: 
Start of recruitment: 3Q 2015 
End of recruitment: 3Q 2016 
Last study visit: 4Q 2016 
Endpoints: 
 
Endpoints for comparing blue light cystoscopy with Cysview to white light 
cystoscopy (surveillance examination): 
Primary efficacy endpoint: 
• 
Proportion of patients with histologically confirmed malignancy where malignancy is only 
detected with blue light cystoscopy with Cysview and not white light cystoscopy  
 
Secondary efficacy endpoints: 

 
 
 
 
 
• 
Proportion of patients with false positive lesion(s) detected only with blue light 
cystoscopy with Cysview and no lesions detected with white light  
• 
Proportion of patients with additional findings detected with blue light cystoscopy with 
Cysview compared to white light 
 
Safety endpoint: 
• 
The proportion of patients with AEs following the surveillance examination 
 
Endpoints for assessment of efficacy and safety of repetitive use of blue light 
cystoscopy with Cysview (examination in OR): 
Secondary efficacy endpoints: 
• 
Proportion of patients where one or more additional malignant lesions were detected 
with blue light cystoscopy with Cysview compared to white light 
• 
Lesion detection rate for blue light cystoscopy with Cysview and for white light 
cystoscopy per lesion type (PUNLMP, CIS, Ta, T1, T2-4) 
• 
Proportion of false positive lesions seen with blue light cystoscopy with Cysview 
compared to white light cystoscopy 
 
Safety endpoints: 
• 
Proportion of patients with adverse events considered causally related to Cysview 
and/or blue light in the surveillance examination compared with the OR examination 
• 
Proportion of patients with a worsening in bladder function as assessed on the bladder 
evaluation form (UDI-6) from surveillance to the OR visit and from the OR visit to the 
one-week follow-up 
• 
Proportion of patients with apparent inflammatory and/or fibrotic changes in the 
surveillance cystoscopic examination compared to the to the OR cystoscopic 
examination 
 
Endpoint for comparing blue light cystoscopy with Cysview to white light cystoscopy 
in the detection of CIS (examination in OR): 
Secondary efficacy endpoint: 
• 
Proportion of patients with one or more CIS lesions detected with blue light cystoscopy 
with Cysview and none with white light cystoscopy 
Efficacy and safety variables and assessments: 
 
Efficacy assessments: 
All suspicious lesions will be biopsied in the OR examination. All biopsies will be 
histologically verified by consensus panel pathology to reduce the variability of the 
pathology diagnosis used in the efficacy analyses. The 1998 World Health 
Organization/International Society of Urologic Pathology consensus classification and the 
2002 TNM classification for staging of bladder cancer will be used to grade and stage 
tumors. Two independent pathologists unaware of the diagnosis of the local pathologist and 
whether the biopsy came from a lesion seen in white light or blue light or both, provide a 
pathology diagnosis independently. If the two pathologists agree on the diagnosis, this is the 
diagnosis. If they disagree, a third independent pathologist will make a diagnosis without 
knowing the diagnosis of the two first pathologists. If this diagnosis is in agreement with the 
diagnosis made by the one of the first pathologists, this result will be the final diagnosis. If 
the three pathologists disagree on the diagnosis, they will sit together at a multi-headed 

 
 
 
 
 
microscope. If they agree on a diagnosis, this will be the final consensus diagnosis. If they 
fail to reach agreement, this lesion will be excluded from the statistical analysis.  
 
A histologically confirmed malignancy is a tumor staged/graded as PUNLMP, CIS, Ta, T1 or 
T2-T4 by the consensus panel. The consensus panel result will be used for assessment of 
the efficacy endpoints.   
For the secondary efficacy endpoint comparing blue light cystoscopy with Cysview to white 
light in surveillance, “additional findings” are defined as fulfilling one of the following criteria:  
 
 
WL: 
BL: 
I 
0 
≥1 lesion seen 
II 
1-4* 
# of lesions seen with BL˃ # lesions seen with WL  
or at least one of the lesions seen with BL ˃ 0.5 cm 
III 
Low grade** High grade** 
*Patient has a history of low grade bladder cancer, and all lesions seen in WL are ≤ 0.5 cm 
**Based on previous disease history. High grade disease suspicion after BL must be confirmed 
histologically in the OR examination 
 
For this endpoint, the number of lesions will be based on lesion count. Only patients with at 
least one histologically confirmed malignancy from the biopsy obtained in the OR 
examination will be included in the analysis of this endpoint. Confirmed malignancy will be 
evaluated on patient level, not per lesion. 
 
The investigator will be asked questions on how the patient would have been managed in 
his/her normal clinical practice based on the findings under blue light examination compared 
to the white light examination during surveillance cystoscopy. 
The question relates to what the investigator would normally do in his/her clinical practice, 
as the study requires that all patients with suspicious findings are sent to the OR.  
 
Safety assessments: 
Safety data will be recorded for all patients, including training patients and patients 
randomized to discontinue the study. The adverse events’ causal relationship to Cysview 
and/or blue light will be assessed by the performing clinical investigator urologist.  
 
Additional safety data will be collected to assess possible effects on the bladder 
endothelium of repetitive use of Cysview. The data will not be registered as adverse events. 
Non-malignant mucosal abnormalities identified during the cystoscopic examination in both 
surveillance setting and OR will be assessed for size and category (inflammation, fibrosis, 
scar, other).  
 
All patients will provide a bladder function assessment by the questions on the UDI-6 form 
prior to the surveillance examination (baseline), prior to the examination in the OR and after 
the OR visit. 
 
 
 
 

 
 
 
 
 
Patient reported outcomes: 
Patient reported outcomes will be collected on the screening, surveillance and telephone 
follow-up visits to capture changes in patients level of anxiety, pain and experience with blue 
light cystoscopy procedure. 
  
Populations and sample size: 
 
Populations: 
The population for comparing the efficacy of blue light cystoscopy with Cysview to white 
light cystoscopy in surveillance is all patients enrolled in the study who underwent 
surveillance cystoscopy and were found to have histologically confirmed malignancy. This is 
also the population for assessing the proportion of patients where additional findings are 
detected with blue light cystoscopy with Cysview compared to white light. The population for 
assessing the safety of blue light cystoscopy with Cysview in surveillance is all patients who 
received a Cysview instillation in the surveillance setting, including training patients and 
patients randomized to discontinue the study.  
 
The repetitive use efficacy population is all patients with with histologically confirmed 
malignancy. The repetitive use safety population is all patients who received a Cysview 
instillation for both the surveillance and OR examinations. 
 
The CIS efficacy population is all patients with histologically confirmed CIS who underwent 
the OR examination. 
 
Determination of sample size: 
The primary endpoint is the proportion of patients with histologically confirmed malignancy 
where malignancy is only detected with blue light cystoscopy with Cysview in surveillance 
(P). Superiority of blue light cystoscopy with Cysview will require that the lower 97.5% 
confidence limit for P exceeds 0.5% (null hypothesis). Under the assumption that P 
(alternative hypothesis) is 9% and a power of 90%, a total of 42 patients with histologically 
confirmed malignancy is needed.  
 
To ensure sufficient data to assess safety of repetitive use, a larger number of patients is 
required. The study will be sized to provide an estimate of the related adverse event rate 
that is sufficiently ‘precise’ to rule out a clinically important upper bound. The related 
adverse event rate following a single administration of Cysview was 7.8% in a pivotal phase 
III study, and the rate is not expected to increase with repeat administrations.15% is 
considered to be a clinically acceptable upper bound on the related adverse event rate to 
determine that patients who receive more than one instillation of Cysview and blue light 
cystoscopy do not experience clinical significantly more related events than after one such 
procedure. For this purpose, 100 patients are needed with repeated administration of 
Cysview. 
Based on epidemiologic data it is assumed that 35% of the patients examined in the 
surveillance setting will have lesions seen with white and/or blue light and be referred to the 
OR for a second Cysview instillation and examination. Including four training patients at 
each site and a small number of patients who will be randomized to terminate the study 
during the surveillance examination, approximately 360 patients must be enrolled in the 
study to get 100 patients with repeated administration of Cysview.  

 
 
 
 
 
Statistical methods and planned analyses: 
 
Efficacy and safety of blue light cystoscopy with Cysview in surveillance: 
The efficacy and safety evaluations will be based on data collected in the surveillance 
examination, and confirmatory biopsies from the OR examination. 
 
Efficacy analyses: 
The intent of the primary efficacy endpoint analysis is to show that malignancy is detected 
with blue light cystoscopy with Cysview in the surveillance setting in cases where no 
malignancy is observed with white light. This will be the group of patients where at least one 
lesion is seen with blue light and none with white light, and where malignancy is confirmed 
histologically in the OR examination.   
 
The primary efficacy endpoint will be analyzed using an exact one-tailed test for a single 
proportion based on the cumulative binomial distribution with a significance level of 2.5%. 
The following hypothesis will be tested: 
 
Null hypothesis: 
 
H0: P ≤ 0.005 (0.5%) 
Alternative hypothesis: 
H1: P > 0.005 (0.5%) 
 
The lower limit of the 97.5% confidence interval for the observed proportion will be 
constructed using exact binomial methods (Wilson scores).  
 
The false detection rate addresses the concern for patients who have an intervention 
unnecessarily due to false positive lesions seen with blue light only. A patient with false 
positive lesions attributable to blue light only is defined as having one or more lesions seen 
with blue light and no lesions seen with white light in the surveillance setting, but with no 
histologically confirmed malignancy from the OR examination. The proportion of patients 
with false positive lesions will be calculated among all patients with suspected lesions in the 
surveillance setting, i.e. all patients where a lesion was seen with white light and/or Cysview 
blue light. This is the group of patients who, in clinical practice, will either have the lesions 
removed in the surveillance setting or referred to the OR for further examination and 
treatment, and is therefore the relevant denominator. For comparison, the corresponding 
white light false detection rate will also be calculated; patients with false positive lesions 
attributable to white light only are those who have one or more lesions seen with white light 
and no lesions seen with blue light, and no histologically confirmed malignancy from the OR 
examination. The denominator for this proportion is the same as for the blue light false 
positive rate.  
 
The assessment of additional findings will be evaluated by calculating exact two-sided 95% 
one-sample confidence limits for the estimated proportion. 
 
The investigators’ assessment of change in patient management based on the findings in 
blue light cystoscopy with Cysview compared to white light cystoscopy will be summarized 
descriptively. 
Safety analysis: 
The proportion of patients with AEs following the surveillance examination will be calculated. 
 
Efficacy and safety of repetitive use: 
Efficacy analyses: 

 
 
 
 
 
The efficacy analysis of repetitive use will be based on data collected in the OR 
examination. 
 
Lesions with a pathology diagnosis from the central pathology read of PUNLMP, CIS, Ta, T1 
or T2-T4 will be considered malignant. 
 
The proportion of patients who have one or more additional PUNLMP, CIS, Ta, T1, T2-T4 
lesions detected with blue light cystoscopy with Cysview compared to white light cystoscopy 
will be evaluated by calculating exact two-sided 95% one-sample confidence limits for the 
estimated proportion. 
 
The lesion detection rate for white light and blue light per lesion type will be calculated on a 
lesion level as the total number of lesions of a specific type that were detected with blue 
light divided by the total number of lesions of the same type that were detected with either 
blue or white light, or both. This will be done as one rate over all patients. The 
corresponding detection rates for white light cystoscopy will be calculated. Proportions and 
exact 95% confidence intervals will be calculated by lesion type. 
 
A false positive lesion is defined as suspected lesion histologically confirmed not to be one 
of the following: PUNLMP, CIS, Ta, T1, T2-T4. The false positive detection rate for blue light 
cystoscopy with Cysview is calculated as the total number of false positive lesions divided 
by the total number of lesions seen with blue light. The false positive detection rate for white 
light cystoscopy will be calculated in the same way. Proportions and exact 95% confidence 
intervals will be calculated for white light and blue light cystoscopy.  
 
Safety analysis: 
Since these groups are not randomized, it is not statistically valid to apply a formal 
hypothesis test to compare the rates, so the analysis of safety data will be descriptive in 
nature. 
 
The frequency and severity of adverse events considered causally related to administration 
of Cysview and/or blue light exposure and the proportion of patients with related adverse 
events will be summarized and compared for the surveillance examination and the OR 
examination.  
  
All AEs will be evaluated by  
• 
number of prior exposures to Cysview and blue light 
• 
timing in relation to the most recent exposure 
• 
repetition of the same AE within a patient following repeated exposure and 
• 
change in severity of a repetitive AE following repeated exposure 
 
UDI-6 scores will be summarized descriptively and compared for the surveillance 
examination, OR examination and the follow-up assessment.   
 
The proportion of patients with apparent inflammatory and/or fibrotic changes visually 
assessed during each cystoscopic examination will be calculated.  
 
Efficacy in the detection of CIS: 
The efficacy analysis of detection of CIS will be based on data collected in the OR 
examination. 

 
 
 
 
 
 
The proportion of patients with one or more CIS lesions detected with blue light and none 
with white light will be evaluated using an exact binomial test for a single proportion with a 
significance level of 2.5% (one-sided) to evaluate the following hypothesis: 
 
Null hypothesis: 
H0: π ≤ 0.001 (0.1%) 
Alternative hypothesis: 
H1: π ˃ 0.001 (0.1%) 
 
Exact one-sided 97.5% confidence limits will be calculated for the estimated proportion. 
 
Patient reported outcomes: 
Data from patient reported outcomes will be summarized descriptively for screening 
examination, surveillance examination and the follow-up assessment.